From the creation of the universe to the explosion of life, to intelligent evolution, and to artificial intelligence, this is a long river of evolution. The times are asking, where do the brain and mind come from and where will they go? What is the future and destiny of human civilization? How can brain intelligence and artificial intelligence illuminate each other? Can artificial intelligence lead to the “mind” through a completely different path from biological evolution? How does intellectual creativity evolve into New Quality Productivity? The core of these questions is still how the human brain works as a whole? Here, I will outline a dialectical unity of complexity and simplicity at the micro-meso-macro-cosmological scale.
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GUO Ai-Ke.Perspective: Exploring The Essence of Brain Intelligence and Illuminating The Path of Brain Like Intelligence[J].,2024,51(10):2268-2273.Export: BibTexEndNote
Nanozymes, a groundbreaking discovery by Chinese scientists, represent a novel and remarkable property of nanomaterials. They not only exhibit catalytic activity comparable to natural enzymes, but also boast exceptional stability, tunable reactivity, and the ability to catalyze reactions under mild conditions. The identification of nanozymes has unveiled the biocatalytic potential of inorganic nanomaterials. In parallel, inorganic minerals have long been regarded as pivotal catalysts in the origin of life, driving the synthesis of early biomolecules. These minerals not only facilitate redox reactions that convert simple inorganic compounds into organic molecules but also enable chiral selection, the synthesis of biomacromolecules, and radioprotective functions via their surface structures. Recent advances suggest that inorganic nanomaterials can delicately catalyze the formation of biomolecules, aid in macromolecular assembly, and provide radiation shielding. Furthermore, nanominerals are found in abundance across Earth and extraterrestrial environments. This paper seeks to explore the potential of nanozymes as catalytic agents in the processes that gave rise to life, integrating the catalytic roles of inorganic minerals with the unique attributes of nanozymes, which will provide a new perspective for research of origin of life.
Life is inseparable from oxygen. The redox state in cells directly regulates the functions of biomacromolecules and mediates cell signal transduction and many physiological and pathological processes such as aging, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and tumors. In view of The Free Radical Theory of Aging proposed in the 1950s, oxidative stress has long been confused with oxidative damage and is regarded as bad. Antioxidation once became synonymous of “anti-aging”. Here in combination the relevant research work of our laboratory and the frontiers of the redox biology field, we propose three new understandings of “oxidative stress”. (1) Oxidative stress is not equal to oxidative damage and has important physiological functions. (2) Oxidative stress is not related to all physiological and pathological processes without specificity, while redox regulation is specific and redox modification of biomacromolecules is the mechanism. (3) Non-targeting antioxidants do not work well, the redox balance has precise properties, 5R principle should be considered for antioxidant pharmacology and the new era of precision redox medicine has begun. Future challenges are reflected in three major aspects: basic research on redox biology and medicine, the specific molecular mechanisms of oxidative stress in physiological and pathological processes and environmental stress, and precise redox intervention against aging and diseases. Multidisciplinary basic research, in-depth cooperation between basic research and clinical research and international collaboration must be enhanced to achieve breakthroughs in the understanding of redox in life processes, breakthroughs in redox mechanisms, and breakthroughs in precision intervention!
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CHEN Chang.Perspectives: Three New Understandings of Oxidative Stress[J].,2024,51(10):2292-2297.Export: BibTexEndNote
Photosynthesis is one of the most important chemical reactions on earth. Oxygenic photosynthetic organisms convert solar energy into chemical energy and release oxygen, thus sustaining almost all life on this planet. Oxygenic phototrophs possess two photosystems, namely photosystem I (PSI) and photosystem II (PSII). Both photosystems are multi-subunit protein complexes embedded in the thylakoid membrane and bind numerous pigment molecules, thereby can efficiently harvest light energy and transfer it to the reaction center. PSI is one of the most efficient nano-photochemical machineries in nature. Its complex structure and sophisticated regulatory mechanisms are crucial for the high photosynthetic efficiency of oxygenic phototrophs. Eukaryotic PSI consists of a core complex where charge separation occurs and a peripheral antenna system that increases the light absorption cross section of the core. The PSI core possesses approximately 12-15 protein subunits, most of them are conserved during evolution, with only several small transmembrane subunits emerging or disappearing. The peripheral antenna system usually contains a number of light-harvesting complexes (LHCs). In contrast to the core, the protein composition and arrangement of LHC antennae vary considerably among different species of photosynthetic organisms. Previous results showed that in angiosperm plants (such as Pisum sativum and Zea mays), the PSI core binds four LHC proteins arranged as an arc-shaped belt, whereas in green algae, the PSI core is associated with more LHCs, presumably a result of adaption to the low-light aquatic environment. In addition, structures of several green algal PSI complexes indicated that green algae can dynamically regulate their light-harvesting capability by adjusting the size of PSI antennae, thereby better adapting to the changing natural environment. In addition to the light harvesting and energy conversion, PSI is also involved in several photosynthetic regulatory processes, including state transitions and cycle electron flow/transfer (CEF/CET). State transitions represent a short-term regulatory mechanism that balances the energy distribution between the two photosystems. During the process of state transitions, when PSII is preferentially excited, a portion of the PSII antenna, the major light-harvesting complex II (LHCII), is phosphorylated, and these phosphorylated LHCIIs bind to the PSI core, forming the PSI-LHCI-LHCII complex. This process is reversible, and when PSI is preferentially excited, LHCII is dephosphorylated, detaches from the PSI and binds to the PSII. Previous reports revealed that although higher plants and green algae possess a similar process of state transitions, their PSI-LHCI-LHCII complexes exhibit specific characteristics in addition to common conserved features. CEF is another important regulatory process in which the PSI participates. In NDH (NAD(P)H dehydrogenase-like complex) dependent CEF, PSI can form supercomplex with NDH to improve the electron transfer efficiency. Previous reports suggested that the PSI bound to NDH and the PSI not bound to NDH possess different LHC compositions, and the exact protein identity and location were recently unraveled based on high-resolution structures. In the past two decades, a number of structures of PSI and PSI-containing complexes have been determined. These structural data provide important information concerning the protein assembly and pigment arrangement of these complexes, allowing for a deeper understanding of the structure and function of green plant PSI. In this review, we summarize the research progresses on the structure of green plant PSIs and PSI-containing complexes involved in photosynthetic regulation, primarily based on the results obtained in our laboratory, and discuss the current state of knowledge concerning the antenna arrangement and the regulatory mechanisms of plant PSI.
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SU Xiao-Dong, LI Mei.Review: Structural Basis of Photosystem I and Its Photosynthesis Regulation in Green Plants[J].,2024,51(10):2298-2310.Export: BibTexEndNote
Pyroptosis is a form of lytic programmed cell death executed by a family of pore-forming proteins named gasdermin (GSDM). Pyroptosis plays crucial roles in host defense against pathogen infection and eliminating abnormal and harmful cells, while excessive pyroptosis causes inflammatory diseases including cytokine storm and septic shock. Mammalian GSDMs, except for pejvakin (PJVK), adopt an autoinhibited two-domain architecture, in which the N-terminal cytotoxic domain (GSDM-N) is restrained in an inactive state by the intramolecular interaction with the C-terminal inhibitory domain (GSDM-C). These two-domain proteins are activated by upstream protease cleavage within the interdomain linkers. The unleashed GSDM-N binds to acidic phospholipids in the cytoplasmic leaf of plasma membranes and undergoes dramatic conformational changes and oligomerization, then assembling into transmembrane pores for pyroptosis induction. GSDM pores lead to membrane rupture, cell swelling, and cytosol release, thereby mobilizing proinflammatory responses. GSDMs are evolutionarily conserved and have been discovered across all kingdoms of life, including bacteria, fungi, invertebrates such as cnidarians and mollusks, and all vertebrates. Proteolytic cleavage to liberate the pore-forming activity of GSDM-N appears to be a universal mechanism for most GSDMs activation, despite low sequence homology among the GSDMs from diverse species. However, recent studies discover that there exist noncanonical GSDMs lack of functional C-terminal inhibitory domains in some lower eukaryotic species. These noncanonical GSDMs are activated by unprecedent mechanisms independent of proteolytic cleavage. TrichoGSDM, present in the basal metazoan Trichoplax adhaerens, is a pore-forming domain-only protein and exists as a disulfides-linked autoinhibited dimer. Reduction of the disulfides by the conserved cytoplasmic antioxidant system, including glutathione (GSH) and thioredoxin (Trx), generates pore-forming active monomers capable of inducing lytic cell death. In filamentous fungus Neurospora crassa, polymorphic regulator of cell death-1 (rcd-1) encodes two GSDM-like proteins RCD-1-1 and RCD-1-2 in incompatible haplostrains, which trigger pyroptosis-like cell death in nonself discrimination (allorecognition) upon encountering during somatic cell fusion. RCD-1-1 and RCD-1-2 are both monomers and structurally similar to mammalian GSDM-N domains, lacking autoinhibitory fragments. They alone could bind acidic phospholipids, and associate with cell membrane in a resting state. Coexistence of RCD-1-1 and RCD-1-2 leads to formation of RCD-1-1/RCD-1-2 heterodimers through molecular mating, which further oligomerize into membrane-inserted pores, causing rapid lytic cell death. These findings reveal mechanistic diversities in GSDM activation and indicate versatile functions of GSDMs. Due to the highly proinflammatory nature of pyroptosis, the pore-forming activities of GSDMs have been illustrated to be precisely regulated at multiple levels. GSDMD transcription and expression is characterized to be induced by interferon regulatory factors 2 (IRF2). mRNA alternative splicing of GSDMB generates various isoforms, some of which exhibit potent pore-forming activity whereas the others bear none. Additionally, different types of post-translational modifications have been identified on GSDMs, playing distinct regulatory roles. For examples, itaconation of GSDMD, succinylation of GSDMD and GSDME, and phosphorylation of GSDMA, GSDMD and GSDME, negatively regulate GSDM pore formation, thereby inhibiting pyroptosis. Conversely, palmitoylation of GSDMD and GSDME, and ubiquitination of GSDMD promote the pore-forming activities and pyroptosis. Moreover, some proteases can cleave within the GSDM-N domains to block their pore-forming activities. On the other hand, bacterial pathogens evolve specific effectors to hijack host pyroptotic defense pathway through targeting upstream caspases, GSDMs or plasma membrane phospholipids. Given the crucial roles of GSDMD in immune defense and pathological inflammation, a few small-molecule inhibitors have been found to directly inhibit GSDMD activity. Since the identification of GSDMs as the executioners of pyroptosis, the GSDM family has attracted broad attention in immunology researches. Significant progress has been made to greatly advance our knowledge about how GSDMs action, and what are the immunological functions of pyroptosis. Investigations of GSDM-targeting therapies are emerging as a promising translational direction. In this paper, we review recent progress in the field of pyroptosis researches, with focus on various molecular mechanisms underlying GSDMs activation and regulation. The biological implication and future direction of pyroptosis research are also discussed.
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HOU Yan-Jie, DING Jing-Jin.Review: Gasdermins, The Executor of Pyroptosis[J].,2024,51(10):2311-2327.Export: BibTexEndNote
Cardiovascular diseases are a group of disorders of the heart and blood vessels, primarily including coronary heart disease, stroke, and other diseases. It is the world’s leading cause of death, and its incidence is increasing yearly. Hypertension is a major risk factor for cardiovascular disease. Wnt signaling comprises a series of highly conservative cascading events controlling fundamental biological processes. Wnt signaling pathways include the canonical Wnt pathway (or Wnt/β-catenin pathway), the non-canonical planar cell-polarity pathway, and the non-canonical calcium-dependent pathways. Abnormal Wnt signaling promotes cell proliferation and differentiation, cardiac malformations, various malignancies, so drugs targeting Wnt signaling play a great therapeutic potential. Wnt/β-catenin pathway is involved in the occurrence and development of cardiovascular diseases such as atherosclerosis and stroke by regulating cell proliferation, migration, apoptosis, blood-brain barrier permeability, inflammation, oxidative stress, and immune response. Based on the latest research progress, this review summarizes the role of Wnt/β-catenin signaling in cardiovascular diseases, in order to provide new ideas for the prevention and treatment of cardiovascular diseases.
Protein palmitoylation, a prevalent and dynamic form of S-acylation modification, plays a critical role in maintaining the functionality of the nervous system. This reversible process involves the attachment of palmitic acid to cysteine residues in proteins, anchoring them to cellular membranes and regulating their spatial distribution. The functioning of palmitoylation is crucial for normal neuronal activities, influencing key processes such as signal transduction, synaptic function, and protein trafficking. Recent research has increasingly underscored the significance of specific zinc finger Asp-His-His-Cys motif-containing (ZDHHC) S-acyltransferases in neuronal development and synaptic plasticity. These enzymes, which catalyze the palmitoylation of proteins, have emerged as pivotal regulators of brain function. Dysregulation of palmitoylation by these enzymes is now recognized as a potential contributor to the pathogenesis of various neurodegenerative diseases. This review provides an in-depth analysis of the expression patterns and functional diversity of ZDHHC enzymes across different brain regions and cell types. ZDHHC enzymes exhibit significant sequence variability and demonstrate region-specific and cell type-dependent expression. Such heterogeneity suggests that these enzymes may have specialized roles in different areas of the nervous system, making them crucial modulators of neuronal function and synaptic transmission. The review also explores the regulatory mechanisms of protein palmitoylation and their implications in neurodegenerative disease onset and progression. Altered palmitoylation can lead to the destabilization and subsequent aggregation of these proteins, exacerbating neurodegenerative processes. Abnormal palmitoylation of α-synuclein can either promote or inhibit its aggregation in Parkinson’s disease pathology. Proteins related to these key pathological factors, including amyloid precursor protein (APP) and beta-secretase 1 (BACE1), are also influenced by palmitoylation, contributing to the formation of amyloid plaques through the aggregation of Aβ. Additionally, ZDHHC13 and ZDHHC17, which are abundantly and widely expressed in the brain, play crucial roles in this process. For instance, reduced interaction between ZDHHC17 and huntingtin could significantly contribute to the pathogenesis of Huntington’s disease. Thus, modulating the palmitoylation status of these proteins presents a promising therapeutic strategy to prevent their toxic aggregation and mitigate neuronal damage. Actually, regulating palmitoylation has shown potential for therapeutic interventions in neurodegenerative diseases, with studies demonstrating that modulation of palmitoylation can restore neuronal function and improve disease symptoms. Regulating palmitoylation holds significant promise for therapeutic strategies in neurodegenerative diseases, as modulation of this process can restore neuronal function and ameliorate disease symptoms. However, progress is hindered by the lack of high-resolution structural data and comprehensive targeting maps for specific ZDHHC enzymes. Additionally, current detection methods for palmitoylation, which focus on labeling and analyzing palmitic acid and cysteine residues, are often complex and time-consuming, and may produce inconsistent palmitoyl-proteomic profiles. These methodological challenges underscore the need for more robust and efficient detection technologies. A deeper understanding of palmitoylation’s role in neurological diseases, coupled with the development of improved detection methods, is essential for advancing our knowledge of the molecular underpinnings of these conditions and for the creation of innovative therapeutic strategies aimed at combating neurodegenerative diseases.
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LIU Wen-Ying, WANG Shu-Heng, JIA Jian-Ping.Review: Pathological Consequences of Altered Palmitoylation in Neurodegenerative Disorders and Its Potential as a Therapeutic Target[J].,2024,51(10):2340-2356.Export: BibTexEndNote
In a recent publication, Hu et al. (2023) have reported that individuals with high trait anxiety exhibit attentional deficits characterized by reduced inhibition of distractors and delayed attentional selection of targets, indicating impaired top-down attentional control. This commentary underscores their significant contributions to the cognitive theory of anxiety. Based on their findings, we propose a novel training approach called attentional inhibition training (AIT), aimed at improving top-down attentional control to alleviate symptoms of anxiety. Furthermore, we also explore the potential application of non-invasive transcranial magnetic stimulation (TMS) for rapidly enhancing attentional control function.
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MA Hao-Yun,LIANG Jian-Hui,LIU Dong-Qiang.Neurological Insights into Attentional Deficits in High Trait Anxiety: a Commentary on Hu et al.’s Paper in Cerebral Cortex (2023)[J]..Export: BibTexEndNote
Objective The aim of this study was to investigate the prophylactic effects of caloric restriction (CR) on lipopolysaccharide (LPS)-induced septic cardiomyopathy (SCM) and to elucidate the mechanisms underlying the cardioprotective actions of CR. This research aims to provide innovative strategies and theoretical support for the prevention of SCM.Methods A total of forty-eight 8-week-old male C57BL/6 mice, weighing between 20–25 g, were randomly assigned to 4 distinct groups, each consisting of 12 mice. The groups were designated as follows: CON (control), LPS, CR, and CR+LPS. Prior to the initiation of the CR protocol, the CR and CR+LPS groups underwent a 2-week acclimatization period during which individual food consumption was measured. The initial week of CR intervention was set at 80% of the baseline intake, followed by a reduction to 60% for the subsequent 5 weeks. After 6-week CR intervention, all 4 groups received an intraperitoneal injection of either normal saline or LPS (10 mg/kg). Twelve hours post-injection, heart function was assessed, and subsequently, heart and blood samples were collected. Serum inflammatory markers were quantified using enzyme-linked immunosorbent assay (ELISA). The serum myocardial enzyme spectrum was analyzed using an automated biochemical instrument. Myocardial tissue sections underwent hematoxylin and eosin (HE) staining and immunofluorescence (IF) staining. Western blot analysis was used to detect the expression of protein in myocardial tissue, including inflammatory markers (TNF-α, IL-9, IL-18), oxidative stress markers (iNOS, SOD2), pro-apoptotic markers (Bax/Bcl-2 ratio, CASP3), and SIRT3/SIRT6.Results 12 hours after LPS injection, there was a significant decrease in ejection fraction (EF) and fractional shortening (FS) ratios, along with a notable increase in left ventricular end-systolic diameter (LVESD). Morphological and serum indicators (AST, LDH, CK, and CK-MB) indicated that LPS injection could induce myocardial structural disorders and myocardial injury. Furthermore, 6-week CR effectively prevented the myocardial injury. LPS injection also significantly increased the circulating inflammatory levels (IL-1β, TNF-α) in mice. IF and Western blot analyses revealed that LPS injection significantly up-regulating the expression of inflammatory-related proteins (TNF-α, IL-9, IL-18), oxidative stress-related proteins (iNOS, SOD2) and apoptotic proteins (Bax/Bcl-2 ratio, CASP3) in myocardial tissue. 6-week CR intervention significantly reduced circulating inflammatory levels and downregulated the expression of inflammatory, oxidative stress-related proteins and pro-apoptotic level in myocardial tissue. Additionally, LPS injection significantly downregulated the expression of SIRT3 and SIRT6 proteins in myocardial tissue, and CR intervention could restore the expression of SIRT3 proteins.Conclusion A 6-week CR could prevent LPS-induced septic cardiomyopathy, including cardiac function decline, myocardial structural damage, inflammation, oxidative stress, and apoptosis. The mechanism may be associated with the regulation of SIRT3 expression in myocardial tissue.
Transmembrane proteins (TMEM) are a type of membrane protein. Most proteins in this family are located in the phospholipid bilayer of the cell membrane, while a smaller portion is found in the membranes of cellular organelles. Transmembrane Protein 43 (TMEM43) is a member of the TMEM protein family and is encoded by the TMEM43 gene. This protein consists of 400 amino acids and has 4 transmembrane domains and 1 membrane-associated domain. TMEM43 is localized to various biological membranes within the cell, such as the cell membrane and nuclear membrane, where it forms transmembrane channels for various ions. Additionally, TMEM43 is expressed in many species, showing high genetic similarity, especially with the four transmembrane domains being highly conserved. Current studies on the TMEM43 gene are still in its early stages, mainly focusing on its association with arrhythmogenic right ventricular cardiomyopathy (ARVC) and cancer. However, recent studies suggest that pathogenic mutations in TMEM43 may cause auditory neuropathy spectrum disorder (ANSD). Patients with TMEM43 p.Ser372Ter exhibited late-onset progressive ANSD. Impact of TMEM43 pathogenic mutations on individual hearing was likely mediated through effects on gap junction (GJ) structures on glia-like supporting cells (GLS) cell membranes. The TMEM43 p.Arg372Ter pathogenic mutation primarily affected the structure and function of TMEM43 protein, leading to premature termination of protein translation and the production of a truncated protein. Abnormal TMEM43 protein significantly reduced K+ influx in GLs cells, disrupting the endolymphatic K+ circulation and cochlear microenvironment homeostasis. When K+ circulation was obstructed, the endocochlear potential (EP) became abnormal, impairing the physiological function of hair cells and potentially leading to hearing impairment. However, it is important to note that studies on the mechanism is limited, and more experimental evidence is needed to confirm this hypothesis. Currently, there is a significant gap in research on TMEM43 and hearing loss, with many issues remaining unresolved. While TMEM43 has been studied in relation to hearing loss in humans, zebrafish, mice, and rats, the research is still preliminary. Detailed investigations into the molecular pathogenic mechanisms, the impact of mutations on hearing damage, and related therapeutic strategies are needed. Additionally, as a newly identified hearing loss-related gene, the mutation frequency and incidence of hearing disorders associated with TMEM43 have not been effectively quantified. For example, the ClinVar database listed 829 mutation sites for the TMEM43 gene, with only three mutations related to auditory neuropathy: c.605A>T (p.Asn202Ile), c.889T>A (p.Phe297Ile), and c.1114C>T (p.Arg372Ter). Aside from the aforementioned TMEM43 c.1114C>T (p.Arg372Ter) mutation observed in patients, the other two mutations were experimentally induced and have not been found in patients. Consequently, these mutations have been classified as unknown significance. We reviewed the current understanding of TMEM43 and hearing loss, analyzed its role in ear development and sound conduction, and explored the impact of TMEM43 gene variations on hearing loss, aiming to provide new insights for future research and precision medicine related to TMEM43.
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CUI Rong-Jie,WEI Jing-Ru,LI Yun-Long.The Current Status of Research on The TMEM43 Gene and Its Association with Hearing Loss[J]..Export: BibTexEndNote
Depression, also known as Major Depressive Disorder (MDD), is an emotional disorder characterized by low mood, decreased interest, and lack of energy, which imposes a heavy burden on families and society. Neuromodulation technology has made significant progress in improving depressive symptoms by using invasive or non-invasive methods, such as electricity and magnetism, to regulate neural activity in specific areas of the brain. Determining objective evaluation indicators can provide reliable basis for the development of neural regulation strategies and efficacy evaluation in major depressive disorder. This article systematically reviews the latest application progress of non-invasive neural regulation techniques such as transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), and transcranial ultrasound stimulation (TUS), as well as invasive neural regulation techniques such as deep brain stimulation (DBS), optogenetics, and chemical genetics in major depressive disorders. The focus is on exploring behavioral, neuroimaging, and neurophysiological evaluation indicators of neural regulation, providing direction for the development of precise and personalized neural regulation schemes and assessment tools for major depressive disorders in the future.
Drug addiction is a worldwide issue that threaten social stability and development. It has been proved to be a chronic, relapsing disease that results from the prolonged effects of drugs on the various neural networks. Over time, plenty of attention has been paid to find new approaches to enhance the sensitivity and accuracy of assessment on addiction. In recent years, researchers found that the expression of neurotransmitters and their receptors in some peripheral blood immunocyte may reflect their expression in the brain. By analyzing the changes of addiction-related neural biomarkers in peripheral blood immunocyte, it is potential to enhance the accuracy and the susceptibility of assessments on addiction and treatment effectiveness, and in turn help to reduce drug relapse. In this review, we summarize the potential biomarkers related to addiction in peripheral blood immunocyte and changing trend of their mRNA expression level in patients using different types of drugs and with different addiction states, and discuss their application prospects and future research directions. Previous studies have found various types of potential addiction biomarkers, including neurotransmitter receptor proteins, hormones, small molecule metabolites, ΔFosB microRNA and other transcriptional (post) regulators. Considering the correlation with addiction and the richness of existing research, this article mainly introduces neurotransmitter receptor proteins closely related to addiction, including dopamine receptors, opioid receptors, cannabinoid receptors, and N-methyl-D-aspartate (NMDA) receptors. The expression levels of these potential biomarkers often change correspondingly at different stages. For example, mRNA expression of dopamine D3 receptor was increased in opioid addicted and methadone-maintained patients, but no change was observed in the heroin abstinent group. In addition, changing patterns of the biomarkers induced by different types of drugs were also various. Although both opioid addiction and alcohol addiction could induce the change of mRNA expression of dopamine D4 receptor, it was decreased in the opioid addiction patients while increased in the alcohol addiction patients. On the basis of the available evidence, dopamine receptors (especially D4 receptors) are most potent at the indicative action across drugs and stages, while cannabinoid receptors mainly specifically reflect different stages of cannabis addiction status. In addition, the mRNA level of the GluN3B subunit showed a steady increase in different stages of opioid addiction and showed a decreased response to methadone treatment, suggesting that it has high potential as a biomarker of heroin addiction. Besides, the mRNA level of D4 receptor showed a clear reverse trend in the stage of alcohol addiction and alcohol withdrawal, which also reflected the potential of D4 receptor mRNA in the state of alcohol addiction. Considering evidences about serum levels changing in patients with drug addiction, immune response induced by drugs may be one possible mechanism of changes in the expression levels of transmitter receptors in the peripheral blood of drug addiction patients. Finally, the current research on biomarkers in peripheral blood for addiction is still relatively fragmented, and lack systematic mechanism exploration. Future studies could further combine animal studies and clinical studies to systematically demonstrate the role of relevant biomarkers and underlying mechanisms. In addition, there are often interactions between multiple biomarker proteins in mediating drug addiction, especially in the process of addiction development. Thus, the overall observation of the dynamic changing of different biomarkers in the addiction process may be helpful to enhance the accuracy of assessment of addiction states. At the same time, when applying peripheral blood biomarkers, corresponding standards should be formulated based on experimental evidences, so as to enhance the pertinence and effectiveness of peripheral blood biomarkers in the diagnosis and treatment of addiction.
In recent years, deep learning-based methods have achieved significant breakthroughs in protein structure prediction. The open-source release of AlphaFold 2 (AF2) in 2021 enabled high-precision prediction of three-dimensional structures for both individual proteins and protein complexes, allowing researchers to rapidly obtain reliable structural information and greatly accelerating advancements in protein structure and function studies. The release of AlphaFold 3 (AF3) in 2024 took this further by achieving accurate predictions of three-dimensional structures for protein-nucleic acid and protein-small molecule complexes. With improved algorithms and a more efficient model, AF3 significantly enhanced prediction accuracy, especially demonstrating outstanding performance in antigen-antibody and protein-small molecule complexes. The success of AlphaFold has not only brought revolutionary progress to structural biology but also showcased immense application potential in fields such as drug development, protein design, and molecular function research, driving innovation in biomedical studies. This article will review the development history of AlphaFold and related protein structure prediction methods, summarize their key technologies and current applications, and, by considering their limitations, provide an outlook on future research directions and applications.
Citation
GONG Wei-Bin.Breakthrough of AlphaFold Structure Prediction and Its Impact and Challenges on Protein Research[J]..Export: BibTexEndNote
Tripartite motif-containing protein 13 (TRIM13) is a crucial member of the TRIM protein family, distinguished by its unique transmembrane domain that anchors it to the endoplasmic reticulum (ER). As an E3 ubiquitin ligase, TRIM13 influences multiple key signaling pathways through ubiquitination regulation, playing significant roles in modulating ER function, immune responses, metabolic disorders, inflammatory diseases, and tumor suppression. TRIM13 possesses the common RING, B-box, and coiled-coil domains of the TRIM family, along with its distinctive transmembrane domain. Its E3 ubiquitin ligase activity serves as the structural basis for its diverse biological functions. TRIM13 acts as a non-canonical ER-phagy receptor to participate in regulating ER stress responses, recruiting LC3 through interaction with SQSTM1/p62 to initiate autophagy-mediated degradation of damaged ER, which is crucial for maintaining ER homeostasis and cellular function under stress conditions. TRIM13 is involved in inflammatory and antiviral immune responses by modulating key molecules in signaling pathways such as MDA5, NF-κB, and STING, highlighting its potential in regulating innate immunity and inflammatory. TRIM13 is associated with various pathological conditions, particularly in cancer and metabolic diseases. In multiple cancers, including non-small cell lung cancer, hepatocellular carcinoma, and acute myeloid leukemia, TRIM13 exhibits tumor-suppressive effects, with its expression levels closely associated with patient prognosis, suggesting its potential as a biomarker or therapeutic target in oncology. In diabetic nephropathy, TRIM13 improves renal function by promoting CHOP ubiquitination and inhibiting interstitial collagen synthesis, demonstrating its protective role in kidney disease. In atherosclerosis, TRIM13 is involved in regulating cholesterol metabolism and inflammatory pathways, indicating its significance in cardiovascular disorders. Recent studies have also implicated TRIM13 in neurodegenerative disorders and metabolic syndromes, with its role in regulating protein quality control and ER stress responses suggesting potential involvement in diseases characterized by protein misfolding and aggregation, such as Alzheimer"s and Parkinson"s diseases. Additionally, TRIM13"s participation in lipid metabolism and insulin signaling pathways points to its possible influence on obesity and diabetes. Despite significant advancements in TRIM13 research, the precise molecular mechanisms underlying its functions in various physiological and pathological processes remain to be elucidated. In this article, we review the structural characteristics and functions of TRIM13 protein, with particular emphasis on its roles in ER-phagy, inflammatory responses, and tumor suppression, as well as its potential significance in various diseases. Future studies should focus on revealing the specific core mechanisms of TRIM13 function and exploring its unique role in ER function regulation. A deeper understanding of TRIM13 protein and its regulatory mechanisms in development of diseases may provide novel targets and strategies for disease diagnosis and treatment.
In recent years, tumor-infiltrating B lymphocytes (TIL-B) play a complex and important role in tumorigenesis and tumor development. TIL-B contains various subpopulations, which can be broadly classified into subpopulations of tumor-suppressing B cells, such as antigen-presenting B cells and plasma cells; and subpopulations of tumor-promoting B cells, such as regulatory B cells (Bregs). The anti-tumor mechanisms of TIL-B contain many aspects, including the secretion of specific antibodies such as IgG and IgA; activation of T cells through antigen presentation; release of cytokines that affect tumor cell growth; direct killing of target cells through the Fas/FasL and perforin pathways; and enhancement of anti-tumor immunity through interactions with T cells. The pro-tumor mechanism of TIL-B also includes many aspects, such as Bregs can inhibit anti-tumor immunity by secreting cytokines, inducing the production of regulatory T cells (Tregs), and inhibiting the interaction between T cells and antigen presenting cells (APCs), etc. Atypical memory (AtM) B cells and leucine-tRNA-synthase-2 (LARS2) -expressing B cells (LARS B) subpopulations can also promote tumor progression by secreting cytokines such as TNF-α and TGF-β. Based on the above mechanisms, a variety of tumor therapies are now available. Firstly, the anti-tumor effect of TIL-B can be enhanced. Immune checkpoint blockade therapy is a classical immunotherapy method, and TIM-1 is a key checkpoint and has achieved certain efficacy. In addition, the development of suitable novel antibodies, safe and effective TIL-B vaccines are also promising therapeutic methods. Adoptive metastatic B-cell therapy, direct activation of B-cells, chemotherapy and targeted drugs is limited because of the high technical requirements, high toxicity and uncertainty of efficacy. In the future, it is expected that further research will gradually expand the scope of its application to achieve more effective treatment for tumor patients. Selective depletion of B cells is an immunotherapy based on the inhibition of Bregs subpopulations to achieve anti-tumor effects. The next step is to develop more efficacious targeted drugs by understanding the phenotypic and functional differences of Bregs. Finally, TIL-B can be involved in the treatment and prognosis of tumors as a predictive tumor immune marker. The efficacy of treatment can be simply assessed by observing TIL-B distribution and density in tumor. Stress-responsive memory B cells and tumor-associated atypical B cells (TAAB) have clearly shown to be associated with shorter and longer survival in cancer patients, thus be used as biomarkers of immunotherapeutic response in human cancers. This paper reviews the current status of TIL-B research, summarizes its mechanism of action in tumor immunity, analyses current therapeutic strategies and prognostic assessment methods. Future focus on understanding the functional heterogeneity and molecular regulatory mechanisms of TIL-B is essential for optimising tumor immunotherapy strategies. The systematic study of TIL-B characteristics and mechanisms of action in different tumor types can help provide a theoretical basis and potential targets for the development of new tumor therapeutic strategies.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by progressive demyelination and neuroinflammation, leading to axonal damage and neuronal degeneration. It is the most prevalent non-traumatic cause of neurological disability in young adults, affecting millions of people worldwide. MS manifests with a wide range of symptoms, including motor dysfunction, sensory deficits, and cognitive impairment, which can severely impact the quality of life. Despite extensive research, the exact pathogenesis of MS remains unclear, and currently available treatments primarily focus on reducing inflammation and relapse rates rather than reversing neurological damage. Thus, one of the major therapeutic challenges is to develop strategies that can not only suppress the aberrant immune response but also enhance endogenous myelin regeneration and neurorepair, ultimately halting or even reversing disease progression. Recent studies have highlighted the critical role of chondroitin sulfate proteoglycans (CSPGs), a family of inhibitory extracellular matrix (ECM) molecules, in regulating CNS repair processes. CSPGs accumulate at the sites of demyelinated lesions and form a dense, inhibitory matrix that impedes the migration and differentiation of oligodendrocyte precursor cells (OPCs), thereby preventing effective myelin regeneration. CSPGs exert their inhibitory effects through several cell surface receptors, including leukocyte common antigen-related receptor (LAR), Nogo receptors (NgR1 and NgR3), and protein tyrosine phosphatase σ (PTPσ). Among these, PTPσ is a predominant receptor that mediates the biological activities of CSPGs via its phosphatase domains, which regulate downstream signaling pathways involved in cell proliferation, differentiation, and cytoskeletal organization. The CSPGs/PTPσ axis has been identified as a major molecular pathway contributing to the inhibition of remyelination in MS. The upregulation of CSPGs and PTPσ in MS lesions has been associated with a failure of OPCs to remyelinate damaged axons effectively. Preclinical studies have shown that pharmacological inhibition or genetic ablation of PTPσ can alleviate the inhibitory effects of CSPGs on OPC migration and differentiation. For instance, systemic administration of the PTPσ inhibitor peptide (ISP) has been shown to enhance OPC differentiation, promote remyelination, and restore motor function in animal models of MS, highlighting the potential of targeting CSPGs/PTPσ as a therapeutic approach for MS. Furthermore, CSPGs and their receptors have been implicated in modulating other biological processes such as immune cell infiltration, synaptic plasticity, and axonal regeneration, which are relevant to the pathogenesis of MS and other neurodegenerative diseases. CSPGs are known to activate downstream signaling pathways, such as the Rho/ROCK, Akt, and ERK pathways, which regulate cytoskeletal dynamics and gene expression in OPCs, ultimately affecting their ability to mature into myelinating oligodendrocytes. Additionally, CSPGs can interact with the N-cadherin/β-catenin pathway, influencing cell adhesion and signaling in OPCs, thereby modulating myelin repair capacity. Given the multifaceted roles of CSPGs/PTPσ in CNS pathology, targeting this pathway represents a promising therapeutic strategy. This article aims to provide a comprehensive overview of the biological properties of CSPGs and PTPσ, focusing on their roles in the inhibition of myelin regeneration. Specifically, it discusses how CSPGs/PTPσ signaling modulates various aspects of OPC biology, including autophagy regulation and immune modulation. Moreover, the review explores potential therapeutic strategies aimed at disrupting CSPGs/PTPσ interactions, such as the use of small-molecule inhibitors, neutralizing antibodies, or gene therapies. In summary, a deeper understanding of CSPGs/PTPσ-mediated signaling in OPCs and other cell types within MS lesions may reveal novel therapeutic targets for promoting remyelination and functional recovery. This review provides a detailed analysis of current findings and highlights the need for further research to translate these findings into effective treatments for MS patients.
Objective Cancer is a global public health issue that has attracted much attention. Detecting and treating cancer at an earlier time point is the key to improving cancer survival rates. However, due to factors such as high equipment cost, slow detection speed, and poor detection accuracy, the promotion of early cancer screening is limited. Therefore, this paper proposes a high-precision and high-speed bioimpedance spectroscopy detection method for tumor identification based on multi-frequency synchronous bioimpedance spectroscopy technology.Methods First, based on the multi-frequency synchronization technology, this paper built a multi-frequency synchronous bioimpedance spectrum detection system, realized the high-speed detection of bioimpedance spectrum, designed concentric circle sensors to reduce the influence of biological tissue anisotropy on impedance detection, and improved the discrimination of bioimpedance spectrum between different tissues. Secondly, a gastric wall tissue model was established, and the degree of anisotropy influence on traditional four-electrode sensors and concentric circle sensors was studied through simulation. Finally, through pork tissue detection experiments and clinical gastric cancer tissue detection experiments, it was verified that the multi-frequency synchronous bioimpedance spectroscopy detection system using concentric circle sensors has higher detection accuracy.Results The experimental results show that when using concentric circle sensors, the average overlap rate of detection results is 13.4%, which is 41.7% lower than that of traditional electrodes, and the average discrete coefficient Cv is 7.6%, which is 54.0% lower than that of traditional electrodes. The multi-frequency synchronous bioimpedance spectrum detection system takes about 20 ms to perform a detection, and the detection method proposed in this paper has higher detection accuracy and detection speed. Finally, the concentric circle electrodes were selected to conduct clinical experiments on human gastric cancer tissue, and normal tissue and tumor tissue were successfully distinguished.Conclusion The high-precision and high-speed bioimpedance spectroscopy detection method for tumor identification proposed in this paper can effectively reduce the influence of anisotropy of biological tissues and obtain higher-precision and higher-speed detection results.
Transcranial Focused Ultrasound (tFUS) technology achieves precise stimulation or treatment of the area of interest in the head by directing ultrasound beams to penetrate the human skull to form an intracranial focal point, with the advantages of eliminating the need for craniotomy and the absence of ionizing radiation. High-intensity tFUS treats brain diseases such as essential tremor or brain tumors through thermal effects, while low-intensity tFUS can safely and reversibly open the blood-brain barrier or conduct neuromodulation studies through mechanical effects. However, in practical applications, ultrasound waves undergo strong phase distortion and energy attenuation due to the strong acoustic attenuation properties and inhomogeneous structure of the skull. Acoustic simulation models the interaction between ultrasound and media based on acoustic fluctuation equations to predict the propagation properties of sound waves in different media. Therefore, acoustic simulation is commonly used to predict the intracranial acoustic field for single-element tFUS or to perform phase correction for each element of multi-element tFUS to ensure accurate focusing of intracranial ultrasound. According to the different methods of solving the acoustic fluctuation equations, the commonly used acoustic simulation methods in tFUS can be categorized into numerical and semi-analytical methods. The numerical methods include k-space pseudo-spectral method, time-domain finite difference method and finite element method, etc., and the semi-analytical methods include ray-tracing method and hybrid angular spectrum method. Simulation tools based on numerical methods synthesize various forms of wave propagation in media, such as nonlinear effects, scattering and diffraction, and are widely used in academic research. The k-Wave toolbox based on the k-space pseudo-spectral method and various programs based on the time-domain finite-difference method are the most widely used simulation tools in the current tFUS accurate simulation and experimental research. Although the finite element method has the advantage of dealing with complex boundary conditions, the excessive consumption of computational resources limits its direct application in complex 3D simulations. Compared to numerical methods, semi-analytical-based simulations cannot accurately model full-wave effects, but their computational speed makes them more suitable for clinical scenarios where simulation time is critical. ray-tracing, developed by Insightec, is currently the only phase-correction method that has been used in clinical applications. Based on geometric acoustic principles, ray tracing enables near real-time tFUS phase correction. At the same time, the hybrid angular spectroscopy method shows higher accuracy in precise targeting than the conventional ray tracing method. In addition, the hybrid application of different simulation methods significantly improves the simulation efficiency and accuracy, e.g., the boundary element method can be coupled with the finite element method to limit the computational area to the region involving only the skull, which drastically reduces the computational load. In recent years, the acoustic simulation for tFUS has continued to make progress, but there is still a huge room for improvement in terms of computational efficiency and accuracy, and the optimal use of computational resources and the combination of multiple simulation techniques may be the direction of the future development of simulation technology. In this paper, the research on simulation techniques based on numerical, semi-analytical and hybrid methods commonly used in the field of tFUS in recent years is reviewed and sorted out, and the research and application of various simulation methods are summarized and prospected.
As the aging population in China continues to grow, the country"s public health sector faces an urgent need to address the significant social challenges posed by Alzheimer"s Disease (AD). The available clinical treatments for AD are extremely limited, and the effectiveness of these drugs often diminishes after a period of use. Despite substantial global investment in drug research and development, the progress of clinical trials for AD treatments has been exceedingly slow. Over the past 30 years, only seven AD drugs have been approved by the U.S. Food and Drug Administration (FDA). Traditional drug therapies are expensive and can only slow the progression of AD, without halting the progressive degeneration of neurons. Therefore, exploring and developing emerging treatment methods for AD is imperative. Photobiomodulation (PBM) is a non-invasive therapeutic approach that uses red or near-infrared light to stimulate cellular metabolism and biological responses. PBM has the potential to improve brain metabolism and blood circulation, repair damaged neurons in the brain, and stimulate dendritic and neuronal growth, making it a promising non-invasive neurotherapeutic method that could complement drug treatments. This paper discusses the pathological characteristics and pathogenic mechanisms of AD, as well as the challenges faced by existing treatment strategies. It also reviews the research on PBM treatment in AD cellular and animal models and clinical studies, summarizes the history of phototherapy and the current state of advanced PBM phototherapy device development, and finally offers a perspective on the future development of advanced photonic technologies and therapeutic devices for PBM treatment of AD.
The two-component system (TCS) is a signaling mechanism extensively found in prokaryotes, playing a pivotal role in bacterial environmental sensing and adaptive responses. Comprising histidine kinase (HK) and response regulator (RR) components, TCS ensures appropriate bacterial reactions to various stimuli. Understanding its structural composition, signal transduction mechanisms, and applications in synthetic biology underscores its significance in both basic research and biotechnological applications. At its core, TCS operates through a sequence of events initiated by the detection of environmental cues. When the HK senses specific signals such as temperature changes, osmolarity shifts, or the presence of ligands, it undergoes autophosphorylation at a conserved histidine residue within its kinase domain. Subsequently, this phosphoryl group is transferred to a conserved aspartate residue on the RR"s receiver domain. This phosphotransfer event activates the RR, inducing a conformational change that alters its activity, often leading to changes in gene expression or other cellular responses. The specificity and fidelity of signal transduction in TCS are critical for bacteria to differentiate between various environmental cues and mount appropriate responses. This specificity is achieved through mechanisms such as unique signal molecule recognition by HKs and precise phosphotransfer from HKs to RRs. Moreover, the directional transfer of phosphoryl groups ensures tightly regulated signaling cascades, contributing to the overall robustness of bacterial response systems. Beyond its natural role, the versatility of TCS has been harnessed by engineers in synthetic biology to create tools like biosensors. By integrating TCS components into synthetic circuits, researchers can develop customized biosensors capable of highly sensitive and specific detection of environmental signals or biomolecules. These engineered biosensors find applications across diverse fields including environmental monitoring, medical diagnostics, and industrial biotechnology. The robustness of TCS-driven biosensors is particularly advantageous in synthetic biology. The modular design of TCS allows for the construction of sensor systems sensitive to a broad range of signals, adaptable to different cellular contexts. This adaptability is crucial for optimizing sensor performance under varying conditions, ensuring reliable and reproducible results. Safety considerations are paramount in synthetic biology, where TCS-based systems offer inherent safety features due to their reliance on natural signaling pathways and components. Well-characterized interactions between HKs and RRs minimize risks such as unintended cross-talk or interference with endogenous cellular processes, enhancing reliability in bioengineering applications requiring predictable and controllable cellular responses. Looking ahead, ongoing research aims to expand the capabilities of TCS-based biosensors through innovative engineering approaches. Advances in synthetic biology techniques, including genome editing and high-throughput screening, facilitate rapid design and optimization of novel sensor systems. These efforts promise next-generation biosensors with enhanced functionalities such as multiplexed sensing and real-time monitoring in complex biological environments. In summary, the Two-Component System stands as a cornerstone of bacterial signal transduction, facilitating precise environmental sensing and adaptive responses. Its structural simplicity, coupled with robust signaling mechanisms and programmability, underpins its utility in synthetic biology for developing advanced biosensors and other bioengineering applications. By leveraging these capabilities, researchers are poised to address critical challenges in healthcare, environmental sustainability, and industrial biotechnology, shaping the future of biologically inspired technologies.
Citation
LUO Bo-Yu,TENG Yue.Structural Characteristics and Signal Transduction Mechanisms of Bacterial Two-component Systems[J]..Export: BibTexEndNote
Objective The aim of this study was to investigate the effect and mechanism of quercetin on lipid droplet formation in foam cells induced by oxidized low-density lipoprotein (ox-LDL).Methods Mouse RAW264.7 cells were induced by 50 mg/L ox-LDL to construct a foam cell model. After different quercetin concentrations were treated for different time, the optimal quercetin concentration and time were screened by CCK8 assay. Based on the constructed foam cell model, the formation of fat droplets was observed by oil red O staining after quercetin treatment with or without AS1842856 (FOXO1 inhibitor). Apoptosis was detected by flow cytometry. The protein expression of FOXO1 in each group was detected by Western blot. Autophagosome formation was observed by acridine orange staining. The mRNA and protein expression levels of Beclin1, LC3Ⅱ and P62 were detected by qRT-PCR and Western blot.Results After being treated with 100 μmol/L quercetin for 12 h, the formation of fat droplets and apoptosis of foam cells were inhibited (P<0.05). Compared with control group, there was an increase in fat droplet formation and apoptosis (P<0.05), a decrease in autophagosome (P<0.05), a decrease in FOXO1 protein expression (P<0.05), a decrease in Beclin1 and LC3Ⅱ protein and mRNA expression levels (P<0.05), and the expression levels of P62 protein and mRNA were found to be increased (P<0.05) in model group. Compared with model group, quercetin treatment up-regulated FOXO1 protein expression (P<0.05), induced autophagosome formation (P<0.05), promoted the protein and mRNA expression levels of Beclin1 and LC3Ⅱ (P<0.05), and inhibited the protein and mRNA expression levels of P62 (P<0.05). In addition, treatment with the FOXO1 inhibitor AS1842856 reversed quercetin"s effect on OX-LDL-induced foam cells.Conclusion Quercetin induced autophagy by upregulating FOXO1 expression and inhibited fat droplet formation induced by OX-LDL.
Electromagnetic fields can regulate the fundamental biological processes involved in bone remodeling. As a non-invasive physical therapy, electromagnetic fields with specific parameters have demonstrated therapeutic effects on bone remodeling diseases, such as fractures and osteoporosis. Electromagnetic fields can be generated by the movement of charged particles or induced by varying currents. Based on whether the strength and direction of the electric field change over time, electromagnetic fields can be classified into static and time-varying fields. The treatment of bone remodeling diseases with static magnetic fields primarily focuses on fractures, often using magnetic splints to immobilize the fracture site while studying the effects of static magnetic fields on bone healing. However, there has been relatively little research on the prevention and treatment of osteoporosis using static magnetic fields. Pulsed electromagnetic fields, a type of time-varying field, have been widely used in clinical studies for treating fractures, osteoporosis, and non-union. However, current clinical applications are limited to low-frequency, and research on the relationship between frequency and biological effects remains insufficient. We believe that different types of electromagnetic fields acting on bone can induce various "secondary physical quantities", such as magnetism, force, electricity, acoustics, and thermal energy, which can stimulate bone cells either individually or simultaneously. Bone cells possess specific electromagnetic properties, and in a static magnetic field, the presence of a magnetic field gradient can exert a certain magnetism on the bone tissue, leading to observable effects. In a time-varying magnetic field, the charged particles within the bone experience varying Lorentz forces, causing vibrations and generating acoustic effects. Additionally, as the frequency of the time-varying field increases, induced currents or potentials can be generated within the bone, leading to electrical effects. When the frequency and power exceed a certain threshold, electromagnetic energy can be converted into thermal energy, producing thermal effects. In summary, external electromagnetic fields with different characteristics can generate multiple physical quantities within biological tissues, such as magnetic, electric, mechanical, acoustic, and thermal effects. These physical quantities may also interact and couple with each other, stimulating the biological tissues in a combined or composite manner, thereby producing biological effects. This understanding is key to elucidating the electromagnetic mechanisms of how electromagnetic fields influence biological tissues. In the study of electromagnetic fields for bone remodeling diseases, attention should be paid to the biological effects of bone remodeling under different electromagnetic wave characteristics. This includes exploring innovative electromagnetic source technologies applicable to bone remodeling, identifying safe and effective electromagnetic field parameters, and combining basic research with technological invention to develop scientifically grounded, advanced key technologies for innovative electromagnetic treatment devices targeting bone remodeling diseases. In conclusion, electromagnetic fields and multiple physical factors have the potential to prevent and treat bone remodeling diseases, and have significant application prospects.
In recent years, it has been discovered that innate immunity also exhibits immune memory characteristics, referred to as trained immunity. This refers to the ability of innate immune cells to acquire a memory-like capacity after being attacked by pathogens, thereby demonstrating enhanced reactivity upon secondary stimulation from the same or different stimuli. Existing research indicates that high-fat diet stimulates innate immune cells to undergo trained immunity, thereby significantly boosting their immune response to secondary metabolic disorders. This process serves as a crucial mechanism underlying the development of insulin resistance-associated metabolic diseases. Breaking the vicious cycle between insulin resistance and trained immunity by inducing innate immune cells to establish immune tolerance and inhibiting excessive inflammatory reactions caused by various secondary metabolic disorders of insulin resistance represents a novel strategy for early prevention and treatment of related metabolic diseases. As is widely known, exercise intervention serves as an effective means to improve insulin resistance-related metabolic diseases. It promotes metabolic homeostasis by exerting anti-inflammatory effects, yet the underlying mechanism of these anti-inflammatory effects remains unclear. Numerous studies suggest that after a high-fat diet generates innate immune memory, exercise intervention may alleviate excessive inflammatory reactions caused by secondary metabolic disorders due to insulin resistance by inducing immune tolerance in innate immune cells, and promote early prevention and treatment of related metabolic diseases. Therefore, targeting innate immune cell immune tolerance to explore the anti-inflammatory mechanism of exercise intervention in insulin resistance holds exciting and vast prospects. Metabolic reprogramming refers to the process in which cells undergo systematic adjustments and transformations in their energy requirements and metabolic patterns to adapt to changes in the external environment and meet their own needs for proliferation and differentiation under specific physiological and pathological conditions. Numerous studies have shown that metabolic reprogramming plays a crucial role in tumor biology, immunology, stem cell research, and the occurrence and development of various diseases. Increasing evidence suggests that metabolic reprogramming is also a key mechanism for innate immune cells to respond to external stimuli and perform immune functions. The process of immune tolerance is also driven by metabolic reprogramming. Studying the mechanisms of innate immune cell immune tolerance from the perspective of metabolic reprogramming is expected to provide new directions for the prevention and treatment of chronic inflammation and related metabolic diseases. Meanwhile, exercise has been proven to regulate metabolic reprogramming in various cells. It may induce immune tolerance in activated innate immune cells by inhibiting glycolysis and enhancing their oxidative phosphorylation levels, thereby mitigating excessive inflammatory reactions and achieving early prevention and treatment of insulin resistance-related metabolic diseases. Itaconate, an intermediate product of the tricarboxylic acid cycle, represents a newly discovered central regulatory point for balancing the trained immunity and immunity tolerance in innate immune cells. Additionally, exercise modulates IRG1/Itaconate signaling. Therefore, conducting an in-depth exploration of the interrelationships between trained immunity, immunity tolerance, metabolic reprogramming, and IRG1/Itaconate signaling in exercise intervention for insulin resistance, as well as summarizing the immune tolerance mechanism of exercise in improving insulin resistance, can provide theoretical support for the preventive and therapeutic effects of exercise in insulin resistance and related metabolic diseases. This can also offer new insights for the development of simulated drugs tailored for individuals with exercise intolerance.
Citation
LUO Wei,GAO Wen-Yue,WANG Yu-Hang,LIU Yan-Song,AI Lei.The Emerged Perspective on Improving Insulin Resistance Through Exercise: Metabolic Reprogramming Induces Trained Immunity Tolerance[J]..Export: BibTexEndNote
Ageing has been identified as one of the risk factors for chronic disease, and the onset and development of many chronic diseases are closely related to gut immune dysfunction in the elderly. Aging profoundly affects the intestinal immune system and the homeostasis of the intestinal flora. We have reviewed the changes in intestinal mucosal immune function that occur with aging, including Toll-like receptors (TLRs), T cells, B cells and inflammatory cytokines such as IL-6, TNF-α and IFN-γ. Age-related changes in typical gut microbiota and their metabolites were discussed. Ageing leads to changes in the composition and diversity of the gut microbiota. Age-related changes occur in intestinal bacteria such as Bacteroides, Bifidobacterium and Clostridium butyricum. The metabolites of the gut flora, including short chain fatty acids (SCFAs), bile, indole and indole derivatives, decrease and the homeostasis of the gut flora becomes unbalanced. The interaction between the intestinal flora and its metabolites and the intestinal immune system has been studied and a high correlation between the intestinal flora and the immune function of the intestinal mucosa has been proposed. Under normal circumstances, a healthy immune system and gut flora are mutually reinforcing and promote the health of the host. However, with age, the integrity of the intestinal mucosa and the homeostasis of the intestinal flora are disrupted, resulting in a decline in the immune response and regulatory capacity and an inability to respond effectively to various exogenous insults. Meanwhile, the ongoing damage to the immune system further exacerbates the imbalance in the gut flora. Changes in the gut flora of the elderly affect the diversity and levels of key immune molecules such as defensins and immunoglobulin A (IgA). Abnormal expression of immune molecules in the gut also leads to changes in the composition of the gut microbiome, affecting gut health and potentially increasing the risk of disease. The metabolites of the intestinal flora interact with intestinal receptors, activate relevant signalling pathways, directly regulate immune cells and control the immune system, influence the intestinal barrier and intestinal immune functions, and exert immunoregulatory effects on the intestine. As the relationship between gut flora and immune ageing becomes clearer, future research can explore strategies for targeted regulation of gut flora for anti-aging and immune enhancement. In this paper, we further explore the regulation of gut flora and gut immune function by dietary intervention and fecal microbiota transplantation (FMT) to achieve the goal of delaying immune ageing. Dietary intervention promotes the growth of beneficial bacteria by adjusting the structure of the elderly"s diet and supplementing with microbial preparations, maintaining the intestinal barrier and reducing chronic inflammation. FMT involves the transplantation of faeces from healthy individuals into recipients to improve mucosal integrity and promote microbial diversity. This paper has discussed the complex mechanism between ageing, gut flora and immune response, highlighted the research progress of gut flora anti-aging methods, with the aim of providing a reference for research on targeted gut flora regulation to promote gut mucosal immune function for health promotion and anti-aging.
Alzheimer"s disease (AD) is the most common form of dementia, and its prevalence is rapidly increasing with the aging population. Among the growing number of genetic risk factors, apolipoprotein E (ApoE) is the most prevalent and strongest risk factor, accounting for nearly three-quarters of AD cases. ApoE is a key protein involved in lipids and cholesterol metabolism in the central nervous system. There are three subtypes of ApoE: ApoE2, ApoE3, and ApoE4, among which ApoE4 is a high-risk factor for the incidence of AD. ApoE4 not only affects lipid efflux and distribution in glial cells, but also affects the lipid metabolism in neurons, resulting in the imbalance of lipid homeostasis. ApoE plays a role in the processing of amyloid precursor protein (APP), which is associated with the early production of amyloid-β (Aβ) peptide and plaque deposition. ApoE4 also reduces the solubility of Tau protein, which contributes to promoting the aberrant phosphorylation and the aggregation of Tau, and resulting in neurofibrillary tangles (NFTs). Moreover, brain regions expressing ApoE4 are more susceptible to Tau diffusion. Furthermore, ApoE4 has been demonstrated to activate the NF-κB inflammatory pathway, convert microglia and astrocytes into the pro-inflammatory phenotypes, secrete pro-inflammatory factors and oxidative mediators, and induce neuroinflammation. Altogether, ApoE participates in AD neuropathology through multiple pathways such as Aβ plaque, Tau pathology, neuroinflammation, neuroplasticity and blood-brain barrier, which all jointly promotes the progression of the disease. It has been demonstrated that anti-ApoE4 antibodies can reduce the formation of Aβ plaques and neuroinflammation. The repurposing of metformin, rapamycin, enoxaparin, DHA, and tamoxifen have been shown to reduce the expression of ApoE4 protein and ameliorate AD pathology. Gene therapies utilising antisense oligonucleotides (ASO) and double-stranded interfering small RNA (siRNA) has been proved to be effective technologies to reduce ApoE4 expression and mitigate AD pathology. Adeno-associated virus (AAV)-mediated ApoE2 has been demonstrated to neutralize the negative effects of ApoE4 by expressing ApoE2 in the ventricular membrane. Traditional Chinese medicine resveratrol and waterside delivered by ApoE-modified liposome nanodrug delivery system can improve the BBB penetration of drugs and provid a new method for the treatment of AD. In addition, targeting the interaction of ApoE with low-density lipoprotein receptor (LDLR) and low density lipoprotein-related protein 1 (LRP1) receptors can indirectly regulate the expression level of ApoE, which provids a new perspective for the treatment of AD. This article aims to elucidate the roles of ApoE and its isoforms in the pathogenesis of AD and summarize the potential therapeutic strategies against ApoE with the hope of providing novel insights for the ApoE-based therapies combat AD.
Objective Electroencephalography (EEG) serves as a non-invasive electrophysiological monitoring technique employed to record brain electrical activity. Nonetheless, traditional EEG electrodes are susceptible to reference activation influences and exhibit limited spatial resolution. Laplacian electrodes, devoid of reference dependencies, possess the potential to amplify the spatial resolution of EEG recordings. Anchored in the utilization of bipolar concentric ring Laplacian electrodes, this study delves into the autonomous referencing attributes intrinsic to Laplacian electrodes. Furthermore, it conducts a comparison of spatial resolution disparities between Laplacian electrodes and their conventional counterparts.Methods A three-dimensional (3D) hemispherical tank experiment was conducted utilizing 21 Ag/AgCl bipolar concentric ring Laplacian electrodes to simulate whole-brain signal acquisitions. A sinusoidal signal with an amplitude of 400 mVpp@13 Hz was employed for detection. The positions of the ground electrodes in the Laplacian electrode array were varied, alongside the reference electrode positions in the case of the traditional electrodes. Subsequently, the spatial distribution of the 13 Hz source frequency component was extracted and subjected to comprehensive analysis.Results With varying ground electrode positions, the spatial distribution of the signal-to-noise ratio (SNR) among Laplacian electrodes maintains remarkable consistency, yielding a correlation coefficient of 0.94. In contrast, for traditional electrodes, the correlation coefficient for SNR distribution under distinct reference electrode positions barely reaches 0.07. While Laplacian electrodes exhibit independence from reference electrodes, traditional counterparts display a notable susceptibility to changes in reference electrode positions. Comparing amplitude"s 3 dB attenuation area ratio, Laplacian electrodes showcase a mere 2.1% reduction, a significantly favorable outcome when juxtaposed with the 6.9% reduction evident in traditional electrodes. Similarly, the SNR"s 3 dB attenuation area ratio for Laplacian electrodes is a mere 1.0%, contrasting with the considerably higher figure of 30.1% for traditional electrodes.Conclusion Laplacian electrodes remain impervious to reference electrode influence, displaying distinctive reference-independent attributes, in addition to boasting a heightened spatial resolution. These characteristics imbue them with the capacity to achieve heightened precision in localizing brain electrical activities, thus constituting a cornerstone for the integration of Laplacian electrodes into brain-computer interfaces (BCIs).
Objective Photoacoustic pump-probe imaging can effectively eliminate the interference of blood background signal in traditional photoacoustic imaging, and realize the imaging of weak phosphorescence molecules and their triplet lifetimes in deep tissues. However, background differential noise in photoacoustic pump-probe imaging often leads to large fitting results of phosphorescent molecule concentration and triplet lifetime. Therefore, this paper proposes a novel triplet lifetime fitting method for photoacoustic pump-probe imaging. By extracting the phase of the triplet differential signal and the background noise, the fitting bias caused by the background noise can be effectively corrected.Methods The advantages and feasibility of the proposed algorithm are verified by numerical simulation, phantom and in vivo experiments, respectively.Results In the numerical simulation, under the condition of noise intensity being 10% of the signal amplitude, the new method can optimize the fitting deviation from 48.5% to about 5%, and has a higher exclusion coefficient(0.88>0.79), which greatly improves the fitting accuracy. The high specificity imaging ability of photoacoustic pump imaging for phosphorescent molecules has been demonstrated by phantom experiments. In vivo experiments have verified the feasibility of the new fitting method proposed in this paper for fitting phosphoometric lifetime to monitor oxygen partial pressure content during photodynamic therapy of tumors in nude mice.Conclusion This work will play an important role in promoting the application of photoacoustic pump-probe imaging in biomedicine.
Objective Stroke is a leading cause of death and disability worldwide, with ischemic stroke accounting for 80%–85% of cases. Despite the prevalence, effective treatments remain scarce. The compelling evidence suggest that high concentrations of ATP in the brain post-stroke can trigger irreversible neuronal damage and necrosis, contributing to a range of neurocellular dysfunctions. Pyroptosis, a recently identified form of programmed cell death, is characterized by caspase-1 activation and the action of the Gasdermin D (GSDMD) protein family, leading to cell perforation and inflammatory death.Methods In this study, human neuroblastoma SH-SY5Y cells were used to investigate the mechanisms of ATP-induced neurotoxicity and the protective effects of hydrogen sulfide (H2S) against this toxicity through the antagonization of pyroptosis. We employed CCK-8 and LDH assays to assess cell viability. YO-PRO-1 fluorescent dyes and flow cytometry were conducted for detecting changes in cell membrane permeability. Western blot analysis was used to measure protein levels associated with cellular dysfunction.Results Our results indicate that high concentrations of ATP enhance cytotoxicity and increase cell membrane permeability in SH-SY5Y cells, effects that are mitigated by the H2S donor NaHS. Furthermore, ATP was found to promote the activation of the NOD-like receptor pyrin domain containing 1 (NLRP-1), caspase-1, and the cleavage of GSDMD, with NaHS significantly attenuating these effects.Conclusion Our research suggests that H2S protects SH-SY5Y cells from ATP-induced neurotoxicity through a mechanism mediated by the NLRP1, caspase-1, and GSDMD pathway.
Objective Tomatoes are one of the highest-yielding and most widely cultivated economic crops globally, playing a crucial role in agricultural production and providing significant economic benefits to farmers and related industries. However, early blight in tomatoes is known for its rapid infection, widespread transmission, and severe destructiveness, which significantly impacts both the yield and quality of tomatoes, leading to substantial economic losses for farmers. Therefore, accurately identifying early symptoms of tomato early blight is essential for the scientific prevention and control of this disease. Additionally, visualizing affected areas can provide precise guidance for farmers, effectively reducing economic losses.Methods This study combines hyperspectral imaging technology with machine learning algorithms to develop a model for the early identification of symptoms of tomato early blight, facilitating early detection of the disease and visual localization of affected areas. To address noise interference present in hyperspectral images, robust principal component analysis (RPCA) is employed for effective denoising, enhancing the accuracy of subsequent analyses. To avoid insufficient information representation caused by the subjective selection of regions of interest, the Otsu"s thresholding method is utilized to extract tomato leaves effectively from the background, with the average spectrum of the entire leaf taken as the primary object of study. Furthermore, a comprehensive spectral preprocessing workflow is established by integrating multivariate scatter correction (MSC) and standardization methods, ensuring the reliability and effectiveness of the data. Based on the processed spectral data, a discriminant model utilizing a linear kernel function support vector machine (SVM) is constructed, focusing on characteristic wavelengths to improve the model"s discriminative capability.Results Compared to full-spectrum modeling, this approach results in an 8.33% increase in accuracy on the test set. After optimizing the parameters of the SVM model, when C=1.64, the accuracies of the training set and test set reach 91.67% and 94.44%, respectively, demonstrating a 1.19% increase in training set accuracy compared to the unoptimized model, while maintaining the same accuracy on the test set, effectively alleviating issues of underfitting.Conclusion This study successfully establishes an early discriminant model for tomato early blight using hyperspectral imaging and achieves visualization of early symptoms. Experimental results indicate that the SVM discriminant model based on characteristic wavelengths and a linear kernel function can effectively identify early symptoms of tomato early blight. Visualization of these symptoms in terms of disease probability allows for a more intuitive detection of early diseases and timely implementation of corresponding control measures. This visual analysis not only enhances the efficiency of disease identification but also provides farmers with more straightforward and practical information, aiding them in formulating more reasonable prevention strategies. These research findings provide valuable references for the early identification and visualization of plant diseases, holding significant practical implications for monitoring, identifying, and scientifically preventing crop diseases. Future research could further explore how to apply this model to disease detection in other crops and how to integrate IoT technology to create intelligent disease monitoring systems, enhancing the scientific and efficient management of crops.
Citation
BAO Hao,HUANG Li,ZHANG Yan,PANG Hao.Early Identification and Visualization of Tomato Early Blight Using Hyperspectral Imagery[J]..Export: BibTexEndNote
Electroencephalography (EEG) is a non-invasive, high temporal-resolution technique for monitoring brain activity. However, affected by the volume conduction effect, EEG has a low spatial resolution and is difficult to locate brain neuronal activity precisely. The surface Laplacian (SL) technique obtains the Laplacian EEG (LEEG) by estimating the second-order spatial derivative of the scalp potential. LEEG can reflect the radial current activity under the scalp, with positive values indicating current flow from the brain to the scalp ("source") and negative values indicating current flow from the scalp to the brain ("sink"). It attenuates signals from volume conduction, effectively improving the spatial resolution of EEG, and is expected to contribute to breakthroughs in neural engineering. This paper provides a systematic overview of the principles and development of SL technology. Currently, there are two implementation paths for SL technology: current source density algorithms (CSD) and concentric ring electrodes (CRE). CSD performs the Laplace transform of the EEG signals acquired by conventional disc electrodes to indirectly estimate the LEEG. It can be mainly classified into local methods, global methods, and realistic Laplacian methods. The global method is the most commonly used approach in CSD, which can achieve more accurate estimation compared with the local method, and it does not require additional imaging equipment compared with the realistic Laplacian method. CRE employs new concentric ring electrodes instead of the traditional disc electrodes, and measures the LEEG directly by differential acquisition of the multi-ring signals. Depending on the structure, it can be divided into bipolar CRE, quasi-bipolar CRE, tripolar CRE, and multi-pole CRE. The tripolar CRE is widely used due to its optimal detection performance. While ensuring the quality of signal acquisition, the complexity of its preamplifier is relatively acceptable. Here, this paper introduces the study of the SL technique in resting rhythms, visual-related potentials, movement-related potentials, and sensorimotor rhythms. These studies demonstrate that SL technology can improve signal quality and enhance signal characteristics, confirming its potential applications in neuroscientific research, disease diagnosis, visual pathway detection, and brain-computer interfaces. CSD is frequently utilized in applications such as neuroscientific research and disease detection, where high-precision estimation of LEEG is required. And CRE tends to be used in brain-computer interfaces, that have stringent requirements for real-time data processing. Finally, this paper summarizes the strengths and weaknesses of SL technology and envisages its future development. SL technology boasts advantages such as reference independence, high spatial resolution, high temporal resolution, enhanced source connectivity analysis, and noise suppression. However, it also has shortcomings that can be further improved. Theoretically, simulation experiments should be conducted to investigate the theoretical characteristics of SL technology. For CSD methods, the algorithm needs to be optimized to improve the precision of LEEG estimation, reduce dependence on the number of channels, and decrease computational complexity and time consumption. For CRE methods, the electrodes need to be designed with appropriate structures and sizes, and the low-noise, high common-mode rejection ratio preamplifier should be developed. We hope that this paper can promote the in-depth research and wide application of SL technology.
Objective To explore the mechanisms of exercise intervention to improve autism-like behaviors in rats induced by Shank3 knockout (Shank3–/–) through 8-week swimming exercise intervention in an autism spectrum disorder (ASD) rat model based on the cellular autophagy perspective.Methods According to the genotype identification and exercise intervention, rats were divided into wild control group (WC group), Shank3–/– group (KC group), wild swimming group (WS group), and Shank3–/– swimming group (KS group), with 15 rats in each group. 8 weeks of swimming exercise were performed in the KS group and the WS group, with the exercise being performed for 5 d per week, and then progressively increased to 40 min per session and maintained. Behavioral tests were performed 24 h after the swimming exercise intervention, including: self-grooming test, buried bead test, and hole test. Sampling was performed 12 h after the behavioral test, and the number of autophagosomes in the striatal region was observed by transmission electron microscopy, the protein expression level of microtubule-associated protein 1 light chain 3 (LC3) protein and selective autophagy junction protein (p62) protein was observed by immunofluorescence staining, and the protein expression level of B-cell lymphoma protein 2 interactions protein 1 (BECLIN1), LC3, p62, autophagy-associated protein 5 (Atg5), autophagy-associated 16-like protein 1 (Atg16L), and lysosome-associated protein 1 (LAMP1) in striatal tissues was detected by qPCR and Western blot.Results Compared with the WC group, rats in the KC group had a significant increase in the number and time of self-grooming (P<0.05), the number of buried beads (P<0.01), and the number of hole explorations and the number of single hole explorations (P<0.05), and after 8 weeks of swimming exercise, rats in the KS group showed a significant decrease in the time of self-grooming, the number of bead burials, and the number of single hole explorations, compared with those of rats in the KC group. In addition, rats in the KC group had a large number of autophagosomes formed in the striatal region compared with the WC group, while the expression of autophagy-related proteins and mRNAs Atg5, Atg16L, p62, and microtubule-associated protein 1 light chain 3 II/I (LC3II/LC3Ⅰ) (P<0.05) increased significantly, Beclin1 protein increased significantly (P<0.05), and LAMP1 protein and mRNA Expression of autophagy-related proteins and mRNAs Atg5, Atg16L, p62, LC3II/LC3Ⅰ (P<0.05) were significantly decreased, BECLIN1 protein was significantly decreased (P<0.05), and LAMP1 protein and mRNA expression was significantly increased in the KS group rats compared to the KC group rats after 8 weeks of swimming exercise (P<0.05).Conclusion Early swimming at 8 weeks could alleviate stereotyped behavior in Shank3–/– rats by enhancing the function of striatal cell autophagy proteins.
Citation
XUE Ya-Qi,LIU Niu,WANG Shi-Jiao,BA Yi,ZHEN Zhi-Ping.Early Swimming Alleviates Stereotypic Behavior in Shank3 Knockout Rats by Enhancing Striatal Cell Autophagy Protein Function[J]..Export: BibTexEndNote
"Runner"s high" refers to a momentary sense of pleasure that suddenly appears during running or other exercise activities, characterized by anti-anxiety, pain relief, and other symptoms. The neurobiological mechanism of "runner"s high" is unclear. This review summarizes human and animal models for studying "runner"s high", analyzes the neurotransmitters and neural circuits involved in runner"s high, and elucidates the evidence and shortcomings of researches related to "runner"s high". This review also provides prospects for future research. Research has found that exercise lasting more than 30 min and with an intensity exceeding 70% of the maximum heart rate can reach a "runner"s high". Human experiments on "runner"s high" mostly use treadmill exercise intervention, and evaluate it through questionnaire surveys, measurement of plasma AEA, miRNA and other indicators. Animal experiments often use voluntary wheel running intervention, and evaluate it through behavioral experiments such as conditional place preference, light dark box experiments (anxiety), hot plate experiments (pain sensitivity), and measurement of plasma AEA and other indicators. Dopamine, endogenous opioid peptides, endogenous cannabinoids, brain-derived neurotrophic factor, and other substances increase after exercise, which may be related to the "runner"s high". However, attention should be paid to the functional differences of these substances in the central and peripheral regions, as well as in different brain regions. Moreover, current studies have not identified the targets of the neurotransmitters or neural factors mentioned above, and further in-depth researches are needed. The mesolimbic dopamine system, prefrontal cortex-nucleus accumbens projection, ventral hippocampus-nucleus accumbens projection, red nucleus-ventral tegmental area projection, cerebellar-ventral tegmental area projection, and brain-gut axis may be involved in the regulation of runner"s high, but there is a lack of direct evidence to prove their involvement. There are still many issues that need to be addressed in the research on the neurobiological mechanisms of "runner"s high". (1) Most studies on "runner"s high" involve one-time exercise, and the characteristics of changes in "runner"s high" during long-term exercise still need to be explored. (2) The using of scales to evaluate subjects lead to the lacking of objective indicators. However, some potential biomarkers (such as endocannabinoids) have inconsistent characteristics of changes after one-time and long-term exercise. (3) The neurotransmitters involved in the formation of the "runner"s high" all increase in the peripheral and/or central nervous system after exercise. Attention should be paid to whether peripheral substances can enter the blood-brain barrier and the binding effects of neurotransmitters to different receptors are completely different in different brain regions. (4) Most of the current evidence show that some brain regions are activated after exercise. Is there a functional circuit mediating "runner"s high" between these brain regions? (5) Although training at a specific exercise intensity can lead to "runner"s high", most runners have not experienced "runner"s high". Can more scientific training methods or technological means be used to make it easier for people to experience the "runner"s high" and thus be more willing to engage in exercise? (6) The "runner"s high" and "addiction" behaviors are extremely similar, and there are evidences that exercise can reverse addictive behaviors. However, why is there still a considerable number of people in the sports population and even athletes who smoke or use addictive drugs instead of pursuing the "pleasure" brought by exercise? Solving the problems above is of great significance for enhancing the desire of exercise, improving the clinical application of neurological and psychiatric diseases through exercise, and enhancing the overall physical fitness of the population.
As a rapidly developing frontier discipline, structural biology has penetrated into every field of life science research. The course of “Structural Biology” plays an important role in expanding the knowledge system of undergraduate students and promoting students’ scientific spirit and innovation. For the high-quality training of highly skilled talents, we aimed to promote the original innovation of students, the ability of thinking, and the ability of engineering practice. The trinity education concept, including shape of the value, passing on knowledge, and ability cultivation, was applied. During the reform, we explored a step-by-step course content and searched for factors involved in ideological and political education. Based on the problem-based learning (PBL) method, a hybrid teaching model was designed to cultivate the problem-thinking and problem-solving skills of students. Meanwhile, a number of evaluation systems for students and teachers were established, which may be generally adopted for the course of “Structural Biology”. The survey data suggested that the exploration has a good effect on teaching and training and is conducive to the cultivation of research-oriented, comprehensive, innovative talents under the background of “New Engineering”.
Serine protease inhibitor Kazal-type (SPINK) is a skin keratinizing protease inhibitor, which was initially found in animal serum and is widely present in plants, animals, bacteria, and viruses, and they act as key regulators of skin keratinizing proteases and are involved in the regulation of keratinocyte proliferation and inflammation, primarily through the inhibition of deregulated tissue kinin-releasing enzymes (KLKs) in skin response. This process plays a crucial role in alleviating various skin problems caused by hyperkeratinization and inflammation, and can greatly improve the overall condition of the skin. Specifically, the different members of the SPINK family, such as SPINK5, SPINK6, SPINK7, and SPINK9, each have unique biological functions and mechanisms of action. The existence of these members demonstrates the diversity and complexity of skin health and disease. First, SPINK5 mutations are closely associated with the development of various skin diseases, such as Netherton"s syndrome and atopic dermatitis, and SPINK5 is able to inhibit the activation of the STAT3 signaling pathway, thereby effectively preventing the metastasis of melanoma cells, which is important in preventing the invasion and migration of malignant tumors. Secondly, SPINK6 is mainly distributed in the epidermis and contains lysine and glutamate residues, which can act as a substrate for epidermal transglutaminase to maintain the normal structure and function of the skin. In addition, SPINK6 can activate the intracellular ERK1/2 and AKT signaling pathways through the activation of epidermal growth factor and protease receptor-2 (EphA2), which can promote the migration of melanoma cells, which further deepens its role in stimulating the migration of malignant tumor cells by inhibiting the activation of STAT3 signaling pathway. This process further deepens its potential impact in stimulating tumor invasive migration. Furthermore, SPINK7 plays a role in the pathology of some inflammatory skin diseases, and is likely to be an important factor contributing to the exacerbation of skin diseases by promoting aberrant proliferation of keratinocytes and local inflammatory responses. Finally, SPINK9 can induce cell migration and promote skin wound healing by activating purinergic receptor 2 (P2R) to induce phosphorylation of epidermal growth factor and further activating the downstream ERK1/2 signaling pathway. In addition, SPINK9 also plays an antimicrobial role, preventing the interference of some pathogenic microorganisms. Taken as a whole, some members of the SPINK family may be potential targets for the treatment of dermatological disorders by regulating multiple biological processes such as keratinization metabolism and immuno-inflammatory processes in the skin. The development of drugs such as small molecule inhibitors and monoclonal antibodies has great potential for the treatment of dermatologic diseases, and future research on SPINK will help to gain a deeper understanding of the physiopathologic processes of the skin. Through its functions and regulatory mechanisms, the formation and maintenance of the skin barrier and the occurrence and development of inflammatory responses can be better understood, which will provide novel ideas and methods for the prevention and treatment of skin diseases.
GPR126, also known as ADGRG6, is one of the most deeply studied aGPCRs. Initially, GPR126 was thought to be a receptor associated with muscle development and was mainly expressed in the muscular and skeletal systems; with the deepening of research, it has been found that GPR126 is expressed in multiple mammalian tissues and organs, and is involved in many biological processes such as embryonic development, nervous system development, and extracellular matrix interaction. GPR126 has a typical seven-transmembrane helix structure of aGPCRs, which can mediate transmembrane signal transduction and participate in the regulation of cell proliferation, differentiation and migration. However, the biological function of GPR126 in various diseases and its potential as a therapeutic target still need to be further studied. This paper focuses on the structure, interspecies differences and conservatism, signal transduction and biological functions of GPR126 to provide ideas and references for future research on GPR126.
With changes in human lifestyle, chronic diseases caused by metabolic disorders, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, have become serious public health issues threatening human health. These diseases not only significantly increase the disease burden on humans but also put immense pressure on global healthcare systems. Therefore, understanding and exploring the molecular mechanisms leading to these diseases, especially the role of metabolic regulators, is crucial for developing effective prevention and treatment strategies. KLF15, one of the highly conserved members of the KLF family, has gained widespread attention due to its expression and regulatory roles in various metabolically active organs. Recent studies have shown that KLF15 regulates glucose, lipid, and amino acid metabolism in adipose tissue, skeletal muscle, and liver, and is closely related to the acquisition, transport, and utilization of nutrients. The role of KLF15 in glucose metabolism is primarily reflected in its regulation of gluconeogenesis and glucose uptake. KLF15 influences blood glucose levels by regulating the expression of key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Research has shown that KLF15 knockout (KO) mice exhibit severe hypoglycemia and reduced liver glycogen content after 18 h of fasting. Additionally, KLF15 interacts with muscle enhancer factor 2 (MEF2A) to activate the GLUT4 promoter, significantly enhancing glucose uptake in skeletal muscle and adipose tissue. In insulin-resistant individuals, KLF15 expression is reduced, affecting insulin sensitivity by regulating genes related to lipid metabolism and mitochondrial function. In terms of lipid metabolism, KLF15 expression significantly increases during adipocyte differentiation, regulating the expression of genes such as C/EBPβ, C/EBPδ, and PPARγ. KLF15 KO mice show reduced lipogenesis and increased lipolysis, highlighting its importance in fat storage and energy balance. In brown adipose tissue (BAT), KLF15 regulates genes involved in lipid uptake and thermogenesis, such as CD36, Slc25a20, and Cpt1a. KLF15 KO mice fail to maintain body temperature during fasting-induced cold exposure, demonstrating the critical role of KLF15 in BAT metabolism and energy balance. Specifically, KLF15 forms positive feedback loops with adipogenic transcription factors such as glucocorticoid receptor (GR), PPARγ, and C/EBP, promoting adipocyte differentiation and maturation. In BAT, KLF15 is crucial not only for regulating lipid uptake but also for promoting non-shivering thermogenesis by regulating thermogenic genes, thereby helping to maintain body temperature in cold environments. In protein metabolism, KLF15 regulates key enzymes involved in branched chain amino acid (BCAA) metabolism, such as BCAT2 and ALT, which are essential for gluconeogenesis and maintaining blood glucose levels. KLF15 KO mice show reduced expression of these enzymes, leading to impaired amino acid catabolism. KLF15 regulates muscle protein synthesis and degradation through the mTOR pathway and E3 ubiquitin ligases (e.g., Atrogin-1 and MuRF1), indicating its significance in muscle protein metabolism and stress response, especially in glucocorticoid-induced muscle atrophy. Studies have shown that KLF15 expression in muscle tissue is regulated by GR. Glucocorticoids regulate KLF15 expression through GR, which in turn affects the mTOR signaling pathway, inhibiting protein synthesis and promoting protein degradation. This mechanism is particularly significant in glucocorticoid-induced muscle atrophy. KLF15 also responds significantly to exercise, particularly acute endurance exercise and long-term aerobic training. Acute endurance exercise increases KLF15 expression in muscle and adipose tissue, enhancing lipid synthesis and protein catabolism. In contrast, chronic exercise reduces KLF15 expression, improving insulin sensitivity and mitigating diabetes-induced myopathy. However, further research is needed to explore the effects of different forms of exercise on KLF15 and its specific roles in various tissues. In conclusion, KLF15 plays a crucial role in maintaining overall metabolic balance. It regulates glucose, lipid, amino acid, and protein metabolism, responding to nutritional status and exercise to maintain energy homeostasis. The role of KLF15 in glucose metabolism involves regulating gluconeogenesis and glucose uptake, in lipid metabolism through regulating fat synthesis and breakdown, and in protein metabolism through influencing branched-chain amino acid metabolism and muscle protein synthesis and degradation. Future research should continue to delve into the specific mechanisms of KLF15 in different metabolic pathways, especially its regulatory roles under various exercise forms and nutritional states, to provide new perspectives and theoretical foundations for treating metabolic diseases.
Collagen is a major structural protein in the matrix of animal cells and the most widely distributed and abundant functional protein in mammals. Collagen"s good biocompatibility, biodegradability and biological activity make it a very valuable biomaterial. According to the source of collagen, it can be broadly categorized into two types: one is animal collagen; the other is recombinant collagen. Animal collagen is mainly extracted and purified from animal connective tissues by chemical methods, such as acid, alkali and enzyme methods, etc. Recombinant collagen refers to collagen produced by gene splicing technology, where the amino acid sequence is first designed and improved according to one"s own needs, and the gene sequence of improved recombinant collagen is highly consistent with that of human beings, and then the designed gene sequence is cloned into the appropriate vector, and then transferred to the appropriate expression vector. The designed gene sequence is cloned into a suitable vector, and then transferred to a suitable expression system for full expression, and finally the target protein is obtained by extraction and purification technology. Recombinant collagen has excellent histocompatibility and water solubility, can be directly absorbed by the human body and participate in the construction of collagen, remodeling of the extracellular matrix, cell growth, wound healing and site filling, etc., which has demonstrated significant effects, and has become the focus of the development of modern biomedical materials. This paper firstly elaborates the structure, type, and tissue distribution of human collagen, as well as the associated genetic diseases of different types of collagen, then introduces the specific process of producing animal source collagen and recombinant collagen, explains the advantages of recombinant collagen production method, and then introduces the various systems of expressing recombinant collagen, as well as their advantages and disadvantages, and finally briefly introduces the application of animal collagen, focusing on the use of animal collagen in the development of biopharmaceutical materials. Applications, focusing on the use of animal disease models to explore the effects of recombinant collagen in wound hemostasis, wound repair, corneal therapy, female pelvic floor dysfunction (FPFD), vaginal atrophy (VA) and vaginal dryness, thin endometrium (TE), chronic endometritis (CE), in vivo regeneration of bone tissue, cardiovascular disease, breast cancer (BC), and anti-ageing, and there are studies proving that the effects of mechanism of action of recombinant collagen in the treatment of FPFD and CE, and also elaborated the clinical therapeutic effects of recombinant collagen in skin burns, skin wounds, dermatitis, acne, and genitourinary syndromes of menopause (GSM). From the exploratory studies and clinical applications, it is evident that recombinant collagen has demonstrated surprising effects in the treatment of all types of diseases, such as reducing inflammation, promoting cell proliferation, migration and adhesion, increasing collagen deposition, and remodeling the extracellular matrix. At the end of the review, the challenges facing recombinant collagen are summarized: to develop new recombinant collagen types and dosage forms; to explore the mechanism of action of recombinant collagen, and to provide an outlook for the future development and application of recombinant collagen.
Objective At present, the most commonly used photosensitizers in photodynamic therapy are still chemical photosensitizers, such as porphyrin, methylene blue, etc., in order to specifically target cellular tissues, and thus poison cells, chemical photosensitizers need to use antibody conjugation or a transgenically encoded tag with affinity for the modified photosensitizing ligand, e.g. FlAsH, ReAsh or Halo Tag. Gene-encoded photosensitizers can directly poison cells by targeting specific cell compartments or organelles. However, currently developed gene-encoded photosensitizers have low reactive oxygen species production and low cytotoxicity, so it is necessary to continue to develop and obtain photosensitizers with higher reactive oxygen species production for the treatment of microbial infections and tumors.Methods In this study, we developed a photosensitizer LovPSO2 based on the light-oxygen-voltage (LOV) structural domain of phototropin-1B-like from Oryza sativejaponica. LovPSO2 was expressed in E. coli BL21(DE3) and purified to obtain protein samples, the purified protein samples were added 3 μmol/L singlet oxygen probe of SOSG and 5 μmol/L superoxide anion probe of DHE after fixed to A445=0.063±0.003, respectively, then measured every 2 min of singlet oxygen production for 10 min and every 1 min of superoxide anion production for 5 min under blue light irradiation at 445 nm, 70 μmol·m-2·s-1.Results The results showed that LovPSO2 could produce a large amount of singlet oxygen under blue light irradiation at 445 nm, 70 μmol·m-2·s-1, and its singlet oxygen quantum yield was 0.61, but its superoxide anion yield was low, so in order to improve the superoxide anion yield of LovPSO2, a mutant with a relatively high superoxide anion yield was obtained by further development and design on its basis LovPRO2. The stability of proteins is crucial for research in drug development and drug delivery, among others. Temperature and light are the key factors affecting the production of ROS by photosensitive proteins and their stability, while the temperature in cell culture and mammals in vivo is about 37 °C, and the temperature inside tumor cells is about 42–45°C. Therefore, we further analyzed the photostability of miniSOG, SOPP3, LovPSO2, and LovPRO2 and their thermostability at 37℃ and 45℃. The analysis of proteins thermostability showed that LovPSO2 and LovPRO2 had better thermostability at 37℃ and 45℃, respectively. Analysis of the photostability of the proteins showed that LovPRO2 had better photostability. In addition, to further determine the phototoxic effects of photosensitizers, LovPSO2 and LovPRO2 were expressed in E. coli BL21(DE3) and HeLa cells, respectively. The results showed that LovPSO2 and LovPRO2 had better phototoxicity to E. coli BL21(DE3) under blue light irradiation, and the cellular phototoxicity lethality was as high as 90% after 30 min of continuous light irradiation, but the phototoxicity was weaker in HeLa cells. The reason for this result may be that the intracellular environment exacerbated the photobleaching of FMN encapsulated by LovPSO2 and LovPRO2, respectively, which attenuated the damage of reactive oxygen species to animal cellular tissues, limiting its use as a mechanistic tool to study oxidative stress.Conclusion LovPSO2 and LovPRO2 can be used as antibacterial photosensitizers, which have broader application prospects in the food and medical fields.
Lactate, with a chemical formula of C3H6O3, is an intermediate product of glucose metabolism in the body and a raw material for hepatic gluconeogenesis. Under physiological resting conditions, the body mainly relies on aerobic oxidation of sugar and fat for energy supply, so the blood lactate concentration is lower. However, during exercise, the enhanced glycolysis in skeletal muscles leads to the significant release of lactate into the bloodstream, causing a marked increase in blood lactate concentration. Traditionally, lactate has been regarded as a metabolic waste product of glycolysis and a contributor to exercise-induced fatigue. Nevertheless, recent studies have revealed that, in humans, lactate is a major vehicle for carbohydrate carbon distribution and metabolism, serving not only as an energy substance alongside glucose but also as a vital component in various biological pathways involved in cardiac energetics, muscle adaptation, brain function, growth and development, and inflammation therapy. Two primary pathways can elevate lactate levels in neurons during exercise. One is peripheral skeletal muscle-derived lactate, which can enter the bloodstream and cross the blood-brain barrier into the brain with the assistance of monocarboxylate transporters (MCTs) from the solute carrier family 16 (SLC16). The other is the central brain-derived pathway. During exercise, neuronal activity is enhanced, promoting the secretion of neuroactive substances such as glutamate, norepinephrine, and serotonin in the brain. This activates astrocytes to break down glycogen into lactate and stimulates glutamate from the presynaptic terminal into the synaptic cleft. It upregulates the glucose transport protein-1 (GLUT-1) expression, allowing astrocytes to convert glucose into lactate through glycolysis. The lactate is produced via peripheral pathways and central pathways during exercise are transported by astrocyte membrane monocarboxylate transporters MCT1 and MCT4 to the extracellular space, where neurons take it up through neuronal cell membrane MCT2. The lactate in neurons can serve as an alternative energy source of glucose for neuronal functional activities, meeting the increased energy demands of synaptic activity during exercise, and maintaining energy balance and normal physiological function in the brain. Additionally, acting as a signaling molecule lactate can enhance synaptic plasticity through the SIRT1/PGC-1α/FNDC5 and ERK1/2 signaling pathways, promote angiogenesis by upregulating VEGF-A expression through the PI3K/Akt and ERK1/2 signaling pathways, stimulate neurogenesis via the Akt/PKB signaling pathway, and reduce neuroinflammation through activation of the "lactate timer." Overall, lactate contributes to the protection of neurons, the promotion of learning and memory, the enhancement of synaptic plasticity, and the reduction of neuroinflammation in the nervous system. While lactate may serve as a potential mediator for information exchange between the peripheral and central nervous systems during exercise, further experimental research is needed to elucidate its action mechanisms in the nervous system. In addition, future studies should utilize advanced neurophysiological and molecular biology techniques to uncover the importance of lactate in maintaining brain function and preventing neurological diseases. Accordingly, this article first reviews the historical research on lactate, then summarizes the metabolic characteristics and neuronal sources of lactate, and finally explores the role and mechanisms of exercise-induced lactate in the nervous system, aiming to provide new perspectives and targets for understanding the mechanisms underlying exercise promotion of brain health.
Citation
MA Jing,BO Shu-Min,CHENG Yang.The Role and Mechanism of Lactate Produced by Exercise in The Nervous System[J]..Export: BibTexEndNote
Diabetes mellitus type 2 (T2DM) is one of the most common metabolic diseases in the world and has a significant impact on the health of patients. As a key factor in cellular mechanical transduction, Piezo1 protein plays a crucial role in regulating the basic life activities of the body. By participating in energy metabolism, it not only promotes the improvement of basic metabolic rate, but also helps to maintain the stability of the internal environment of the body. The activation of Piezo1 pathway has a significant effect on the release of insulin by islet beta cells, and also plays an important role in the production of adipose tissue after food intake. This study explores the effects of exercise intervention on the expression and function of Piezo1 protein, as well as its role in metabolic regulation and insulin level regulation in T2DM patients. The study showed that a modest exercise intervention activated Piezo1 signaling pathway, which improved insulin sensitivity and improved sugar metabolism. In addition, the activation of Piezo1 pathway is closely related to the metabolic regulation of adipose tissue, helping to regulate the differentiation and maturation of adipose cells, thereby affecting the metabolic function of adipose tissue. Based on a comprehensive analysis of existing literature, Piezo1 pathway is found to play a complex role in the pathogenesis of T2DM. Exercise intervention, as a non-drug therapy, provides a new strategy for the treatment of T2DM by activating Piezo1 signaling pathway. However, the exact mechanism of action of Piezo1 pathway in T2DM still needs further investigation. Future studies should focus on the interaction between the Piezo1 pathway and T2DM, and how to regulate the Piezo1 pathway to optimize treatment for T2DM. The effects of exercise intervention on Piezo1 protein and its role in metabolic regulation and insulin level regulation of T2DM patients were comprehensively analyzed in this paper, aiming to provide a new perspective for further research and development of therapeutic strategies for metabolic diseases such as diabetes and obesity.
Citation
DONG Zi-Xuan,MA Zhan-Ke.The Ameliorate Effect of Piezo1 Signaling Pathway on Diabetes Mellitus Type 2 in Exercise Intervention[J]..Export: BibTexEndNote
Objective To investigate the role of paraventricular nucleus (PVN) corticotropin releasing hormone (CRH) neurons in chronic restraint stress (CRS)-induced anxiety-like behavior. And whether exercise relieves chronic restraint stress-induced anxiety through PVN CRH neurons.Methods Twenty 8-week-old male C57BL/6J mice were randomly divided into control (Ctrl) group and chronic restraint stress (CRS) group. The open field test (OFT) and elevated plus maze (EPM) were used to evaluate anxiety-like behavior of the mice. Food intake was recorded after CRS. Immunofluorescence staining was used to label the expression of c-Fos expression in PVN and calculate the co-expression of c-Fos and CRH neurons. We used chemogenetic activation of PVN CRH neurons to observed the anxiety-like behavior. 8-week treadmill training (10–16 m/min, 60 min/d, 6 d/week) were used to explore the role of exercise in ameliorating CRS-induced anxiety behavior and how PVN CRH neurons involved in it.Results Compared with Ctrl group, CRS group exhibited significant anxiety-like behavior. In OFT, the mice in CRS groups spent less time in center area (P<0.001). In EPM, the time in open arm in CRS group were significantly decreased (P<0.001). Besides, food intake was also suppressed in CRS group compared with Ctrl group (P<0.05). Compared with Ctrl group, CRS significantly increase c-Fos expression in PVN and most of CRH neurons co-express c-Fos (P<0.001). Chemogenetic activation of PVN CRH neurons induced anxiety-like behavior (P<0.05) and inhibited feeding behavior (P<0.01). Exercise relieves chronic restraint stress-induced anxiety (P<0.001) and relieved the anorexia caused by chronic restraint stress (P<0.05). Aerobic exercise inhibited the CRS labeled c-Fos in PVN CRH neurons (P<0.001). Furthermore, ablation of PVN CRH neurons attenuated CRS induced anxiety-like behavior.Conclusion CRS activated PVN CRH neurons, induced anxiety-like behavior and reduced food intake. 8-week exercise attenuated CRS-induced anxiety-like behavior through inhibiting PVN CRH neuron. Ablation of CRH PVN neurons ameliorated CRS-induced anxiety-like behavior. These finding reveals a potential neural mechanism of exercise-relieving CRS-induced anxiety-like behavior. This provides a new idea and theoretical basis for the treatment of anxiety and related mental disorders.
Objective Chemotherapy is one of the important therapeutic approaches for cancer treatment. However, the emergence of multidrug resistance and side effects during chemotherapy seriously limit its application. Therefore chemotherapy is often combined with other drugs or therapies. Among the 13 human fucosyltransferases (FUTs) that have been identified, alpha-(1,6)-fucosyltransferase (FUT8) is the only enzyme responsible for core fucosylation. Core fucosylation plays an important role in the occurrence, metastasis and chemotherapy resistance of cancer, and suppression of FUT8 is a potential method of reversing multidrug resistance. This study aims to explore the feasibility of using the small molecule 2FF inhibitor 2-deoxy-2-fluoro-L-fucose (2FF) of FUT8 and the clinical chemotherapeutic drug doxorubicin (DOX) to treat malignant tumors in combination.Methods Human hepatocellular carcinoma cell line HepG2 and mouse colon cancer cell line CT26 cells were treated with 2FF, DOX or their combination and the core fucosylation levels of tumor cells were detected by Lectin Blot. We treated HepG2 and CT26 cells with 50 μmol/L 2FF for a duration of 72 h, followed by exposure to a gradient concentration of DOX for 24 h. Then cell viability and IC50 values were determined using the CCK8 assay. Transwell invasion assays were used to investigate the effect of 2FF combined with DOX on the invasion ability of HepG2. Flow cytometry was performed to analyse the effect of 2FF, DOX and their combination on the membrane PD-L1 expression of HepG2 cells. To explore the inhibitory effect of 2FF combined with DOX on tumor growth in vivo, 6 to 8 week old female BALB/c mice weighing approximately 20-25 g, were subcutaneously injected with 1×106 CT26 cells in the right axilla (four groups, six mice in each group). After the average tumor volume reached 100 mm3, DOX or 2FF or DOX combined with 2FF was then injected into mice every other day. In DOX group, each mice was intraperitoneally injected with 2 mg/kg DOX; In 2FF group, each mice was intravenously injected with 5 mg/kg 2FF; In 2FF combined with DOX group, each mice was intraperitoneally injected with 2 mg/kg DOX and intravenously injected with 5 mg/kg 2FF. In mock group, each mice was injected with the same volume of saline as in the experimental group; These mice were observed daily and the tumor size was measured and recorded every other day using a vernier caliper.Results In this study, we found that DOX upregulates the core fucosylation level of HepG2 and CT26 cells,while 2FF effectively inhibits the tumor cell core fucosylation levels-induced by COX. 2FF effectively enhances the sensitivity of HepG2 and CT26 cells to DOX. In addition, 2FF combined with DOX synergistically inhibits the invasion ability of HepG2 cells, enhances the anti-tumor efficacy of CT26 subcutaneous tumor model in BALB/c mice. However the combination leads to weight loss in mice. In addition, DOX upregulates the cell surface PD-L1 expression of HepG2 cells, and 2FF inhibits this effect-induced by DOX.Conclusion The FUT8 inhibitor 2FF effectively suppresses the upregulation of core fucosylation and PD-L1 levels-induced by DOX in tumor cells, and 2FF synergistically enhances the anticancer efficacy of DOX.
Citation
XIE Zhi-Dong,ZHANG Xiao-Lian.Synergistic Effect and Mechanism of FUT8 Inhibitor 2FF With DOX for Cancer Treatment[J]..Export: BibTexEndNote
Triple-negative breast cancer (TNBC) represents a distinctive subtype, characterized by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2). Owing to its high inter-tumor and intra-tumor heterogeneity, it poses significant obstacles to the implementation of personalized diagnosis and treatment for TNBC. Alongside the advancement of clustered regular interspaced short palindromic repeats (CRISPR) system, it has profoundly enhanced our comprehension of the structure and function of the TNBC genome, offering a straightforward and promising instrument for investigating the occurrence and development of diseases. In this review, we zero in on the application of CRISPR/Cas technology in the personalized diagnosis and treatment of TNBC. We initially deliberate on the unique attributes of TNBC and the constraints of current diagnostic and treatment approaches: conventional diagnostic methods have a restricted understanding of TNBC; conventional chemotherapy drugs have limited efficacy and severe side effects. The CRISPR/Cas system, which activates Cas enzymes through complementary guide RNA (gRNA) to initiate the selective degradation of exogenous nucleic acids, has emerged as a potent tool for TNBC research, providing precise gene editing capabilities. CRISPR technology enables a comprehensive grasp of the heterogeneity of TNBC by marking and tracking different TNBC cell clones. Additionally, CRISPR facilitates high-throughput screening to promptly identify genes associated with TNBC growth, metastasis, and drug resistance, furnishing new targets and strategies for treatment. The application of CRISPR/Cas in TNBC diagnostics encompasses the development of molecular diagnostic systems based on Cas9, Cas12, and Cas13, each employing distinct detection principles. These systems can detect a variety of TNBC biomarkers, including cell-specific DNA/RNA and circulating tumor DNA (ctDNA), providing sensitive and specific diagnoses. In precision therapy, CRISPR/Cas has been utilized to identify key genes implicated in TNBC progression and treatment resistance. CRISPR screening has facilitated the discovery of potential therapeutic targets, and the gene-editing capabilities of the system have been applied to develop combination therapies with traditional chemotherapy drugs, enhancing their efficacy. The clinical translation of CRISPR/Cas technology is still in its nascent stage, with several clinical trials currently underway to assess its safety and efficacy in the treatment of various genetic diseases and cancers. While the applications of CRISPR/Cas in TNBC therapy hold great promise, challenges such as off-target effects, editing efficiency, and delivery methods need to be tackled. The integration of CRISPR/Cas with other technologies, such as 3D cell culture systems, human induced pluripotent stem cells (hiPSCs), and artificial intelligence, is anticipated to further advance precision medicine for TNBC. These technological convergences can offer deeper insights into disease mechanisms and facilitate the development of personalized treatment strategies. In conclusion, the CRISPR/Cas system holds immense potential in the precise diagnosis and treatment of TNBC. As the technology progresses and costs decline, the establishment of clinical relevance and the translation of CRISPR/Cas system data into clinical applications will clear the path for the optimal diagnosis and treatment strategies for TNBC patients. Nevertheless, the journey ahead is accompanied by technical challenges and ethical considerations that require further research and regulation to ensure safety and efficacy.
Alzheimer"s disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory loss. As the incidence of AD continues to rise annually, researchers have shown keen interest in the active components found in natural plants and their neuroprotective effects against AD. Quercetin, a flavonol widely present in fruits and vegetables, has multiple biological effects including anticancer, anti-inflammatory, and antioxidant. Oxidative stress plays a central role in the pathogenesis of AD, and the antioxidant properties of quercetin are essential for its neuroprotective function. Quercetin can modulate multiple signaling pathways related to AD, such as Nrf2-ARE, JNK, p38 MAPK, PON2, PI3K/Akt, and PKC, all of which are closely related to oxidative stress. Furthermore, quercetin is capable of inhibiting the aggregation of amyloid-beta (Aβ) protein and the phosphorylation of tau protein, as well as the activity of β-secretase 1 and acetylcholinesterase, thus slowing down the progression of the disease.The review also provides insights into the pharmacokinetic properties of quercetin, including its absorption, metabolism , and excretion, as well as its bioavailability challenges and clinical applications. To improve the bioavailability and enhance the targeting of quercetin, the potential of quercetin nanomedicine delivery systems in the treatment of AD is also discussed . In summary, the multifaceted mechanisms of quercetin against AD provide a new perspective for drug development. However, translating these findings into clinical practice requires overcoming current limitations and ongoing research. In this way, its therapeutic potential in the treatment of AD can be fully utilized.
Objective INF2 is a member of the formins family. Abnormal expression and regulation of INF2 have been associated with the progression of various tumors, but the expression and role of INF2 in hepatocellular carcinoma (HCC) remain unclear. HCC is a highly lethal malignant tumor. Given the limitations of traditional treatments, this study explored the expression level, clinical value and potential mechanism of INF2 in HCC in order to seek new therapeutic targets.Methods In this study, we used public databases to analyze the expression of INF2 in pan-cancer and HCC, as well as the impact of INF2 expression levels on HCC prognosis. Quantitative real time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry were used to detect the expression level of INF2 in liver cancer cells and human HCC tissues. The correlation between INF2 expression and clinical pathological features was analyzed using public databases and clinical data of human HCC samples. Subsequently, the effects of INF2 expression on the biological function and Drp1 phosphorylation of liver cancer cells were elucidated through in vitro and in vivo experiments. Finally, the predictive value and potential mechanism of INF2 in HCC were further analyzed through database and immunohistochemical experiments.Results INF2 is aberrantly high expression in HCC samples and the high expression of INF2 is correlated with overall survival, liver cirrhosis and pathological differentiation of HCC patients. The expression level of INF2 has certain diagnostic value in predicting the prognosis and pathological differentiation of HCC. In vivo and in vitro HCC models, upregulated expression of INF2 triggers the proliferation and migration of the HCC cell, while knockdown of INF2 could counteract this effect. INF2 in liver cancer cells may affect mitochondrial division by inducing Drp1 phosphorylation and mediate immune escape by up-regulating PD-L1 expression, thus promoting tumor progression.Conclusion INF2 is highly expressed in HCC and is associated with poor prognosis. High expression of INF2 may promote HCC progression by inducing Drp1 phosphorylation and up-regulation of PD-L1 expression, and targeting INF2 may be beneficial for HCC patients with high expression of INF2.
Alzheimer"s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.
Immobilized enzyme-based enzyme electrode biosensors, characterized by high sensitivity and efficiency, strong specificity, and compact size, demonstrate broad application prospects in life science research, disease diagnosis and monitoring, etc. Immobilization of enzyme is a critical step in determining the performance (stability, sensitivity, and reproducibility) of the biosensors. Random immobilization (physical adsorption, covalent cross-linking, etc.) can easily bring about problems, such as decreased enzyme activity and relatively unstable immobilization. Whereas, directional immobilization utilizing amino acid residue mutation, affinity peptide fusion, or nucleotide-specific binding to restrict the orientation of the enzymes provides new possibilities to solve the problems caused by random immobilization. In this paper, the principles, advantages and disadvantages and the application progress of enzyme electrode biosensors of different directional immobilization strategies for enzyme molecular sensing elements by specific amino acids (lysine, histidine, cysteine, unnatural amino acid) with functional groups introduced based on site-specific mutation, affinity peptides (gold binding peptides, carbon binding peptides, carbohydrate binding domains) fused through genetic engineering, and specific binding between nucleotides and target enzymes (proteins) were reviewed, and the application fields, advantages and limitations of various immobilized enzyme interface characterization techniques were discussed, hoping to provide theoretical and technical guidance for the creation of high-performance enzyme sensing elements and the manufacture of enzyme electrode sensors.
Alzheimer"s disease (AD) is a chronic neurodegenerative disorder that severely affects the health of the elderly, marked by its incurability, high prevalence, and extended latency period. The current approach to AD prevention and treatment emphasizes early detection and intervention, particularly during the pre-AD stage of mild cognitive impairment (MCI), which provides an optimal "window of opportunity" for intervention. Clinical detection methods for MCI, such as cerebrospinal fluid monitoring, genetic testing, and imaging diagnostics, are invasive and costly, limiting their broad clinical application. Speech, as a vital cognitive output, offers a new perspective and tool for computer-assisted analysis and screening of cognitive decline. This is because elderly individuals with cognitive decline exhibit distinct characteristics in semantic and audio information, such as reduced lexical richness, decreased speech coherence and conciseness, and declines in speech rate, voice rhythm, and hesitation rates. The objective presence of these semantic and audio characteristics lays the groundwork for computer-based screening of cognitive decline. Speech information is primarily sourced from databases or collected through tasks involving spontaneous speech, semantic fluency, and reading, followed by analysis using computer models. Spontaneous language tasks include dialogues/interviews, event descriptions, narrative recall, and picture descriptions. Semantic fluency tasks assess controlled retrieval of vocabulary items, requiring participants to extract information at the word level during lexical search. Reading tasks involve participants reading a passage aloud. Summarizing past research, the speech characteristics of the elderly can be divided into two major categories: semantic information and audio information. Semantic information focuses on the meaning of speech across different tasks, highlighting differences in vocabulary and text content in cognitive impairment. Overall, discourse pragmatic disorders in AD can be studied along three dimensions: cohesion, coherence, and conciseness. Cohesion mainly examines the use of vocabulary by participants, with a reduction in the use of nouns, pronouns, verbs, and adjectives in AD patients. Coherence assesses the ability of participants to maintain topics, with a decrease in the number of subordinate clauses in AD patients. Conciseness evaluates the information density of participants, with AD patients producing shorter texts with less information compared to normal elderly individuals. Audio information focuses on acoustic features that are difficult for the human ear to detect. There is a significant degradation in temporal parameters in the later stages of cognitive impairment; AD patients require more time to read the same paragraph, have longer vocalization times, and produce more pauses or silent parts in their spontaneous speech signals compared to normal individuals. Researchers have extracted audio and speech features, developing independent systems for each set of features, achieving an accuracy rate of 82% for both, which increases to 86% when both types of features are combined, demonstrating the advantage of integrating audio and speech information. Currently, deep learning and machine learning are the main methods used for information analysis. The overall diagnostic accuracy rate for AD exceeds 80%, and the diagnostic accuracy rate for MCI also exceeds 80%, indicating significant potential. Deep learning techniques require substantial data support, necessitating future expansion of database scale and continuous algorithm upgrades to transition from laboratory research to practical product implementation.
Brain"s neural activities encompass both periodic rhythmic oscillations and aperiodic neural fluctuations. Among them, rhythmic oscillations manifest as spectral peaks of neural signals, directly reflecting the synchronized activities of the brain neural population and being intimately tied to cognitive and behavioral states. Conversely, aperiodic fluctuations exhibit a power-law decaying spectral trend, unveiling the multiscale dynamics of brain neural activity. In recent years, researchers have made notable progress in the study of brain aperiodic dynamics. These studies demonstrate that aperiodic activity bears significant physiological relevance, correlating with various physiological states such as external stimuli, drug induction, sleep states, and aging. It serves as a reflection of the brain"s sensory capacity, consciousness level, and cognitive ability. In clinical research, the aperiodic exponent emerges as a significant potential biomarker, capable of reflecting the progression and trends of brain diseases while being intricately intertwined with the excitation-inhibition balance of neural system. The physiological mechanisms underlying aperiodic dynamics span multiple neural scales, with neural activities at the levels of individual neurons, neuronal ensembles, and neural networks each expletively influencing the frequency, oscillatory patterns, and spatiotemporal characteristics of aperiodic activities. Currently, aperiodic dynamics boasts broad application prospects, not only providing a fresh perspective for investigating brain neural dynamics but also holding immense potential as neural markers in neuromodulation technologies or brain-computer interface technologies. This paper summarizes methods for extracting characteristic parameters of aperiodic activity, comparatively analyzes its physiological relevance and potential as a biomarker in brain diseases, summarizes its physiological mechanisms, and finally, based on these findings, elaborates on the research prospects of aperiodic dynamics.
With the rapid development of sequencing technologies, the detection of alternative polyadenylation (APA) in mammals has become more precise. APA precisely regulates gene expression by altering the length and position of the poly(A) tail, and is involved in various biological processes such as disease occurrence and embryonic development. The research on APA in mammals mainly focuses on the following aspects: (1) Identifying APA based on transcriptome data and elucidating their characteristics; (2) Investigating the relationship between APA and gene expression regulation to reveal its important role in life regulation. (3) Exploring the intrinsic connections between APA and disease occurrence, embryonic development, differentiation, and other life processes to provide new perspectives and methods for disease diagnosis and treatment, as well as uncovering embryonic development regulatory mechanisms. In this review, the classification, mechanisms and functions of APA were elaborated in detail and the methods for APA identifying and APA data resources based on various transcriptome data were systematically summarized. Moreover, we epitomized and provided an outlook on research on APA, emphasizing the role of sequencing technologies in driving studies on APA in mammals. In the future, with the further development of sequencing technology, the regulatory mechanisms of APA in mammals will become clearer.
Distinct from the complementary inhibition mechanism through binding to the target with three-dimensional conformation of small molecule inhibitors, targeted protein degradation technology takes tremendous advantage of endogenous protein degradation pathway inside cells to degrade plenty of "undruggable" target proteins, which provides a novel route for the treatment of many serious diseases, mainly including proteolysis-targeting chimeras, lysosome-targeting chimeras, autophagy-targeting chimeras, antibody-based proteolysis-targeting chimeras, etc. Unlike proteolysis-targeting chimeras first found in 2001, which rely on ubiquitin-proteasome system to mainly degrade intracellular proteins of interest, lysosome-targeting chimeras identified in 2020, which was act as the fastly developing technology, utilize cellular lysosomal pathway through endocytosis mediated by lysosome-targeting receptor to degrade both extracellular and membrane proteins. As an emerging biomedical technology, nucleic acid-driven lysosome-targeting chimeras utilize nucleic acids as certain components of chimera molecule to replace with ligand to lysosome-targeting receptor or protein of interest, exhibiting broad application prospects and potential clinical value in disease treatment and drug development. This review mainly introduced present progress of nucleic acid-driven lysosome-targeting chimeras technology, including its basic composition, its advantages compared with antibody or glycopeptide-based lysosome-targeting chimeras, and focused on its chief application, in terms of the type of lysosome-targeting receptors. Most research about the development of nucleic acid-driven lysosome-targeting chimeras focused on those which utilized cation-independent mannose-6-phosphonate receptor as the lysosome-targeting receptor. Both mannose-6-phosphonate-modified glycopeptide and nucleic aptamer targeting cation-independent mannose-6-phosphonate receptor, even double-stranded DNA molecule moiety can be taken advantage as the ligand to lysosome-targeting receptor. The same as classical lysosome-targeting chimeras, asialoglycoprotein receptor can also be used for advance of nucleic acid-driven lysosome-targeting chimeras. Another new-found lysosome-targeting receptor, scavenger receptor, can bind dendritic DNA molecules to mediate cellular internalization of complex and lysosomal degradation of target protein, suggesting the successful application of scavenger receptor-mediated nucleic acid-driven lysosome-targeting chimeras. In addition, this review briefly overviewed the history of lysosome-targeting chimeras, including first-generation and second-generation lysosome-targeting chimeras through cation-independent mannose-6-phosphonate receptor-mediated and asialoglycoprotein receptor-mediated endocytosis respectively, so that a clear timeline can be presented for the advance of chimera technique. Meantime, current deficiency and challenge of lysosome-targeting chimeras was also mentioned to give some direction for deep progress of lysosome-targeting chimeras. Finally, according to faulty lysosomal degradation efficiency, more cellular mechanism where lysosome-targeting chimeras perform degradation of protein of interest need to be deeply explored. In view of current progress and direction of nucleic acid-driven lysosome-targeting chimeras, we discussed its current challenges and development direction in the future. Stability of natural nucleic acid molecule and optimized chimera construction have a great influence on the biological function of lysosome-targeting chimeras. Discovery of novel lysosome-targeting receptors and nucleic aptamer with higher affinity to the target will greatly facilitate profound advance of chimera technique. In summary, nucleic acid-driven lysosome-targeting chimeras have many superiorities, such as lower immunogenicity, expedient synthesis of chimera molecules and so on, in contrast to classical lysosome-targeting chimeras, making it more valuable. Also, the chimera technology provides new ideas and methods for biomedical research, drug development and clinical treatment, and can be used more widely through further research and optimization.
Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca2+ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca2+ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.
Objective For prepubertal and urgently treated malignant tumor patients, ovarian tissue cryopreservation and transplantation represent more appropriate fertility preservation methods. Current clinical practices often involve freezing ovarian tissue with high concentrations of cryoprotectants (CPAs) and thawing with water baths. These processes lead to varying degrees of toxicity and devitrification damage to ovarian tissue. Therefore, this paper proposes optimized methods for vitrification of ovarian tissues based on sodium alginate hydrogel encapsulation and magnetic induction nanowarming technology.Methods Firstly, the study investigated the effects of sodium alginate concentration, the sequence of hydrogel encapsulation and CPAs loading on vitrification efficiency of encapsulated ovarian tissue. Additionally, the capability of sodium alginate hydrogel encapsulation to reduce the required concentration of CPAs was validated. Secondly, a platform combining water bath and magnetic induction nanowarming was established to rewarm ovarian tissue under various concentrations of magnetic nanoparticles and magnetic field strengths. The post-warming follicle survival rate, antioxidant capacity, and ovarian tissue integrity were evaluated to assess the efficacy of the method.Results The study found that ovarian tissue encapsulated with 2% sodium alginate hydrogel exhibited the highest follicle survival rate after vitrification. The method of loading CPAs prior to encapsulation proved more suitable for ovarian tissue cryopreservation, effectively reducing the required concentration of CPAs by 50%. A combination of 8 g/L Fe3O4 nanoparticles and an alternating magnetic field of 300 Gs showed optimal warming effectiveness for ovarian tissue. Combining water bath rewarming with magnetic induction nanowarming yielded the highest follicle survival rate, enhanced antioxidant capacity, and preserved tissue morphology.Conclusion Sodium alginate hydrogel encapsulation of ovarian tissue reduces the concentration of CPAs required during the freezing process. The combination of magnetic induction nanowarming with water bath provides an efficient method ovarian tissue rewarming. This study offers novel approaches to optimize ovarian tissues vitrification.
Citation
CAO Yu-Kun,YE Na,ZHOU Xin-Li.Optimization of Ovarian Tissue Vitrification Using Hydrogel Encapsulation and Magnetic Induction Nanowarming[J]..Export: BibTexEndNote
Diabetes is a very complex endocrine disease whose common finding is the increase in blood glucose concentration. Persistent hyperglycemia can lead to blindness, kidney and heart disease, neurodegeneration, and many other serious complications that have a significant impact on human health and quality of life. The number of people with diabetes is increasing yearly. The global diabetes prevalence in 20–79 year olds in 2021 was estimated to be 10.5% (536.6 million), and it will rise to 12.2% (783.2 million) in 2045. The main modes of intervention for diabetes include medication, dietary management, and exercise conditioning. Medication is the mainstay of treatment. Marketed diabetes drugs such as metformin and insulin, as well as GLP-1 receptor agonists, are effective in controlling blood sugar levels to some extent, but the preventive and therapeutic effects are still unsatisfactory. Peptide drugs have many advantages such as low toxicity, high target specificity, and good biocompatibility, which opens up new avenues for the treatment of diabetes and other diseases. Currently, insulin and its analogs are by far the main life-saving drugs in clinical diabetes treatment, enabling effective control of blood glucose levels, but the risk of hypoglycemia is relatively high and treatment is limited by the route of delivery. New and oral anti-diabetic drugs have always been a market demand and research hotspot. Inhibitor Cystine Knot (ICK) peptides are a class of multifunctional cyclic peptides. In structure, they contain three conserved disulfide bonds (C3-C20, C7-C22, and C15-C32) form a compact "knot" structure, which can resist degradation of digestive protease. Recent studies have shown that ICK peptides derived from legume, such as PA1b, Aglycin, Vglycin, Iglycin, Dglycin, and Am1, exhibit excellent regulatory activities on glucose and lipid metabolism at the cellular and animal levels. Mechanistically, ICK peptides promote glucose utilization by muscle and liver through activation of IR/AKT signaling pathway, which also improves insulin resistance. They can repair the damaged pancrease through activation of PI3K/AKT/Erk signaling pathway, thus lowering blood glucose. The biostability and hypoglycemic efficacy of the ICK peptides meet the requirements for commercialization of oral drugs, and in theory, they can be developed into natural oral anti-diabetes peptide drugs. In this review, the structural properties, activity and mechanism of ICK pattern peptides in regulating glucose and lipid metabolism were summaried, which provided a reference for the development of new oral peptides for diabetes.
Objective Ulcerative colitis is a prevalent immunoinflammatory disease. Th17/Treg cell imbalance and gut microbiota dysregulation are key factors in its pathogenesis. The actin cytoskeleton contributes to regulating the proliferation, differentiation, and migration of Th17 and Treg cells. Wdr63, a gene containing the WD repeat domain, participates in the structure and functional modulation of the actin cytoskeleton. Recent research indicates that WDR63 may serve as a regulator of cell migration and metastasis via actin polymerization inhibition. This article aims to explore the effect of Wdr63 deletion on Th17/Treg cells and ulcerative colitis.Methods We constructed Wdr63-/- mice, induced colitis in mice using dextran sulfate sodium salt, collected colon tissue for histopathological staining, collected mesenteric lymph nodes for flow cytometry analysis, and collected healthy mouse feces for microbial diversity detection.Results Compared with wild-type colitis mice, Wdr63-/- colitis mice had a more pronounced shortening of colonic tissue, higher scores on disease activity index and histological damage index, Treg cells decreased and Th17 cells increased in colonic tissue and mesenteric lymph nodes, a lower level of anti-inflammatory cytokine IL-10, and a higher level of pro-inflammatory cytokine IL-17A. In addition, WDR63 has shown positive effects in maintaining intestinal microbiota homeostasis. It maintains the balance of Bacteroidota and Firmicutes, promoting the formation of beneficial intestinal bacteria linked to immune inflammation.ConclusionWdr63 deletion aggravates ulcerative colitis in mice; WDR63 inhibits colonic inflammation likely by regulating Th17/Treg balance and maintains intestinal microbiota homeostasis.
It has been demonstrated that long-term space flights have a significantly greater impact on the cardiovascular, skeletal, and nervous systems of astronauts. The structural and functional alterations in the skeletal and muscular systems resulting from exposure to weightlessness can lead to the development of low back pain, significantly impairing the ability of astronauts to perform tasks and respond to emergencies. Both space flight and simulated microgravity have been shown to result in low back pain among astronauts, with the following factors identified as primary contributors to this phenomenon. The occurrence of intervertebral disc (IVD) edema results in the stimulation of Type IV mechanoreceptors, which subsequently activate nociceptive afferents. The protrusion of an IVD causes compression of the spinal nerve roots. Furthermore, the elongation of the vertebral column and/or the diminished lumbar curvature of the spine exert traction on the dorsal root nerves. Paravertebral muscle degeneration leads to the inhibition of decreased nociceptive activity of the wide-dynamic range neurons of the spinal dorsal horn. Moreover, endogenous pain descending facilitation triggered by conditioning stimulation can be enhanced via the thalamic mediodorsal nuclei, while endogenous pain descending inhibition triggered by conditioning stimulation can be weakened via the thalamic ventromedial nuclei. Psychological factors may contribute to the development of low back pain. The mechanisms governing the generation, maintenance, and alleviation of low back pain in weightlessness differ from those observed in normal gravitational environments. This presents a significant challenge for space medicine research. Therefore, the elucidation of the occurrence and development mechanism of low back pain in weightlessness is important for the prevention and treatment during space flight. To reduce the incidence of low back pain during long-term missions on the space station, astronauts may choose to wear specialized space clothing that can provide axial physiological loads, designed to stimulate both musculature and skeletal structures, mitigating potential increases in vertebral column length, diminished lumbar curvature, and intervertebral disc edema and/or muscular atrophy. Additionally, assuming a "fetal tuck position" described as the knees to chest position may increase lumbar IVD hydrostatic pressure, subsequently reducing disc volume, rectifying diminished lumbar curvature, and alleviating dorsal root nerve tensions. Moreover, this position may reduce Type IV mechanoreceptor facilitation and nerve impulse propagation from the sinuvertebral nerves of the annulus fibrosus. Elongated posterior soft tissues (apophyseal joint capsules and ligaments) with spinal flexion may potentially stimulate Type I and II mechanoreceptors. It is also recommended to exercise the paraspinal muscles to prevent and alleviate the decrease in their cross-sectional area and maintain their structure and function. Photobiomodulation has been proved to be an effective means of activating the pain descending inhibition pathway of the central nervous system. In addition, astronauts should be encouraged to participate in mission-related activities and strive to avoid psychological problems caused by the long-term confinement in a small space station. The article presents a concise review of potential causes and targeted treatment strategies for low back pain induced by space flight or simulated microgravity in recent years. Its objective is to further elucidate the mechanisms underlying the occurrence and development of low back pain in weightless environments while providing scientific evidence to inform the development of guidelines for preventing, treating, and rehabilitating low back pain during long-term space flights.
Citation
LIU Yan-Feng,LEI Jing,YOU Hao-Jun.Progress in Etiology and Management of Astronaut Low Back Pain Induced by Space Flight or Simulated Microgravity[J]..Export: BibTexEndNote
Currently, the drug delivery system (DDS) based on nanomaterials has become a hot interdisciplinary research topic. One of the core issues is drug loading and controlled release, in which the key lever is carriers. Vaterite, as an inorganic porous nano-material, is one metastable structure of calcium carbonate, full of micro or nano porous. Recently, vaterite has attracted more and more attention, due to its significant advantages, such as rich resources, easy preparations, low cost, simple loading procedures, good biocompatibility and many other good points. Vaterite, gained from suitable preparation strategies, can not only possess the good drug carrying performance, like high loading capacity and stable loading efficiency, but also improve the drug release ability, showing the better drug delivery effects, such as targeting release, pH sensitive release, photothermal controlled release, magnetic assistant release, optothermal controlled release. At the same time, the vaterite carriers, with good safety itself, can protect proteins, enzymes, or other drugs from degradation or inactivation, help imaging or visualization with loading fluorescent drugs in vitro and in vivo as well, and play synergistic effects with other therapy approaches, like photodynamic therapy, sonodynamic therapy, and thermochemotherapy. Latterly, some renewed reports in drug loading and controlled release have led to their widespread applications in diverse fields, from cell level to clinical studies. This review introduces the basic characteristics of vaterite and briefly summarizes its research history, followed by synthesis strategies. We subsequently highlight recent developments in drug loading and controlled release, with an emphasis on the advantages, quantity capacity, and comparations. Furthermore, new opportunities for using vaterite in cell level and animal level are detailed. Finally, the possible problems and development trends are discussed.
The innate immune system can be boosted in response to subsequent triggers by pre-exposure to microbes or microbial products, known as "trained immunity". Compared to classical immune memory, innate trained immunity has several different features. Firstly, the molecules involved in trained immunity differ from those involved in classical immune memory. Innate trained immunity mainly involves innate immune cells (e.g., myeloid immune cells, natural killer cells, innate lymphoid cells) and their effector molecules (e.g., pattern recognition receptor (PRR), various cytokines), as well as some kinds of non-immune cells (e.g., microglial cells). Secondly, the increased responsiveness to secondary stimuli during innate trained immunity is not specific to a particular pathogen, but influences epigenetic reprogramming in the cell through signaling pathways, leading to the sustained changes in genes transcriptional process, which ultimately affects cellular physiology without permanent genetic changes (e.g., mutations or recombination). Finally, innate trained immunity relies on an altered functional state of innate immune cells that could persist for weeks to months after initial stimulus removal. An appropriate inducer could induce trained immunity in innate lymphocytes, such as exogenous stimulants (including vaccines) and endogenous stimulants, which was firstly discovered in bone marrow derived immune cells. However, mature bone marrow derived immune cells are short-lived cells, that may not be able to transmit memory phenotypes to their offspring and provide long-term protection. Therefore, trained immunity is more likely to be relied on long-lived cells, such as epithelial stem cells, mesenchymal stromal cells and non-immune cells such as fibroblasts. Epigenetic reprogramming is one of the key molecular mechanisms that induces trained immunity, including DNA modifications, non-coding RNAs, histone modifications and chromatin remodeling. In addition to epigenetic reprogramming, different cellular metabolic pathways are involved in the regulation of innate trained immunity, including aerobic glycolysis, glutamine catabolism, cholesterol metabolism and fatty acid synthesis, through a series of intracellular cascade responses triggered by the recognition of PRR specific ligands. In the view of evolutionary, trained immunity is beneficial in enhancing protection against secondary infections with an induction in the evolutionary protective process against infections. Therefore, innate trained immunity plays an important role in therapy against diseases such as tumors and infections, which has signature therapeutic effects in these diseases. In organ transplantation, trained immunity has been associated with acute rejection, which prolongs the survival of allografts. However, trained immunity is not always protective but pathological in some cases, and dysregulated trained immunity contributes to the development of inflammatory and autoimmune diseases. Trained immunity provides a novel form of immune memory, but when inappropriately activated, may lead to an attack on tissues, causing autoinflammation. In autoimmune diseases such as rheumatoid arthritis and atherosclerosis, trained immunity may lead to enhance inflammation and tissue lesion in diseased regions. In Alzheimer"s disease and Parkinson"s disease, trained immunity may lead to over-activation of microglial cells, triggering neuroinflammation even nerve injury. This paper summarizes the basis and mechanisms of innate trained immunity, including the different cell types involved, the impacts on diseases and the effects as a therapeutic strategy to provide novel ideas for different diseases.
Obstructive sleep apnea (OSA) is an increasingly widespread sleep-breathing disordered disease, and is an independent risk factor for many high-risk chronic diseases such as hypertension, coronary heart disease, stroke, arrhythmias and diabetes, which is potentially fatal. The key to the prevention and treatment of OSA is early diagnosis and treatment, so the assessment and diagnostic technologies of OSA have become a research hotspot. This paper reviews the research progresses of severity assessment parameters and diagnostic technologies of OSA, and discusses their future development trends. In terms of severity assessment parameters of OSA, apnea hypopnea index (AHI), as the gold standard, together with the percentage of duration of apnea hypopnea (AH%), lowest oxygen saturation (LSpO?), heart rate variability (HRV), oxygen desaturation index (ODI) and the emerging biomarkers, constitute a multi-dimensional evaluation system. Specifically, the AHI, which measures the frequency of sleep respiratory events per hour, does not fully reflect the patients" overall sleep quality or the extent of their daytime functional impairments. To address this limitation, the AH%, which measures the proportion of the entire sleep cycle affected by apneas and hypopneas, deepens our understanding of the impact on sleep quality. The LSpO? plays a critical role in highlighting the potential severe hypoxic episodes during sleep, while the HRV offers a different perspective by analyzing the fluctuations in heart rate thereby revealing the activity of the autonomic nervous system. The ODI provides a direct and objective measure of patients" nocturnal oxygenation stability by calculating the number of desaturation events per hour, and the biomarkers offers novel insights into the diagnosis and management of OSA, and fosters the development of more precise and tailored OSA therapeutic strategies. In terms of diagnostic techniques of OSA, the standardized questionnaire and Epworth sleepiness scale (ESS) is a simple and effective method for preliminary screening of OSA, and the polysomnography (PSG) which is based on recording multiple physiological signals stands for gold standard, but it has limitations of complex operations, high costs and inconvenience. As a convenient alternative, the home sleep apnea testing (HSAT) allows patients to monitor their sleep with simplified equipment in the comfort of their own homes, and the cardiopulmonary coupling (CPC) offers a minimal version that simply analyzes the electrocardiogram (ECG) signals. As an emerging diagnostic technology of OSA, machine learning (ML) and artificial intelligence (AI) adeptly pinpoint respiratory incidents and expose delicate physiological changes, thus casting new light on the diagnostic approach to OSA. In addition, imaging examination utilizes detailed visual representations of the airway"s structure and assists in recognizing structural abnormalities that may result in obstructed airways, while sound monitoring technology records and analyzes snoring and breathing sounds to detect the condition subtly, and thus further expands our medical diagnostic toolkit. As for the future development directions, it can be predicted that interdisciplinary integrated researches, the construction of personalized diagnosis and treatment models, and the popularization of high-tech in clinical applications will become the development trends in the field of OSA evaluation and diagnosis.
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc), primarily manifesting as motor dysfunctions such as resting tremor, muscle rigidity, and bradykinesia. According to the classical model of basal ganglia motor control, approximately half of the medium spiny neurons (MSNs) in the striatum are D1-MSNs, which constitute the direct pathway. These neurons express D1-dopamine receptor (D1R) and substance P, and they mainly participate in the selection, initiation, and execution of movements. The other half are D2-MSNs, which constitute the indirect pathway. These neurons express D2-dopamine receptor (D2R) and adenosine 2A receptors and are involved in inhibiting unnecessary movements or terminating ongoing movements, thereby adjusting movement sequences to perform more precise motor behaviors. The direct pathway in the striatum modulates the activity of motor cortex neurons by exciting D1-MSNs through neurotransmitters such as glutamate (Glu), allowing the motor cortex to send signals more freely to the motor system, thus facilitating the generation and execution of specific motor behaviors. Studies using D1-Cre and D2-Cre mice with neurons labeled for D1R and D2R have shown that both types of neurons are involved in the execution of movements, with D1-MSNs participating in movement initiation and D2-MSNs in inhibiting actions unrelated to the target movement. These findings suggest that the structural and functional plasticity of D1-MSNs and D2-MSNs in the basal ganglia circuitry enables motor learning and behavioral regulation. Additionally, when SNpc DA neurons begin to degenerate, D1-MSNs are initially affected but do not immediately cause motor impairments. In contrast, when D2-MSNs undergo pathological changes, they are first activated by upstream projecting neurons, leading to the inhibition of most motor behaviors and resulting in motor dysfunction. Therefore, it is hypothesized that motor impairments such as bradykinesia and initiation difficulties are more closely related to the functional activity of D2-MSNs. The extracellular signal-regulated kinase (Erk)/mitogen-activated protein kinase (MAPK) signaling pathway has been identified as a critical modulator in the pathophysiology of PD. Recent findings indicate that Erk/MAPK signaling pathway can mediate DA and Glu signaling in the central nervous system, maintaining normal functional activity of striatal MSNs and influencing the transmission of motor control signals. Within this complex regulatory network, the Erk/MAPK signaling pathway plays a key role in transmitting motor information to downstream neurons, regulating normal movements, avoiding unnecessary movements, and finely tuning motor behaviors. Our laboratory"s previous research found that 4 weeks of aerobic exercise intervention improved motor dysfunction in PD mice by inhibiting the Erk1/2 signaling upstream of striatal MSNs, primarily involving the Erk1/2 signaling in D2-MSNs rather than D1-MSNs. This review summarizes the neurobiological mechanisms of Erk/MAPK signaling pathway in D2-MSNs for the prevention and treatment of motor dysfunction in PD. By exploring the role of this signaling pathway in regulating motor abnormalities and preventing motor dysfunction in the central nervous system of PD, this review provides new theoretical perspectives for related mechanistic research and therapeutic strategies.
Citation
GAO Bo,LAI Yi-Ning,GE Yi-Tong,CHEN Wei.Erk Signaling Pathway in Striatal D2-MSNs: an Essential Pathway for Exercise-induced Improvement in Parkinson’s Disease[J]..Export: BibTexEndNote
Objective Magnetoencephalography (MEG), a non-invasive neuroimaging technique, meticulously captures the magnetic fields emanating from brain electrical activity. Compared with MEG based on superconducting quantum interference devices (SQUID), MEG based on optically pump magnetometer (OPM) has the advantages of higher sensitivity, better spatial resolution and lower cost. However, most of the current studies are clinical studies, and there is a lack of animal studies on MEG based on OPM technology. Pain, a multifaceted sensory and emotional phenomenon, induces intricate alterations in brain activity, exhibiting notable sex differences. Despite clinical revelations of pain-related neuronal activity through MEG, specific properties remain elusive, and comprehensive laboratory studies on pain-associated brain activity alterations are lacking. The aim of this study was to investigate the effects of inflammatory pain (induced by Complete Freund"s Adjuvant (CFA)) on brain activity in a rat model using the MEG technique, to analysis changes in brain activity during pain perception, and to explore sex differences in pain-related MEG signaling.Methods This study established a rat model for MEG methodology to explore disparities in brain activity during CFA-induced inflammatory pain in both male and female rats.Results MEG recordings in anesthetized rats during resting states and hind paw mechanical stimulation were compared, before and after saline/CFA injections. Mechanical stimulation elevated alpha activity in both male and female rats pre- and post-saline/CFA injections. Saline/CFA injections augmented average power in both sexes compared to pre-injection states. Remarkably, female rats exhibited higher average spectral power 1 h after CFA injection than after saline injection during resting states. Furthermore, despite comparable pain thresholds measured by classical pain behavioral tests post-CFA treatment, female rats displayed higher average power than males in the resting state after CFA injection.Conclusion These results imply an enhanced perception of inflammatory pain in female rats compared to their male counterparts. In conclusion, our study exhibits sex differences in alpha activities following CFA injection, highlighting heightened brain alpha activity in female rats during acute inflammatory pain in the resting state. Our study provides a method for OPM-based MEG recordings to be used to study brain activity in anaesthetized animals. In addition, the findings of this study contribute to a deeper understanding of pain-related neural activity and pain sex differences.
Parkinson’s disease (PD) is a common neurodegenerative disorder with profound impact on patients’ quality of life and long-term health, and early detection and intervention are particularly critical. In recent years, the search for precise and reliable biomarkers has become one of the key strategies to effectively address the clinical challenges of PD. In this paper, we systematically evaluated potential biomarkers, including proteins, metabolites, epigenetic markers, and exosomes, in the peripheral blood of PD patients. Protein markers are one of the main directions of biomarker research in PD. In particular, α-synuclein and its phosphorylated form play a key role in the pathological process of PD. It has been shown that aggregation of α-synuclein may be associated with pathologic protein deposition in PD and may be a potential marker for early diagnosis of PD. In terms of metabolites, uric acid, as a metabolite, plays an important role in oxidative stress and neuroprotection in PD. It has been found that changes in uric acid levels may be associated with the onset and progression of PD, showing its potential as an early diagnostic marker. Epigenetic markers, such as DNA methylation modifications and miRNAs, have also attracted much attention in Parkinson’s disease research. Changes in these markers may affect the expression of PD-related genes and have an important impact on the onset and progression of the disease, providing new research perspectives for the early diagnosis of PD. In addition, exosomes, as a potential biomarker carrier for PD, are able to carry a variety of biomolecules involved in intercellular communication and pathological regulation. Studies have shown that exosomes may play an important role in the pathogenesis of PD, and their detection in blood may provide a new breakthrough for early diagnosis. It has been shown that exosomes may play an important role in the pathogenesis of PD, and their detection in blood may provide new breakthroughs in early diagnosis. In summary, through in-depth evaluation of biomarkers in the peripheral blood of PD patients, this paper demonstrates the important potential of these markers in the early diagnosis of PD and in the study of pathological mechanisms. Future studies will continue to explore the clinical application value of these biomarkers to promote the early detection of PD and individualized treatment strategies.
Sleep is an instinctive behavior alternating awakening state, sleep entails many active processes occurring at the cellular, circuit and organismal levels. The function of sleep is to restore cellular energy, enhance immunity, promote growth and development, consolidate learning and memory to ensure normal life activities. However, with the increasing of social pressure involved in work and life, the incidence of sleep disorders (SD) is increasing year by year. In the short term, sleep disorders lead to impaired memory and attention; in the longer term, it produces neurological dysfunction or even death. There are many ways to directly or indirectly contribute to sleep disorder and keep the hormones, including pharmacological alternative treatments, light therapy and stimulus control therapy. Exercise is also an effective and healthy therapeutic strategy for improving sleep. The intensities, time periods, and different types of exercise have different health benefits for sleep, which can be found through indicators such as sleep quality, sleep efficiency and total sleep time. So it is more and more important to analyze the mechanism and find effective regulation targets during sleep disorder through exercise. Dopamine (DA) is an important neurotransmitter in the nervous system, which not only participates in action initiation, movement regulation and emotion regulation, but also plays a key role in the steady-state remodeling of sleep-awakening state transition. Appreciable evidence shows that sleep disorder on humans and rodents evokes anomalies in the dopaminergic signaling, which are also implicated in the development of psychiatric illnesses such as schizophrenia or substance abuse. Experiments have shown that DA in different neural pathways plays different regulatory roles in sleep behavior, we found that increasing evidence from rodent studies revealed a role for ventral tegmental area DA neurons in regulating sleep-wake patterns. DA signal transduction and neurotransmitter release patterns have complex interactions with behavioral regulation. In addition, experiments have shown that exercise causes changes in DA homeostasis in the brain, which may regulate sleep through different mechanisms, including cAMP response element binding protein signal transduction, changes in the circadian rhythm of biological clock genes, and interactions with endogenous substances such as adenosine, which affect neuronal structure and play a neuroprotective role. This review aims to introduce the regulatory effects of exercise on sleep disorder, especially the regulatory mechanism of DA in this process. The analysis of intracerebral DA signals also requires support from neurophysiological and chemical techniques. Our laboratory has established and developed an in vivo brain neurochemical analysis platform, which provides support for future research on the regulation of sleep-wake cycles by movement. We hope it can provide theoretical reference for the formulation of exercise prescription for clinical sleep disorder and give some advice to the combined intervention of drugs and exercise.
Sleep deprivation (SD) not only directly affects an individual’s work efficiency but also negatively impacts various cognitive functions such as memory, attention, and learning as fatigue increases. Over the past few decades, numerous researchers have conducted lots of studies on the effects of SD on cognition, particularly memory. In this paper, we first review the effects of SD on memory function based on behavioral studies. Then, we further elaborate on recent advances in the physiological mechanisms of SD, including synaptic plasticity in structure and function, levels of excitatory and inhibitory neurotransmitters, and the expression of related synaptic protein signals. It has been observed that SD modulates the expression of synaptic protein signals and downstream signaling pathways by influencing changes in synaptic activities (such as dendritic spine density, synaptic connectivity strength, and the balance of excitatory and inhibitory synapses), ultimately affecting behavior. This review aims to provide insights into the research progress on the effects of SD on memory and its underlying mechanisms, providing a reference for future studies on sleep function and related mechanisms, as well as the development of strategies to mitigate memory deficits caused by SD.
Neuroinflammation is a complex process triggered by various factors such as injury, infection, oxidative stress, and other activators. In central immune system, microglia and astrocytes release a wide range of inflammatory mediators like cytokines and chemokines in response. Initially, acute neuroinflammation can have protective effects by promoting neuronal repair and maintaining homeostasis. However, chronic activation of neuroinflammation leads to excessive production of inflammatory mediators, resulting in neuronal dysfunction and degeneration. This can contribute to various neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and Huntington’s disease (HD).In vitro cellular models are crucial for elucidating the underlying mechanisms of neuroinflammation. Investigating neuroinflammatory signaling pathways is essential for understanding the intricate network of molecules and cells involved. Key signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2/HO-1, and NLRP3 play critical roles in regulating neuroinflammation. During inflammation, activation of glial cells involves multiple signaling pathways simultaneously, primarily orchestrated by two key factors: MAPK and NF-κB. These pathways guide the inflammatory cascade, leading to the release of numerous inflammatory factors and reactive oxygen species (ROS). These inflammatory factors and ROS have dual effects. Firstly, they can directly harm neighboring neurons, promoting the accumulation of abnormal proteins and triggering neuronal apoptosis. Secondly, inflammatory factor receptors on cell membranes can initiate positive feedback loops that exacerbate the inflammatory response. Neuroinflammation encompasses various cell types within the central nervous system, forming a complex and interconnected malignant cycle. This ultimately culminates in irreversible brain damage. Moreover, innovative therapeutic approaches targeting specific signaling pathways and molecular targets show promise in treating diseases related to neuroinflammation.Various cellular models are commonly employed to investigate neuroinflammation, each focusing on different aspects: pathogen-related models involve substances like lipopolysaccharide (LPS), amyloid β-protein (Aβ), CpG-DNA, and viruses; cytokine models utilize interferon-γ (IFN-γ); metabolic stress models include oxygen-glucose deprivation (OGD), 1-methyl-4-phenylpyridinium (MPP+), rotenone, and oxyhemoglobin; environmental toxin models encompass substances such as bisphenol A (BPA), particulate matter (PM2.5), various metals, and nanoparticles; additive substance models involve alcohol, morphine, and methamphetamine (METH). Each model offers distinct advantages and drawbacks for studying neuroinflammation. In conclusion, research on these cellular models and their associated signaling pathways provides crucial insights into the mechanisms underlying neuroinflammation-related diseases. These insights are essential for developing effective therapeutic strategies and advancing clinical practice to address the complexities of neuroinflammatory diseases.
Alternative splicing is an important regulatory mechanism in organisms, influencing the expression of genes involved in processes such as drug metabolism, pathway activation, and apoptosis. It refers to the process of removing introns from precursor mRNA and joining the remaining exons to produce mature mRNA. During this process, different combinations of exons can result in multiple mature mRNAs. This process is known as alternative splicing. Alternative splicing allows the same gene to produce different transcript variants and protein isoforms, increasing protein diversity and functional complexity. Transcriptomics and proteomics are two main approaches for identifying alternative splicing events. Transcriptomics identifies alternative splicing by analyzing differences between RNA sequencing data and reference sequences in databases. This method relies on the development of modern sequencing technologies. It also depends on increasingly improved splicing identification algorithms. Examples of these algorithms include alignment mapping and sequencing data quality control. The other approach is proteomic data analysis, which identifies corresponding protein products. We consider alternative splicing events more meaningful when they can be detected at the protein level. Alternative splicing proteoforms can be identified using bottom-up proteomics based on mass spectrometry. Due to the high sequence similarity between these alternative splicing proteoforms, general proteomic data analysis pipelines do not achieve good discrimination between them. To improve the identification of proteoforms and obtain differentiation information for different isoforms in proteomic data, two strategies have been developed for improving data processing: the construction of special databases and targeted identification algorithms. We believe that this potential protein isoform information may play a crucial role in life science research. In terms of databases, it is not enough to only use ordinary public databases for searching. To ensure the discovery of as many isoforms as possible, the method of constructing sample-specific databases assisted by RNA sequencing data has been widely used, which can increase the probability of detecting proteoforms. Another key strategy is the improvement of protein identification algorithms. Traditional identification algorithms often struggle to distinguish between highly similar or mutually inclusive proteoforms. To address the complex identification of alternative splicing proteoforms, several inference algorithms have been developed, which are combined with existing search engines to better characterize and detect alternative splicing proteoforms. These include peptide grouping (PeptideClassifier, SEPepQuant, GpGrouper), peptide quantitative correlation (PQPQ, PeCorA, COPF, SpliceVista), machine learning (IsoSVM, Re-Fraction, LibSVM), and major splice isoform theory (ASV-ID). Such methods have shown promising results in focusing on alternative splicing proteoforms. When using these algorithms, we should try different ones based on actual situations. Additionally, the performance of these algorithms is limited by the quality of input data. To ensure reliable identification, it is also essential to perform proper peptide identification and quality control at the front end. In general, the detection and differentiation of spliced protein isoforms are still inadequate, requiring continued attention. This article reviews recent research progress on alternative splicing and its biological functions, as well as the detection of alternative splicing at different levels, and introduces the main methods for identifying alternative splicing proteoforms using bottom-up proteomic data. Identifying different alternative splicing proteoforms helps us understand the comprehensive functions of proteins and is of great significance for discovering related biomarkers and key drug targets.
Objective Early blight is a common destructive disease in the growth process of Solanaceae crops, which can lead to crop failure and serious losses. Traditional crop disease detection methods are difficult to detect disease characteristics in a timely manner during the incubation period of disease, and thus take scientific and effective prevention and control measures. This study obtained hyperspectral images of early blight of peppers at different infection stages through continuous monitoring with a hyperspectral imager. The earliest identifiable time during the incubation period of early blight in peppers (the earliest identifiable time during the incubation period in this experiment was 24 h after inoculation) was determined using the spectral angle cosine-correlation coefficient and Chebyshev distance.Methods Taking the symptoms of the latent period of early blight in peppers as the research object, 13 characteristic wavelengths were selected using a genetic algorithm. An identification model of crop disease latent period symptoms based on spectral features was established through optimized combinations of characteristic wavelengths combined with a logistic regression model. Simultaneously, a recognition model of the latent period of early blight in peppers based on image texture features was established using local binary patterns.Results The experiment was tested with 120 samples. The accuracy of the identification model of crop disease latent period symptoms based on spectral features reached over 93% in both the training set and the test set. The accuracy of the identification model of crop disease latent period symptoms based on texture features reached 98.96% and 100% in the training set and test set, respectively.Conclusion Both spectral features and texture features can be used to detect and identify crop disease latent period symptoms. Texture features more significantly revealed the characteristics of the latent period of the disease compared to spectral features, effectively improving the detection performance of the model. The research results in this article can provide theoretical references for monitoring and identifying other crop disease latent period symptoms.
Citation
SHEN Meng-Jiao,BAO Hao,ZHANG Yan.Research on Hyperspectral Image Detection and Recognition of Pepper Early Blight Incubation Period Based on Spectral and Texture Features[J]..Export: BibTexEndNote
As the global population continues to age, the incidence of Alzheimer’s disease (AD), one of the most common neurodegenerative diseases, continues to rise significantly. As the disease progresses, the patient’s daily living abilities gradually decline, potentially leading to a complete loss of self-care abilities. According to estimates by the Alzheimer’s Association and the World Health Organization, AD accounts for 60%-70% of all other dementia cases, affecting over 55 million people worldwide. The case number is estimated to double by 2050. Despite extensive research, the precise etiology and pathogenesis of AD remain elusive. Researchers have a profound understanding of the disease’s pathological hallmarks, which include amyloid plaques and neurofibrillary tangles resulting from the abnormal phosphorylation of Tau protein. However, the exact causes and mechanisms of the disease are still not fully understood, leaving a vital gap in our knowledge and understanding of this debilitating disease. A crucial player that has recently emerged in the field of AD research is the α7 nicotinic acetylcholine receptor (α7nAChR). α7nAChR is composed of five identical α7 subunits that form a homopentamer. This receptor is a significant subtype of acetylcholine receptor in the central nervous system and is widely distributed in various regions of the brain. It is particularly prevalent in the hippocampus and cortical areas, which are regions associated with learning and memory. α7nAChR plays a pivotal role in several neurological processes, including neurotransmitter release, neuronal plasticity, cell signal transduction, and inflammatory response, suggesting its potential involvement in numerous neurodegenerative diseases, including AD. In recent years, the role of α7nAChR in AD has been the focus of extensive research. Emerging evidence suggests that α7nAChR is involved in several critical steps in the disease progression of AD. These include involvement in the metabolism of amyloid β-protein (Aβ), the phosphorylation of Tau protein, neuroinflammatory response, and oxidative stress. Each of these processes contributes to the development and progression of AD, and the involvement of α7nAChR in these processes suggests that it may play a crucial role in the disease’s pathogenesis. The potential significance of α7nAChR in AD is further reinforced by the observation that alterations in its function or expression can have significant effects on cognitive abilities. These findings suggest that α7nAChR could be a promising target for therapeutic intervention in AD. At present, the results of drug clinical studies targeting α7nAChR show that these compounds have improvement and therapeutic effects in AD patients, but they have not reached the degree of being widely used in clinical practice, and their drug development still faces many challenges. Therefore, more research is needed to fully understand its role and to develop effective treatments based on this understanding. This review aims to summarize the current understanding of the association between α7nAChR and AD pathogenesis. We provide an overview of the latest research developments and insights, and highlight potential avenues for future research. As we deepen our understanding of the role of α7nAChR in AD, it is hoped that this will pave the way for the development of novel therapeutic strategies for this devastating disease. By targeting α7nAChR, we may be able to develop more effective treatments for AD, ultimately improving the quality of life for patients and their families.
Cyclin-dependent kinases (CDKs) are proline-induced serine/threonine kinases that are primarily involved in the regulation of cell cycle, gene transcription, and cell differentiation. In general, CDKs are activated by binding to specific regulatory subunits of cell cycle proteins and are regulated by phosphorylation of specific T-loops by CDK activated kinases. In the CDKs family, cyclin-dependent kinase 5 (CDK5) is a specialized member whose activity is triggered only by interaction with p35 and p39, which do not have the same sequence as the cell cycle proteins, and this may be one reason why CDK5 is distinguished from other CDK members by its structural and functional differences. In addition, unlike most CDK members that require phosphorylation at specific sites to function, CDK5 does not require such phosphorylation, and it can be activated simply by binding to p35 and p39. More notably, inhibitors that are commonly used to inhibit the activity of other CDK members have almost zero effect on CDK5. In contrast, CDK5, as a unique CDK family member, plays an important role in the development of numerous diseases. In metabolic diseases, elevated CDK5 expression leads to decreased insulin secretion, increased foam cell formation and triggers decreased bone mass in the body, thus accelerating metabolic diseases, and the role of CDK5 in bone biology is gradually gaining attention, and the role of CDK5 in bone metabolic diseases may become a hotspot for research in the future; in neurodegenerative diseases, hyperphosphorylation of Tau protein is an important hallmark of Alzheimer’s disease development, and changes in CDK5 expression are associated with Tau protein phosphorylation and nerve death, indicating that CDK5 is highly related to the development of the nervous system; in tumor diseases, the role of CDK5 in the proliferation, differentiation and migration and invasion of tumor cells marks the development of tumorigenesis, but different researchers hold different views, and further studies are needed in the follow-up. Therefore, the study of its mechanism of action in diseases can help to reveal the pathogenesis and pathological process of diseases. Appropriate exercise not only helps in the prevention of diseases, but also plays a positive role in the treatment of diseases. Exercise-induced mechanical stress can improve bone microstructure and increase bone mass in osteoporosis patients. In addition, exercise can effectively inhibit neuronal apoptosis and improve mitochondrial dysfunction, more importantly, appropriate exercise can inhibit the proliferation of cancer cells to a certain extent. It can be seen that exercise occupies a pivotal position in the prevention and treatment of pathologic diseases. It has been shown that exercise can reduce the expression of CDK5 and affect the pathological process of neurological diseases. Currently, there is a dearth of research on the specific mechanisms of CDK5’s role in improving disease outcomes through exercise. In order to understand its effects more comprehensively, subsequent studies need to employ diverse exercise modalities, targeting patients with various types of diseases or corresponding animal models for in-depth exploration. This article focuses on the pathological functions of CDK5 and its relationship with exercise, with a view to providing new insights into the prevention and treatment of disease by CDK5.
Traumatic spinal cord injury (SCI) refers to damage to the structure and function of spinal cord caused by external trauma. This damage results in the loss of sensation, movement, or autonomous functions, which can lead to partial or complete paralysis and impact the patients" independence and quality of life. Studying drugs related to spinal cord injuries and their mechanisms of action will help enhance patients’ quality of life and alleviate social and economic burdens. Traumatic spinal cord injury can be categorized into primary and secondary injuries. It leads to ongoing neurodegeneration, inflammation, and scarring, necessitating continuous intervention to reduce the cascading effects of secondary injuries. Regenerative repair of SCI has been one of the most challenging problems in medicine. It is characterized by the involvement of microglia, phagocytes (including neutrophils and monocytes), and antigen-presenting cells of the central nervous system, such as dendritic cells. These inflammatory mediators contribute to axonal demyelination and degeneration, leading to severe nerve damage. Currently, there has been little progress in the clinical treatment of SCI. Current clinical modalities, such as surgical interventions and hormone shock therapies, have not yielded specific pharmacotherapeutic options, hindering significant functional recovery. The current treatment methods are ineffective in alleviating oxidative stress and neuroinflammatory responses caused by spinal cord injury. They also do not offer neural protection, resulting in ongoing neurofunctional degradation. Intravenous injection of methylprednisolone through the arm has been used as a treatment option for spinal cord injury. Recent studies have shown that the potential side effects of the drug, such as blood clots and pneumonia, outweigh its benefits. Methylprednisolone is no longer recommended for the routine treatment of spinal cord injury. In recent years, significant progress has been made in spinal cord injury intervention through the use of nanotechnology and biomaterials. Nanozymes can enhance the therapeutic efficacy of spinal cord injury by catalyzing the clearance of free radicals similar to enzymes and suppressing inflammatory responses. Nanozymes can reduce the degree of fibrosis, promote neuron survival and angiogenesis, and provide favorable conditions for tissue regeneration. Through in vitro and in vivo toxicology experiments, it was found that the nanozyme demonstrates good biocompatibility and safety. It did not cause any significant changes in body weight, hematological indicators, or histopathology. These findings indicate the potential for its clinical applications. Based on current research results and discoveries, nanozymes have broad application prospects in the biomedical field. There are numerous potential research directions and application areas that are worthy of further exploration and development. Although there have been preliminary studies on the catalytic performance of nanozymes, further research is needed to thoroughly investigate their catalytic mechanisms. Further exploration of the interaction between nanozymes and substrates, reaction kinetics, and factors affecting catalytic activity will help to better understand their mechanism of action in the field of biocatalysis.
Objective Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties with communication and social interaction, restricted and repetitive behaviors. Previous studies have indicated that individuals with ASD exhibit early and lifelong attention deficits, which are closely related to the core symptoms of ASD. Basic visual attention processes may provide a critical foundation for their social communication and interaction abilities. Therefore, this study explores the behavior of children with ASD in capturing attention to changes in topological properties.Methods Our study recruited twenty-seven ASD children diagnosed by professional clinicians according to DSM-5 and twenty-eight typically developing (TD) age-matched controls. In an attention capture task, we recorded the saccadic behaviors of children with ASD and TD children in response to topological change (TC) and non-topological change (nTC) stimuli. Saccadic reaction time (SRT), visual search time (VS), and first fixation dwell time (FFDT) were used as indicators of attentional bias. Pearson correlation tests between the clinical assessment scales and attentional bias were conducted.Results This study found that TD children had significantly faster SRT (P<0.05) and VS (P<0.05) for the TC stimuli compared to the nTC stimuli, while the children with ASD did not exhibit significant differences in either measure (P>0.05). Additionally, ASD children demonstrated significantly less attention towards the TC targets (measured by FFDT), in comparison to TD children (P<0.05). Furthermore, ASD children exhibited a significant negative linear correlation between their attentional bias (measured by VS) and their scores on the Compulsive subscale (P<0.05).Conclusion The results suggest that children with ASD have difficulty shifting their attention to objects with topological changes during change detection. This atypical attention may affect the child"s cognitive and behavioral development, thereby impacting their social communication and interaction. In sum, our findings indicate that difficulties in attentional capture by TC may be a key feature of ASD.
Objective This work examines the impact of external electric fields at terahertz (THz) frequencies on double-stranded deoxyribonucleic acid (dsDNA) systems adsorbed on Au(111) surfaces in aqueous environments.Methods The investigation utilizes a molecular dynamics (MD) approach at the atomic level and vibrational dynamics calculations using the GolDNA-Amber force field.Results The results reveal that the sugar-phosphate backbone of the DNA exhibits reduced adherence to the gold surface, while the side chains display a stronger affinity. When subjecting the hydrated DNA strands to an electric field with frequencies up to 10 THz, peak intensities of vibrational dynamic density (VDoS) are observed at five different frequencies. Moreover, the strong electric field causes hydrogen bonds in the DNA within the slit to break. The sensitivity to the electric field is particularly pronounced at 8.8 THz and 9.6 THz, with different vibrational modes observed at varying electric field strengths.Conclusion These findings contribute to an enhanced understanding of the molecular organization of gold-plated charged biological interfaces.
Enzyme therapy, known for its high efficiency and high selectivity, is an emerging treatment method that utilizes the catalytic activity of exogenous enzyme molecules to initiate specific chemical reactions in the diseased area for disease treatment. With the development of nanoscience and nanotechnology, nanomaterials have brought a new revolution in enzyme therapy. Firstly, nanomaterials with enzyme-like activity (known as nanozymes) have the ability to replace enzymes for catalytic therapy due to their advantages such as tunable nanostructures, high stability, and low cost. Secondly, the construction of nanohybrid enzymes using enzyme engineering techniques can improve the poor stability and limited application performance of enzymes. Finally, many nanomaterials exhibit unique responsiveness to external stimuli such as light, electricity, magnetism, sound, etc., allowing the catalytic activity of nanozymes and nanohybrid enzymes to be precisely controlled by remote physical fields. Compared to other stimuli, magnetic fields have advantages such as deep tissue penetration, no radiation hazard, remote manipulability, and high spatiotemporal resolution. Under the action of different magnetic fields, magnetic nanomaterials can produce magnetothermal,magnetomechanical,and magnetoelectric effects, respectively. In recent years, significant research progress has been made in utilizing these effects to regulate the catalytic behaviors of nanobiocatalysts. The magnetothermal effect is the process in which magnetic nanomaterials convert electromagnetic energy into heat energy when subjected to a high frequency alternating magnetic field. This effect has been harnessed to remotely regulate the nanobiocatalysts by inducing changes in the surrounding temperature. The magnetomechanical effect refers to the magnetic force generated by the interaction between the magnetic field and magnetic particle when exposed to a low frequency static magnetic field, rotating magnetic field, or gradient magnetic field. This effect regulates enzyme catalytic reactions by altering enzyme conformation or the interaction between an enzyme and its substrate. The magnetoelectric effect involves the charge polarization of a material under the influence of an external alternating magnetic field. This effect enables the energy conversion between magnetic and electric fields. The electrons generated in this process can trigger the redox reaction of nanozymes. These three effects are shown to control the catalytic activity of nanozymes or nanohybrid enzymes under different settings, leading to improved performance of nanobiocatalysts in various biomedical applications. Currently, the concept of magneto-controlled nanobiocatalysis has been applied in the treatment of cancer, bacterial infection and Alzheimer’s disease, demonstrating tremendous potential in precision catalytic therapy. In this paper, the magnetothermal, magnetomechanical, and magnetoelectric effects mediated by magnetic materials were first introduced. Then, current research status on the regulation of nanobiocatalysts under control of magnetic field was comprehensively discussed. Finally, future research suggestions in the field of magneto-controlled nanobiocatalysis was proposed.
The dynamin superfamily protein (DSP) encompasses a group of large GTPases that are involved in various membrane remodeling processes within the cell. These proteins are characterized by their ability to hydrolyze GTP, which provides the energy necessary for their function in membrane fission, fusion, and tubulation activities. Dynamin superfamily proteins play critical roles in cellular processes such as endocytosis, organelle division, and vesicle trafficking. It is typically classified into classical dynamins and dynamin-related proteins (Drp), which have distinct roles and structural features. Understanding these proteins is crucial for comprehending their functions in cellular processes, particularly in membrane dynamics and organelle maintenance. Classical dynamins are primarily involved in clathrin-mediated endocytosis (CME), a process crucial for the internalization of receptors and other membrane components from the cell surface into the cell. These proteins are best known for their role in pinching off vesicles from the plasma membrane. Structually, classical dynamins are composed of a GTPase domain, a middle domain, a pleckstrin homology (PH) domain that binds phosphoinositides, a GTPase effector domain (GED), and a proline-rich domain (PRD) that interacts with SH3 domain-containing proteins. Functionally, the classical dynamins wrap around the neck of budding vesicles, using GTP hydrolysis to constrict and eventually acting as a “membrane scissor” to cut the vesicle from the membrane. In mammals, there are three major isoforms: dynamin 1 (predominantly expressed in neurons), dynamin 2 (ubiquitously expressed), and dynamin 3 (expressed in testes, lungs, and neurons). Recent studies have also revealed some non-classical functions of classical dynamins, such as regulating the initiation and stabilization of clathrin-coated pits (CCPs) at the early stages of CME, influencing the formation of the actin cytoskeleton and cell division. Drps share structural similarities with classical dynamins but are involved in a variety of different cellular processes, primarily related to the maintenance and remodeling of organelles, and can be mainly categorized into “mediating membrane fission”, “mediating membrane fusion” and “non-membrane-dependent functions”. Proteins like Drp1 are crucial for mitochondrial division, while others like Fis1, Mfn1, and Mfn2 are involved in mitochondrial and peroxisomal fission and fusion processes, which are essential for the maintenance of mitochondrial and peroxisomal integrity and affect energy production and apoptosis. Proteins like the Mx protein family exhibit antiviral properties by interfering with viral replication or assembly, which is critical for the innate immune response to viral infections. Some other proteins are involved in the formation of tubular structures from membranes, which is crucial for the maintenance of organelle morphology, particularly in the endoplasmic reticulum and Golgi apparatus. Studies on dynamin superfamily proteins have been extensive and have significantly advanced our understanding of cellular biology, disease mechanisms, and therapeutic potential. These studies encompass a broad range of disciplines, including molecular biology, biochemistry, cell biology, genetics, and pharmacology. By comprehensively summarizing and organizing the structural features and functions of various members of the dynamin superfamily protein, this review not only deepens the understanding of its molecular mechanisms, but also provides valuable insights for clinical drug research related to human diseases, potentially driving further advancements in the field.
Benzo[a]pyrene (B[α]P) is a common environmental carcinogen, mainly from the smoke generated by the incomplete combustion of coal, oil and natural gas in the industrial production and living process, which undergoes a series of metabolic reactions in vivo, and ultimately generates the active metabolite, benzopyrene dihydroxy epoxide (B[α]PDE) to exert a strong carcinogenic effect. In this paper, we provide an overview of the mechanisms involved in the malignant transformation of bronchial epithelial cells induced by B[α]PDE in terms of DNA base mutations, DNA repair function, related signaling pathways and epigenetic variations. B[α]PDE covalently binds to DNA bases to form B[α]PDE-DNA adducts, which cause DNA base mutations, inducing malignant transformation of bronchial epithelial cells and ultimate tumor formation. Interestingly, it was found that B[α]PDE-DNA adducts showed a high GC-dependent distribution and the single-nucleotide resolution profile of DNA damage profile was highly similar to that of mutations previously identified in the lung cancer genomes of smokers. B[α]PDE can also regulate the expression or silencing of proto-oncogenes and oncogenes by activating the classical AhR signaling pathway, as well as the PI3K/AKT/mTOR and NF-κB signaling pathways, inducing epithelial-mesenchymal transition (EMT) in bronchial epithelial cells, and interfering with cellular metabolism and the cell cycle, thereby inducing the development of lung cancer. The genes mutated in B[α]PDE-induced malignant transformation of bronchial epithelial cells include the proto-oncogenes RAS, KIF11, and PPP1R13L as well as the oncogenes PHLPP2 and p53. B[α]PDE exposure leads to single nucleotide polymorphisms in the 3"-UTR of the DNA repair enzyme gene, which inhibits the transcription of genes encoding proteins related to DNA damage repair, and subsequently affects the cell cycle, proliferation, and apoptosis of tumor cells. B[α]PDE exposure can induce lung carcinogenesis and progression by inducing hypomethylation of specific gene promoter regions to activate proto-oncogenes and hypermethylation to silence oncogenes. The aberrantly expressed miRNAs or lncRNAs may regulate the expression and signaling of lung cancer-related genes, thereby affecting lung cancer-related biological functions, including cell proliferation, apoptosis, migration and invasion. poly (ADP-ribose) glycohydrolase (PARG) regulates DNA damage repair and maintains genomic stability, whereas silencing PARG inhibits B[α]PDE-induced deterioration of bronchial epithelial cells. B[α]PDE exposure induces metabolic reprogramming in cancer cells, which provides energy to cancer cells rapidly proliferation by increasing glucose uptake and glycolysis, and also regulates cancer cell growth and survival by affecting lipid and nucleic acid metabolism. In conclusion, in B[α]PDE-induced lung cancer, epigenetic changes such as DNA methylation, miRNAs, lncRNAs, metabolic reprogramming, and PARG work together to form a complex regulatory network that affects gene expression, cellular metabolism, and genomic stability. An in-depth study of the mechanism of B[α]PDE-induced malignant transformation of bronchial epithelial cells can provide a theoretical basis for the study of potential targets for the development of anti-tumor drugs, which will help to guide the prevention and treatment of lung cancer in polluted environments and exposure to smoky environments, and also provide theoretical support for the Healthy China measures of tobacco control and smoking ban.
Citation
YIN Zhang-Ya,LI Cong-Ya,ZHU Jun-Lan.Mechanism of Malignant Transformation in Bronchial Epithelial Cells Induced by The Environmental Carcinogen B[α]PDE[J]..Export: BibTexEndNote
Extracellular vesicles (EVs) are nanoscale vesicles secreted by cells and play a pivotal role in intercellular communication. As crucial mediators in cell-to-cell signaling, EVs are instrumental in physiological and pathological processes. They serve not only as significant biomarkers in disease diagnosis but also hold promise as new drug and drug delivery system candidates due to their unique biological properties. The process begins with the cell membrane invagination to form a cup-like structure, selectively encapsulating surface proteins and soluble proteins to create early endosomes. Under the influence of the endosomal sorting complex required for transport (ESCRT), Rab-GTPase, and tetraspanins, these early endosomes evolve into late sorting endosomes, which form multivesicular bodies. Upon fusion with the plasma membrane, these bodies release EVs into the extracellular space. EVs are internalized by target cells through ligand-receptor interactions, endocytosis, and membrane fusion, thereby executing biological functions. Endocytosis is a common uptake mechanism for EVs, with various pathways including clathrin-dependent pathways, caveolae-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization. Once inside the recipient cell, EVs interact with the endosomal system, fuse, and release their contents into the cytoplasm. The absorption and distribution of EVs in the body are influenced by factors such as their origin, targeting, administration method, size, and surface characteristics. Through engineering, EVs can be loaded with specific proteins or RNA to achieve targeted drug delivery to specific organs or cells. In terms of disease diagnosis, the components of EVs can serve as biomarkers, offering new avenues for early detection, progression monitoring, and therapeutic efficacy assessment. They carry RNA and protein molecules that can reveal pathological changes in their originating cells. In terms of disease treatment, EVs have the potential for targeted delivery, serving as platforms for vaccine development and as drug delivery systems to transport drugs directly to specific cells or tissues. Moreover, EVs themselves can be used as therapeutic agents for autoimmune diseases and cancer. In the realm of EV separation and purification technology, common methods include ultracentrifugation, immunoaffinity chromatography, polymer co-precipitation, ultrafiltration, size exclusion chromatography, and microfluidics. However, due to the limitations of a single separation technique in meeting the demand for high-quality and high-purity EVs, multiple methods are often combined to separate and purify EVs effectively. This article concludes by summarizing the broad application prospects of EVs in the prevention and treatment of human diseases and highlights several key scientific questions that require further in-depth research. The potential of EVs in diagnostics and therapeutics, as well as the challenges in their isolation and characterization, underscores the need for continued exploration and innovation in this field.
Objective To investigate the expression of cyclin-dependent kinase 8 (CDK8) in esophageal squamous cell carcinoma (ESCC) and its effect on ESCC cells, and to explore its potential molecular mechanism.Methods The expression level of CDK8 mRNA was analyzed by UALCAN database, and then the expression level of CDK8 protein in tumor tissues of ESCC patients was detected by immunohistochemistry (IHC). Esophageal cancer cell lines Kyse-30 and Kyse-150 were stably transfected with lentivirus to achieve knockdown and overexpression of CDK8. EdU proliferation assay, cell colony formation assay, cell cycle assay, cell scratch assay and invasion assay were used to explore the effect of CDK8 protein expression level on the phenotype of ESCC cells. Subsequently, the effect of CDK8 on the growth of esophageal cancer xenografts in vitro was observed by subcutaneous tumor formation assay in mice. Finally, the expression of proliferation and metastasis related proteins was detected by Western blot.Results CDK8 showed high transcription and protein expression levels in ESCC tissues compared with normal esophageal tissues. Knockdown of CDK8 expression significantly inhibited the proliferation, migration and invasion of ESCC cells. In addition, inhibition of CDK8 expression significantly affected the JAK2/STAT3 pathway and the expression of E-cadherin/N-cadherin, while overexpression of CDK8 reversed these effects. Inhibition of STAT3 pathway reversed the promoting effect of CDK8 overexpression on ESCC cell phenotype.Conclusion CDK8 is a cancer-promoting factor of ESCC, which mediates the phosphorylation of JAK2/ STAT3 and epithelial-mesenchymal transition (EMT).
Objective The controllability changes of structural brain network were explored based on the control and brain network theory in young smokers, this may reveal that the controllability indicators can serve as a powerful factor to predict the sleep status in young smokers.Methods Fifty young smokers and 51 healthy controls from Inner Mongolia University of Science and Technology were enrolled. Diffusion tensor imaging (DTI) was used to construct structural brain network based on fractional anisotropy (FA) weight matrix. According to the control and brain network theory, the average controllability and the modal controllability were calculated. Two-sample t-test was used to compare the differences between the groups and Pearson correlation analysis to examine the correlation between significant average controllability and modal controllability with Fagerstr?m Test of Nicotine Dependence (FTND) in young smokers. The nodes with the controllability score in the top 10% were selected as the super-controllers. Finally, we used BP neural network to predict the Pittsburgh Sleep Quality Index (PSQI) in young smokers.Results The average controllability of the dorsolateral superior frontal gyrus, supplementary motor area, lenticular nucleus putamen, and lenticular nucleus pallidum in the young smokers’ group, and the modal controllability of the orbital inferior frontal gyrus, supplementary motor area, gyrus rectus, and posterior cingulate gyrus, were all significantly different from those of the healthy controls group (P<0.05). The average controllability of the right supplementary motor area (SMA. R) in the young smokers group was positively correlated with FTND (r=0.393 0, P=0.004 8), while modal controllability was negatively correlated with FTND (r=-0.330 1, P=0.019 2).Conclusion The controllability of the structural brain network in young smokers is abnormal. which may serve as an indicator to predict sleep condition. It may provide the imaging evidence for evaluating the cognitive function impairment in young smokers.
Objective Dust has steadily emerged as a frontier research in the field of forensic science because it is a material evidence with significant features and application potential that carries rich environmental DNA information. However, as a crucial foundational step in forensic applications, the collection and DNA extraction research of dust on object surfaces from the perspective of practical applications in forensic science are still in urgent need of development.Methods Dust was collected from object surfaces using a Copan Liquid Amies Elution Swab. DNA was extracted separately from the swab head, sediment, and supernatant within the sample collection tube to evaluate DNA content, thereby determining which components within the tube should be processed and lysed. Dust samples were collected according to five different sampling areas (25-400 cm2) and the DNA concentration was measured to determine the optimal sampling area. The extraction efficiency of three commercial DNA extraction kits for dust samples was compared. The size of the DNA fragments extracted from the dust was analyzed, as well as the presence of human DNA. Additionally, 16S rDNA amplicon sequencing was used to analyze the bacterial information in dust DNA from object surfaces. This process aimed to establish a quality control method for dust DNA extraction. Regarding the critical step of cell lysis in DNA extraction, the quantity of DNA extracted was compared and evaluated under different cell lysis methods and varying vortexing times. This was done to establish an appropriate cell lysis method for dust DNA extraction.Results The sediment and swab head in the dust sampling tube are the primary sources of DNA, and both should be included in subsequent extraction processes. The sampling area of dust is positively correlated with dust DNA concentration, and it is recommended that the sampling area be larger than 5×5 cm2. Using the DNeasy PowerSoil Pro kit can yield a higher amount of DNA. Additionally, there were no significant differences in the sizes of DNA fragments extracted by the three different DNA extraction kits. No human DNA was detected in the DNA extracted from the dust samples, while bacterial DNA was present in the dust from object surfaces. Furthermore, there were differences in microbial species composition between different sampling points. Additionally, using a biological sample homogenizer to grind and lyse for 4 min (2 min× 2 times) resulted in the highest concentration of dust DNA.Conclusion The extraction of dust DNA is influenced by the sampling area, extraction kits, and lysis methods. It is crucial to establish a comprehensive and suitable dust DNA extraction scheme. This not only lays the foundation for researching and extracting environmental DNA data from dust, but also provides a methodological reference for forensic case work involving environmental samples.
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by muscle rigidity, resting tremor, and postural instability, which severely impair the quality of life in middle-aged and elderly individuals. PD’s pathogenesis is complex, involving oxidative stress, immune inflammation, and genetic factors. Despite extensive research, precise therapeutic targets for PD remain elusive, necessitating further investigation into its underlying mechanisms. Recent studies highlight the pivotal role of regional brain iron overload, oxidative stress, and lipid peroxidation in PD’s pathogenesis. Ferroptosis, a form of regulated cell death driven by iron dependency and lipid peroxidation, has emerged as a critical factor in PD pathology. This review examines the relationship between ferroptosis and PD and explores the potential of exercise as a therapeutic intervention to modulate ferroptosis and alleviate PD symptoms. Ferroptosis, distinct from other forms of cell death such as necrosis, autophagy, pyroptosis, and apoptosis, is characterized by mitochondrial shrinkage, reduced cristae, and membrane collapse, without nuclear fragmentation, DNA cleavage, or caspase activation. It is induced by the accumulation of intracellular Fe2+, which enhances lipid peroxidation and reactive oxygen species (ROS) generation, ultimately leading to cell death. Studies show disrupted iron metabolism in PD patients, with elevated iron levels in dopaminergic neurons of the substantia nigra correlating with disease severity. Iron chelation therapy has shown promise in alleviating PD symptoms by reducing brain iron levels, highlighting the significance of iron metabolism in PD pathogenesis. Lipid peroxidation, a hallmark of ferroptosis, involves the oxidation of polyunsaturated fatty acids (PUFAs) in cell membranes, compromising membrane integrity and increasing permeability. Elevated lipid peroxidation in the substantia nigra contributes to neuronal damage in PD. Enzymes such as ACSL4 and LPCAT3, crucial in PUFA metabolism, play significant roles in ferroptosis. Exercise has been shown to modulate these enzymes, potentially reducing lipid peroxidation and preventing ferroptosis in PD. Glutathione (GSH) metabolism is another crucial factor in ferroptosis regulation. GSH depletion impairs ROS detoxification, exacerbating oxidative stress and lipid peroxidation. PD patients exhibit reduced GSH levels in the substantia nigra, making dopaminergic neurons more vulnerable to oxidative damage. Exercise enhances GSH synthesis and activity, mitigating oxidative stress and ferroptosis in PD. α-Synuclein aggregation, a hallmark of PD, is closely linked to iron metabolism and oxidative stress. Excessive α-synuclein binds to iron, promoting its aggregation and inducing ferroptosis. Exercise has been found to reduce α-synuclein accumulation and its pathological phosphorylation, potentially through the upregulation of neuroprotective proteins like DJ-1 and Irisin. These proteins enhance antioxidant defenses and facilitate α-synuclein degradation, providing a protective effect against PD progression. Additionally, glutamate excitotoxicity, driven by dysregulated glutamate metabolism and receptor activity, contributes to ferroptosis in PD. Exercise modulates glutamate levels and receptor expression, reducing excitotoxicity and iron-induced neuronal damage. In conclusion, emerging research suggests that exercise may inhibit ferroptosis through multiple mechanisms, including regulation of iron metabolism, enhancement of antioxidant defenses, reduction of α-synuclein aggregation, and modulation of glutamate metabolism. These findings highlight the potential of exercise as a non-pharmacological intervention in the prevention and treatment of PD. Further research is needed to elucidate precise mechanisms and optimize exercise protocols for maximum therapeutic benefit.
Objective Chronic stress can induce cognitive dysfunction, but the underlying mechanisms remain unknown. Studies have confirmed that the high mobility group box 1/Toll-like receptor 4 (HMGB1/TLR4) pathway is closely associated with cognitive impairment. Therefore, this research aimed to explore whether the HMGB1/TLR4 pathway involves in chronic stress-induced cognitive dysfunction.Methods The chronic unpredictable mild stress (CUMS) mouse model was established by randomly giving different types of stress every day for four consecutive weeks. Cognitive function was detected by novel object recognition test, Y-maze test, and Morris water maze test. The protein expressions of HMGB1, TLR4, B-cell lymphoma 2 (BCL2), and BCL2 associated X (BAX) were determined by Western blot. The damage of neurons in the hippocampal CA1 region was observed by hematoxylin-eosin (HE) staining.Results The protein expressions of HMGB1 and TLR4 were significantly increased in the hippocampus of chronic stress mice. Furthermore, inhibition of the HMGB1/TLR4 pathway induced by ethyl pyruvate (EP, a specific inhibitor of HMGB1) and TAK-242 (a selective inhibitor of TLR4) treatment attenuated cognitive impairment in chronic stress mice, according to the novel object recognition test, Y-maze test, and Morris water maze test. In addition, administration of EP and TAK-242 also mitigated the increase of apoptosis in the hippocampus of chronic stress mice.Conclusion These results indicate that the hippocampal HMGB1/TLR4 pathway contributes to chronic stress-induced apoptosis and cognitive dysfunction.
Integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network. When the body encounters adverse stimuli, ISR is activated to assist cells, tissues, and the body in adapting to the changing environment and maintaining health by reprogramming genes. ISR is implicated in the onset and progression of various diseases, including cardiovascular disease, diabetes, obesity, cancer, and neurological disorders. A key factor in ISR is the eukaryotic initiation factor 2α (eIF2α) kinase. Four eIF2α kinases have been identified, namely general control non-derepressible-2 (GCN2), protein kinase double-stranded RNA-dependent (PKR), PKR-like ER kinase (PERK), and heme-regulated inhibitor (HRI). GCN2, PKR, PERK, and HRI kinases share a common kinase catalytic domain but have distinct regulatory domains that are activated by endoplasmic reticulum stress (ERS), viral infection, heme deficiency, and amino acid deficiency, respectively. Various stress conditions promote the phosphorylation of eIF2α at serine 51 by its 4 kinases. This inhibits the eIF2B-mediated GTP acquisition of eIF2α and reduces the translation rate. At the same time, ISR upregulates ATF4 expression. ATF4 and CCAAT-enhancer binding protein (CHOP) can promote downstream growth arrest and DNA damage-inducible protein 34 (GADD34) to mediate eIF2α dephosphorylation. At the same time, it can promote the downstream expression of Sestrin 2 (SESN2) protein, increase autophagy induced by mTORC1 and AMPK, and thereby reduce the risk of cardiovascular disease. Numerous animal and cellular studies have demonstrated that exercise, drugs, and molecular compounds can prevent and improve pathological myocardial hypertrophy, diabetic cardiomyopathy, ischemic cardiomyopathy, cardiotoxicity, and atherosclerosis by modulating ISR. The relevant mechanism involves gene knockout or inhibitors that directly inhibit the expression of eIF2α kinase. Aerobic exercise, editing of specific molecules, or drugs can indirectly inhibit the expression of eIF2α kinase, ultimately leading to the inhibition of the downstream expression of eIF2α/ATF4. In light of the significant pathological role of ISR in cardiovascular disease, current research on ISR primarily aims to develop medications that can regulate the upstream and downstream signaling activities of ISR. This involves targeting ISR to regulate intracellular protein homeostasis, ultimately aiming to delay or reverse the progression of cardiovascular disease. At present, drugs targeting ISR in cardiovascular disease research mainly include ISRIB, 4-PBA, and Salubrinal. ISRIB reverses eIF2α phosphorylation by suppressing the inhibitory effect of eIF2α on protein synthesis and blocking eIF2α/ATF4 signaling. 4-PBA can inhibit endoplasmic reticulum stress. Salubrinal inhibits eIF2α dephosphorylation by inhibiting the binding of GADD34-PP1 and CReP-PP1 complexes to eIF2α. In conclusion, the integrated stress response mediated by the four eIF2α kinases is essential for the body to adapt to various stress stimuli affecting the heart and blood vessels under normal or pathological conditions. Integrated stress response inhibitors should be promptly administered to clinical cardiovascular patients to assess their effectiveness in the onset and development of various cardiovascular diseases, as well as to evaluate potential side effects. Future studies are needed to explore the role and mechanism of eIF2α kinase-mediated integrative stress response in various diseases. It is also essential to investigate whether the integrative stress response yields different effects in various organs and can potentially exert cross-organ efficacy through inter-organ interaction.
Objective The inference of biogeographical ancestry (BGA) using DNA is a significant focus within anthropology and forensic science. Current methods often utilize dozens of ancestry-informative SNPs, employing principal component analysis (PCA) and likelihood ratios (LR) to ascertain individual ancestries. Nonetheless, the selection of these SNPs tends to be population-specific and shows limitations in population differentiation. With the development of high-throughput sequencing technologies, acquiring high-density SNP datasets has become easier, challenging traditional statistical models which are often reliant on prior assumptions and struggle with high-density genetic data. The integration of machine learning, which prioritizes data learning and algorithmic iteration over prior knowledge, has propelled forward new developments in BGA research. This study aims to construct a BGA inference model suitable for high-density SNP data, characterized by broad population applicability, higher accuracy, and strong generalization capabilities.Methods Initially, intersection sites of autosomes from the phase III data of the 1000 Genomes Project and commonly used commercial chips were selected to build a reference dataset after thorough site quality control and filtering. This dataset was analyzed using PCA and ADMIXTURE to study population clustering, ancestral component mixing, and genetic substructures. Utilizing spaces of different principal component (PC), combinations, this study visually assessed the PCs" capabilities to differentiate between continental and intercontinental populations. Following this, the study employed the supervised learning classification model XGBoost, establishing a multidimensional PC-based PCA-XGBoost model with hyperparameters set through ten-fold cross-validation and a greedy strategy. Subsequently, the model was optimized and evaluated based on the LR, considering accuracy and runtime to determine the optimal number of PCs and training rounds, culminating in the study"s optimal BGA inference model. Finally, the performance of the model was subsequently validated at national and regional levels using test sets from other public data to assess its post-optimization generalization capabilities.Results The reference dataset created contains 307 866 SNP sites. Top PCs reflect varying levels of population differentiation capabilities, with some PCs showing population specificity. Under smaller K values in ADMIXTURE results, genetic ancestral components between continents are elucidated, while larger K values reveal some specific ancestral components of certain populations within continents. The number of PCs and training rounds significantly affect the classification accuracy and efficiency of the XGBoost supervised model. With LR-based evaluation methods, the optimized PCA-XGBoost model achieved a continental prediction accuracy of over 98% in the reference set. For subcontinental population levels within the continents, the model achieved an accuracy of over 95% in the reference set and over 90% in the test set.Conclusion The reference dataset effectively represents the genetic substructures of populations at selected sites. Information derived from PC dimensions significantly aids in population differentiation and inference issues, and incorporating more PC dimensions as features in supervised learning models can increase the accuracy of BGA inference. The model of this study is suitable for high-density SNP data and is not confined to specific regional populations, offering enhanced population-wide applicability. Compared to previous ancestry inference models, the optimized PCA-XGBoost model demonstrates high intercontinental population predictive accuracy. LR-based evaluation methods further enhance the reliability of predictions. Additionally, the model"s strong generalization capabilities suggest that updating the reference population data could enable more detailed population analysis and inference.
Chimeric antigen receptor T (CAR-T) cell therapy is an innovative and cutting-edge treatment in the field of adoptive cell therapy. It represents an important milestone in personalized and precision medicine. T cell immunotherapy has gone through more than 30 years of development, making CAR-T cell therapy increasingly mature. Currently, CAR-T cell therapy has achieved significant success in the treatment of hematological system tumors, and the FDA has approved 6 CAR-T cell therapies for the treatment of hematopoietic cancers. However, on one hand, the preparation of CAR-T cells is a highly technical process involving multiple steps, each requiring precise operation and strict condition control to ensure the quality and activity of the cells. The high-quality materials, specialized equipment, and highly specialized personnel required in the production process have led to very high preparation costs for CAR-T cell therapy. The high cost has led to increased treatment fees, which may limit the popularization and accessibility of CAR-T therapy. On the other hand, CAR-T cell therapy faces a series of difficulties and challenges in the treatment of solid tumors. The first is the insufficient targeting and infiltration ability of CAR-T cells to tumors. The tumor microenvironment (TME) of solid tumors is usually composed of dense extracellular matrix, forming a physical barrier that severely limits the targeting and penetration ability of CAR-T cells to tumors. The second is the immunosuppressive factors in the TME. In the TME, there are a large number of immunosuppressive factors, such as interleukin-10, transforming growth factor β, and suppressive cells including regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. These factors not only weaken the persistence of CAR-T cells but also severely hinder their effective anti-tumor effect. Finally, CAR-T cell therapy can cause serious cytotoxicity. The activation of CAR-T cells may cause cytokine release syndrome and attack normal cells expressing the CAR-T target antigen, causing “off-target” toxicity, and thus causing systemic inflammatory reactions and potential serious side effects. These factors lead to unsatisfactory therapeutic effects of CAR-T cell therapy. Fortunately, the advancement of nanotechnology has brought new hope to this field. In particular, nano drug delivery systems have become an extremely active research direction in the development of anti-tumor drugs. Nanoparticle delivery systems can address the challenges encountered by CAR-T cell therapy in treating solid tumors through various mechanisms. These mechanisms include enhancing tumor targeting and CAR-T cell penetration ability, regulating the tumor"s suppressive microenvironment, and overcoming the side effects of CAR-T cell therapy. The implementation of these strategies is expected to significantly improve the efficacy of CAR-T cell therapy in the treatment of solid tumors, thereby bringing more significant therapeutic effects to patients. This article focuses on the background of CAR-T therapy and solid tumor treatment, systematically reviews the application of nanotechnology in CAR-T cell preparation and solid tumor treatment in vitro and in vivo in recent years, and provides a forward-looking perspective on future development directions.
Proteins in biological systems rarely act alone, but instead bind with other biomolecules to trigger specific cellular reactions. These biomolecules are usually astonishing number of proteins self-assemble to form dimers, which are both in a relatively isolated state and in a protein interaction network and cascade. Dimerization can endow proteins with various structural and functional advantages, including improving stability, controlling the accessibility and specificity of active sites, and increasing complexity. The self-association of proteins to form dimers is a very common phenomenon, and the functional importance of homologous protein dimerization cannot be overestimated. It provides diversity and specificity in many pathways, and most cellular events, such as signal transduction, transcription cofactor recruitment, enzyme activation, and even pathogenic pathways, are significantly regulated through homologous protein-protein interactions. The regulation of protein dimerization is an important process for the growth and development of organisms under internal or external stimuli in the natural environment. Therefore, regulating the dimerization process of homologous proteins and understanding their molecular mechanisms are crucial for biomedical applications and analyzing complex biological regulatory networks. Proximity effects or physical proximity effects of molecules are essential regulatory factors in biological processes, which can be controlled through induced dimerization methods. The application range of induced proximity ranges from manipulating protein folding, activation, localization, and degradation to controlling gene transcription or cell therapy. The chemical induced dimerization (CID) system and light induced dimerization (LID) system based on proximity induction provide powerful tools for regulating the function of dimerized proteins, and have been gradually developed. The concept of CID was proposed as early as 1993. The basic principle of CID is that a small molecule controls the dimerization of a pair of proteins or domains, while binding two proteins and bringing them closer together. Small molecules in the CID system form ternary complexes with target proteins, which can bind to various sites, including “hotspot” and “allosteric sites”. Small molecules play a role by regulating protein proximity. The light induced dimerization system uses photosensitive proteins to undergo conformational changes under light, thereby inducing protein interactions. Multiple photosensitive proteins derived from plants and microorganisms can undergo photo induced homologous interactions, and relying on LID systems, they can be used to study various biological processes, including cell signal transduction, microbial synthesis, and biomedical applications. In recent years, metal ions, nucleic acids, and molecular host guest systems have been proposed as new methods for orthogonal control of homologous protein dimerization, expanding the development and application of dimerization systems. In addition, the chemo-optogenetic approach combines the advantages of CID and LID systems and has also been applied in inducing protein dimerization. In this review, it is explained that through the CID system, The methods and applications of LID system and supramolecular chemistry to induce homologous protein dimerization are summarized, and the advantages and disadvantages of dimerization systems are discussed. The development direction of dimerization systems is also discussed, in order to provide some reference and ideas for the future application and development of homologous protein dimerization.
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GUO Jun-Xia,LIU Sen.Methods for Inducing Homologous Protein Dimerization[J]..Export: BibTexEndNote
Isocitrate dehydrogenase 1 (IDH1) R132H is the most common mutated gene in grade II-III gliomas and oligodendrogliomas. Instead of activating telomerase (a reverse transcriptase which using RNA as a template to extend telomere length), the majority of IDH1R132H mutant glioma maintain telomere length through an alternative mechanism that relies on homologous recombination (HR), which is known as alterative lengthening of telomere (ALT).The phenotype of ALT mechanism include: ALT associated promyelocytic leukemia protein (PML) bodies (APBs); extrachromosomal telomeric DNA repeats such as C- and T-loops; telomeric sister chromatid exchange (T-SCE), etc. The mechanism of ALT activation is not fully understood. Recent studies have shown that mutation IDH1 contributes to ALT phenotype in glioma cells in at least three key ways. Firstly, the IDH1R132H mutation mediates RAP1 down-regulation leading to telomere dysfunction, thus ensuring persistent endogenous telomeric DNA damage, which is important for ALT activation. Spontaneous DNA damage at telomeres may provide a substrate for mutation break-induced replication (BIR)-mediated ALT telomere lengthening, and it has been demonstrated that RAP1 inhibits telomeric repeat-containing RNA, transcribed from telomeric DNA repeat sequences (TERRA) transcription to down-regulate ALT telomere DNA replication stress and telomeric DNA damage, thereby inhibiting ALT telomere synthesis. Similarly, in ALT cells, knockdown of telomere-specific RNaseH1 nuclease triggers TERRA accumulation, which leads to increased replication pressure. Overexpression of RNaseH1, on the other hand, attenuates the recombination capacity of ALT telomeres, leading to telomere depletion, suggesting that RAP1 can regulate the level of replication pressure and thus ALT activity by controlling TERRA expression. Secondly, the IDH1R132H also alters the preference of the telomere damage repair pathway by down-regulating XRCC1, which inhibits the alternative non-homologous end joining (A-NHEJ) pathway at telomeres and alters cellular preference for the HR pathway to promote ALT. Finally, the IDH1R132H has a decreased affinity for isocitric acid and NADP+ and an increased affinity for α ketoglutarate (α-KG) and NADPH, so that the mutant IDH1R132H catalysis the hydrogenation of α-KG to produce 2-hydroxyglutarate (2-HG)in a NADPH-dependent manner. Because 2-HG is structurally similar to α-KG, which maintains the trimethylation level of H3k9me3 by competitively inhibiting the activity of the α-KG-dependent histone demethylase KDM4B, and recruits heterochromatin protein HP1α to heterochromatinize telomeres, and promote ALT phenotypes in cooperation with the inactivating of ATRX. In addition, it has been shown that APBs contain telomeric chromatin, which is essentially heterochromatin, and HP1α is directly involved in the formation of APBs. Based on these studies, this article reviews the mechanism of IDH1R132H mediated telomere dysfunction and the preference of DNA repair pathway at telomeres in cooperate with ATRX loss to promote ALT, which may provide references for clinical targeted therapy of IDH1R132H mutant glioma.
G-protein coupled receptors (GPCRs) are an essential family of proteins on the cell membrane, widely distributed in various types of tissues and cells. Typical GPCRs are composed of characteristic 7 transmembrane α-helix domains, extracellular domain and intracellular domain. They play a key role in transmitting information inside and outside cells. These receptors can sense and respond to a variety of external signals, including odor molecules, hormones, neurotransmitters, chemokines, and so on. thereby regulating the physiological functions and metabolic activities of cells. When external signal molecules bind, these receptors undergo conformational changes, thereby activating signal transduction pathways inside cells. The most common downstream signal pathway is the activation of G proteins, but it may also activate the β-arrestin signaling pathway. This series of signal transduction processes ultimately regulates physiological processes such as cell metabolism, proliferation, and differentiation, and also plays an important role in the occurrence and development of diseases. Due to its importance in regulating cell functions and participating in the development of diseases, GPCRs have become important targets in the field of drug research and development. The mechanism of action of many drugs is achieved by intervening in the GPCR signaling pathway. As important form of function regulating, dimerization has attracted widespread attention in the research of GPCR field. In the early days, the formation of GPCR dimerization and its effect on receptor function were mainly studied by immunoprecipitation, immunofluorescence and radioligand binding experiments in overexpression systems. Nowadays, with the continuous development of biochemical and biophysical methods, more and more GPCR dimers have been identified. GPCR dimer refers to the process in which two GPCR subunits bind to each other to form a complex. The same GPCR subunits form homodimers, and different GPCR subunits form heterodimers through direct interaction. Dimerization changes the activity, affinity, internalization, localization and transport, and signal transduction characteristics of GPCR, thereby producing more complex and delicate regulation of cellular physiological processes. In recent years, the research on GPCR dimers has been continuously deepened, revealing its important role in a variety of physiological and pathological processes. In general, the structure of GPCR dimers is complex and diverse, and its formation and stability are affected by many factors, including the specificity of receptor interaction interface, the conformational changes of receptor, and the regulation of intracellular and extracellular environment. By understanding the mechanism of GPCR dimerization, we can better understand the behavior of these receptors in signal transduction and provide new ideas and opportunities for the development of novel drug targets. More and more studies have reported the dimerization of GPCR and its structure and function regulation mechanism. This article reviews the research progress on the structure and function of GPCR dimers, and summarizes some research methods and technologies, which provide a basis for understanding the discovery of GPCR dimers, dimerization methods, structure and function regulation mechanisms, and further targeting GPCR dimers. Polymeric drug development provides a research basis.
Sponsored by:Institute of Biophysics, The Chinese Academy of Sciences; Biophysical Society of ChinaEdited by: Editorial Office of Progress in Biochemistry and BiophysicsPublished by:Editorial Office of PIBBEditor-in-Chief:HE Rong-Qiao Adress:15 Datun Road, Chaoyang District,Beijing 100101,China Telephone:86-10-64888459 Email:prog@ibp.ac.cn Journal inclusion:SCI, CA, Scopus, AJ ISSN 1000-3282 CN 11-2161/Q
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