The main characteristics of neurodegenerative diseases represented by Alzheimer’s disease (AD) and Parkinson’s disease (PD) is the progressive irreversible loss of neurons, leading to varying degrees of pathological changes and loss of cognitive function. There is still no effective treatment. With the acceleration of global aging society, the incidence of neurodegenerative diseases is rapidly increasing, becoming a serious global public health concern that urgently requires the development of effective therapeutic strategies. The Hippo signaling pathway, a highly evolutionarily conserved pathway, consists of the core components MST1/2, LATS1/2, and downstream effectors, transcriptional co-activators YAP and TAZ. It plays a crucial role in the regulation of various biological processes such as cell proliferation, differentiation, development, and apoptosis. Dysregulation of the Hippo pathway contributes to the development of many diseases, including cancer, cardiovascular diseases, immune disorders, etc. Therefore, targeting the dysregulated components of the Hippo pathway may be an effective strategy for treating various diseases. Increasing evidence indicates that the Hippo pathway is excessively activated in the development of neurodegenerative diseases, manifested by increased expression of MST1 and downregulation of YAP. Stabilizing the Hippo pathway levels has shown improvements in AD and PD. However, most studies on the Hippo pathway in AD and PD focus on changes in the expression levels of Hippo pathway components, and research in other neurodegenerative diseases is still lacking. Therefore, further investigation is needed to fully understand the mechanistic role of the Hippo pathway in neurodegenerative diseases. Meanwhile, miRNA, similarly dysregulated in neurodegenerative diseases and serving as biomarkers, is a primary target for miRNA therapy in neurodegenerative diseases, including AD and PD. Activating or inhibiting dysregulated miRNAs is the main strategy of miRNA therapy during the neurodegenerative disease development. Evidence suggests that the interaction between the Hippo pathway and miRNA can result in widespread biological effects and crosstalk in the occurrence of different types of diseases. However, studies on the interplay between the Hippo pathway and miRNA in neurodegenerative diseases are relatively scarce. In this paper, we predicted the miRNAs related to Hippo pathway through bioinformatics database, and further screened the miRNAs with crosstalk relationship with Hippo signaling pathway through experiments in combination with PubMed. Then, the mechanism of action of Hippo signaling pathway related miRNAs in AD and PD is further elucidated. It is reported that the Hippo pathway and its related miRNA may exert neuroprotective effects by reducing oxidative stress, improving neuroinflammation, stabilizing autophagy levels, maintaining neuronal mitochondrial function, and ameliorating blood-brain barrier dysfunction, thereby delaying the progression of AD and PD. However, research on miRNA directly regulating the Hippo pathway to improve AD and PD is limited, and observations of the Hippo pathway and its related miRNA in other neurodegenerative diseases are scarce. However, considering the regulatory relationship between the Hippo pathway and miRNA in multiple diseases and their respective roles in key mechanisms of neurodegenerative diseases, such as oxidative stress and neuroinflammation, the crosstalk between miRNA and the Hippo pathway holds a crucial regulatory role in the development of neurodegenerative diseases. Thus, the interaction pathways of the Hippo pathway and its related miRNA may be a pivotal avenue for exploring effective therapeutic strategies for neurodegenerative diseases in the future.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment, and there is a lack of effective drugs to treat AD clinically. Existing medications for the treatment of AD, such as Tacrine, Donepezil, Rivastigmine, and Aducanumab, only serve to delay symptoms and but not cure disease. To add insult to injury, these medications are associated with very serious adverse effects. Therefore, it is urgent to explore effective therapeutic drugs for AD. Recently, studies have shown that a variety of enzyme inhibitors, such as cholinesterase inhibitors, monoamine oxidase (MAO)inhibitors, secretase inhibitors, can ameliorate cholinergic system dysfunction, Aβ production and deposition, Tau protein hyperphosphorylation, oxidative stress damage, and the decline of synaptic plasticity, thereby improving AD symptoms and cognitive function. Some plant extracts from natural sources, such as Umbelliferone, Aaptamine, Medha Plus, have the ability to inhibit cholinesterase activity and act to improve learning and cognition. Isochromanone derivatives incorporating the donepezil pharmacophore bind to the catalytic active site (CAS) and peripheral anionic site (PAS) sites of acetylcholinesterase (AChE), which can inhibit AChE activity and ameliorate cholinergic system disorders. A compound called Rosmarinic acid which is found in the Lamiaceae can inhibit monoamine oxidase, increase monoamine levels in the brain, and reduce Aβ deposition. Compounds obtained by hybridization of coumarin derivatives and hydroxypyridinones can inhibit MAO-B activity and attenuate oxidative stress damage. Quinoline derivatives which inhibit the activation of AChE and MAO-B can reduce Aβ burden and promote learning and memory of mice. The compound derived from the combination of propargyl and tacrine retains the inhibitory capacity of tacrine towards cholinesterase, and also inhibits the activity of MAO by binding to the FAD cofactor of monoamine oxidase. A series of hybrids, obtained by an amide linker of chromone in combine with the benzylpiperidine moieties of donepezil, have a favorable safety profile of both cholinesterase and monoamine oxidase inhibitory activity. Single domain antibodies (such as AAV-VHH) targeted the inhibition of BACE1 can reduce Aβ production and deposition as well as the levels of inflammatory cells, which ultimately improve synaptic plasticity. 3-O-trans-p-coumaroyl maslinic acid from the extract of Ligustrum lucidum can specifically inhibit the activity of γ-secretase, thereby rescuing the long-term potentiation and enhancing synaptic plasticity in APP/PS1 mice. Inhibiting γ-secretase activity which leads to the decline of inflammatory factors (such as IFN-γ, IL-8) not only directly improves the pathology of AD, but also reduces Aβ production. Melatonin reduces the transcriptional expression of GSK-3β mRNA, thereby decreasing the levels of GSK-3β and reducing the phosphorylation induced by GSK-3β. Hydrogen sulfide can inhibit GSK-3β activity via sulfhydration of the Cys218 site of GSK-3β, resulting in the suppression of Tau protein hyperphosphorylation, which ameliorate the motor deficits and cognitive impairment in mice with AD. This article reviews enzyme inhibitors and conformational optimization of enzyme inhibitors targeting the regulation of cholinesterase, monoamine oxidase, secretase, and GSK-3β. We are hoping to provide a comprehensive overview of drug development in the enzyme inhibitors, which may be useful in treating AD.

Vitamin D is a unique fat-soluble vitamin that plays an indispensable role in human health. It exists in various forms, the most significant being vitamin D₂ (derived from plant sources) and vitamin D₃ (synthesized naturally in human skin upon exposure to sunlight). Vitamin D’s primary function is to facilitate the absorption of calcium and phosphorus, which are crucial for maintaining healthy bones. Beyond its role in bone health, vitamin D significantly influences the immune system, muscle function, cardiovascular health, and the regulation of brain functions. A deficiency in vitamin D can lead to various chronic diseases such as rickets, osteoporosis, decreased immunity, increased risk of mental disorders, and cancers. The synthesis of vitamin D in the human body, both peripherally and centrally, relies on sunlight exposure, dietary sources, and various supplements. As a neuroactive steroid, vitamin D impacts both the physiological and pathological processes of the nervous system and plays a key role in brain health. It profoundly affects the brain by regulating neurotransmitter synthesis and maintaining intracellular calcium balance. As an essential chemical molecule, vitamin D participates in complex signal transduction pathways, impacting neurotransmitter functions and synaptic plasticity. Vitamin D’s role in regulating dopamine (DA)—a neurotransmitter critical for motivation, reward perception, and other higher cognitive functions—is particularly noteworthy. Recent studies have revealed that vitamin D not only promotes the synthesis of DA but also plays a role in regulating DA levels within the brain. It exerts neuroprotective effects on DA neurons through anti-inflammatory, antioxidant actions, and neurotrophic support, thereby creating an optimal environment for DA neurons, influencing neuronal structure, and affecting the movement of calcium ions within nerve cells, positively impacting the overall health and functionality of the DA system. Furthermore, vitamin D can regulate the synthesis and release of DA, thus affecting the signal transmission of various DA neural projection pathways in the brain. This function is vital for understanding the complex interactions between neural mechanisms and their effects on key behaviors and cognitive functions. This review aims to delve deeply into the synthesis, metabolism, and pathways of vitamin D’s action, especially its regulatory mechanisms on DA neurons. Through this exploration, this article seeks to provide a solid theoretical foundation and research framework for a deeper understanding of vitamin D’s role in motivation and reward behaviors. This understanding is crucial for appreciating the broader significance of vitamin D in the fields of neuroscience and neurology. In summary, research and discoveries regarding vitamin D’s impact on the nervous system highlight its importance in neural health and function. These insights not only enhance our understanding of the complex workings of the nervous system but also open new avenues for the prevention and treatment of neurological diseases. The exploration of vitamin D’s multifaceted roles offers promising prospects for developing new therapeutic strategies, underscoring the compound’s potential in addressing a range of neural dysfunctions and diseases. As research continues to evolve, the profound implications of vitamin D in the field of neurology and beyond become increasingly apparent, marking it as a key target for ongoing and future scientific inquiry.

There are huge differences between tumor cells and normal cells in material metabolism, and tumor cells mainly show increased anabolism, decreased catabolism, and imbalance in substance metabolism. These differences provide the necessary material basis for the growth and reproduction of tumor cells, and also provide important targets for the treatment of tumors. Ferroptosis is an iron-dependent form of cell death characterized by an imbalance of iron-dependent lipid peroxidation and lipid membrane antioxidant systems in cells, resulting in excessive accumulation of lipid peroxide, causing damage to lipid membrane structure and loss of function, and ultimately cell death. The regulation of ferroptosis involves a variety of metabolic pathways, including glucose metabolism, lipid metabolism, amino acid metabolism, nucleotide metabolism and iron metabolism. In order for tumor cells to grow rapidly, their metabolic needs are more vigorous than those of normal cells. Tumor cells are metabolically reprogrammed to meet their rapidly proliferating material and energy needs. Metabolic reprogramming is mainly manifested in glycolysis and enhancement of pentose phosphate pathway, enhanced glutamine metabolism, increased nucleic acid synthesis, and iron metabolism tends to retain more intracellular iron. Metabolic reprogramming is accompanied by the production of reactive oxygen species and the activation of the antioxidant system. The state of high oxidative stress makes tumor cells more susceptible to redox imbalances, causing intracellular lipid peroxidation, which ultimately leads to ferroptosis. Therefore, in-depth study of the molecular mechanism and metabolic basis of ferroptosis is conducive to the development of new therapies to induce ferroptosis in cancer treatment. Ferroptosis, as a regulated form of cell death, can induce ferroptosis in tumor cells by pharmacologically or genetically targeting the metabolism of substances in tumor cells, which has great potential value in tumor treatment. This article summarizes the effects of cellular metabolism on ferroptosis in order to find new targets for tumor treatment and provide new ideas for clinical treatment.

Apolipoprotein E (apoE) is a critical molecule in lipid metabolism, which also plays important roles in the occurrence and development of several kinds of cancers by regulating processes including cell proliferation, energy metabolism, oxidative stress and innate immune, etc., and shows influence in patients’ response to treatment. Therefore, apoE has become a potential biomarker and treatment target for cancer. Further research of apoE will help us build deep and systematic understanding of etiology of cancer to promote the prevention and to develop new therapeutic strategies for cancer. In this review, we introduced the properties of apoE from the views of biophysics, biochemistry, molecular biology, evolution and epidemiology, in which we demonstrated the similarities and differences among the structures of 3 subtypes of apoE; we also recapitulated the role of apoE in the genesis and development of cancers in main types of malignancies including gastric cancer, colorectal cancer, hepatobiliary cancer, melanoma, pancreatic cancer, etc.; we summarized the relationship between apoE and the hallmarks of cancer, highlighting the position of apoE in immune system and its critical role for understanding the different nature of immunological background of cancers originated from different organs, and discussed its potential value for application as tumor biomarkers and therapeutic targets by demonstrating the structures of its subtypes. We further discussed the possibility of transferring the drug designing strategy of “structure corrector” from neurology to oncology.

Bladder cancer is one of the most prevalent cancers worldwide, with a high rate of recurrence and mortality, which is the ninth most common malignancy globally. Cystoscopy remains the gold standard for clinical bladder cancer diagnosis, but its invasive nature can lead to bacterial infection and inflammation. Urine cytology is a non-invasive and simple diagnostic method, but it has lower sensitivity in detecting low-grade bladder cancer and may yield false negative results. Therefore, identifying ideal diagnostic and prognostic biomarkers is crucial for accurate diagnosis and effective treatment of bladder cancer. Aptamers, characterized as single-stranded DNA or RNA with unique three-dimensional conformations, exhibit the ability to identify various targets, ranging from small molecules to tumor cells. Aptamers, also known as chemical antibodies, are generated by systematic evolution of ligands by exponential enrichment (SELEX) process and can function similarly to traditional antibodies. They hold numerous advantages over antibodies, such as ease of modification, low immunogenicity, and rapid tissue penetration and cell internalization due to their nucleic acid molecule structure. Since their discovery in the 1990s, aptamers have been widely used in biochemical analysis, disease detection, new drug research and other fields. This article provides an overview of aptamer selection and characterization for bladder cancer, discussing the research advancements involving aptamers in diagnosing and treating this disease. It covers aptamers obtained through different SELEX methods, including protein-SELEX, cell-SELEX, tissue-SELEX, and aptamers from other cancer SELEX; the detection in blood samples and urine samples; and application in targeted therapy and immunotherapy for bladder cancer. Currently, several aptamers capable of identifying bladder cancer have been generated, serving as molecular probes that have played a pivotal role in the early detection and treatment of bladder cancer. Bladder cancer perfusion therapy is well-suited for aptamer drug therapy because it does not require internal circulation, making it a suitable clinical indication for aptamer drug development. In addition, bladder cancer can be detected and monitored by collecting urine samples from patients, making it a preferred disease for clinical conversion of aptamers. While aptamers show promise, there is still much room for development compared with antibodies. There are still many clinically applied cancer biomarkers without corresponding aptamers, and more aptamers targeting different biomarkers should be selected and optimized to improve the sensitivity and accuracy for cancer detection and therapy. The field of aptamers urgently needs successful commercial products to promote its development, and home rapid detection/monitoring, imaging and targeted therapy of bladder cancer by infusion may be the breakthrough point for future application of aptamers.

The pathogenesis of osteoarthritis (OA) is related to a variety of factors such as mechanical overload, metabolic dysfunction, aging, etc., and is a group of total joint diseases characterized by intra-articular chondrocyte apoptosis, cartilage fibrillations, synovial inflammation, and osteophyte formation. At present, the treatment methods for osteoarthritis include glucosamine, non-steroidal anti-inflammatory drugs, intra-articular injection of sodium hyaluronate, etc., which are difficult to take effect in a short period of time and require long-term treatment, so the patients struggle to adhere to doctor’s advice. Some methods can only provide temporary relief without chondrocyte protection, and some even increase the risk of cardiovascular disease and gastrointestinal disease. In the advanced stages of OA, patients often have to undergo joint replacement surgery due to pain and joint dysfunction. Mitochondrial dysfunction plays an important role in the development of OA. It is possible to improve mitochondrial biogenesis, quality control, autophagy balance, and oxidative stress levels, thereby exerting a protective effect on chondrocytes in OA. Therefore, compared to traditional treatments, improving mitochondrial function may be a potential treatment for OA. Here, we collected relevant literature on mitochondrial research in OA in recent years, summarized the potential pathogenic factors that affect the development of OA through mitochondrial pathways, and elaborated on relevant treatment methods, in order to provide new diagnostic and therapeutic ideas for the research field of osteoarthritis.

Osteoporosis leads to an imbalance in bone remodelling, where bone resorption is greater than bone formation and osteoclast degradation increases, resulting in severe bone loss. Autophagy is a lysosomal degradation pathway that regulates the proliferation, differentiation, and apoptosis of various bone cells (including osteoblasts, osteoclasts, and osteoclasts), and is deeply involved in the bone remodelling process. In recent years, the role of autophagy in the progression of osteoporosis and related bone metabolic diseases has received more and more attention, and it has become a research hotspot in this field. Summarising the existing studies, it is found that senile osteoporosis is the result of a combination of factors. On the one hand, it is the imbalance of bone remodelling and the increase of bone resorption/bone formation ratio with ageing, which causes progressive bone loss. On the other hand, aging leads to a general decrease in the level of autophagy, a decrease in the activity of osteoblasts and osteoclasts, and an inhibition of osteogenic differentiation. The lack of oestrogen leads to the immune system being in a low activation state, and the antioxidant capacity is weakened and inflammatory response is increased, inducing autophagy-related proteins to participate in the transmission of inflammatory signals, excessive accumulation of reactive oxygen species (ROS) in the skeleton, and negatively regulating bone formation. In addition, with aging and the occurrence of related diseases, glucocorticoid treatments also mediate autophagy in bone tissue cells, contributing to the decline in bone strength. Exercise, as an effective means of combating osteoporosis, improves bone biomechanical properties and increases bone density. It has been found that exercise induces oxidative stress, energy imbalance, protein defolding and increased intracellular calcium ions in the organism, which in turn activates autophagy. In bone, exercise of different intensities activates messengers such as ROS, PI3K, and AMP. These messengers signal downstream cascades, which in turn induce autophagy to restore dynamic homeostasis in vivo. During exercise, increased production of AMP, PI3K, and ROS activate their downstream effectors, AMPK, Akt, and p38MAPK, respectively, and these molecules in turn lead to activation of the autophagy pathway. Activation of AMPK inhibits mTOR activity and phosphorylates ULK1 at different sites, inducing autophagy. AMPK and p38 up-regulate per-PGC-1α activity and activate transcription factors in the nucleus, resulting in increased autophagy and lysosomal genes. Together, they activate FoxOs, whose transcriptional activity controls cellular processes including autophagy and can act on autophagy key proteins, while FoxOs proteins are expressed in osteoblasts. Exercise also regulates the expression of mTORC1, FoxO1, and PGC-1 through the PI3K/Akt signalling pathway, which ultimately plays a role in the differentiation and proliferation of osteoblasts and regulates bone metabolism. In addition, BMPs signaling pathway and long chain non-coding RNAs also play a role in the proliferation and differentiation of osteoblasts and autophagy process under exercise stimulation. Therefore, exercise may become a new molecular regulatory mechanism to improve osteoporosis through the bone autophagy pathway, but the specific mechanism needs to be further investigated. How exercise affects bone autophagy and thus prevents and treats bone-related diseases will become a future research hotspot in the fields of biology, sports medicine and sports science, and it is believed that future studies will further reveal its mechanism and provide new theoretical basis and ideas.

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.

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.

Objective Alveolar macrophages (AMs) are critical for maintaining the homeostasis of pulmonary microenvironment. They process surfactants to ensure alveoli patency, and also serve as the first line of immune defense against pathogen invasion. Available studies have shown that monocyte-derived AMs continuously release pro-inflammatory cytokines and chemokines, recruiting other immune cells to the damaged area during pulmonary fibrosis. These monocyte-derived AMs maintains and amplifies inflammation, playing a negative role in pulmonary fibrosis progression. Current researches have predominantly focused on the gene expression levels of AMs in pulmonary fibrosis microenvironment, with less emphasis on the function and regulation of proteins. This study aims to investigate the differentially expressed proteins (DEPs) of AMs under normal physiological conditions and after pulmonary fibrosis, in order to gain a more comprehensive understanding of the role of AMs in the progression of pulmonary fibrosis.Methods Firstly, the construction of the bleomycin-induced pulmonary fibrosis mouse models was evaluated through using measurements such as body weight, lung coefficient, lung wet-to-dry weight ratio, H&E staining and Masson staining. Subsequently, AMs from both the saline controls and the pulmonary fibrosis models (2.5×10⁵ cells per sample) were collected using FACS sorting, and protein expression profiles of these cells were obtained through label-free proteomics approach. The quality of the proteomic data was assessed by comparing our saline control proteomic data with public proteomic data of physiological AMs. Thirdly, DEPs analysis between the saline controls and the bleomycin groups was carried out using R package Prostar. Functional enrichment analyses of significantly upregulated DEPs were performed using R package Clusterprofiler for GO and KEGG pathways. Finally, the STRING database was used to explore the protein-protein interaction networks related to phagocytosis regulation, inflammatory response regulation, and I-κB/NF-κB signaling pathway. The expression levels of Tlr2 and Pycard were detected respectively by FACS and western blotting.Results Compared to the saline controls, mice in the bleomycin groups exhibited a lower average body weight, extensive infiltration of inflammatory cells, and deposition of collagen in the lungs. This indicates that bleomycin successfully induced pulmonary fibrosis in mouse models. The proteomic data of AMs obtained from these models was of high quality and fulfilled the research requirements. A comprehensive analysis showed that 778 proteins were upregulated in pulmonary fibrosis groups compared with control groups. Moreover, the signal pathways enriched in up-regulated DEPs were related to the I-κB/NF-κB pathway, inflammatory response regulation, phagocytosis regulation, TGF-β signaling, and HIF-1 pathway, indicating that AMs in pulmonary fibrosis microenvironment exerted pro-inflammatory and pro-fibrotic functions. Protein-protein interaction network analysis of the DEPs suggested that the interactions between Tlr2 and Pycard were control nodes for the pro-inflammatory phenotype of AMs, thereby contributing to pulmonary fibrosis progression. Further validation by FACS and western blotting respectively confirmed that the expression levels of Tlr2 and Pycard in AMs were significantly increased after pulmonary fibrosis.Conclusion This study investigates the changes in the protein expression profile of AMs in the pulmonary fibrosis microenvironment. The results show that AMs notably enhanced the activity of various pathways associated with inflammation and fibrosis, suggesting that the interaction between Tlr2 and Pycard serves as a key control node for the highly pro-inflammatory behavior of AMs.

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.

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.

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 LPS (lipopolysaccharide), Aβ (amyloid beta), CpG-DNA, and viruses; cytokine models utilize IFN-γ (interferon-gamma); metabolic stress models include OGD (oxygen-glucose deprivation), MPP+ (1-methyl-4-phenylpyridinium), rotenone, and oxyhemoglobin; environmental toxin models encompass substances such as BPA (bisphenol A), PM2.5 (particulate matter), various metals, and nanoparticles; additive substance models involve alcohol, morphine, and METH (methamphetamine). 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.

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. The 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-beta (Aβ) proteins, 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 To investigate the effect of 8-week aerobic exercise on the improvement of core behaviors of male and female autistic mice induced by valproic acid (VPA).Methods Experimental mice were randomly divided into the control group (CTL), VPA-induced autism group (VPA) and VPA+aerobic exercise group (VEX), with 10 mice in each group. The pregnant mice were injected with VPA intraperitoneally at E12.5, and their offspring were used as autistic mice. Pups were weaned 28 d after birth and began an 8-week aerobic exercise intervention. The day after exercise, mice were tested in behavioral experiments to detect exploratory behavior, social skills, repetitive stereotypic behavior, cognitive ability and mood. The mice were tested for social skills, repetitive stereotyped behaviors, cognitive and learning memory abilities, exploratory behaviors, and emotions by behavioral assays on the following day after the exercise.Results Both male and female mice in the CTL group showed a significant decrease in the total distance and percentage of time spent in the interaction zone in the 4th socialization compared to the 1st socialization (P<0.01); the total distance and percentage of time spent in the interaction zone in the 5th socialization was significantly increased compared to the 4th socialization (P<0.01); in VPA group, both male and female mice showed no significant change in the total distance and percentage of time spent in the interaction zone in the 4th and 5th socialization; in the VEX group, the total distance and percentage of time spent in the interaction zone by male mice in the 4th socialization was significantly decreased compared to the 1st socialization (P<0.01, P<0.05); and in the VEX group the total distance and percentage of time spent in the social interaction zone by both male and female mice in the 5th socialization was significantly increased compared to the 4th socialization (P<0.01, P<0.05). The results of the first phase of the three-box socialization experiment showed that male and female mice in the CTL group spent more time socializing with their social partners than in contact with the empty cages (P<0.01); there was no difference in the time spent by male and female mice in the VPA group in socializing with their social partners and the empty cages; and male and female mice in the VEX group spent a longer time socializing with their social partners (P<0.01). The results of the second phase of the three-box test showed that male and female mice in the CTL group showed a significant tendency to socialize with new social partners (P<0.01), whereas no significant changes were observed in the mice of VPA group; aerobic exercise significantly ameliorated this deficit in male and female mice with autism. Compared with the CTL group, VPA-induced significant decreases were observed in the total distance freely moved in the central area of the open field, the time and percentage of time spent in the open arm of cross maze, and the distance and time spent in the white box in both male and female autistic mice (P<0.01); a significant increase in the number of bead burials and time spent in self-grooming (P<0.01); a significant decrease in the cognitive index (P<0.01); a significantly longer latency to find the platform, and significantly decreased the percentage of time spent in the target quadrant and the number of times they traversed the platform (P<0.01). Compared with the VPA group, after 8 weeks of aerobic intervention, male and female mice in the VEX group showed a significant increase in total distance, open-arm dwell time, and percentage of free movement in the central area of the empty field (P<0. 05), and a trend toward a decrease in the dwell time of females in the white box was not significant, the number of beads burying and the time of self-combing were significantly lower (P<0.01, P<0.05); and a significant increase in cognitive index (P<0.05), a significantly shorter time to find the platform, and significantly increased percentage of time spent in the target quadrant and the number of times they traversed the platform (P<0.01), showing excellent learning memory.Conclusion Autistic mice severely suffer from social and cognitive impairments, repetitive stereotyped behaviors, decreased activity level, and the exhibition of anxiety. 8 weeks of aerobic exercise can improve the social and cognitive abilities, alleviate the stereotyped repetitive behaviors, increase the activity level, and positively regulate the anxiety in autistic mice. It is hypothesized that aerobic exercise has an important role in motor rehabilitation of autism, in order to provide a theoretical basis for clinical research.

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 the 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.

Pancreatic cancer (PC) is a highly fatal disease which originated from pancreatic epithelial and acinar cells, and the survival rate of pancreatic cancer patients is only about 12%. Approximately 95% of pancreatic cancer presents as ductal adenocarcinoma (PDAC). Pancreatic cancer is characterized by high aggressiveness, rapid progression and progression, and high resistance to treatment. Common somatic mutated genes in the early stage of pancreatic cancer include KRAS, CDKN2A, TP53, and SMAD4. Most pancreatic cancer patients are affected by environmental risk factors such as age, sex and diet. Malignant pancreatic cancer is associated with non-invasive, preneoplastic lesions that are thoughted to be precursors, such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystadenoma (MCN). In recent years, people have gradually improved the therapy and diagnosis of pancreatic cancer, and the contribution of imaging technology, which enhancing the usage of minimally invasive pancreatectomy that typically includes pancreaticoduodenectomy and distal pancreatectomy. However, combined administration of the chemotherapeutic gemcitabine and erlotinib is still considered a potential first-line treatment for advanced pancreatic cancer, but the development of chemoresistance often leads to poor therapeutic outcomes. Based on the current research progress for pancreatic cancer, its treatment currently remains one of the most important challenges in the medical field. Although some new treatment options have been provided, there were minor clinical success achieved and therefore new safe and effective therapies of pancreatic cancer are still an urgent need for patients. Among these new therapies for pancreatic cancer, short peptide-based treatment protocols have attracted great attention. Peptide is a compound formed by linking α-amino acids together in peptide chains. It is also an intermediate product of proteolysis. The short peptide-based therapy has many advantages such as precise targeting, easy preparation and low toxicity. Short peptides usually act as tumor suppressors by targeting and recognizing tumor-specific expressed proteins. Currently, there is an increased interest in peptides in pharmaceutical and development research, and approximate 140 peptide therapeutics are currently being evaluated in clinical trials. These peptides provide excellent prospects for targeted drug delivery because of their high selectivity, specificity and simplicity of modification. Peptides have high bioactivity and excellent biodegradability. Clinically, short peptides are increasingly used as combination drugs with chemotherapy for tumor treatment. Peptides can induce cancer cell death by numerous mechanisms and peptides have emerged as a promising drug for the treatment of pancreatic cancer. Here we mainly review the roles of peptides on Wnt/β-catenin, NF-κB, autophagy, and the use of peptides as tracer in pancreatic cancer. We also analyzed the benefits and disadvantages existing in the development process of short peptides, which provide the feasibility of targeted short peptides to become new therapeutic approaches for cancer therapy.

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.

Mitochondria, as the center of energy metabolism within the cell, play a crucial role in maintaining cell homeostasis. The regulation of its morphology and function is essential for the normal functioning of cells. In this complex regulatory network, the small ubiquitin-like modifier (SUMO) and dynamin-related protein 1 (DRP1) have become the focus of research, especially their close association with mitochondrial dynamics. SUMOylation is an important form of protein modification that regulates the function of target proteins by binding them to SUMO. This modification also plays a significant role in mitochondrial dynamics. The complex network of interactions between SUMOylation and DRP1 plays a key role in mitochondrial division, fusion and autophagy. DRP1, as a mitochondrial fission protein, regulates the morphology and function of mitochondria with the participation of the endoplasmic reticulum (ER). Recent studies have revealed the complex relationship between DRP1 and SUMOylation. DRP1 completes SUMOylation under the action of mitochondrial-anchored protein ligase (MAPL). SUMOylation mainly occurs in the variable domain of DRP1, and eight lysine residues have been identified as its targets. DRP1 serves as the target protein of SUMO1 and SUMO2/3, which play different regulatory roles in mitochondrial fission. SUMO1 modification can enrich DRP1 into mitochondria, thus promoting mitochondrial fission. However, SUMO2/3 modification can transfer DRP1 to cytoplasm and reduce mitochondrial fission. This dynamic regulatory mechanism allows the cell to flexibly adjust the state of the mitochondria according to energy requirements. Correspondingly, there is also deSUMOylation. SUMO-specific proteases (SENPs) is responsible for the deSUMOylation of proteins, with seven subtypes identified so far. Among them, SENP3/5 is a SUMO2/3 specific deSUMOylation protease. In actual cellular processes, the SUMO1 and SUMO2/3 modifications of DRP1 occur simultaneously, which can be regarded as a competitive relationship between the them. So, the SUMOylation of DRP1 in cells is often determined by SENPs. By increasing the level of SENP3/5, the SUMO2/3 modification level of DRP1 can be reduced, and the SUMO1 modification level can be indirectly increased, thus promoting the division of mitochondria. This dual regulatory mechanism enables cells to more finely control the state of mitochondria and adapt to different cellular environments and physiological needs. In addition, as an important energy supply organelle in the cell, the abnormal dynamic level of mitochondria often leads to the occurrence of a variety of diseases. In some diseases, the increase of the SUMO1 modification level of DRP1 leads to the increase of DRP1 activity, which leads to the increase of mitochondrial fission and mitophagy. For example, myocardial ischemia-reperfusion injury, ischemic stroke and retinopathy.According to current research progress, the interaction between SUMOylation and DRP1 plays a key role in the regulation of mitochondrial dynamics. The in-depth study of this regulatory mechanism not only helps to reveal the basic principle of cell regulation, but also provides an important reference for the treatment strategy of related diseases. In addition, it also could help identify new therapeutic targets and provide additional tools for disease prevention and treatment. In this review, we review the advances in the study of the interaction between SUMOylation and DRP1 on the regulation of mitochondrial dynamics, and further explore the potential of inhibiting DRP1-SUMOylation as a target for the treatment of related diseases in the future.

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 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 esophageal squamous cell carcinoma 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.

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 IDH1^R132H 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), and 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 IDH1^R132H 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 TERRA(Telomeric Repeat-containing RNA, transcribed from telomeric DNA repeat sequences)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 IDH1^R132H 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 IDH1^R132H has a decreased affinity for isocitric acid and NADP+ and an increased affinity for α-ketoglutarate(α-KG)and NADPH, so that the mutant IDH1^R132H 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 IDH1^R132H 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 IDH1^R132H 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.