Tumor immunotherapy has achieved impressive therapeutic effects in clinical practice and has attracted increasing attention. Among them, chimeric antigen receptor T (CAR-T) cell therapy has made breakthrough progress in the treatment of hematological malignancies. However, with prolonged exposure to tumor antigens, CAR-T cells may become exhausted in vivo. The exhaustion of CAR-T cells can lead to poor treatment efficacy or tumor recurrence. The mechanism of CAR-T cell exhaustion involves a series of processes, such as the expression of exhaustion-associated transcription factors, the role of the immunosuppressive tumor microenvironment, and the influence of CAR structure itself. Here, we summarize the process and underlying mechanisms of CAR-T cell exhaustion, as well as potential solutions to improve T cell exhaustion and enhance the efficacy of CAR-T cell therapy, with the aim of expanding the application of CAR-T cell therapy in tumor treatment.

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by classic clinical features including motor symptoms such as tremor, muscle rigidity, bradykinesia, and abnormal posture and gait, as well as a variety of non-motor symptoms. Mitochondrial dysfunction plays a crucial role in the pathogenesis of PD, propelling genes associated with mitochondrial function to the forefront of current research endeavors. Some gene mutations are closely related to the pathogenesis of PD. Mitochondrial-related PD pathogenic genes include genes involved in mitochondrial dynamics, mitochondrial DNA homeostasis, mitochondrial protein translation, the mitochondrial respiratory chain, and mitochondrial metabolism, participating in the regulation of mitochondrial function and mitochondrial quality control, ultimately leading to structural and functional abnormalities in mitochondria. This article provides an overview of the mitochondrial-related PD pathogenic genes that are directly or indirectly associated with the onset and development of PD. Through in-depth studies of the functions and mechanisms of these genes, it is hoped that better therapeutic methods and prevention strategies for PD can be identified.

Ferroptosis is a form of programmed cell death associated with abnormal iron metabolism and excessive accumulation of lipid peroxides, characterized by unique biological processes and pathophysiological features. Lipid peroxidation represents the most fundamental mechanism underlying ferroptosis. Increasing evidence indicates that ferroptosis plays significant regulatory roles in the onset, development, and treatment of tumors.Induction of ferroptosis in tumor cells can effectively inhibit tumor growth and metastasis, and improve the therapeutic sensitivity of anti-tumor drugs. This article reviews the mechanisms by which lipid metabolic processes, such as the synthesis and remodeling of phospholipids,the storage and release of phospholipids,as well as the uptake and oxidation of fatty acids,regulate ferroptosis.It summarizes the effects of lipid metabolism-associated signaling pathways on ferroptosis and targeted therapeutic strategies, aiming to provide new insights for ferroptosis-associated basic research and clinical tumor therapy.

The intestinal mucosal barrier is the first barrier between the intestine and the external environment, preventing harmful substances and pathogens from entering the internal environment and maintaining intestinal homeostasis. Bile acids, synthesized from cholesterol in the liver and subsequently converted into secondary bile acids by gut microbiota, interact with bile acid receptors and the gut microbiome, playing a key role in maintaining the homeostasis of the intestinal mucosal barrier. This review will elaborate on the role of bile acids and bile acid metabolism in the structure of the intestinal mucosal barrier, as well as the relationship between bile acids and intestinal diseases, aiming to provide insights for future strategies in the prevention and treatment of intestinal barrier dysfunction and associated intestinal diseases.

Diabetic kidney disease(DKD)is a severe microvascular complication of diabetes mellitus, representing the most common form of chronic kidney disease and a major cause of end-stage renal disease. Currently, available treatment options have notable limitations, including poor bioavailability, hepatorenal toxicity of oral medica-tions, and a lack of precise targeting. In recent years, nano-drug delivery systems (NDDS) have demonstrated significant potential in the treatment of kidney diseases. Nanocarriers are capable of targeting drugs to specific areas, addressing the issue of inadequate drug delivery to particular sites, and enhancing therapeutic efficacy. This article reviews the pathogenesis of DKD and the limitations of current treatment methods, while focusing on the application of NDDS in treating DKD. Finally, it presents the challenges and new visions for the future development of nanoplatforms, providing insights for achieving efficient targeted therapy for the kidney diseases.

神经精神疾病的病因复杂,涉及基因和环境因素的相互作用。表观遗传学(epigenetics)调控并不改变DNA 序列,而是通过DNA 甲基化、组蛋白修饰、非编码RNA、RNA 修饰等多种机制来调节基因表达和活性。近年来,表观遗传学调控被认为是介导环境-基因相互作用的重要机制,逐渐引起了人们的广泛关注。表观遗传学机制在神经系统的发育、功能维持及疾病进展中发挥关键作用。大量研究探讨了表观遗传修饰在神经系统中的重要作用。例如,DNA 甲基化作为调节神经元内基因表达的重要机制,在精神分裂症、自闭症谱系障碍等精神疾病中呈现出显著异常。此外,组蛋白修饰,尤其是组蛋白乙酰化,作为调节神经元可塑性与记忆形成的关键过程,其异常与多种神经退行性疾病的发生密切相关。全文请点击PDF链接知网阅读。

RNAs are subject to a variety of chemical modifications that confer structural diversity to the nucleotides and are involved in the regulation of RNA metabolism, protein synthesis and a variety of cellular functions.N4-acetylcytidine (ac4C) is the only known form of RNA acetylation in eukaryotes.Ac4C has long been identified in ribosomal RNA (rRNA) and transfer RNA (tRNA). Recent studies have shown that ac4C also occurs in messenger RNA (mRNA), promoting mRNA stability and translation efficiency. Compared with the widely studied mRNA methylation modifications (e.g.m6A), the functions and regulatory mechanisms of ac4C modifications of mR-NA are far less well-known. This review aims to summarize the function of ac4C modifications of mRNA in physiological and pathological processes in the nervous system, such as learning and memory, pain, and Alzheimer’s disease. Moreover, this review will discuss the critical questions that should be addressed in the ac4C field to promote the research of RNA modification in the nervous system.

Neuropsychiatric disorders impact the lives of tens of millions of people globally and have become an increasingly severe social problem. Genetics is one of the critical factors contributing to the etiology of neuropsychiatric disorders. However, disease-associated risk loci, identified by genome-wide association studies (GWAS), are primarily located in non-coding regions of the human genome, presenting one of the most significant challenges in identifying disease-associated risk genes and elucidating the pathogenesis. Three-dimensional (3D) genomics focuses on spatial chromatin architecture and long-distance chromatin interactions. The development and application of 3D genomic technologies contribute to the identification of disease-associated risk genes, providing direct evidence of the chromatin interactions between disease-associated risk loci and their target genes. Meanwhile, cell-type-specific interactions bring new insights into the comprehension of pathogenesis. Lastly, the reorganization of spatial chromatin architectures regulates the transcription of multiple genes collectively, which may explain the complexity and heterogeneity of neuropsychiatric disorders. Based on a brief introduction to the basic concepts and applications of 3D genomics, this review primarily discusses the research progress of 3D genomics in the field of neuropsychiatric disorders, including schizophrenia (SCZ), Alzheimer's disease (AD), autism spectrum disorder (ASD), and others, aiming to offer new perspectives on associated diseases pathogenesis.

To date, over 170 types of RNA modifications have been identified. As reversible and dynamic processes, RNA modifications participate in post-transcriptional regulation of mRNA, as well as chromatin and transcriptional regulation. N6-methyladenosine (m6A) modification, the most prevalent one, is currently the most extensively studied and understood type of RNA modification, with an increasing body of research revealing its relevance to the occurrence, development, and treatment of various diseases. The roles of other RNA modifications are also being progressively elucidated. Previous studies and discussions on RNA modifications in diseases have mainly focused on cancer; however, recent studies have confirmed the participation of RNA modifications in the regulation of neurological and psychiatric disorders. This review aims to summarize the roles and mechanisms of RNA modifications in neurological and psychiatric disorders, providing new insights for drug development and clinical treatment.

Epigenetic regulation plays critical roles in the development and homeostasis of the nervous system. Protein arginine methylation is a post-translational modification commonly found in nearly all eukaryotic cells, which regulates a variety of physiological events, such as gene transcription regulation or RNA splicing, via mediating the methylation of histone or nonhistone targets. This review aims to recapitulate the regulatory mechanism underlying protein arginine methyltransferase 5 (PRMT5) function, and summarize the crucial roles of PRMT5 in neural development and neurological diseases, highlighting its epigenetic regulatory mechanism in the nervous system.

Atherosclerosis is the pathophysiological basis of a variety of cardiovascular diseases, with monocytes/macrophages being a key cell type that participates in the initiation of vascular inflammation, the formation, progression and rupture of atherosclerotic plaques. In recent years, with the rapid development of single-cell sequencing technology, the high heterogeneity and plasticity of mononuclear macrophages in plaques have been gradually elucidated. This article reviews the latest monocyte/macrophage subtypes identified in patients and mouse models of atherosclerosis through single-cell sequencing technology, summarizes their markers, functional heterogeneity, and underlying mechanisms, with the aim of providing more precise directions for the diagnosis and treatment of atherosclerosis.

In recent years, significant progress has been made in the field of chimeric antigen receptor T (CAR-T) cell immunotherapy for the treatment of hematologic malignancies, while its application in solid tumors has proven to be less than optimal. This article provides an introduction to the structure and function of CAR-T cells, encompassing key mechanisms underlying tumor cytotoxicity such as the formation of non-classical immune synapses, cytokine secretion, perforin and granzyme release, the Fas (factor-associated suicide)-FasL (Fas ligand) pathway, and alterations in the components constituting the CAR structure. The features of three CAR cell types are compared, and in light of the challenges associated with CAR-T cell therapy for solid tumors, the article analyzes future research directions for CAR-T cells in the field of cancer immunotherapy.

Macrophages are important components of the immune system and play a core role in immune regulation and tissue repair. Macrophages are plastic cells that can polarize into many subtypes with different functions under different stimuli. Macrophages in different polarization states play crucial roles in disease development and prognosis. In-depth studies of macrophage polarization contribute to exploring new strategies for disease prevention and treatment. In this article, we summarize the different polarization phenotypes and main functions of macrophages under different microenvironmental signal stimuli, focusing on the role of macrophage polarization in the tumor, atherosclerosis, and type 2 diabetes, as well as the therapeutic strategies targeting macrophage polarization.

Lactic acid is a decomposed product of anaerobic oxidation of glucose. Recent studies have shown that lactic acid is an important energy substance, signaling molecule, and immunomodulatory molecule, playing a significant role in cellular physiological and pathological processes. In vivo, both histone and non-histone proteins can undergo lactylation modification, thereby participating in the regulation of gene transcription, induction of macrophage polarization, and other processes. The discovery of protein lactylation modification has provided new directions for research on tumors and inflammation. Given the increasing attention paid to lactylation in the study of disease pathogenesis, this article summarizes the research progress of histone and nonhistone lactylation modification, and expound the key roles of lactylation modification in inflammation, cancer, cardiovascular and cerebrovascular diseases, as well as neurodegenerative diseases.

Chronic pain and depression are two common diseases that endanger human health. They often co-occur and mutually influence each other, greatly increasing the difficulty of treatment. The occurrence of chronic pain and depression involves common or interacting neural circuits and neurotransmitter systems. Neuroinflammation also plays an important role in the pathogenesis of chronic pain and depression. Dysfunction in related neural circuitry and neuroinflammation are important mechanisms underlying the comorbidity between chronic pain and depression. Chronic stress is a critical cause of inducing depression and chronic pain. Previous studies have shown that dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is the pathological basis for chronic stress-induced depression and comorbid pain. Chronic stress may promote neuroinflammatory response and dysfunction of neural circuits through HPA axis dysfunction, leading to the comorbidity of chronic pain and depression. This review discusses the pathogenesis of chronic stress-induced pain comorbid with depression, and elaborates on the pathogenesis of chronic stress-induced comorbidity of chronic pain and depression from the aspects of the HPA axis function, neuroinflammation, brain structure and neural circuits involved.

Ischemic stroke is a leading cause of death and disability worldwide, with a complex pathogenesis and limited therapeutic options. In recent years, nano-drug delivery systems (NDDS) have shown great potential in the treatment of brain diseases. Nanocarriers can transport drugs across the blood-brain barrier and target diseased cells through the modification of targeting ligands. This article reviews the pathogenesis of ischemic stroke and the limitations of current therapeutic approaches, focusing on the progress of nano-drug delivery systems in the treatment of ischemic stroke. The challenges and future directions in this field are proposed, aiming to advance the development of nanomedicine delivery systems for the treatment of ischemic stroke.

本期我刊特邀请了王迪浔教授撰写了刊头专文。王迪浔教授是我国著名的病理生理学专家,1930年出生于南昌,华中科技大学同济医学院病理生理学教授,从事病理生理学教学与科研半个多世纪。主编《人体病理生理学》,曾任中国病理生理学会常务理事,湖北省墍武汉市病理生理学会理事长,卫生部呼吸系疾病重点实验室首任主任。一生致力于缺氧性肺动脉高压机制的探讨研究和中国病理生理学科的建设。如今已93岁高龄仍坚持执笔撰文,文中他还提出的一些独到的想法,字字珠玑启人深思。高山仰止,他对科研的执着热爱以及谦逊的精神值得后辈们学习和景仰。全文请在知网或万方数据下载阅读。

The intricate interactions among the nervous system, endocrine system, and immune system constitute a sophisticated network. Neuroimmunology is an emerging interdisciplinary field that delves into the structure and function of the neuro-endocrine-immune regulatory network at the molecular, cellular, tissue, organ, and whole-body levels. Neuroimmune interactions persist throughout the entire lifespan, the dysregulation of which can lead to the onset and development of multiple diseases. In recent years, significant breakthroughs have been made in China in the frontier of the neuro-endocrine-immune-metabolism interdisciplinary field, with a primary focus on the regulation of the central nervous system. On one hand, novel mechanisms concerning the neural control of peripheral system functions have been revealed. The "brainspleen" axis was identified for the first time, shedding light on how emotions modulate immunity via the central nervous system. Additionally, mechanisms through which neurotrophic factors secreted by neurons regulate the immune function of the spleen have been elucidated. Moreover, neurological mechanisms underlying the anti-inflammatory effects of acupuncture therapy in traditional Chinese medicine have been clarified, detailing how stimulation of the Zusanli acupoint regulates immune function through specific neural populations. On the other hand, breakthroughs have been achieved concerning how peripheral organs regulate neural function, including investigations into the role of the "gut-brain" axis in processes such as animal vomiting and lightcontrolled blood glucose metabolism. These accomplishments have strengthened China's research foundation, propelling further exploration in the neuro-endocrine-immune-metabolism interdisciplinary field. This article spotlights recent advances in basic research of neuroimmunology conducted by domestic scientists, summarizing significant achievements and key scientific issues in five aspects: "basic units of neuro-immune interactions", "systemic physiological neuro-endocrine- immune regulation", "neuro-immune interactions and diseases", "physiological and pathological functions of glymphatic system", and "technical approaches and methodologies in neuroimmune interaction research".

 

Bone remodeling is an important process for maintaining bone homeostasis, and it is commonly believed that bone remodeling is mainly regulated by endocrine hormones. In recent years, there has been increasing evidence suggesting that the central nervous system is directly involved in regulating bone homeostasis through efferent nerves. Although it has been demonstrated that there are clear neural connections between the brain and skeletal tissues, the role of these neural connections in the brain's regulation of bone homeostasis is not well understood. In this paper, we will present recent advances in the field of brain regulation of bone metabolism, focusing on the neural connections between bone and brain, the regulation of bone homeostasis by the central nervous system and neural circuit, the regulation of bone homeostasis by the autonomic nervous system and sensory nervous system, respectively.

Stress can be found almost anywhere. Perceiving stress and regulating bodily functions to respond to danger constitute crucial mechanisms on which individuals rely for their survival. However, excessive or chronic stress can lead to the development of anxiety, posing a threat to individuals’ health. In recent years, many studies have indicated that stress and anxiety can promote the initiation and progression of cancer. These effects are primarily operated through the activation of the sympathetic nervous system, resulting in the release of relevant hormones or peripheral neurotransmitters. This process triggers the promotion of cell proliferation, survival, and angiogenesis by activating the relevant receptors on both tumor cells and the microenvironment. Consequently, it accelerates cancer progression. Simultaneously, it compromises the body 's immune response, enabling tumor cells to evade immune surveillance. Nonetheless, the precise mechanisms underlying how the neural circuits associated with stress perception and anxiety response are interconnected with tumors and influence the occurrence and development of tumors through the sympathetic nervous system remain unclear. This article surveys a comprehensive overview and summary of the connections between anxiety-related neural systems and the sympathetic nervous system, as well as the pathways through which the sympathetic nervous system affects tumors, laying the theoretical foundation for future cancer treatments.

The visceromotor reflex is an important component of autonomic nervous system regulation, controlling the autonomous movements of many visceral organs, including the gastrointestinal tract, bladder, and cardiovascular system. The reflex movements of these organs are controlled by both the sympathetic and parasympathetic nervous systems to maintain their normal functions. In different states, the sympathetic/parasympathetic nervous systems are regulated accordingly to adapt to different physiological and environmental demands. When there are problems with the regulation of the autonomic reflex loop that governs the viscera, it may lead to various related diseases, seriously affecting physical and mental health. Therefore, a comprehensive understanding of the structure, function, and regulation of the visceromotor reflexes is of great significance for scientific research and clinical treatment.

Adipose tissue is an important metabolic and endocrine organ, distributed in the subcutaneous tissue and around internal organs. Based on its morphological and functional characteristics, adipose tissue can be divided into white, brown and beige adipose tissue, which plays a key role in regulating glucose and lipid metabolism, as well as insulin sensitivity, and affects energy homeostasis. Sympathetic and sensory nerve fibers are distributed in adipose tissue. By releasing norepinephrine (NE), sympathetic nerves can promote lipolysis in white adipocytes and thermogenesis in brown adipocytes. The sympathetic regulation of adipose tissue is modulated by different stromal cells and immune cells within adipose tissue. Simultaneously, sensory nerves transmit signals from adipose tissue to the central nervous system. Disorders of neural innervation in adipose tissue usually lead to a series of health problems, such as obesity, diabetes, cardiovascular diseases, and cerebrovascular diseases.

Gut is an important organ for communication between the organism and the external environment. It collects nutrients and removes waste, contributing significantly to maintaining the body's homeostasis and physiological functions. The gut contains various cell types and neural signaling molecules. Previous studies have indicated that specific receptors on the intestinal cells are activated by food, allowing for the perception of taste and nutritional components and conveying this information directly or indirectly to the brain. Intestinal perception is ubiquitous in many organisms in nature and conserved among species. Therefore, investigations into intestinal perception have critical implications for understanding the evolution of species and the adaptive mechanisms of organisms in nature. This review aims to provide a brief overview of current research on the molecular and circuit mechanisms underlying the perception of various substances in the gastrointestinal tract, which provides a theoretical basis for future investigations into the roles of the gut-brain axis in the adaptive evolution of individual organisms and the evolution of facilitation in organism-environment symbiosis.

Programmed death protein-1 (PD-1) and its ligand, PD-L1, are critical immune checkpoints in tumors whose interaction negatively regulates the activation and proliferation of effector T cells, playing a crucial role in tumor cells evading immune surveillance. Blocking the binding of PD-1 to PD-L1 can relieve the inhibition of T cells by tumor cells or antigen-presenting cells, restoring their recognition and cytotoxicity against tumor cells. However, the expression of PD-L1 is intricately regulated and varies among different types of tumors, primarily occurring at genetic, transcriptional, and post-transcriptional levels. In this article, we review the regulatory processes involved in PD-L1 expression and its roles in tumor immunotherapy, which are of great significance in oncotherapy, as the focus of future research lies in achieving precise immunotherapy targeting tumors with distinct characteristics, guided by the regulatory mechanisms.

Exosomes (EXs) are important vesicles for intercellular signaling and play an important role in organismal homeostasis. Exosomal microRNAs (miRNAs) are one of the key components of EXs to protect against myocardial infarction (MI), which is one of the major killers threatening human health, characterized by high morbidity, high disability and high mortality. Ischemia/reperfusion is the main treatment for MI. The myocardial ischemic condition caused by MI changes the components of exosomes, in the meanwhile, exercise stimulates the secretion of exosomes, exerts their biological and cardioprotective effects, inhibits the pathological progression of MI. In this review, by summarizing the role of exosomal miRNAs in MI, we propose the possible mechanism by which exercise improves cardiac function in MI, aiming to provide new ideas and targets for experimental research and clinical treatment involving exercise intervention in control of coronary heart disease.

Depression is a common and serious psychiatric disorder, the pathogenesis of which remains incompletely elucidated. Currently, there are several hypotheses about the pathogenesis of depression, and the latest evidence suggests that neuroinflammation is closely associated with the onset and development of depression. With the advancement of neuroscientific technology, the role of astrocytes in depression has been receiving increasing attention. Studies have shown that depression is associated with astrocyte-mediated neuroinflammation, in which microglia, the NF-κB signaling pathway, and NLRP inflammasomes are involved, providing potential targets for the treatment of depression. In this article, we review the research progress on astrocyte-mediated neuroinflammation associated with depression.

Hypothyroidism is a common condition resulting from a deficiency in the thyroid hormone. While it can typically be effectively corrected with hormone replacement therapy, it may become fatal if left untreated. The thyroid hormone plays a crucial role in human growth, development, and functions of multiple organs. Clinical manifestations of hypothyroidism vary according to factors such as age and sex. Experimental animal models of hypothyroidism are widely used in preclinical studies of the pathophysiological mechanisms of hypothyroidism, as well as in the evaluation of treatment and prevention effects. Currently, effective models of hypothyroidism include surgical, dietary, pharmacological, genetic, radiological, and immunological methods. Each model has its own advantages and disadvantages based on different principles and can be selected according to the experimental purpose. In this article, we review recent studies on the animal models of hypothyroidism, discussing the modeling methods, as well as the advantages and disadvantages of each model, with the aim of selecting the optimal model for experiments.

 

Osteoarthritis is a chronic degenerative joint disease that occurs mostly in the elderly and is one of the most common bone metabolic diseases, in which cells involved in the metabolic abnormalities mainly include chondrocytes. As an important cause of the abnormal metabolism of chondrocytes, mitochondrial dysfunction is closely associated with the occurrence and development of osteoarthritis. Mitophagy, the selective mitochondrial autophagy for damaged or dysfunctional mitochondria, plays an important role in the maintenance of mitochondrial quality control and mitochondria homeostasis. Accumulating evidence suggests that mitophagy plays a vital regulatory role in osteoarthritis, indicating that regulating the level of mitophagy may be a new strategy for its prevention and treatment. Therefore, we review the potential mechanism underlying the involvement of mitophagy in osteoarthritis, aiming to provide a theoretical basis for research related to mitophagy as a target for osteoarthritis treatment.