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.

Mechanotransduction occurs when tissues or cells are stimulated by external mechanical forces, initiating a series of signaling processes, with mechanosensitive ion channels playing a pivotal role in this signaling cascade. Among these channels, Piezo1 has been widely studied. Piezo1 has been found in a variety of mammalian tissues and can affect multiple signaling pathways after mechanical stimulation, involving processes such as vasodilation, cell migration, and inflammatory response. To explore the potential therapeutic value of Piezo1 and improve the understanding of its function, this article reviews literature on Piezo1 and summarizes the latest research progress on Piezo1 in the cardiovascular system, locomotor system, nervous system, respiratory system, digestive system, and reproductive system.

IL-15 is a key molecule in immune regulation and is secreted by myeloid cells. IL-15 plays an important role in the homeostasis and function of T cells, natural killer (NK) cells, and memory CD8+ T cells. Due to its characteristics of wide expression and strict secretion, IL-15 holds significant therapeutic potential in various immune-related diseases. After IL-15 specifically binds to IL-15 receptor, it activates a variety of signaling pathways such as JAK/STAT, Ras/Raf/MAPK and PI3K/AKT, inducing cell proliferation, differentiation and apoptosis, thus exerting biological effects such as anti-tumor and anti-infection effects. This article reviews the role and associated mechanisms of IL-15 in diseases such as tumors, autoimmune diseases, cardiovascular diseases, and neuropsychiatric diseases, and summarizes the small molecule agonists and antagonists with IL-15 as potential therapeutic targets, aiming to provide a scientific basis for further investigation of the pathogenesis and drug research of IL-15 in immune system diseases and neuropsychiatric diseases.

Short-chain fatty acids (SCFAs) are produced by the gut microbiota through the fermentation of dietary fibers, which include acetic acid, propionic acid, and butyric acid. These SCFAs regulate various physiological functions in the body, such as immune, metabolic, and neurological functions, and are considered key factors affecting host health. SCFAs contribute to promoting lactate metabolism, increasing glycogen storage, and improving intestinal barrier function, thereby enhancing exercise performance. However, different types of SCFAs exhibit variations in their mechanisms of action and effects. This review discusses how SCFAs synthesized by the gut microbiota influence exercise performance and the underlying mechanisms, providing new insights and directions for the use of SCFAs derived from the gut microbiota to improve exercise performance.

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.

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.

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.

Over the past decade, since the initial elucidation of self-assembling brain organoid construction protocols, significant progress has been made in this field. These brain organoids exhibit cell types and structures highly similar to those of the developing human brain, making them ideal models for studying the pathogenesis and etiology of both acquired and inherited brain diseases. In addition, the development of region-specific brain organoids has provided targeted platforms for drug discovery and toxicity testing. As a research tool, brain organoids offer new perspectives for unraveling the molecular mechanisms underlying human neurological diseases. In this article, we review the techniques for constructing brain organoids, and their applications in modeling neurological diseases, to provide valuable insights and references for applied research in this field.

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.

N6-methyladenosine (m6A), which belongs to the field of the epigenetic modifications, is a common and reversible mRNA modification in eukaryotic RNA. Regulated by methyltransferases, demethyltransferases, and reader proteins, m6A modification affects the expression of relevant proteins by mediating RNA transcription, splicing, translation, and other processes, thereby regulating the physiological and biochemical processes of the organism. Major depressive disorder (MDD), characterized by a high incidence, low cure rate, and a high recurrence rate, is a psychiatric disorder with multiple etiological factors, including genetic factors, environmental factors and epigenetic factors. However, the specific mechanisms underlying MDD remain unclear. Recent studies have found a close relationship between m6A modification and the pathogenesis of MDD, making it a hot topic in MDD research. This article reviews the m6A methylation, as well as the expression and roles of related enzymes in the central nervous system of MDD patients, aiming to provide new insights and potential drug targets for the research and treatment of MDD.

Exosomes are a subtype of extracellular vesicles derived from endosomes and released by membrane fusion and exocytosis. Exosome-mediated intercellular communication plays a critical role in multiple physiological and pathological processes. Due to their low immunogenicity and ability to mediate long-distance transport of bioactive substances, exosomes are considered ideal biological carriers for drugs. Engineered exosomes can improve the targeting of drug delivery, making research on exosome-based drug delivery exceedingly promising. However, some studies have indicated that exosomes can facilitate pathological processes in diseased organisms. For instance, exosomes secreted by tumor cells can "mislead" immune cells or establish a favorable microenvironment, thus promoting tumor proliferation and migration. In neurodegenerative diseases, exosomes exacerbate the disease by promoting inflammatory responses and the spread of pathogenic proteins. This article reviews the development and pathological propagation of neurodegenerative diseases mediated by exosomes carrying toxic pathogenic proteins , offering new insights into the occurrence and development of neurodegenerative diseases, as well as cautions and recommendations for exosome engineering and clinical applications.

2024年10月7日,瑞典卡罗琳医学院宣布,授予美国科学家Victor Ambros 和Gary Ruvkun 2024年诺贝尔生理学或医学奖,以表彰他们在基因表达调控研究中的杰出贡献:发现微小RNA(microRNA, miRNA)及其在转录后基因调控中的作用(http://www.nobelprizemedicine.org)。Victor Ambros在1953年出生于美国新罕布 什尔州汉诺威。他于1979年在马萨诸塞州剑桥的麻省理工学院(MIT)获得博士学位,并于1979年至1985年在那里从事博士后研究。1985年,他成为哈佛大学的主要研究员。1992年至2007年期间,他担任达特茅斯医学院的教授。如今,他是马萨诸塞大学医学院伍斯特分校的自然科学教授。Gary Ruvkun在1952年出生于美国加利福尼亚州伯克利。他于1982年在哈佛大学获得博士学位,并于1982年至1985年在MIT 从事博士后研究。1985年,他成为马萨诸塞总医院和哈佛医学院的主要研究员,现任遗传学教授。Victor Ambros和Gary Ruvkun发现的miRNA调控机制描述了一种全新的基因表达调控机制,这一机制促进了越来越复杂的生物体的进化和多样性。（全文请点击PDF链接知网下载阅读）

肥胖(obesity)是指由于食物摄入过多导致的机体脂肪蓄积过度或分布异常;其常伴有运动缺乏及相关精神症状等。肥胖具有高发病率及全球流行趋势。目前,常用体重指数(body mass index, BMI)作为判断肥胖的标准;在我国,成人BMI≥24为超重,BMI≥28为肥胖。促进脂肪水解利用,是治疗肥胖的重要策略。因此,脂肪水解(lipolysis)机制研究成为世界医学界研究热点。脂肪水解的典型途径是由支配脂肪组织的交感神经释放去甲肾上腺素(norepinephrine, NE),激活脂 肪细胞表面β-肾上腺素能受体,由此活化环腺苷酸(cAMP)-蛋白激酶A(PKA)-激素敏感性脂肪酶(HSL)和脂滴蛋白1(PLIN1)信号轴以启动脂肪水解。然而,美国哈佛医学院的Erwei Li团队的发现,对上述经典机制进行了补充。2023年12月13日,该团队在Nature杂志发表论文揭示:催产素(oxytocin, OXT)/催产素受体-细胞外信号调节激酶(extracellular signal-regulated kinase, ERK)信号,对NE能交感神经启动脂肪水解过程发挥重要调节作用。催产素是由9个氨基酸组成的肽类激素,由下丘脑室旁核和视上核合成,经垂体后叶分泌,对分娩哺乳等生理过程发挥重要调节作用。研究人员发现,催产素受体(oxytocin receptor, OXTR)在小鼠白色脂肪组织高表达,且在内脏白色脂肪组织表达水平最高。体外研究发现,用催产素处理人类或小鼠脂肪细胞,均可引起脂肪细胞甘油释放。值得注意的是,将OXTR-flox小鼠和AdipoqCRE小鼠杂交,以特异性敲除小鼠白色脂肪细胞催产素受体,可导致该小鼠在禁食、冷暴露情况下,血清游离脂肪酸和甘油水平显著低于野生型小鼠,证实催产素对脂肪水解过程有上调作用。催产素对NE启动的β-肾上腺素受体活化有显著协同作用。该研究显示,催产素可增加NE敏感性,从 而提升异丙肾上腺素驱动的脂肪水解水平;而催产素受体拮抗剂阿托西班(Atosiban)或特异性敲除小鼠白色脂肪细胞催产素受体,均可有效抵消上述现象。这些发现表明,催产素是脂肪水解的内源性调节因子,催产素-催产素受体信号传导NE启动的白色脂肪细胞中的脂肪水解。禁食及冷暴露条件下,催产素在脂肪组织的表达水平显著高于血清水平,提示脂肪组织的催产素可能并非源于下丘脑。研究人员将OXT-Cre小鼠与Ai9小鼠杂交杂交,以用红色荧光蛋白tdTomato标记产生催产素的细胞;又将OXT-Cre小鼠与表达绿色荧光GFP或红色荧光mCherry的Nuclear Tagging and Translating Ribosome Affinity Purification(NuTRAP)小鼠杂交以标记产生催产素的细胞;并使用脂肪组织特异三维成像技术(Adipo-Clear Three-Dimensional Imaging)来可视化荧光蛋白;同时,用交感神经标记物酪氨 酸羟化酶(tyrosine hydroxylase, TH)抗体标记交感神经神经元。研究者发现,在支配附睾白色脂肪组织(eWAT)和腹股沟白色脂肪组织(iWAT)的交感神经节神经元,催产素与TH 共定位。进一步地,将表达Cre诱导型mCherry的逆向腺相关病毒(AAV)注射到OXT-Cre小鼠eWAT 和iWAT,亦证实上述催产素与TH 共定位。支配白色脂肪组织的交感神经元可释放催产素。研究人员采用化学遗传技术(DREADD),将AAV8-hSyn-DIO-hM3Dq-mCherry注射到Vglut3-IRES-Cre小鼠脑中缝苍白球核团,从而在该核团的谷氨酸能神经元表达hM3Dq,以用皮下植入微型泵递送氯氮平N-氧化物(CNO)特异激活这些神经元;该激活显著导致小鼠血清血脂水平升高,表明激活中缝苍白球可经交感神经启动脂肪水解。进一步,研究人员将OXT-Cre小鼠与Ai32小鼠杂交,使Ai32小鼠以Cre依赖的方式表达视紫红质,并用蓝光照射离体白色脂肪组织,导致培养基甘油水平显著增加。以上结果证实了脑中缝苍白球谷氨酸能神经元对脂肪水解的调控作用、以及脂肪组织内部交感神经末梢可释放催产素激活脂肪细胞启动脂肪水解。综上所述,该研究发现:支配白色脂肪组织的交感神经元表达分泌催产素,该催产素具有促进脂肪水解、 或提升去甲肾上腺素敏感性从而间接促进脂肪水解脂解的功能。该研究完善了脂肪分解的调节机制,为肥胖等相关疾病治疗提供了新思路。

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that primarily affects the lungs and causes coronavirus disease 2019 (COVID-19). Recent clinical cases have reported the cardiovascular complications of COVID-19, including myocarditis, arrhythmia, myocardial infarction, and so on. Among them, COVID-19-related myocarditis exhibits diverse symptoms, which can occur at different ages and has a delayed onset. Moreover, COVID-19-related myocarditis is positively correlated with the poor prognosis and mortality of COVID-19 patients. The exploration of its clinical characteristics, potential pathogenesis and treatment may provide new ideas and strategies for the prevention and drug development of COVID-19-related myocarditis in the future. This article provides an overview of both domestic and foreign researches on COVID-19-related myocarditis.

Autophagy is a dynamic protective mechanism that degrades macromolecules and organelles within cells to maintain organismal balance. Most eukaryotic cells rely on autophagy to regulate intracellular homeostasis. Under certain stress conditions, such as ischemia and hypoxia, autophagy exerts protective effects to counteract cellular damage. However, selective overactivation of autophagy can lead to a unique form of programmed cell death, distinct from apoptosis and necrosis, termed autosis. This review summarizes the distinctions between autosis and other cell death modalities, the morphological characteristics of autosis, the conditions that induce autosis, and current research progress on autosis, aiming to provide a theoretical basis for further research on autosis and to offer a scientific reference for subsequent studies and future clinical disease treatment.

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.

Protein lactylation is a recently discovered post-translational modification, and its neuroprotective effect in cerebral ischemia-reperfusion injury has garnered increasing attention. Cerebral ischemia-reperfusion injury is a complex pathological process that occurs following reperfusion therapy after ischemic stroke, involving oxidative stress and inflammatory responses. This article reviews the neuroprotective mechanisms of protein lactylation in cerebral ischemia-reperfusion injury and highlights recent research progress. Lactate molecules can covalently bind to lysine residues and affect the function and activity of proteins, thus playing significant roles in cell metabolism, gene expression regulation, and cell signaling. Research has indicated that protein lactylation exerts neuroprotective effects by regulating inflammatory and oxidative stress responses, helping to reduce neuronal damage and apoptosis. In-depth studies of the biological functions of protein lactylation and its mechanism of action in cerebral ischemia-reperfusion injury not only aid in elucidating the pathophysiological mechanisms underlying cerebral ischemia-reperfusion injury, but also provide potential targets and theoretical basis for the development of new therapeutic drugs for cerebral ischemia-reperfusion injury.

Atherosclerosis (AS) is a chronic inflammatory vascular disease and the main pathological basis for numerous cardiovascular and cerebrovascular diseases. The pathogenesis of AS is complex and not yet fully elucidated. Vascular smooth muscle cells (VSMCs) are one of the main cell types that constitute the vascular wall. They are involved in regulating the systolic and diastolic functions of the vascular wall and maintaining the vascular tone. However, under the stimulation of AS promoting factors, the phenotypic switch occurs in systolic VSMCs, exhibiting characteristics such as proliferation, migration, adhesion, and calcification, which may directly lead to the formation or rupture of AS plaques. Integrins play a critical role in coordinating the transmembrane connections between the extracellular matrix and cytoskeleton, contributing to pathological processes of various diseases. They also play key roles in regulating the transdifferentiation of VSMCs into mesenchymal stem cells, myofibroblasts, macrophages, osteoblasts, and other cell types. To conclude, integrins can indirectly affect the formation and progression of AS by regulating the phenotypic transformation of VSMC, thereby presenting the potential as a new therapeutic target for AS. In this article, we review the classification of VSMC phenotypic transformation and the regulatory role of integrins in VSMC phenotypic transformation, aiming to provide new targets and strategies for the early treatment and intervention of AS.

Hypoxic cell damage is implicated in the etiology of various diseases, posing a significant threat to human health. Therefore, a comprehensive exploration of the underlying mechanisms of hypoxic cell damage is of crucial importance. Recent research has elucidated a compelling correlation between hypoxic cell damage and key cellular processes, including apoptosis, autophagy, pyroptosis, ferroptosis, cuproptosis, and parthanatos. The aim of this article is to integrate current knowledge on the mechanisms underlying hypoxic cell injury. It seeks to clarify the critical determinants and regulatory pathways involved in these processes, and to offer innovative perspectives on preventive and therapeutic approaches for hypoxia-induced diseases.

Suplatast Tosilate is a specific Th2 cell inhibitor that has been widely used in the treatment of various allergic and inflammatory diseases such as asthma and atopic dermatitis, with good efficacy and high safety. Research has shown that Suplatast Tosilate can inhibit the production and function of Th2 cells and Th2-type cytokines such as IL-4 by regulating GATA3 and chloride channels, thereby exerting a therapeutic effect on allergic diseases. Additionally, Suplatast Tosilate also has regulatory effects on dendritic cells, monocytes, eosinophils, and neurons. Therefore, Suplatast Tosilate has become a focus of attention in the research field of treating Th2 cell-mediated allergic inflammatory diseases.