Titin (TTN), the largest protein by molecular weight in humans, extends beyond its roles in providing structural stability to the sarcomere and storing elastic potential energy. It also plays a crucial regulatory role in muscle hypertrophy and protein quality control. The protein complex encompassing the Z-disk, I-band, and M-line regions of TTN acts as a mechanosensor, dynamically modulating the transduction of myocellular hypertrophic signaling in response to mechanical tension. TTN induces skeletal muscle remodeling after exercise, mediating the repair and degradation of damaged TTN through protein protection and quality control mechanisms. Under appropriate mechanical stimulation, the TTN mechanosensory complex is activated, thereby triggering a series of hypertrophic responses. Conversely, following overload exercise, severely damaged TTN promotes its degradation through interactions of T-cap with MDM2, the proximal Ig region with calpain 1, and the N2A and M-line regions with calpain 3, as well as engagement of the MuRF1 binding site within the M-line domain. In this article, we delve into the role of the cytoskeletal protein TTN as a central signaling hub for skeletal muscle remodeling. Initially, the basic structure of TTN is elucidated, followed by an in-depth analysis of the mechanisms by which different regions contribute to muscle hypertrophy and protein quality control.

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）

The aorta is one of the most important arteries in the human body. Although its basic vascular functions have been extensively studied, its multiple physiological roles as an independent organ have often been overlooked. Recent studies have shown that the aorta not only plays a central role in blood pressure maintenance, but also participates in key physiological processes such as metabolism, endocrinology, nervous system regulation, and immune stress. The unique structure and function of the aorta endow it with significant roles in a variety of physiological and pathological states. This article reviews the importance of the aorta as an independent organ and discusses its structural and functional uniqueness. Emphasis is placed on the metabolic and endocrine regulatory functions of aortic endothelial cells and smooth muscle cells, as well as the role of the aorta in neuroregulation and immune stress. The discussion of these research advances provides new perspectives for an in-depth understanding of the physiological and pathological functions of the aorta and offers potential research directions for future studies.

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.

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.

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.

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.

Exosomes play an important role in intercellular communication by transferring substances such as proteins, lipids and nucleic acids between cells. The types and quantities of substances carried by exosomes vary depending on their cellular origin, resulting in heterogeneity in both the characteristics and functions of exosomes derived from different cell types. This heterogeneity underpins the basis of exosome function. Focusing on the heterogeneity of exosomes in terms of cellular origin and content, this article systematically elucidates the biological characteristics and functions of exosomes, providing a basis for future exosome screening and applications.

Sphingosine-1-phosphate (S1P), a metabolite of cell membrane sphingolipids, exerts its physiological functions by binding to G protein-coupled sphingosine-1-phosphate receptors (S1PRs) in various tissues of the human body. The S1P-S1PR signaling pathway plays a crucial role in mediating inflammatory responses, cardiac development, angiogenesis, as well as the migration, proliferation, and differentiation of immune cells. S1PRs have emerged as promising therapeutic targets for a variety of diseases, including autoimmune diseases, inflammation, cardiovascular diseases, and even cancer. However, the lack of in-depth understanding of S1PRs has hindered the development of clinical drugs. Therefore, this article reviews the current research status of S1PRs, focusing on S1PR-associated physiological functions, disease progression, and the development of representative drugs, with the aim of providing new insights for the clinical treatment of associated 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.

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.

Copper plays a crucial role in a variety of cellular processes, such as energy metabolism, mitochondrial respiration, and antioxidation. Intracellular copper homeostasis relies on the dynamic balance among copper intake, storage, and efflux. Disruptions in copper metabolism can impact cellular function and viability. Elevated copper levels have been observed in various neurodegenerative diseases and tumors, with the underlying pathological mechanisms closely associated with cuproptosis induced by copper overload. This article provides in-depth insights into intracellular copper homeostasis and its maintenance, as well as the roles and molecular mechanisms of copper metabolic disorders and cuproptosis in neurodegenerative diseases and tumorigenesis.

Cardiovascular diseases significantly affect human health and represent an urgent public health issue that needs to be addressed.Reactive oxygen species (ROS) generated by mitochondrial metabolism are risk factors for the occurrence and progression of cardiovascular diseases. When mitochondrial function is impaired,excess ROS are generated.If the endogenous antioxidant system fails to eliminate the excess ROS,oxidative stress damage occurs,thereby compromising cardiovascular health.Therefore,improving mitochondrial function and reducing ROS through nutritional interventions has become a crucial approach to prevent and treat cardiovascular diseases.Mitoquinol mesylate (MitoQ),a mitochondria-targeted antioxidant,accumulates in the inner mitochondrial membrane,quenching mitochondrial ROS.This article reviews the molecular properties and mechanisms of action of MitoQ,as well as its benefits in improving cardiovascular diseases.Additionally,it compares the similarities and differences between MitoQ and coenzyme Q10 (CoQ10),providing a scientific basis for the future application of MitoQ in the treatment of cardiovascular diseases.

Circadian rhythm is a biological process that operates on an approximately 24-hour cycle, encompassing various physiological functions including blood pressure, heart rate, and body temperature. The normal circadian rhythm of blood pressure typically exhibits a characteristic “two-peak and one-valley” pattern, which is regulated by a combination of exogenous factors, including light exposure, exercise, and diet, as well as endogenous factors such as the autonomic nervous system, stress hormones, and clock genes. In recent years, lifestyle factors such as nocturnal light exposure, shift work, and jet lag have increasingly led to circadian rhythm disruption. The normal circadian rhythm of blood pressure is also often affected, contributing to circadian rhythm disorders of blood pressure. Numerous studies indicate that exercise can prevent cardiovascular diseases such as hypertension and heart failure, serving as an important non-pharmacological strategy to mitigate the disruptions in the circadian rhythm of blood pressure. Therefore, this review will take the factors influencing the circadian rhythm of blood pressure as a starting point, aiming to clarify the possible mechanisms through which exercise participates in regulating the blood pressure circadian rhythm, and to provide a theoretical basis for improving the circadian rhythm disorders of blood pressure through exercise.

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.

Post-stroke cognitive impairment (PSCI) is a common complication following stroke, posing a significant threat to patients' quality of life and survival time. Microglia, the major immune cells in the central nervous system, play a crucial role in the pathogenesis of PSCI by mediating immune responses and exerting neuroprotective effects. Research has indicated that triggering receptor expressed on myeloid cells 2 (TREM2), an immune response receptor predominantly expressed on microglia, is involved in the regulation of microglial number, phagocytosis, cytokine release, and metabolic functions. In this article, we elucidate the effect of TREM2-mediated regulation of microglial activity on PSCI, and explore the potential of TREM2 as a therapeutic target for the prevention and treatment of PSCI.

Metabolites produced by the gut microbiota play various physiological regulatory roles through interactions with the host and are closely related to human health. Imidazole propionate, a metabolite derived from histidine by the gut microbiota, has garnered significant attention in recent years due to its close association with chronic diseases such as type 2 diabetes and cardiovascular diseases. This article reviews the metabolic pathways of imidazole propionate, its correlation with metabolic and cardiovascular diseases, its mechanisms of action, and current methods for its detection and associated interventions. The aim is to provide a reference for the prevention and control of chronic diseases targeting imidazole propionate.

Lysosomal storage disorders (LSD) are a rare class of diseases caused by mutations in genes encoding lysosomal hydrolases, leading to metabolic disorders. These disorders arise from either the absence of functional lysosomal hydrolases or damage to the lysosomes. Impaired degradation of complex macromolecules leads to the accumulation of substrates in tissues and subsequent dysfunction of cells and organs. Current treatment options for LSDs primarily include enzyme replacement therapy, substrate reduction therapy, and chaperone therapy. However, most of these treatments do not cure the disease, but merely delay its progression. They necessitate continuous administration of medications, which can be financially burdensome, and often fail to effectively reach target sites due to various challenges, resulting in diminished therapeutic effects. Therefore, there is an urgent need for more effective and thorough treatment options. Extracellular vesicles (EVs) are naturally secreted components with potential applications in various diseases. However, their role and therapeutic potential in the context of LSDs remain unclear. This article summarizes current research progress on EVs in two common LSDs, Fabry disease and Gaucher disease, by reviewing literature from PubMed. It discusses biomarkers associated with EVs in the diagnosis and treatment of LSDs, as well as advancements in engineered EVs for therapeutic applications.

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。