Sub-cellular biochemistry最新文献

The human gut microbiome and noncoding RNAs (ncRNAs) represent interconnected regulatory networks that profoundly influence cancer development, particularly in gastrointestinal and endocrine-related malignancies. This chapter delineates the intricate interplay of microbiome-ncRNA crosstalk in the context of gastrointestinal and endocrine-related cancers.The chapter begins with a comprehensive overview of the taxonomic and functional landscape of the healthy adult gut microbiome. The gut microbiome, comprising trillions of microorganisms, plays a crucial role in endocrine regulation through hormone metabolism, synthesis of bioactive compounds, and modulation of immune responses, thereby establishing a critical crosstalk with the host endocrine system. Dysbiosis, or microbial imbalance, has been linked to endocrine dysfunction and the pathogenesis of various diseases, including gastrointestinal and endocrine-related cancers.We then elucidate the classifications of noncoding RNAs and their function as key molecular regulators in cellular communication, gene expression, and disease progression. NcRNAs contribute significantly to the development and progression of endocrine-related malignancies. The intricate crosstalk between the gut microbiome and host ncRNAs demonstrates how gut dysbiosis can disrupt host ncRNA expression patterns, thereby affecting oncogenic pathways, immune surveillance, and metabolic reprogramming linked to tumor initiation, progression, and metastasis. Conversely, host-derived ncRNAs, secreted into the gut lumen, can directly shape microbial gene expression. In this section, we explore how dysregulation of this axis contributes to carcinogenesis through the promotion of chronic inflammation, epithelial barrier dysfunction, and oncogenic signaling. Therapeutic strategies targeting this interplay, including probiotics, prebiotics, fecal microbiota transplantation, and dietary interventions, are introduced in the context of restoring microbial balance.This comprehensive chapter provides crucial insights into the molecular mechanisms governing microbiome-ncRNA interactions and their implications for cancer biology, offering new perspectives for therapeutic interventions in gastrointestinal and endocrine-related malignancies.

There is an urgent need for reliable noninvasive indicators of the occurrence and course of liver disease. According to research conducted in recent decades, the risk scores for liver-related complications can be determined by utilizing the genetic and epigenetic components involved in the development of liver disease. This might potentially indicate the feasibility of implementing programs for target screening and monitoring of complications.Precision medicine may be used to treat liver illnesses, thanks to recent advancements in our knowledge of the epigenetics of liver cells. In a multicellular organism, each cell has a distinct phenotype, even if they all have the same genetics. Chromatin states determined by epigenetic processes are necessary for this heritable yet dynamic cell identity. Genetic, environmental, and metabolic factors that determine DNA accessibility to the transcriptional machinery governing gene expression and cellular states in various liver illnesses can alter the epigenomic landscapes unique to the liver. Noncoding RNAs (ncRNAs) are examples of the epigenetic regulation of chromatin. The coordinated actions of numerous epigenetic factors that modify nucleosome positioning and structure (remodelers), create epigenetic marks in DNA and histones (writers), identify and interpret the marks (readers), and eliminate these marks (erasers) preserve this epigenetic information.Here, we summarize the literature on how epigenetic changes contribute to the development of liver cancers. Along with talking about the potential of epigenetic therapy approaches, we also address their usefulness as epigenetic biomarkers for the diagnosis and prognosis of hepatocellular carcinoma.

Actin was first identified as a major muscle protein with two key activities: polymerization and ATPase. Although the significance of these activities in muscle contraction was unclear, subsequent cell biological studies revealed that actin is abundant also in non-muscle cells, where it drives dynamic remodeling through ATP-dependent treadmilling. Biochemical studies revealed that the polymerization coupled with ATP hydrolysis produces two distinct F-actin states: a stable ADP-P_i state and an unstable ADP state. The transition between the ADP-P_i and ADP states (i.e., P_i release) likely generates the free energy that drives treadmilling.In this chapter, we introduce our structural biological studies of these states and the mechanisms underlying their formation. Our F-actin model showed that polymerization induces a rotation between its two rigid domains, shifting actin from a twisted G-form to a flat F-form. We also resolved the cryo-EM structure of cofilin-decorated F-actin, in which actin adopts a distinct C-form. Analysis of PDB data classified actin structures into four conformations: G-, F-, C-, and O-forms, each linked to specific functions-G-form for nucleotide exchange, F-form for ATP hydrolysis, and C-form for filament severing. High-resolution F-form structures further elucidated the ATP hydrolysis pathway and the basis for the stability of the ADP-P_i state.Despite these advances, key questions remain. Although the global structure of F-form actin is identical across nucleotide states, its properties differ: ATP/ADP-P_i states are stable and cofilin-resistant, whereas the ADP state is prone to depolymerization and cofilin-mediated severing. We suggest that each state should be characterized by the distinct nature of conformational fluctuations from F-form back to G-form.

The world population is ageing rapidly. The over-60s now outnumber the under- 5s, and 1 in 6 people will be over 60 by 2030 (WHO). Collagen is a key structural component of many tissues and organs, and although a fraction of the collagenous component of tissues is remarkably long-lived, it progressively accumulates damage over a lifetime. The capacity for new collagen synthesis and post-translational modification is altered and dysregulated during ageing. The mature crosslinks that stabilise collagenous tissues can remain stable or increase with age, whereas age-related glycation end-products can increase and affect tissue biomechanics. At the fibrillar nanoscale, changes associated with ageing and disease influence fibril deformation and stress transfer in a tissue-specific manner. Age-related loss of collagen can be caused by proteolytic degradation, but normal collagen turnover is also affected by ageing and its dysregulation is detrimental to tissue homeostasis. Age-related accumulation of senescent cells may contribute to the aberrant turnover of collagen during ageing. Finally, collagen itself may hold the key to counteracting some of the detrimental effects of ageing, with ingested hydrolysed collagen peptides demonstrating beneficial effects on skin and the musculoskeletal system.

Amyloids play critical functional roles in biology, including microbial virulence, innate immunity, and cellular organization, broadening their traditional association with neurodegenerative and systemic diseases. This chapter explores the structural and functional plasticity of amyloids, emphasizing how a single protein sequence can adopt multiple fibrillar conformations, termed polymorphs, each with distinct biological outcomes. We synthesise recent high-resolution structural insights from cryo-EM, NMR, and microcrystallography that elucidate the polymorphic behaviour of amyloids in both pathogenic and functional contexts. Particular focus is placed on bacterial functional amyloids that stabilise biofilms and modulate host-pathogen interactions and on antimicrobial peptides that form reversible fibrils with cytotoxic or immune-stimulatory functions. We also highlight the emerging paradigm of amyloid-nucleic acid co-assemblies and their role in immune recognition, autoimmunity, and possibly the origin of life. By examining structure-function relationships across a broad evolutionary spectrum, we argue that amyloid polymorphism constitutes a general mechanism of biological regulation. Understanding how these fibrils shift between states, including cross-β, cross-α, nanotubular, or phase-separated condensates, offers insight into their dual roles in health and disease. This perspective repositions amyloids not merely as pathological end-products but as versatile, ancient scaffolds for structural adaptation and functional innovation.

This work examined the integration of epigenetics and precision medicine in the management of various blood disorders, including anemias, antiphospholipid syndrome, hemochromatosis, hemophilia, leukemia, lymphoma, multiple myeloma, porphyria, thalassemia, thrombocytopenia, thrombocytosis, polycythemia, von Willebrand disease, and coagulopathy. It begins with an overview of key concepts and the significance of precision medicine in treating blood diseases, supported by current statistics. The role of noncoding RNAs (ncRNAs) is highlighted, detailing their mechanisms of action and clinical implications as potential biomarkers and therapeutic targets. Additionally, the chapter explores natural products used in personalized medicine, examining their sources, mechanisms, and successful case studies in blood disorders. A comprehensive review of recent clinical trials provides insights into the impact of innovative therapies and FDA approvals on treatment protocols, emphasizing the importance of combination therapies. Future directions address emerging research technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) and ethical considerations surrounding genetic testing and patient consent. The synthesis of findings underscores the contributions of epigenetics and precision medicine to blood disease treatment, advocating for interdisciplinary research and ongoing education to enhance patient care and outcomes.

Striated muscle is composed of overlapping arrays of thick myosin filaments and thin actin filaments. The thick filaments are composed of myosin molecules, which are hexamers of two heavy chains and two pairs of light chains. The heavy chain has an N-terminal head domain and a C-terminal helical rod domain. The latter dimerises to form a two-stranded coiled-coil rod. The distal two-thirds of these rods aggregate in parallel to form the filament backbone, while the heads lie on the surface to facilitate interactions with actin. The molecules aggregate in an antiparallel manner in the centre of the A-band to form the so-called bare zone. The proximal one-third of the rod can swivel and thereby allow the myosin heads to interact with actin. The atomic structure of the head, determined in the 1990s, was a major milestone in the muscle field. Over the next three decades, great strides were made in cryo-electron microscope technology and software. This led to the high-resolution structure of the insect flight muscle thick filament, showing the structure of the myosin tails at 6 Å resolution and the structure of the heads. There has been great excitement recently with the high-resolution structures of relaxed cardiac muscle thick filaments showing details of all the important players: three types of myosin crowns and the paths of their tails, the structure and interactions of cMyBP-C and the structure of two unique forms of titin and its role in filament assembly. Hypertrophic cardiomyopathy, which results from mutations in sarcomeric proteins, especially myosin and cMyBP-C, is a major health burden and insight gained from the new studies will help to devise new therapies.

Much is now known about the structures of the β-filaments and the intermediate filaments that together constitute the bulk of the avian and reptilian (sauropsid) appendages (claws, scales, feathers and beaks). New sequence data from the Rhynchocephalia (the tuatara), the last branch of the phylogenetic classification of the sauropsids to be studied, has confirmed that all members of the sauropsids are based on common structures. In addition, an examination of the sequence data has revealed that the β-filaments in the lepidosaurs (lizards, snakes and tuatara) contain a chain that is likely to be a structural component of two separate filaments, thereby providing a unique feature that could facilitate ordered filament aggregation. Similarly, a Type II IF chain (K80) in lizards appears capable of forming an interaction in inter-filament space that would link adjacent IF through tail-tail interactions. A Type II IF chain in zebra finch (K78LT) also seems likely to play a similar role. More details of the surface lattice structure in the IF have also been obtained, as has information on the lateral packing of the protofilaments in the IF. Consequently, an increasingly detailed picture has emerged of the structure and assembly of the filamentous structures that comprise the corneous appendages in the sauropsids.

This chapter explores the role of fibrillar collagens, mainly collagen I, in developing fibrotic disorders associated with acute or chronic injuries. While collagen molecules' fundamental structure, composition, and intracellular biosynthesis steps remain similar in healthy and scar tissues, their extracellular architecture and physical properties significantly differ. These differences arise from the excessive production of collagen I and auxiliary proteins associated with collagen I folding and posttranslational modifications. As a result, the overaccumulation of collagen I-based fibrotic deposits creates a rigid mechanical environment that, through mechanotransduction, amplifies pro-fibrotic signaling in resident fibroblasts.In reviewing the literature, this chapter highlights key players that create, transmit, and sustain these signals, thereby perpetuating fibrosis. Given the growing recognition of mechanotransduction as a valid therapeutic target to limit fibrosis, this chapter also discusses strategies to inhibit different elements of this process. A significant challenge with these strategies is that both balanced and excessive scarring rely on the exact underlying mechanisms of scar tissue formation. Consequently, conventional anti-fibrotic agents may inadvertently impair the essential scarring needed to preserve tissue integrity after injury. Therefore, mechanotherapeutics that reduce collagen accumulation-driven scar stiffness represent a novel approach for developing more targeted anti-fibrotic therapies.

The collagen superfamily has evolved over nearly a billion years to produce a set of at least 28 proteins that are present in all vertebrates. Of these, the fibrillar collagens (Types I-III, V, XI, XIV, and XVII) comprise a diverse, fibrous structural polymer system that extensively invests and mechanically supports connective tissue. The chemistry, structure, and mechanics of single collagen molecules will be reviewed to provide insight into why collagen's triple helical motif is such an effective, efficient, and versatile structural building block. Review of the integration of molecular collagen into each successive length scale: fibrils, fibers, and tissues will show how the mechanical signature of each level in the hierarchy reflects the mechanical behavior of the smaller length scales from which it is composed. The remarkable structural and mechanical versatility of multiple whole connective tissues with completely different structural roles will demonstrate how each of them relies on collagen to perform their diverse mechanical functions. Finally, multiple themes that address more transcendent phenomena such as fibril diameter modulation, crosslinking, fatigue, and collagen mechanochemistry will be examined to provide a broader view of the field and open new directions for research.