Sub-cellular biochemistry最新文献

The budding yeast Saccharomyces cerevisiae is tremendously useful for revealing basic principles of cell biology. An example is the characterization of the endomembrane system, which consists of secretory, endocytic, and autophagic compartments that exchange material by membrane traffic pathways and undergo dynamic transformations. Yeast studies of this topic continue to uncover components and molecular mechanisms. However, questions persist about high-level features of the yeast endomembrane system, including the identities and life cycles of endocytic compartments and the traffic pathways followed by resident proteins of the Golgi apparatus. Time-lapse imaging of endosome and Golgi compartments points to a new synthesis that revises several long-standing assumptions. This updated picture has implications for understanding conserved aspects of the endomembrane system.

Epigenetic modifications function as central controllers of gene expression in cancer, coordinating crucial cellular activities that trigger the initiation and progression of the tumor, besides their importance in therapeutic response. These modifications can control the gene expression without changing the sequence of DNA. In colorectal cancer (CRC), these alterations involving DNA methylation, histone modifications, chromatin rearrangement, and noncoding ribonucleic acids play a significant role in the pathogenesis of CRC. Abnormal DNA methylation silences the tumor suppressor genes, meanwhile leading to the instability of the genome via reduction of the whole methylation. Specific methylation signatures, such as CpG islands, help in categorizing the subtypes of the tumor and predicting the clinical outcomes. In addition, histone-modifying enzymes, including enhancer of zeste homolog 2 and histone deacetylases, are frequently uncontrolled in cancer, leading to alterations in gene expression. Moreover, small regulatory ribonucleic acids such as microRNA-21 and microRNA-143 contribute to the complex networks that regulate cell survival and growth. Collectively, these epigenetic alterations trigger the transition from benign growth to malignant cancer by continuously suppressing crucial genes. Furthermore, the epigenetic markers can be detected in blood and stool specimens, offering promising tools for the early detection of cancer. The major obstacle in cancer treatment is the resistance to chemotherapy drugs, which is mainly caused by epigenetic modifications in cancer cells. Therefore, the new therapeutic ways target the modifications that occur in DNA methylation and histone, mostly in conjunction with conventional therapies. As the metabolites produced by the gut microbiome can alter the host epigenetics, they can promote cancer development. Promising technologies help in the concise proofreading of epigenetic marks, and advanced single-cell analysis is paving the way for personalized treatment approaches. This cutting-edge knowledge of epigenetic regulation mechanisms offers new prospects for enhancing diagnosis, prognosis, and targeted therapies in colorectal cancer.

The significance of epigenetics and precision medicine in the context of uncommon cancers, referred to as "rare cancers," is investigated in this chapter.A comprehensive review of the current literature on noncoding RNAs (ncRNAs), natural products, and clinical trials specific to uncommon cancers was conducted. The role of ncRNAs in tumor biology is elaborated, revealing their dual influence on tumor suppression and oncogenesis, alongside current therapeutic strategies targeting these molecules. Recent clinical trial outcomes were analyzed to assess therapeutic potentials and innovations. The role of epigenetic mechanisms in rare cancer development and treatment, particularly focusing on how natural products can modify epigenetic mechanisms, such as DNA methylation, histone modifications, and the regulation of ncRNAs, was discussed in detail. The chapter emphasizes the potential of these natural products as therapeutic agents, or "epi-drugs," in cancer prevention and treatment.

In this review, we have collected and analysed collagen glycosylation data in an effort to better understand its possible function in fibrillogenesis. Towards that end, we have identified glycosylation sites in many different fibril-forming collagen molecules (Types I, II, III, V, XI and XXIV) and, more importantly, the glycan itself as well as the percentage of collagen molecules in the sample that contain it. As the numbers of quantitative analyses of different collagen types from different species and tissues taken under different physiological conditions grows, a more accurate picture is emerging of the role that collagen O-glycosylation may play in fibrillogenesis. It is becoming increasingly clear that glycosylation does play an important part in the initial stages of the axial assembly of collagen molecules as well as in the lateral control of fibril size. Much remains unknown of the precise mechanisms involved, however, and further detailed analyses will be required before a complete picture of the various in vivo roles played by the glycans emerges.

Epigenetic regulation plays a central role in immune cell development, specialization, and memory formation by dynamically modifying DNA, histones, and RNA. These processes enable adaptation to environmental cues, precise pathogen responses, and maintenance of immune tolerance, while their disruption contributes to autoimmune, inflammatory, and cancer pathogenesis. DNA methylation, histone modifications, and noncoding RNA regulation shape the lineage and activation states of T cells, B cells, macrophages, and natural killer (NK) cells, with specific alterations linked to diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Emerging insights also highlight roles for RNA modifications and exosome-mediated RNA transfer in immune activation, trained immunity, and antigen presentation. Advances in single-cell epigenomics, CRISPR-based editing, and RNA sequencing are driving the development of targeted therapies-such as DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, RNA-based interventions, and exosome delivery systems-that aim to reprogram immune responses. Understanding immune cell epigenetics paves the way for precision immunotherapies tailored to patient-specific profiles, offering highly specific, effective treatments with minimal immune suppression.

Polyphenols (PPs) are secondary metabolites that are present in more than 80% of plants. They possess a plethora of medicinal properties by modulating key pathological pathways, including epigenetics and those involved in oncogenesis or tumorigenesis. PPs have been shown to inhibit tumor cell proliferation, metastasis, and cancer cell resistance to chemotherapeutic medications. Their coadministration, either as plant-rich extracts or in advanced pharmaceutical formulations like nano-formulations, significantly impacts the tolerability, efficiency, and cytotoxicity of traditional chemotherapeutic drugs. Both clinical and preclinical studies, including in vitro and in vivo models, demonstrated the potent anticancer activity of PPs. Combining PPs with conventional chemotherapeutic agents has led to a significant improvement in the efficiency and safety index of these agents. Advances in PP nano-formulations have enhanced their bioavailability and therapeutic efficacy. The current chapter highlights the potential of PPs and recent advances in their formulation for targeting cancer.

Myosin motor-heads projecting from muscle thick filaments interact cyclically with actin-based thin filament tracks, thereby driving inter-filament sliding that powers muscle contraction. Here, controlled recruitment of myosin heads from thick filaments leads pre-powerstroke myosin to bind weakly to actin. Myosin then isomerizes into strongly bound post-powerstroke conformations on actin, thus producing crossbridge motion in active muscles. In striated muscles, this process is regulated by a steric mechanism involving coiled-coil tropomyosin controlling access to myosin-binding sites on actin. Biochemical and structural studies suggest the regulatory mechanism involves tropomyosin occupying three average configurations on the actin thin filament, dependent on Ca²⁺, troponin, and myosin binding. Once Ca²⁺-activation of muscle occurs, tropomyosin pivots away from a troponin subunit-I (TnI) imposed B-state (myosin-blocking) position to a C-state position on actin, allowing initial weak myosin-binding to actin. The thin filament reconfiguration only partially relieves tropomyosin-troponin imposed steric inhibition of the myosin binding. However, the initial weak myosin-binding causes further tropomyosin translocation to an M-state position as myosin transitions from its pre-powerstroke to its post-powerstroke conformation, thereby fully activating the thin filament and resulting in contraction. This review summarizes the evolving structural evidence that has accumulated over many years, and which has shaped our current understanding of the troponin-tropomyosin steric regulatory mechanism that governs muscle contractility.

Larval aculeate insects (bees, ants and hornets) have evolved a silk for cocoon and nest construction based on entirely different design principles from the convergently evolved silk of spiders and silkworms. The silk is based on the coiled coil protein structure: a structure proposed in the 1950s by Francis Crick, where multiple α-helical proteins wrap around each other to form a supercoil. Whilst now recognised as a ubiquitous protein assembly motif, the purity of silk pulled from the honeybee silk gland made it one of the earliest experimentally validated examples of this structure. Here, we describe the current state of understanding of the relationship between the coiled coil structure and aculeate silk biology gained from early studies dating from the mid-twentieth century up to the present time. Further, efforts to replicate the natural material and functional materials generated from the silk are outlined. Finally, we consider the future of research in this area, focusing on mimicking natural silk and the use of recombinant silk for rational design of functional materials.

Fibrin is a fibrous biopolymer that plays a crucial role in hemostasis, thrombosis, wound healing, and various other biological functions and pathological conditions. The X-ray crystallographic structure of fibrinogen, along with computational reconstructions of missing regions and extensive biochemical and biophysical studies, has provided significant insights into the molecular mechanisms of fibrin formation, its structural organization, and its biological and mechanical properties. Upon cleavage of fibrinopeptides by thrombin, the blood protein fibrinogen is converted into fibrin monomers, which then interact through "knobs" exposed by the removal of fibrinopeptides in the central region and "holes" that are constitutively available at the ends of the molecules. The result is half-staggered, double-stranded oligomers that elongate into protofibrils, which then aggregate laterally to form fibers, and branch to create a three-dimensional network. Much has been learned about how the structure of fibrin contributes to the mechanical properties of the clot, including changes in fiber orientation, stretching, buckling, and the forced unfolding of molecular domains. Recent research into the mechanical stability of fibrin has enhanced our understanding of its rupture resistance, which is relevant to thrombotic embolization and mechanical thrombectomy. The fibrinolytic system, in which plasminogen, along with tissue-type plasminogen activator, binds to fibrin and is activated to plasmin, leads to the digestion of fibrin at specific lysine residues. Fibrin has been utilized in hemostatic fibrin sealants and as a biomaterial in tissue engineering and regenerative medicine. Despite significant advances in our understanding of these interconnected processes, much remains unknown about the molecular mechanisms underlying fibrin's biological functions, particularly concerning the molecular origins of its mechanical properties and the more complex structure and properties of hemostatic clots and pathological thrombi and their clinical implications.

Intermediate filaments (IFs) possess unique mechanical properties that distinguish them from actin filaments and microtubules. In particular, they exhibit high flexibility, pronounced extensibility, and complete stability during biochemical extractions from cells and tissues. These characteristics stem from their molecular structure, which is typical of fibrous proteins. A defining feature is the central ~300 amino acid long α-helical segment with a distinct hydrophobic sequence pattern, facilitating the formation of a parallel coiled-coil dimer. Under low ionic strength conditions, two such dimers interact via their basic amino-terminal domains with the acidic coiled-coil domains to form distinct, rod-like tetrameric complexes. Upon addition of salt, the tetramers first assemble laterally into full-width, unit-length filaments, which then anneal longitudinally into micrometer-long filaments with a characteristic, 10-nm diameter. Advanced experimental techniques enable us to measure piconewton forces and micrometer length scales. By combining, for example, optical tweezers or atomic force microscopy with sophisticated data analysis and numeric modeling, we have deepened our understanding of the structure-mechanics relationship in IFs, including their force-extension behavior and the low bending rigidity. These findings enable us to hypothesize about the mechanical roles of these filaments within the living cell and speculate about biomimetic, synthetic materials.