Advances in protein chemistry and structural biology最新文献

Antimicrobial resistance (AMR) remains a critical global health threat, necessitating innovative approaches to combat drug-resistant bacteria. This study investigates the genetic basis of resistance in Enterococcus faecalis, a Gram-positive bacterium, in response to the antibiotic Teixobactin, with potential importance on the development of antimicrobial peptides (AMPs). Leveraging whole transcriptome RNA-Seq analysis and advanced bioinformatics tools, we identified ten central hub genes: guaA, guaB, lepA, der, secA, ftsH, obg, nusG, dnaA, and ffh. These genes demonstrate significant upregulation and robust interactions within the bacterial genome. Our comprehensive analysis reveals the involvement of these genes in crucial cellular functions linked to AMP resistance, including purine metabolism, protein export, stress response, transcriptional regulation, and ribosomal activities. These findings provide vital insights into the complex molecular mechanisms underlying Enterococcus faecalis' resistance to AMPs, these genes reflect an adaptive response to antibiotic exposure, which is critical for understanding the overall resistance mechanisms in E. faecalis. As the global battle against AMR intensifies, the identified hub genes present promising opportunities for the discovery of novel antibiotics, reinforcing efforts to combat drug-resistant bacterial infections.

Staphylococcus aureus infections are difficult to treat due to the widespread emergence of antibiotic resistant strains, complex virulence mechanisms, and the ability to form recalcitrant biofilms. Infections with multi-drug resistant variants such as the methicillin resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) lead to increased morbidity and mortality and result in higher treatment cost compared to those with sensitive strains. While vaccines are sought as a preventive strategy, a clinically viable vaccine has not surfaced yet. Considering the rapid dissemination of resistant strains across the globe, the World Health Organisation has categorised S. aureus as an ESKAPE pathogen that requires the immediate development of alternative therapeutics. One of the most promising alternative to conventional antibiotics are bacteriophage endolysins, a family of peptidoglycan hydrolases capable of destabilising the peptidoglycan cell wall in bacteria by cleaving essential bonds in the peptidoglycan structure. Bacteriophages employ these for lysing the host cell during the last stage of their lytic life cycle to release progeny virions. A study published in 2001 demonstrated that purified endolysins can lyse bacterial cells rapidly and effectively when administered exogenously. Endolysins offer many advantages over conventional antibiotics: they are not likely to develop resistance as they target a highly conserved and indispensable component of the bacterial cell wall; they act faster than conventional antibiotics; they are species-selective in their lytic activity, sparing non-target organisms. Despite the numerous challenges in their clinical deployment, a large number of phage endolysins have been studied for their antibacterial potential against bacterial pathogens, including S. aureus. The present chapter provides a comprehensive account of the various endolysins, natural and engineered, studied as antimicrobial agents against drug resistant S. aureus.

With the ever-increasing challenge of antibiotic resistance and the rise in multidrug-resistant strain-associated mortality, antimicrobial peptides and proteins have emerged as a potential therapeutic solution. Antimicrobial peptides (AMPs) are host defence peptides that not only display activity against several pathogens but have been utilised clinically to treat infections caused by multidrug and pan-drug resistant superbugs, working in synergy with existing therapeutics for better clinical outcomes. The chapter discusses clinical perspectives of AMPs, beginning with the fundamentals to current clinical perspectives and challenges faced in AMP research, along with their solutions. The chapter gives detailed insight into the pharmacology of all clinically approved AMPs, including their pharmacokinetics and mechanism of action. Further, the chapter explores various peptide modifications and peptide delivery methods to increase therapeutic potency and applicability of these peptides, and artificial intelligence-based computational tools and databases that can be utilised for peptide prediction and accelerate AMP discovery.

The global antimicrobial resistance (AMR) crisis drives the demand for novel therapeutics, positioning marine-derived antimicrobial peptides (AMPs) as sustainable alternatives with unique structural and functional advantages. These cationic, amphipathic molecules, from the source of diverse marine organisms, such as invertebrates, extremophiles, and cyanobacteria, exhibit broad-spectrum activity against drug-resistant pathogens through mechanisms like membrane disruption and immunomodulation. Their low resistance propensity and multifunctional bioactivity (eg., antioxidant, antimicrobial, anticancer) underscore therapeutic potential beyond the conventional antibiotics. Advances in genomic and metagenomic tools, machine learning, and synthetic biology are revolutionizing AMP discovery, enabling targeted mining of marine biodiversity and peptide optimization for enhanced stability and specificity. Biotechnological innovations support scalable production through heterologous expression and marine biomass valorization, which aligns with the principles of the circular economy. Marine-sourced AMPs demonstrate transformative applications across various healthcare, aquaculture, food safety, and environmental remediation, that majorly reduce the dependence on synthetic chemicals. Their integration into blue bioeconomy frameworks is promoting sustainable bio-prospects, marine ecosystem conservation, and progress towards the United Nations Sustainable Development Goals. This review narrates the collective research and also addresses the critical challenges, including production scalability and regulatory frameworks, to outline a clear pathway for the marine sourced AMP commercialization. By bridging the antimicrobial innovation with circular biotechnology, marine-sourced AMPs are exemplifying the ocean's role as a reservoir of sustainable solutions for global health and bioeconomic resilience.

Histones are positively charged proteins found in the chromatin of eukaryotic cells. They regulate gene expression and are required for the organization and packaging of DNA within the nucleus. Histones are extremely conserved, allowing for transcription, replication, and repair. This review delves into their complex structure and function in DNA assembly, their role in nucleosome assembly, and the higher-order chromatin structures they generate. We look at the five different types of histone proteins: H1, H2A, H2B, H3, H4, and their variations. These histones bind with DNA to produce nucleosomes, the basic units of chromatin that are essential for compacting DNA and controlling its accessibility. Their dynamic control of chromatin accessibility has important implications for genomic stability and cellular activities. We elucidate regulatory mechanisms in both normal and pathological situations by investigating their structural features, diverse interaction mechanisms, and chromatin impact. In addition, we discuss the functions of histone post-translational modifications (PTMs) and their significance in various disorders. These alterations, which include methylation, acetylation, phosphorylation, and ubiquitination, are crucial in regulating histone function and chromatin dynamics. We specifically describe and explore the role of changed histones in the evolution of cancer, neurological disorders, sepsis, autoimmune illnesses, and inflammatory conditions. This comprehensive review emphasizes histone's critical role in genomic integrity and their potential as therapeutic targets in various diseases.

The nuclear envelope has for long been considered more than just the physical border between the nucleoplasm and the cytoplasm, emerging as a crucial player in genome organisation and regulation within the 3D nucleus. Consequently, its study has become a valuable topic in the research of cancer, ageing and several other diseases where chromatin organisation is compromised. In this chapter, we will delve into its several sub-elements, such as the nuclear lamina, nuclear pore complexes and nuclear envelope proteins, and their diverse roles in nuclear function and maintenance. We will explore their functions beyond nuclear structure and transport focusing on their interactions with chromatin and their paramount influence in its organisation, regulation and expression at the nuclear periphery. Finally, we will outline how this chromatin organisation and regulation at the nuclear envelope is affected in diseases, including laminopathies, cancer, neurodegenerative diseases and during viral infections.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks hormone receptors, which makes it more likely to metastasize and have a poor prognosis. Despite some effectiveness of chemotherapy, TNBC remains challenging to manage, with high relapse and mortality rates. Recent findings have highlighted the role of the ubiquitin-protease system in TNBC, with ABI2 identified as a significant regulator. Reduced ABI2 expression is associated with aggressive disease and poor outcomes, whereas ABI2 overexpression (OE-ABI2) inhibits TNBC cell proliferation by modulating the PI3K/Akt signaling pathway. Although ABI2 is not a nuclear protein, it influences critical nuclear functions such as DNA repair and gene expression. Nuclear proteins, particularly those in the nuclear pore complex and nuclear matrix, are essential for cellular functions and have been linked to various diseases, including cancer. This study used RNA sequencing (RNA-seq) to examine the gene expression in MDA-MB-231 cell line and ABI2-overexpressing cells. Differentially expressed genes were annotated, and a protein-protein interaction network was constructed. Network and enrichment analysis identified the nucleoporins NUP54 and NUP153 as potential novel targets for TNBC. This study emphasizes the impact of ABI2 on nuclear proteins and suggests that targeting NUP54 and NUP153 could offer new therapeutic options for TNBC.

High-mobility group box 1 (HMGB1) is a highly conserved nuclear protein involved in key nuclear processes such as DNA repair, replication, and gene regulation. Beyond its established nuclear roles, HMGB1 has crucial functions in the cytoplasm and extracellular environment. When translocated to the cytoplasm, HMGB1 plays a role in autophagy, cell survival, and immune response modulation. In its extracellular form, HMGB1 acts as a damage-associated molecular pattern molecule, initiating inflammatory responses by interacting with receptors such as Receptor for advanced glycation endproducts and Toll-like receptors. Recent studies have shown its role in promoting tissue regeneration, wound healing, and angiogenesis, highlighting its dual role in both inflammation and tissue repair. Notably, the redox status of HMGB1 influences its function, with the reduced form promoting autophagy and the disulfide form driving inflammation. Dysregulation of HMGB1 contributes to the progression of various diseases, including cancer, where it influences tumor growth, metastasis, and resistance to therapy. This review provides an overview of the nuclear, cytoplasmic, and extracellular roles of HMGB1, discussing its involvement in nuclear homeostasis, rare genetic diseases, autophagy, inflammation, cancer progression, and tissue regeneration.

Over the years, extensive research has been dedicated to performing in-depth analysis of cancer to uncover the intricate details of its nature - including the types of cancer, causative agents, stimulators of disease progression, factors contributing to poor prognosis, and efficient therapies to restrict the metastatic aggressiveness. This chapter highlights the mechanisms through which different arms of the host immune system - namely cytokines, lymphocytes, antigen-presenting cells (APCs) -can be mobilized to eradicate cancer. Most malignant tumors are either poorly immunogenic, or are harbored in a highly immuno-suppressive microenvironment. This is why reinforcing the host's anti-tumor defenses, through infusion of pro-inflammatory cytokines, tumor antigen-loaded APCs, and anti-tumor cytotoxic cells has emerged as a viable treatment option against cancer. The chapter also highlights the ongoing preclinical and clinical studies in different malignancies and the outcome of various therapies. Although these methods are not foolproof, and antigen escape variants can still evade or develop resistance to customized therapies, they achieve disease stabilization in several cases when conventional treatments fail. In many instances, combination therapies involving cytokines, T cells, and vaccinations prove more effective than monotherapies. The limitations of the current therapies are also discussed, along with ongoing modifications aimed at improving efficacy.

Lipids play an essential role in synaptic function, significantly impacting synaptic physiology through their dynamic nature and signaling capabilities. Membrane lipids, including cholesterol, phospholipids, and gangliosides, are crucial for synaptic organization and function. They act as structural integrators and signaling molecules, guiding vesicle intracellular movement and regulating enzyme activity to support neuronal activity. The lipid compositions of pre-synaptic and post-synaptic membranes influence vesicle generation and receptor mobility, highlighting their active involvement in synaptic processes. Astrocytes also contribute to synaptic health by upholding the blood-brain barrier, regulating ion levels, and providing metabolic support. Lipid-mediated processes control synaptic plasticity and development, with astrocytes playing a crucial role in glutamate homeostasis. Amyloid-beta and Tau proteins are key in Alzheimer's disease (AD), where synaptic disruption leads to cognitive deficits. Clathrin-mediated endocytosis (CME) and caveolin-mediated endocytosis are critical pathways for lipid-mediated synaptic function, with disruptions in these pathways contributing to AD pathogenesis.