Essays in biochemistry最新文献

The emergence of immunotherapy has led to the clinical approval of several related drugs. However, their efficacy against solid tumors remains limited. As the hub of immune activation, lymph nodes (LNs) play a critical role in tumor immunotherapy by initiating and amplifying immune responses. Nevertheless, the intricate physiological structure and barriers within LNs, combined with the immunosuppressive microenvironment induced by tumor cells, significantly impede the therapeutic efficacy of immunotherapy. Engineered nanoparticles (NPs) have shown great potential in overcoming these challenges by facilitating targeted drug transport to LNs and directly or indirectly activating T cells. This review systematically examines the structural features of LNs, key factors influencing the targeting efficiency of NPs, and current strategies for remodeling the immunosuppressive microenvironment of LNs. Additionally, it discusses future opportunities for optimizing NPs to enhance tumor immunotherapy, addressing challenges in clinical translation and safety evaluation.

Bacterial outer membrane vesicles (OMVs), naturally released by Gram-negative bacteria, are a type of lipid bilayer nanoparticles containing many components found within the parent bacterium. Despite OMVs were first considered mere by-products of bacterial growth, recent studies have shown them as a highly adaptable platform for tumor vaccine. Here, we first demonstrate the biogenesis of OMVs, then review the strong immunogenicity of OMVs as an immune adjuvant in tumor vaccine and its excellent vaccine delivery capability, and finally discuss OMVs' engineering potentials through summarizing recent scientific advancements in genetic engineering, chemical modification, and nanotechnology. We also point out the clinical trials and future challenges of OMV-based vaccine. Overall, this review offers valuable insights into cancer immunotherapy, providing a roadmap for leveraging OMVs as a versatile platform for next-generation cancer vaccines.

Hypertension represents a highly prevalent chronic condition and stands among the foremost contributors to premature mortality on a global scale. Its etiopathogenesis is intricate and multifaceted, being shaped by a diverse array of elements such as age, genetic predisposition, and activation of the neuroendocrine apparatus. Mounting evidence has shed light on the significant part that autoimmune responses play in hypertension and the ensuing damage to end organs. Virtually all varieties of immune cells, spanning both innate and adaptive immune compartments, exhibit a close correlation with the progression of hypertension. These immune cells infiltrate the kidney and vascular mesenchyme, subsequently discharging potent cytokines, reactive oxygen species, and metalloproteinases. This cascade of events can affect the functionality of local blood vessels and potentially precipitate adverse structural and functional alterations in crucial organs like the heart and kidney. In recent times, the management of end-organ damage in hypertension has emerged as a pivotal scientific focus. A multitude of researchers are actively engaged in probing efficacious intervention regimens, among which immunotherapy strategies hold considerable promise and anticipation as a prospective avenue.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a crucial component of the host's innate immunity and plays a central role in detecting cytosolic double-stranded DNA from endogenous and exogenous sources. Upon activation, cGAS synthesizes cGAMP, which binds to STING, triggering a cascade of immune responses, including the production of type I interferons and pro-inflammatory cytokines. In the context of cancers, the cGAS-STING pathway can exert dual roles: on the one hand, it promotes anti-tumor immunity by enhancing antigen presentation, stimulating T-cell responses, and inducing direct tumor cell apoptosis. On the other hand, chronic activation, particularly in tumors with chromosomal instability, can lead to immune suppression and tumor progression. Persistent cGAS-STING signaling results in the up-regulation of immune checkpoint molecules such as PD-L1, contributing to immune evasion and metastasis. Consequently, anti-tumor strategies targeting the cGAS-STING pathway have to consider the balance of immune activation and the immune tolerance caused by chronic activation. This review explores the mechanisms underlying both the anti-tumor and protumor roles of the cGAS-STING pathway, with a focus on potential therapeutic approaches, and the challenges faced in their clinical application, along with corresponding solutions.

Inflammatory bowel disease (IBD), a chronic and relapsing-remitting condition, is inadequately managed by conventional therapies that often lack targeting specificity and carry significant side effects, particularly failing to address intestinal barrier repair and microbial balance. Probiotics, with their strong colonization capabilities, present a novel approach to drug delivery. Various engineering strategies have been developed to enhance the targeting ability of probiotics to inflammation sites, enabling precise delivery or in situ synthesis of therapeutic molecules to expand their multifunctional potential. This review discusses the recent advancements in bacterial modifications, including surface physico-chemical and biological coating, genetic engineering, outer membrane vesicles, minicells, and bacterial ghosts, all of which can enhance therapeutic localization. We also outline critical preclinical considerations, such as delivery frequency, systemic distribution, immune evasion, and gene contamination risks, for clinical translation. These engineered bacteria and bacterial derivatives hold great promise for personalized and sustained IBD treatments, providing a new frontier for therapy tailored to the complex inflammatory environment of IBD.

Hormones play pivotal roles in our well-being, and even more so in times of stress or disease. They determine body composition and govern reproductive processes. Hormonal compounds tend to be evolutionarily very old compounds, but only coevolved receptor systems make up powerful biological signals. We will discuss what makes some metabolites good building materials for hormones and how information may be encoded, using these scaffolds. Starting with hormone biosynthesis and regulated release from secreting cells, we will look at different stages of the whole hormone signaling process: the distribution of the hormonal "message-in-a-bottle" throughout the body, the passing of some hormones through membranes, and pre-receptor metabolism. Binding to different classes of receptors is not the end of hormone signaling, but the beginning of a second phase of signaling via second messengers, before hormonal messages are switched off again. Studying hormone biochemistry will produce exciting new findings in the future.

One Health aims to bring together human, animal, and environmental research to achieve optimal health for all. Bacteriophages (phages) are viruses that kill bacteria and their utilisation as biocontrol agents in the environment and as therapeutics for animal and human medicine will aid in the achievement of One Health objectives. Here, we assess the diversity of phages used in One Health in the last 5 years and place them in the context of global phage diversity. Our review shows that 98% of phages applied in One Health belong to the class Caudoviricetes, compared to 85% of sequenced phages belonging to this class. Only three RNA phages from the realm Riboviria have been used in environmental biocontrol and human therapy to date. This emphasises the lack in diversity of phages used commercially and for phage therapy, which may be due to biases in the methods used to both isolate phages and select them for applications. The future of phages as biocontrol agents and therapeutics will depend on the ability to isolate genetically novel dsDNA phages, as well as in improving efforts to isolate ssDNA and RNA phages, as their potential is currently undervalued. Phages have the potential to reduce the burden of antimicrobial resistance, however, we are underutilising the vast diversity of phages present in nature. More research into phage genomics and alternative culture methods is required to fully understand the complex relationships between phages, their hosts, and other organisms in the environment to achieve optimal health for all.

Bacteriophages, viruses that infect bacteria, play a crucial role in manipulating the gut microbiome, with implications for human health and disease. Despite the vast amount of data available on the human gut virome, the number of cultured phages that infect human gut bacteria-particularly obligate anaerobes-remains strikingly limited. Here, we summarize the resources and basic characteristics of phages that infect the human gut obligate anaerobe. We review various methods for isolating these phages and suggest a strategy for their isolation. Additionally, we outline their impact on the field of viral biology, their interactions with bacteria and humans, and their potential for disease intervention. Finally, we discuss the value and prospects of research on these phages, providing a comprehensive 'Roadmap' that sheds light on the 'dark matter' of phages that infect human gut obligate anaerobes.

Bacteria host various foreign genetic elements, most notably plasmids and bacteriophages (or phages). Historically, these two classes were seen as separate, but recent research has shown considerable interplay between them. Phage-plasmids (P-Ps) exhibit characteristics of both phages and plasmids, allowing them to exist extrachromosomally within bacterial hosts as plasmids, but also to infect and lyse bacteria as phages. This dual functionality enables P-Ps to utilize the modes of transmission of both phage and plasmids, facilitating the rapid dissemination of genetic material, including antibiotic resistance and virulence genes, throughout bacterial populations. Additionally, P-Ps have been found to encode toxin-antitoxin and CRISPR-Cas adaptive immune systems, which enhance bacterial survival under stress and provide immunity against other foreign genetic elements. Despite a growing body of literature on P-Ps, large gaps remain in our understanding of their ecological roles and environmental prevalence. This review aims to synthesise existing knowledge and identify research gaps on the impacts of P-Ps on microbial communities.

Klebsiella pneumoniae is an opportunistic pathogen with significant clinical relevance. K. pneumoniae-targeting bacteriophages encode specific polysaccharide depolymerases with the ability to selectively degrade the highly varied protective capsules, allowing for access to the bacterial cell wall. Bacteriophage depolymerases have been proposed as novel antimicrobials to combat the rise of multidrug-resistant K. pneumoniae strains. These enzymes display extraordinary diversity, and are key determinants of phage host range, however with limited data available our current knowledge of their mechanisms and ability to predict their efficacy is limited. Insight into the resolved structures of Klebsiella-specific capsule depolymerases reveals varied catalytic mechanisms, with the intra-chain cleavage mechanism providing opportunities for recombinant protein engineering. A detailed comparison of the 58 characterised depolymerases hints at structural and mechanistic patterns, such as the conservation of key domains for substrate recognition and phage tethering, as well as diversity within groups of depolymerases that target the same substrate. Another way to understand depolymerase specificity is by analyzing the targeted capsule structures, as these may share similarities recognizable by bacteriophage depolymerases, leading to broader substrate specificities. Although we have only begun to explore the complexity of Klebsiella capsule depolymerases, further research is essential to thoroughly characterise these enzymes. This will be crucial for understanding their mechanisms, predicting their efficacy, and engineering optimized enzymes for therapeutic applications.