Essays in biochemistry最新文献

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.

Phage therapy has attracted attention again owing to the increasing number of drug-resistant bacteria. Although the efficacy of phage therapy has been reported, numerous studies have indicated that the generation of phage-specific antibodies resulting from phage administration might have an impact on clinical outcomes. Phage-specific antibodies promote phage uptake by macrophages and contribute to their rapid clearance from the body. In addition, phage-specific neutralizing antibodies bind to the phages and diminish their antibacterial activity. Thus, phage-specific antibody production and its role in phage therapy have been analyzed both in vitro and in vivo. Strategies for prolonging the blood circulation time of phages have also been investigated. However, despite these efforts, the results of clinical trials are still inconsistent, and a consensus on whether phage-specific antibodies influence clinical outcomes has not yet been reached. In this review, we summarize the phage-specific antibody production during phage therapy. In addition, we introduce recently performed clinical trials and discuss whether phage-specific antibodies affect clinical outcomes and what we can do to further improve phage therapy regimens.

The growing threat of antimicrobial resistant (AMR) bacterial pathogens coupled with the relative dearth of promising novel antibiotics requires the discovery and development additional medical interventions. Over the past decade bacteriophages have emerged one of the most promising new tools to combat AMR pathogens. Anecdotal clinical experiences under so-called 'compassionate use' regulatory pathways as well as a limited number of clinical trials have provided ample evidence of safety and early evidence of efficacy. For phages to reach their full potential it is critical that rigorous clinical trials be conducted that define their optimal use and that enable regulatory authorities to support the commercialization required to afford global access. The clinical development of phage therapeutics requires the design and execution of clinical trials that take full advantage of lessons learned from a century of antibiotic development and that use clinical investigation as a platform in which aspects of phage biology that are critical to therapeutics are more clearly elucidated. Translational research that elucidates phage biology in the context of clinical trials will promote highly relevant hypothesis-driven work in basic science laboratories and will greatly accelerate the development of the field of phage therapeutics.

The discovery of viruses that can devour bacteria, bacteriophages (phages), was in 1915. Phages are ubiquitous, outnumbering the organisms they devour, and genomically, morphologically, and ecologically diverse. They were critical in our development of molecular biology and biotechnology tools and have been used as therapeutics for over 100 years, primarily in Eastern Europe with thousands of patients from all over the world treated in Georgia. The rise of antimicrobial resistance and the lack of new antimicrobials, has brought them back into the spotlight dawning the New Age of the Phage. This special issue will provide further insight to phage diversity across ecosystems, including humans, animals, and plants, i.e. the basis of a One Health approach, and the requirements for turning phages into viable medicines for the many and not just for the few.