Molecular Aspects of Medicine最新文献

{"title":"Frustration in physiology and molecular medicine","authors":"R. Gonzalo Parra ,&nbsp;Elizabeth A. Komives ,&nbsp;Peter G. Wolynes ,&nbsp;Diego U. Ferreiro","doi":"10.1016/j.mam.2025.101362","DOIUrl":"10.1016/j.mam.2025.101362","url":null,"abstract":"<div><div>Molecules provide the ultimate language in terms of which physiology and pathology must be understood. Myriads of proteins participate in elaborate networks of interactions and perform chemical activities coordinating the life of cells. To perform these often amazing tasks, proteins must move and we must think of them as dynamic ensembles of three dimensional structures formed first by folding the polypeptide chains so as to minimize the conflicts between the interactions of their constituent amino acids. It is apparent however that, even when completely folded, not all conflicting interactions have been resolved so the structure remains ‘locally frustrated’. Over the last decades it has become clearer that this local frustration is not just a random accident but plays an essential part of the inner workings of protein molecules. We will review here the physical origins of the frustration concept and review evidence that local frustration is important for protein physiology, protein-protein recognition, catalysis and allostery. Also, we highlight examples showing how alterations in the local frustration patterns can be linked to distinct pathologies. Finally we explore the extensions of the impact of frustration in higher order levels of organization of systems including gene regulatory networks and the neural networks of the brain.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"103 ","pages":"Article 101362"},"PeriodicalIF":8.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycine receptors: Structure, function, and therapeutic implications","authors":"Nicole Mizzi ,&nbsp;Renald Blundell","doi":"10.1016/j.mam.2025.101360","DOIUrl":"10.1016/j.mam.2025.101360","url":null,"abstract":"<div><div>Glycine receptors are considered as an integral part of higher brain function in mammals. The main function of glycine receptor is fast inhibitory transmission brought about by glycine neurotransmitter, its full agonist. This receptor is part of the glycinergic system which controls key physiological functions such as motor coordination, regulation of the rhythm of respiration and pain signalling. Glycine, a non-essential amino acid, causes hyperpolarisation within the glycine receptor, leading this ion channel to open and allow influx of chloride ion. The glycine receptor is found within the central nervous system and peripheral nervous system. It has also been found within amacrine cells, as well as renal medulla and cortex. The glycine receptor is a pentameric ligand-gated channel, part of the Cys-loop superfamily. It is composed of large ECD, C terminus, transmembrane domain M1-M4, and a 4α:1β glycine receptor subunit stoichiometry. The glycine receptor can be found as either homomeric or heteromeric subtypes. Alpha subtypes are crucial for important physiological functions such as breathing control and nociceptive system processing while the beta subunit aids in glycine receptor clustering and synapse stabilisation with its interaction with gephyrin scaffold protein. When hyperpolarised, the receptor transitions between close, open, and desensitised states. Factors that affect the activity and function of glycine receptors are gephyrin, ivermectin, strychnine and picrotoxin while certain endogenous modulators include partial agonists, positive allosteric modulator, antagonists, and bidirectional modulator are used for pharmacological modulation. Further studies need to be carried out on how glycine receptors are also implicated in chronic pain and nociception, epilepsy, autoimmune diseases and hyperekplexia.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"103 ","pages":"Article 101360"},"PeriodicalIF":8.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of obesity-mediated cellular dysfunction and adipocytokine signaling pathways in the pathogenesis of osteoarthritis","authors":"Dahye Kim ,&nbsp;Md Meraj Ansari ,&nbsp;Mrinmoy Ghosh ,&nbsp;Yunji Heo ,&nbsp;Ki-Choon Choi ,&nbsp;Young-Ok Son","doi":"10.1016/j.mam.2025.101361","DOIUrl":"10.1016/j.mam.2025.101361","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, bone sclerosis, and chronic low-grade inflammation. Aging and injury play key roles in OA pathogenesis by triggering the release of proinflammatory factors from adipose tissue and other sources. Obesity and aging impair the function of endoplasmic reticulum (ER) chaperones, leading to ER stress, protein misfolding, and cellular apoptosis. Obesity also induces mitochondrial dysfunction in OA through oxidative stress and disrupts mitochondrial dynamics, exacerbating chondrocyte damage. These factors contribute to inflammation, matrix imbalance, and chondrocyte apoptosis. Adipocytes, the primary source of adipokines, release inflammatory mediators that affect joint cells. Several adipocytokines have a central role in the regulation of many aspects of inflammation. Adiponectin and leptin are the two most abundant adipocytokines that are strongly associated with OA progression. This literature review suggests that adipokines activate many signaling pathways to exert downstream effects and play significant roles in obesity-induced OA. Understanding this rapidly growing family of mainly adipocyte-derived mediators and obesity-mediated cellular dysfunction may be important in the development of new therapies for obesity-associated OA management.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"103 ","pages":"Article 101361"},"PeriodicalIF":8.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Duration of systemic antifungal therapy for patients with invasive fungal diseases: A reassessment","authors":"Simon B. Gressens ,&nbsp;Claire Rouzaud ,&nbsp;Frederic Lamoth ,&nbsp;Thierry Calandra ,&nbsp;Fanny Lanternier ,&nbsp;Olivier Lortholary","doi":"10.1016/j.mam.2025.101347","DOIUrl":"10.1016/j.mam.2025.101347","url":null,"abstract":"<div><div>Invasive fungal diseases are associated with significant morbidity and mortality, especially among immunocompromised patients, and often prompt for rapid and aggressive treatment aiming cure. Due to the expanding magnitude of patients burdened by chronic immunosuppression and affected by fungal diseases, the diversity of clinical settings has risen. This often results in prolonged therapy (induction, consolidation and maintenance) associated with potentially severe side effects, and clinicians face the challenging decisions of when and how to stop anti-fungal therapy. Adequate duration of therapy is poorly defined, hampered by the lack of dedicated trials to the question, the heterogeneity of cases (type of fungal pathogen, localization of infection, underlying host conditions) and various confounding factors that may influence the clinical response (e.g. persistence vs recovery of immunosuppression, impact of surgery). In this review, we aim to evaluate the existing data underlying the guidelines and recommendations of treatment duration for the most frequent invasive fungal diseases (cryptococcal meningitis, <em>Pneumocystis</em> pneumonia, invasive aspergillosis, invasive candidiasis and mucormycosis), as well as specific localizations of deep-seated diseases (osteo-articular or central nervous system diseases and endocarditis) and emerging considerations and strategies.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"103 ","pages":"Article 101347"},"PeriodicalIF":8.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting and engineering biomarkers for prostate cancer therapy","authors":"Dhirodatta Senapati ,&nbsp;Santosh Kumar Sahoo ,&nbsp;Bhabani Shankar Nayak ,&nbsp;Satyanarayan Senapati ,&nbsp;Gopal C. Kundu ,&nbsp;Subrat Kumar Bhattamisra","doi":"10.1016/j.mam.2025.101359","DOIUrl":"10.1016/j.mam.2025.101359","url":null,"abstract":"<div><div>Prostate cancer (PCa) is the second most commonly occurring cancer among men worldwide. Although the clinical management of PCa has significantly improved, a number of limitations have been identified in both early diagnosis and therapeutic treatment. Because multiple studies show that prostate-specific antigen (PSA) screening frequently results in overdiagnosis and overtreatment, the use of PSA alone as a diagnostic marker for PCa screening has been controversial. For individuals with locally advanced or metastatic PCa, androgen deprivation therapy (ADT) is the standard initially successful treatment; nonetheless, the majority of patients will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Alternative treatment options, including chemo-, immuno-,or radio-therapy, can only prolong the survival of CRPC patients for several months with the most developing resistance. Considering this background, there is an urgent need to discuss about selective prostate-specific biomarkers that can predict clinically relevant PCa diagnosis and to develop biomarker-driven treatments to counteract CRPC. This review addresses several PCa-specific biomarkers that will assist physicians in determining which patients are at risk of having high-grade PCa, focusing on the clinical relevance of these biomarker-based tests among PCa patients. Secondly, this review highlights the effective use of these markers as drug targets to develop precision medicine or targeted therapies to counteract CRPC. Altogether, translating this biomarker-based research into the clinic will pave the way for the effective execution of personalized therapies for the benefit of healthcare providers, the biopharmaceutical industry, and patients.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"103 ","pages":"Article 101359"},"PeriodicalIF":8.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding driver and phenotypic genes in cancer: Unveiling the essence behind the phenomenon","authors":"Dequan Liu ,&nbsp;Lei Liu ,&nbsp;Xiaoman Zhang ,&nbsp;Xinming Zhao ,&nbsp;Xiaorui Li ,&nbsp;Xiangyu Che ,&nbsp;Guangzhen Wu","doi":"10.1016/j.mam.2025.101358","DOIUrl":"10.1016/j.mam.2025.101358","url":null,"abstract":"<div><div>Gray hair, widely regarded as a hallmark of aging. While gray hair is associated with aging, reversing this trait through gene targeting does not alter the fundamental biological processes of aging. Similarly, certain oncogenes (such as CXCR4, MMP-related genes, etc.) can serve as markers of tumor behavior, such as malignancy or prognosis, but targeting these genes alone may not lead to tumor regression. We pioneered the name of this class of genes as \"phenotypic genes\". Historically, cancer genetics research has focused on tumor driver genes, while genes influencing cancer phenotypes have been relatively overlooked. This review explores the critical distinction between driver genes and phenotypic genes in cancer, using the MAPK and PI3K/AKT/mTOR pathways as key examples. We also discuss current research techniques for identifying driver and phenotypic genes, such as whole-genome sequencing (WGS), RNA sequencing (RNA-seq), RNA interference (RNAi), CRISPR-Cas9, and other genomic screening methods, alongside the concept of synthetic lethality in driver genes. The development of these technologies will help develop personalized treatment strategies and precision medicine based on the characteristics of relevant genes. By addressing the gap in discussions on phenotypic genes, this review significantly contributes to clarifying the roles of driver and phenotypic genes, aiming at advancing the field of targeted cancer therapy.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"103 ","pages":"Article 101358"},"PeriodicalIF":8.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between pathological and functional amyloid: A match made in Heaven or Hell?","authors":"Daniel E. Otzen ,&nbsp;Samuel Peña-Díaz ,&nbsp;Jeremias Widmann ,&nbsp;Anders Ogechi Hostrup Daugberg ,&nbsp;Zhefei Zhang ,&nbsp;Yanting Jiang ,&nbsp;Chandrika Mittal ,&nbsp;Morten K.D. Dueholm ,&nbsp;Nikolaos Louros ,&nbsp;Huabing Wang ,&nbsp;Ibrahim Javed","doi":"10.1016/j.mam.2025.101351","DOIUrl":"10.1016/j.mam.2025.101351","url":null,"abstract":"<div><div>The amyloid state of proteins occurs in many different contexts in Nature and in modern society, ranging from the pathological kind (neurodegenerative diseases and amyloidosis) via man-made forms (food processing and – to a much smaller extent - protein biologics) to functional versions (bacterial biofilm, peptide hormones and signal transmission). These classes all come together in the human body which endogenously produces amyloidogenic protein able to form pathological human amyloid (PaHA), hosts a microbiome which continuously makes functional bacterial amyloid (FuBA) and ingests food which can contain amyloid. This can have grave consequences, given that PaHA can spread throughout the body in a “hand-me-down” fashion from cell to cell through small amyloid fragments, which can kick-start growth of new amyloid wherever they encounter monomeric amyloid precursors. Amyloid proteins can also self- and cross-seed across dissimilar peptide sequences. While it is very unlikely that ingested amyloid plays a role in this crosstalk, FuBA-PaHA interactions are increasingly implicated <em>in vivo</em> amyloid propagation. We are now in a position to understand the structural and bioinformatic basis for this cross-talk, thanks to the very recently obtained atomic-level structures of the two major FuBAs CsgA (<em>E. coli</em>) and FapC (<em>Pseudomonas</em>). While there are many reports of homology-driven heterotypic interactions between different PaHA, the human proteome does not harbor significant homology to CsgA and FapC. Yet we and others have uncovered significant cross-stimulation (and in some cases inhibition) of FuBA and PaHA both <em>in vitro</em> and <em>in vivo,</em> which we here rationalize based on structure and sequence. These interactions have important consequences for the transmission and development of neurodegenerative diseases, not least because FuBA and PaHA can come into contact via the gut-brain interface, recurrent infections with microbes and potentially even through invasive biofilm in the brain. Whether FuBA and PaHA first interact in the gut or the brain, they can both stimulate and block each other's aggregation as well as trigger inflammatory responses. The microbiome may also affect amyloidogenesis in other ways, <em>e.g.</em> through their own chaperones which recognize and block growth of both PaHA and FuBA as we show both experimentally and computationally. Heterotypic interactions between and within PaHA and FuBA both <em>in vitro</em> and <em>in vivo</em> are a vital part of the amyloid phenomenon and constitute a vibrant and exciting frontier for future research.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"103 ","pages":"Article 101351"},"PeriodicalIF":8.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming shapes post-translational modification in macrophages","authors":"Ziyi Han ,&nbsp;Yinhao Shen ,&nbsp;Yuqi Yan ,&nbsp;Peng Bin ,&nbsp;Meimei Zhang ,&nbsp;Zhending Gan","doi":"10.1016/j.mam.2025.101338","DOIUrl":"10.1016/j.mam.2025.101338","url":null,"abstract":"<div><div>Polarized macrophages undergo metabolic reprogramming, as well as extensive epigenetic and post-translational modifications (PTMs) switch. Metabolic remodeling and dynamic changes of PTMs lead to timely macrophage response to infection or antigenic stimulation, as well as its transition from a pro-inflammatory to a reparative phenotype. The transformation of metabolites in the microenvironment also determines the PTMs of macrophages. Here we reviewed the current understanding of the altered metabolites of glucose, lipids and amino acids in macrophages shape signaling and metabolism pathway during macrophage polarization via PTMs, and how these metabolites in some macrophage-associated diseases affect disease progression by shaping macrophage PTMs.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"102 ","pages":"Article 101338"},"PeriodicalIF":8.7,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The recent blooming of therapeutic aptamers","authors":"Valeriana Cesarini ,&nbsp;Silvia Lucia Appleton ,&nbsp;Vittorio de Franciscis ,&nbsp;Daniele Catalucci","doi":"10.1016/j.mam.2025.101350","DOIUrl":"10.1016/j.mam.2025.101350","url":null,"abstract":"<div><div>In the dynamic landscape of biomedical research, therapeutic RNA aptamers have recently come to the forefront, showing significant potential in diagnostics and therapeutics. This review aims to raise awareness of aptamer technology within the scientific community by exploring the progress made in the therapeutic field, from the lessons learned in research to the future opportunities and impact that these innovative molecules are increasingly having on society to meet current health needs, <em>i.e.</em> targeted and personalized therapies.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"102 ","pages":"Article 101350"},"PeriodicalIF":8.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143377571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disentangling the nutrition-microbiota liaison in inflammatory bowel disease","authors":"Marilina Florio ,&nbsp;Lucilla Crudele ,&nbsp;Fabio Sallustio ,&nbsp;Antonio Moschetta ,&nbsp;Marica Cariello ,&nbsp;Raffaella M. Gadaleta","doi":"10.1016/j.mam.2025.101349","DOIUrl":"10.1016/j.mam.2025.101349","url":null,"abstract":"<div><div>Inflammatory Bowel Disease (IBD) is a set of chronic intestinal inflammatory disorders affecting the gastrointestinal (GI) tract. Beside compromised intestinal barrier function and immune hyperactivation, a common IBD feature is dysbiosis, characterized by a reduction of some strains of <em>Firmicutes</em>, <em>Bacteroidetes</em>, <em>Actinobacteria</em> and an increase in <em>Proteobacteria</em> and pathobionts. Emerging evidence points to diet and nutrition-dependent gut microbiota (GM) modulation, as etiopathogenetic factors and adjuvant therapies in IBD. Currently, no nutritional regimen shows universal efficacy, and advice are controversial, especially those involving restrictive diets potentially resulting in malnutrition. This review provides an overview of the role of macronutrients, dietary protocols and GM modulation in IBD patients. A Western-like diet contributes to an aberrant mucosal immune response to commensal bacteria and impairment of the intestinal barrier integrity, thereby triggering intestinal inflammation. Conversely, a Mediterranean nutritional pattern appears to be one of the most beneficial dietetic regimens able to restore the host intestinal physiology, by promoting eubiosis and preserving the intestinal barrier and immune function, which in turn create a virtuous cycle improving patient adherence to the pattern. Further clinical studies are warranted, to corroborate current IBD nutritional guidelines, and develop more accurate models to move forward precision nutrition and ameliorate patients’ quality of life.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"102 ","pages":"Article 101349"},"PeriodicalIF":8.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}