Molecular Aspects of Medicine最新文献

{"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":"2025-06-01","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":"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":"2025-06-01","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":"Autophagy signaling mediated by non-coding RNAs: Impact on breast cancer progression and treatment","authors":"Lei Yan ,&nbsp;Zhuo Quan ,&nbsp;Tiantian Sun ,&nbsp;Jiajun Wang","doi":"10.1016/j.mam.2025.101365","DOIUrl":"10.1016/j.mam.2025.101365","url":null,"abstract":"<div><div>Autophagy, a conserved cellular mechanism which detoxifies and degrades intracellular structures or biomolecules, has been identified as an important factor in the progression of human breast cancer and the development of treatment resistance. Non-coding RNAs (ncRNAs), a broad family of RNA, have the ability to influence various processes, including autophagy, due to their diverse downstream targets. ncRNAs play an important role in suppressing or activating autophagy by targeting autophagy-triggering components such as the ULK1 complex, Beclin1, and ATGs. Recent research has uncovered the intricate regulatory networks that govern autophagy dynamics, with ncRNAs emerging as key participants in this network. miRNAs, lncRNAs, and circRNAs are the three subfamilies of ncRNAs that have the most well-known interactions with autophagy, particularly macroautophagy. The high prevalence of breast cancer necessitates research into finding new biological processes that can help in early detection as well as enhance the effectiveness of treatment. The positive/negative link between autophagy and ncRNAs can be exploited as a supplementary therapy to improve sensitivity to treatment in breast cancer. This review investigates the regulatory roles of ncRNAs, particularly microRNAs (miRNAs), in modifying autophagy pathways in human breast cancer progression and treatment. However, future studies and clinical practice are needed to determine the most relevant microRNAs as biomarkers and also to better understand their role in breast cancer progression or treatment through modifying autophagy.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"103 ","pages":"Article 101365"},"PeriodicalIF":8.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881590","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":"Metabolic reprogramming of drug resistance in pancreatic cancer: mechanisms and effects","authors":"Jinyi Zhang ,&nbsp;Xueqing Kong ,&nbsp;Boyan Zhou ,&nbsp;Rui Li ,&nbsp;Zhaoan Yu ,&nbsp;Jinrong Zhu ,&nbsp;Qing Xi ,&nbsp;Yan Li ,&nbsp;Zichao Zhao ,&nbsp;Rongxin Zhang","doi":"10.1016/j.mam.2025.101368","DOIUrl":"10.1016/j.mam.2025.101368","url":null,"abstract":"<div><div>Pancreatic cancer is a highly aggressive gastrointestinal malignancy, often termed the “king of cancers” due to its notoriously high mortality rate. Its clinical characteristics, including late diagnosis, low surgical resectability, high recurrence rates, significant chemoresistance, and poor prognosis have collectively driven the persistent rise in incidence and mortality. Despite ongoing advancements in therapeutic strategies, the management of pancreatic cancer, particularly at advanced stages, remains challenging. Chemotherapy remains the mainstay of current treatment. However, the prevalent problem of chemotherapy resistance poses a significant obstacle to effective treatment. Metabolic reprogramming, characterized by alterations in glucose metabolism, lipid biosynthesis, and amino acid utilization, supports the high energy demands and rapid proliferation of cancer cells. Emerging evidence suggests that these metabolic changes, possibly mediated by epigenetic mechanisms, also contribute to tumorigenesis and metastasis. These findings highlight the critical role of metabolic alterations in pancreatic cancer pathogenesis. This review explores the relationship between metabolic reprogramming and chemotherapy resistance, discussing underlying mechanisms and summarizing preclinical studies and drug development targeting metabolism. The aim is to provide a comprehensive perspective on potential therapeutic strategies for pancreatic cancer.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"103 ","pages":"Article 101368"},"PeriodicalIF":8.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089107","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":"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":"2025-04-01","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":"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":"2025-04-01","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}

{"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":"2025-04-01","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":"When to suspect and how properly early detect and treat patients with endemic mycoses","authors":"Arnaldo L. Colombo ,&nbsp;Paula M. Peçanha-Pietrobom ,&nbsp;Daniel Wagner de C.L. Santos ,&nbsp;Diego H. Caceres","doi":"10.1016/j.mam.2025.101348","DOIUrl":"10.1016/j.mam.2025.101348","url":null,"abstract":"<div><div>Endemic mycoses are caused by dimorphic fungi and eventually molds, as the case of implantation mycoses. In general, these diseases are acquired through trauma or inhalation of fungal elements in the environment, and less frequently by zoonotic acquisition or transmitted during organ transplantation. The target population for endemic mycoses is usually represented by normal hosts with low-income and intensive outdoor activities. Awareness of these diseases remains limited, even in regions with high prevalence, resulting in delayed diagnosis, and affecting the quality of life and outcomes of patients who suffer from these entities. In this review, we summarized relevant information about epidemiological, clinical, diagnostic, and treatment aspects of the most common endemic mycoses, including blastomycosis, coccidioidomycosis, histoplasmosis, paracoccidioidomycoses, talaromycosis, and implantation mycoses. The main goal of this review is to provide key concepts in terms of when to suspect, how early diagnose, and properly treat patients with these mycoses.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"102 ","pages":"Article 101348"},"PeriodicalIF":8.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143295999","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 molecular code of kidney cancer: A path of discovery for gene mutation and precision therapy","authors":"Deqian Xie ,&nbsp;Guandu Li ,&nbsp;Zunwen Zheng ,&nbsp;Xiaoman Zhang ,&nbsp;Shijin Wang ,&nbsp;Bowen Jiang ,&nbsp;Xiaorui Li ,&nbsp;Xiaoxi Wang ,&nbsp;Guangzhen Wu","doi":"10.1016/j.mam.2024.101335","DOIUrl":"10.1016/j.mam.2024.101335","url":null,"abstract":"<div><div>Renal cell carcinoma (RCC) is a malignant tumor with highly heterogeneous and complex molecular mechanisms. Through systematic analysis of TCGA, COSMIC and other databases, 24 mutated genes closely related to RCC were screened, including VHL, PBRM1, BAP1 and SETD2, which play key roles in signaling pathway transduction, chromatin remodeling and DNA repair. The PI3K/AKT/mTOR signaling pathway is particularly important in the pathogenesis of RCC. Mutations in genes such as PIK3CA, MTOR and PTEN are closely associated with metabolic abnormalities and tumor cell proliferation. Clinically, mTOR inhibitors and VEGF-targeted drugs have shown significant efficacy in personalized therapy. Abnormal regulation of metabolic reprogramming, especially glycolysis and glutamine metabolic pathways, provides tumor cells with continuous energy supply and survival advantages, and GLS1 inhibitors have shown promising results in preclinical studies. This paper also explores the potential of immune checkpoint inhibitors in combination with other targeted drugs, as well as the promising application of nanotechnology in drug delivery and targeted therapy. In addition, unique molecular mechanisms are revealed and individualized therapeutic strategies are explored for specific subtypes such as TFE3, TFEB rearrangement type and SDHB mutant type. The review summarizes the common gene mutations in RCC and their molecular mechanisms, emphasizes their important roles in tumor diagnosis, treatment and prognosis, and looks forward to the application prospects of multi-pathway targeted therapy, metabolic targeted therapy, immunotherapy and nanotechnology in RCC treatment, providing theoretical support and clinical guidance for individualized treatment and new drug development.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"101 ","pages":"Article 101335"},"PeriodicalIF":8.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923554","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":"The folding and misfolding of multidomain proteins","authors":"Stefano Gianni,&nbsp;Maurizio Brunori","doi":"10.1016/j.mam.2025.101337","DOIUrl":"10.1016/j.mam.2025.101337","url":null,"abstract":"<div><div>Protein folding represents a vital process for any living organism. While significant insights have been gained from studying single-domain proteins, our current knowledge on the folding mechanisms of multidomain proteins remains relatively limited, primarily due to their inherent complexity. The principal aim of this review lies in summarizing the emerging view pertaining multi-domain folding, emphasizing their modular nature, which minimizes misfolding and facilitates evolutionary innovation. We discuss the energetic interplay between domains, highlighting particularly the cases where domain interactions lead to transient misfolded intermediates. These interactions can result in diverse effects, including cooperative folding and domain-specific perturbations, which are particularly relevant to the pathogenesis of neurodegenerative diseases like polyglutamine disorders. The review underscores the critical need to understand multidomain folding, to better comprehend and potentially mitigate the molecular underpinnings of protein misfolding diseases.</div></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"101 ","pages":"Article 101337"},"PeriodicalIF":8.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967331","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}