Molecular biomedicine最新文献

{"title":"The disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases.","authors":"Min Tao, Yingfeng Shi, Hui Chen, Jinqing Li, Yi Wang, Xiaoyan Ma, Lin Du, Yishu Wang, Xinyu Yang, Yan Hu, Xun Zhou, Qin Zhong, Danying Yan, Andong Qiu, Shougang Zhuang, Na Liu","doi":"10.1186/s43556-023-00161-z","DOIUrl":"10.1186/s43556-023-00161-z","url":null,"abstract":"<p><p>The disruptor of telomeric silencing 1-like (DOT1L), a specific histone methyltransferase that catalyzed methylation of histone H3 on lysine 79, was associated with the pathogenesis of many diseases, but its role in peritoneal fibrosis remained unexplored. Here, we examined the role of DOT1L in the expression and activation of protein tyrosine kinases and development of peritoneal fibrosis. We found that a significant rise of DOT1L expression in the fibrotic peritoneum tissues from long-term PD patients and mice. Inhibition of DOT1L significantly attenuated the profibrotic phenotypic differentiation of mesothelial cells and macrophages, and alleviated peritoneal fibrosis. Mechanistically, RNA sequencing and proteomic analysis indicated that DOT1L was mainly involved in the processes of protein tyrosine kinase binding and extracellular matrix structural constituent in the peritoneum. Chromatin immunoprecipitation (ChIP) showed that intranuclear DOT1L guided H3K79me2 to upregulate EGFR in mesothelial cells and JAK3 in macrophages. Immunoprecipitation and immunofluorescence showed that extranuclear DOT1L could interact with EGFR and JAK3, and maintain the activated signaling pathways. In summary, DOT1L promoted the expression and activation of tyrosine kinases (EGFR in mesothelial cells and JAK3 in macrophages), promoting cells differentiate into profibrotic phenotype and thus peritoneal fibrosis. We provide the novel mechanism of dialysis-related peritoneal fibrosis (PF) and the new targets for clinical drug development. DOT1L inhibitor had the PF therapeutic potential.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"5 1","pages":"3"},"PeriodicalIF":4.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10764708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139089643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of a promising 5-gene prognostic model for pediatric acute myeloid leukemia.","authors":"Yu Tao, Li Wei, Norio Shiba, Daisuke Tomizawa, Yasuhide Hayashi, Seishi Ogawa, Li Chen, Hua You","doi":"10.1186/s43556-023-00162-y","DOIUrl":"10.1186/s43556-023-00162-y","url":null,"abstract":"<p><p>Risk classification in pediatric acute myeloid leukemia (P-AML) is crucial for personalizing treatments. Thus, we aimed to establish a risk-stratification tool for P-AML patients and eventually guide individual treatment. A total of 256 P-AML patients with accredited mRNA-seq data from the TARGET database were divided into training and internal validation datasets. A gene-expression-based prognostic score was constructed for overall survival (OS), by using univariate Cox analysis, LASSO regression analysis, Kaplan-Meier (K-M) survival, and multivariate Cox analysis. A P-AML-5G prognostic score bioinformatically derived from expression levels of 5 genes (ZNF775, RNFT1, CRNDE, COL23A1, and TTC38), clustered P-AML patients in training dataset into high-risk group (above optimal cut-off) with shorter OS, and low-risk group (below optimal cut-off) with longer OS (p < 0.0001). Meanwhile, similar results were obtained in internal validation dataset (p = 0.005), combination dataset (p < 0.001), two treatment sub-groups (p < 0.05), intermediate-risk group defined with the Children's Oncology Group (COG) (p < 0.05) and an external Japanese P-AML dataset (p = 0.005). The model was further validated in the COG study AAML1031(p = 0.001), and based on transcriptomic analysis of 943 pediatric patients and 70 normal bone marrow samples from this dataset, two genes in the model demonstrated significant differential expression between the groups [all log2(foldchange) > 3, p < 0.001]. Independent of other prognostic factors, the P-AML-5G groups presented the highest concordance-index values in training dataset, chemo-therapy only treatment subgroups of the training and internal validation datasets, and whole genome-sequencing subgroup of the combined dataset, outperforming two Children's Oncology Group (COG) risk stratification systems, 2022 European LeukemiaNet (ELN) risk classification tool and two leukemic stem cell expression-based models. The 5-gene prognostic model generated by a single assay can further refine the current COG risk stratification system that relies on numerous tests and may have the potential for the risk judgment and identification of the high-risk pediatric AML patients receiving chemo-therapy only treatment.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"5 1","pages":"1"},"PeriodicalIF":4.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10758381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139076143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomaterials barcoding: a high-throughput breakthrough.","authors":"Masoud Mozafari","doi":"10.1186/s43556-023-00163-x","DOIUrl":"10.1186/s43556-023-00163-x","url":null,"abstract":"","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"5 1","pages":"2"},"PeriodicalIF":4.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139081135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Activation and induction of antigen-specific T follicular helper cells play a critical role in recombinant SARS-CoV-2 RBD vaccine-induced humoral responses.","authors":"Songhao Yang, Liangwei Duan, Chan Wang, Cuiying Zhang, Siyu Hou, Hao Wang, Jiahui Song, Tingting Zhang, Zihua Li, Mingxia Wang, Jing Tang, Qianqian Zheng, Hui Wang, Qi Wang, Wei Zhao","doi":"10.1186/s43556-023-00152-0","DOIUrl":"10.1186/s43556-023-00152-0","url":null,"abstract":"","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"4 1","pages":"50"},"PeriodicalIF":4.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10728380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biofilm formation: mechanistic insights and therapeutic targets.","authors":"Xinyu Wang, Ming Liu, Chuanjiang Yu, Jing Li, Xikun Zhou","doi":"10.1186/s43556-023-00164-w","DOIUrl":"10.1186/s43556-023-00164-w","url":null,"abstract":"<p><p>Biofilms are complex multicellular communities formed by bacteria, and their extracellular polymeric substances are observed as surface-attached or non-surface-attached aggregates. Many types of bacterial species found in living hosts or environments can form biofilms. These include pathogenic bacteria such as Pseudomonas, which can act as persistent infectious hosts and are responsible for a wide range of chronic diseases as well as the emergence of antibiotic resistance, thereby making them difficult to eliminate. Pseudomonas aeruginosa has emerged as a model organism for studying biofilm formation. In addition, other Pseudomonas utilize biofilm formation in plant colonization and environmental persistence. Biofilms are effective in aiding bacterial colonization, enhancing bacterial resistance to antimicrobial substances and host immune responses, and facilitating cell‒cell signalling exchanges between community bacteria. The lack of antibiotics targeting biofilms in the drug discovery process indicates the need to design new biofilm inhibitors as antimicrobial drugs using various strategies and targeting different stages of biofilm formation. Growing strategies that have been developed to combat biofilm formation include targeting bacterial enzymes, as well as those involved in the quorum sensing and adhesion pathways. In this review, with Pseudomonas as the primary subject of study, we review and discuss the mechanisms of bacterial biofilm formation and current therapeutic approaches, emphasizing the clinical issues associated with biofilm infections and focusing on current and emerging antibiotic biofilm strategies.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"4 1","pages":"49"},"PeriodicalIF":6.3,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10721784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delivery of nucleic acids using nanomaterials.","authors":"Yuyang Qin, Liyuan Ou, Lili Zha, Yue Zeng, Ling Li","doi":"10.1186/s43556-023-00160-0","DOIUrl":"https://doi.org/10.1186/s43556-023-00160-0","url":null,"abstract":"<p><p>The increasing number of approved nucleic acid therapeutics demonstrates the potential for the prevention and treatment of a broad spectrum of diseases. This trend underscores the significant impact and promise of nucleic acid-based treatments in the field of medicine. Nevertheless, employing nucleic acids as therapeutics is challenging due to their susceptibility to degradation by nucleases and their unfavorable physicochemical characteristics that hinder delivery into cells. Appropriate vectors play a pivotal role in improving nucleic acid stability and delivering nucleic acids into specific cells. The maturation of delivery systems has led to breakthroughs in the development of therapeutics based on nucleic acids such as DNA, siRNA, and mRNA. Non-viral vectors have gained prominence among the myriad of nanomaterials due to low immunogenicity, ease of manufacturing, and simplicity of cost-effective, large-scale production. Here, we provide an overview of the recent advancements in nanomaterials for nucleic acid delivery. Specifically, we give a detailed introduction to the characteristics of polymers, lipids, and polymer-lipid hybrids, and provide comprehensive descriptions of their applications in nucleic acid delivery. Also, biological barriers, administration routes, and strategies for organ-selective delivery of nucleic acids are discussed. In summary, this review offers insights into the rational design of next-generation delivery vectors for nucleic acid delivery.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"4 1","pages":"48"},"PeriodicalIF":4.0,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10719232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure, function and drug discovery of GPCR signaling.","authors":"Lin Cheng, Fan Xia, Ziyan Li, Chenglong Shen, Zhiqian Yang, Hanlin Hou, Suyue Sun, Yuying Feng, Xihao Yong, Xiaowen Tian, Hongxi Qin, Wei Yan, Zhenhua Shao","doi":"10.1186/s43556-023-00156-w","DOIUrl":"10.1186/s43556-023-00156-w","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes and responses, such as sensory perception (e.g., vision, taste, and smell), immune response, hormone regulation, and neurotransmission. Their diverse and essential roles in the body make them a significant focus for pharmaceutical research and drug development. Currently, approximately 35% of marketed drugs directly target GPCRs, underscoring their prominence as therapeutic targets. Recent advances in structural biology have substantially deepened our understanding of GPCR activation mechanisms and interactions with G-protein and arrestin signaling pathways. This review offers an in-depth exploration of both traditional and recent methods in GPCR structure analysis. It presents structure-based insights into ligand recognition and receptor activation mechanisms and delves deeper into the mechanisms of canonical and noncanonical signaling pathways downstream of GPCRs. Furthermore, it highlights recent advancements in GPCR-related drug discovery and development. Particular emphasis is placed on GPCR selective drugs, allosteric and biased signaling, polyphamarcology, and antibody drugs. Our goal is to provide researchers with a thorough and updated understanding of GPCR structure determination, signaling pathway investigation, and drug development. This foundation aims to propel forward-thinking therapeutic approaches that target GPCRs, drawing upon the latest insights into GPCR ligand selectivity, activation, and biased signaling mechanisms.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"4 1","pages":"46"},"PeriodicalIF":4.0,"publicationDate":"2023-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10695916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein E (ApoE) orchestrates adipose tissue inflammation and metabolic disorders through NLRP3 inflammasome","authors":"Yulin Zhang, Ziwei Cheng, Liyu Hong, Jia Liu, Xinyue Ma, Wenjing Wang, Ran Pan, Wenjie Lu, Qichao Luo, Shan Gao, Qin Kong","doi":"10.1186/s43556-023-00158-8","DOIUrl":"https://doi.org/10.1186/s43556-023-00158-8","url":null,"abstract":"","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":" 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138617074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms by which the intestinal microbiota affects gastrointestinal tumours and therapeutic effects.","authors":"Jikai He, Haijun Li, Jiaqi Jia, Yang Liu, Ning Zhang, Rumeng Wang, Wenhao Qu, Yanqi Liu, Lizhou Jia","doi":"10.1186/s43556-023-00157-9","DOIUrl":"10.1186/s43556-023-00157-9","url":null,"abstract":"<p><p>The intestinal microbiota is considered to be a forgotten organ in human health and disease. It maintains intestinal homeostasis through various complex mechanisms. A significant body of research has demonstrated notable differences in the gut microbiota of patients with gastrointestinal tumours compared to healthy individuals. Furthermore, the dysregulation of gut microbiota, metabolites produced by gut bacteria, and related signal pathways can partially explain the mechanisms underlying the occurrence and development of gastrointestinal tumours. Therefore, this article summarizes the latest research progress on the gut microbiota and gastrointestinal tumours. Firstly, we provide an overview of the composition and function of the intestinal microbiota and discuss the mechanisms by which the intestinal flora directly or indirectly affects the occurrence and development of gastrointestinal tumours by regulating the immune system, producing bacterial toxins, secreting metabolites. Secondly, we present a detailed analysis of the differences of intestinal microbiota and its pathogenic mechanisms in colorectal cancer, gastric cancer, hepatocellular carcinoma, etc. Lastly, in terms of treatment strategies, we discuss the effects of the intestinal microbiota on the efficacy and toxic side effects of chemotherapy and immunotherapy and address the role of probiotics, prebiotics, FMT and antibiotic in the treatment of gastrointestinal tumours. In summary, this article provides a comprehensive review of the pathogenic mechanisms of and treatment strategies pertaining to the intestinal microbiota in patients with gastrointestinal tumours. And provide a more comprehensive and precise scientific basis for the development of microbiota-based treatments for gastrointestinal tumours and the prevention of such tumours.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"4 1","pages":"45"},"PeriodicalIF":4.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10689341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138464900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteopontin enhances the effect of treadmill training and promotes functional recovery after spinal cord injury.","authors":"Yunhang Wang, Hong Su, Juan Zhong, Zuxiong Zhan, Qin Zhao, Yuan Liu, Sen Li, Haiyan Wang, Ce Yang, Lehua Yu, Botao Tan, Ying Yin","doi":"10.1186/s43556-023-00154-y","DOIUrl":"10.1186/s43556-023-00154-y","url":null,"abstract":"<p><p>In this study, we examined the combined impact of osteopontin (OPN) and treadmill training on mice with spinal cord injury (SCI). OPN was overexpressed by injecting AAV9-SPP1-GFP into the sensorimotor cortex, followed by a left incomplete C5 crush injury two weeks later. Mice (Ex or Ex + OPN group) were trained at 50% maximum running speed for 8 weeks. To analyze the effects, we used biotinylated dextran amine (BDA) for tracing the corticospinal tract (CST) and performed Western blotting and immunohistochemical methods to assess the activation of the mammalian target of rapamycin (mTOR). We also examined axonal regeneration and conducted behavioral tests to measure functional recovery. The results demonstrated that treadmill training promoted the expression of neurotrophic factors such as brain-derived neurotrophic factor (BNDF) and insulin-like growth factor I (IGF-1) and activated mTOR signaling. OPN amplified the effect of treadmill training on activating mTOR signaling indicated by upregulated phosphorylation of ribosomal protein S6 kinase (S6). The combination of OPN and exercise further promoted functional recovery and facilitated limited CST axonal regeneration which did not occur with treadmill training and OPN treatment alone. These findings indicate that OPN enhances the effects of treadmill training in the treatment of SCI and offer new therapeutic insights for spinal cord injury.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"4 1","pages":"44"},"PeriodicalIF":4.0,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10684450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138447428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}