Genes & Diseases最新文献

SIRT5 promotes the osteo-inductive potential of BMP9 by stabilizing the HIF-1α protein in mouse embryonic fibroblasts

IF 6.9 2区医学

Genes & Diseases Pub Date : 2025-02-18 DOI: 10.1016/j.gendis.2025.101563

Lu Liu , Fanglin Ye , Yue Jiang , Wenting Liu , Dongmei He , Wenge He , Xiang Gao , Hang Liu , Junyi Liao , Baicheng He , Fang He

{"title":"SIRT5 promotes the osteo-inductive potential of BMP9 by stabilizing the HIF-1α protein in mouse embryonic fibroblasts","authors":"Lu Liu , Fanglin Ye , Yue Jiang , Wenting Liu , Dongmei He , Wenge He , Xiang Gao , Hang Liu , Junyi Liao , Baicheng He , Fang He","doi":"10.1016/j.gendis.2025.101563","DOIUrl":"10.1016/j.gendis.2025.101563","url":null,"abstract":"<div><div>Bone morphogenetic protein 9 (BMP9) exhibits remarkable osteogenic potential. However, the intricate mechanisms driving this function of BMP9 remain elusive. This study endeavors to investigate the potential role of sirtuin 5 (SIRT5) in enhancing BMP9's osteogenic capacity and decipher the underlying molecular pathways. To achieve this aim, we employed real-time PCR, western blotting, histochemical staining, and a cranial defect repair model to assess the impact of SIRT5 on BMP9-mediated osteogenesis. We utilized real-time PCR, western blotting, immunofluorescent staining, and immunoprecipitation assay to explore the associated mechanisms. Our results revealed that SIRT5 significantly up-regulated BMP9-induced osteogenic markers, while SIRT5 knockdown reduced their expression. Concurrently, hypoxia-inducible factor 1 subunit alpha (HIF-1α) level was increased by SIRT5, but reduced by SIRT5 knockdown. Notably, HIF-1α potentiated the SIRT5's ability to strengthen BMP9's osteogenic potential, whereas HIF-1α silencing reduced this effect, which was confirmed by bone defect repair assay. The acetylation and malonylation levels of HIF-1α were reduced by SIRT5, which may enhance its stability to promote BMP9's osteogenic effect. Conversely, SIRT5 knockdown reversed these effects and promoted the degradation of HIF-1α. Collectively, our results demonstrated that the BMP9's osteogenic potential could be promoted by SIRT5, potentially through stabilizing HIF-1α by reducing its acetylation and malonylation modification. This discovery may offer a novel strategy to accelerate bone tissue engineering by enhancing osteogenic differentiation, and it also sheds light on the possible mechanisms underlying BMP9-mediated osteogenic differentiation.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 4","pages":"Article 101563"},"PeriodicalIF":6.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859155","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}

引用次数: 0

Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease

IF 6.9 2区医学

Genes & Diseases Pub Date : 2025-02-15 DOI: 10.1016/j.gendis.2025.101554

Yannian Gou , Aohua Li , Xiangyu Dong , Ailing Hao , Jiajia Li , Han Xiang , Saidur Rahaman , Tong-Chuan He , Jiaming Fan

{"title":"Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease","authors":"Yannian Gou , Aohua Li , Xiangyu Dong , Ailing Hao , Jiajia Li , Han Xiang , Saidur Rahaman , Tong-Chuan He , Jiaming Fan","doi":"10.1016/j.gendis.2025.101554","DOIUrl":"10.1016/j.gendis.2025.101554","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) patients have multiple metabolic disturbances, with markedly elevated levels of lactate. Lactate accumulations play pleiotropic roles in disease progression through metabolic rearrangements and epigenetic modifications. Monocarboxylate transporter 4 (MCT4) is highly expressed in hepatocytes and responsible for transporting intracellular lactate out of the cell. To explore whether elevated MCT4 levels played any role in NAFLD development, we overexpressed and silenced MCT4 in hepatocytes and performed a comprehensive <em>in vitro</em> and <em>in vivo</em> analysis. Our results revealed that MCT4 overexpression down-regulated the genes for lipid synthesis while up-regulating the genes involved in lipid catabolism. Conversely, silencing MCT4 expression or inhibiting MCT4 expression led to the accumulation of intracellular lipid and glucose metabolites, resulting in hepatic steatosis. In a mouse model of NAFLD, we found that exogenous MCT4 overexpression significantly reduced lipid metabolism and alleviated hepatocellular steatosis. Mechanistically, MCT4 alleviated hepatic steatosis by regulating a group of hub genes such as <em>Arg2</em>, <em>Olr1</em>, <em>Cd74</em>, <em>Mmp8, Irf7</em>, <em>Spp1</em>, and <em>Apoe</em>, which in turn impacted multiple pathways involved in lipid metabolism and inflammatory response, such as PPAR, HIF-1, TNF, IL-17, PI3K-AKT, Wnt, and JAK-STAT. Collectively, our results strongly suggest that MCT4 may play an important role in regulating lipid metabolism and inflammation and thus serve as a potential therapeutic target for NAFLD.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 4","pages":"Article 101554"},"PeriodicalIF":6.9,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859269","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}

引用次数: 0

A causal association between immune cells and hypertrophic cardiomyopathy: A bidirectional Mendelian randomization study

IF 6.9 2区医学

Genes & Diseases Pub Date : 2025-01-21 DOI: 10.1016/j.gendis.2025.101539

Fang He , Qiangzhong Pi , Jun Yang , Mengning Wan , Jiang Yu , Ding Yang , Yongzheng Guo , Xiaorong Li

引用次数: 0

In vivo consequences of varying degrees of OTOA alteration elucidated using knock-in mouse models and pseudogene contamination-free long-read sequencing

IF 6.9 2区医学

Genes & Diseases Pub Date : 2025-01-18 DOI: 10.1016/j.gendis.2025.101533

Ju Ang Kim , Bong Jik Kim , Chung Lee , Go Hun Seo , Hane Lee , Jin Hee Han , Ava Niazi , Joosang Park , Byung Yoon Choi , Sungjin Park

引用次数: 0

NADK tetramer defective mutants affect lung cancer response to chemotherapy via controlling NADK activity

IF 6.9 2区医学

Genes & Diseases Pub Date : 2025-01-07 DOI: 10.1016/j.gendis.2024.101510

Mengxue Hu , Fuxing Wang , Yue Zhu , Yi Yao , Huadong Pei , Zheng Liu , Pingfeng Zhang

{"title":"NADK tetramer defective mutants affect lung cancer response to chemotherapy via controlling NADK activity","authors":"Mengxue Hu , Fuxing Wang , Yue Zhu , Yi Yao , Huadong Pei , Zheng Liu , Pingfeng Zhang","doi":"10.1016/j.gendis.2024.101510","DOIUrl":"10.1016/j.gendis.2024.101510","url":null,"abstract":"<div><div>Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) kinase (NADK) phosphorylates NAD<sup>+</sup> to generate NADP<sup>+</sup>, which plays a crucial role in maintaining NAD<sup>+</sup>/NADP<sup>+</sup> homeostasis, cellular redox balance, and metabolism. However, how human NADK activity is regulated, and how dysregulation or mutation of NADK is linked to human diseases, such as cancers, are still not fully understood. Here, we present a cryo-EM structure of human tetrameric NADK and elaborate on the necessity of the NADK tetramer for its activity. The N-terminal region of human NADK, which does not exist in bacterial NADKs, modulates tetramer conformation, thereby regulating its activity. A methylation-deficient mutant, R45H, within the N-terminal region results in increased NADK activity and confers cancer chemotherapy resistance. Conversely, mutations in NADK identified among cancer patients alter the tetramer conformation, resulting in NADK inactivation and increasing the sensitivity of lung cancer cells to chemotherapy. Our findings partially unveil the structural basis for NADK regulation, offering insights into the cancer etiology of patients carrying NADK mutations.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 4","pages":"Article 101510"},"PeriodicalIF":6.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852196","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}

引用次数: 0

Integrated multi-omics characterization of neuroblastoma with bone or bone marrow metastasis 神经母细胞瘤骨转移或骨髓转移的多组学综合表征

IF 6.9 2区医学

Genes & Diseases Pub Date : 2025-01-03 DOI: 10.1016/j.gendis.2024.101511

Kai Huang , Linyu Yang , Yue Ma, Lijian Cao, Suwen Li, Zhenzhen Zhao, Jianwu Zhou, Shan Wang

{"title":"Integrated multi-omics characterization of neuroblastoma with bone or bone marrow metastasis","authors":"Kai Huang , Linyu Yang , Yue Ma, Lijian Cao, Suwen Li, Zhenzhen Zhao, Jianwu Zhou, Shan Wang","doi":"10.1016/j.gendis.2024.101511","DOIUrl":"10.1016/j.gendis.2024.101511","url":null,"abstract":"<div><div>The pathogenesis of neuroblastoma with bone or bone marrow metastasis (NB-BBM) and its complex immune microenvironment remain poorly elucidated, hampering the advancement of effective risk prediction for BBM and limiting therapeutic strategies. Feature recognition of 142 paraffin-embedded hematoxylin-eosin-stained tumor section images was conducted using a Swin-Transformer for pathological histology to predict NB-BBM occurrence. Single-cell transcriptomics identified a tumor cell subpopulation (NB3) and two tumor-associated macrophage (TAM) subpopulations (SPP1<sup>+</sup> TAMs and IGHM<sup>+</sup> TAMs) closely associated with BBM and highlighted transketolase (TKT) as a key molecular marker for metastatic progression in NB. This extensive multi-omics investigation into NB-BBM enhances our understanding of single-cell transcriptional dynamics in NB beyond existing research, outlining the evolution from <em>in situ</em> carcinoma through tumorigenesis to bone marrow metastases. Furthermore, exploration of the immune microenvironment identified specific subpopulations of TAMs crucial in promoting NB-BBM, presenting new avenues for immunotherapy. These insights enhance our understanding of the metastatic process from NB to BBM and facilitate the development of more effective diagnostic and therapeutic strategies for this aggressive pediatric cancer.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 3","pages":"Article 101511"},"PeriodicalIF":6.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464631","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}

引用次数: 0

The role of lncRNAs in AKI and CKD: Molecular mechanisms, biomarkers, and potential therapeutic targets lncRNA 在 AKI 和 CKD 中的作用：分子机制、生物标记物和潜在治疗靶点

IF 6.9 2区医学

Genes & Diseases Pub Date : 2024-12-30 DOI: 10.1016/j.gendis.2024.101509

Minhui Zheng , Zixuan Yang , Lei Shi , Liyuan Zhao , Kelan Liu , Naping Tang

引用次数: 0

GATA2 up-regulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer

IF 6.9 2区医学

Genes & Diseases Pub Date : 2024-12-28 DOI: 10.1016/j.gendis.2024.101508

Tianyi Zhou , Chengtai Yu , Yali Han , Bin He , Qin Feng

引用次数: 0

Bcl6 controls the stability and suppressive function of regulatory T cells in head and neck squamous cell carcinoma

IF 6.9 2区医学

Genes & Diseases Pub Date : 2024-12-26 DOI: 10.1016/j.gendis.2024.101505

Shuqiong Wen , Xingxing Su , Junyi Guo , Zhanpeng Ou , Lisha Wang , Zhengliang Yue , Jing Zhao , Ling Ran , Jianjun Hu , Yuzhu Wang , Mengqu Ran , Qinyi He , Ping Ji , Lilin Ye , Zhiyu Chen , Lifan Xu , Qizhao Huang

引用次数: 0

A novel BCAT1 inhibitor bufalin sensitizes pancreatic cancer cells to chemotherapy

IF 6.9 2区医学

Genes & Diseases Pub Date : 2024-12-24 DOI: 10.1016/j.gendis.2024.101503

Wei Zhang , Yibao Fan , Milad Ashrafizadeh , Dan Shi , Gautam Sethi , Yavuz Nuri Ertas , A.M. Abd El-Aty , Xianbin Zhang , Si Chen , Peng Gong

引用次数: 0