Disease Models & Mechanisms最新文献_第9页

A zebrafish model of diabetic nephropathy shows hyperglycemia, proteinuria and activation of the PI3K/Akt pathway. 开发新型糖尿病肾病斑马鱼模型。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-29 DOI: 10.1242/dmm.050438

Liqing Zang, Sei Saitoh, Kan Katayama, Weibin Zhou, Norihiro Nishimura, Yasuhito Shimada

{"title":"A zebrafish model of diabetic nephropathy shows hyperglycemia, proteinuria and activation of the PI3K/Akt pathway.","authors":"Liqing Zang, Sei Saitoh, Kan Katayama, Weibin Zhou, Norihiro Nishimura, Yasuhito Shimada","doi":"10.1242/dmm.050438","DOIUrl":"10.1242/dmm.050438","url":null,"abstract":"Diabetic nephropathy (DN), as a complication of diabetes, is a substantial healthcare challenge owing to the high risk of morbidity and mortality involved. Although significant progress has been made in understanding the pathogenesis of DN, more efficient models are required to develop new therapeutics. Here, we created a DN model in zebrafish by crossing diabetic Tg(acta1:dnIGF1R-EGFP) and proteinuria-tracing Tg(l-fabp::VDBP-GFP) lines, named zMIR/VDBP. Overfed adult zMIR/VDBP fish developed severe hyperglycemia and proteinuria, which were not observed in wild-type zebrafish. Renal histopathology revealed human DN-like characteristics, such as glomerular basement membrane thickening, foot process effacement and glomerular sclerosis. Glomerular dysfunction was restored upon calorie restriction. RNA sequencing analysis demonstrated that DN zebrafish kidneys exhibited transcriptional patterns similar to those seen in human DN pathogenesis. Notably, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was activated, a phenomenon observed in the early phase of human DN. In addition, metformin improved hyperglycemia and proteinuria in DN zebrafish by modulating Akt phosphorylation. Our results indicate that zMIR/VDBP fish are suitable for elucidating the mechanisms underlying human DN and could be a powerful tool for therapeutic discovery.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11152558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Modelling human genetic disorders in Xenopus tropicalis. 在热带爪蟾中模拟人类遗传疾病。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-06-04 DOI: 10.1242/dmm.050754

Helen Rankin Willsey, Eleanor G Seaby, Annie Godwin, Sarah Ennis, Matthew Guille, Robert M Grainger

引用次数: 0

DMM Outstanding Paper Prize 2023 winners: Lídia Faria, Ffion R. Hammond and Amy Lewis. 2023 年 DMM 优秀论文奖获得者：Lídia Faria、Ffion R. Hammond 和 Amy Lewis。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-06-05 DOI: 10.1242/dmm.050893

Rachel Hackett

引用次数: 0

The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease. 糖皮质激素受体在局部发挥作用，在疾病期间保护肌营养不良的肌肉和心脏。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-21 DOI: 10.1242/dmm.050397

Trinitee Oliver, Nhu Y Nguyen, Christopher B Tully, Nikki M McCormack, Christina M Sun, Alyson A Fiorillo, Christopher R Heier

{"title":"The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease.","authors":"Trinitee Oliver, Nhu Y Nguyen, Christopher B Tully, Nikki M McCormack, Christina M Sun, Alyson A Fiorillo, Christopher R Heier","doi":"10.1242/dmm.050397","DOIUrl":"10.1242/dmm.050397","url":null,"abstract":"Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD. Here, we knocked out the glucocorticoid receptor (GR, encoded by Nr3c1) specifically in myofibers and cardiomyocytes within wild-type and mdx52 mice to dissect its role in muscular dystrophy. Double-knockout mice showed significantly worse phenotypes than mdx52 littermate controls in measures of grip strength, hang time, inflammatory pathology and gene expression. In the heart, GR deletion acted additively with dystrophin loss to exacerbate cardiomyopathy, resulting in enlarged hearts, pathological gene expression and systolic dysfunction, consistent with imbalanced mineralocorticoid signaling. The results show that physiological GR functions provide a protective role during muscular dystrophy, directly contrasting its degenerative role in other disease states. These data provide new insights into corticosteroids in disease pathophysiology and establish a new model to investigate cell-autonomous roles of nuclear receptors and mechanisms of pharmacological corticosteroids.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner. 一种与渐冻症相关的突变以性别特异性的方式使小胶质细胞衍生的细胞外microRNA失调。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-29 DOI: 10.1242/dmm.050638

Eleni Christoforidou, Libby Moody, Greig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid Hafezparast

{"title":"An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.","authors":"Eleni Christoforidou, Libby Moody, Greig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid Hafezparast","doi":"10.1242/dmm.050638","DOIUrl":"10.1242/dmm.050638","url":null,"abstract":"Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner. 与ALS相关的TDP-43M337V突变以性别特异性的方式使小胶质细胞衍生的细胞外microRNA失调。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-29 DOI: 10.1242/dmm.050638

Eleni Christoforidou, Libby Moody, Greig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid Hafezparast

{"title":"An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.","authors":"Eleni Christoforidou, Libby Moody, Greig Joilin, Fabio A Simoes, David Gordon, Kevin Talbot, Majid Hafezparast","doi":"10.1242/dmm.050638","DOIUrl":"10.1242/dmm.050638","url":null,"abstract":"Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11152562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Investigating pulmonary neuroendocrine cells in human respiratory diseases with airway models. 利用气道模型研究人类呼吸系统疾病中的肺神经内分泌细胞。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-30 DOI: 10.1242/dmm.050620

Noah Candeli, Talya Dayton

引用次数: 0

Evaluating protein prenylation of human and viral CaaX sequences using a humanized yeast system. 利用人源化酵母系统评估人类和病毒 CaaX 序列的蛋白质前酰化。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-31 DOI: 10.1242/dmm.050516

Emily R Hildebrandt, Anushka Sarkar, Rajani Ravishankar, June H Kim, Walter K Schmidt

{"title":"Evaluating protein prenylation of human and viral CaaX sequences using a humanized yeast system.","authors":"Emily R Hildebrandt, Anushka Sarkar, Rajani Ravishankar, June H Kim, Walter K Schmidt","doi":"10.1242/dmm.050516","DOIUrl":"10.1242/dmm.050516","url":null,"abstract":"Prenylated proteins are prevalent in eukaryotic biology (∼1-2% of proteins) and are associated with human disease, including cancer, premature aging and infections. Prenylated proteins with a C-terminal CaaX sequence are targeted by CaaX-type prenyltransferases and proteases. To aid investigations of these enzymes and their targets, we developed Saccharomyces cerevisiae strains that express these human enzymes instead of their yeast counterparts. These strains were developed in part to explore human prenyltransferase specificity because of findings that yeast FTase has expanded specificity for sequences deviating from the CaaX consensus (i.e. atypical sequence and length). The humanized yeast strains displayed robust prenyltransferase activity against CaaX sequences derived from human and pathogen proteins containing typical and atypical CaaX sequences. The system also recapitulated prenylation of heterologously expressed human proteins (i.e. HRas and DNAJA2). These results reveal that substrate specificity is conserved for yeast and human farnesyltransferases but is less conserved for type I geranylgeranyltransferases. These yeast systems can be easily adapted for investigating the prenylomes of other organisms and are valuable new tools for helping define the human prenylome, which includes physiologically important proteins for which the CaaX modification status is unknown.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11152559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Modelling the micro- and macro- environment of pancreatic cancer: from patients to pre-clinical models and back. 胰腺癌微观和宏观环境建模：从患者到临床前模型再到临床前模型。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-04-19 DOI: 10.1242/dmm.050624

Eloise G Lloyd, Joaquín Araos Henríquez, Giulia Biffi

引用次数: 0

Improving access to gene therapy for rare diseases. 改善罕见病基因治疗的可及性。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-04-19 DOI: 10.1242/dmm.050623

Thomas A Fox, Claire Booth

引用次数: 0