Disease Models & Mechanisms最新文献_第4页

Compromised COPII vesicle trafficking leads to glycogenic hepatopathy. COPII囊泡贩运功能受损导致斑马鱼糖源性肝病

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1242/dmm.050748

Yuxi Yang, Xue Zhang, Qingshun Zhao, Jingzi Zhang, Xin Lou

{"title":"Compromised COPII vesicle trafficking leads to glycogenic hepatopathy.","authors":"Yuxi Yang, Xue Zhang, Qingshun Zhao, Jingzi Zhang, Xin Lou","doi":"10.1242/dmm.050748","DOIUrl":"10.1242/dmm.050748","url":null,"abstract":"Being a vital cellular process, coat protein complex II (COPII) vesicle trafficking has been found to play a crucial role in liver metabolism. However, its functions and the underlying mechanisms in systemic metabolic homeostasis have not been fully understood. Here, with a newly identified gene trap zebrafish line (sec31anju221), we show that compromised COPII vesicle trafficking leads to biphasic abnormal hepatic metabolism. During the larval stage, deficiency of COPII-mediated trafficking leads to activation of the unfolded protein response and the development of hepatic steatosis. By using epistasis analysis, we found that the eIF2α-ATF4 pathway serves as the primary effector for liver steatosis. In adult sec31anju221 fish, the hepatosteatosis was reversed and the phenotype switched to glycogenic hepatopathy. Proteomic profiling and biochemical assays indicate that sec31anju221 fish are in a state of hypothyroidism. Moreover, our study shows that thyroid hormone treatment alleviates the metabolic defects. This study provides insights into processes of liver diseases associated with vesicle trafficking impairments and expands our understanding of the pathological interplay between thyroid and liver.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975265","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

Correction: Stimulating the sir2-spargel axis rescues exercise capacity and mitochondrial respiration in a Drosophila model of Barth syndrome. 更正：在巴特综合征果蝇模型中，刺激sir2-spargel轴可恢复运动能力和线粒体呼吸。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-26 DOI: 10.1242/dmm.052040

Deena Damschroder, Rubén Zapata-Pérez, Kristin Richardson, Frédéric M Vaz, Riekelt H Houtkooper, Robert Wessells

引用次数: 0

Activation of the heat shock response as a therapeutic strategy for tau toxicity. 激活热休克反应作为治疗 tau 毒性的一种策略。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-10-01 DOI: 10.1242/dmm.050635

Taylor R Stanley, Elizabeth M Otero, Amy L Knight, Aleen D Saxton, Xinxing Ding, Melissa Borgen, Brian C Kraemer, Karen S Kim Guisbert, Eric Guisbert

{"title":"Activation of the heat shock response as a therapeutic strategy for tau toxicity.","authors":"Taylor R Stanley, Elizabeth M Otero, Amy L Knight, Aleen D Saxton, Xinxing Ding, Melissa Borgen, Brian C Kraemer, Karen S Kim Guisbert, Eric Guisbert","doi":"10.1242/dmm.050635","DOIUrl":"10.1242/dmm.050635","url":null,"abstract":"Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343409","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

Staphylococcus aureus lipid factors modulate melanoma cell clustering and invasion. 金黄色葡萄球菌脂质因子调节黑色素瘤细胞的聚集和侵袭

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-16 DOI: 10.1242/dmm.050770

Morgan A Giese, Gayathri Ramakrishnan, Laura H Steenberge, Jerome X Dovan, John-Demian Sauer, Anna Huttenlocher

引用次数: 0

Generation and characterization of a novel mouse model of Becker Muscular Dystrophy with a deletion of exons 52 to 55. 外显子 52 至 55 缺失的贝克尔肌肉营养不良症新型小鼠模型的生成和特征描述。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-08-05 DOI: 10.1242/dmm.050595

Lucie O M Perillat, Tatianna W Y Wong, Eleonora Maino, Abdalla Ahmed, Ori Scott, Elzbieta Hyatt, Paul Delgado-Olguin, Shagana Visuvanathan, Evgueni A Ivakine, Ronald D Cohn

{"title":"Generation and characterization of a novel mouse model of Becker Muscular Dystrophy with a deletion of exons 52 to 55.","authors":"Lucie O M Perillat, Tatianna W Y Wong, Eleonora Maino, Abdalla Ahmed, Ori Scott, Elzbieta Hyatt, Paul Delgado-Olguin, Shagana Visuvanathan, Evgueni A Ivakine, Ronald D Cohn","doi":"10.1242/dmm.050595","DOIUrl":"https://doi.org/10.1242/dmm.050595","url":null,"abstract":"Becker Muscular Dystrophy (BMD) is a rare X-linked recessive neuromuscular disorder frequently caused by in-frame deletions in the DMD gene that result in the production of a truncated, yet functional, dystrophin protein. The consequences of BMD-causing in-frame deletions on the organism are difficult to predict, especially in regard to long-term prognosis. Here, we employed CRISPR-Cas9 to generate a new Dmd del52-55 mouse model by deleting exons 52-55, resulting in a BMD-like in-frame deletion. To delineate the long-term effects of this deletion, we studied these mice over 52 weeks by performing histology and echocardiography analyses and assessing motor functions. Our results suggest that a truncated dystrophin is sufficient to maintain wildtype-like muscle and heart histology and functions in young mice. However, the truncated protein appears insufficient to maintain normal muscle homeostasis and protect against exercise-induced damage at 52 weeks. To further delineate the effects of this exon52-55 in-frame deletion, we performed RNA-Seq pre- and post-exercise and identified several differentially expressed pathways that reflect the abnormal muscle phenotype observed at 52 weeks in the BMD model.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888756","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

CCL2 signaling promotes skeletal muscle wasting in non-tumor and breast tumor models. C-C 趋化因子配体 2 信号传导促进了非肿瘤和乳腺肿瘤小鼠模型中骨骼肌的萎缩。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-08-01 Epub Date: 2024-09-09 DOI: 10.1242/dmm.050398

Nadia Alissa, Wei Bin Fang, Marcela Medrano, Nick Bergeron, Yuuka Kozai, Qingting Hu, Chloe Redding, John Thyfault, Jill Hamilton-Reeves, Cory Berkland, Nikki Cheng

{"title":"CCL2 signaling promotes skeletal muscle wasting in non-tumor and breast tumor models.","authors":"Nadia Alissa, Wei Bin Fang, Marcela Medrano, Nick Bergeron, Yuuka Kozai, Qingting Hu, Chloe Redding, John Thyfault, Jill Hamilton-Reeves, Cory Berkland, Nikki Cheng","doi":"10.1242/dmm.050398","DOIUrl":"10.1242/dmm.050398","url":null,"abstract":"Despite advancements in treatment, approximately 25% of patients with breast cancer experience long-term skeletal muscle wasting (SMW), which limits mobility, reduces drug tolerance and adversely impacts survival. By understanding the underlying molecular mechanisms of SMW, we may be able to develop new strategies to alleviate this condition and improve the lives of patients with breast cancer. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of C-C chemokine ligand 2 (CCL2) correlates with unfavorable prognosis. Elevated levels of CCL2 in peripheral blood indicate possible systemic effects of this chemokine in patients with breast cancer. Here, we investigated the role of CCL2 signaling on SMW in tumor and non-tumor contexts. In vitro, increasing concentrations of CCL2 inhibited myoblast and myotube function through C-C chemokine receptor 2 (CCR2)-dependent mechanisms involving JNK, SMAD3 and AMPK signaling. In healthy mice, delivery of recombinant CCL2 protein promoted SMW in a dose-dependent manner. In vivo knockdown of breast tumor-derived CCL2 partially protected against SMW. Overall, chronic, upregulated CCL2-CCR2 signaling positively regulates SMW, with implications for therapeutic targeting.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554350","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

Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic cardiomyopathy. 肥厚型心肌病模型中连接蛋白-43表达减少、传导缓慢和再极化弥散。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-08-01 Epub Date: 2024-08-27 DOI: 10.1242/dmm.050407

Seakcheng Lim, Melissa M Mangala, Mira Holliday, Henrietta Cserne Szappanos, Samantha Barratt-Ross, Serena Li, Jordan Thorpe, Whitney Liang, Ginell N Ranpura, Jamie I Vandenberg, Christopher Semsarian, Adam P Hill, Livia C Hool

{"title":"Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic cardiomyopathy.","authors":"Seakcheng Lim, Melissa M Mangala, Mira Holliday, Henrietta Cserne Szappanos, Samantha Barratt-Ross, Serena Li, Jordan Thorpe, Whitney Liang, Ginell N Ranpura, Jamie I Vandenberg, Christopher Semsarian, Adam P Hill, Livia C Hool","doi":"10.1242/dmm.050407","DOIUrl":"10.1242/dmm.050407","url":null,"abstract":"Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia. Analysis of rhythmonome protein expression in MYH7 R403Q cardiomyocytes showed reduced expression of connexin-43 (also known as GJA1), sodium channels and inward rectifier potassium channels - a three-way hit that reduces electrotonic coupling and slows cardiac conduction. Our data represent a previously unreported, biophysical basis for arrhythmia in HCM that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic phenotypes may be accentuated by myocyte disarray and fibrosis to contribute to sudden death.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11381919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072319","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

Understanding the interplay between dNTP metabolism and genome stability in cancer. 了解癌症中 dNTP 代谢与基因组稳定性之间的相互作用。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-08-01 Epub Date: 2024-08-29 DOI: 10.1242/dmm.050775

Miriam Yagüe-Capilla, Sean G Rudd

{"title":"Understanding the interplay between dNTP metabolism and genome stability in cancer.","authors":"Miriam Yagüe-Capilla, Sean G Rudd","doi":"10.1242/dmm.050775","DOIUrl":"10.1242/dmm.050775","url":null,"abstract":"The size and composition of the intracellular DNA precursor pool is integral to the maintenance of genome stability, and this relationship is fundamental to our understanding of cancer. Key aspects of carcinogenesis, including elevated mutation rates and induction of certain types of DNA damage in cancer cells, can be linked to disturbances in deoxynucleoside triphosphate (dNTP) pools. Furthermore, our approaches to treat cancer heavily exploit the metabolic interplay between the DNA and the dNTP pool, with a long-standing example being the use of antimetabolite-based cancer therapies, and this strategy continues to show promise with the development of new targeted therapies. In this Review, we compile the current knowledge on both the causes and consequences of dNTP pool perturbations in cancer cells, together with their impact on genome stability. We outline several outstanding questions remaining in the field, such as the role of dNTP catabolism in genome stability and the consequences of dNTP pool expansion. Importantly, we detail how our mechanistic understanding of these processes can be utilised with the aim of providing better informed treatment options to patients with cancer.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11381932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105255","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

Negative equity - the value of reporting negative results. 负资产--报告负面结果的价值。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-08-01 Epub Date: 2024-08-30 DOI: 10.1242/dmm.050937

Owen Sansom, Debora Bogani, Linus Reichenbach, Sara Wells

引用次数: 0

Characterization of a monkey model with experimental retinal damage induced by N-methyl-D-aspartate. N-甲基-D-天冬氨酸诱导的实验性视网膜损伤猴子模型的特征。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-08-01 Epub Date: 2024-07-26 DOI: 10.1242/dmm.050033

Guo Liu, Longxiang Huang, Junkai Tan, Yun Wang, Chunlin Lan, Yaxi Chen, Yukai Mao, Xizhen Wang, Ning Fan, Yihua Zhu, Xianjun Zhu, Xuyang Liu

{"title":"Characterization of a monkey model with experimental retinal damage induced by N-methyl-D-aspartate.","authors":"Guo Liu, Longxiang Huang, Junkai Tan, Yun Wang, Chunlin Lan, Yaxi Chen, Yukai Mao, Xizhen Wang, Ning Fan, Yihua Zhu, Xianjun Zhu, Xuyang Liu","doi":"10.1242/dmm.050033","DOIUrl":"10.1242/dmm.050033","url":null,"abstract":"N-methyl-D-aspartate (NMDA)-induced retinal damage has been well studied in rodents, but the detailed mechanisms have not yet been characterized in nonhuman primates. Here, we characterized the retinal degenerative effects of NMDA on rhesus monkeys in vivo. NMDA saline or saline-only control was injected intravitreally to the randomly assigned eyes and contralateral eyes of four rhesus monkeys, respectively. The structural and functional changes of retina were characterized by optical coherence tomography and electroretinography on days 0, 4, 30 and 60 post injection. Both optic discs and macular areas of the NMDA-injected eyes initially presented with a transient retinal thickening, followed by continued retinal thinning. The initial, transient retinal thickening has also been observed in glaucoma patients, but this has not been reported in rodent NMDA models. This initial response was followed by loss of retina ganglion cells (RGCs), which is similar to glaucomatous optic neuropathy and other RGC-related retinal degenerations. The amplitudes of both the photopic negative response and pattern electroretinogram decreased significantly and remained low until the end of the study. Thus, the NMDA monkey model may serve as a more clinically relevant animal model of retinal damage.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757733","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