Disease Models & Mechanisms最新文献_第10页

Circulatory CCL2 distinguishes Duchenne muscular dystrophy dogs. 循环CCL2区分杜氏肌营养不良犬。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-03-14 DOI: 10.1242/dmm.052137

Dennis O Pérez-López, Matthew J Burke, Chady H Hakim, James A Teixeira, Jin Han, Yongping Yue, Zewei Ren, Jianguo Sun, Shi-Jie Chen, Roland W Herzog, Gang Yao, Dongsheng Duan

{"title":"Circulatory CCL2 distinguishes Duchenne muscular dystrophy dogs.","authors":"Dennis O Pérez-López, Matthew J Burke, Chady H Hakim, James A Teixeira, Jin Han, Yongping Yue, Zewei Ren, Jianguo Sun, Shi-Jie Chen, Roland W Herzog, Gang Yao, Dongsheng Duan","doi":"10.1242/dmm.052137","DOIUrl":"10.1242/dmm.052137","url":null,"abstract":"To establish a minimally invasive approach to studying body-wide muscle inflammation in the canine Duchenne muscular dystrophy (DMD) model, we evaluated 13 cytokines/chemokines in frozen sera from 90 affected (239 sera) and 73 normal (189 sera) dogs (0.00 to 45.2 months of age). Linear mixed-effects model analysis suggested that ten cytokines/chemokines were significantly elevated in affected dogs, including interleukin (IL)-2, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 1 (CXCL1) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Further, cytokine/chemokine elevation coincided with the onset of muscle disease. Importantly, only CCL2 showed consistent changes at all ages, with the most pronounced increase occurring between 3 and 9 months. To study the effects of sample storage and type, we compared fresh versus frozen, and serum versus plasma, samples from the same dog. Similar readings were often obtained in fresh and frozen sera. Although plasma readings were significantly lower for many cytokines/chemokines, this did not compromise the robustness of CCL2 as a biomarker. Our study establishes a baseline for using circulatory cytokines/chemokines as biomarkers in canine DMD studies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623878","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

Science under siege: protecting scientific progress in turbulent times. 围攻中的科学：在动荡时期保护科学进步。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-03-13 DOI: 10.1242/dmm.052348

James Briscoe, Craig E Franklin, Daniel A Gorelick, E Elizabeth Patton, Michael Way

引用次数: 0

Evolving our understanding of cancer: an interview with Charles Swanton. 进化我们对癌症的理解：采访查尔斯·斯旺顿。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-03-12 DOI: 10.1242/dmm.052318

Charles Swanton

引用次数: 0

Oral administration of aripiprazole to Drosophila causes intestinal toxicity. 阿立哌唑对果蝇口服可引起肠道毒性。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-03-24 DOI: 10.1242/dmm.052180

James D Hurcomb, Amrita Mukherjee, Anna E Lindell, Rebeka Popovic, Yizhou Yu, Kiran R Patil, Samantha H Y Loh, L Miguel Martins

{"title":"Oral administration of aripiprazole to Drosophila causes intestinal toxicity.","authors":"James D Hurcomb, Amrita Mukherjee, Anna E Lindell, Rebeka Popovic, Yizhou Yu, Kiran R Patil, Samantha H Y Loh, L Miguel Martins","doi":"10.1242/dmm.052180","DOIUrl":"10.1242/dmm.052180","url":null,"abstract":"Aripiprazole is a third-generation antipsychotic medication that was introduced to mitigate the poor tolerability of older antipsychotics. In contrast to the older antipsychotic drugs that act as dopamine receptor antagonists in the brain, aripiprazole functions as a partial agonist. Aripiprazole has been identified as an off-target inhibitor of mitochondrial respiratory complex I. We observed that patients prescribed aripiprazole often report gastrointestinal disturbances, but the mechanism underlying these side effects is not clear. We modelled the potential mitochondrial toxicity of aripiprazole in the gastrointestinal system using the fruit fly (Drosophila melanogaster). Aripiprazole consumption impaired Drosophila gut function and faecal output. It also reduced the mitochondrial membrane potential and increased reactive oxygen species (ROS) levels in intestinal cells. ROS activate the c-Jun N-terminal kinase (JNK) pathway, which induces cellular stress and cell death. Aripiprazole increased JNK activation in the intestinal cells of flies, resulting in cell death, which was suppressed by antioxidants. We conclude that aripiprazole activates the JNK pathway of cell death via mitochondrial ROS production. Using antioxidant supplements may help reduce aripiprazole-induced toxicity.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691422","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

KNTC1 introduces segmental heterogeneity to mitochondria. KNTC1引入线粒体的片段异质性。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-03-04 DOI: 10.1242/dmm.052063

Atsushi Tsukamura, Hirotaka Ariyama, Natsuki Hayashi, Satoko Miyatake, Satoko Okado, Sara Sultana, Ichiro Terakado, Takefumi Yamamoto, Shoji Yamanaka, Satoshi Fujii, Haruka Hamanoue, Ryoko Asano, Taichi Mizushima, Naomichi Matsumoto, Yoshihiro Maruo, Masaki Mori

{"title":"KNTC1 introduces segmental heterogeneity to mitochondria.","authors":"Atsushi Tsukamura, Hirotaka Ariyama, Natsuki Hayashi, Satoko Miyatake, Satoko Okado, Sara Sultana, Ichiro Terakado, Takefumi Yamamoto, Shoji Yamanaka, Satoshi Fujii, Haruka Hamanoue, Ryoko Asano, Taichi Mizushima, Naomichi Matsumoto, Yoshihiro Maruo, Masaki Mori","doi":"10.1242/dmm.052063","DOIUrl":"10.1242/dmm.052063","url":null,"abstract":"Mitochondria contribute to cellular metabolism by providing a specialised milieu for energising cells by incorporating and processing the metabolites. However, heterogeneity between mitochondria has only partially been elucidated. Mitochondria dynamically alter their morphology and function during the life of an animal, when cells proliferate and grow. We here show that Kntc1, a highly evolutionarily conserved protein, translocates from the Golgi apparatus to linear mitochondrial segments (LMSs) upon glutamine deprivation and plays an essential role in maintaining LMSs. The LMSs to which Kntc1 localised exhibited an increase in the mitochondrial membrane potential, suggesting the role of Kntc1 in functioning as a reservoir for the energy-generating potential. Suppression of Kntc1 led to glutamine consumption and lactate production, thus impacting cellular metabolism, eventually leading to anchorage-independent growth of cells. Indeed, a KNTC1 variant was identified in a patient with ovarian cancer, suggesting that segmental regulation of the mitochondrial function is essential for maintaining tissue integrity.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11911638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001338","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

Tumor suppressor genes in the tumor microenvironment. 肿瘤微环境中的肿瘤抑制基因。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-03-20 DOI: 10.1242/dmm.052049

Bahareh Tabanifar, Hannah Lau, Kanaga Sabapathy

引用次数: 0

Establishment and functional studies of a model of cardiomyopathy with cardiomyocyte-specific conditional knockout of Arhgef18. 心肌细胞特异性条件敲除Arhgef18心肌病模型的建立及功能研究。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-03-31 DOI: 10.1242/dmm.052172

Xiaoqiong Fu, Wenjing Yuan, Jiajin Li, Kun Wan, Mei Ge, Bo Pan, Tiewei Lu

{"title":"Establishment and functional studies of a model of cardiomyopathy with cardiomyocyte-specific conditional knockout of Arhgef18.","authors":"Xiaoqiong Fu, Wenjing Yuan, Jiajin Li, Kun Wan, Mei Ge, Bo Pan, Tiewei Lu","doi":"10.1242/dmm.052172","DOIUrl":"10.1242/dmm.052172","url":null,"abstract":"The rising incidence of cardiomyopathies poses a significant threat to the physical and mental health of patients. The establishment of an animal model that accurately reflects the clinicopathological characteristics of cardiomyopathy is essential for investigating its pathogenesis. In this study, a cardiomyocyte-specific Arhgef18 conditional knockout (cKO) mouse model was established with Cre/LoxP technology, and the results confirmed that the protein encoded by Arhgef18 (Rho/Rac guanine nucleotide exchange factor 18) was knocked out effectively in the myocardium of Arhgef18flox/flox; Nkx2.5-Cre (Arhgef18fl/fl cKO) mice. Compared to Arhgef18fl/fl mice, Arhgef18fl/fl cKO mice presented with slower body weight growth and no differences in survival curves. Cardiac structure and function revealed that Arhgef18fl/fl cKO mice developed biventricular enlargement, ventricular wall thinning and left-ventricular systolic dysfunction, along with increased Nppa and Nppb mRNA expression levels. Additionally, Arhgef18fl/fl cKO mice showed cardiomyocyte cytoskeletal rearrangements and cell polarity disorders. Our study results suggest that Arhgef18 cKO mice could provide an ideal animal model for the genetic investigation of cardiomyopathy.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11992352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751749","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

Nonlinear progression during the occult transition establishes cancer lethality. 隐匿性转移期间的非线性进展确定了癌症的致死率。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-03-01 Epub Date: 2025-03-19 DOI: 10.1242/dmm.052113

Joshua D Ginzel, Henry Chapman, Joelle E Sills, Edwin J Allen, Lawrence S Barak, Robert D Cardiff, Alexander D Borowsky, Herbert Kim Lyerly, Bruce W Rogers, Joshua C Snyder

{"title":"Nonlinear progression during the occult transition establishes cancer lethality.","authors":"Joshua D Ginzel, Henry Chapman, Joelle E Sills, Edwin J Allen, Lawrence S Barak, Robert D Cardiff, Alexander D Borowsky, Herbert Kim Lyerly, Bruce W Rogers, Joshua C Snyder","doi":"10.1242/dmm.052113","DOIUrl":"10.1242/dmm.052113","url":null,"abstract":"Cancer screening relies upon a linear model of neoplastic growth and progression. Yet, historical observations suggest that malignant progression is uncoupled from growth, which may explain the paradoxical increase in early-stage breast cancer detection without a dramatic reduction in metastasis. Here, we lineage trace millions of transformed cells and thousands of tumors using a cancer rainbow mouse model of HER2 (also known as ERBB2)-positive breast cancer. Transition rates from field cell to screen-detectable tumor to symptomatic tumor were estimated from a dynamical model of tumor development. Field cells were orders of magnitude less likely to transition to a screen-detectable tumor than the subsequent transition from screen-detectable tumor to symptomatic tumor. Our model supports a critical 'occult' transition in tumor development during which a transformed cell becomes a bona fide neoplasm. Lineage tracing and test by transplantation revealed that nonlinear progression during the occult transition gives rise to nascent lethal cancers at screen detection. Simulations illustrated how occult transition rates are a critical determinant of tumor growth and malignancy. Our data provide direct experimental evidence that cancers can deviate from the predictable linear progression model that is foundational to current screening paradigms.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656325","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 a pathological GSX2 variant that selectively alters DNA binding reveals hypomorphic mouse brain defects. 模拟病理GSX2变异，选择性地改变DNA结合，揭示了亚型小鼠基底神经节和后脑缺陷。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-02-01 Epub Date: 2025-02-20 DOI: 10.1242/dmm.052110

Laura Tweedie, Matthew R Riccetti, Brittany Cain, Shenyue Qin, Joseph Salomone, Jordan A Webb, Amy Riesenberg, Lisa A Ehrman, Ronald R Waclaw, Rhett A Kovall, Brian Gebelein, Kenneth Campbell

{"title":"Modelling a pathological GSX2 variant that selectively alters DNA binding reveals hypomorphic mouse brain defects.","authors":"Laura Tweedie, Matthew R Riccetti, Brittany Cain, Shenyue Qin, Joseph Salomone, Jordan A Webb, Amy Riesenberg, Lisa A Ehrman, Ronald R Waclaw, Rhett A Kovall, Brian Gebelein, Kenneth Campbell","doi":"10.1242/dmm.052110","DOIUrl":"10.1242/dmm.052110","url":null,"abstract":"Gsx2 is a homeodomain transcription factor critical for development of the ventral telencephalon and hindbrain in mouse. Loss of Gsx2 function results in severe basal ganglia dysgenesis and defects in the nucleus tractus solitarius (nTS) of the hindbrain, together with respiratory failure at birth. De Mori et al. (2019) reported two patients with severe dystonia and basal ganglia dysgenesis that encode distinct recessive GSX2 variants, including a missense variant within the homeodomain (GSX2Q251R). Hence, we modelled the homologous Gsx2 mutation (i.e. Gsx2Q252R) in mouse, and our biochemical analysis revealed that this variant selectively altered DNA binding. Moreover, mice carrying the Gsx2Q252R allele exhibited basal ganglia dysgenesis, albeit to a lesser extent than did Gsx2 null mice. A notable difference between Gsx2Q252R and Gsx2 null mice was that Gsx2Q252R mice survived, and hindbrain analysis revealed relative sparing of the glutamatergic nTS neurons and catecholaminergic A1/C1 and A2/C2 groups. Thus, the Gsx2Q252R variant is a hypomorph that compromises a subset of Gsx2-dependent neuronal subtypes and highlights a critical role for distinct thresholds of catecholaminergic and/or glutamatergic nTS neurons for viability.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064260","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

Notch3 deletion regulates HIV-1 gene expression and systemic inflammation to ameliorate chronic kidney disease. Notch3缺失调节HIV-1基因表达和全身性炎症以改善慢性肾脏疾病。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-02-01 Epub Date: 2025-02-25 DOI: 10.1242/dmm.052056

Mackenzie Thornton, Nicole Sommer, Mercedes McGonigle, Anil Kumar Ram, Sireesha Yerrathota, Henrietta Ehirim, Aakriti Chaturvedi, Johnny Dinh Phan, Anubhav Chakraborty, V Praveen Chakravarthi, Sumedha Gunewardena, Mudit Tyagi, Jaya Talreja, Tao Wang, Pravin Singhal, Pamela V Tran, Timothy A Fields, Patricio E Ray, Navneet K Dhillon, Madhulika Sharma

{"title":"Notch3 deletion regulates HIV-1 gene expression and systemic inflammation to ameliorate chronic kidney disease.","authors":"Mackenzie Thornton, Nicole Sommer, Mercedes McGonigle, Anil Kumar Ram, Sireesha Yerrathota, Henrietta Ehirim, Aakriti Chaturvedi, Johnny Dinh Phan, Anubhav Chakraborty, V Praveen Chakravarthi, Sumedha Gunewardena, Mudit Tyagi, Jaya Talreja, Tao Wang, Pravin Singhal, Pamela V Tran, Timothy A Fields, Patricio E Ray, Navneet K Dhillon, Madhulika Sharma","doi":"10.1242/dmm.052056","DOIUrl":"10.1242/dmm.052056","url":null,"abstract":"Anti-retroviral therapy (ART) has decreased human immunodeficiency virus (HIV)-1-associated morbidity. However, despite ART, immune cells remain latently infected, leading to chronic inflammation and HIV-1-associated comorbidities. New strategies are needed to target viral proteins and inflammation. We found activation of Notch3 in renal cells of the HIV-1 transgenic mouse model (HIV-Tg26) and in patients with HIV-associated nephropathy. We hypothesized that targeting NOTCH3 activation constitutes an effective therapy for HIV-related chronic kidney disease. We generated HIV-Tg26 mice with Notch3 knocked out (Tg-N3KO). Compared to HIV-Tg26 mice at 3 months, Tg-N3KO mice showed a marked reduction in renal injury, skin lesions and mortality rate. They also showed reduced renal infiltrating cells and significantly reduced expression of HIV genes. Moreover, Notch3 activated the HIV long terminal repeat promoter, and induction of HIV-1 increased Notch3 activation, indicating a feedback mechanism. Further, bone marrow-derived macrophages from HIV-Tg26 mice showed activation of Notch3, indicating systemic effects. Consistent with that observation, systemic levels of TNF and MCP-1 were reduced in Tg-N3KO compared to HIV-Tg26 mice. Thus, Notch3 deletion/inhibition has a dual-therapeutic effect in HIV-related chronic kidney disease, which might extend to other HIV-related pathologies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255104","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