Disease Models & Mechanisms最新文献

The role of mesenchymal cells in cholangiocarcinoma. 间质细胞在胆管癌中的作用。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-11-04 DOI: 10.1242/dmm.050716

Mireia Sueca-Comes, Elena Cristina Rusu, Jennifer C Ashworth, Pamela Collier, Catherine Probert, Alison Ritchie, Marian Meakin, Nigel P Mongan, Isioma U Egbuniwe, Jesper Bøje Andersen, David O Bates, Anna M Grabowska

{"title":"The role of mesenchymal cells in cholangiocarcinoma.","authors":"Mireia Sueca-Comes, Elena Cristina Rusu, Jennifer C Ashworth, Pamela Collier, Catherine Probert, Alison Ritchie, Marian Meakin, Nigel P Mongan, Isioma U Egbuniwe, Jesper Bøje Andersen, David O Bates, Anna M Grabowska","doi":"10.1242/dmm.050716","DOIUrl":"https://doi.org/10.1242/dmm.050716","url":null,"abstract":"The tumour microenvironment (TME) significantly influences tumour formation and progression through dynamic interactions. Cholangiocarcinoma (CCA), a highly desmoplastic tumour, lacks early diagnostic biomarkers and has limited effective treatments due to an incomplete understanding of its molecular pathogenesis. Investigating the TME's role in CCA progression could lead to better therapies. RNA sequencing was performed on seven CCA PDXs and their corresponding patient samples. Differential expression analysis was conducted, and Qiagen Ingenuity Pathway Analysis (IPA) was used to predict dysregulated pathways and upstream regulators. PDX and cell line-derived spheroids, with and without immortalised mesenchymal stem cells, were grown and analysed for morphology, growth, and viability. Histological analysis confirmed biliary phenotypes. RNA sequencing indicated upregulation of ECM-receptor interaction and PI3K-Akt pathways in the presence of MSCs, with several genes linked to poor survival. MSCs restored the activity of inhibited cancer-associated kinases (ICAKs). This study shows that adding MSCs to CCA spheroid models restores key paracrine signalling pathways lost in PDXs, enhancing tumour growth and viability. These findings highlight the importance of including stromal components in cancer models to improve pre-clinical studies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567801","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

High-fat and high-sucrose diets induce an experimental rabbit model for age-related macular degeneration (AMD). 高脂肪和高蔗糖饮食可诱导老年性黄斑变性（AMD）实验兔模型。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-28 DOI: 10.1242/dmm.052015

Yujiao Wang, Zhongping Lv, Yongjiang Chen, Xiaobo Cen, Hui Zhang, Danian Chen

{"title":"High-fat and high-sucrose diets induce an experimental rabbit model for age-related macular degeneration (AMD).","authors":"Yujiao Wang, Zhongping Lv, Yongjiang Chen, Xiaobo Cen, Hui Zhang, Danian Chen","doi":"10.1242/dmm.052015","DOIUrl":"https://doi.org/10.1242/dmm.052015","url":null,"abstract":"Age-related macular degeneration (AMD) is a leading cause of blindness. Metabolic disorders and diets are risk factors. We compared lipid profiles and retinal phenotypes with long-term feeding of four diets in male Chinchilla rabbits. Animals were fed with a normal diet (ND), high-fat (HFD), high-sucrose (HSD), or high-fat and high-sucrose diet (HFSD) for six months. The eyes were examined using multimodal imaging modalities and electroretinogram (ERG). Retinal sections were analyzed using H&E staining, toluidine blue staining, immunostaining, and transmission electron microscopy. Lipids and complement C3 in serum or aqueous humour were measured. RNA sequencing was performed to evaluate the retinal transcriptomes. HFD and HSD had minor effects on lipid profiles but synergistically induced severe dyslipidemia. All diets did not cause obesity. HFSD feeding induced retinal lesions like reticular pseudo-drusen (RPD) and pigmentary abnormalities. The RPD-like lesions were mainly lipid droplets around RPE cells. HFSD induced elevated ocular C3 levels and reduced retinal vessel density. In conclusion, HFD and HSD can synergistically induce normal-weight dyslipidemia and RPD-like retinal lesions. HFSD-fed male Chinchilla rabbits are a good model of early AMD.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496810","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

Early life cisplatin exposure induces nerve growth factor mediated neuroinflammation and chemotherapy induced neuropathic pain. 早年接触顺铂会诱发神经生长因子介导的神经炎症和化疗引起的神经病理性疼痛。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-21 DOI: 10.1242/dmm.052062

Marlene Da Vitoria Lobo, Lydia Hardowar, Tameille Valentine, Lucy Tomblin, Charlotte Guest, Dhyana Sharma, Benjamin Dickins, Mark Paul-Clark, Richard Philip Hulse

{"title":"Early life cisplatin exposure induces nerve growth factor mediated neuroinflammation and chemotherapy induced neuropathic pain.","authors":"Marlene Da Vitoria Lobo, Lydia Hardowar, Tameille Valentine, Lucy Tomblin, Charlotte Guest, Dhyana Sharma, Benjamin Dickins, Mark Paul-Clark, Richard Philip Hulse","doi":"10.1242/dmm.052062","DOIUrl":"https://doi.org/10.1242/dmm.052062","url":null,"abstract":"Chemotherapy-induced neuropathic pain (CINP) is a common adverse health related comorbidity that manifests later in life in paediatric cancer patients. Current analgesia is ineffective, aligning closely with our lack of understanding of CINP. The aim of this study was to investigate how cisplatin induces nerve growth factor mediated neuroinflammation and nociceptor sensitisation. In a rodent model of cisplatin induced survivorship pain, cisplatin induced a neuroinflammatory environment in the dorsal root ganglia (DRG) demonstrated by nerve growth factor (NGF) positive macrophages infiltrating into the DRG. Cisplatin treated CD11b/F480 positive macrophages expressed more NGF compared to vehicle treated. Primary DRG sensory neuronal cultures demonstrated enhanced NGF-dependent TRPV1 mediated nociceptor activity after cisplatin treatment. Increased nociceptor activity was also observed when cultured DRG neurons were treated with conditioned media from cisplatin activated macrophages. Elevated nociceptor activity was dose-dependently inhibited by a neutralising NGF antibody. Intraperitoneal administration of a NGF neutralising antibody reduced cisplatin-induced mechanical hypersensitivity and aberrant nociceptor intraepidermal nerve fibre density. These findings identify that a monocyte/macrophage driven NGF/TrkA pathway is a novel analgesic target for adult survivors of childhood cancer.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460065","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

Hippo signaling cooperates with p53 to regulate lung airway mucous cell metaplasia. Hippo信号与p53合作调控肺气道粘液细胞增生。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-21 DOI: 10.1242/dmm.052074

Jiangying Liu, Dan Luo, Haidi Huang, Rongzi Mu, Jianghong Yuan, Ming Jiang, Chuwen Lin, Honggang Xiang, Xinhua Lin, Haihan Song, Yongchun Zhang

引用次数: 0

Generation of a zebrafish neurofibromatosis model via inducible knockout of nf2. 通过诱导性敲除 nf2 生成斑马鱼神经纤维瘤病模型。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-17 DOI: 10.1242/dmm.050862

Ayyappa Raja Desingu Rajan, Yuanyun Huang, Jan Stundl, Katelyn Chu, Anushka Irodi, Zihan Yang, Brian E Applegate, Marianne E Bronner

{"title":"Generation of a zebrafish neurofibromatosis model via inducible knockout of nf2.","authors":"Ayyappa Raja Desingu Rajan, Yuanyun Huang, Jan Stundl, Katelyn Chu, Anushka Irodi, Zihan Yang, Brian E Applegate, Marianne E Bronner","doi":"10.1242/dmm.050862","DOIUrl":"https://doi.org/10.1242/dmm.050862","url":null,"abstract":"Neurofibromatosis Type 2 (NF-2) is a dominantly inherited genetic disorder that results from mutations in the tumor suppressor gene, neurofibromin 2 (NF2) gene. Here, we report the generation of a conditional zebrafish model of neurofibromatosis established by an inducible genetic knockout of nf2a/b, the zebrafish homolog of human NF2. Analysis of nf2a and nf2b expression reveals ubiquitous expression of nf2b in the early embryo, with overlapping expression in the neural crest and its derivatives and in the cranial mesenchyme. In contrast, nf2a displays lower expression levels. Induction of nf2a/b knockout at early stages increases the proliferation of larval Schwann cells and meningeal fibroblasts. Subsequently, in adult zebrafish, nf2a/b knockout triggers the development of a spectrum of tumors, including vestibular Schwannomas, spinal Schwannomas, meningiomas, and retinal hamartomas, mirroring the tumor manifestations observed in patients with NF-2. Collectively, these findings highlight the generation of a novel zebrafish model that mimics the complexities of the human NF-2 disorder. Consequently, this model holds significant potential for facilitating therapeutic screening and elucidating key driver genes implicated in NF-2 onset.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460066","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

Optimised methods to image hepatic lipid droplets in zebrafish larvae. 斑马鱼幼体肝脏脂滴成像的优化方法。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-07 DOI: 10.1242/dmm.050786

Nouf Khan, Talhah M Salmi, Anthony P Karamalakis, Anjana Ramdas Nair, Kirsten C Sadler, Andrew G Cox

{"title":"Optimised methods to image hepatic lipid droplets in zebrafish larvae.","authors":"Nouf Khan, Talhah M Salmi, Anthony P Karamalakis, Anjana Ramdas Nair, Kirsten C Sadler, Andrew G Cox","doi":"10.1242/dmm.050786","DOIUrl":"https://doi.org/10.1242/dmm.050786","url":null,"abstract":"The optical transparency of zebrafish larvae enables visualization of subcellular structures in intact organs, and these vertebrates are widely used to study lipid biology and liver disease. Lipid droplet (LD) presence is a prevalent feature of healthy cells but under conditions such as nutrient excess, toxicant exposure or metabolic imbalance, LD accumulation in hepatocytes can be a harbinger of more severe forms of liver disease. We undertook a comprehensive analysis of approaches useful to investigate LD distribution and dynamics in physiological and pathological conditions in the liver of zebrafish larvae. This comparative analysis of the lipid dyes oil red O (ORO), Nile Red (NR), LipidTox and LipidSpot as well as transgenic LD reporters that rely on EGFP fusions of the LD decorating protein perilipin 2 (PLIN2) demonstrate the strengths and limitations of each approach. These protocols are amenable to detection methods ranging from low resolution stereomicroscopy to confocal imaging, which enables measurements of hepatic LD size, number and dynamics at cellular resolution in live and fixed animals. This resource will benefit investigators studying LD biology in zebrafish disease models.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380183","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

Welcoming new Editorial Advisory Board members. 欢迎新的编辑顾问委员会成员。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-28 DOI: 10.1242/dmm.052155

Dina Mikimoto, Kirsty Hooper

引用次数: 0

Sex hormone receptors, calcium-binding protein and Yap1 signaling regulate sex-dependent liver cell proliferation following partial hepatectomy. 肝部分切除术后斑马鱼肝细胞增殖的性别差异受性激素受体和 S100A1-YAP 信号级联的调控。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-30 DOI: 10.1242/dmm.050900

Mingkai Zhu, Yan Li, Qiaosen Shen, Zhiyuan Gong, Dong Liu

{"title":"Sex hormone receptors, calcium-binding protein and Yap1 signaling regulate sex-dependent liver cell proliferation following partial hepatectomy.","authors":"Mingkai Zhu, Yan Li, Qiaosen Shen, Zhiyuan Gong, Dong Liu","doi":"10.1242/dmm.050900","DOIUrl":"10.1242/dmm.050900","url":null,"abstract":"Partial hepatectomy (PH) is commonly used to treat patients with hepatocellular carcinoma. The recovery of patients from PH depends on the initiation of liver regeneration, a process that mainly relies on liver cell proliferation. As sex affects the human liver regeneration progress, we investigated sex disparity in PH-induced liver regeneration in adult zebrafish. We found that, after PH, males began liver regeneration earlier than females in terms of liver cell proliferation and liver mass recovery, and this was associated with earlier activation of Yap1 signaling in male than female livers. We also found that androgen receptors regulated the sex-biased liver regeneration in a Yap1-dependent manner and that activated estrogen receptors are responsible for the later onset of female hepatocyte proliferation. Furthermore, we identified that S100A1, a calcium-binding protein, regulates the sex disparity in liver regeneration, as heterozygous S100A1 knockout inhibited Yap1 activity in male livers and delayed hepatocyte proliferation in males following PH. Thus, multiple pathways and/or their interplays contribute to the sex disparity in liver regeneration, suggesting that sex-biased therapeutic strategies are required for patients who have received PH-based therapies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460133","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

Functional cardiac consequences of β-adrenergic stress-induced injury in a model of Duchenne muscular dystrophy. 在杜氏肌营养不良症 mdx 小鼠模型中，β 肾上腺素能应激诱导损伤对心脏功能的影响。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-09 DOI: 10.1242/dmm.050852

Conner C Earl, Areli J Javier, Alyssa M Richards, Larry W Markham, Craig J Goergen, Steven S Welc

{"title":"Functional cardiac consequences of β-adrenergic stress-induced injury in a model of Duchenne muscular dystrophy.","authors":"Conner C Earl, Areli J Javier, Alyssa M Richards, Larry W Markham, Craig J Goergen, Steven S Welc","doi":"10.1242/dmm.050852","DOIUrl":"10.1242/dmm.050852","url":null,"abstract":"Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD); however, in the mdx mouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to stimulate injury and enhance cardiac pathology in the mdx model, many methods lead to high mortality with variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model in mdx mice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progression in vivo. mdx and wild-type mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathological assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels and enhanced fibrosis in mdx mice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes and diminished cardiac reserve in mdx compared to wild-type mice. Our findings highlight the utility of challenging mdx mice with low-dose isoproterenol as a valuable model for exploring therapies targeting DMD-associated cardiac pathologies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281731","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

Neuromuscular junction dysfunction in Lafora disease. 拉弗拉病小鼠模型的神经肌肉接头功能障碍

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-14 DOI: 10.1242/dmm.050905

Monica Shukla, Deepti Chugh, Subramaniam Ganesh

{"title":"Neuromuscular junction dysfunction in Lafora disease.","authors":"Monica Shukla, Deepti Chugh, Subramaniam Ganesh","doi":"10.1242/dmm.050905","DOIUrl":"10.1242/dmm.050905","url":null,"abstract":"Lafora disease (LD), a fatal neurodegenerative disorder, is caused by mutations in the EPM2A gene encoding laforin phosphatase or NHLRC1 gene encoding malin ubiquitin ligase. LD symptoms include epileptic seizures, ataxia, dementia and cognitive decline. Studies on LD have primarily concentrated on the pathophysiology in the brain. A few studies have reported motor symptoms, muscle weakness and muscle atrophy. Intriguingly, skeletal muscles are known to accumulate Lafora polyglucosan bodies. Using laforin-deficient mice, an established model for LD, we demonstrate that LD pathology correlated with structural and functional impairments in the neuromuscular junction (NMJ). Specifically, we found impairment in NMJ transmission, which coincided with altered expression of NMJ-associated genes and reduced motor endplate area, fragmented junctions and loss of fully innervated junctions at the NMJ. We also observed a reduction in alpha-motor neurons in the lumbar spinal cord, with significant presynaptic morphological alterations. Disorganised myofibrillar patterns, slight z-line streaming and muscle atrophy were also evident in LD animals. In summary, our study offers insight into the neuropathic and myopathic alterations leading to motor deficits in LD.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281732","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