Disease Models & Mechanisms最新文献

A frameshift mutation in the murine Prkra gene exhibits cerebellar abnormality and reduced eIF2α phosphorylation. 小鼠Prkra基因的框架移位突变表现出小脑异常和eIF2α磷酸化减少。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-11-08 DOI: 10.1242/dmm.050929

Samuel B Burnett, Allison M Culver, Tricia A Simon, Taylor Rowson, Kenneth Frederick, Kristina Palmer, Stephen A Murray, Shannon W Davis, Rekha C Patel

{"title":"A frameshift mutation in the murine Prkra gene exhibits cerebellar abnormality and reduced eIF2α phosphorylation.","authors":"Samuel B Burnett, Allison M Culver, Tricia A Simon, Taylor Rowson, Kenneth Frederick, Kristina Palmer, Stephen A Murray, Shannon W Davis, Rekha C Patel","doi":"10.1242/dmm.050929","DOIUrl":"10.1242/dmm.050929","url":null,"abstract":"Mutations in Prkra gene, which encodes PACT/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkralear-5J exhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of the Prkralear-5J mutation. Our results indicate that the truncated PACT/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygous Prkralear-5J mice. These results indicate that PACT/RAX mediated regulation of PKR activity and eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603053","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

Slc26a2-mediated sulfate metabolism is significant for the tooth development. Slc26a2- 介导的硫酸盐代谢对牙齿的发育至关重要。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-11-07 DOI: 10.1242/dmm.052107

Y Yoshida, T Inubushi, M Yokoyama, P Nag, J I Sasaki, A Oka, T Murotani, R Kani, Y Shiraishi, H Kurosaka, Y Takahata, R Nishimura, S Imazato, P Papagerakis, T Yamashiro

{"title":"Slc26a2-mediated sulfate metabolism is significant for the tooth development.","authors":"Y Yoshida, T Inubushi, M Yokoyama, P Nag, J I Sasaki, A Oka, T Murotani, R Kani, Y Shiraishi, H Kurosaka, Y Takahata, R Nishimura, S Imazato, P Papagerakis, T Yamashiro","doi":"10.1242/dmm.052107","DOIUrl":"https://doi.org/10.1242/dmm.052107","url":null,"abstract":"The sulfate transporter gene SLC26A2 is crucial for skeletal formation, as evidenced by its role in diastrophic dysplasia, a type of skeletal dysplasia in humans. While SLC26A2-related chondrodysplasia also affects craniofacial and tooth development, its specific role in these processes remains unclear. In this study, we explore the pivotal roles of SLC26A2-mediated sulfate metabolism during tooth development. We found that Slc26a2 is predominantly expressed in dental tissues, including odontoblasts and ameloblasts. Slc26a2 knockout mice (Slc26a2-KO-Δexon2) exhibit distinct craniofacial abnormalities, such as a retrognathic upper jaw, small upper incisors, and upper molar hypoplasia. These mice also show flattened odontoblasts and loss of nuclear polarity in upper incisors and molars, with significant reductions in odontoblast differentiation markers Dspp and Dmp1. Ex vivo and in vitro studies further reveal dentin matrix hypoplasia, tooth root shortening, and downregulation of Wnt signaling in Slc26a2-deficient cells. These findings highlight the significant role of SLC26A2-mediated sulfate metabolism in tooth development and offer insights into the mechanisms underlying dental abnormalities in patients with SLC26A2-related chondrodysplasias.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603132","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

Modelling quiescence exit of neural stem cells reveals a FOXG1-FoxO6 axis. 神经干细胞静止退出模型揭示了 FOXG1-FoxO6 轴。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-11-05 DOI: 10.1242/dmm.052005

Kirsty M Ferguson, Carla Blin, Claudia Garcia-Diaz, Harry Bulstrode, Raul Bardini Bressan, Katrina McCarten, Steven M Pollard

{"title":"Modelling quiescence exit of neural stem cells reveals a FOXG1-FoxO6 axis.","authors":"Kirsty M Ferguson, Carla Blin, Claudia Garcia-Diaz, Harry Bulstrode, Raul Bardini Bressan, Katrina McCarten, Steven M Pollard","doi":"10.1242/dmm.052005","DOIUrl":"https://doi.org/10.1242/dmm.052005","url":null,"abstract":"The molecular mechanisms controlling the balance of quiescence and proliferation in adult neural stem cells (NSCs) are often deregulated in brain cancers such as glioblastoma (GBM). Previously, we reported that FOXG1, a forebrain-restricted neurodevelopmental transcription factor, is frequently upregulated in glioblastoma stem cells (GSCs) and limits the effects of cytostatic pathways, in part by repression of the tumour suppressor Foxo3. Here, we show that increased FOXG1 upregulates FoxO6, a more recently discovered FoxO family member with potential oncogenic functions. Although genetic ablation of FoxO6 in proliferating NSCs has no effect on the cell cycle or entry into quiescence, we find that FoxO6-null NSCs can no longer efficiently exit quiescence following FOXG1 elevation. Increased FoxO6 results in the formation of large acidic vacuoles, reminiscent of Pak1-regulated macropinocytosis. Consistently, Pak1 expression is upregulated by FOXG1 overexpression and downregulated upon FoxO6 loss in proliferative NSCs. These data suggest a pro-oncogenic role for FoxO6, downstream of GBM-associated elevated FOXG1, in controlling quiescence exit, and shed light on the potential functions of this underexplored FoxO family member.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582573","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

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":" ","pages":""},"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

Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping. 通过系统建模和表型，超越先天性心脏缺陷的基因组研究。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-11-01 Epub Date: 2024-11-22 DOI: 10.1242/dmm.050913

Deborah J Henderson, Ahlam Alqahtani, Bill Chaudhry, Andrew Cook, Lorraine Eley, Lucile Houyel, Marina Hughes, Bernard Keavney, José Luis de la Pompa, John Sled, Nadine Spielmann, Lydia Teboul, Stephane Zaffran, Pleasantine Mill, Karen J Liu

{"title":"Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping.","authors":"Deborah J Henderson, Ahlam Alqahtani, Bill Chaudhry, Andrew Cook, Lorraine Eley, Lucile Houyel, Marina Hughes, Bernard Keavney, José Luis de la Pompa, John Sled, Nadine Spielmann, Lydia Teboul, Stephane Zaffran, Pleasantine Mill, Karen J Liu","doi":"10.1242/dmm.050913","DOIUrl":"https://doi.org/10.1242/dmm.050913","url":null,"abstract":"Congenital heart defects (CHDs), the most common congenital anomalies, are considered to have a significant genetic component. However, despite considerable efforts to identify pathogenic genes in patients with CHDs, few gene variants have been proven as causal. The complexity of the genetic architecture underlying human CHDs likely contributes to this poor genetic discovery rate. However, several other factors are likely to contribute. For example, the level of patient phenotyping required for clinical care may be insufficient for research studies focused on mechanistic discovery. Although several hundred mouse gene knockouts have been described with CHDs, these are generally not phenotyped and described in the same way as CHDs in patients, and thus are not readily comparable. Moreover, most patients with CHDs carry variants of uncertain significance of crucial cardiac genes, further complicating comparisons between humans and mouse mutants. In spite of major advances in cardiac developmental biology over the past 25 years, these advances have not been well communicated to geneticists and cardiologists. As a consequence, the latest data from developmental biology are not always used in the design and interpretation of studies aimed at discovering the genetic causes of CHDs. In this Special Article, while considering other in vitro and in vivo models, we create a coherent framework for accurately modelling and phenotyping human CHDs in mice, thereby enhancing the translation of genetic and genomic studies into the causes of CHDs in patients.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 11","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686215","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 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 5.4 3区医学

Disease Models & Mechanisms Pub Date : 2024-11-01 Epub Date: 2024-11-18 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

{"title":"Hippo cooperates with p53 to regulate lung airway mucous cell metaplasia.","authors":"Jiangying Liu, Dan Luo, Haidi Huang, Rongzi Mu, Jianghong Yuan, Ming Jiang, Chuwen Lin, Honggang Xiang, Xinhua Lin, Haihan Song, Yongchun Zhang","doi":"10.1242/dmm.052074","DOIUrl":"10.1242/dmm.052074","url":null,"abstract":"Airway mucous cell metaplasia is a significant feature of many chronic airway diseases, such as chronic obstructive pulmonary disease, cystic fibrosis and asthma. However, the mechanisms underlying this process remain poorly understood. Here, we employed in vivo mouse genetic models to demonstrate that Hippo and p53 (encoded by Trp53) cooperate to modulate the differentiation of club cells into goblet cells. We revealed that ablation of Mst1 (Stk4) and Mst2 (Stk3), encoding the core components of Hippo signaling, significantly reduces mucous metaplasia in the lung airways in a lipopolysaccharide (LPS)-induced lung inflammation murine model while promoting club cell proliferation in a Yap (Yap1)-dependent manner. Additionally, we showed that deleting Mst1/2 is sufficient to suppress p53 deficiency-mediated goblet cell metaplasia. Finally, single-cell RNA-sequencing analysis revealed downregulation of YAP and p53 signaling in goblet cells in human airways. These findings underscore the important role of Hippo and p53 signaling in regulating airway mucous metaplasia.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460067","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

Modulation of SNARE-dependent exocytosis in astrocytes improves neuropathology in Huntington's disease. 调节星形胶质细胞的 SNARE 依赖性外泌可改善亨廷顿氏病的神经病理学。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-11-01 Epub Date: 2024-11-11 DOI: 10.1242/dmm.052002

Annesha C King, Emily Payne, Emily Stephens, Jahmel A Fowler, Tara E Wood, Efrain Rodriguez, Michelle Gray

{"title":"Modulation of SNARE-dependent exocytosis in astrocytes improves neuropathology in Huntington's disease.","authors":"Annesha C King, Emily Payne, Emily Stephens, Jahmel A Fowler, Tara E Wood, Efrain Rodriguez, Michelle Gray","doi":"10.1242/dmm.052002","DOIUrl":"10.1242/dmm.052002","url":null,"abstract":"Huntington's disease (HD) is a fatal, progressive neurodegenerative disorder. Prior studies revealed an increase in extracellular glutamate levels after evoking astrocytic SNARE-dependent exocytosis from cultured primary astrocytes from mutant huntingtin (mHTT)-expressing BACHD mice compared to control astrocytes, suggesting alterations in astrocytic SNARE-dependent exocytosis in HD. We used BACHD and dominant-negative (dn)SNARE mice to decrease SNARE-dependent exocytosis from astrocytes to determine whether reducing SNARE-dependent exocytosis from astrocytes could rescue neuropathological changes in vivo. We observed significant protection against striatal atrophy and no significant rescue of cortical atrophy in BACHD/dnSNARE mice compared to BACHD mice. Amino acid transporters are important for modulating the levels of extracellular neurotransmitters. BACHD mice had no change in GLT1 expression, decreased striatal GAT1 expression and increased levels of GAT3. There was no change in GAT1 after reducing astrocytic SNARE-dependent exocytosis, and increased GAT3 expression in BACHD mice was normalized in BACHD/dnSNARE mice. Thus, modulation of astrocytic SNARE-dependent exocytosis in BACHD mice is protective against striatal atrophy and modulates GABA transporter expression.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 11","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616452","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

Distinct fingerprints of tRNA-derived small non-coding RNA in animal models of neurodegeneration. 神经变性动物模型中 tRNA 衍生的小非编码 RNA 的独特指纹。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-11-01 Epub Date: 2024-11-18 DOI: 10.1242/dmm.050870

Sharada Baindoor, Hesham A Y Gibriel, Morten T Venø, Junyi Su, Elena Perez Morrissey, Elisabeth Jirström, Ina Woods, Aidan Kenny, Mariana Alves, Luise Halang, Paola Fabbrizio, Maria Bilen, Tobias Engel, Marion C Hogg, Caterina Bendotti, Giovanni Nardo, Ruth S Slack, Jørgen Kjems, Jochen H M Prehn

{"title":"Distinct fingerprints of tRNA-derived small non-coding RNA in animal models of neurodegeneration.","authors":"Sharada Baindoor, Hesham A Y Gibriel, Morten T Venø, Junyi Su, Elena Perez Morrissey, Elisabeth Jirström, Ina Woods, Aidan Kenny, Mariana Alves, Luise Halang, Paola Fabbrizio, Maria Bilen, Tobias Engel, Marion C Hogg, Caterina Bendotti, Giovanni Nardo, Ruth S Slack, Jørgen Kjems, Jochen H M Prehn","doi":"10.1242/dmm.050870","DOIUrl":"https://doi.org/10.1242/dmm.050870","url":null,"abstract":"Transfer RNA-derived small RNAs (tsRNAs) - categorized as tRNA-derived fragments (tRFs), tRNA-derived stress-induced RNAs (tiRNAs) and internal tRF (itRF) - are small non-coding RNAs that participate in various cellular processes such as translation inhibition and responses to cellular stress. We here identified tsRNA profiles within susceptible tissues in animal models of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) to pinpoint disease-specific tsRNAs and those shared across neurodegenerative diseases. We performed small RNA sequencing in the SOD1G93A and TDP43A315T mouse models of ALS (spinal cord), the TauP301S model of FTD (hippocampus), and the parkin/POLG model of PD (substantia nigra). Bioinformatic analysis showed higher expression of 5' tiRNAs selectively in the two ALS models, lower expression of 3' tRFs in both the ALS and FTD mouse models, and lower expression of itRF Arg in the PD model. Experimental validation confirmed the expression of tsRNAs. Gene Ontology analysis of targets associated with validated 3' tRFs indicated functions in the regulation of synaptic and neuronal pathways. Our profiling of tsRNAs indicates disease-specific fingerprints in animal models of neurodegeneration, which require validation in human disease.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 11","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647589","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":" ","pages":""},"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":" ","pages":""},"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