Pub Date : 2024-12-31DOI: 10.1016/j.trsl.2024.12.007
Hao Chen, Qianchao Hu, Zhongshan Lu, Jie Zhao, Anxiong Liu, Zhongzhong Liu, Jun Luo, Qifa Ye, Zibiao Zhong
Renal ischemia-reperfusion injury (IRI) is a prevalent clinical syndrome, yet its underlying pathogenesis remains largely unknown. Aldehyde dehydrogenase 2 (ALDH2), an enzyme responsible for detoxifying lipid aldehydes, has been suggested to play a protective role against IRI. In our study, we observed that Aldh2 knock-out C57BL/6 mice experienced more severe renal functional impairment following IRI. This was characterized by elevated levels of creatinine and blood urea nitrogen, as well as increased apoptosis. Proteomic analysis further revealed that ALDH2 deficiency significantly disrupted lipid metabolism, resulting in higher levels of the proinflammatory protein CYP4A and its metabolic byproduct, 20-HETE. This metabolic disruption exacerbated renal inflammation and triggered endoplasmic reticulum stress. However, we found that administration of the CYP4A inhibitor, HET0016, could ameliorate these effects. Mechanistically, we discovered that after IRI, ALDH2 translocates to the nucleus and interacts with nuclear receptor corepressor 1 (NCOR1) to repress Cyp4a transcription. ALDH2 specifically interacts with the N-terminal domain of NCOR1, which is responsible for its interaction with its E3 ligase SIAH2. This interaction inhibits the proteasome degradation of NCOR1, ultimately stabilizing the NCOR1 transcriptional repression complex. In summary, our research uncovers the role of ALDH2 in mitigating renal IRI by inhibiting 20-HETE synthesis through the transcriptional repression of Cyp4a.
{"title":"Aldehyde dehydrogenase 2 attenuates renal injury through inhibiting CYP4A expression.","authors":"Hao Chen, Qianchao Hu, Zhongshan Lu, Jie Zhao, Anxiong Liu, Zhongzhong Liu, Jun Luo, Qifa Ye, Zibiao Zhong","doi":"10.1016/j.trsl.2024.12.007","DOIUrl":"10.1016/j.trsl.2024.12.007","url":null,"abstract":"<p><p>Renal ischemia-reperfusion injury (IRI) is a prevalent clinical syndrome, yet its underlying pathogenesis remains largely unknown. Aldehyde dehydrogenase 2 (ALDH2), an enzyme responsible for detoxifying lipid aldehydes, has been suggested to play a protective role against IRI. In our study, we observed that Aldh2 knock-out C57BL/6 mice experienced more severe renal functional impairment following IRI. This was characterized by elevated levels of creatinine and blood urea nitrogen, as well as increased apoptosis. Proteomic analysis further revealed that ALDH2 deficiency significantly disrupted lipid metabolism, resulting in higher levels of the proinflammatory protein CYP4A and its metabolic byproduct, 20-HETE. This metabolic disruption exacerbated renal inflammation and triggered endoplasmic reticulum stress. However, we found that administration of the CYP4A inhibitor, HET0016, could ameliorate these effects. Mechanistically, we discovered that after IRI, ALDH2 translocates to the nucleus and interacts with nuclear receptor corepressor 1 (NCOR1) to repress Cyp4a transcription. ALDH2 specifically interacts with the N-terminal domain of NCOR1, which is responsible for its interaction with its E3 ligase SIAH2. This interaction inhibits the proteasome degradation of NCOR1, ultimately stabilizing the NCOR1 transcriptional repression complex. In summary, our research uncovers the role of ALDH2 in mitigating renal IRI by inhibiting 20-HETE synthesis through the transcriptional repression of Cyp4a.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-17DOI: 10.1530/endoabs.83.erco1
J. Jiménez-Vacas, Antonio J Montero-Hidalgo, E. Gómez-Gómez, P. Sáez-Martínez, A. C. Fuentes-Fayos, A. Closa, T. González-Serrano, Ana Martínez-López, R. Sánchez-Sánchez, P. López-Casas, André Sarmento-Cabral, D. Olmos, E. Eyras, Justo P. Castaño, M. Gahete, R. Luque
Prostate cancer (PCa) is one the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in three human cohorts and two preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using two additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (i.e., RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease.
{"title":"Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes.","authors":"J. Jiménez-Vacas, Antonio J Montero-Hidalgo, E. Gómez-Gómez, P. Sáez-Martínez, A. C. Fuentes-Fayos, A. Closa, T. González-Serrano, Ana Martínez-López, R. Sánchez-Sánchez, P. López-Casas, André Sarmento-Cabral, D. Olmos, E. Eyras, Justo P. Castaño, M. Gahete, R. Luque","doi":"10.1530/endoabs.83.erco1","DOIUrl":"https://doi.org/10.1530/endoabs.83.erco1","url":null,"abstract":"Prostate cancer (PCa) is one the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in three human cohorts and two preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using two additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (i.e., RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease.","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":"110 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90081671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-01DOI: 10.1016/j.trsl.2022.03.011
V. Akmaev, S. Ghiassian, Johanna B. Withers, Marc Santolini, Alif Saleh
{"title":"Retraction notice to \"Network-based response module comprised of gene expression biomarkers predicts response to infliximab at treatment initiation in ulcerative colitis\" Translational Research 239C (2021) 35-43.","authors":"V. Akmaev, S. Ghiassian, Johanna B. Withers, Marc Santolini, Alif Saleh","doi":"10.1016/j.trsl.2022.03.011","DOIUrl":"https://doi.org/10.1016/j.trsl.2022.03.011","url":null,"abstract":"","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":"36 1","pages":"137"},"PeriodicalIF":0.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89578788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-01DOI: 10.1016/j.trsl.2022.04.001
Xiaokang Zhang, Dingdong He, Yang Xiang, Chen Wang, Bin Liang, Boyu Li, Daoxi Qi, Qianyun Deng, Hong Yu, Zhibing Lu, Fang-fang Zheng
{"title":"DYSF promotes monocyte activation in atherosclerotic cardiovascular disease as a DNA methylation-driven gene.","authors":"Xiaokang Zhang, Dingdong He, Yang Xiang, Chen Wang, Bin Liang, Boyu Li, Daoxi Qi, Qianyun Deng, Hong Yu, Zhibing Lu, Fang-fang Zheng","doi":"10.1016/j.trsl.2022.04.001","DOIUrl":"https://doi.org/10.1016/j.trsl.2022.04.001","url":null,"abstract":"","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75449885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-26DOI: 10.21203/rs.3.rs-734933/v1
In-Ho Seo, Da-Hye Son, H. Lee, Yongjae Lee
Non-HDL cholesterol is a simple measure to analyze the total amount of proatherogenic lipoproteins in the blood and to predict development of cardiovascular disease. However, it is unclear whether non-HDL cholesterol has a relationship with incident type 2 diabetes. This study aimed to evaluate the association between non-HDL cholesterol and incident type 2 diabetes with a large-sample, community-based Korean cohort over a 12-year period. Among the 10,038 total participants, 7,608 (3,662 men and 3,946 women) without diabetes were selected from the Korean Genome and Epidemiology Study (KoGES). Their non-HDL cholesterol level was divided into quartiles. The hazard ratios (HRs) with 95% confidence intervals (CIs) for incident type 2 diabetes were calculated using multivariate Cox proportional hazards regression models after adjusting for potentially confounding variables. In total, 1,442 individuals (18.9%: 1442 of 7608) developed type 2 diabetes during the 12-year follow up period, with an incident rate of 3.0-5.0. Compared to the reference first quartile, the HRs (95% CIs) of incident type 2 diabetes for the second, third, and fourth quartiles increased in a dose-response manner after adjusting for potentially confounding variables, including the HOMA-IR marker. Non-HDL cholesterol level at baseline could be a future predictor of type 2 diabetes even when prior glucose or insulin (HOMA-IR) levels are normal.
{"title":"Non-HDL cholesterol as a predictor for incident type 2 diabetes in community-dwelling adults: Longitudinal findings over 12 years.","authors":"In-Ho Seo, Da-Hye Son, H. Lee, Yongjae Lee","doi":"10.21203/rs.3.rs-734933/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-734933/v1","url":null,"abstract":"Non-HDL cholesterol is a simple measure to analyze the total amount of proatherogenic lipoproteins in the blood and to predict development of cardiovascular disease. However, it is unclear whether non-HDL cholesterol has a relationship with incident type 2 diabetes. This study aimed to evaluate the association between non-HDL cholesterol and incident type 2 diabetes with a large-sample, community-based Korean cohort over a 12-year period. Among the 10,038 total participants, 7,608 (3,662 men and 3,946 women) without diabetes were selected from the Korean Genome and Epidemiology Study (KoGES). Their non-HDL cholesterol level was divided into quartiles. The hazard ratios (HRs) with 95% confidence intervals (CIs) for incident type 2 diabetes were calculated using multivariate Cox proportional hazards regression models after adjusting for potentially confounding variables. In total, 1,442 individuals (18.9%: 1442 of 7608) developed type 2 diabetes during the 12-year follow up period, with an incident rate of 3.0-5.0. Compared to the reference first quartile, the HRs (95% CIs) of incident type 2 diabetes for the second, third, and fourth quartiles increased in a dose-response manner after adjusting for potentially confounding variables, including the HOMA-IR marker. Non-HDL cholesterol level at baseline could be a future predictor of type 2 diabetes even when prior glucose or insulin (HOMA-IR) levels are normal.","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81387167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Tsutsumi, Y. Yamasaki, J. Takeo, H. Miyahara, Mayu Sebe, M. Bando, Yousuke Tanba, Yuna Mishima, Kana Takeji, Nanako Ueshima, Masashi Kuroda, Saeko Masumoto, N. Harada, D. Fukuda, Ryoko Yoshimoto, Y. Tsutsumi, K. Aihara, M. Sata, H. Sakaue
Fish oil-derived long-chain monounsaturated fatty acids (LCMUFAs) with a carbon chain length longer than 18 units ameliorate cardiovascular risk in mice. In this study, we investigated whether LCMUFAs could improve endothelial functions in mice and humans. In a double-blind, randomized, placebo-controlled, parallel-group, multi-center study, healthy subjects were randomly assigned to either an LCMUFA oil (saury oil) or a control oil (olive and tuna oils) group. Sixty subjects were enrolled and administrated each oil for 4 weeks. For the animal study, ApoE-/- mice were fed a Western diet supplemented with 3% of either gadoleic acid (C20:1) or cetoleic acid (C22:1) for 12 weeks. Participants from the LCMUFA group showed improvements in endothelial function and a lower trimethylamine-N-oxide level, which is a predictor of coronary artery disease. C20:1 and C22:1 oils significantly improved atherosclerotic lesions and plasma levels of several inflammatory cytokines, including IL-6 and TNF-α. These beneficial effects were consistent with an improvement in the gut microbiota environment, as evident from the decreased ratio of Firmicutes/Bacteroidetes, increase in the abundance of Akkermansia, and upregulation of short-chain fatty acid (SCFA)-induced glucagon-like peptide-1 (GLP-1) expression and serum GLP-1 level. These data suggest that LCMUFAs alter the microbiota environment that stimulate the production of SCFAs, resulting in the induction of GLP-1 secretion. Fish oil-derived long-chain monounsaturated fatty acids might thus help to protect against cardiovascular disease.
碳链长度大于18个单位的鱼油衍生长链单不饱和脂肪酸(LCMUFAs)可改善小鼠心血管风险。在这项研究中，我们研究了LCMUFAs是否可以改善小鼠和人的内皮功能。在一项双盲、随机、安慰剂对照、平行组、多中心研究中，健康受试者被随机分配到LCMUFA油(金盏花油)组或对照油(橄榄油和金枪鱼油)组。60名受试者被纳入研究，每组给药4周。在动物实验中，ApoE-/-小鼠喂食添加3%甘油酸(C20:1)或鲸烯酸(C22:1)的西式饮食12周。LCMUFA组的参与者表现出内皮功能的改善和较低的三甲胺- n -氧化物水平，三甲胺- n -氧化物是冠状动脉疾病的预测因子。C20:1和C22:1油显著改善动脉粥样硬化病变和几种炎症细胞因子的血浆水平，包括IL-6和TNF-α。这些有益效果与肠道菌群环境的改善是一致的，这可以从厚壁菌门/拟杆菌门的比例下降、Akkermansia丰度增加以及短链脂肪酸(SCFA)诱导的胰高血糖素样肽-1 (GLP-1)表达和血清GLP-1水平上调中得到证明。这些数据表明，LCMUFAs改变了刺激SCFAs产生的微生物群环境，导致GLP-1分泌的诱导。因此，鱼油衍生的长链单不饱和脂肪酸可能有助于预防心血管疾病。
{"title":"Long-chain monounsaturated fatty acids improve endothelial function with altering microbial flora.","authors":"R. Tsutsumi, Y. Yamasaki, J. Takeo, H. Miyahara, Mayu Sebe, M. Bando, Yousuke Tanba, Yuna Mishima, Kana Takeji, Nanako Ueshima, Masashi Kuroda, Saeko Masumoto, N. Harada, D. Fukuda, Ryoko Yoshimoto, Y. Tsutsumi, K. Aihara, M. Sata, H. Sakaue","doi":"10.2139/ssrn.3701558","DOIUrl":"https://doi.org/10.2139/ssrn.3701558","url":null,"abstract":"Fish oil-derived long-chain monounsaturated fatty acids (LCMUFAs) with a carbon chain length longer than 18 units ameliorate cardiovascular risk in mice. In this study, we investigated whether LCMUFAs could improve endothelial functions in mice and humans. In a double-blind, randomized, placebo-controlled, parallel-group, multi-center study, healthy subjects were randomly assigned to either an LCMUFA oil (saury oil) or a control oil (olive and tuna oils) group. Sixty subjects were enrolled and administrated each oil for 4 weeks. For the animal study, ApoE-/- mice were fed a Western diet supplemented with 3% of either gadoleic acid (C20:1) or cetoleic acid (C22:1) for 12 weeks. Participants from the LCMUFA group showed improvements in endothelial function and a lower trimethylamine-N-oxide level, which is a predictor of coronary artery disease. C20:1 and C22:1 oils significantly improved atherosclerotic lesions and plasma levels of several inflammatory cytokines, including IL-6 and TNF-α. These beneficial effects were consistent with an improvement in the gut microbiota environment, as evident from the decreased ratio of Firmicutes/Bacteroidetes, increase in the abundance of Akkermansia, and upregulation of short-chain fatty acid (SCFA)-induced glucagon-like peptide-1 (GLP-1) expression and serum GLP-1 level. These data suggest that LCMUFAs alter the microbiota environment that stimulate the production of SCFAs, resulting in the induction of GLP-1 secretion. Fish oil-derived long-chain monounsaturated fatty acids might thus help to protect against cardiovascular disease.","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73601760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-08-19DOI: 10.21203/rs.3.rs-52488/v1
Chia-Feng Liu, Y. Ng, Varun Thachil, M. Morley, C. Moravec, W. Tang
The Sry-related high-mobility-group box (SOX) gene family, with 20 known transcription factors in humans, plays an essential role during development and disease processes. Several SOX proteins (SOX4, 11, and 9) are required for normal heart morphogenesis. SOX9 was shown to contribute to cardiac fibrosis. However, differential expression of other SOXs and their roles in the failing human myocardium have not been explored. Here we used the whole-transcriptome sequencing (RNA-seq), gene co-expression, and meta-analysis to examine whether any SOX factors might play a role in the failing human myocardium. RNA-seq analysis was performed for cardiac tissue samples from heart failure (HF) patients due to dilated cardiomyopathy (DCM), or hypertrophic cardiomyopathy (HCM) and healthy donors (NF). The RNA levels of 20 SOX genes from RNA-seq data were extracted and compared to the three groups. Four SOX genes whose RNA levels were significantly upregulated in DCM or HCM compared to NF. However, only SOX4 and SOX8 proteins were markedly increased in the HF groups. A moderate to strong correlation was observed between the RNA level of SOX4/8 and fibrotic genes among each individual. Gene co-expression network analysis identified genes associated and respond similarly to perturbations with SOX4 in cardiac tissues. Using a meta-analysis combining epigenetics and genome-wide association data, we reported several genomic variants associated with HF phenotype linked to SOX4 or SOX8. In summary, our results implicate that SOX4 and SOX8 have a role in cardiomyopathy, leading to HF in humans. The molecular mechanism associated with them in HF warrants further investigation. BACKGROUND: : Heart failure (HF) affects 5.7 million people in the U.S. with more than 500,000 new cases added annually. New therapeutic strategies remain needed for HF. The cardiac-pathological features are driven by transcriptome reprogramming. Understanding transcriptional control of HF is beneficial for developing novel therapies. TRANSLATIONAL SIGNIFICANCE: : This study revealed that SOX4 and SOX8 were significantly increased in cardiac tissues of HF patients and the HF-genetic variants and epigenetic changes associated with these two genes. Understanding the role of SOX4 and SOX8 in failing human myocardium and gene regulatory networks related to them may help to identify potential therapeutic targets for HF.
{"title":"Differential Expression of Members of SOX Family of Transcription Factors in Failing Human Hearts.","authors":"Chia-Feng Liu, Y. Ng, Varun Thachil, M. Morley, C. Moravec, W. Tang","doi":"10.21203/rs.3.rs-52488/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-52488/v1","url":null,"abstract":"The Sry-related high-mobility-group box (SOX) gene family, with 20 known transcription factors in humans, plays an essential role during development and disease processes. Several SOX proteins (SOX4, 11, and 9) are required for normal heart morphogenesis. SOX9 was shown to contribute to cardiac fibrosis. However, differential expression of other SOXs and their roles in the failing human myocardium have not been explored. Here we used the whole-transcriptome sequencing (RNA-seq), gene co-expression, and meta-analysis to examine whether any SOX factors might play a role in the failing human myocardium. RNA-seq analysis was performed for cardiac tissue samples from heart failure (HF) patients due to dilated cardiomyopathy (DCM), or hypertrophic cardiomyopathy (HCM) and healthy donors (NF). The RNA levels of 20 SOX genes from RNA-seq data were extracted and compared to the three groups. Four SOX genes whose RNA levels were significantly upregulated in DCM or HCM compared to NF. However, only SOX4 and SOX8 proteins were markedly increased in the HF groups. A moderate to strong correlation was observed between the RNA level of SOX4/8 and fibrotic genes among each individual. Gene co-expression network analysis identified genes associated and respond similarly to perturbations with SOX4 in cardiac tissues. Using a meta-analysis combining epigenetics and genome-wide association data, we reported several genomic variants associated with HF phenotype linked to SOX4 or SOX8. In summary, our results implicate that SOX4 and SOX8 have a role in cardiomyopathy, leading to HF in humans. The molecular mechanism associated with them in HF warrants further investigation. BACKGROUND: : Heart failure (HF) affects 5.7 million people in the U.S. with more than 500,000 new cases added annually. New therapeutic strategies remain needed for HF. The cardiac-pathological features are driven by transcriptome reprogramming. Understanding transcriptional control of HF is beneficial for developing novel therapies. TRANSLATIONAL SIGNIFICANCE: : This study revealed that SOX4 and SOX8 were significantly increased in cardiac tissues of HF patients and the HF-genetic variants and epigenetic changes associated with these two genes. Understanding the role of SOX4 and SOX8 in failing human myocardium and gene regulatory networks related to them may help to identify potential therapeutic targets for HF.","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":"75 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90827017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-11-21DOI: 10.1182/BLOOD-2018-99-119998
Jiawen Yang, Sharon K. Wu, Houda Alachkar
The role of adhesion G protein-coupled receptors (aGPCRs) in cancer has become increasingly evident in recent years. Yet, data supporting the contribution of this family of genes to hematological malignancies, particularly acute myeloid leukemia (AML) are limited. Here, we use publicly available genomic data to characterize the expression of the 33 aGPCRs in patients with AML and examine whether upregulation of these genes is associated with the clinical and molecular characteristics of patients. Upregulation in one or more of eight aGPCR genes (ADGRB1, ADGRC2, ADGRD1, ADGRE1, ADGRE2, ADGRE5, ADGRG1, and/or ADGRG3) was significantly associated with shorter overall survival (OS) (median OS: 11.8 vs 55.4 months; P < 0.0001). This was also significant in multivariate survival analysis (hazard ratio: 1.73; 95% confidence interval 1.11-2.69; P = 0.015) after adjusting for age, molecular risk status, and transplant status. High expression of the eight aGPCRs was significantly associated with older age (≥60; P = 0.011). Patients with high aGPCRs expression were more frequently classified in the poor molecular risk status group and less in the good risk status group compared with patients with low aGPCRs expression (31% vs 17% P = 0.049 and 14% vs 28% P = 0.027, respectively). Via Ingenuity Pathway Analysis, we identified the interleukin-8 signaling pathway among the most activated pathways in patients with high aGPCRs expression. Overall, our data suggest that particular aGPCRs are frequently upregulated in AML and associated with poor clinical outcome. Future functional and mechanistic analyses are needed to address the role of aGPCRs in AML.
近年来，粘附G蛋白偶联受体(agpcr)在癌症中的作用越来越明显。然而，支持该基因家族对血液系统恶性肿瘤，特别是急性髓性白血病(AML)的贡献的数据有限。在这里，我们使用公开可用的基因组数据来表征AML患者中33种agpcr的表达，并检查这些基因的上调是否与患者的临床和分子特征相关。8个aGPCR基因(ADGRB1、ADGRC2、ADGRD1、ADGRE1、ADGRE2、ADGRE5、ADGRG1和/或ADGRG3)中的一个或多个基因上调与总生存期(OS)缩短显著相关(中位OS: 11.8 vs 55.4个月;P < 0.0001)。这在多变量生存分析中也是显著的(风险比:1.73;95%置信区间1.11-2.69;P = 0.015)，在调整了年龄、分子危险状态和移植状态后。8种agpcr的高表达与老年显著相关(≥60;P = 0.011)。与agpcr低表达的患者相比，agpcr高表达的患者更常被归为不良分子风险状态组，而较低表达的患者更少被归为良好风险状态组(分别为31%对17% P = 0.049和14%对28% P = 0.027)。通过匠心通路分析，我们发现白细胞介素-8信号通路是agpcr高表达患者中最活跃的通路之一。总的来说，我们的数据表明，特定的agpcr在AML中经常上调，并与不良的临床结果相关。未来的功能和机制分析需要解决agpcr在AML中的作用。
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Pub Date : 2017-03-01DOI: 10.1016/j.trsl.2016.10.001
Mingjiao Weng, Di Wu, Chao Yang, Haisheng Peng, Guangyu Wang, Tianzhen Wang, Xiaobo Li
{"title":"Noncoding RNAs in the development, diagnosis, and prognosis of colorectal cancer.","authors":"Mingjiao Weng, Di Wu, Chao Yang, Haisheng Peng, Guangyu Wang, Tianzhen Wang, Xiaobo Li","doi":"10.1016/j.trsl.2016.10.001","DOIUrl":"https://doi.org/10.1016/j.trsl.2016.10.001","url":null,"abstract":"","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":"19 1","pages":"108-120"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87416681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-03-01DOI: 10.1016/j.trsl.2016.11.008
W. Tong, Zhouyu Lu, L. Qin, R. Mauck, Harvey E. Smith, Lachlan J. Smith, N. Malhotra, M. Heyworth, F. Caldera, M. Enomoto-Iwamoto, Yejia Zhang
{"title":"Cell therapy for the degenerating intervertebral disc.","authors":"W. Tong, Zhouyu Lu, L. Qin, R. Mauck, Harvey E. Smith, Lachlan J. Smith, N. Malhotra, M. Heyworth, F. Caldera, M. Enomoto-Iwamoto, Yejia Zhang","doi":"10.1016/j.trsl.2016.11.008","DOIUrl":"https://doi.org/10.1016/j.trsl.2016.11.008","url":null,"abstract":"","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":"123 1","pages":"49-58"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85675035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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