Dachuan Guo, Chong Zhang, Mingyan Zhang, Zhenguo Wu, Xiaoyu Liu, Ye-min Zhang, Li Liu, Meili Sun, Jianmin Yang
Background: The Metabolic Score for Insulin Resistance (METS-IR) index serves as a simple surrogate marker for insulin resistance (IR) and is associated with the presence and severity of coronary artery disease (CAD). However, the prognostic significance of METS-IR in patients with premature CAD remains unclear. This study aims to investigate the prognostic value of METS-IR in premature CAD. Methods: This retrospective study included 582 patients diagnosed with premature CAD between December 2012 and July 2019. The median follow-up duration was 63 months (interquartile range, 44-81 months). The primary endpoint was Major Adverse Cardiovascular Events (MACE), defined as a composite of all-cause death, non-fatal myocardial infarction (MI), repeat coronary artery revascularization, and non-fatal stroke. Results: Patients with MACE had significantly higher METS-IR levels than those without MACE (44.88±8.11 vs. 41.68±6.87, p<0.001). Kaplan-Meier survival curves based on METS-IR tertiles demonstrated a statistically significant difference (log-rank test, p<0.001). In the fully adjusted model, the Hazard Ratio (95% CI) for MACE was 1.41 (1.16-1.72) per SD increase in METS-IR, and the P for trend based on METS-IR tertiles was 0.001 for MACE. Time-dependent Receiver Operator Characteristic (ROC) analysis of METS-IR yielded an Area Under the Curve (AUC) of 0.74 at 2 years, 0.69 at 4 years, and 0.63 at 6 years. Conclusions: METS-IR serves as a reliable prognostic predictor of MACE in patients with premature CAD. Therefore, METS-IR may be considered a novel, cost-effective, and dependable indicator for risk stratification and early intervention in premature CAD.
{"title":"Metabolic score for insulin resistance predicts major adverse cardiovascular event in premature coronary artery disease","authors":"Dachuan Guo, Chong Zhang, Mingyan Zhang, Zhenguo Wu, Xiaoyu Liu, Ye-min Zhang, Li Liu, Meili Sun, Jianmin Yang","doi":"10.18632/aging.205710","DOIUrl":"https://doi.org/10.18632/aging.205710","url":null,"abstract":"Background: The Metabolic Score for Insulin Resistance (METS-IR) index serves as a simple surrogate marker for insulin resistance (IR) and is associated with the presence and severity of coronary artery disease (CAD). However, the prognostic significance of METS-IR in patients with premature CAD remains unclear. This study aims to investigate the prognostic value of METS-IR in premature CAD. Methods: This retrospective study included 582 patients diagnosed with premature CAD between December 2012 and July 2019. The median follow-up duration was 63 months (interquartile range, 44-81 months). The primary endpoint was Major Adverse Cardiovascular Events (MACE), defined as a composite of all-cause death, non-fatal myocardial infarction (MI), repeat coronary artery revascularization, and non-fatal stroke. Results: Patients with MACE had significantly higher METS-IR levels than those without MACE (44.88±8.11 vs. 41.68±6.87, p<0.001). Kaplan-Meier survival curves based on METS-IR tertiles demonstrated a statistically significant difference (log-rank test, p<0.001). In the fully adjusted model, the Hazard Ratio (95% CI) for MACE was 1.41 (1.16-1.72) per SD increase in METS-IR, and the P for trend based on METS-IR tertiles was 0.001 for MACE. Time-dependent Receiver Operator Characteristic (ROC) analysis of METS-IR yielded an Area Under the Curve (AUC) of 0.74 at 2 years, 0.69 at 4 years, and 0.63 at 6 years. Conclusions: METS-IR serves as a reliable prognostic predictor of MACE in patients with premature CAD. Therefore, METS-IR may be considered a novel, cost-effective, and dependable indicator for risk stratification and early intervention in premature CAD.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"512 ","pages":"6364 - 6383"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140780154","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}
Aims: N6-methyladenosine (m6A), the most abundant and conserved epigenetic modification of mRNA, participates in various physiological and pathological processes. However, the roles of m6A modification in liver lipid metabolism have yet to be understood entirely. We aimed to investigate the roles of the m6A “writer” protein methyltransferase-like 3 (Mettl3) in liver lipid metabolism and the underlying mechanisms. Main Methods: We assessed the expression of Mettl3 in liver tissues of diabetes (db/db) mice, obese (ob/ob) mice, high saturated fat-, cholesterol-, and fructose-induced non-alcoholic fatty liver disease (NAFLD) mice, and alcohol abuse and alcoholism (NIAAA) mice by quantitative reverse-transcriptase PCR (qRT-PCR). Hepatocyte-specific Mettl3 knockout mice were used to evaluate the effects of Mettl3 deficiency in mouse liver. The molecular mechanisms underlying the roles of Mettl3 deletion in liver lipid metabolism were explored by multi-omics joint analysis of public data from the Gene Expression Omnibus database and further validated by qRT-PCR and Western blot. Key Findings: Significantly decreased Mettl3 expression was associated with NAFLD progression. Hepatocyte-specific knockout of Mettl3 resulted in significant lipid accumulation in the liver, increased serum total cholesterol levels, and progressive liver damage in mice. Mechanistically, loss of Mettl3 significantly downregulated the expression levels of multiple m6A-modified mRNAs related to lipid metabolism, including Adh7, Cpt1a, and Cyp7a1, further promoting lipid metabolism disorders and liver injury in mice. Significance: In summary, our findings demonstrate that the expression alteration of genes related to lipid metabolism by Mettl3-mediated m6A modification contributes to the development of NAFLD.
{"title":"Mettl3-mediated m6A modification plays a role in lipid metabolism disorders and progressive liver damage in mice by regulating lipid metabolism-related gene expression","authors":"Guanqi Dai, Shihao Huang, Yonglong Li, Xueyi Tu, Jiawei Xia, Zhihao Zhou, Wanyi Chen, Ao Zhang, Jintao Lin, Yingchun Li, Dan-hua He, Tao-yan Lin, Jing Cong, Ye Lei, Liuxin Han, Zhenxia Yao, Weiwei Liu, Ying Zhou, Qiwen Li, Jing Li, Yuqin Zhang, Aibing Wu, Dong Xiao, Wanshan Wang, Wen-tao Zhao, Jun-shuang Jia, Xiaolin Lin","doi":"10.2139/ssrn.4363559","DOIUrl":"https://doi.org/10.2139/ssrn.4363559","url":null,"abstract":"Aims: N6-methyladenosine (m6A), the most abundant and conserved epigenetic modification of mRNA, participates in various physiological and pathological processes. However, the roles of m6A modification in liver lipid metabolism have yet to be understood entirely. We aimed to investigate the roles of the m6A “writer” protein methyltransferase-like 3 (Mettl3) in liver lipid metabolism and the underlying mechanisms. Main Methods: We assessed the expression of Mettl3 in liver tissues of diabetes (db/db) mice, obese (ob/ob) mice, high saturated fat-, cholesterol-, and fructose-induced non-alcoholic fatty liver disease (NAFLD) mice, and alcohol abuse and alcoholism (NIAAA) mice by quantitative reverse-transcriptase PCR (qRT-PCR). Hepatocyte-specific Mettl3 knockout mice were used to evaluate the effects of Mettl3 deficiency in mouse liver. The molecular mechanisms underlying the roles of Mettl3 deletion in liver lipid metabolism were explored by multi-omics joint analysis of public data from the Gene Expression Omnibus database and further validated by qRT-PCR and Western blot. Key Findings: Significantly decreased Mettl3 expression was associated with NAFLD progression. Hepatocyte-specific knockout of Mettl3 resulted in significant lipid accumulation in the liver, increased serum total cholesterol levels, and progressive liver damage in mice. Mechanistically, loss of Mettl3 significantly downregulated the expression levels of multiple m6A-modified mRNAs related to lipid metabolism, including Adh7, Cpt1a, and Cyp7a1, further promoting lipid metabolism disorders and liver injury in mice. Significance: In summary, our findings demonstrate that the expression alteration of genes related to lipid metabolism by Mettl3-mediated m6A modification contributes to the development of NAFLD.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"63 1","pages":"5550 - 5568"},"PeriodicalIF":0.0,"publicationDate":"2023-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81374106","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}
Yan Pu, Jing Han, Mengmeng Zhang, Mengxue Liu, Gulnazar Abdusamat, Hui-Bin Liu
The most hostile form of urologic cancer, clear cell renal cell carcinoma (ccRCC), has a high fatality rate and poor prognosis due to tumor metastasis at initial presentation. The complex process driving ccRCC metastasis is still unknown, though. In this study, we demonstrate that Spindle and kinetochore-associated protein 1 (SKA1) expression is significantly upregulated in ccRCC tissues and associated with aggressive clinicopathologic characteristics. Functionally, SKA1 knockdown on ccRCC cells reduced cancer cell motility both in vivo and in vitro research. These bioactivities of SKA1 may be brought on by its specific interaction with scaffold attachment factor B, according to the proposed mechanism (SAFB), which could further depress the transcription of dual specificity phosphatase 6 (DUSP6). Our findings may provide a new way of researching SKA1-regulated tumor metastasis, and indicate that SKA1 is a prospective therapeutic target for renal carcinoma.
{"title":"SKA1 promotes tumor metastasis via SAFB-mediated transcription repression of DUSP6 in clear cell renal cell carcinoma","authors":"Yan Pu, Jing Han, Mengmeng Zhang, Mengxue Liu, Gulnazar Abdusamat, Hui-Bin Liu","doi":"10.2139/ssrn.3881734","DOIUrl":"https://doi.org/10.2139/ssrn.3881734","url":null,"abstract":"The most hostile form of urologic cancer, clear cell renal cell carcinoma (ccRCC), has a high fatality rate and poor prognosis due to tumor metastasis at initial presentation. The complex process driving ccRCC metastasis is still unknown, though. In this study, we demonstrate that Spindle and kinetochore-associated protein 1 (SKA1) expression is significantly upregulated in ccRCC tissues and associated with aggressive clinicopathologic characteristics. Functionally, SKA1 knockdown on ccRCC cells reduced cancer cell motility both in vivo and in vitro research. These bioactivities of SKA1 may be brought on by its specific interaction with scaffold attachment factor B, according to the proposed mechanism (SAFB), which could further depress the transcription of dual specificity phosphatase 6 (DUSP6). Our findings may provide a new way of researching SKA1-regulated tumor metastasis, and indicate that SKA1 is a prospective therapeutic target for renal carcinoma.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"58 1","pages":"9679 - 9698"},"PeriodicalIF":0.0,"publicationDate":"2022-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73830011","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}
D. Zi, Qing Li, Chengmin Xu, Zhiwei Zhou, Guan-Bin Song, Cheng-Bin Hu, Fang Wen, Hanxiao Yang, Lei Nie, Xing Zhao, Jun Tan, Shufeng Zhou, Zhi-xu He
1Department of Obstetrics and Gynecology, Guizhou Provincial People’s Hospital, Guiyang 550002, Guizhou, China 2Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China 3Key Laboratory of Adult Stem Cell Transformation Research, Chinese Academy of Medical Sciences/Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang 550004, China 4Key Laboratory of Endemic and Ethnic Diseases and Key Laboratory of Molecular Biology, Ministry of Education, Guizhou Medical University, Guiyang 550004, China 5Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA 6 Cancer Center, Daping Hospital and Research Institute of Surgery, The Third Military Medical University, Yuzhong 40042, Chongqing, China 7Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 8Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China 9Department of Computer Science and Engineering, University of South Florida, Tampa, FL 33620, USA 10Department of Bioengineering and Biotechnology, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian, China 11Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
{"title":"Correction for: CXCR4 knockdown enhances sensitivity of paclitaxel via the PI3K/Akt/mTOR pathway in ovarian carcinoma","authors":"D. Zi, Qing Li, Chengmin Xu, Zhiwei Zhou, Guan-Bin Song, Cheng-Bin Hu, Fang Wen, Hanxiao Yang, Lei Nie, Xing Zhao, Jun Tan, Shufeng Zhou, Zhi-xu He","doi":"10.18632/aging.204367","DOIUrl":"https://doi.org/10.18632/aging.204367","url":null,"abstract":"1Department of Obstetrics and Gynecology, Guizhou Provincial People’s Hospital, Guiyang 550002, Guizhou, China 2Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China 3Key Laboratory of Adult Stem Cell Transformation Research, Chinese Academy of Medical Sciences/Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang 550004, China 4Key Laboratory of Endemic and Ethnic Diseases and Key Laboratory of Molecular Biology, Ministry of Education, Guizhou Medical University, Guiyang 550004, China 5Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA 6 Cancer Center, Daping Hospital and Research Institute of Surgery, The Third Military Medical University, Yuzhong 40042, Chongqing, China 7Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 8Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China 9Department of Computer Science and Engineering, University of South Florida, Tampa, FL 33620, USA 10Department of Bioengineering and Biotechnology, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian, China 11Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"68 1","pages":"8876 - 8878"},"PeriodicalIF":0.0,"publicationDate":"2022-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84090216","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}
Jing Zhen, Yuni Ke, Jingying Pan, Minqin Zhou, H. Zeng, G. Song, Zichuan Yu, Bidong Fu, Yue Liu, Da Huang, Honghu Wu
Hepatocellular carcinoma (HCC) is one of the most deadly and common malignant cancers around the world, and the prognosis of HCC patients is not optimistic. ZNF320 belongs to Krüppel like zinc finger gene family. However, no studies have focused on the influence of ZNF320 in HCC. We first analyzed ZNF320 expression in HCC by using data from TCGA and ICGC, then conducted a joint analysis with TIMER and UALCAN, and validated by immunohistochemistry in clinical HCC samples. Then we applied UALCAN to explore the correlation between ZNF320 expression and clinicopathological characteristics. Consequently, using Kaplan-Meier Plotter analysis and the Cox regression, we can predict the prognostic value of ZNF320 for HCC patients. Next, the analysis by GO, KEGG, and GSEA revealed that ZNF320 was significantly correlated to cell cycle and immunity. Finally, TIMER and GEPIA analysis verified that ZNF320 expression is closely related to tumor infiltrating immune cells (TIIC), including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. The analysis of the TCGA and ICGC data sets revealed that ZNF320 expression was significantly correlated with m6A related genes (RBMX, YTHDF1, and METTL3). In conclusion, ZNF320 may be a prognostic biomarker related to immunity as a candidate for liver cancer.
{"title":"ZNF320 is a hypomethylated prognostic biomarker involved in immune infiltration of hepatocellular carcinoma and associated with cell cycle","authors":"Jing Zhen, Yuni Ke, Jingying Pan, Minqin Zhou, H. Zeng, G. Song, Zichuan Yu, Bidong Fu, Yue Liu, Da Huang, Honghu Wu","doi":"10.18632/aging.204350","DOIUrl":"https://doi.org/10.18632/aging.204350","url":null,"abstract":"Hepatocellular carcinoma (HCC) is one of the most deadly and common malignant cancers around the world, and the prognosis of HCC patients is not optimistic. ZNF320 belongs to Krüppel like zinc finger gene family. However, no studies have focused on the influence of ZNF320 in HCC. We first analyzed ZNF320 expression in HCC by using data from TCGA and ICGC, then conducted a joint analysis with TIMER and UALCAN, and validated by immunohistochemistry in clinical HCC samples. Then we applied UALCAN to explore the correlation between ZNF320 expression and clinicopathological characteristics. Consequently, using Kaplan-Meier Plotter analysis and the Cox regression, we can predict the prognostic value of ZNF320 for HCC patients. Next, the analysis by GO, KEGG, and GSEA revealed that ZNF320 was significantly correlated to cell cycle and immunity. Finally, TIMER and GEPIA analysis verified that ZNF320 expression is closely related to tumor infiltrating immune cells (TIIC), including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. The analysis of the TCGA and ICGC data sets revealed that ZNF320 expression was significantly correlated with m6A related genes (RBMX, YTHDF1, and METTL3). In conclusion, ZNF320 may be a prognostic biomarker related to immunity as a candidate for liver cancer.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"34 1","pages":"8411 - 8436"},"PeriodicalIF":0.0,"publicationDate":"2022-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82105150","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}
Lushun Ma, Rui Li, Zhiwei Yao, Bo Wang, Yong Liu, Chun-xia Liu, Heng Wang, Shuxian Chen, Daqing Sun
Traf2 and Nck-interacting kinase (TNIK) is the downstream molecule of Wnt/β-catenin signal pathway. As the activation kinase of β-catenin/T-cell factor 4 transcription complex, it can fully activate Wnt signalling and promote the growth and invasion of tumor cells. We conducted computer-assisted virtual screening and a series of analyses to find potential inhibitors of TNIK. First, LibDock was used for molecular docking of natural small molecules. Then, ADME (Adsorption, Distribution, Metabolism and Excretion) analysis and toxicity prediction were performed on the top 80 small molecules which have higher scores. Additionally, in order to further determine the affinity and binding mechanism of TNIK-ligands, we analyzed the pharmacophores and used CDOCKER for more accurate molecular docking. Last but not least, molecular, dynamics simulation was used to evaluate the stability of receptor-ligand complexes in natural environment. The results showed that natural small molecules (ZINC000040976869 and ZINC000008214460) had high affinity and low interaction energy with TNIK. They were predicted to have excellent pharmacological properties, such as high plasma protein binding capacity and water solubility, no hepatotoxicity, no blood-brain barrier permeability and tolerant with cytochrome P450 2D6 (CYP2D6). In addition, they have less rodent carcinogenicity, AMES mutagenicity, and developmental toxicity potential. Molecular dynamics simulations showed that the two compounds could achieve the stability of potential energy and Root-Mean-Square Deviation (RMSD) at different time nodes. This study proves that ZINC000040976869 and ZINC000008214460 are ideal lead compounds with inhibition targeting to TNIK. These compounds provide valuable ideas and information for the development of new colorectal cancer targeting drugs.
{"title":"Computational study on new natural compound inhibitors of Traf2 and Nck-interacting kinase (TNIK)","authors":"Lushun Ma, Rui Li, Zhiwei Yao, Bo Wang, Yong Liu, Chun-xia Liu, Heng Wang, Shuxian Chen, Daqing Sun","doi":"10.18632/aging.204349","DOIUrl":"https://doi.org/10.18632/aging.204349","url":null,"abstract":"Traf2 and Nck-interacting kinase (TNIK) is the downstream molecule of Wnt/β-catenin signal pathway. As the activation kinase of β-catenin/T-cell factor 4 transcription complex, it can fully activate Wnt signalling and promote the growth and invasion of tumor cells. We conducted computer-assisted virtual screening and a series of analyses to find potential inhibitors of TNIK. First, LibDock was used for molecular docking of natural small molecules. Then, ADME (Adsorption, Distribution, Metabolism and Excretion) analysis and toxicity prediction were performed on the top 80 small molecules which have higher scores. Additionally, in order to further determine the affinity and binding mechanism of TNIK-ligands, we analyzed the pharmacophores and used CDOCKER for more accurate molecular docking. Last but not least, molecular, dynamics simulation was used to evaluate the stability of receptor-ligand complexes in natural environment. The results showed that natural small molecules (ZINC000040976869 and ZINC000008214460) had high affinity and low interaction energy with TNIK. They were predicted to have excellent pharmacological properties, such as high plasma protein binding capacity and water solubility, no hepatotoxicity, no blood-brain barrier permeability and tolerant with cytochrome P450 2D6 (CYP2D6). In addition, they have less rodent carcinogenicity, AMES mutagenicity, and developmental toxicity potential. Molecular dynamics simulations showed that the two compounds could achieve the stability of potential energy and Root-Mean-Square Deviation (RMSD) at different time nodes. This study proves that ZINC000040976869 and ZINC000008214460 are ideal lead compounds with inhibition targeting to TNIK. These compounds provide valuable ideas and information for the development of new colorectal cancer targeting drugs.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"110 1","pages":"8394 - 8410"},"PeriodicalIF":0.0,"publicationDate":"2022-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82460253","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}
Hong-juan Fang, Runsheng Zhao, Shuang Cui, Weiqing Wan
Objective: To evaluate whether sex differences in the associations of subclinical hypothyroidism (SH) and subclinical hyperthyroidism (SCH) with the risks of major adverse cardiovascular events (MACE) and fractures. Methods: The PubMed, EmBase, and Cochrane Library databases were searched for eligible studies from inception until November 2021. The relative risk (RR) ratio with the 95% confidence interval (CI) was used to identify sex differences in the associations of SH and SCH with the risks of MACE and fractures. All analyses were performed using a random-effects model. Results: Twenty-four cohort studies (in 3,480,682 patients) were selected for meta-analysis. There were no sex differences in the associations of SH and SCH with the risks of atrial fibrillation, all-cause mortality, cardiac death, coronary heart disease, heart failure, MACE, stroke, fracture. Subgroup analyses indicated a greater risk of MACE in men than in women with SH if follow-up was ≥10.0 years (RR ratio 2.44; 95% CI 1.17–5.10; P = 0.017). The risk of any fracture was greater in men than in women with SH if follow-up was <10.0 years (RR ratio 1.17; 95% CI 1.03–1.34; P = 0.017) and in studies with a high level of adjustment (RR ratio 1.16; 95% CI 1.02–1.32; P = 0.022). However, the risk of hip fracture was lower in men than in women with SH on pooling of studies with low adjustment (RR ratio 0.53; 95% CI 0.29–0.97; P = 0.039). Conclusions: There may be sex-related differences in the risks of MACE, any fracture, and hip fracture in patients with SH.
目的:探讨亚临床甲状腺功能减退症(SH)和亚临床甲状腺功能亢进症(SCH)与主要不良心血管事件(MACE)和骨折风险的性别差异。方法:检索PubMed、EmBase和Cochrane图书馆数据库，从成立到2021年11月检索符合条件的研究。采用95%可信区间(CI)的相对危险度(RR)来确定SH和SCH与MACE和骨折风险相关性的性别差异。所有分析均采用随机效应模型。结果:24项队列研究(3,480,682例患者)入选meta分析。在SH和SCH与房颤、全因死亡率、心源性死亡、冠心病、心力衰竭、MACE、中风、骨折风险的相关性方面，没有性别差异。亚组分析显示，如果随访≥10.0年，男性发生MACE的风险高于女性(RR比2.44;95% ci 1.17-5.10;P = 0.017)。如果随访时间<10.0年，男性发生骨折的风险大于女性(RR比1.17;95% ci 1.03-1.34;P = 0.017)，在调整水平较高的研究中(RR比1.16;95% ci 1.02-1.32;P = 0.022)。然而，在低校正的研究中，男性髋部骨折的风险低于女性(RR比0.53;95% ci 0.29-0.97;P = 0.039)。结论:SH患者发生MACE、任何骨折和髋部骨折的风险可能存在性别差异。
{"title":"Sex differences in major cardiovascular outcomes and fractures in patients with subclinical thyroid dysfunction: a systematic review and meta-analysis","authors":"Hong-juan Fang, Runsheng Zhao, Shuang Cui, Weiqing Wan","doi":"10.18632/aging.204352","DOIUrl":"https://doi.org/10.18632/aging.204352","url":null,"abstract":"Objective: To evaluate whether sex differences in the associations of subclinical hypothyroidism (SH) and subclinical hyperthyroidism (SCH) with the risks of major adverse cardiovascular events (MACE) and fractures. Methods: The PubMed, EmBase, and Cochrane Library databases were searched for eligible studies from inception until November 2021. The relative risk (RR) ratio with the 95% confidence interval (CI) was used to identify sex differences in the associations of SH and SCH with the risks of MACE and fractures. All analyses were performed using a random-effects model. Results: Twenty-four cohort studies (in 3,480,682 patients) were selected for meta-analysis. There were no sex differences in the associations of SH and SCH with the risks of atrial fibrillation, all-cause mortality, cardiac death, coronary heart disease, heart failure, MACE, stroke, fracture. Subgroup analyses indicated a greater risk of MACE in men than in women with SH if follow-up was ≥10.0 years (RR ratio 2.44; 95% CI 1.17–5.10; P = 0.017). The risk of any fracture was greater in men than in women with SH if follow-up was <10.0 years (RR ratio 1.17; 95% CI 1.03–1.34; P = 0.017) and in studies with a high level of adjustment (RR ratio 1.16; 95% CI 1.02–1.32; P = 0.022). However, the risk of hip fracture was lower in men than in women with SH on pooling of studies with low adjustment (RR ratio 0.53; 95% CI 0.29–0.97; P = 0.039). Conclusions: There may be sex-related differences in the risks of MACE, any fracture, and hip fracture in patients with SH.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"110 1","pages":"8448 - 8485"},"PeriodicalIF":0.0,"publicationDate":"2022-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80792386","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}
Mingzhou Gao, Hao Zhang, Ya Sun, Zhan Gao, Chunyan Sun, F. Wei, Dong-mei Gao
Background: Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with pathological changes rooted in GABRB2 copy number variation. Here, we aimed to elucidate the gene dose effect and allopregnanolone binding mechanism of Gabrb2 on possible PMDD-like and comorbid phenotypes in knockout mice. Methods: PMDD-like behaviors of Gabrb2-knockout mice were measured through various tests. Western Blot and ELISA were used to detect changes in the GABAAR subunits and related neurotransmitter changes in mice respectively for the internal mechanism. The response of mice to allopregnanolone (ALLO) was examined through an exogenous ALLO injection, then validated by the patch-clamp technique to elaborate the potential mechanism of ALLO-mediated GABAAR. Results: Gabrb2-knockout mice displayed changes in anxiety-like and depression-like emotions opposite to PMDD symptoms, changes in social, learning, and memory capacities similar to PMDD symptoms, and pain threshold changes opposite to PMDD symptoms. GABAAR δ subunit expression in the brains of the Gabrb2-knockout mice was significantly higher than that of Wild-type mice (P<0.05). Gabrb2-knockout mice demonstrated neurotransmitter metabolism disturbance of GABA, Glu, acetylcholine, DA, norepinephrine, and epinephrine. Moreover, Gabrb2-knockout mice did not display the expected phenotypic effect after ALLO injection. Relative to WT mice, the knockout of the β2 subunit gene enhanced the agonistic effect of ALLO on GABAA receptors in cortical neuronal cells. Conclusions: GABAAR β 2 regulates PMDD-like behaviors. The ALLO binding site may not be located on β two subunits, abnormal δ and ε subunit expression in the mouse brain and the disturbance of neurotransmitters may result in ALLO sensitivity.
{"title":"Gabrb2 knock-out mice exhibit double-directed PMDD-like symptoms: GABAAR subunits, neurotransmitter metabolism disruption, and allopregnanolone binding","authors":"Mingzhou Gao, Hao Zhang, Ya Sun, Zhan Gao, Chunyan Sun, F. Wei, Dong-mei Gao","doi":"10.18632/aging.204351","DOIUrl":"https://doi.org/10.18632/aging.204351","url":null,"abstract":"Background: Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with pathological changes rooted in GABRB2 copy number variation. Here, we aimed to elucidate the gene dose effect and allopregnanolone binding mechanism of Gabrb2 on possible PMDD-like and comorbid phenotypes in knockout mice. Methods: PMDD-like behaviors of Gabrb2-knockout mice were measured through various tests. Western Blot and ELISA were used to detect changes in the GABAAR subunits and related neurotransmitter changes in mice respectively for the internal mechanism. The response of mice to allopregnanolone (ALLO) was examined through an exogenous ALLO injection, then validated by the patch-clamp technique to elaborate the potential mechanism of ALLO-mediated GABAAR. Results: Gabrb2-knockout mice displayed changes in anxiety-like and depression-like emotions opposite to PMDD symptoms, changes in social, learning, and memory capacities similar to PMDD symptoms, and pain threshold changes opposite to PMDD symptoms. GABAAR δ subunit expression in the brains of the Gabrb2-knockout mice was significantly higher than that of Wild-type mice (P<0.05). Gabrb2-knockout mice demonstrated neurotransmitter metabolism disturbance of GABA, Glu, acetylcholine, DA, norepinephrine, and epinephrine. Moreover, Gabrb2-knockout mice did not display the expected phenotypic effect after ALLO injection. Relative to WT mice, the knockout of the β2 subunit gene enhanced the agonistic effect of ALLO on GABAA receptors in cortical neuronal cells. Conclusions: GABAAR β 2 regulates PMDD-like behaviors. The ALLO binding site may not be located on β two subunits, abnormal δ and ε subunit expression in the mouse brain and the disturbance of neurotransmitters may result in ALLO sensitivity.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"52 1","pages":"8437 - 8447"},"PeriodicalIF":0.0,"publicationDate":"2022-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84463512","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 : 2022-09-02DOI: 10.1101/2022.09.01.505710
Archit Kumar, Jiawei Wang, Haowen Zhou, C. Radcliffe, B. V. Wyk, H. Allore, S. Tsang, L. Barakat, S. Mohanty, Hongyu Zhao, A. Shaw, Heidi J. Zapata
Dectin-1 is an innate immune receptor that recognizes and binds β-1,3/1,6 glucans on fungi. We evaluated Dectin-1 function in myeloid cells in a cohort of HIV-positive and HIV-negative young and older adults. Stimulation of monocytes with β-D-glucans induced a pro-inflammatory phenotype in monocytes of HIV-infected individuals that was characterized by increased levels of IL-12, TNF-α, and IL-6, with some age-associated cytokine increases also noted. Dendritic cells showed a striking HIV-associated increase in IFN-α production. These increases in cytokine production paralleled increases in Dectin-1 surface expression in both monocytes and dendritic cells that were noted with both HIV and aging. Differential gene expression analysis showed that HIV-positive older adults had a distinct gene signature compared to other cohorts characterized by a robust TNF-α and coagulation response (increased at baseline), a persistent IFN-α and IFN-γ response, and an activated dendritic cell signature/M1 macrophage signature upon Dectin-1 stimulation. Dectin-1 stimulation induced a strong upregulation of MTORC1 signaling in all cohorts, although increased in the HIV-Older cohort (stimulation and baseline). Overall, our study demonstrates that the HIV Aging population has a distinct immune signature in response to Dectin-1 stimulation. This signature may contribute to the pro-inflammatory environment that is associated with HIV and Aging.
Dectin-1是一种天然免疫受体，可识别并结合真菌上的β-1,3/1,6葡聚糖。我们评估了Dectin-1在hiv阳性和hiv阴性的年轻人和老年人的骨髓细胞中的功能。用β- d -葡聚糖刺激单核细胞诱导hiv感染者单核细胞的促炎表型，其特征是IL-12、TNF-α和IL-6水平升高，同时也注意到一些与年龄相关的细胞因子升高。树突状细胞显示出与hiv相关的IFN-α产生的显著增加。这些细胞因子产生的增加与单核细胞和树突状细胞中Dectin-1表面表达的增加是平行的，这些都是在HIV和衰老中注意到的。差异基因表达分析显示，与其他队列相比，hiv阳性的老年人具有明显的基因特征，其特征是强大的TNF-α和凝血反应(在基线时增加)，持续的IFN-α和IFN-γ反应，以及在Dectin-1刺激下激活的树突状细胞特征/M1巨噬细胞特征。Dectin-1刺激在所有队列中诱导MTORC1信号的强烈上调，尽管在HIV-Older队列中(刺激和基线)有所增加。总之，我们的研究表明HIV老龄人群对Dectin-1刺激有明显的免疫特征。这一特征可能促成了与HIV和衰老相关的促炎环境。
{"title":"Dectin-1 stimulation promotes a distinct inflammatory signature in the setting of HIV-infection and aging","authors":"Archit Kumar, Jiawei Wang, Haowen Zhou, C. Radcliffe, B. V. Wyk, H. Allore, S. Tsang, L. Barakat, S. Mohanty, Hongyu Zhao, A. Shaw, Heidi J. Zapata","doi":"10.1101/2022.09.01.505710","DOIUrl":"https://doi.org/10.1101/2022.09.01.505710","url":null,"abstract":"Dectin-1 is an innate immune receptor that recognizes and binds β-1,3/1,6 glucans on fungi. We evaluated Dectin-1 function in myeloid cells in a cohort of HIV-positive and HIV-negative young and older adults. Stimulation of monocytes with β-D-glucans induced a pro-inflammatory phenotype in monocytes of HIV-infected individuals that was characterized by increased levels of IL-12, TNF-α, and IL-6, with some age-associated cytokine increases also noted. Dendritic cells showed a striking HIV-associated increase in IFN-α production. These increases in cytokine production paralleled increases in Dectin-1 surface expression in both monocytes and dendritic cells that were noted with both HIV and aging. Differential gene expression analysis showed that HIV-positive older adults had a distinct gene signature compared to other cohorts characterized by a robust TNF-α and coagulation response (increased at baseline), a persistent IFN-α and IFN-γ response, and an activated dendritic cell signature/M1 macrophage signature upon Dectin-1 stimulation. Dectin-1 stimulation induced a strong upregulation of MTORC1 signaling in all cohorts, although increased in the HIV-Older cohort (stimulation and baseline). Overall, our study demonstrates that the HIV Aging population has a distinct immune signature in response to Dectin-1 stimulation. This signature may contribute to the pro-inflammatory environment that is associated with HIV and Aging.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"80 1","pages":"7866 - 7908"},"PeriodicalIF":0.0,"publicationDate":"2022-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89071768","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 : 2022-07-23DOI: 10.1101/2022.07.22.501095
Elena Fueyo-Marcos, Gema Lopez-Pernas, C. Fustero-Torre, M. E. Antón, F. Al-Shahrour, O. Fernandez-Capetillo, M. Murga
Antibodies targeting the PD-1 receptor and its ligand PD-L1 have shown impressive responses in some tumors of bad prognosis. We hypothesized that the selective elimination of PD-L1 expressing cells could similarly have antitumoral effects. To address this question, we developed an inducible suicidal knock-in mouse allele of Pd-l1 (PD-L1ATTAC) which allows for the tracking and specific elimination of PD-L1-expressing cells in adult tissues. Elimination of PD-L1 expressing cells from the mouse peritoneum increased the septic response to lipopolysaccharide (LPS), due to an exacerbated inflammatory response to the endotoxin. In addition, mice depleted of PD-L1+ cells were resistant to colon cancer peritoneal allografts, which was associated with a loss of immunosuppresive B cells and macrophages, concomitant with an increase in activated cytotoxic CD8 T cells. Collectively, these results illustrate the usefulness of PD-L1ATTAC mice and provide genetic support to the concept of targeting PD-L1 expressing cells in cancer therapy.
{"title":"PD-L1ATTAC mice reveal the potential of depleting PD-L1 expressing cells in cancer therapy","authors":"Elena Fueyo-Marcos, Gema Lopez-Pernas, C. Fustero-Torre, M. E. Antón, F. Al-Shahrour, O. Fernandez-Capetillo, M. Murga","doi":"10.1101/2022.07.22.501095","DOIUrl":"https://doi.org/10.1101/2022.07.22.501095","url":null,"abstract":"Antibodies targeting the PD-1 receptor and its ligand PD-L1 have shown impressive responses in some tumors of bad prognosis. We hypothesized that the selective elimination of PD-L1 expressing cells could similarly have antitumoral effects. To address this question, we developed an inducible suicidal knock-in mouse allele of Pd-l1 (PD-L1ATTAC) which allows for the tracking and specific elimination of PD-L1-expressing cells in adult tissues. Elimination of PD-L1 expressing cells from the mouse peritoneum increased the septic response to lipopolysaccharide (LPS), due to an exacerbated inflammatory response to the endotoxin. In addition, mice depleted of PD-L1+ cells were resistant to colon cancer peritoneal allografts, which was associated with a loss of immunosuppresive B cells and macrophages, concomitant with an increase in activated cytotoxic CD8 T cells. Collectively, these results illustrate the usefulness of PD-L1ATTAC mice and provide genetic support to the concept of targeting PD-L1 expressing cells in cancer therapy.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"53 1","pages":"1791 - 1807"},"PeriodicalIF":0.0,"publicationDate":"2022-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81884890","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：