Our research investigated the effects of hsa-miR-134-5p on glioma progression, focusing on its interaction with the BDNF/ERK signaling pathway. U251 and U87 cell lines were analyzed post-transfection with hsa-miR-134-5p mimics and inhibitors, confirming the miRNA’s binding to BDNF using dual luciferase assays. Q-PCR was employed to measure expression changes, revealing that hsa-miR-134-5p markedly inhibited glioma cell proliferation, migration, and invasion, as evidenced by CCK8, monoclonal formation, and Transwell assays. Scratch tests and Western blotting demonstrated hsa-miR-134-5p’s modulation of the BDNF/ERK pathway and associated decrease in MMP2/9 protein levels. Flow cytometry suggested that hsa-miR-134-5p might also block the G0/S phase transition. In vivo studies using nude mice corroborated the tumor-suppressing effects of hsa-miR-134-5p, which were negated by elevated BDNF levels. Comparative protein analysis across groups confirmed the pathway’s significance in tumorigenesis. Our findings identify hsa-miR-134-5p as a key molecule impeding glioma cell growth by curtailing the BDNF/ERK pathway, with the reversal by BDNF upregulation pointing to the potential of therapeutically exploiting the hsa-miR-134-5p/BDNF axis in glioma care.
{"title":"has-miR-134-5p inhibits the proliferation and migration of glioma cells by regulating the BDNF/ERK signaling pathway","authors":"Zeshang Guo, Pingxv An, Xinyu Hong","doi":"10.18632/aging.205720","DOIUrl":"https://doi.org/10.18632/aging.205720","url":null,"abstract":"Our research investigated the effects of hsa-miR-134-5p on glioma progression, focusing on its interaction with the BDNF/ERK signaling pathway. U251 and U87 cell lines were analyzed post-transfection with hsa-miR-134-5p mimics and inhibitors, confirming the miRNA’s binding to BDNF using dual luciferase assays. Q-PCR was employed to measure expression changes, revealing that hsa-miR-134-5p markedly inhibited glioma cell proliferation, migration, and invasion, as evidenced by CCK8, monoclonal formation, and Transwell assays. Scratch tests and Western blotting demonstrated hsa-miR-134-5p’s modulation of the BDNF/ERK pathway and associated decrease in MMP2/9 protein levels. Flow cytometry suggested that hsa-miR-134-5p might also block the G0/S phase transition. In vivo studies using nude mice corroborated the tumor-suppressing effects of hsa-miR-134-5p, which were negated by elevated BDNF levels. Comparative protein analysis across groups confirmed the pathway’s significance in tumorigenesis. Our findings identify hsa-miR-134-5p as a key molecule impeding glioma cell growth by curtailing the BDNF/ERK pathway, with the reversal by BDNF upregulation pointing to the potential of therapeutically exploiting the hsa-miR-134-5p/BDNF axis in glioma care.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"58 3","pages":"6510 - 6520"},"PeriodicalIF":0.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140745483","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}
X. Ruan, Yu Liu, Shuping Wu, Guiming Fu, Mei Tao, Yue Huang, Dapeng Li, S. Wei, Ming Gao, Shicheng Guo, Junya Ning, Xiangqian Zheng
Background: Thyroid cancer represents the most prevalent malignant endocrine tumour, with rising incidence worldwide and high mortality rates among patients exhibiting dedifferentiation and metastasis. Effective biomarkers and therapeutic interventions are warranted in aggressive thyroid malignancies. The transcription factor 19 (TCF19) gene has been implicated in conferring a malignant phenotype in cancers. However, its contribution to thyroid neoplasms remains unclear. Results: In this study, we performed genome-wide and phenome-wide association studies to identify a potential causal relationship between TCF19 and thyroid cancer. Our analyses revealed significant associations between TCF19 and various autoimmune diseases and human cancers, including cervical cancer and autoimmune thyroiditis, with a particularly robust signal for the deleterious missense variation rs2073724 that is associated with thyroid function, hypothyroidism, and autoimmunity. Furthermore, functional assays and transcriptional profiling in thyroid cancer cells demonstrated that TCF19 regulates important biological processes, especially inflammatory and immune responses. We demonstrated that TCF19 could promote the progression of thyroid cancer in vitro and in vivo and the C>T variant of rs2073724 disrupted TCF19 protein binding to target gene promoters and their expression, thus reversing the effect of TCF19 protein. Conclusions: Taken together, these findings implicate TCF19 as a promising therapeutic target in aggressive thyroid malignancies and designate rs2073724 as a causal biomarker warranting further investigation in thyroid cancer.
{"title":"Multidimensional data analysis revealed thyroiditis-associated TCF19 SNP rs2073724 as a highly ranked protective variant in thyroid cancer","authors":"X. Ruan, Yu Liu, Shuping Wu, Guiming Fu, Mei Tao, Yue Huang, Dapeng Li, S. Wei, Ming Gao, Shicheng Guo, Junya Ning, Xiangqian Zheng","doi":"10.18632/aging.205718","DOIUrl":"https://doi.org/10.18632/aging.205718","url":null,"abstract":"Background: Thyroid cancer represents the most prevalent malignant endocrine tumour, with rising incidence worldwide and high mortality rates among patients exhibiting dedifferentiation and metastasis. Effective biomarkers and therapeutic interventions are warranted in aggressive thyroid malignancies. The transcription factor 19 (TCF19) gene has been implicated in conferring a malignant phenotype in cancers. However, its contribution to thyroid neoplasms remains unclear. Results: In this study, we performed genome-wide and phenome-wide association studies to identify a potential causal relationship between TCF19 and thyroid cancer. Our analyses revealed significant associations between TCF19 and various autoimmune diseases and human cancers, including cervical cancer and autoimmune thyroiditis, with a particularly robust signal for the deleterious missense variation rs2073724 that is associated with thyroid function, hypothyroidism, and autoimmunity. Furthermore, functional assays and transcriptional profiling in thyroid cancer cells demonstrated that TCF19 regulates important biological processes, especially inflammatory and immune responses. We demonstrated that TCF19 could promote the progression of thyroid cancer in vitro and in vivo and the C>T variant of rs2073724 disrupted TCF19 protein binding to target gene promoters and their expression, thus reversing the effect of TCF19 protein. Conclusions: Taken together, these findings implicate TCF19 as a promising therapeutic target in aggressive thyroid malignancies and designate rs2073724 as a causal biomarker warranting further investigation in thyroid cancer.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"11 4","pages":"6488 - 6509"},"PeriodicalIF":0.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140745072","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}
Stigmasterol is a common dietary phytosterol with high nutritional value and physiological activity. In this study, we evaluated the effects of stigmasterol on inflammatory cytokines and the TGF-β1/Smad2 and IL-17A signaling pathway in an ovalbumin (OVA)-induced asthma mouse model. Stigmasterol treatment improved airway remodeling. In addition, it significantly attenuated the symptoms of asthma attacks, reduced the number of macrophages, lymphocytes, neutrophils, and eosinophils in BALF and inflammatory cytokines, including IL-1β, IL-5, IL-6, and IL-13. It further decreased the level of IL-17A in BALF, serum and spleen. Spleen single-cell suspension analysis via flow cytometry showed that IL-17A level was consistent with the results obtained in BALF, serum and spleen. Stigmasterol decreased the protein expression levels of TGF-β, p-Smad2 and IL-17A in the spleen, by increasing the protein expression level of IL-10. After 24 h of co-culture of TGF-β, IL-6 and stigmasterol, the level of IL-17 in CD4+ T cell supernatant was lower relative to levels in the group without stigmasterol. Meanwhile, stigmasterol treatment attenuated the expression level of TGF- β, p-Smad2 and IL-17A proteins in CD4+ T cells and enhanced the expression levels of IL-10 protein. These data suggested that stigmasterol inhibited the TGF-β1/Smad2 and IL-17A signaling pathway to achieve anti-asthmatic effects in the OVA-induced asthma mouse model. Collectively, the results of this study are that stigmasterol has achieved preliminary efficacy in the non-clinical laboratory, further studies are needed to consider the clinical application of stigmasterol.
{"title":"Stigmasterol alleviates airway inflammation in OVA-induced asthmatic mice via inhibiting the TGF-β1/Smad2 and IL-17A signaling pathways","authors":"Sihong Huang, Rong Zhou, Yuyun Yuan, Yiyun Shen","doi":"10.18632/aging.205716","DOIUrl":"https://doi.org/10.18632/aging.205716","url":null,"abstract":"Stigmasterol is a common dietary phytosterol with high nutritional value and physiological activity. In this study, we evaluated the effects of stigmasterol on inflammatory cytokines and the TGF-β1/Smad2 and IL-17A signaling pathway in an ovalbumin (OVA)-induced asthma mouse model. Stigmasterol treatment improved airway remodeling. In addition, it significantly attenuated the symptoms of asthma attacks, reduced the number of macrophages, lymphocytes, neutrophils, and eosinophils in BALF and inflammatory cytokines, including IL-1β, IL-5, IL-6, and IL-13. It further decreased the level of IL-17A in BALF, serum and spleen. Spleen single-cell suspension analysis via flow cytometry showed that IL-17A level was consistent with the results obtained in BALF, serum and spleen. Stigmasterol decreased the protein expression levels of TGF-β, p-Smad2 and IL-17A in the spleen, by increasing the protein expression level of IL-10. After 24 h of co-culture of TGF-β, IL-6 and stigmasterol, the level of IL-17 in CD4+ T cell supernatant was lower relative to levels in the group without stigmasterol. Meanwhile, stigmasterol treatment attenuated the expression level of TGF- β, p-Smad2 and IL-17A proteins in CD4+ T cells and enhanced the expression levels of IL-10 protein. These data suggested that stigmasterol inhibited the TGF-β1/Smad2 and IL-17A signaling pathway to achieve anti-asthmatic effects in the OVA-induced asthma mouse model. Collectively, the results of this study are that stigmasterol has achieved preliminary efficacy in the non-clinical laboratory, further studies are needed to consider the clinical application of stigmasterol.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"9 1","pages":"6478 - 6487"},"PeriodicalIF":0.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140745083","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}
Sushi domain-containing protein 4 (SUSD4) is a complement regulatory protein whose primary function is to inhibit the complement system, and it is involved in immune regulation. The role of SUSD4 in cancer progression has largely remained elusive. SUSD4 was studied across a variety of cancer types in this study. According to the results, there is an association between the expression level of SUSD4 and prognosis in multiple types of cancer. Further analysis demonstrated that SUSD4 expression level was related to immune cell infiltration, immune-related genes, tumor heterogeneity, and multiple cancer pathways. Additionally, we validated the function of SUSD4 in colorectal cancer cell lines and found that knockdown of SUSD4 inhibited cell growth and impacted the JAK/STAT pathway. By characterizing drug sensitivity in organoids, we found that the expression of SUSD4 showed a positive correlation trend with IC50 of Selumetinib, YK-4-279, and Piperlongumine. In conclusion, SUSD4 is a valuable prognostic indicator for diverse types of cancer, and it has the potential to be a target for cancer therapy.
{"title":"Pan-cancer analysis of Sushi domain-containing protein 4 (SUSD4) and validated in colorectal cancer","authors":"Yuchen Zhong, Chaojing Zheng, Weiyuan Zhang, Hongyu Wu, Qian Zhang, Dechuan Li, Haixing Ju, Haiyang Feng, Yinbo Chen, Yong-tian Fan, Weiping Chen, Meng Wang, Guiyu Wang","doi":"10.18632/aging.205712","DOIUrl":"https://doi.org/10.18632/aging.205712","url":null,"abstract":"Sushi domain-containing protein 4 (SUSD4) is a complement regulatory protein whose primary function is to inhibit the complement system, and it is involved in immune regulation. The role of SUSD4 in cancer progression has largely remained elusive. SUSD4 was studied across a variety of cancer types in this study. According to the results, there is an association between the expression level of SUSD4 and prognosis in multiple types of cancer. Further analysis demonstrated that SUSD4 expression level was related to immune cell infiltration, immune-related genes, tumor heterogeneity, and multiple cancer pathways. Additionally, we validated the function of SUSD4 in colorectal cancer cell lines and found that knockdown of SUSD4 inhibited cell growth and impacted the JAK/STAT pathway. By characterizing drug sensitivity in organoids, we found that the expression of SUSD4 showed a positive correlation trend with IC50 of Selumetinib, YK-4-279, and Piperlongumine. In conclusion, SUSD4 is a valuable prognostic indicator for diverse types of cancer, and it has the potential to be a target for cancer therapy.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"39 4","pages":"6417 - 6444"},"PeriodicalIF":0.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140746116","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}
Yaming Yang, Zheng Yan, Qinwen Xie, Yong Wang, Zhiying Liu, Min Lei
Background: The purpose of this study is to observe LP45 (Lactobacillus plantarum 45) to investigate the mechanism by which LP45 attenuates oxidative stress-induced damage and regulates the osteoblast-osteoclast balance. Materials and Methods: The oxidative stress level and osteoblast- and osteoclast-related proteins were detected by immunofluorescence staining, Western blotting, ROS fluorescent probe and ELISA. Osteoblast cell proliferation capacity was determined by the CCK-8 assay. X-ray observation and HE staining were used to detect the effect of LP45 on osteoporosis. Results: The expression level of SHP2 and Src was significantly increased, and the expression levels of NOX4, P22, P47, IL-1β, NLRP3, IRF3, RANK, β-catenin and INF-β were inhibited in LP45 group and LPS + LP45 group as compared to those in LPS group. Compared with that in LPS group, the concentration of SOD was increased and the concentration of MDA was decreased in LPS + LP45 group. The protein expressions of OPG, RANKL, RUNX3, RANK and β-catenin in LP45 group and LPS + LP45 group increased. The protein expressions of NF-κB, CREB and AP-1 in LP45 group and LPS + LP45 group decreased significantly. The results were also confirmed by immunofluorescence staining and ROS fluorescent probe. X-ray observation and HE staining showed that LP45 could inhibit the progression of osteoporosis. Conclusion: LP45 can exert its antioxidant effect by inhibiting the production of oxidative stress to activate the SHP2 signaling pathway, thus promoting osteoblast differentiation and repressing osteoclast formation to maintain bone homeostasis and improve bone metabolism.
{"title":"Lactobacillus plantarum 45 activates SHP2 through inhibition of oxidative stress to regulate osteoblast and osteoclast differentiation","authors":"Yaming Yang, Zheng Yan, Qinwen Xie, Yong Wang, Zhiying Liu, Min Lei","doi":"10.18632/aging.205708","DOIUrl":"https://doi.org/10.18632/aging.205708","url":null,"abstract":"Background: The purpose of this study is to observe LP45 (Lactobacillus plantarum 45) to investigate the mechanism by which LP45 attenuates oxidative stress-induced damage and regulates the osteoblast-osteoclast balance. Materials and Methods: The oxidative stress level and osteoblast- and osteoclast-related proteins were detected by immunofluorescence staining, Western blotting, ROS fluorescent probe and ELISA. Osteoblast cell proliferation capacity was determined by the CCK-8 assay. X-ray observation and HE staining were used to detect the effect of LP45 on osteoporosis. Results: The expression level of SHP2 and Src was significantly increased, and the expression levels of NOX4, P22, P47, IL-1β, NLRP3, IRF3, RANK, β-catenin and INF-β were inhibited in LP45 group and LPS + LP45 group as compared to those in LPS group. Compared with that in LPS group, the concentration of SOD was increased and the concentration of MDA was decreased in LPS + LP45 group. The protein expressions of OPG, RANKL, RUNX3, RANK and β-catenin in LP45 group and LPS + LP45 group increased. The protein expressions of NF-κB, CREB and AP-1 in LP45 group and LPS + LP45 group decreased significantly. The results were also confirmed by immunofluorescence staining and ROS fluorescent probe. X-ray observation and HE staining showed that LP45 could inhibit the progression of osteoporosis. Conclusion: LP45 can exert its antioxidant effect by inhibiting the production of oxidative stress to activate the SHP2 signaling pathway, thus promoting osteoblast differentiation and repressing osteoclast formation to maintain bone homeostasis and improve bone metabolism.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"103 ","pages":"6334 - 6347"},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140750540","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}
Background: Immunogenic cell death (ICD) is a regulated form of cell death that triggers an adaptive immune response. The objective of this study was to investigate the correlation between ICD-related genes (ICDGs) and the prognosis and the immune microenvironment of patients with lung adenocarcinoma (LUAD). Methods: ICD-associated molecular subtypes were identified through consensus clustering. Subsequently, a prognostic risk model comprising 5 ICDGs was constructed using Lasso-Cox regression in the TCGA training cohort and further tested in the GEO cohort. Enriched pathways among the subtypes were analyzed using GO, KEGG, and GSVA. Furthermore, the immune microenvironment was assessed using ESTIMATE, CIBERSORT, and ssGSEA analyses. Results: Consensus clustering divided LUAD patients into three ICDG subtypes with significant differences in prognosis and the immune microenvironment. A prognostic risk model was constructed based on 5 ICDGs and it was used to classify the patients into two risk groups; the high-risk group had poorer prognosis and an immunosuppressive microenvironment characterized by low immune score, low immune status, high abundance of immunosuppressive cells, and high expression of tumor purity. Cox regression, ROC curve analysis, and a nomogram indicated that the risk model was an independent prognostic factor. The five hub genes were verified by TCGA database, cell sublocalization immunofluorescence analysis, IHC images and qRT-PCR, which were consistent with bioinformatics analysis. Conclusions: The molecular subtypes and a risk model based on ICDGs proposed in our study are both promising prognostic classifications in LUAD, which may provide novel insights for developing accurate targeted cancer therapies.
{"title":"Identifying an immunogenic cell death-related gene signature contributes to predicting prognosis, immunotherapy efficacy, and tumor microenvironment of lung adenocarcinoma","authors":"Xue Li, Dengfeng Zhang, Pengfei Guo, Shaowei Ma, Shao Gao, Shujun Li, Yadong Yuan","doi":"10.18632/aging.205705","DOIUrl":"https://doi.org/10.18632/aging.205705","url":null,"abstract":"Background: Immunogenic cell death (ICD) is a regulated form of cell death that triggers an adaptive immune response. The objective of this study was to investigate the correlation between ICD-related genes (ICDGs) and the prognosis and the immune microenvironment of patients with lung adenocarcinoma (LUAD). Methods: ICD-associated molecular subtypes were identified through consensus clustering. Subsequently, a prognostic risk model comprising 5 ICDGs was constructed using Lasso-Cox regression in the TCGA training cohort and further tested in the GEO cohort. Enriched pathways among the subtypes were analyzed using GO, KEGG, and GSVA. Furthermore, the immune microenvironment was assessed using ESTIMATE, CIBERSORT, and ssGSEA analyses. Results: Consensus clustering divided LUAD patients into three ICDG subtypes with significant differences in prognosis and the immune microenvironment. A prognostic risk model was constructed based on 5 ICDGs and it was used to classify the patients into two risk groups; the high-risk group had poorer prognosis and an immunosuppressive microenvironment characterized by low immune score, low immune status, high abundance of immunosuppressive cells, and high expression of tumor purity. Cox regression, ROC curve analysis, and a nomogram indicated that the risk model was an independent prognostic factor. The five hub genes were verified by TCGA database, cell sublocalization immunofluorescence analysis, IHC images and qRT-PCR, which were consistent with bioinformatics analysis. Conclusions: The molecular subtypes and a risk model based on ICDGs proposed in our study are both promising prognostic classifications in LUAD, which may provide novel insights for developing accurate targeted cancer therapies.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"43 2","pages":"6290 - 6313"},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140747591","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}
Background: COVID-19 pandemic poses a heavy burden on public health and accounts for substantial mortality and morbidity. Proteins are building blocks of life, but specific proteins causally related to COVID-19, healthspan and lifespan have not been systematically examined. Methods: We conducted a Mendelian randomization study to assess the effects of 1,361 plasma proteins on COVID-19, healthspan and lifespan, using large GWAS of severe COVID-19 (up to 13,769 cases and 1,072,442 controls), COVID-19 hospitalization (32,519 cases and 2,062,805 controls) and SARS-COV2 infection (122,616 cases and 2,475,240 controls), healthspan (n = 300,477) and parental lifespan (~0.8 million of European ancestry). Results: We identified 35, 43, and 63 proteins for severe COVID, COVID-19 hospitalization, and SARS-COV2 infection, and 4, 32, and 19 proteins for healthspan, father’s attained age, and mother’s attained age. In addition to some proteins reported previously, such as SFTPD related to severe COVID-19, we identified novel proteins involved in inflammation and immunity (such as ICAM-2 and ICAM-5 which affect COVID-19 risk, CXCL9, HLA-DRA and LILRB4 for healthspan and lifespan), apoptosis (such as FGFR2 and ERBB4 which affect COVID-19 risk and FOXO3 which affect lifespan) and metabolism (such as PCSK9 which lowers lifespan). We found 2, 2 and 3 proteins shared between COVID-19 and healthspan/lifespan, such as CXADR and LEFTY2, shared between severe COVID-19 and healthspan/lifespan. Three proteins affecting COVID-19 and seven proteins affecting healthspan/lifespan are targeted by existing drugs. Conclusions: Our study provided novel insights into protein targets affecting COVID-19, healthspan and lifespan, with implications for developing new treatment and drug repurposing.
{"title":"Using genetics and proteomics data to identify proteins causally related to COVID-19, healthspan and lifespan: a Mendelian randomization study","authors":"Jie V Zhao, M. Yao, Zhonghua Liu","doi":"10.18632/aging.205711","DOIUrl":"https://doi.org/10.18632/aging.205711","url":null,"abstract":"Background: COVID-19 pandemic poses a heavy burden on public health and accounts for substantial mortality and morbidity. Proteins are building blocks of life, but specific proteins causally related to COVID-19, healthspan and lifespan have not been systematically examined. Methods: We conducted a Mendelian randomization study to assess the effects of 1,361 plasma proteins on COVID-19, healthspan and lifespan, using large GWAS of severe COVID-19 (up to 13,769 cases and 1,072,442 controls), COVID-19 hospitalization (32,519 cases and 2,062,805 controls) and SARS-COV2 infection (122,616 cases and 2,475,240 controls), healthspan (n = 300,477) and parental lifespan (~0.8 million of European ancestry). Results: We identified 35, 43, and 63 proteins for severe COVID, COVID-19 hospitalization, and SARS-COV2 infection, and 4, 32, and 19 proteins for healthspan, father’s attained age, and mother’s attained age. In addition to some proteins reported previously, such as SFTPD related to severe COVID-19, we identified novel proteins involved in inflammation and immunity (such as ICAM-2 and ICAM-5 which affect COVID-19 risk, CXCL9, HLA-DRA and LILRB4 for healthspan and lifespan), apoptosis (such as FGFR2 and ERBB4 which affect COVID-19 risk and FOXO3 which affect lifespan) and metabolism (such as PCSK9 which lowers lifespan). We found 2, 2 and 3 proteins shared between COVID-19 and healthspan/lifespan, such as CXADR and LEFTY2, shared between severe COVID-19 and healthspan/lifespan. Three proteins affecting COVID-19 and seven proteins affecting healthspan/lifespan are targeted by existing drugs. Conclusions: Our study provided novel insights into protein targets affecting COVID-19, healthspan and lifespan, with implications for developing new treatment and drug repurposing.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"109 ","pages":"6384 - 6416"},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140750535","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}
Background: Coagulation system is currently known associated with the development of ischemic stroke (IS). Thus, the current study is designed to identify diagnostic value of coagulation genes (CGs) in IS and to explore their role in the immune microenvironment of IS. Methods: Aberrant expressed CGs in IS were input into unsupervised consensus clustering to classify IS subtypes. Meanwhile, key CGs involved in IS were further selected by weighted gene co-expression network analysis (WGCNA) and machine learning methods, including random forest (RF), support vector machine (SVM), generalized linear model (GLM) and extreme-gradient boosting (XGB). The diagnostic performance of key CGs were evaluated by receiver operating characteristic (ROC) curves. At last, quantitative PCR (qPCR) was performed to validate the expressions of key CGs in IS. Results: IS patients were classified into two subtypes with different immune microenvironments by aberrant expressed CGs. Further WGCNA, machine learning methods and ROC curves identified ACTN1, F5, TLN1, JMJD1C and WAS as potential diagnostic biomarkers of IS. In addition, their expressions were significantly correlated with macrophages, neutrophils and/or T cells. GSEA also revealed that those biomarkers may regulate IS via immune and inflammation. Moreover, qPCR verified the expressions of ACTN1, F5 and JMJD1C in IS. Conclusions: The current study identified ACTN1, F5 and JMJD1C as novel coagulation-related biomarkers associated with IS immune microenvironment, which enriches our knowledge of coagulation-mediated pathogenesis of IS and sheds light on next-step in vivo and in vitro experiments to elucidate the relevant molecular mechanisms.
背景：目前已知凝血系统与缺血性脑卒中（IS）的发生有关。因此，本研究旨在确定凝血基因（CGs）在 IS 中的诊断价值，并探讨它们在 IS 免疫微环境中的作用。研究方法将IS中异常表达的凝血基因输入无监督共识聚类，对IS亚型进行分类。同时，通过加权基因共表达网络分析（WGCNA）和机器学习方法，包括随机森林（RF）、支持向量机（SVM）、广义线性模型（GLM）和极梯度提升（XGB），进一步筛选出参与IS的关键CGs。接收者操作特征曲线（ROC）评估了主要 CG 的诊断性能。最后，采用定量 PCR（qPCR）技术验证了关键 CGs 在 IS 中的表达。结果显示通过异常表达的CG将IS患者分为两种亚型，其免疫微环境各不相同。进一步的WGCNA、机器学习方法和ROC曲线确定了ACTN1、F5、TLN1、JMJD1C和WAS为IS的潜在诊断生物标志物。此外，它们的表达与巨噬细胞、中性粒细胞和/或 T 细胞明显相关。GSEA 还显示，这些生物标志物可能通过免疫和炎症调节 IS。此外，qPCR 验证了 ACTN1、F5 和 JMJD1C 在 IS 中的表达。结论：本研究发现 ACTN1、F5 和 JMJD1C 是与 IS 免疫微环境相关的新型凝血相关生物标志物，这丰富了我们对凝血介导的 IS 发病机制的认识，并为下一步体内和体外实验阐明相关分子机制提供了启示。
{"title":"Machine learning identifies novel coagulation genes as diagnostic and immunological biomarkers in ischemic stroke","authors":"Jinzhi Liu, Zhihua Si, Ju Liu, Xu Zhang, Cong Xie, Wei Zhao, Aihua Wang, Zhangyong Xia","doi":"10.18632/aging.205706","DOIUrl":"https://doi.org/10.18632/aging.205706","url":null,"abstract":"Background: Coagulation system is currently known associated with the development of ischemic stroke (IS). Thus, the current study is designed to identify diagnostic value of coagulation genes (CGs) in IS and to explore their role in the immune microenvironment of IS. Methods: Aberrant expressed CGs in IS were input into unsupervised consensus clustering to classify IS subtypes. Meanwhile, key CGs involved in IS were further selected by weighted gene co-expression network analysis (WGCNA) and machine learning methods, including random forest (RF), support vector machine (SVM), generalized linear model (GLM) and extreme-gradient boosting (XGB). The diagnostic performance of key CGs were evaluated by receiver operating characteristic (ROC) curves. At last, quantitative PCR (qPCR) was performed to validate the expressions of key CGs in IS. Results: IS patients were classified into two subtypes with different immune microenvironments by aberrant expressed CGs. Further WGCNA, machine learning methods and ROC curves identified ACTN1, F5, TLN1, JMJD1C and WAS as potential diagnostic biomarkers of IS. In addition, their expressions were significantly correlated with macrophages, neutrophils and/or T cells. GSEA also revealed that those biomarkers may regulate IS via immune and inflammation. Moreover, qPCR verified the expressions of ACTN1, F5 and JMJD1C in IS. Conclusions: The current study identified ACTN1, F5 and JMJD1C as novel coagulation-related biomarkers associated with IS immune microenvironment, which enriches our knowledge of coagulation-mediated pathogenesis of IS and sheds light on next-step in vivo and in vitro experiments to elucidate the relevant molecular mechanisms.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"191 1","pages":"6314 - 6333"},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140748415","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}
Purpose: The aim of this study was to investigate whether young patients with endometrial carcinoma can preserve adnexa and lymph nodes to improve their quality of life without compromising their prognosis. Methods: A total of 319 patients with type I endometrial carcinoma (high or moderate differentiation and less than 1/2 myometrial invasion) hospitalized in the First Affiliated Hospital of Zhengzhou University from May 2012 to July 2021 were included. The patients were divided into four groups: high differentiation without myometrial invasion group (G1MI-), high differentiation with superficial myometrial invasion group (G1MI+), moderate differentiation without myometrial invasion group (G2MI-), and moderate differentiation with superficial myometrial invasion group (G2MI+). Logistic regression analysis was conducted to identify risk factors for extra-uterine involvement. Kaplan-Meier method was used to draw the survival curve to compare the prognosis in subgroups and rates of extra-uterine involvement were also compared using Chi-square test or Fisher’s exact test. Results: Multivariable logistic regression revealed that differentiation (HR = 14.590, 95%CI = 1.778-119.754, p = 0.013) and myometrial invasion (HR = 10.732, 95%CI = 0.912-92.780, p = 0.037) were the independent risk factors for extra-uterine involvement. The overall difference was statistically significant (p < 0.001). In the subgroups analysis, both adnexal metastasis and lymph node metastasis were statistically significant in the G2MI+ group compared with G1MI- (p = 0.007, p = 0.008). There were no significant differences in the overall survival (OS) rate and progression free survival (PFS) rate among the four subgroups (p > 0.05). Conclusions: Surgery with adnexal preservation and without systematic lymphadenectomy could be employed for the patients who are high differentiation with less than 1/2 myometrial invasion or moderate differentiation without myometrial invasion, but not recommended to the patients with moderate differentiation and superficial myometrial invasion.
{"title":"Risk assessment of extra-uterine involvement and prognosis in young type I endometrial carcinoma with high or moderate differentiation and less than 1/2 myometrial invasion","authors":"Yi Sun, Pin Han, Yuanpei Wang, Xiaoran Cheng, Weijia Wu, Qianwen Liu, Fang Ren","doi":"10.18632/aging.205714","DOIUrl":"https://doi.org/10.18632/aging.205714","url":null,"abstract":"Purpose: The aim of this study was to investigate whether young patients with endometrial carcinoma can preserve adnexa and lymph nodes to improve their quality of life without compromising their prognosis. Methods: A total of 319 patients with type I endometrial carcinoma (high or moderate differentiation and less than 1/2 myometrial invasion) hospitalized in the First Affiliated Hospital of Zhengzhou University from May 2012 to July 2021 were included. The patients were divided into four groups: high differentiation without myometrial invasion group (G1MI-), high differentiation with superficial myometrial invasion group (G1MI+), moderate differentiation without myometrial invasion group (G2MI-), and moderate differentiation with superficial myometrial invasion group (G2MI+). Logistic regression analysis was conducted to identify risk factors for extra-uterine involvement. Kaplan-Meier method was used to draw the survival curve to compare the prognosis in subgroups and rates of extra-uterine involvement were also compared using Chi-square test or Fisher’s exact test. Results: Multivariable logistic regression revealed that differentiation (HR = 14.590, 95%CI = 1.778-119.754, p = 0.013) and myometrial invasion (HR = 10.732, 95%CI = 0.912-92.780, p = 0.037) were the independent risk factors for extra-uterine involvement. The overall difference was statistically significant (p < 0.001). In the subgroups analysis, both adnexal metastasis and lymph node metastasis were statistically significant in the G2MI+ group compared with G1MI- (p = 0.007, p = 0.008). There were no significant differences in the overall survival (OS) rate and progression free survival (PFS) rate among the four subgroups (p > 0.05). Conclusions: Surgery with adnexal preservation and without systematic lymphadenectomy could be employed for the patients who are high differentiation with less than 1/2 myometrial invasion or moderate differentiation without myometrial invasion, but not recommended to the patients with moderate differentiation and superficial myometrial invasion.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"180 ","pages":"6445 - 6454"},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140750827","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}
Objective: The purpose of this study was to explore the therapeutic characteristics of mesenchymal stem cells generated from human umbilical cord (hUC-MSCs) when utilized in conjunction with auto-crosslinked hyaluronic acid gel (HA-gel) for the management of intrauterine adhesion (IUA). The goal was to see how this novel therapy could enhance healing and improve outcomes for IUA patients. Methods: In this study, models of intrauterine adhesion (IUA) were established in Sprague-Dawley (SD) rats, which were then organized and divided into hUC-MSCs groups. The groups involved: hUC-MSCs/HA-gel group, control group, and HA-gel group. Following treatment, the researchers examined the uterine cavities and performed detailed analyses of the endometrial tissues to determine the effectiveness of the interventions. Results: The results indicated that in comparison with to the control group, both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel groups showed partial repair of IUA. However, in a more notable fashion transplantation of hUC-MSCs/HA-gel complex demonstrated significant dual repair effects. Significant outcomes were observed in the group treated with hUC-MSCs and HA-gel, they showed thicker endometrial layers, less fibrotic tissue, and a higher number of endometrial glands. This treatment strategy also resulted in a significant improvement in fertility restoration, indicating a profound therapeutic effect. Conclusions: The findings of this study suggest that both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel complexes have the potential for partial repair of IUA and fertility restoration caused by endometrium mechanical injury. Nonetheless, the transplantation of the hUC-MSCs/HA-gel complex displayed exceptional dual healing effects, combining effective anti-adhesive properties with endometrial regeneration stimuli.
{"title":"Human umbilical cord-derived mesenchymal stem cells and auto-crosslinked hyaluronic acid gel complex for treatment of intrauterine adhesion","authors":"Jiaying Fan, Jingying Xie, Yunsheng Liao, Baoyu Lai, Guixin Zhou, Wenqin Lian, Jian Xiong","doi":"10.18632/aging.205704","DOIUrl":"https://doi.org/10.18632/aging.205704","url":null,"abstract":"Objective: The purpose of this study was to explore the therapeutic characteristics of mesenchymal stem cells generated from human umbilical cord (hUC-MSCs) when utilized in conjunction with auto-crosslinked hyaluronic acid gel (HA-gel) for the management of intrauterine adhesion (IUA). The goal was to see how this novel therapy could enhance healing and improve outcomes for IUA patients. Methods: In this study, models of intrauterine adhesion (IUA) were established in Sprague-Dawley (SD) rats, which were then organized and divided into hUC-MSCs groups. The groups involved: hUC-MSCs/HA-gel group, control group, and HA-gel group. Following treatment, the researchers examined the uterine cavities and performed detailed analyses of the endometrial tissues to determine the effectiveness of the interventions. Results: The results indicated that in comparison with to the control group, both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel groups showed partial repair of IUA. However, in a more notable fashion transplantation of hUC-MSCs/HA-gel complex demonstrated significant dual repair effects. Significant outcomes were observed in the group treated with hUC-MSCs and HA-gel, they showed thicker endometrial layers, less fibrotic tissue, and a higher number of endometrial glands. This treatment strategy also resulted in a significant improvement in fertility restoration, indicating a profound therapeutic effect. Conclusions: The findings of this study suggest that both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel complexes have the potential for partial repair of IUA and fertility restoration caused by endometrium mechanical injury. Nonetheless, the transplantation of the hUC-MSCs/HA-gel complex displayed exceptional dual healing effects, combining effective anti-adhesive properties with endometrial regeneration stimuli.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"42 10","pages":"6273 - 6289"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140797400","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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