Pub Date : 2024-12-10DOI: 10.1016/j.jare.2024.12.014
Di Zhao, Ran Xu, Yufei Zhou, Jiaying Wu, Xiaoxue Zhang, Hong Lin, Jienan Wang, Zhiwen Ding, Yunzeng Zou
Introduction
Oxysterol binding protein (OSBP)-related protein 5 (ORP5) mainly functions as a lipid transfer protein at membrane contact sites (MCS). ORP5 facilitates cell proliferation through the activation of mTORC1 signaling. While the pro-hypertrophic effects of mTORC1 are well-documented, the specific role of ORP5 in the context of pathological cardiac hypertrophy remains inadequately understood.
Methods
To investigate the role of ORP5 in pathological cardiac hypertrophy, AAV9-treated mice and neonatal rat ventricular myocytes (NRVMs) were utilized. Cardiac function, morphology, and mTORC1 signaling alterations induced by pro-hypertrophic stimuli were assessed in both myocardium and NRVMs. Additionally, a range of molecular techniques were employed to elucidate the regulatory mechanisms of ORP5 on mTORC1 in hypertrophied hearts.
Results
Increased expression of ORP5 was observed in the hearts of patients with hypertrophic cardiomyopathy (HCM), in mice subjected to transverse aortic constriction (TAC), and in NRVMs treated with angiotensin II (AngII). We found that ORP5 binds to mTOR in cardiomyocytes. Upon exposure to TAC surgery, ORP5-deficient hearts exhibited enhanced cardiac function, reduced cardiomyocyte hypertrophy, and diminished collagen deposition than wild type. Conversely, overexpression of ORP5 significantly aggravated hypertrophic responses in both hearts and NRVMs. Notably, the promotion of cardiac hypertrophy induced by ORP5 overexpression was reversed by rapamycin, an inhibitor of mTORC1. Mechanistically, our study elucidated that the ORD domain of ORP5 interacts with mTORC1, facilitating its translocation to the outer membrane of the lysosome for subsequent activation. This activation triggers the downstream signaling pathways involving S6K1 and 4E-BP1, which initiate protein synthesis, thereby promoting pathological cardiac hypertrophy.
Conclusions
Our findings provide the inaugural evidence that ORP5 facilitates pathological ventricular hypertrophy through the translocation of mTORC1 to the lysosome for subsequent activation. Consequently, ORP5 has the potential to serve as a diagnostic biomarker or therapeutic target for pathological cardiac hypertrophy in the future.
{"title":"ORP5 promotes cardiac hypertrophy by regulating the activation of mTORC1 on lysosome","authors":"Di Zhao, Ran Xu, Yufei Zhou, Jiaying Wu, Xiaoxue Zhang, Hong Lin, Jienan Wang, Zhiwen Ding, Yunzeng Zou","doi":"10.1016/j.jare.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.jare.2024.12.014","url":null,"abstract":"<h3>Introduction</h3>Oxysterol binding protein (OSBP)-related protein 5 (ORP5) mainly functions as a lipid transfer protein at membrane contact sites (MCS). ORP5 facilitates cell proliferation through the activation of mTORC1 signaling. While the pro-hypertrophic effects of mTORC1 are well-documented, the specific role of ORP5 in the context of pathological cardiac hypertrophy remains inadequately understood.<h3>Methods</h3>To investigate the role of ORP5 in pathological cardiac hypertrophy, AAV9-treated mice and neonatal rat ventricular myocytes (NRVMs) were utilized. Cardiac function, morphology, and mTORC1 signaling alterations induced by pro-hypertrophic stimuli were assessed in both myocardium and NRVMs. Additionally, a range of molecular techniques were employed to elucidate the regulatory mechanisms of ORP5 on mTORC1 in hypertrophied hearts.<h3>Results</h3>Increased expression of ORP5 was observed in the hearts of patients with hypertrophic cardiomyopathy (HCM), in mice subjected to transverse aortic constriction (TAC), and in NRVMs treated with angiotensin II (AngII). We found that ORP5 binds to mTOR in cardiomyocytes. Upon exposure to TAC surgery, ORP5-deficient hearts exhibited enhanced cardiac function, reduced cardiomyocyte hypertrophy, and diminished collagen deposition than wild type. Conversely, overexpression of ORP5 significantly aggravated hypertrophic responses in both hearts and NRVMs. Notably, the promotion of cardiac hypertrophy induced by ORP5 overexpression was reversed by rapamycin, an inhibitor of mTORC1. Mechanistically, our study elucidated that the ORD domain of ORP5 interacts with mTORC1, facilitating its translocation to the outer membrane of the lysosome for subsequent activation. This activation triggers the downstream signaling pathways involving S6K1 and 4E-BP1, which initiate protein synthesis, thereby promoting pathological cardiac hypertrophy.<h3>Conclusions</h3>Our findings provide the inaugural evidence that ORP5 facilitates pathological ventricular hypertrophy through the translocation of mTORC1 to the lysosome for subsequent activation. Consequently, ORP5 has the potential to serve as a diagnostic biomarker or therapeutic target for pathological cardiac hypertrophy in the future.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"10 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.jare.2024.12.009
Lihua Tan, Zhimin Miao, Yuxin Zhao, Yongkai Liang, Nan Xu, Xin Chen, Yanbei Tu, Chengwei He
Introduction
Osteoporosis is an osteolytic disorder resulting from an inequilibrium between osteoblast-mediated osteogenesis and osteoclast-driven bone absorption. Safe and effective approaches for osteoporosis management are still highly demanded.
Purpose
This study aimed to examine the osteoprotective effect and the mechanisms of phaseol (PHA) in vitro and in vivo.
Methods
Virtual screening identified the potential inhibitors of transforming growth factor-beta-activated kinase 1 (TAK1) from coumestans. The interaction between PHA and TAK1 was investigated by molecular simulation, pronase and thermal resistance assays. The maturation and function of osteoclasts were determined using tartrate-resistant acid phosphatase staining, bone absorption and F-actin ring formation assays. The differentiation and calcification of osteoblasts were assessed by alkaline phosphatase staining and Alizarin Red S staining. The activity of related targets and pathways were detected using immunoblotting, immunofluorescence and co-immunoprecipitation assays. The in vivo osteoprotective effect of PHA was evaluated using a lipopolysaccharide (LPS)-induced mouse osteoporosis model.
Results
Firstly, we confirmed that TAK1 was essential in controlling bone remodeling by regulating osteogenesis and osteoclastogenesis. Moreover, PHA, a coumestan compound predominantly present in leguminous plants, was identified as a potent TAK1 inhibitor through virtual and real experiments. Subsequently, PHA was observed to enhance osteoblast differentiation and calcification, while suppress osteoclast maturation and bone resorptive function in vitro. Mechanistically, PHA remarkably inhibited the TRAF6-TAK1 complex formation, and inhibited the activation of TAK1, MAPK and NF-κB pathways by targeting TAK1. In the in vivo study, PHA strongly attenuated bone loss, inflammatory responses, and osteoclast over-activation in lipopolysaccharide-induced osteoporosis mice.
Conclusion
PHA had a dual-functional regulatory impact on osteogenesis and osteoclastogenesis by targeting TAK1, suppressing TRAF6-TAK1 complex generation, and modulating its associated signaling pathways, ultimately leading to mitigating osteoporosis. This study offered compelling evidence in favor of using PHA for preventing and managing osteoporosis as both a bone anabolic and anti-resorptive agent.
{"title":"Dual regulation of phaseol on osteoclast formation and osteoblast differentiation by targeting TAK1 kinase for osteoporosis treatment","authors":"Lihua Tan, Zhimin Miao, Yuxin Zhao, Yongkai Liang, Nan Xu, Xin Chen, Yanbei Tu, Chengwei He","doi":"10.1016/j.jare.2024.12.009","DOIUrl":"https://doi.org/10.1016/j.jare.2024.12.009","url":null,"abstract":"<h3>Introduction</h3>Osteoporosis is an osteolytic disorder resulting from an inequilibrium between osteoblast-mediated osteogenesis and osteoclast-driven bone absorption. Safe and effective approaches for osteoporosis management are still highly demanded.<h3>Purpose</h3>This study aimed to examine the osteoprotective effect and the mechanisms of phaseol (PHA) <em>in vitro</em> and <em>in vivo</em>.<h3>Methods</h3>Virtual screening identified the potential inhibitors of transforming growth factor-beta-activated kinase 1 (TAK1) from coumestans. The interaction between PHA and TAK1 was investigated by molecular simulation, pronase and thermal resistance assays. The maturation and function of osteoclasts were determined using tartrate-resistant acid phosphatase staining, bone absorption and F-actin ring formation assays. The differentiation and calcification of osteoblasts were assessed by alkaline phosphatase staining and Alizarin Red S staining. The activity of related targets and pathways were detected using immunoblotting, immunofluorescence and co-immunoprecipitation assays. The <em>in vivo</em> osteoprotective effect of PHA was evaluated using a lipopolysaccharide (LPS)-induced mouse osteoporosis model.<h3>Results</h3>Firstly, we confirmed that TAK1 was essential in controlling bone remodeling by regulating osteogenesis and osteoclastogenesis. Moreover, PHA, a coumestan compound predominantly present in leguminous plants, was identified as a potent TAK1 inhibitor through virtual and real experiments. Subsequently, PHA was observed to enhance osteoblast differentiation and calcification, while suppress osteoclast maturation and bone resorptive function <em>in vitro</em>. Mechanistically, PHA remarkably inhibited the TRAF6-TAK1 complex formation, and inhibited the activation of TAK1, MAPK and NF-κB pathways by targeting TAK1. In the <em>in vivo</em> study, PHA strongly attenuated bone loss, inflammatory responses, and osteoclast over-activation in lipopolysaccharide-induced osteoporosis mice.<h3>Conclusion</h3>PHA had a dual-functional regulatory impact on osteogenesis and osteoclastogenesis by targeting TAK1, suppressing TRAF6-TAK1 complex generation, and modulating its associated signaling pathways, ultimately leading to mitigating osteoporosis. This study offered compelling evidence in favor of using PHA for preventing and managing osteoporosis as both a bone anabolic and anti-resorptive agent.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"4 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
DNA topoisomerases (TOPs) are essential components in a diverse range of biological processes including DNA replication, transcription and genome integrity. Although the functions and mechanisms of TOPs, particularly type I TOP (TOP1s), have been extensively studied in bacteria, yeast and animals, researches on these proteins in plants have only recently commenced.
Aim of Review
In this review, the function and mechanism studies of TOP1s in plants and the structural biology of plant TOP1 are presented, providing readers with a comprehensive understanding of the current research status of this essential enzyme.The future research directions for exploring the working mechanism of plant TOP1s is also discussed.
Key Scientific Concepts of Review
Over the past decade, it has been discovered TOP1s play a vital role in multiphasic processes of plant development, such as maintaining meristem activity, gametogenesis, flowering time, gravitropic response and so on. Plant TOP1s affects gene transcription by modulating chromatin status, including chromatin accessibility, DNA/RNA structure, and nucleosome positioning. However, the function and mechanism of this vital enzyme is poorly summarized although it has been systematically summarized in other species. This review summarized the research progresses of plant TOP1s according to the diverse functions and working mechanism in different tissues.
{"title":"Not only the top: Type I topoisomerases function in multiple tissues and organs development in plants","authors":"Hao Zhang, Lirong Tian, Yuru Ma, Jiahui Xu, Tianyu Bai, Qian Wang, Xigang Liu, Lin Guo","doi":"10.1016/j.jare.2024.12.011","DOIUrl":"https://doi.org/10.1016/j.jare.2024.12.011","url":null,"abstract":"<h3>Background</h3>DNA topoisomerases (TOPs) are essential components in a diverse range of biological processes including DNA replication, transcription and genome integrity. Although the functions and mechanisms of TOPs, particularly type I TOP (TOP1s), have been extensively studied in bacteria, yeast and animals, researches on these proteins in plants have only recently commenced.<h3>Aim of Review</h3>In this review, the function and mechanism studies of TOP1s in plants and the structural biology of plant TOP1 are presented, providing readers with a comprehensive understanding of the current research status of this essential enzyme.The future research directions for exploring the working mechanism of plant TOP1s is also discussed.<h3>Key Scientific Concepts of Review</h3>Over the past decade, it has been discovered TOP1s play a vital role in multiphasic processes of plant development, such as maintaining meristem activity, gametogenesis, flowering time, gravitropic response and so on. Plant TOP1s affects gene transcription by modulating chromatin status, including chromatin accessibility, DNA/RNA structure, and nucleosome positioning. However, the function and mechanism of this vital enzyme is poorly summarized although it has been systematically summarized in other species. This review summarized the research progresses of plant TOP1s according to the diverse functions and working mechanism in different tissues.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"58 20 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cardiac fibrosis, including reactive fibrosis and replacement fibrosis, is a common pathological process in most cardiovascular diseases. The ubiquitin proteasome system (UPS) plays an important role in the development of fibrosis by mediating the degradation and synthesis of proteins involved in transforming growth factor-β (TGF-β)-dependent and TGF-β-independent fibrous pathways.
Aim of review
This review aims to provide an overview of ubiquitinated and deubiquitinated molecules that participating in cardiac fibrosis, with the ultimate purpose to identify promising targets for therapeutic strategies.
Key scientific concepts of review
The UPS primarily impacts cardiac fibrosis through modulation of the TGF-β signaling pathway targeting key molecules involved, including the TGF-β receptors, Smad2/3/4 complexes, and inhibitory Smad7, thereby influencing fibrotic processes. In addition to its effect on TGF-β signaling, UPS also regulates pro-fibrotic pathways independent of TGF-β, including p53, AKT1-p38, and JNK1/2. Understanding these pathways is critical due to their involvement in diverse fibrotic mechanisms. The interplay between ubiquitination and deubiquitination of crucial pathways and molecules is pivotal in cardiac fibrosis and represents a promising area for identifying novel therapeutic targets. Different types of cardiac fibrosis involve distinct fibrotic pathways, leading to differential effects of E3 ligases and DUBs across various cardiac fibrotic diseases. Insights into UPS-mediated regulation of cardiac fibrosis provides potential anti-fibrotic therapeutic strategies, emphasizing the importance of targeting UPS components specific to the heart for effective therapy against cardiac fibrosis.
{"title":"Ubiquitin proteasome system in cardiac fibrosis","authors":"Linqi Zeng, Xiaokai Zhang, Zihang Huang, Shuai Song, Mohan Li, Tongyao Wang, Aijun Sun, Junbo Ge","doi":"10.1016/j.jare.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.jare.2024.12.006","url":null,"abstract":"<h3>Background</h3>Cardiac fibrosis, including reactive fibrosis and replacement fibrosis, is a common pathological process in most cardiovascular diseases. The ubiquitin proteasome system (UPS) plays an important role in the development of fibrosis by mediating the degradation and synthesis of proteins involved in transforming growth factor-β (TGF-β)-dependent and TGF-β-independent fibrous pathways.<h3>Aim of review</h3>This review aims to provide an overview of ubiquitinated and deubiquitinated molecules that participating in cardiac fibrosis, with the ultimate purpose to identify promising targets for therapeutic strategies.<h3>Key scientific concepts of review</h3>The UPS primarily impacts cardiac fibrosis through modulation of the TGF-β signaling pathway targeting key molecules involved, including the TGF-β receptors, Smad2/3/4 complexes, and inhibitory Smad7, thereby influencing fibrotic processes. In addition to its effect on TGF-β signaling, UPS also regulates pro-fibrotic pathways independent of TGF-β, including p53, AKT1-p38, and JNK1/2. Understanding these pathways is critical due to their involvement in diverse fibrotic mechanisms. The interplay between ubiquitination and deubiquitination of crucial pathways and molecules is pivotal in cardiac fibrosis and represents a promising area for identifying novel therapeutic targets. Different types of cardiac fibrosis involve distinct fibrotic pathways, leading to differential effects of E3 ligases and DUBs across various cardiac fibrotic diseases. Insights into UPS-mediated regulation of cardiac fibrosis provides potential anti-fibrotic therapeutic strategies, emphasizing the importance of targeting UPS components specific to the heart for effective therapy against cardiac fibrosis.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"47 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-06DOI: 10.1016/j.jare.2024.11.036
Fanhao Wei, Binjia Ruan, Jian Dong, Bin Yang, Guofu Zhang, Wai Kwok Kelvin Yeung, Hongwei Wang, Wangsen Cao, Yongxiang Wang
Introduction
Diabetic osteoporosis (DOP) is an insidious complication of diabetes with limited therapeutic options. DOP is pathologically associated with various types of regulated cell death, but the precise role of ferroptosis in the process remains poorly understood. Asperosaponin VI (AVI), known for its clinical efficacy in treating bone fractures and osteoporosis, may exert its osteoprotective effects through mechanisms involving ferroptosis, however this has not been established.
Objectives
This study aimed to investigate the role of AVI in modulating ferroptosis in a mouse model of DOP and to explore the underlying mechanisms.
Methods
We assessed OP alterations in femurs of DOP-conditioned mice and primary bone cells. We generated a strain of osteoblast-specific Gpx4-deficient mice. A combination of micro-CT, immunohistochemistry, immunofluorescence, methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), western blotting (WB), and AVI pull-down assays were employed to elucidate the mechanism and therapeutic target of AVI in DOP.
Results
Our findings revealed that femurs from DOP-conditioned mice exhibited significant ferroptosis and suppression of the core anti-ferroptosis factor GPX4, mainly due to hypermethylation of the Gpx4 promoter mediated by DNA methyltransferases DNMT1and DNMT3a. Notably, treatment with AVI effectively reversed the hypermethylation, restored GPX4 expression, and reduced ferroptotic pathologies associated with DOP by inhibiting DNMT1/3a. In primary osteoblasts, AVI alleviated GPX4 suppression and reduced ferroptosis in DOP-conditioned primary osteoblasts through a mechanism dependent on DNMT inhibition and GPX4 restoration. Importantly, the anti-ferroptotic and osteoprotective effects of AVI were abolished in osteoblastic Gpx4 haplo-deficient mice (Gpx4Ob-/+) or when GPX4 was pharmacologically inactivated with RSL3.
Conclusions
Our study identifies a pivotal epigenetic ferroptotic pathway that contributes significantly to DOP and uncovers a crucial pharmacological property of AVI that is potentially effective in treating patients with DOP and related osteoporotic disorders.
糖尿病性骨质疏松症（DOP）是糖尿病的一种潜在并发症，治疗选择有限。DOP在病理上与多种类型的受调节细胞死亡相关，但铁下垂在这一过程中的确切作用仍知之甚少。Asperosaponin VI （AVI）以其治疗骨折和骨质疏松症的临床疗效而闻名，其保护骨的作用机制可能与铁下垂有关，但尚未确定。目的探讨AVI在DOP小鼠模型中对铁下垂的调节作用及其机制。方法观察dopo小鼠股骨及原代骨细胞的OP变化。我们培育了一株成骨细胞特异性gpx4缺陷小鼠。采用显微ct、免疫组织化学、免疫荧光、甲基化特异性PCR （MSP）、亚硫酸氢盐测序PCR （BSP）、western blotting （WB）和AVI拉下实验等方法，探讨AVI在DOP中的作用机制和治疗靶点。结果dopo条件小鼠的股骨表现出明显的铁下垂和核心抗铁下垂因子GPX4的抑制，主要是由于DNA甲基转移酶dnmt1和DNMT3a介导的GPX4启动子的超甲基化。值得注意的是，AVI治疗有效地逆转了高甲基化，恢复了GPX4的表达，并通过抑制DNMT1/3a减少了与DOP相关的铁致凋亡病理。在原代成骨细胞中，AVI通过依赖于DNMT抑制和GPX4恢复的机制减轻了dopo条件下的原代成骨细胞的GPX4抑制和铁下沉。重要的是，在成骨细胞Gpx4单倍体缺陷小鼠（Gpx4Ob-/+）或用RSL3药理学灭活Gpx4时，AVI的抗铁和骨保护作用被取消。结论我们的研究发现了一个对DOP有重要作用的关键表观遗传铁致凋亡通路，并揭示了AVI的一个重要药理特性，该特性可能有效治疗DOP及相关骨质疏松症患者。
{"title":"Asperosaponin VI inhibition of DNMT alleviates GPX4 suppression-mediated osteoblast ferroptosis and diabetic osteoporosis","authors":"Fanhao Wei, Binjia Ruan, Jian Dong, Bin Yang, Guofu Zhang, Wai Kwok Kelvin Yeung, Hongwei Wang, Wangsen Cao, Yongxiang Wang","doi":"10.1016/j.jare.2024.11.036","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.036","url":null,"abstract":"<h3>Introduction</h3>Diabetic osteoporosis (DOP) is an insidious complication of diabetes with limited therapeutic options. DOP is pathologically associated with various types of regulated cell death, but the precise role of ferroptosis in the process remains poorly understood. Asperosaponin VI (AVI), known for its clinical efficacy in treating bone fractures and osteoporosis, may exert its osteoprotective effects through mechanisms involving ferroptosis, however this has not been established.<h3>Objectives</h3>This study aimed to investigate the role of AVI in modulating ferroptosis in a mouse model of DOP and to explore the underlying mechanisms.<h3>Methods</h3>We assessed OP alterations in femurs of DOP-conditioned mice and primary bone cells. We generated a strain of osteoblast-specific <em>Gpx4</em>-deficient mice. A combination of micro-CT, immunohistochemistry, immunofluorescence, methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), western blotting (WB), and AVI pull-down assays were employed to elucidate the mechanism and therapeutic target of AVI in DOP.<h3>Results</h3>Our findings revealed that femurs from DOP-conditioned mice exhibited significant ferroptosis and suppression of the core anti-ferroptosis factor GPX4, mainly due to hypermethylation of the <em>Gpx4</em> promoter mediated by DNA methyltransferases DNMT1and DNMT3a. Notably, treatment with AVI effectively reversed the hypermethylation, restored GPX4 expression, and reduced ferroptotic pathologies associated with DOP by inhibiting DNMT1/3a. In primary osteoblasts, AVI alleviated GPX4 suppression and reduced ferroptosis in DOP-conditioned primary osteoblasts through a mechanism dependent on DNMT inhibition and GPX4 restoration. Importantly, the anti-ferroptotic and osteoprotective effects of AVI were abolished in osteoblastic Gpx4 haplo-deficient mice (<em>Gpx4<sup>Ob-/+</sup></em>) or when GPX4 was pharmacologically inactivated with RSL3.<h3>Conclusions</h3>Our study identifies a pivotal epigenetic ferroptotic pathway that contributes significantly to DOP and uncovers a crucial pharmacological property of AVI that is potentially effective in treating patients with DOP and related osteoporotic disorders.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"216 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-06DOI: 10.1016/j.jare.2024.12.004
Huachun Yin, Hongrui Duo, Song Li, Dan Qin, Lingling Xie, Yingxue Xiao, Jing Sun, Jingxin Tao, Xiaoxi Zhang, Yinghong Li, Yue Zou, Qingxia Yang, Xian Yang, Youjin Hao, Bo Li
Background
Identifying differentially expressed genes (DEGs) is a core task of transcriptome analysis, as DEGs can reveal the molecular mechanisms underlying biological processes. However, interpreting the biological significance of large DEG lists is challenging. Currently, gene ontology, pathway enrichment and protein–protein interaction analysis are common strategies employed by biologists. Additionally, emerging analytical strategies/approaches (such as network module analysis, knowledge graphs, drug repurposing, cell marker discovery, trajectory analysis, and cell communication analysis) have been proposed. Despite these advances, comprehensive guidelines for systematically and thoroughly mining the biological information within DEGs remain lacking.
Aim
of review: This review aims to provide an overview of essential concepts and methodologies for the biological interpretation of DEGs, enhancing the contextual understanding. It also addresses the current limitations and future perspectives of these approaches, highlighting their broad applications in deciphering the molecular mechanism of complex diseases and phenotypes. To assist users in extracting insights from extensive datasets, especially various DEG lists, we developed DEGMiner (https://www.ciblab.net/DEGMiner/), which integrates over 300 easily accessible databases and tools.
Key scientific concepts of review
This review offers strong support and guidance for exploring DEGs, and also will accelerate the discovery of hidden biological insights within genomes.
{"title":"Unlocking biological insights from differentially expressed Genes: Concepts, methods, and future perspectives","authors":"Huachun Yin, Hongrui Duo, Song Li, Dan Qin, Lingling Xie, Yingxue Xiao, Jing Sun, Jingxin Tao, Xiaoxi Zhang, Yinghong Li, Yue Zou, Qingxia Yang, Xian Yang, Youjin Hao, Bo Li","doi":"10.1016/j.jare.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.jare.2024.12.004","url":null,"abstract":"<h3>Background</h3>Identifying differentially expressed genes (DEGs) is a core task of transcriptome analysis, as DEGs can reveal the molecular mechanisms underlying biological processes. However, interpreting the biological significance of large DEG lists is challenging. Currently, gene ontology, pathway enrichment and protein–protein interaction analysis are common strategies employed by biologists. Additionally, emerging analytical strategies/approaches (such as network module analysis, knowledge graphs, drug repurposing, cell marker discovery, trajectory analysis, and cell communication analysis) have been proposed. Despite these advances, comprehensive guidelines for systematically and thoroughly mining the biological information within DEGs remain lacking.<h3>Aim</h3><em>of review:</em> This review aims to provide an overview of essential concepts and methodologies for the biological interpretation of DEGs, enhancing the contextual understanding. It also addresses the current limitations and future perspectives of these approaches, highlighting their broad applications in deciphering the molecular mechanism of complex diseases and phenotypes. To assist users in extracting insights from extensive datasets, especially various DEG lists, we developed DEGMiner (<span><span>https://www.ciblab.net/DEGMiner/</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>), which integrates over 300 easily accessible databases and tools.<h3>Key scientific concepts of review</h3>This review offers strong support and guidance for exploring DEGs, and also will accelerate the discovery of hidden biological insights within genomes.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"27 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment, being implicated in enhancing tumor growth and fostering drug resistance. Nonetheless, the mechanisms underlying their function in prostate cancer (PCa) remain incompletely understood, which is essential for devising effective therapeutic strategies.
Objectives
The main objective of this study was to explore the mechanisms by which CAFs mediate PCa growth and chemoresistance.
Methods
We validated through data analysis and experimentation that CAFs significantly impact PCa cell proliferation and chemoresistance. Subsequently, we conducted a comprehensive proteomic analysis of the conditioned media from CAFs and PCa cells and identified angiopoietin-like protein 4 (ANGPTL4) as a key factor. We employed ELISA and multiplex immunofluorescence assays, all of which indicated that ANGPTL4 was primarily secreted by CAFs.Next, we conducted metabolomics analysis, GST pull-down assays, Co-IP, and other experiments to explore the specific molecular mechanisms of ANGPTL4 and its precise effects on PCa cells. Through drug screening, we identified Quercetin 3-O-(6′-galactopyranosyl)-β-D-galactopyranoside (QGGP) as an effective inhibitor of CAFs function. Finally, we thoroughly assessed the therapeutic potential of QGGP both as a monotherapy and in combination with docetaxel in PCa cells
Results
We discovered that the extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. When ANGPTL4 binds to IQ motif-containing GTPase-activating protein 1 (IQGAP1) on the PCa cell membrane, it activates the Raf-MEK-ERK-PGC1α axis, promoting mitochondrial biogenesis and OXPHOS metabolism, and thereby facilitating PCa growth and chemoresistance. Furthermore, virtual and functional screening strategies identified QGGP as a specific inhibitor of IQGAP1 that promotes its degradation. Combined with docetaxel treatment, QGGP can reverse the effects of CAFs and improve the responsiveness of PCa to chemotherapy.
Conclusions
This study uncovers a paracrine mechanism of chemoresistance in PCa and proposes that targeting the stroma could be a therapeutic choice.
癌症相关成纤维细胞（CAFs）是肿瘤微环境的关键组成部分，与促进肿瘤生长和培养耐药性有关。尽管如此，它们在前列腺癌（PCa）中的作用机制仍不完全清楚，这对于制定有效的治疗策略至关重要。本研究的主要目的是探讨CAFs介导PCa生长和化疗耐药的机制。方法通过数据分析和实验验证了CAFs对前列腺癌细胞增殖和化疗耐药的影响。随后，我们对来自CAFs和PCa细胞的条件培养基进行了全面的蛋白质组学分析，并确定血管生成素样蛋白4 （ANGPTL4）是一个关键因素。ELISA和多重免疫荧光检测均表明，ANGPTL4主要由caf分泌。接下来，我们通过代谢组学分析、GST pull-down实验、Co-IP等实验，探索ANGPTL4的具体分子机制及其对PCa细胞的确切作用。通过药物筛选，我们鉴定出槲皮素3-O-（6′-半乳糖吡喃基）-β- d -半乳糖吡喃苷（QGGP）是一种有效的CAFs功能抑制剂。最后，我们全面评估了QGGP作为单一疗法和与多西紫杉醇联合治疗PCa细胞的治疗潜力。结果我们发现外分泌因子ANGPTL4主要在PCa的CAFs中表达。当ANGPTL4与PCa细胞膜上含有IQ基序的gtpase激活蛋白1 （IQGAP1）结合时，激活Raf-MEK-ERK-PGC1α轴，促进线粒体生物发生和OXPHOS代谢，从而促进PCa生长和耐药。此外，虚拟和功能筛选策略确定QGGP是促进其降解的IQGAP1的特异性抑制剂。QGGP联合多西紫杉醇治疗可逆转CAFs的作用，提高PCa对化疗的反应性。结论本研究揭示了前列腺癌化疗耐药的旁分泌机制，并提出靶向间质可能是一种治疗选择。
{"title":"Cancer-associated fibroblasts regulate mitochondrial metabolism and inhibit chemosensitivity via ANGPTL4-IQGAP1 axis in prostate cancer","authors":"Zhi Xiong, Rui-Lin Zhuang, Shun-Li Yu, Zhao-Xiang Xie, Shi-Rong Peng, Ze-An Li, Bing-Heng Li, Jun-Jia Xie, Yi-Ning Li, Kai-Wen Li, Hai Huang","doi":"10.1016/j.jare.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.jare.2024.12.003","url":null,"abstract":"<h3>Introduction</h3>Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment, being implicated in enhancing tumor growth and fostering drug resistance. Nonetheless, the mechanisms underlying their function in prostate cancer (PCa) remain incompletely understood, which is essential for devising effective therapeutic strategies.<h3>Objectives</h3>The main objective of this study was to explore the mechanisms by which CAFs mediate PCa growth and chemoresistance.<h3>Methods</h3>We validated through data analysis and experimentation that CAFs significantly impact PCa cell proliferation and chemoresistance. Subsequently, we conducted a comprehensive proteomic analysis of the conditioned media from CAFs and PCa cells and identified angiopoietin-like protein 4 (ANGPTL4) as a key factor. We employed ELISA and multiplex immunofluorescence assays, all of which indicated that ANGPTL4 was primarily secreted by CAFs.Next, we conducted metabolomics analysis, GST pull-down assays, Co-IP, and other experiments to explore the specific molecular mechanisms of ANGPTL4 and its precise effects on PCa cells. Through drug screening, we identified Quercetin 3-O-(6′-galactopyranosyl)-β-D-galactopyranoside (QGGP) as an effective inhibitor of CAFs function. Finally, we thoroughly assessed the therapeutic potential of QGGP both as a monotherapy and in combination with docetaxel in PCa cells<h3>Results</h3>We discovered that the extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. When ANGPTL4 binds to IQ motif-containing GTPase-activating protein 1 (IQGAP1) on the PCa cell membrane, it activates the Raf-MEK-ERK-PGC1α axis, promoting mitochondrial biogenesis and OXPHOS metabolism, and thereby facilitating PCa growth and chemoresistance. Furthermore, virtual and functional screening strategies identified QGGP as a specific inhibitor of IQGAP1 that promotes its degradation. Combined with docetaxel treatment, QGGP can reverse the effects of CAFs and improve the responsiveness of PCa to chemotherapy.<h3>Conclusions</h3>This study uncovers a paracrine mechanism of chemoresistance in PCa and proposes that targeting the stroma could be a therapeutic choice.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"9 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-04DOI: 10.1016/j.jare.2024.11.037
Renhong Lu, Bowen Lin, Zheyi Lin, Hui Xiong, Junyang Liu, Li Li, Zheng Gong, Siyu Wang, Mingshuai Zhang, Jie Ding, Chengwen Hang, Huixin Guo, Duanyang Xie, Yi Liu, Dan Shi, Dandan Liang, Zhen Liu, Jian Yang, Yi-Han Chen
Introduction
Cell fate determination and transition are of paramount importance in biology and medicine. Naive pluripotency could be achieved by reprogramming differentiated cells. However, the mechanism is less clear. Osmolarity is an essential physical factor that acts on living cells, especially for pluripotent cells, but its significance in cell fate transition remains unexplored.
Objectives
To investigate the role of osmolarity in cell fate transition and its underlying mechanism.
Methods
Flow cytometry, quantitative PCR, teratoma and chimeric mice assays were performed to assess reprogramming efficiency and characterize iPSCs. TEM, immunofluorescence staining, western blot, chemical treatment and genetic modification were utilized to evaluate cell morphology, signaling pathways, cytoskeleton and nuclear structure. Multiomic sequencings were applied to unveil the transcriptome, histone markers and chromatin accessibility of EpiSCs in hypo-osmotic condition.
Result
In hypo-osmotic condition, the reprogramming efficiency of hypo-osmotic EpiSCs increased over 60-fold than that of iso-osmotic cells (1100 vs 18 colonies per 3 × 105 cells), whereas no colony formed in hyper-osmotic cells. The converted cells displayed naive pluripotency. The hypo-osmotic EpiSCs exhibited larger cell size, nuclear area and less heterochromatin; ATAC-seq and ChIP-seq confirmed the increased accessibility of naive pluripotent gene loci with more H3K27ac. Mechanistically, hypo-osmolarity activated PI3K-AKT-SP1 signaling in EpiSCs, which reshaped cytoskeleton and nucleoskeleton, resulting in genome reorganization and pluripotent gene expression. In contrast, hypo-osmolarity delayed the ESCs’ exit from naive pluripotency. Moreover, in MEFs reprograming, hypo-osmolarity promoted the conversion to naive pluripotency.
Conclusion
Hypo-osmolarity promotes cell fate transition by remodeling cytoskeleton, nucleoskeleton and genome via PI3K-AKT-SP1 pathway.
细胞命运的决定和转变在生物学和医学中是至关重要的。原始多能性可以通过对分化细胞进行重编程来实现。然而，其机制尚不清楚。渗透压是作用于活细胞，尤其是多能细胞的一个重要物理因素，但其在细胞命运转变中的意义尚不清楚。目的探讨渗透压在细胞命运转变中的作用及其机制。方法采用流式细胞术、定量PCR、畸胎瘤和嵌合小鼠实验来评估iPSCs的重编程效率和特性。利用透射电镜（TEM）、免疫荧光染色、免疫印迹（western blot）、化学处理和基因修饰等方法观察细胞形态、信号通路、细胞骨架和细胞核结构。应用多组测序揭示EpiSCs在低渗透条件下的转录组、组蛋白标记和染色质可及性。结果在低渗透条件下，低渗透EpiSCs的重编程效率（1100 vs 18菌落/ 3 × 105细胞）比等渗透细胞高60倍以上，而在高渗透细胞中未形成菌落。转化的细胞显示出初始多能性。低渗透EpiSCs表现出较大的细胞大小、核面积和较少的异染色质；ATAC-seq和ChIP-seq证实了具有更多H3K27ac的原始多能基因位点的可及性增加。从机制上讲，低渗透压激活EpiSCs中的PI3K-AKT-SP1信号，从而重塑细胞骨架和核骨架，导致基因组重组和多能基因表达。相反，低渗透压延迟了ESCs从初始多能性的退出。此外，在mef重编程中，低渗透压促进了向初始多能性的转化。结论低渗透压通过PI3K-AKT-SP1通路重塑细胞骨架、核骨架和基因组，促进细胞命运转变。
{"title":"Hypo-osmolarity promotes naive pluripotency by reshaping cytoskeleton and increasing chromatin accessibility","authors":"Renhong Lu, Bowen Lin, Zheyi Lin, Hui Xiong, Junyang Liu, Li Li, Zheng Gong, Siyu Wang, Mingshuai Zhang, Jie Ding, Chengwen Hang, Huixin Guo, Duanyang Xie, Yi Liu, Dan Shi, Dandan Liang, Zhen Liu, Jian Yang, Yi-Han Chen","doi":"10.1016/j.jare.2024.11.037","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.037","url":null,"abstract":"<h3>Introduction</h3>Cell fate determination and transition are of paramount importance in biology and medicine. Naive pluripotency could be achieved by reprogramming differentiated cells. However, the mechanism is less clear. Osmolarity is an essential physical factor that acts on living cells, especially for pluripotent cells, but its significance in cell fate transition remains unexplored.<h3>Objectives</h3>To investigate the role of osmolarity in cell fate transition and its underlying mechanism.<h3>Methods</h3>Flow cytometry, quantitative PCR, teratoma and chimeric mice assays were performed to assess reprogramming efficiency and characterize iPSCs. TEM, immunofluorescence staining, western blot, chemical treatment and genetic modification were utilized to evaluate cell morphology, signaling pathways, cytoskeleton and nuclear structure. Multiomic sequencings were applied to unveil the transcriptome, histone markers and chromatin accessibility of EpiSCs in hypo-osmotic condition.<h3>Result</h3>In hypo-osmotic condition, the reprogramming efficiency of hypo-osmotic EpiSCs increased over 60-fold than that of <em>iso</em>-osmotic cells (1100 <em>vs</em> 18 colonies per 3 × 10<sup>5</sup> cells), whereas no colony formed in hyper-osmotic cells. The converted cells displayed naive pluripotency. The hypo-osmotic EpiSCs exhibited larger cell size, nuclear area and less heterochromatin; ATAC-seq and ChIP-seq confirmed the increased accessibility of naive pluripotent gene loci with more H3K27ac. Mechanistically, hypo-osmolarity activated PI3K-AKT-SP1 signaling in EpiSCs, which reshaped cytoskeleton and nucleoskeleton, resulting in genome reorganization and pluripotent gene expression. In contrast, hypo-osmolarity delayed the ESCs’ exit from naive pluripotency. Moreover, in MEFs reprograming, hypo-osmolarity promoted the conversion to naive pluripotency.<h3>Conclusion</h3>Hypo-osmolarity promotes cell fate transition by remodeling cytoskeleton, nucleoskeleton and genome via PI3K-AKT-SP1 pathway.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"27 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Promoting adipose thermogenesis is considered as a promising therapeutic intervention in obesity. However, endeavors to develop anti-obesity medications by targeting the canonical thermogenesis regulatory pathway, particularly β3-adrenergic receptor (β3-AR)-dependent mechanism, have failed due to the off-target effects of β3-AR agonists, exacerbating the risk of cardiovascular disease. Hyperforin (HPF), a natural compound extracted from the traditional herbal St. John’s Wort, binds to Dihydrolipoamide s-acetyltransferase (Dlat) and exerts effective anti-obesity properties through promoting adipose thermogenesis.
Objectives
The objective of this study was to investigate the oral efficacy and pharmacokinetics profile of HPF, and explore the detailed mechanism by which Dlat modulates HPF-mediated adipose thermogenesis.
Methods
To assess the anti-obesity efficacy of orally administered HPF in vivo, Dlat heterozygous knockout (Dlat+/-) mice and wild-type (WT) mice, both fed a high-fat diet (HFD), underwent a validation process that involved the use of metabolic cages, NMR analysis, and infrared imaging. Sprague Dawley rats were employed to determine the pharmacokinetic parameters of HPF. Seahorse assays, JC-1 staining, qPCR, and immunoblotting were performed to evaluate cellular thermogenic efficacy of HPF and Dlat in vitro.
Results
Our study uncovered a non-canonical thermogenesis pathway involving Dlat, transient receptor potential vanilloid 3 (Trpv3, a calcium channel) and AMPK. Dlat interacted with Trpv3 to activate it, resulting in an increase in intracellular calcium (Ca2+) and the activation of Camkkβ. Camkkβ then stimulated AMPK, leading to elevated Ucp1 expression and initiating adipose thermogenesis. HPF promoted thermogenesis in adipose tissues through enhancing the Dlat-Trpv3 interaction independently of β3AR, causing minimal cardiac side effects. Notably, HPF’s thermogenic effects were reduced in Dlat+/- mice. Moreover, HPF exerted favorable oral bioavailability, a relatively long half-life, and extensive distribution within adipose tissues.
Conclusion
In summary, our study demonstrates that HPF targets a novel mechanism for promoting adipose thermogenesis and exhibits potent and safe anti-obesity efficacy.
{"title":"Targeting Dlat-Trpv3 pathway by hyperforin elicits non-canonical promotion of adipose thermogenesis as an effective anti-obesity strategy","authors":"Sijia Lu, Quanxin Jiang, Peihui Zhou, Limin Yin, Ning Wang, Junting Xu, Qiqi Qian, Mijia Tao, Hanrui Yin, Liu Han, Yunqing Gu, Fei Gao, Junli Liu, Suzhen Chen","doi":"10.1016/j.jare.2024.11.035","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.035","url":null,"abstract":"<h3>Introduction</h3>Promoting adipose thermogenesis is considered as a promising therapeutic intervention in obesity. However, endeavors to develop anti-obesity medications by targeting the canonical thermogenesis regulatory pathway, particularly β3-adrenergic receptor (β3-AR)-dependent mechanism, have failed due to the off-target effects of β3-AR agonists, exacerbating the risk of cardiovascular disease. Hyperforin (HPF), a natural compound extracted from the traditional herbal St. John’s Wort, binds to Dihydrolipoamide s-acetyltransferase (Dlat) and exerts effective anti-obesity properties through promoting adipose thermogenesis.<h3>Objectives</h3>The objective of this study was to investigate the oral efficacy and pharmacokinetics profile of HPF, and explore the detailed mechanism by which Dlat modulates HPF-mediated adipose thermogenesis.<h3>Methods</h3>To assess the anti-obesity efficacy of orally administered HPF <em>in vivo</em>, Dlat heterozygous knockout (Dlat<sup>+/-</sup>) mice and wild-type (WT) mice, both fed a high-fat diet (HFD), underwent a validation process that involved the use of metabolic cages, NMR analysis, and infrared imaging. Sprague Dawley rats were employed to determine the pharmacokinetic parameters of HPF. Seahorse assays, JC-1 staining, qPCR, and immunoblotting were performed to evaluate cellular thermogenic efficacy of HPF and Dlat <em>in vitro</em>.<h3>Results</h3>Our study uncovered a non-canonical thermogenesis pathway involving Dlat, transient receptor potential vanilloid 3 (Trpv3, a calcium channel) and AMPK. Dlat interacted with Trpv3 to activate it, resulting in an increase in intracellular calcium (Ca<sup>2+</sup>) and the activation of Camkkβ. Camkkβ then stimulated AMPK, leading to elevated Ucp1 expression and initiating adipose thermogenesis. HPF promoted thermogenesis in adipose tissues through enhancing the Dlat-Trpv3 interaction independently of β3AR, causing minimal cardiac side effects. Notably, HPF’s thermogenic effects were reduced in Dlat<sup>+/-</sup> mice. Moreover, HPF exerted favorable oral bioavailability, a relatively long half-life, and extensive distribution within adipose tissues.<h3>Conclusion</h3>In summary, our study demonstrates that HPF targets a novel mechanism for promoting adipose thermogenesis and exhibits potent and safe anti-obesity efficacy.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"26 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-29DOI: 10.1016/j.jare.2024.11.032
Junlin Pu, Xiuli Yan, Hui Zhang
Background
Gastric cancer (GC) is a global health concern, contributing significantly to cancer-related mortality rates. Early detection is vital for improving patient outcomes. Recently, circular RNAs (circRNAs) have emerged as crucial players in the development and progression of various cancers, including GC.
Aim
of Review: This comprehensive review underscores the promising potential of circRNAs as innovative biomarkers for the early diagnosis of GC, as well as their possible utility as therapeutic targets for this life-threatening disease. Specifically, the review focuses on recent findings, mechanistic insights, and clinical applications of circRNAs in GC.Key Scientific Concepts of Review: Dysregulation of circRNAs has been consistently observed in GC tissues, offering potential diagnostic value due to their stability in bodily fluids such as blood and urine. For instance, circPTPN22 and hsa_circ_000200. Furthermore, the expression levels of circRNAs such as circCUL2, hsa_circ_0000705 and circSHKBP1 have shown strong associations with critical clinical features of GC, including diagnosis, prognosis, tumor size, lymph node metastasis, tumor-node-metastasis (TNM) stage, and treatment response. Additionally, circRNAs such as circBGN, circLMO7, and circMAP7D1 have shown interactions with specific microRNAs (miRNAs), proteins, and other molecules that play key roles in development and progression of GC. This further highlighting their potential as therapeutic targets. Despite their potential, several challenges need to be addressed to effectively apply circRNAs as GC biomarkers. These include standardizing detection methods, establishing cutoff values for diagnostic accuracy, and validating findings in larger patient cohorts. Moreover, the functional mechanisms by which circRNAs contribute to GC pathogenesis and therapeutic resistance warrant further investigation. Advances in circRNAs research could provide valuable insights into the early detection and targeted treatment of GC, ultimately improving patient outcomes.
{"title":"The potential of circular RNAs as biomarkers and therapeutic targets for gastric cancer: A comprehensive review","authors":"Junlin Pu, Xiuli Yan, Hui Zhang","doi":"10.1016/j.jare.2024.11.032","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.032","url":null,"abstract":"<h3>Background</h3>Gastric cancer (GC) is a global health concern, contributing significantly to cancer-related mortality rates. Early detection is vital for improving patient outcomes. Recently, circular RNAs (circRNAs) have emerged as crucial players in the development and progression of various cancers, including GC.<h3>Aim</h3><em>of Review</em>: This comprehensive review underscores the promising potential of circRNAs as innovative biomarkers for the early diagnosis of GC, as well as their possible utility as therapeutic targets for this life-threatening disease. Specifically, the review focuses on recent findings, mechanistic insights, and clinical applications of circRNAs in GC.<em>Key Scientific Concepts of Review</em>: Dysregulation of circRNAs has been consistently observed in GC tissues, offering potential diagnostic value due to their stability in bodily fluids such as blood and urine. For instance, circPTPN22 and hsa_circ_000200. Furthermore, the expression levels of circRNAs such as circCUL2, hsa_circ_0000705 and circSHKBP1 have shown strong associations with critical clinical features of GC, including diagnosis, prognosis, tumor size, lymph node metastasis, tumor-node-metastasis (TNM) stage, and treatment response. Additionally, circRNAs such as circBGN, circLMO7, and circMAP7D1 have shown interactions with specific microRNAs (miRNAs), proteins, and other molecules that play key roles in development and progression of GC. This further highlighting their potential as therapeutic targets. Despite their potential, several challenges need to be addressed to effectively apply circRNAs as GC biomarkers. These include standardizing detection methods, establishing cutoff values for diagnostic accuracy, and validating findings in larger patient cohorts. Moreover, the functional mechanisms by which circRNAs contribute to GC pathogenesis and therapeutic resistance warrant further investigation. Advances in circRNAs research could provide valuable insights into the early detection and targeted treatment of GC, ultimately improving patient outcomes.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"5 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142742449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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