Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular ...Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular energy metabolism,has been implicated in various cancers.but its role in MM remains unclear.Methods:ERRγexpres-sion was assessed using bioinformatics and RT-qPCR.Functional studies were conducted through siRNA-mediated ERRγknockdown and treatment with the inverse agonist GSK5182 to examine their effects on MM cell proliferation and apoptosis.Results:ERRγwas significantly upregulated in the bone marrow of MM patients,correlating with advanced clinical stages and pathological fractures.Inhibition of ERRγreduced MM cell expansion both in vitro and in vivo,while promoting mitochondrial-dependent apoptosis.Co-immunoprecipitation assays demonstrated a physical association between ERRγand P65.Inhibition of ERRγattenuated canonical nuclear factor-kappa B(NF-κB)signaling by blocking the nuclear translocation of its key effector p65.Additionally,modulation of ERRγaltered receptor activator of nuclear factor-κB ligand(RANKL)levels,implying a potential role in bone degradation observed in MM cases.Conclusion:Collectively,the data broaden understanding of ERRγ’s contribution to MM development and propose it as a viable target for therapeutic intervention.展开更多
目的探究大蒜素对动脉粥样硬化模型小鼠骨代谢的改善作用及其潜在作用机制。方法SPF级ApoE-/-雄性小鼠经高脂饲料喂养8周后,采用随机分组法进行分组,每组8只,包括模型组、大蒜素组及阿托伐他汀组,连续给药9周。另取C57BL/6N野生型小鼠8...目的探究大蒜素对动脉粥样硬化模型小鼠骨代谢的改善作用及其潜在作用机制。方法SPF级ApoE-/-雄性小鼠经高脂饲料喂养8周后,采用随机分组法进行分组,每组8只,包括模型组、大蒜素组及阿托伐他汀组,连续给药9周。另取C57BL/6N野生型小鼠8只,作为对照组,给予普通饲料常规喂养。利用生化法测定小鼠血脂变化,包括总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)和低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平。利用ELISA法测定血清骨吸收标志物,包括TRAP和CTX-1的变化。此外,利用Micro-CT检测小鼠骨微结构改变,并通过傅里叶变换红外光谱法检测骨材料特性,利用HE染色与TRAP染色观察骨组织病理学变化,利用Western blotting检测骨组织内骨吸收以及PPARγ/ERRα/PGC-1β通路相关蛋白的表达。结果大蒜素干预能显著降低动脉粥样硬化小鼠的血清TG、TC、HDL-C和LDL-C水平,同时抑制小鼠骨微结构的破坏,改善骨材料特性,以及抑制骨组织结构的病理损伤。此外,大蒜素能下调动脉粥样硬化小鼠血清中TRAP与CTX-1的水平,并降低其骨组织NFATc1、c-Fos、Cathepsin K蛋白的表达,抑制PPARγ、ERRα和PGC-1β蛋白的表达。结论大蒜素能通过抑制PPARγ/ERRα/PGC-1β通路,改善动脉粥样硬化小鼠的骨质量,进而防治骨质疏松的发生和发展。展开更多
Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study...Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study aimed to elucidate mechanism of mitochondria mediating HFD-induced hepatic fat accumulation.Results In the present study,yellow catfish were fed three diets with dietary fat at 6.31%(low fat;LFD,control),12.03%(middle fat;MFD)and 15.32%(high fat;HFD),respectively,for 8 weeks.High dietary fat addition raised hepatic lipid accumulation,and declined mRNA and protein levels of Parkin-dependent mitophagy,down-regulated the Parkin protein expression and the estrogen-related receptor alpha(Errα)ubiquitination,and induced Errαprotein levels;fatty acid(FA)incubation reduced Parkin-dependent mitophagy,inhibited Errαubiquitination and increased Errαprotein expression,and raised TG accumulation.Furthermore,yellow catfish hepatocytes were isolated and cultured.Nicotinamide mononucleotide,N-acetyl-L-cysteine,Parkin and errαsiRNA knockdown were used under FA incubation,respectively.Parkin downregulation mediated FA incubation-induced TG accumulation and mitoautophagic inhibition;Parkin ubiquitinated Errα,and K63 was an important ubiquitination site for deubiquitinating Parkin activity;Errαtargets fas,acca and pparγgenes,whose activation contributed to FA-induced lipogenesis and lipid accumulation.Thus,high fat diet(HFD)and FA incubation inhibited Parkin activity,suppressed mitophagy and activated Errαpathway,and induced hepatic lipogenic metabolism and lipotoxicity.Conclusions Overall,our study provided new targets against HFD-induced hepatic lipid accumulation and nonalcoholic fatty liver disease in the vertebrates.展开更多
文摘Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular energy metabolism,has been implicated in various cancers.but its role in MM remains unclear.Methods:ERRγexpres-sion was assessed using bioinformatics and RT-qPCR.Functional studies were conducted through siRNA-mediated ERRγknockdown and treatment with the inverse agonist GSK5182 to examine their effects on MM cell proliferation and apoptosis.Results:ERRγwas significantly upregulated in the bone marrow of MM patients,correlating with advanced clinical stages and pathological fractures.Inhibition of ERRγreduced MM cell expansion both in vitro and in vivo,while promoting mitochondrial-dependent apoptosis.Co-immunoprecipitation assays demonstrated a physical association between ERRγand P65.Inhibition of ERRγattenuated canonical nuclear factor-kappa B(NF-κB)signaling by blocking the nuclear translocation of its key effector p65.Additionally,modulation of ERRγaltered receptor activator of nuclear factor-κB ligand(RANKL)levels,implying a potential role in bone degradation observed in MM cases.Conclusion:Collectively,the data broaden understanding of ERRγ’s contribution to MM development and propose it as a viable target for therapeutic intervention.
文摘目的探究大蒜素对动脉粥样硬化模型小鼠骨代谢的改善作用及其潜在作用机制。方法SPF级ApoE-/-雄性小鼠经高脂饲料喂养8周后,采用随机分组法进行分组,每组8只,包括模型组、大蒜素组及阿托伐他汀组,连续给药9周。另取C57BL/6N野生型小鼠8只,作为对照组,给予普通饲料常规喂养。利用生化法测定小鼠血脂变化,包括总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)和低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平。利用ELISA法测定血清骨吸收标志物,包括TRAP和CTX-1的变化。此外,利用Micro-CT检测小鼠骨微结构改变,并通过傅里叶变换红外光谱法检测骨材料特性,利用HE染色与TRAP染色观察骨组织病理学变化,利用Western blotting检测骨组织内骨吸收以及PPARγ/ERRα/PGC-1β通路相关蛋白的表达。结果大蒜素干预能显著降低动脉粥样硬化小鼠的血清TG、TC、HDL-C和LDL-C水平,同时抑制小鼠骨微结构的破坏,改善骨材料特性,以及抑制骨组织结构的病理损伤。此外,大蒜素能下调动脉粥样硬化小鼠血清中TRAP与CTX-1的水平,并降低其骨组织NFATc1、c-Fos、Cathepsin K蛋白的表达,抑制PPARγ、ERRα和PGC-1β蛋白的表达。结论大蒜素能通过抑制PPARγ/ERRα/PGC-1β通路,改善动脉粥样硬化小鼠的骨质量,进而防治骨质疏松的发生和发展。
基金funded by National Key R&D Program of China(2024YFD2402000)。
文摘Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study aimed to elucidate mechanism of mitochondria mediating HFD-induced hepatic fat accumulation.Results In the present study,yellow catfish were fed three diets with dietary fat at 6.31%(low fat;LFD,control),12.03%(middle fat;MFD)and 15.32%(high fat;HFD),respectively,for 8 weeks.High dietary fat addition raised hepatic lipid accumulation,and declined mRNA and protein levels of Parkin-dependent mitophagy,down-regulated the Parkin protein expression and the estrogen-related receptor alpha(Errα)ubiquitination,and induced Errαprotein levels;fatty acid(FA)incubation reduced Parkin-dependent mitophagy,inhibited Errαubiquitination and increased Errαprotein expression,and raised TG accumulation.Furthermore,yellow catfish hepatocytes were isolated and cultured.Nicotinamide mononucleotide,N-acetyl-L-cysteine,Parkin and errαsiRNA knockdown were used under FA incubation,respectively.Parkin downregulation mediated FA incubation-induced TG accumulation and mitoautophagic inhibition;Parkin ubiquitinated Errα,and K63 was an important ubiquitination site for deubiquitinating Parkin activity;Errαtargets fas,acca and pparγgenes,whose activation contributed to FA-induced lipogenesis and lipid accumulation.Thus,high fat diet(HFD)and FA incubation inhibited Parkin activity,suppressed mitophagy and activated Errαpathway,and induced hepatic lipogenic metabolism and lipotoxicity.Conclusions Overall,our study provided new targets against HFD-induced hepatic lipid accumulation and nonalcoholic fatty liver disease in the vertebrates.
