Objective:Cisplatin is a widely used chemotherapeutic agent due to its ability to damage DNA in the treatment of cancer.However,its clinical application is often limited by adverse effects on normal tissues,especially...Objective:Cisplatin is a widely used chemotherapeutic agent due to its ability to damage DNA in the treatment of cancer.However,its clinical application is often limited by adverse effects on normal tissues,especially the kidneys.Understanding the molecular mechanisms of cisplatin-induced nephrotoxicity is crucial for developing strategies to mitigate its side effects.In this study,we aimed to elucidate the molecular mechanisms underlying cisplatin-induced DNA damage and apoptosis in human renal epithelial cells,with a focus on key signaling pathways and mediators that drive nephrotoxicity.Methods:To explore these mechanisms,human proximal tubule epithelial cells(HK-2)were treated with cisplatin.The study assessed DNA damage response(DDR)and stress-related protein expression,cell cycle distribution,and apoptosis.Activation of mitogen-activated protein kinases(MAPKs),particularly Extracellular signal-regulated Kinase(ERK),was analyzed,along with the expression and functional role of activating transcription factor 3(ATF3)and tumor protein p53(p53).Results:Cisplatin treatment upregulated DDR and stress response proteins,induced S phase arrest,and increased the SubG1 population,indicating apoptotic cell death.ERK was identified as a critical mediator of cisplatin-induced DNA damage and stress responses.ATF3 expression was significantly elevated in an ERK-dependent manner and required p53 activation.Knockdown of ATF3 reduced cisplatin-induced DNA damage,highlighting its role in the cytotoxic response.Conclusions:Cisplatin induces nephrotoxicity through ERK-and p53-dependent upregulation of ATF3,which is associated with DNA damage and cell death,suggesting a modulatory role in the cellular stress response.These findings provide novel insights into the molecular basis of cisplatin-induced renal injury and suggest potential therapeutic targets to alleviate its adverse effects.展开更多
It is well known that appropriate aerobic exercise can effectively alleviate fatty liver and enhance brain function.The concept of multi-organ crosstalk coordinating disease progression has become the current research...It is well known that appropriate aerobic exercise can effectively alleviate fatty liver and enhance brain function.The concept of multi-organ crosstalk coordinating disease progression has become the current research hot topic.However,there remains an urgent need to elucidate its specific mechanisms.This study aimed to explore the impact of a high-fat diet(HFD)on liver health and cognitive function,and to further uncover the regulatory effect of aerobic exercise by liver-specific activating transcription factor 3(Atf3)knockout(ATF3cKO)mice in a“liver-brain”axis mode.The 5-week-old C57BL/6 and ATF3cKO mice were fed with HFD for 32 weeks,and sequentially subjected to aerobic exercise intervention at the 20th week for another 12 consecutive weeks.Meanwhile,C57BL/6 mice were provided with a normal diet as the control group.The functional parameters of liver and brain of all mice were assessed.Cognitive capacity of all mice was assessed by the Morris water maze(MWM).Inflammatory factors in the serum and brain of mice were quantified using enzyme-linked immunosorbent assay(ELISA),and the expression of inflammasomes was detected by immunohistochemistry(IHC).Additionally,the activation of nuclear factor-κB(NF-κB)and phosphoinositide 3-kinase(PI3K)signal pathways was analyzed by Western blotting.In this study,HFD impaired hepatic and brain functions,while aerobic exercise and liver-specific Atf3 knockout suppressed inflammatory factors in the peripheral circulation through hepatoprotective mechanisms,thereby attenuating cerebral inflammation and preserving neurological integrity,as well as mitigating HFD-induced cognitive decline.展开更多
目的检测散发性单纯性尿道下裂患者包皮组织中激活转录因子3(Activating transcription factor 3,ATF3)的表达情况,探索ATF3与散发性单纯性尿道下裂之间的关系。方法方便选择2014年1月—2017年1月该院收治的散发性单纯性尿道下裂患者在...目的检测散发性单纯性尿道下裂患者包皮组织中激活转录因子3(Activating transcription factor 3,ATF3)的表达情况,探索ATF3与散发性单纯性尿道下裂之间的关系。方法方便选择2014年1月—2017年1月该院收治的散发性单纯性尿道下裂患者在尿道成形术中切除的包皮组织(共35例,其中轻度10例,中度15例,重度10例)作为尿道下裂组样品,单纯包皮过长(含包茎)患者在包皮环切术中去除的多余的包皮组织(共20例)作为对照组样品。通过RT-PCR方法检测实验组和对照组ATF3 m RNA的表达情况。采用SPSS 12.0统计学软件进行数据录入,构建数据库。结果通过RT-PCR方法测得散发性单纯性尿道下裂患者包皮组织中ATF3 m RNA的相对表达量为:(0.54±0.06),对照组的包皮组织中ATF3 m RNA的相对表达量为:(0.44±0.07),从结果中可以得出在散发性单纯性尿道下裂患者的包皮组织中ATF3的表达情况比正常的尿道组织中明显增加,两组结果比较,差异有统计学意义(t=5.89,P=0.00)。比较不同严重程度中尿道下裂患者ATF3 m RNA相对表达量,不同严重程度相对表达量差异无统计学意义(F=0.13,P=0.88)。结论散发性单纯性尿道下裂患者中ATF3的表达水平明显高于正常对照组,这提示ATF3与散发性单纯性尿道下裂存在着密切的关系。为将来研究ATF3在尿道下裂中产生的相关信号转导通路提供相关实验基础,及研究尿道下裂的发病机制提供理论依据。展开更多
基金supported by the research grant of Gyeongsang National University in 2023supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(RS-2025-00516213)+3 种基金the Brain Pool Program of the National Research Foundation(NRF)of Korea funded by theKorea government(MSIT)(RS-2025-25439144)AKorea Basic Science Institute(National Research Facilities and Equipment Center)grant funded by the Ministry of Education(2022R1A6C10B724)supported by the Regional Innovation System&Education(RISE)programthrough the RISE Center,Gyeongsangnam-do Provincial Government,Republic of Korea(2025-RISE-16-001)Learning&Academic research institution for Master’s⋅PhD students,and Postdocs(LAMP)Program of the National Research Foundation of Korea(NRF)grant funded by the Ministry of Education(RS-2023-00301974 and RS-2023-00301914).
文摘Objective:Cisplatin is a widely used chemotherapeutic agent due to its ability to damage DNA in the treatment of cancer.However,its clinical application is often limited by adverse effects on normal tissues,especially the kidneys.Understanding the molecular mechanisms of cisplatin-induced nephrotoxicity is crucial for developing strategies to mitigate its side effects.In this study,we aimed to elucidate the molecular mechanisms underlying cisplatin-induced DNA damage and apoptosis in human renal epithelial cells,with a focus on key signaling pathways and mediators that drive nephrotoxicity.Methods:To explore these mechanisms,human proximal tubule epithelial cells(HK-2)were treated with cisplatin.The study assessed DNA damage response(DDR)and stress-related protein expression,cell cycle distribution,and apoptosis.Activation of mitogen-activated protein kinases(MAPKs),particularly Extracellular signal-regulated Kinase(ERK),was analyzed,along with the expression and functional role of activating transcription factor 3(ATF3)and tumor protein p53(p53).Results:Cisplatin treatment upregulated DDR and stress response proteins,induced S phase arrest,and increased the SubG1 population,indicating apoptotic cell death.ERK was identified as a critical mediator of cisplatin-induced DNA damage and stress responses.ATF3 expression was significantly elevated in an ERK-dependent manner and required p53 activation.Knockdown of ATF3 reduced cisplatin-induced DNA damage,highlighting its role in the cytotoxic response.Conclusions:Cisplatin induces nephrotoxicity through ERK-and p53-dependent upregulation of ATF3,which is associated with DNA damage and cell death,suggesting a modulatory role in the cellular stress response.These findings provide novel insights into the molecular basis of cisplatin-induced renal injury and suggest potential therapeutic targets to alleviate its adverse effects.
基金supported by the National Natural Science Foundation of China(32471186 and 31771318)the 14th Five-Year-Plan Advantageous and Characteristic Disciplines(Groups)of Colleges and Universities in Hubei Province for Exercise and Brain Science+1 种基金as well as the Leading Talent Program and Innovative Start-up Foundation from Wuhan Sports University to Ning Chensupported by the Hubei Natural Science Foundation(2022CFB929)and China Postdoctoral Science Foundation(2023M732727)to Tong Wu.
文摘It is well known that appropriate aerobic exercise can effectively alleviate fatty liver and enhance brain function.The concept of multi-organ crosstalk coordinating disease progression has become the current research hot topic.However,there remains an urgent need to elucidate its specific mechanisms.This study aimed to explore the impact of a high-fat diet(HFD)on liver health and cognitive function,and to further uncover the regulatory effect of aerobic exercise by liver-specific activating transcription factor 3(Atf3)knockout(ATF3cKO)mice in a“liver-brain”axis mode.The 5-week-old C57BL/6 and ATF3cKO mice were fed with HFD for 32 weeks,and sequentially subjected to aerobic exercise intervention at the 20th week for another 12 consecutive weeks.Meanwhile,C57BL/6 mice were provided with a normal diet as the control group.The functional parameters of liver and brain of all mice were assessed.Cognitive capacity of all mice was assessed by the Morris water maze(MWM).Inflammatory factors in the serum and brain of mice were quantified using enzyme-linked immunosorbent assay(ELISA),and the expression of inflammasomes was detected by immunohistochemistry(IHC).Additionally,the activation of nuclear factor-κB(NF-κB)and phosphoinositide 3-kinase(PI3K)signal pathways was analyzed by Western blotting.In this study,HFD impaired hepatic and brain functions,while aerobic exercise and liver-specific Atf3 knockout suppressed inflammatory factors in the peripheral circulation through hepatoprotective mechanisms,thereby attenuating cerebral inflammation and preserving neurological integrity,as well as mitigating HFD-induced cognitive decline.
文摘目的检测散发性单纯性尿道下裂患者包皮组织中激活转录因子3(Activating transcription factor 3,ATF3)的表达情况,探索ATF3与散发性单纯性尿道下裂之间的关系。方法方便选择2014年1月—2017年1月该院收治的散发性单纯性尿道下裂患者在尿道成形术中切除的包皮组织(共35例,其中轻度10例,中度15例,重度10例)作为尿道下裂组样品,单纯包皮过长(含包茎)患者在包皮环切术中去除的多余的包皮组织(共20例)作为对照组样品。通过RT-PCR方法检测实验组和对照组ATF3 m RNA的表达情况。采用SPSS 12.0统计学软件进行数据录入,构建数据库。结果通过RT-PCR方法测得散发性单纯性尿道下裂患者包皮组织中ATF3 m RNA的相对表达量为:(0.54±0.06),对照组的包皮组织中ATF3 m RNA的相对表达量为:(0.44±0.07),从结果中可以得出在散发性单纯性尿道下裂患者的包皮组织中ATF3的表达情况比正常的尿道组织中明显增加,两组结果比较,差异有统计学意义(t=5.89,P=0.00)。比较不同严重程度中尿道下裂患者ATF3 m RNA相对表达量,不同严重程度相对表达量差异无统计学意义(F=0.13,P=0.88)。结论散发性单纯性尿道下裂患者中ATF3的表达水平明显高于正常对照组,这提示ATF3与散发性单纯性尿道下裂存在着密切的关系。为将来研究ATF3在尿道下裂中产生的相关信号转导通路提供相关实验基础,及研究尿道下裂的发病机制提供理论依据。
