Energy status is linked to the production of reactive oxygen species(ROS)in macrophages,which is elevated in obesity.However,it is unclear how ROS production is upregulated in macrophages in response to energy overloa...Energy status is linked to the production of reactive oxygen species(ROS)in macrophages,which is elevated in obesity.However,it is unclear how ROS production is upregulated in macrophages in response to energy overload for mediating the development of obesity.Here,we show that the Rab-GTPase activating protein(Rab GAP)TBC1D1,a substrate of the energy sensor AMP-activated protein kinase(AMPK),is a critical regulator of macrophage ROS production and consequent adipose inflammation for obesity development.TBC1D1 deletion decreases,whereas an energy overload-mimetic non-phosphorylatable TBC1D1^(S231A)Amutation increases,ROS production and M1-like polarization in macrophages.Mechanistically,TBC1D1 and its downstream target Rab8a form an energy-responsive complex with NOX2 for ROS generation.Transplantation of TBC1D1^(S231A)bone marrow aggravates diet-induced obesity whereas treatment with an ultra-stable Tt SOD for removal of ROS selectively in macrophages alleviates both TBC1D1~(S231A)mutation-and diet-induced obesity.Our findings therefore have implications for drug discovery to combat obesity.展开更多
Objective:To investigate the effect of honokiol on oxidative damage in HaCaT human keratinocytes.Methods:HaCaT cells were exposed to hydrogen peroxide(H_(2)O_(2)),following pretreatment with various concentrations of ...Objective:To investigate the effect of honokiol on oxidative damage in HaCaT human keratinocytes.Methods:HaCaT cells were exposed to hydrogen peroxide(H_(2)O_(2)),following pretreatment with various concentrations of honokiol.The alleviating effects of honokiol on HaCaT cell viability and cell death,reactive oxygen species(ROS)production,DNA damage,mitochondrial dynamics,and inhibition of adenosine triphoaphate production against H_(2)O_(2)were investigated.Western blotting analysis was used to analyze the expression levels of specific proteins.Results:Honokiol suppressed H_(2)O_(2)-induced cytotoxicity and DNA damage by blocking abnormal ROS accumulation.Honokiol also prevented apoptosis by inhibiting loss of mitochondrial membrane potential and release of cytochrome c from the mitochondria into the cytosol,decreasing the Bax/Bcl-2 ratio,and reducing the activity of caspase-3 in H_(2)O_(2)-stimulated HaCaT cells.In addition,honokiol attenuated H_(2)O_(2)-induced reduction of adenosine triphosphate content,and activation of AMP-activated protein kinase(AMPK)was markedly promoted by honokiol in H_(2)O_(2)-stimulated cells.Importantly,the anti-apoptosis and anti-proliferative activity of honokiol against H_(2)O_(2)was further enhanced by adding an activator of AMPK,indicating that honokiol activated AMPK in HaCaT keratinocytes to protect against oxidative damage.Conclusions:The present results indicate that honokiol may be useful as a potential therapeutic agent against various oxidative stress-related skin diseases.展开更多
Lung cancer causes more deaths than breast, colorectal and prostate cancers combined. Despite major advances in targeted therapy in a subset of lung adenocarcinomas, the overall 5-year survival rate for lung cancer wo...Lung cancer causes more deaths than breast, colorectal and prostate cancers combined. Despite major advances in targeted therapy in a subset of lung adenocarcinomas, the overall 5-year survival rate for lung cancer worldwide has not significantly changed for the last few decades. DNA repair deficiency is known to contribute to lung cancer development. In fact, human polymorphisms in DNA repair genes such as xeroderma pigmentosum group C （XPC） are highly associated with lung cancer incidence. However, the direct genetic evidence for the role of XPC for lung cancer development is still lacking. Mutations of the Kirsten rat sarcoma viral oncogene homolog （Kras） or its downstream effector genes occur in almost all lung cancer cells, and there are a number of mouse models for lung cancer with these mutations. Using activated Kras, KrasTM, as a driver for lung cancer development in mice, we showed for the first time that mice with KrasTM and Xpc knockout had worst outcomes in lung cancer development, and this phenotype was associated with accumulated DNA damage. Using cultured ceils, we demonstrated that induced expression of oncogenic KR.ASG12v led to increased levels of reactive oxygen species （ROS） as well as DNA damage, and both can be suppressed by anti-oxidants. Our results suggest that XPC may help repair DNA damage caused by KRAS-mediated production of ROS.展开更多
基金the Ministry of Science and Technology of China(Grant Nos.2018YFA0801100 and 2021YFF0702100)the National Natural Science Foundation of China(Grant Nos.32025019 and 31970719 to S.C.,31971067)the Fundamental Research Funds for the Central Universities(021414380533,021414380505)for financial support。
文摘Energy status is linked to the production of reactive oxygen species(ROS)in macrophages,which is elevated in obesity.However,it is unclear how ROS production is upregulated in macrophages in response to energy overload for mediating the development of obesity.Here,we show that the Rab-GTPase activating protein(Rab GAP)TBC1D1,a substrate of the energy sensor AMP-activated protein kinase(AMPK),is a critical regulator of macrophage ROS production and consequent adipose inflammation for obesity development.TBC1D1 deletion decreases,whereas an energy overload-mimetic non-phosphorylatable TBC1D1^(S231A)Amutation increases,ROS production and M1-like polarization in macrophages.Mechanistically,TBC1D1 and its downstream target Rab8a form an energy-responsive complex with NOX2 for ROS generation.Transplantation of TBC1D1^(S231A)bone marrow aggravates diet-induced obesity whereas treatment with an ultra-stable Tt SOD for removal of ROS selectively in macrophages alleviates both TBC1D1~(S231A)mutation-and diet-induced obesity.Our findings therefore have implications for drug discovery to combat obesity.
文摘Objective:To investigate the effect of honokiol on oxidative damage in HaCaT human keratinocytes.Methods:HaCaT cells were exposed to hydrogen peroxide(H_(2)O_(2)),following pretreatment with various concentrations of honokiol.The alleviating effects of honokiol on HaCaT cell viability and cell death,reactive oxygen species(ROS)production,DNA damage,mitochondrial dynamics,and inhibition of adenosine triphoaphate production against H_(2)O_(2)were investigated.Western blotting analysis was used to analyze the expression levels of specific proteins.Results:Honokiol suppressed H_(2)O_(2)-induced cytotoxicity and DNA damage by blocking abnormal ROS accumulation.Honokiol also prevented apoptosis by inhibiting loss of mitochondrial membrane potential and release of cytochrome c from the mitochondria into the cytosol,decreasing the Bax/Bcl-2 ratio,and reducing the activity of caspase-3 in H_(2)O_(2)-stimulated HaCaT cells.In addition,honokiol attenuated H_(2)O_(2)-induced reduction of adenosine triphosphate content,and activation of AMP-activated protein kinase(AMPK)was markedly promoted by honokiol in H_(2)O_(2)-stimulated cells.Importantly,the anti-apoptosis and anti-proliferative activity of honokiol against H_(2)O_(2)was further enhanced by adding an activator of AMPK,indicating that honokiol activated AMPK in HaCaT keratinocytes to protect against oxidative damage.Conclusions:The present results indicate that honokiol may be useful as a potential therapeutic agent against various oxidative stress-related skin diseases.
基金supported by National Cancer Institute (Nos. R01CA155086 and R01CA94160) to J. Xie,National Institute of Environmental Sciences (No. RO1 ES018948) to I. Boldorgh
文摘Lung cancer causes more deaths than breast, colorectal and prostate cancers combined. Despite major advances in targeted therapy in a subset of lung adenocarcinomas, the overall 5-year survival rate for lung cancer worldwide has not significantly changed for the last few decades. DNA repair deficiency is known to contribute to lung cancer development. In fact, human polymorphisms in DNA repair genes such as xeroderma pigmentosum group C （XPC） are highly associated with lung cancer incidence. However, the direct genetic evidence for the role of XPC for lung cancer development is still lacking. Mutations of the Kirsten rat sarcoma viral oncogene homolog （Kras） or its downstream effector genes occur in almost all lung cancer cells, and there are a number of mouse models for lung cancer with these mutations. Using activated Kras, KrasTM, as a driver for lung cancer development in mice, we showed for the first time that mice with KrasTM and Xpc knockout had worst outcomes in lung cancer development, and this phenotype was associated with accumulated DNA damage. Using cultured ceils, we demonstrated that induced expression of oncogenic KR.ASG12v led to increased levels of reactive oxygen species （ROS） as well as DNA damage, and both can be suppressed by anti-oxidants. Our results suggest that XPC may help repair DNA damage caused by KRAS-mediated production of ROS.
