目的探讨发育及DNA损伤反应调节基因1（regulated in development and DNA damage responses 1,REDD1）在人胎盘组织中的表达及其意义。方法选择早孕绒毛组织（6~10周）、中孕（24~28周）及足月晚孕（38~39周）胎盘组织各8例,采用免疫...目的探讨发育及DNA损伤反应调节基因1（regulated in development and DNA damage responses 1,REDD1）在人胎盘组织中的表达及其意义。方法选择早孕绒毛组织（6~10周）、中孕（24~28周）及足月晚孕（38~39周）胎盘组织各8例,采用免疫组织化学染色技术,Western blot杂交以及实时荧光定量聚合酶链反应（polymerase chain reaction,PCR）检测REDD1 mRNA及蛋白在不同孕周胎盘组织中的表达。结果 REDD1蛋白表达于胎盘滋养细胞的细胞质中,随着孕周增加,REDD1在mRNA及蛋白在胎盘组织中的表达呈现下降趋势。结论 REDD1可能早期参与了滋养细胞侵袭的过程。展开更多
Although cisplatin is one of the chemotherapeutics most frequently used in oral squamous cell carcinoma(OSCC)treatment,it exerts multiple side effects and poor chemosensitivity.Nitrate reportedly demonstrates several ...Although cisplatin is one of the chemotherapeutics most frequently used in oral squamous cell carcinoma(OSCC)treatment,it exerts multiple side effects and poor chemosensitivity.Nitrate reportedly demonstrates several beneficial biological functions,and synthesized nitrates enhance the therapeutic efficacy of chemotherapy.However,the role of inorganic nitrate in cisplatin chemotherapy remains unclear.We therefore investigated the effect of inorganic nitrate exerted on cisplatin sensitivity in OSCC.We found that nitrate did not affect OSCC cell growth and apoptosis in OSCC cells and OSCC xenograft tumor animal studies.Cisplatin induced REDD1 expression and AKT activation in OSCC.However,nitrate could increase cisplatin chemosensitivity,reduce its REDD1 expression,and attenuate AKT signaling activation in OSCC cells.Dysregulation of high levels of REDD1,which could enhance AKT activation,was positively associated with poor prognosis in OSCC patients.Thus,reduced REDD1 expression and retarded AKT activation induced by inorganic nitrate might be a new potential approach to the sensitization of oral cancer to cisplatin treatment in the future.展开更多
Maternal stress during pregnancy is prevailing worldwide, which exposes fetuses to intrauterine hyper glucocorticoids(GC), programming offspring to obesity and metabolic diseases. Despite the importance of brown adipo...Maternal stress during pregnancy is prevailing worldwide, which exposes fetuses to intrauterine hyper glucocorticoids(GC), programming offspring to obesity and metabolic diseases. Despite the importance of brown adipose tissue(BAT) in maintaining long-term metabolic health, impacts of prenatal hyper GC on postnatal BAT thermogenesis and underlying regulations remain poorly defined. Pregnant mice were administrated with synthetic GC dexamethasone(DEX) at levels comparable to fetal GC exposure of stressed mothers. Prenatal GC exposure dose-dependently reduced BAT thermogenic activity, contributing to lower body temperature and higher mortality of neonates;such difference was abolished under thermoneutrality, underscoring BAT deficiency was the major contributor to adverse changes in postnatal thermogenesis due to excessive GC. Prenatal GC exposure highly activated Redd1 expression and reduced Ppargc1 a transcription from the alternative promoter(Ppargc1 a-AP) in neonatal BAT. During brown adipocyte differentiation, ectopic Redd1 expression reduced Ppargc1 a-AP expression and mitochondrial biogenesis;and the inhibitory effects of GC on mitochondrial biogenesis and Ppargc1 a-AP expression were blocked by Redd1 ablation. Redd1 reduced protein kinase A phosphorylation and suppressed cyclic adenosine monophosphate(c AMP)-responsive element-binding protein(CREB) binding to the c AMP regulatory element(CRE) in Ppargc1 a-AP promoter, leading to Ppargc1 a-AP inactivation. In summary, excessive maternal GC exposure during pregnancy dysregulates Redd1-Ppargc1 a-AP axis, which impairs fetal BAT development, hampering postnatal thermogenic adaptation and metabolic health of offspring.展开更多
文摘目的探讨发育及DNA损伤反应调节基因1（regulated in development and DNA damage responses 1,REDD1）在人胎盘组织中的表达及其意义。方法选择早孕绒毛组织（6~10周）、中孕（24~28周）及足月晚孕（38~39周）胎盘组织各8例,采用免疫组织化学染色技术,Western blot杂交以及实时荧光定量聚合酶链反应（polymerase chain reaction,PCR）检测REDD1 mRNA及蛋白在不同孕周胎盘组织中的表达。结果 REDD1蛋白表达于胎盘滋养细胞的细胞质中,随着孕周增加,REDD1在mRNA及蛋白在胎盘组织中的表达呈现下降趋势。结论 REDD1可能早期参与了滋养细胞侵袭的过程。
基金This work was supported by the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-031)Beijing Hospitals Authority of Hospitals’Mission Plan(SML20151401,Capital Medical University)+1 种基金Beijing Municipality Government grants(Beijing Scholar Program—PXM2020_014226_000005,PXM2019_014226_000039,PXM2019_014226_000011,PXM2018_014226_000021,PXM2017_014226_000023,PXM2018_193312_000006_0028S643_FCG,PXM2016_014226_000034)the National Natural Science Foundation of China(91649124).
文摘Although cisplatin is one of the chemotherapeutics most frequently used in oral squamous cell carcinoma(OSCC)treatment,it exerts multiple side effects and poor chemosensitivity.Nitrate reportedly demonstrates several beneficial biological functions,and synthesized nitrates enhance the therapeutic efficacy of chemotherapy.However,the role of inorganic nitrate in cisplatin chemotherapy remains unclear.We therefore investigated the effect of inorganic nitrate exerted on cisplatin sensitivity in OSCC.We found that nitrate did not affect OSCC cell growth and apoptosis in OSCC cells and OSCC xenograft tumor animal studies.Cisplatin induced REDD1 expression and AKT activation in OSCC.However,nitrate could increase cisplatin chemosensitivity,reduce its REDD1 expression,and attenuate AKT signaling activation in OSCC cells.Dysregulation of high levels of REDD1,which could enhance AKT activation,was positively associated with poor prognosis in OSCC patients.Thus,reduced REDD1 expression and retarded AKT activation induced by inorganic nitrate might be a new potential approach to the sensitization of oral cancer to cisplatin treatment in the future.
基金This work was supported by the National Institute of Health(NIH R01-HD067449)。
文摘Maternal stress during pregnancy is prevailing worldwide, which exposes fetuses to intrauterine hyper glucocorticoids(GC), programming offspring to obesity and metabolic diseases. Despite the importance of brown adipose tissue(BAT) in maintaining long-term metabolic health, impacts of prenatal hyper GC on postnatal BAT thermogenesis and underlying regulations remain poorly defined. Pregnant mice were administrated with synthetic GC dexamethasone(DEX) at levels comparable to fetal GC exposure of stressed mothers. Prenatal GC exposure dose-dependently reduced BAT thermogenic activity, contributing to lower body temperature and higher mortality of neonates;such difference was abolished under thermoneutrality, underscoring BAT deficiency was the major contributor to adverse changes in postnatal thermogenesis due to excessive GC. Prenatal GC exposure highly activated Redd1 expression and reduced Ppargc1 a transcription from the alternative promoter(Ppargc1 a-AP) in neonatal BAT. During brown adipocyte differentiation, ectopic Redd1 expression reduced Ppargc1 a-AP expression and mitochondrial biogenesis;and the inhibitory effects of GC on mitochondrial biogenesis and Ppargc1 a-AP expression were blocked by Redd1 ablation. Redd1 reduced protein kinase A phosphorylation and suppressed cyclic adenosine monophosphate(c AMP)-responsive element-binding protein(CREB) binding to the c AMP regulatory element(CRE) in Ppargc1 a-AP promoter, leading to Ppargc1 a-AP inactivation. In summary, excessive maternal GC exposure during pregnancy dysregulates Redd1-Ppargc1 a-AP axis, which impairs fetal BAT development, hampering postnatal thermogenic adaptation and metabolic health of offspring.
