Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood.The results of our recent exp...Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood.The results of our recent experiments indicated that curcumin could protect dopaminergic neurons from apoptosis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)mouse model of Parkinson’s disease(PD).The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by curcumin in MPTP mouse model.Further studies showed that curcumin inhibited JNKs hyperphosphorylation induced by MPTP treatment.JNKs phosphorylation can cause translocation of Bax to mitochondria and the release of cytochrome c which both ultimately contribute to mitochondria-mediated apoptosis.These pro-apoptosis effect can be diminished by curcumin.Our experiments demonstrated that curcumin can prevent nigrostriatal degeneration by inhibiting the dysfunction of mitochondrial through suppressing hyperphosphorylation of JNKs induced by MPTP.Our results suggested that JNKs/mitochondria pathway may be a novel target in the treatment of PD patients.展开更多
前期研究发现骨形态发生蛋白9(bone morphogenetic protein 9,BMP9)除了通过经典Smad途径外,也可通过丝裂原活化蛋白激酶(mitogen activated protein kinases,MAPKs)中的p38激酶途径调控间充质干细胞成骨分化.本研究继续探讨MAPKs的重...前期研究发现骨形态发生蛋白9(bone morphogenetic protein 9,BMP9)除了通过经典Smad途径外,也可通过丝裂原活化蛋白激酶(mitogen activated protein kinases,MAPKs)中的p38激酶途径调控间充质干细胞成骨分化.本研究继续探讨MAPKs的重要成员c-Jun氨基末端激酶(c-Jun N-terminal kinases,JNKs)对于BMP9诱导间充质干细胞成骨分化的调控作用.利用BMP9重组腺病毒感染间充质干细胞,通过体外细胞实验和体内动物实验,初步分析BMP9是否可通过JNKs激酶途径调控间充质干细胞成骨分化.结果表明:BMP9可通过促进JNKs激酶磷酸化而导致其活化;JNKs抑制剂SP600125可抑制由BMP9诱导的间充质干细胞的碱性磷酸酶(alkaline phosphatase,ALP)活性、骨桥蛋白(osteocpontin,OPN)和骨钙素(osteocalcin,OCN)表达以及钙盐沉积;利用抑制剂SP600125抑制JNKs激酶活性后,BMP9诱导Runx2的表达和转录活性,以及Smad经典途径的激活也相应受到抑制;RNA干扰导致JNKs基因沉默同样也可抑制BMP9诱导的间充质干细胞成骨分化以及裸鼠皮下异位成骨.因此,BMP9可通过活化JNKs激酶途径,从而调控间充质干细胞成骨分化.展开更多
Running is believed to be beneficial for human health. Many studies have focused on the neuroprotective effects of voluntary running on animal models. There were both primary and secondary degeneration in neurodegener...Running is believed to be beneficial for human health. Many studies have focused on the neuroprotective effects of voluntary running on animal models. There were both primary and secondary degeneration in neurodegenerative diseases, including glaucoma. However, whether running can delay primary or secondary degeneration or both of them was not clear. Partial optic nerve transection model is a valuable glaucoma model for studying both primary and secondary degeneration because it can separate primary(mainly in the superior retina) from secondary(mainly in the inferior retina) degeneration. Therefore, we compared the survival of retinal ganglion cells between Sprague-Dawley rat runners and non-runners both in the superior and inferior retinas. Excitotoxicity, oxidative stress, and apoptosis are involved in the degeneration of retinal ganglion cells in glaucoma. So we also used western immunoblotting to compare the expression of some proteins involved in apoptosis(phospho-c-Jun N-terminal kinases, p-JNKs), oxidative stress(manganese superoxide dismutase, MnSOD) and excitotoxicity(glutamine synthetase) between runners and non-runners after partial optic nerve transection. Results showed that voluntary running delayed the death of retinal ganglion cells vulnerable to primary degeneration but not those to secondary degeneration. In addition, voluntary running decreased the expression of glutamine synthetase, but not the expression of p-JNKs and MnSOD in the superior retina after partial optic nerve transection. These results illustrated that primary degeneration of retinal ganglion cells might be mainly related with excitotoxicity rather than oxidative stress; and the voluntary running could down-regulate excitotoxicity to delay the primary degeneration of retinal ganglion cells after partial optic nerve transection.展开更多
BACKGROUND Human spermatogonial stem cells(SSCs)are the basis of spermatogenesis.However,little is known about the developmental regulatory mechanisms of SSC due to sample origin and species differences.AIM To investi...BACKGROUND Human spermatogonial stem cells(SSCs)are the basis of spermatogenesis.However,little is known about the developmental regulatory mechanisms of SSC due to sample origin and species differences.AIM To investigates the mechanisms involved in the proliferation of human SSC.METHODS The expression of mitogen-activated protein kinase kinase 7(MKK7)in human testis was identified using immunohistochemistry and western blotting(WB).MKK7 was knocked down using small interfering RNA,and cell proliferation and apoptosis were detected by WB,EdU,cell counting kit-8 and fluorescenceactivated cell sorting.After bioinformatic analysis,the interaction of MKK7 with c-Jun N-terminal kinases(JNKs)was verified by protein co-immunoprecipitation and WB.The phosphorylation of JNKs was inhibited by SP600125,and the phenotypic changes were detected by WB,cell counting kit-8 and fluorescenceactivated cell sorting.RESULTS MKK7 is mainly expressed in human SSCs,and MKK7 knockdown inhibits SSC proliferation and promotes their apoptosis.MKK7 mediated the phosphorylation of JNKs,and after inhibiting the phosphorylation of JNKs,the phenotypic changes of the cells were similar to those after MKK7 downregulation.The expression of MKK7 was significantly downregulated in patients with abnormal spermatogenesis,suggesting that abnormal MKK7 may be associated with spermatogenesis impairment.CONCLUSION MKK7 regulates the proliferation and apoptosis of human SSC by mediating the phosphorylation of JNKs.展开更多
c-Jun,the most extensively studied protein of the activator protein-1(AP-1)complex,is involved in numerous cell activities,such as proliferation,apoptosis,survival,tumorigenesis and tissue morphogenesis.Earlier studie...c-Jun,the most extensively studied protein of the activator protein-1(AP-1)complex,is involved in numerous cell activities,such as proliferation,apoptosis,survival,tumorigenesis and tissue morphogenesis.Earlier studies focused on the structure and function have led to the identification of c-Jun as a basic leucine zipper(bZIP)transcription factor that acts as homo-or heterodimer,binding to DNA and regulating gene transcription.Later on,it was shown that extracellular signals can induce post-translational modifications of c-Jun,resulting in altered transcriptional activity and target gene expression.More recent work has uncovered multiple layers of a complex regulatory scheme in which c-Jun is able to crosstalk,amplify and integrate different signals for tissue development and disease.One example of such scheme is the autocrine amplification loop,in which signal-induced AP-1 activates the c-Jun gene promoter,while increased c-Jun expression feedbacks to potentiate AP-1 activity.Another example of such scheme,based on recent characterization of gene knockout mice,is that c-Jun integrates signals of several developmental pathways,including EGFR-ERK,EGFR-RhoA-ROCK,and activin B-MAP3K1-JNK for embryonic eyelid closure.After more than two decades of extensive research,c-Jun remains at the center stage of a molecular network with mysterious functional properties,some of which are yet to be discovered.In this article,we will provide a brief historical overview of studies on c-Jun regulation and function,and use eyelid development as an example to illustrate the complexity of c-Jun crosstalking with signaling pathways.展开更多
The levels of the products of RNA polymeraseⅢ-dependent genes(PolⅢgenes),including tRNAs and 5S rRNA,are elevated in transformed and tumor cells,which potentiate tumorigenesis.TFIIB-related factor 1(Brf1)is a key tr...The levels of the products of RNA polymeraseⅢ-dependent genes(PolⅢgenes),including tRNAs and 5S rRNA,are elevated in transformed and tumor cells,which potentiate tumorigenesis.TFIIB-related factor 1(Brf1)is a key transcription factor and specifically regulates the transcription of PolⅢgenes.In vivo and in vitro studies have demonstrated that a decrease in Brf1 reduces PolⅢgene transcription and is sufficient for inhibiting cell transformation and tumor formation.Emerging evidence indicates that dysregulation of Brf1 and PolⅢgenes is linked to the development of hepatocellular carcinoma(HCC)in humans and animals.We have reported that Brf1 is overexpressed in human liver cancer patients and that those with high Brf1 levels have shorter survivals.This review summarizes the effects of dysregulation of these genes on HCC and their regulation by signaling pathways and epigenetics.These novel data should help us determine the molecular mechanisms of HCC from a different perspective and guide the development of therapeutic approaches for HCC patients.展开更多
基金This work was supported by grants from the National Program of Basic Research(2010CB945200,2011CB504104)of ChinaNational Natural Science Fund(34900454,30900454,30971031)+4 种基金Key Discipline Program of Shanghai Municipality(S30202)Shanghai Key Project of Basic Science Research(10411954500)Program for Outstanding Medical Academic Leader(LJ 06003)Research Fund for the Doctoral Program of Higher Education of China(20090073120090)Special funding for original sci-tech research supported by Shanghai Municipal Education Commission(09YZ87).
文摘Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood.The results of our recent experiments indicated that curcumin could protect dopaminergic neurons from apoptosis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)mouse model of Parkinson’s disease(PD).The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by curcumin in MPTP mouse model.Further studies showed that curcumin inhibited JNKs hyperphosphorylation induced by MPTP treatment.JNKs phosphorylation can cause translocation of Bax to mitochondria and the release of cytochrome c which both ultimately contribute to mitochondria-mediated apoptosis.These pro-apoptosis effect can be diminished by curcumin.Our experiments demonstrated that curcumin can prevent nigrostriatal degeneration by inhibiting the dysfunction of mitochondrial through suppressing hyperphosphorylation of JNKs induced by MPTP.Our results suggested that JNKs/mitochondria pathway may be a novel target in the treatment of PD patients.
文摘前期研究发现骨形态发生蛋白9(bone morphogenetic protein 9,BMP9)除了通过经典Smad途径外,也可通过丝裂原活化蛋白激酶(mitogen activated protein kinases,MAPKs)中的p38激酶途径调控间充质干细胞成骨分化.本研究继续探讨MAPKs的重要成员c-Jun氨基末端激酶(c-Jun N-terminal kinases,JNKs)对于BMP9诱导间充质干细胞成骨分化的调控作用.利用BMP9重组腺病毒感染间充质干细胞,通过体外细胞实验和体内动物实验,初步分析BMP9是否可通过JNKs激酶途径调控间充质干细胞成骨分化.结果表明:BMP9可通过促进JNKs激酶磷酸化而导致其活化;JNKs抑制剂SP600125可抑制由BMP9诱导的间充质干细胞的碱性磷酸酶(alkaline phosphatase,ALP)活性、骨桥蛋白(osteocpontin,OPN)和骨钙素(osteocalcin,OCN)表达以及钙盐沉积;利用抑制剂SP600125抑制JNKs激酶活性后,BMP9诱导Runx2的表达和转录活性,以及Smad经典途径的激活也相应受到抑制;RNA干扰导致JNKs基因沉默同样也可抑制BMP9诱导的间充质干细胞成骨分化以及裸鼠皮下异位成骨.因此,BMP9可通过活化JNKs激酶途径,从而调控间充质干细胞成骨分化.
基金supported by the National Natural Science Foundation of China,No.81501091(to HYL)Natural Science Foundation of Guangdong Province of China,No.2015A030310201(to HYL)+4 种基金Medical Scientific Research Foundation of Guangdong Province of China,No.A2015393(to HYL)funds of Leading Talents of Guangdong Province of China,No.2013(to KFS)Programme of Introducing Talents of Discipline to Universities,No.B14036(to KFS)National Basic Research Program of China(973 Program),No.2015CB351800(to KFS)Fundamental Research Funds for the Central Universities,No.21609101(to KFS)
文摘Running is believed to be beneficial for human health. Many studies have focused on the neuroprotective effects of voluntary running on animal models. There were both primary and secondary degeneration in neurodegenerative diseases, including glaucoma. However, whether running can delay primary or secondary degeneration or both of them was not clear. Partial optic nerve transection model is a valuable glaucoma model for studying both primary and secondary degeneration because it can separate primary(mainly in the superior retina) from secondary(mainly in the inferior retina) degeneration. Therefore, we compared the survival of retinal ganglion cells between Sprague-Dawley rat runners and non-runners both in the superior and inferior retinas. Excitotoxicity, oxidative stress, and apoptosis are involved in the degeneration of retinal ganglion cells in glaucoma. So we also used western immunoblotting to compare the expression of some proteins involved in apoptosis(phospho-c-Jun N-terminal kinases, p-JNKs), oxidative stress(manganese superoxide dismutase, MnSOD) and excitotoxicity(glutamine synthetase) between runners and non-runners after partial optic nerve transection. Results showed that voluntary running delayed the death of retinal ganglion cells vulnerable to primary degeneration but not those to secondary degeneration. In addition, voluntary running decreased the expression of glutamine synthetase, but not the expression of p-JNKs and MnSOD in the superior retina after partial optic nerve transection. These results illustrated that primary degeneration of retinal ganglion cells might be mainly related with excitotoxicity rather than oxidative stress; and the voluntary running could down-regulate excitotoxicity to delay the primary degeneration of retinal ganglion cells after partial optic nerve transection.
基金Supported by China Postdoctoral Science Foundation,No.2019M661521and National Natural Science Foundation of China,No.82001634.
文摘BACKGROUND Human spermatogonial stem cells(SSCs)are the basis of spermatogenesis.However,little is known about the developmental regulatory mechanisms of SSC due to sample origin and species differences.AIM To investigates the mechanisms involved in the proliferation of human SSC.METHODS The expression of mitogen-activated protein kinase kinase 7(MKK7)in human testis was identified using immunohistochemistry and western blotting(WB).MKK7 was knocked down using small interfering RNA,and cell proliferation and apoptosis were detected by WB,EdU,cell counting kit-8 and fluorescenceactivated cell sorting.After bioinformatic analysis,the interaction of MKK7 with c-Jun N-terminal kinases(JNKs)was verified by protein co-immunoprecipitation and WB.The phosphorylation of JNKs was inhibited by SP600125,and the phenotypic changes were detected by WB,cell counting kit-8 and fluorescenceactivated cell sorting.RESULTS MKK7 is mainly expressed in human SSCs,and MKK7 knockdown inhibits SSC proliferation and promotes their apoptosis.MKK7 mediated the phosphorylation of JNKs,and after inhibiting the phosphorylation of JNKs,the phenotypic changes of the cells were similar to those after MKK7 downregulation.The expression of MKK7 was significantly downregulated in patients with abnormal spermatogenesis,suggesting that abnormal MKK7 may be associated with spermatogenesis impairment.CONCLUSION MKK7 regulates the proliferation and apoptosis of human SSC by mediating the phosphorylation of JNKs.
文摘c-Jun,the most extensively studied protein of the activator protein-1(AP-1)complex,is involved in numerous cell activities,such as proliferation,apoptosis,survival,tumorigenesis and tissue morphogenesis.Earlier studies focused on the structure and function have led to the identification of c-Jun as a basic leucine zipper(bZIP)transcription factor that acts as homo-or heterodimer,binding to DNA and regulating gene transcription.Later on,it was shown that extracellular signals can induce post-translational modifications of c-Jun,resulting in altered transcriptional activity and target gene expression.More recent work has uncovered multiple layers of a complex regulatory scheme in which c-Jun is able to crosstalk,amplify and integrate different signals for tissue development and disease.One example of such scheme is the autocrine amplification loop,in which signal-induced AP-1 activates the c-Jun gene promoter,while increased c-Jun expression feedbacks to potentiate AP-1 activity.Another example of such scheme,based on recent characterization of gene knockout mice,is that c-Jun integrates signals of several developmental pathways,including EGFR-ERK,EGFR-RhoA-ROCK,and activin B-MAP3K1-JNK for embryonic eyelid closure.After more than two decades of extensive research,c-Jun remains at the center stage of a molecular network with mysterious functional properties,some of which are yet to be discovered.In this article,we will provide a brief historical overview of studies on c-Jun regulation and function,and use eyelid development as an example to illustrate the complexity of c-Jun crosstalking with signaling pathways.
基金This work was supported in part by NIAAA/NIH grants AA017288,AA021114,AA023247,and AA024169 to SZ.
文摘The levels of the products of RNA polymeraseⅢ-dependent genes(PolⅢgenes),including tRNAs and 5S rRNA,are elevated in transformed and tumor cells,which potentiate tumorigenesis.TFIIB-related factor 1(Brf1)is a key transcription factor and specifically regulates the transcription of PolⅢgenes.In vivo and in vitro studies have demonstrated that a decrease in Brf1 reduces PolⅢgene transcription and is sufficient for inhibiting cell transformation and tumor formation.Emerging evidence indicates that dysregulation of Brf1 and PolⅢgenes is linked to the development of hepatocellular carcinoma(HCC)in humans and animals.We have reported that Brf1 is overexpressed in human liver cancer patients and that those with high Brf1 levels have shorter survivals.This review summarizes the effects of dysregulation of these genes on HCC and their regulation by signaling pathways and epigenetics.These novel data should help us determine the molecular mechanisms of HCC from a different perspective and guide the development of therapeutic approaches for HCC patients.
