BACKGROUND Insomnia is closely associated with anxiety and depression,with its pathogenesis involving biological,psychological,and social factors.Sini powder and Suanzaoren decoction are clinically effective tradition...BACKGROUND Insomnia is closely associated with anxiety and depression,with its pathogenesis involving biological,psychological,and social factors.Sini powder and Suanzaoren decoction are clinically effective traditional Chinese medicine formulas for insomnia,demonstrating promising bioactivity.However,the capability of the active components of Sini-Suanzaoren decoction(SNSZRD)to cross the bloodbrain barrier(BBB)and their precise molecular mechanisms,particularly concerning the MT-SIRT1 pathway and mitochondrial function,remain largely unexplored.AIM To elucidate the bioactive components of SNSZRD that are capable of BBB penetration and investigate the therapeutic mechanism of SNSZRD against insomnia.METHODS The chemical components of SNSZRD were analyzed through liquid chromatography-mass spectrometry(LC-MS).Male Sprague-Dawley rats were intraperitoneally injected with DL-4-chlorophenylalanine(PCPA)to establish an insomnia model.Rats were divided into control,model,eszopiclone(positive control),and SNSZRD low-/medium-/high-dose groups.Molecular docking predicted BBBpenetrating components and their binding affinity for SIRT1.Key pathways were analyzed through open-field tests,elevated plus-maze tests,pentobarbital-induced sleep experiments,Haematoxylin and eosin staining,Nissl staining,ELISA,Western blot analysis,quantitative real-time PCR,and immunohistochemistry.RESULTS LC-MS identified 1574 compounds in SNSZRD,of which eight prototype components(e.g.,pachymic acid and senkyunolide G)could cross the BBB.Molecular docking revealed that these components formed stable hydrogen bonds with the SIRT1 protein.SNSZRD treatment significantly ameliorated PCPA-induced anxiety-like behaviors and sleep latency/sleep duration,as well as reduced neuronal degeneration and Nissl body loss in the hypothalamus of treated rats.Additionally,SNSZRD elevated serum melatonin and hypothalamus ATP levels and upregulated the mRNA and protein expression levels of arylalkylamine N-acetyltransferase,SIRT1,PPARγcoactivator-1α,nuclear respiratory factor-1,and mitochondrial transcription factor A in the MT-SIRT1-mitochondrial biogenesis pathway.CONCLUSION SNSZRD might exert its therapeutic effects on insomnia by modulating MT-SIRT1 axis-regulated mitochondrial biogenesis in rats and might serve as an effective therapeutic agent for insomnia.展开更多
Subject Code:C08With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Qi Hai(祁海)from the School of Medicine,Tsinghua University revealed a novel mechanism tha...Subject Code:C08With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Qi Hai(祁海)from the School of Medicine,Tsinghua University revealed a novel mechanism that regulates the germinal center reaction,aphysiological process that underlies high-quality展开更多
Ghrelin is a neuropeptide that has various physiological functions and has been demonstrated to be neuroprotective in a number of neurological disease models.However,the underlying mechanisms of ghrelin in Parkinson’...Ghrelin is a neuropeptide that has various physiological functions and has been demonstrated to be neuroprotective in a number of neurological disease models.However,the underlying mechanisms of ghrelin in Parkinson’s disease remain largely unexplored.The current study aimed to study the effects of ghrelin in a 6-hydroxydopamine(6-OHDA)-induced Parkinson’s disease model and evaluate the potential underlying mechanisms.In the present study,we treated an SH-SY5 Y cell model with 6-OHDA,and observed that pretreatment with different concentrations of ghrelin(1,10,and 100 nM)for 30 minutes relieved the neurotoxic effects of 6-OHDA,as revealed by Cell Counting Kit-8 and Annexin V/propidium iodide(PI)apoptosis assays.Reverse transcription quantitative polymerase chain reaction and western blot assay results demonstrated that 6-OHDA treatment upregulatedα-synuclein and lincRNA-p21 and downregulated TG-interacting factor 1(TGIF1),which was predicted as a potential transcription regulator of the gene encodingα-synuclein(SNCA).Ghrelin pretreatment was able to reverse the trends caused by 6-OHDA.The Annexin V/PI apoptosis assay results revealed that inhibiting eitherα-synuclein or lincRNA-p21 expression with small interfering RNA(siRNA)relieved 6-OHDA-induced cell apoptosis.Furthermore,inhibiting lincRNA-p21 also partially upregulated TGIF1.By retrieving information from a bioinformatics database and performing both double luciferase and RNA immunoprecipitation assays,we found that lincRNA-p21 and TGIF1 were able to form a double-stranded RNA-binding protein Staufen homolog 1(STAU1)binding site and further activate the STAU1-mediated mRNA decay pathway.In addition,TGIF1 was able to transcriptionally regulateα-synuclein expression by binding to the promoter of SNCA.The Annexin V/PI apoptosis assay results showed that either knockdown of TGIF1 or overexpression of lincRNA-p21 notably abolished the neuroprotective effects of ghrelin against 6-OHDA-induced neurotoxicity.Collectively,these findings suggest that ghrelin exerts neuroprotective effects against 6-OHDA-induced neurotoxicity via the lincRNA-p21/TGIF1/α-synuclein pathway.展开更多
This study aims to investigate the role of metal regulatory transcription factor 1(MTF1)-mediated metal response in cadmium(Cd)-induced cerebellar injury,and to evaluate the antagonistic effects of nanoselenium(Nano-S...This study aims to investigate the role of metal regulatory transcription factor 1(MTF1)-mediated metal response in cadmium(Cd)-induced cerebellar injury,and to evaluate the antagonistic effects of nanoselenium(Nano-Se)against Cd toxicity.A total of 80 chicks(1 d old,male,Hy-Line Variety White)were randomly allocated to 4 treatment groups for 3 months:the control group(fed with a basic diet,n=20),the Nano-Se group(basic diet with 1 mg/kg nano-Se 1 mg/kg Nano-Se in basic diet,n=20),the NanoSe+Cd group(basic diet with 1 mg/kg Nano-Se and 140 mg/kg Cd Cl_(2),n=20)and the Cd group(basic diet with 140 mg/kg Cd Cl_(2),n=20).The results of the experiment showed that the Purkinje cells were significantly decreased with their degradation and indistinct nucleoli after Cd exposure.Moreover,exposure to Cd caused a significant accumulation of Cd and cupper.However,the contents of Se,iron,and zinc were decreased,thereby disturbing the metal homeostasis in the cerebellum.The Cd exposure also resulted in high levels of malondialdehyde(MDA)and down regulation of selenoprotein transcriptome.Furthermore,the expressions of MTF1,metallothionein 1(MT1),MT2,zinc transporter 3(ZNT3),ZNT5,ZNT10,zrt,irt-like protein 8(ZIP8),ZIP10,transferrin(TF),ferroportin 1(FPN1),ATPase copper transporting beta(ATP7B),and copper uptake protein 1(CTR1)were inhibited by Cd exposure.However,all these changes were significantly alleviated by the supplementation of Nano-Se.This study proved that Cd could disorder metal homeostasis and induce oxidative stress,whereas Nano-Se could relieve all these negative effects caused by Cd via activating the MTF1-mediated metal response in the cerebellum of chicken.展开更多
基金Supported by the Beijing Natural Science Foundation,No.7232289.
文摘BACKGROUND Insomnia is closely associated with anxiety and depression,with its pathogenesis involving biological,psychological,and social factors.Sini powder and Suanzaoren decoction are clinically effective traditional Chinese medicine formulas for insomnia,demonstrating promising bioactivity.However,the capability of the active components of Sini-Suanzaoren decoction(SNSZRD)to cross the bloodbrain barrier(BBB)and their precise molecular mechanisms,particularly concerning the MT-SIRT1 pathway and mitochondrial function,remain largely unexplored.AIM To elucidate the bioactive components of SNSZRD that are capable of BBB penetration and investigate the therapeutic mechanism of SNSZRD against insomnia.METHODS The chemical components of SNSZRD were analyzed through liquid chromatography-mass spectrometry(LC-MS).Male Sprague-Dawley rats were intraperitoneally injected with DL-4-chlorophenylalanine(PCPA)to establish an insomnia model.Rats were divided into control,model,eszopiclone(positive control),and SNSZRD low-/medium-/high-dose groups.Molecular docking predicted BBBpenetrating components and their binding affinity for SIRT1.Key pathways were analyzed through open-field tests,elevated plus-maze tests,pentobarbital-induced sleep experiments,Haematoxylin and eosin staining,Nissl staining,ELISA,Western blot analysis,quantitative real-time PCR,and immunohistochemistry.RESULTS LC-MS identified 1574 compounds in SNSZRD,of which eight prototype components(e.g.,pachymic acid and senkyunolide G)could cross the BBB.Molecular docking revealed that these components formed stable hydrogen bonds with the SIRT1 protein.SNSZRD treatment significantly ameliorated PCPA-induced anxiety-like behaviors and sleep latency/sleep duration,as well as reduced neuronal degeneration and Nissl body loss in the hypothalamus of treated rats.Additionally,SNSZRD elevated serum melatonin and hypothalamus ATP levels and upregulated the mRNA and protein expression levels of arylalkylamine N-acetyltransferase,SIRT1,PPARγcoactivator-1α,nuclear respiratory factor-1,and mitochondrial transcription factor A in the MT-SIRT1-mitochondrial biogenesis pathway.CONCLUSION SNSZRD might exert its therapeutic effects on insomnia by modulating MT-SIRT1 axis-regulated mitochondrial biogenesis in rats and might serve as an effective therapeutic agent for insomnia.
文摘Subject Code:C08With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Qi Hai(祁海)from the School of Medicine,Tsinghua University revealed a novel mechanism that regulates the germinal center reaction,aphysiological process that underlies high-quality
基金supported by the National Natural Science Foundation of China,No.81901417(to XH)the Natural Science Foundation Doctoral Research Initiation Plan of Liaoning Province of China,No.2019-BS-287(to XH)the China Postdoctoral Science Foundation,No.2019M661173(to XH)。
文摘Ghrelin is a neuropeptide that has various physiological functions and has been demonstrated to be neuroprotective in a number of neurological disease models.However,the underlying mechanisms of ghrelin in Parkinson’s disease remain largely unexplored.The current study aimed to study the effects of ghrelin in a 6-hydroxydopamine(6-OHDA)-induced Parkinson’s disease model and evaluate the potential underlying mechanisms.In the present study,we treated an SH-SY5 Y cell model with 6-OHDA,and observed that pretreatment with different concentrations of ghrelin(1,10,and 100 nM)for 30 minutes relieved the neurotoxic effects of 6-OHDA,as revealed by Cell Counting Kit-8 and Annexin V/propidium iodide(PI)apoptosis assays.Reverse transcription quantitative polymerase chain reaction and western blot assay results demonstrated that 6-OHDA treatment upregulatedα-synuclein and lincRNA-p21 and downregulated TG-interacting factor 1(TGIF1),which was predicted as a potential transcription regulator of the gene encodingα-synuclein(SNCA).Ghrelin pretreatment was able to reverse the trends caused by 6-OHDA.The Annexin V/PI apoptosis assay results revealed that inhibiting eitherα-synuclein or lincRNA-p21 expression with small interfering RNA(siRNA)relieved 6-OHDA-induced cell apoptosis.Furthermore,inhibiting lincRNA-p21 also partially upregulated TGIF1.By retrieving information from a bioinformatics database and performing both double luciferase and RNA immunoprecipitation assays,we found that lincRNA-p21 and TGIF1 were able to form a double-stranded RNA-binding protein Staufen homolog 1(STAU1)binding site and further activate the STAU1-mediated mRNA decay pathway.In addition,TGIF1 was able to transcriptionally regulateα-synuclein expression by binding to the promoter of SNCA.The Annexin V/PI apoptosis assay results showed that either knockdown of TGIF1 or overexpression of lincRNA-p21 notably abolished the neuroprotective effects of ghrelin against 6-OHDA-induced neurotoxicity.Collectively,these findings suggest that ghrelin exerts neuroprotective effects against 6-OHDA-induced neurotoxicity via the lincRNA-p21/TGIF1/α-synuclein pathway.
基金National Natural Science Foundation of China(No.32172932 and No.32102739)Key Program of Natural Science Foundation of Heilongjiang Province of China(No.ZD2021C003)+5 种基金High-level Talent Scientific Research Start-up Foundation of Wanxi University(No.WGKQ2022031)China Agricultural Research System of MOF and MARA(No.CARS35)Distinguished Professor of Longjiang Scholars Support Project(No.T201908)Outstanding Talents of Henan Agricultural University(Grant No.30500997)Project funded by China Postdoctoral Science Foundation(2021M690925)Heilongjiang Touyan Innovation Team Program。
文摘This study aims to investigate the role of metal regulatory transcription factor 1(MTF1)-mediated metal response in cadmium(Cd)-induced cerebellar injury,and to evaluate the antagonistic effects of nanoselenium(Nano-Se)against Cd toxicity.A total of 80 chicks(1 d old,male,Hy-Line Variety White)were randomly allocated to 4 treatment groups for 3 months:the control group(fed with a basic diet,n=20),the Nano-Se group(basic diet with 1 mg/kg nano-Se 1 mg/kg Nano-Se in basic diet,n=20),the NanoSe+Cd group(basic diet with 1 mg/kg Nano-Se and 140 mg/kg Cd Cl_(2),n=20)and the Cd group(basic diet with 140 mg/kg Cd Cl_(2),n=20).The results of the experiment showed that the Purkinje cells were significantly decreased with their degradation and indistinct nucleoli after Cd exposure.Moreover,exposure to Cd caused a significant accumulation of Cd and cupper.However,the contents of Se,iron,and zinc were decreased,thereby disturbing the metal homeostasis in the cerebellum.The Cd exposure also resulted in high levels of malondialdehyde(MDA)and down regulation of selenoprotein transcriptome.Furthermore,the expressions of MTF1,metallothionein 1(MT1),MT2,zinc transporter 3(ZNT3),ZNT5,ZNT10,zrt,irt-like protein 8(ZIP8),ZIP10,transferrin(TF),ferroportin 1(FPN1),ATPase copper transporting beta(ATP7B),and copper uptake protein 1(CTR1)were inhibited by Cd exposure.However,all these changes were significantly alleviated by the supplementation of Nano-Se.This study proved that Cd could disorder metal homeostasis and induce oxidative stress,whereas Nano-Se could relieve all these negative effects caused by Cd via activating the MTF1-mediated metal response in the cerebellum of chicken.
