Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. Howev-er, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evalua...Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. Howev-er, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evaluate the therapeutic effects and mechanisms of action of apolipoprotein E mimetic peptide on diffuse brain injury. Apolipoprotein E mimetic peptide was administered into the caudal vein of rats with diffuse brain injury before and after injury. We found that apo-lipoprotein E mimetic peptide signiifcantly decreased the number of apoptotic neurons, reduced extracellular signal-regulated kinase1/2 phosphorylation, down-regulated Bax and cytochrome c expression, decreased malondialdehyde content, and increased superoxide dismutase activity in a dose-dependent manner. These experimental ifndings demonstrate that apolipoprotein E mimetic peptide improves learning and memory function and protects against diffuse brain injury-induced apoptosis by inhibiting the extracellular signal-regulated kinase1/2-Bax mito-chondrial apoptotic pathway.展开更多
Background:Sirtuin-3(Sirt3)has been documented to protect against mitochondrial dysfunction and apoptosis.Honokiol(HKL)is a Sirt3 pharmacological activator with reported neuroprotective effects in multiple neurologica...Background:Sirtuin-3(Sirt3)has been documented to protect against mitochondrial dysfunction and apoptosis.Honokiol(HKL)is a Sirt3 pharmacological activator with reported neuroprotective effects in multiple neurological disorders.The present study aimed to explore the neuroprotective effects of HKL and the role of Sirt3 following intracerebral hemorrhage(ICH).Methods:An in vivo ICH model in rats was established by injecting autologous blood into the right basal ganglia.PC12 cells were stimulated with hemin.For the in vivo investigation,the modified Neurological Severity Scores and the Morris water maze test were performed to assess neurological deficits.Hematoxylin-Eosin and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining were employed to evaluate the histopathology and apoptosis.Immunohistochemical staining was used to investigate the expression of Sirt3.Adenosine triphosphate(ATP)levels were quantified to assess mitochondrial dysfunction.Cell counting kit-8,lactate dehydrogenase assay,and flow cytometry were used to analyze cell vitality and apoptosis in vitro.Immunofluorescence staining was performed to observe mitochondrial morphology and dynamin-related protein 1(Drp1)localization to mitochondria.Western blot was applied to quantify the expression of Sirt3,Bax,Bcl-2,cleaved-caspase-3,Drp1,phosphorylation of Drp1 at serine-616,and phosphorylation of Drp1 at serine-637 in vivo and in vitro.Results:HKL treatment alleviated neurological deficits,attenuated the histopathological damage and cell apoptosis,and restored the decreased ATP levels in ICH rats.HKL improved cell survival rate,reduced cell apoptosis,and inhibited mitochondrial fission in PC12 cells.Moreover,both in vivo and in vitro models showed increased phosphorylation of Drp1 at Ser616,and reduced phosphorylation of Drp1 at Ser637.Meanwhile,immunofluorescence co-localization analysis revealed that hemin increased the overlap of Drp1 and mitochondria in PC12 cells.The phosphorylation and mitochondrial translocation of Drp1 were effectively reversed by HKL treatment.Importantly,the selective Sirt3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine suppressed these effects.Conclusion:Our findings demonstrated that HKL ameliorated ICH-induced apoptosis and mitochondrial fission by Sirt3,suggesting that HKL has immense prospects for the treatment of ICH.展开更多
Dimethylarginine dimethylaminohydrolase 1(DDAH1)is an important regulator of plasma asymmetric dimethylarginine(ADMA)levels,which are associated with insulin resistance in patients with nonalcoholic fatty liver diseas...Dimethylarginine dimethylaminohydrolase 1(DDAH1)is an important regulator of plasma asymmetric dimethylarginine(ADMA)levels,which are associated with insulin resistance in patients with nonalcoholic fatty liver disease(NAFLD).To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD,we used hepatocyte-specific Ddah1-knockout mice(Ddah1HKO)to examine the progress of high-fat diet(HFD)-induced NAFLD.Compared to diet-matched flox/flox littermates(Ddah1f/f),Ddah1HKO mice exhibited higher serum ADMA levels.After HFD feeding for 16 weeks,Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice.On the contrary,overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice.RNA-seq analysis showed that DDAH1 affects NF-kB signaling,lipid metabolic processes,and immune system processes in fatty livers.Furthermore,DDAH1 reduces S100 calcium-binding protein A11(S100A11)possibly via NF-kB,JNK and oxidative stress-dependent manner in fatty livers.Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice.In summary,our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice.Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.展开更多
基金supported by Scientific Research and Development Plan of Hebei Province,No.20276102DKey Project of Scientific Research in Universities of Hebei Province in China,No.ZD2010106
文摘Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. Howev-er, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evaluate the therapeutic effects and mechanisms of action of apolipoprotein E mimetic peptide on diffuse brain injury. Apolipoprotein E mimetic peptide was administered into the caudal vein of rats with diffuse brain injury before and after injury. We found that apo-lipoprotein E mimetic peptide signiifcantly decreased the number of apoptotic neurons, reduced extracellular signal-regulated kinase1/2 phosphorylation, down-regulated Bax and cytochrome c expression, decreased malondialdehyde content, and increased superoxide dismutase activity in a dose-dependent manner. These experimental ifndings demonstrate that apolipoprotein E mimetic peptide improves learning and memory function and protects against diffuse brain injury-induced apoptosis by inhibiting the extracellular signal-regulated kinase1/2-Bax mito-chondrial apoptotic pathway.
基金Natural Science Foundation of Hebei Province(No.H2019105137)
文摘Background:Sirtuin-3(Sirt3)has been documented to protect against mitochondrial dysfunction and apoptosis.Honokiol(HKL)is a Sirt3 pharmacological activator with reported neuroprotective effects in multiple neurological disorders.The present study aimed to explore the neuroprotective effects of HKL and the role of Sirt3 following intracerebral hemorrhage(ICH).Methods:An in vivo ICH model in rats was established by injecting autologous blood into the right basal ganglia.PC12 cells were stimulated with hemin.For the in vivo investigation,the modified Neurological Severity Scores and the Morris water maze test were performed to assess neurological deficits.Hematoxylin-Eosin and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining were employed to evaluate the histopathology and apoptosis.Immunohistochemical staining was used to investigate the expression of Sirt3.Adenosine triphosphate(ATP)levels were quantified to assess mitochondrial dysfunction.Cell counting kit-8,lactate dehydrogenase assay,and flow cytometry were used to analyze cell vitality and apoptosis in vitro.Immunofluorescence staining was performed to observe mitochondrial morphology and dynamin-related protein 1(Drp1)localization to mitochondria.Western blot was applied to quantify the expression of Sirt3,Bax,Bcl-2,cleaved-caspase-3,Drp1,phosphorylation of Drp1 at serine-616,and phosphorylation of Drp1 at serine-637 in vivo and in vitro.Results:HKL treatment alleviated neurological deficits,attenuated the histopathological damage and cell apoptosis,and restored the decreased ATP levels in ICH rats.HKL improved cell survival rate,reduced cell apoptosis,and inhibited mitochondrial fission in PC12 cells.Moreover,both in vivo and in vitro models showed increased phosphorylation of Drp1 at Ser616,and reduced phosphorylation of Drp1 at Ser637.Meanwhile,immunofluorescence co-localization analysis revealed that hemin increased the overlap of Drp1 and mitochondria in PC12 cells.The phosphorylation and mitochondrial translocation of Drp1 were effectively reversed by HKL treatment.Importantly,the selective Sirt3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine suppressed these effects.Conclusion:Our findings demonstrated that HKL ameliorated ICH-induced apoptosis and mitochondrial fission by Sirt3,suggesting that HKL has immense prospects for the treatment of ICH.
基金supported by grants from National Natural Science Foundation of China(82070250,32200631)Beijing Natural Science Foundation(5222029,China)+1 种基金China Postdoctoral Science Foundation(2022T150640)the Fundamental Research Funds for the Central Universities。
文摘Dimethylarginine dimethylaminohydrolase 1(DDAH1)is an important regulator of plasma asymmetric dimethylarginine(ADMA)levels,which are associated with insulin resistance in patients with nonalcoholic fatty liver disease(NAFLD).To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD,we used hepatocyte-specific Ddah1-knockout mice(Ddah1HKO)to examine the progress of high-fat diet(HFD)-induced NAFLD.Compared to diet-matched flox/flox littermates(Ddah1f/f),Ddah1HKO mice exhibited higher serum ADMA levels.After HFD feeding for 16 weeks,Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice.On the contrary,overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice.RNA-seq analysis showed that DDAH1 affects NF-kB signaling,lipid metabolic processes,and immune system processes in fatty livers.Furthermore,DDAH1 reduces S100 calcium-binding protein A11(S100A11)possibly via NF-kB,JNK and oxidative stress-dependent manner in fatty livers.Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice.In summary,our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice.Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.
