Objective: To demonstrate whether the expression of silent mating type information regulation 2 homolog 1 (SIRT1) affects the level of TGF-β1 and Smad3 in HEK293 cells through regulating mTOR. Methods: First, recombi...Objective: To demonstrate whether the expression of silent mating type information regulation 2 homolog 1 (SIRT1) affects the level of TGF-β1 and Smad3 in HEK293 cells through regulating mTOR. Methods: First, recombinant plasmids DNA (rSIRT1) and siRNA targeting SIRT1 were constructed which were transfected into Human Embryonic Kidney 293 cell (HEK293) cells, respectively. Then, the generation of intracellular ROS in cells was examined by flow cytometry using the oxidation-sensitive probe. Last, the expressions of TGF-β1, smad3, P53, mTOR, p-mTOR, LC3-I and LC3-II in cells were detected to observe the effect of SIRT1 on TGF-β1 Pathway by western blot analysis. Results: We demonstrated that overexpressing of SIRT1 may decrease TGF-β1 and Smad3 expression in HEK293 cells through regulating mTOR. In addition, the result is the opposite when SIRT1 was silent in HEK293 cells. Conclusions: SIRT1 is closely related to TGF-β1/Smad3 pathway that correlates with the regulation of mTOR and ROS generation and causes diabetic nephropathy. The available evidence implies that SIRT1 has great potential as a clinical target for the prevention and treatment of renal fibrosis in the development of DN.展开更多
BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple b...BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple biological processes,including cellular senescence,apoptosis,sugar and lipid metabolism,oxidative stress,and inflammation.AIM To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms.METHODS This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)testing.C57BL/6 mice were also intraperitoneally pretreated with SIRT1,p53,or glutathione peroxidase 4(GPX4)inducers and inhibitors and injected with lipopolysaccharide(LPS)/D-galactosamine(D-GalN)to induce ALF.Gasdermin D(GSDMD)^(-/-)mice were used as an experimental group.Histological changes in liver tissue were monitored by hematoxylin and eosin staining.ALT,AST,glutathione,reactive oxygen species,and iron levels were measured using commercial kits.Ferroptosis-and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction.SIRT1,p53,and GSDMD were assessed by immunofluorescence analysis.RESULTS Serum AST and ALT levels were elevated in patients with ALF.SIRT1,solute carrier family 7a member 11(SLC7A11),and GPX4 protein expression was decreased and acetylated p5,p53,GSDMD,and acyl-CoA synthetase long-chain family member 4(ACSL4)protein levels were elevated in human ALF liver tissue.In the p53 and ferroptosis inhibitor-treated and GSDMD^(-/-)groups,serum interleukin(IL)-1β,tumour necrosis factor alpha,IL-6,IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated.In mice with GSDMD knockout,p53 was reduced,GPX4 was increased,and ferroptotic events(depletion of SLC7A11,elevation of ACSL4,and iron accumulation)were detected.In vitro,knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels,the cytostatic rate,and GSDMD expression,restoring SLC7A11 depletion.Moreover,SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group,accompanied by reduced p53,GSDMD,and ACSL4,and increased SLC7A11 and GPX4.Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalNinduced in vitro and in vivo models.CONCLUSION SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.展开更多
The global increase in lifespan noted not only in developed nations,but also in large developing countries parallels an observed increase in a significant number of noncommunicable diseases,most notable neurodegenerat...The global increase in lifespan noted not only in developed nations,but also in large developing countries parallels an observed increase in a significant number of noncommunicable diseases,most notable neurodegenerative disorders.Neurodegenerative disorders present a number of challenges for treatment options that do not resolve disease progression.Furthermore,it is believed by the year 2030,the services required to treat cognitive disorders in the United States alone will exceed$2 trillion annually.Mammalian forkhead transcription factors,silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae),the mechanistic target of rapamycin,and the pathways of autophagy and apoptosis offer exciting avenues to address these challenges by focusing upon core cellular mechanisms that may significantly impact nervous system disease.These pathways are intimately linked such as through cell signaling pathways involving protein kinase B and can foster,sometimes in conjunction with trophic factors,enhanced neuronal survival,reduction in toxic intracellular accumulations,and mitochondrial stability.Feedback mechanisms among these pathways also exist that can oversee reparative processes in the nervous system.However,mammalian forkhead transcription factors,silent mating type information regulation 2 homolog 1,mechanistic target of rapamycin,and autophagy can lead to cellular demise under some scenarios that may be dependent upon the precise cellular environment,warranting future studies to effectively translate these core pathways into successful clinical treatment strategies for neurodegenerative disorders.展开更多
BACKGROUND In degenerative intervertebral disc(IVD),an unfavorable IVD environment leads to increased senescence of nucleus pulposus(NP)-derived mesenchymal stem cells(NPMSCs)and the inability to complete the differen...BACKGROUND In degenerative intervertebral disc(IVD),an unfavorable IVD environment leads to increased senescence of nucleus pulposus(NP)-derived mesenchymal stem cells(NPMSCs)and the inability to complete the differentiation from NPMSCs to NP cells,leading to further aggravation of IVD degeneration(IDD).Urolithin A(UA)has been proven to have obvious effects in delaying cell senescence and resisting oxidative stress.AIM To explore whether UA can alleviate NPMSCs senescence and to elucidate the underlying mechanism.METHODS In vitro,we harvested NPMSCs from rat tails,and divided NPMSCs into four groups:the control group,H2O2 group,H2O2+UA group,and H2O2+UA+SR-18292 group.Senescence-associatedβ-Galactosidase(SA-β-Gal)activity,cell cycle,cell proliferation ability,and the expression of senescence-related and silent information regulator of transcription 1/PPAR gamma coactivator-1α(SIRT1/PGC-1α)pathway-related proteins and mRNA were used to evaluate the protective effects of UA.In vivo,an animal model of IDD was constructed,and Xrays,magnetic resonance imaging,and histological analysis were used to assess whether UA could alleviate IDD in vivo.RESULTS We found that H2O2 can cause NPMSCs senescence changes,such as cell cycle arrest,reduced cell proliferation ability,increased SA-β-Gal activity,and increased expression of senescence-related proteins and mRNA.After UA pretreatment,the abovementioned senescence indicators were significantly alleviated.To further demonstrate the mechanism of UA,we evaluated the mitochondrial membrane potential and the SIRT1/PGC-1αpathway that regulates mitochondrial function.UA protected mitochondrial function and delayed NPMSCs senescence by activating the SIRT1/PGC-1αpathway.In vivo,we found that UA treatment alleviated an animal model of IDD by assessing the disc height index,Pfirrmann grade and the histological score.CONCLUSION In summary,UA could activate the SIRT1/PGC-1αsignaling pathway to protect mitochondrial function and alleviate cell senescence and IDD in vivo and vitro.展开更多
Diabetes and associated complications represent major global public health issues which are associated with impaired quality of life and premature death.Although some diabetic complications have decreased in the devel...Diabetes and associated complications represent major global public health issues which are associated with impaired quality of life and premature death.Although some diabetic complications have decreased in the developed world,the majority are still prevalent,with an increasing trend in the developing world.Currently used therapies are mainly‘glucocentric’,focusing on the optimization of glycemic control to prevent,delay or manage diabetes-associated complications-other common comorbidities,such as dyslipidemia and hypertension are often underestimated.Although a number of novel therapeutic approaches have been reported recently,some of them have not received comparable attention in relation to either further studies or potential clinical implementation.This editorial briefly discusses some recent therapeutic approaches to the prevention and management of diabetes and its associated complications,as well as potential directions for future research and development in this area.展开更多
Objective:To explore the possible effects and mechanism of Zhizhu Decoction(ZZD)on the pathophysiology of slow transit constipation(STC).Methods A total of 54 C57BL/6 mice was randomly divided into the following 6 gro...Objective:To explore the possible effects and mechanism of Zhizhu Decoction(ZZD)on the pathophysiology of slow transit constipation(STC).Methods A total of 54 C57BL/6 mice was randomly divided into the following 6 groups by a random number table,including control,STC model(model),positive control,and low-,medium-and high-doses ZZD treatment groups(5,10,20 g/kg,namely L,M-,and H-ZZD,respectively),9 mice in each group.Following 2-week treatment,intestinal transport rate(ITR)and fecal water content were determined,and blood and colon tissue samples were collected.Hematoxylin-eosin and periodic acid-Schiff staining were performed to evaluate the morphology of colon tissues and calculate the number of goblet cells.To determine intestinal permeability,serum levels of lipopolysaccharide(LPS),low-density lipoprotein(LDL)and mannose were measured using enzyme-linked immunosorbent assay(ELISA).Western blot analysis was carried out to detect the expression levels of intestinal tight junction proteins zona-occludens-1(ZO-1),claudin-1,occludin and recombinant mucin 2(MUC2).The mRNA expression levels of inflammatory cytokines including tumor necrosis factor(TNF)-α,interleukin(IL)-1β,IL-6,IL-4,IL-10 and IL-22 were determined using reverse transcription-quantitative reverse transcription reaction.Colon indexes of oxidative stress were measured by ELISA,and protein expression levels of colon silent information regulator 1/forkhead box O transcription factor 1(SIRT1/FoxO1)antioxidant signaling pathway were detected by Western blot.Results Compared with the model group,ITR and fecal moisture were significantly enhanced in STC mice in the M-ZZD and H-ZZD groups(P<0.01).Additionally,ZZD treatment notably increased the thickness of mucosal and muscular tissue,elevated the number of goblet cells in the colon of STC mice,reduced the secretion levels of LPS,LDL and mannose,and upregulated ZO-1,claudin-1,occludin and MUC2 expressions in the colon in a dose-dependent manner,compared with the model group(P<0.05 or P<0.01).In addition,ZZD significantly attenuated intestinal inflammation and oxidative stress and activated the SIRT1/FoxO1 signaling pathway(P<0.05 or P<0.01).Conclusion ZZD exhibited beneficial effects on the intestinal system of STC mice and alleviated intestinal inflammation and oxidative stress via activating SIRT1/FoxO1 antioxidant signaling pathway in the colon.展开更多
Throughout the globe,diabetes mellitus(DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affe...Throughout the globe,diabetes mellitus(DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin(m TOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1(m TORC1) and m TOR Complex 2(m TORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase(PI 3-K),protein kinase B(Akt),AMP activated protein kinase(AMPK),silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae)(SIRT1),Wnt1 inducible signaling pathway protein 1(WISP1),and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.展开更多
Objective:To observe the changes of ischemic myocardial cells apoptosis in rats following intervention with Xuefu Zhuyu Oral Liquid(血府逐瘀口服液,XFZY),as well as changes of protein expression of silent information r...Objective:To observe the changes of ischemic myocardial cells apoptosis in rats following intervention with Xuefu Zhuyu Oral Liquid(血府逐瘀口服液,XFZY),as well as changes of protein expression of silent information regulator 1(SIRT1)and SIRT1 pathway-related genes.Methods:H9c2 rat myocardial cells were divided into 6 groups:control group,oxygen glucose deprivation(OGD)group,SIRT1 siRNA group,OGD+SIRT1 siRNA group,OGD+XFZY group,and OGD+SIRT1 siRNA+XFZY group.Quantitative fluorescent polymerase chain reaction(PCR)and Western blot were used to detect the concentration variations of SIRT1 and its pathway-related genes and corresponding protein expression after XFZY intervention and SIRT1 transfection.Results:Compared with the control group,the mRNA and protein expressions of SIRT1 were decreased obviously,while the mRNA and protein levels of P53,forkhead box protein O1(FoxO1),FoxO3,FoxO4 and nuclear factor kappa B(NF-κB)were increased in the OGD group,SIRT1 siRNA group,and OGD+SIRT1 siRNA group(P<0.01).Compared with the OGD group and OGD+SIRT1 siRNA group,the treatment of XFZY inhibited the decline in SIRT1 mRNA and protein expressions(P<0.01),and down-regulated the mRNA and protein levels of P53,FoxO1,FoxO3,FoxO4 and NF-κB,respectively(P<0.05 or P<0.01).Conclusion:XFZY could prevent myocardial cells apoptosis probably by increasing the mRNA and protein expressions of SIRT1 and inhibiting the mRNA and protein expressions of P53,NF-κB,FoxO1,FoxO3 and FoxO4.展开更多
文摘Objective: To demonstrate whether the expression of silent mating type information regulation 2 homolog 1 (SIRT1) affects the level of TGF-β1 and Smad3 in HEK293 cells through regulating mTOR. Methods: First, recombinant plasmids DNA (rSIRT1) and siRNA targeting SIRT1 were constructed which were transfected into Human Embryonic Kidney 293 cell (HEK293) cells, respectively. Then, the generation of intracellular ROS in cells was examined by flow cytometry using the oxidation-sensitive probe. Last, the expressions of TGF-β1, smad3, P53, mTOR, p-mTOR, LC3-I and LC3-II in cells were detected to observe the effect of SIRT1 on TGF-β1 Pathway by western blot analysis. Results: We demonstrated that overexpressing of SIRT1 may decrease TGF-β1 and Smad3 expression in HEK293 cells through regulating mTOR. In addition, the result is the opposite when SIRT1 was silent in HEK293 cells. Conclusions: SIRT1 is closely related to TGF-β1/Smad3 pathway that correlates with the regulation of mTOR and ROS generation and causes diabetic nephropathy. The available evidence implies that SIRT1 has great potential as a clinical target for the prevention and treatment of renal fibrosis in the development of DN.
基金Supported by National Natural Science Foundation of China,No.82060123Doctoral Start-up Fund of Affiliated Hospital of Guizhou Medical University,No.gysybsky-2021-28+1 种基金Fund Project of Guizhou Provincial Science and Technology Department,No.[2020]1Y299Guizhou Provincial Health Commission,No.gzwjk2019-1-082。
文摘BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple biological processes,including cellular senescence,apoptosis,sugar and lipid metabolism,oxidative stress,and inflammation.AIM To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms.METHODS This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)testing.C57BL/6 mice were also intraperitoneally pretreated with SIRT1,p53,or glutathione peroxidase 4(GPX4)inducers and inhibitors and injected with lipopolysaccharide(LPS)/D-galactosamine(D-GalN)to induce ALF.Gasdermin D(GSDMD)^(-/-)mice were used as an experimental group.Histological changes in liver tissue were monitored by hematoxylin and eosin staining.ALT,AST,glutathione,reactive oxygen species,and iron levels were measured using commercial kits.Ferroptosis-and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction.SIRT1,p53,and GSDMD were assessed by immunofluorescence analysis.RESULTS Serum AST and ALT levels were elevated in patients with ALF.SIRT1,solute carrier family 7a member 11(SLC7A11),and GPX4 protein expression was decreased and acetylated p5,p53,GSDMD,and acyl-CoA synthetase long-chain family member 4(ACSL4)protein levels were elevated in human ALF liver tissue.In the p53 and ferroptosis inhibitor-treated and GSDMD^(-/-)groups,serum interleukin(IL)-1β,tumour necrosis factor alpha,IL-6,IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated.In mice with GSDMD knockout,p53 was reduced,GPX4 was increased,and ferroptotic events(depletion of SLC7A11,elevation of ACSL4,and iron accumulation)were detected.In vitro,knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels,the cytostatic rate,and GSDMD expression,restoring SLC7A11 depletion.Moreover,SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group,accompanied by reduced p53,GSDMD,and ACSL4,and increased SLC7A11 and GPX4.Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalNinduced in vitro and in vivo models.CONCLUSION SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.
基金supported by American Diabetes AssociationAmerican Heart Association+3 种基金National Institutes of Health-National Institute of Environmental Health SciencesNational Institutes of Health-National Institute on AgingNational Institutes of Health-National Institute of Neurological DisordersNational Institutes of Health-American Recovery and Reinvestment(to KM)。
文摘The global increase in lifespan noted not only in developed nations,but also in large developing countries parallels an observed increase in a significant number of noncommunicable diseases,most notable neurodegenerative disorders.Neurodegenerative disorders present a number of challenges for treatment options that do not resolve disease progression.Furthermore,it is believed by the year 2030,the services required to treat cognitive disorders in the United States alone will exceed$2 trillion annually.Mammalian forkhead transcription factors,silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae),the mechanistic target of rapamycin,and the pathways of autophagy and apoptosis offer exciting avenues to address these challenges by focusing upon core cellular mechanisms that may significantly impact nervous system disease.These pathways are intimately linked such as through cell signaling pathways involving protein kinase B and can foster,sometimes in conjunction with trophic factors,enhanced neuronal survival,reduction in toxic intracellular accumulations,and mitochondrial stability.Feedback mechanisms among these pathways also exist that can oversee reparative processes in the nervous system.However,mammalian forkhead transcription factors,silent mating type information regulation 2 homolog 1,mechanistic target of rapamycin,and autophagy can lead to cellular demise under some scenarios that may be dependent upon the precise cellular environment,warranting future studies to effectively translate these core pathways into successful clinical treatment strategies for neurodegenerative disorders.
基金National Natural Science Foundation of China,No.81972136Young Medical Scholars Major Program of Jiangsu Province,No.QNRC2016342+1 种基金Key Funding Project of Maternal and Child Health Research of Jiangsu Province,No.F201801and Highlevel Health Professionals"Six projects"Top-notch Talent Research Program of Jiangsu Province,No.LGY2019035.
文摘BACKGROUND In degenerative intervertebral disc(IVD),an unfavorable IVD environment leads to increased senescence of nucleus pulposus(NP)-derived mesenchymal stem cells(NPMSCs)and the inability to complete the differentiation from NPMSCs to NP cells,leading to further aggravation of IVD degeneration(IDD).Urolithin A(UA)has been proven to have obvious effects in delaying cell senescence and resisting oxidative stress.AIM To explore whether UA can alleviate NPMSCs senescence and to elucidate the underlying mechanism.METHODS In vitro,we harvested NPMSCs from rat tails,and divided NPMSCs into four groups:the control group,H2O2 group,H2O2+UA group,and H2O2+UA+SR-18292 group.Senescence-associatedβ-Galactosidase(SA-β-Gal)activity,cell cycle,cell proliferation ability,and the expression of senescence-related and silent information regulator of transcription 1/PPAR gamma coactivator-1α(SIRT1/PGC-1α)pathway-related proteins and mRNA were used to evaluate the protective effects of UA.In vivo,an animal model of IDD was constructed,and Xrays,magnetic resonance imaging,and histological analysis were used to assess whether UA could alleviate IDD in vivo.RESULTS We found that H2O2 can cause NPMSCs senescence changes,such as cell cycle arrest,reduced cell proliferation ability,increased SA-β-Gal activity,and increased expression of senescence-related proteins and mRNA.After UA pretreatment,the abovementioned senescence indicators were significantly alleviated.To further demonstrate the mechanism of UA,we evaluated the mitochondrial membrane potential and the SIRT1/PGC-1αpathway that regulates mitochondrial function.UA protected mitochondrial function and delayed NPMSCs senescence by activating the SIRT1/PGC-1αpathway.In vivo,we found that UA treatment alleviated an animal model of IDD by assessing the disc height index,Pfirrmann grade and the histological score.CONCLUSION In summary,UA could activate the SIRT1/PGC-1αsignaling pathway to protect mitochondrial function and alleviate cell senescence and IDD in vivo and vitro.
文摘Diabetes and associated complications represent major global public health issues which are associated with impaired quality of life and premature death.Although some diabetic complications have decreased in the developed world,the majority are still prevalent,with an increasing trend in the developing world.Currently used therapies are mainly‘glucocentric’,focusing on the optimization of glycemic control to prevent,delay or manage diabetes-associated complications-other common comorbidities,such as dyslipidemia and hypertension are often underestimated.Although a number of novel therapeutic approaches have been reported recently,some of them have not received comparable attention in relation to either further studies or potential clinical implementation.This editorial briefly discusses some recent therapeutic approaches to the prevention and management of diabetes and its associated complications,as well as potential directions for future research and development in this area.
基金Supported by the General Project of National Natural Science Foundation of China(No.82074429)。
文摘Objective:To explore the possible effects and mechanism of Zhizhu Decoction(ZZD)on the pathophysiology of slow transit constipation(STC).Methods A total of 54 C57BL/6 mice was randomly divided into the following 6 groups by a random number table,including control,STC model(model),positive control,and low-,medium-and high-doses ZZD treatment groups(5,10,20 g/kg,namely L,M-,and H-ZZD,respectively),9 mice in each group.Following 2-week treatment,intestinal transport rate(ITR)and fecal water content were determined,and blood and colon tissue samples were collected.Hematoxylin-eosin and periodic acid-Schiff staining were performed to evaluate the morphology of colon tissues and calculate the number of goblet cells.To determine intestinal permeability,serum levels of lipopolysaccharide(LPS),low-density lipoprotein(LDL)and mannose were measured using enzyme-linked immunosorbent assay(ELISA).Western blot analysis was carried out to detect the expression levels of intestinal tight junction proteins zona-occludens-1(ZO-1),claudin-1,occludin and recombinant mucin 2(MUC2).The mRNA expression levels of inflammatory cytokines including tumor necrosis factor(TNF)-α,interleukin(IL)-1β,IL-6,IL-4,IL-10 and IL-22 were determined using reverse transcription-quantitative reverse transcription reaction.Colon indexes of oxidative stress were measured by ELISA,and protein expression levels of colon silent information regulator 1/forkhead box O transcription factor 1(SIRT1/FoxO1)antioxidant signaling pathway were detected by Western blot.Results Compared with the model group,ITR and fecal moisture were significantly enhanced in STC mice in the M-ZZD and H-ZZD groups(P<0.01).Additionally,ZZD treatment notably increased the thickness of mucosal and muscular tissue,elevated the number of goblet cells in the colon of STC mice,reduced the secretion levels of LPS,LDL and mannose,and upregulated ZO-1,claudin-1,occludin and MUC2 expressions in the colon in a dose-dependent manner,compared with the model group(P<0.05 or P<0.01).In addition,ZZD significantly attenuated intestinal inflammation and oxidative stress and activated the SIRT1/FoxO1 signaling pathway(P<0.05 or P<0.01).Conclusion ZZD exhibited beneficial effects on the intestinal system of STC mice and alleviated intestinal inflammation and oxidative stress via activating SIRT1/FoxO1 antioxidant signaling pathway in the colon.
基金supported by American Diabetes Association,American Heart Association,NIH NIEHS,NIH NIA,NIH NINDS,and NIH ARRA
文摘Throughout the globe,diabetes mellitus(DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin(m TOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1(m TORC1) and m TOR Complex 2(m TORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase(PI 3-K),protein kinase B(Akt),AMP activated protein kinase(AMPK),silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae)(SIRT1),Wnt1 inducible signaling pathway protein 1(WISP1),and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.
基金Supported by the National Natural Science Foundation of China(Nos.81173449,81473466)。
文摘Objective:To observe the changes of ischemic myocardial cells apoptosis in rats following intervention with Xuefu Zhuyu Oral Liquid(血府逐瘀口服液,XFZY),as well as changes of protein expression of silent information regulator 1(SIRT1)and SIRT1 pathway-related genes.Methods:H9c2 rat myocardial cells were divided into 6 groups:control group,oxygen glucose deprivation(OGD)group,SIRT1 siRNA group,OGD+SIRT1 siRNA group,OGD+XFZY group,and OGD+SIRT1 siRNA+XFZY group.Quantitative fluorescent polymerase chain reaction(PCR)and Western blot were used to detect the concentration variations of SIRT1 and its pathway-related genes and corresponding protein expression after XFZY intervention and SIRT1 transfection.Results:Compared with the control group,the mRNA and protein expressions of SIRT1 were decreased obviously,while the mRNA and protein levels of P53,forkhead box protein O1(FoxO1),FoxO3,FoxO4 and nuclear factor kappa B(NF-κB)were increased in the OGD group,SIRT1 siRNA group,and OGD+SIRT1 siRNA group(P<0.01).Compared with the OGD group and OGD+SIRT1 siRNA group,the treatment of XFZY inhibited the decline in SIRT1 mRNA and protein expressions(P<0.01),and down-regulated the mRNA and protein levels of P53,FoxO1,FoxO3,FoxO4 and NF-κB,respectively(P<0.05 or P<0.01).Conclusion:XFZY could prevent myocardial cells apoptosis probably by increasing the mRNA and protein expressions of SIRT1 and inhibiting the mRNA and protein expressions of P53,NF-κB,FoxO1,FoxO3 and FoxO4.
