Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the m...Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.展开更多
Objective:Overexpression of microRNA-21(miR-21)has been well-recognized during fibrosis in a wide range of tissue types through regulation of fibrogenesis via diverse pathways.Curcumin exhibits antifibrotic effects in...Objective:Overexpression of microRNA-21(miR-21)has been well-recognized during fibrosis in a wide range of tissue types through regulation of fibrogenesis via diverse pathways.Curcumin exhibits antifibrotic effects in various organs.We and others have previously demonstrated that curcumin has positive effects on the protection against fibrosis.However,the effect of curcumin on miR-21 expression has not been reported.Methods:In this study,transforming growth factor-b1(TGF-b1)-stimulated rat renal fibroblast cells(NRK-49F)were transfected with miR-21 inhibitors,then the expression of Smad3,a-smooth muscle actin(a-SMA),type I collagen(COL1A1),and type III collagen(COL3A1)was determined using quantitative real-time-PCR(qRT-PCR)and western blot analysis.The effect of curcumin on production of the extracellular matrix was evaluated using immunofluorescence,qRT-PCR,and western blot analysis.Results:TGF-b1 stimulation upregulated the expression of miR-21 and induced fibrogenesis in NRK-49F cells.Transfection with miR-21 inhibitors selectively decreased smad3 activity,and noticeably reduced the expression of a-SMA,COL1A1,and COL3A1.Curcumin treatment significantly inhibited the expressions of smad3,a-SMA,COL1A1,COL3A1,as well as miR-21 expression in NRK-49F cells in a dosedependent manner.Conclusion:Curcumin exerted its anti-fibrotic effects by targeting the TGF-b1/smad3 signaling pathway and suppressing miR-21 expression,thereby provides novel insight in the protective effects of curcumin against fibrosis in various organs.展开更多
Mitochondrial dysfunction is pivotal in the occurrence and development of Parkinson's disease(PD).Interventions to increase mitochondrial biogenesis and maintain the balance in mitochondrial turnover have the pote...Mitochondrial dysfunction is pivotal in the occurrence and development of Parkinson's disease(PD).Interventions to increase mitochondrial biogenesis and maintain the balance in mitochondrial turnover have the potential to protect against neurological damage.In addition to their crucial role in the tricarboxylic acid cycle,mitochondria impact diverse activities,including cellular metabolism,cellular quality control,and the production of reactive oxygen species.Thus,it has become imperative to better understand the regulation and function of mitochondria in PD.With this review,we aim to stimulate research that explores mitochondria-oriented neuroprotection strategies to maintain the balance in mitochondrial turnover.First,we summarize research on newly discovered genes that regulate PD mitochondrial autophagy through PTEN-induced kinase 1(PINK1),namely AMBRA1,SYNJ2BP,and SIAH3.Second,we review PD-related mitochondrial proteins,including STRT3 and SIRT6,and the mitochondrial unfolded protein response,covering their mechanisms of involvement in PD.Third,we emphasize the roles of the mitochondrial complex,pyroptosis,and copper-induced cell death in mitochondrial damage in PD.Finally,we present a brief overview of new therapeutic strategies to correct mitochondrial defects that may be applicable for targeting mitochondria in PD patients.展开更多
基金supported by the Key Science and Technology Research of Henan Province,No.222102310351(to JW)Luoyang 2022 Medical and Health Guiding Science and Technology Plan Project,No.2022057Y(to JY)Henan Medical Science and Technology Research Program Province-Ministry Co-sponsorship,No.SBGJ202002099(to JY)。
文摘Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.
基金This study was supported by the National Natural Science Foundation of China of China(No.81573716).
文摘Objective:Overexpression of microRNA-21(miR-21)has been well-recognized during fibrosis in a wide range of tissue types through regulation of fibrogenesis via diverse pathways.Curcumin exhibits antifibrotic effects in various organs.We and others have previously demonstrated that curcumin has positive effects on the protection against fibrosis.However,the effect of curcumin on miR-21 expression has not been reported.Methods:In this study,transforming growth factor-b1(TGF-b1)-stimulated rat renal fibroblast cells(NRK-49F)were transfected with miR-21 inhibitors,then the expression of Smad3,a-smooth muscle actin(a-SMA),type I collagen(COL1A1),and type III collagen(COL3A1)was determined using quantitative real-time-PCR(qRT-PCR)and western blot analysis.The effect of curcumin on production of the extracellular matrix was evaluated using immunofluorescence,qRT-PCR,and western blot analysis.Results:TGF-b1 stimulation upregulated the expression of miR-21 and induced fibrogenesis in NRK-49F cells.Transfection with miR-21 inhibitors selectively decreased smad3 activity,and noticeably reduced the expression of a-SMA,COL1A1,and COL3A1.Curcumin treatment significantly inhibited the expressions of smad3,a-SMA,COL1A1,COL3A1,as well as miR-21 expression in NRK-49F cells in a dosedependent manner.Conclusion:Curcumin exerted its anti-fibrotic effects by targeting the TGF-b1/smad3 signaling pathway and suppressing miR-21 expression,thereby provides novel insight in the protective effects of curcumin against fibrosis in various organs.
文摘Mitochondrial dysfunction is pivotal in the occurrence and development of Parkinson's disease(PD).Interventions to increase mitochondrial biogenesis and maintain the balance in mitochondrial turnover have the potential to protect against neurological damage.In addition to their crucial role in the tricarboxylic acid cycle,mitochondria impact diverse activities,including cellular metabolism,cellular quality control,and the production of reactive oxygen species.Thus,it has become imperative to better understand the regulation and function of mitochondria in PD.With this review,we aim to stimulate research that explores mitochondria-oriented neuroprotection strategies to maintain the balance in mitochondrial turnover.First,we summarize research on newly discovered genes that regulate PD mitochondrial autophagy through PTEN-induced kinase 1(PINK1),namely AMBRA1,SYNJ2BP,and SIAH3.Second,we review PD-related mitochondrial proteins,including STRT3 and SIRT6,and the mitochondrial unfolded protein response,covering their mechanisms of involvement in PD.Third,we emphasize the roles of the mitochondrial complex,pyroptosis,and copper-induced cell death in mitochondrial damage in PD.Finally,we present a brief overview of new therapeutic strategies to correct mitochondrial defects that may be applicable for targeting mitochondria in PD patients.
