Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in m...Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.展开更多
Background The IL-23/Th17 pathway plays an important role in the development of chronic in?ammatory diseases and autoimmune diseases.However,the role of the IL-23/Th17 axis in the regulation of virus myocarditis is st...Background The IL-23/Th17 pathway plays an important role in the development of chronic in?ammatory diseases and autoimmune diseases.However,the role of the IL-23/Th17 axis in the regulation of virus myocarditis is still largely unknown.We aim to determine the role of IL-23/Th17 axis in virus myocartidis.Methods and Results Balb/c male mice were peritoneally injected with 100TICD50 Coxsackie virus B3 to establish virus myocarditis(VMC),mice injected with PBS peritoneally were taken as the controls.0,1,2,3,4 and 6 weeks After injection,IL-23,L-17 and RORγt mRNA in the myocardium of VMC were assessed by Semi-quantitative RT-PCR,and IL-23 protein from plasm was evaluated by ELISA.Flow cytometric analysis was used to evaluate the frequencies of Th17 subsets in CD4,To investigated whether the IL-23 is important during IL-23/Th-17 pathway challenge,we isolated CD4+T cells and cultured with rIL-23 in vitro,and examined the Th17 cells.Results show that,comparing with the controls,IL-23,IL-17 and RORγt mRNA was steadly expressed in the myocardiums of infected mice from 1 week after virus injection.Conclusions IL-23/Th-17 pathway may therefore play an essential role in VMC.Comparative studies are required to reveal further the roles of these cytokines in the pathogenesis of?these immune-related diseases.展开更多
Tendon injuries are often exacerbated by persistent inflammation,which hampers tissue regeneration.In this study,we developed a noninvasive,wirelessly controlled,and self-powered piezoelectric nanofilm fabricated by c...Tendon injuries are often exacerbated by persistent inflammation,which hampers tissue regeneration.In this study,we developed a noninvasive,wirelessly controlled,and self-powered piezoelectric nanofilm fabricated by coaxial electrospinning of polycaprolactone(PCL)and tetragonal barium titanate nanoparticles(BTO),and investigated its roles in modulating inflammation and repairing Achilles tendon defects as well as the mechanism in a rat model.In vitro study and in vivo study upon subcutaneous implantation showed that the piezoelectric PCL/BTO nanofilms could inhibit M1 macrophage polarization and reduce the secretion of inflammatory factors.Moreover,when bridging an Achilles tendon defect,the nanofilms could promote tenogenic gene expression including collagen deposition,and collagen remodeling,facilitate functional tendon recovery and significantly reduce tissue inflammation by suppressing M1 macrophage polarization and promoting M2 polarization.Moreover,the piezoelectric stimulation could also enhance tendon regeneration by inhibiting angiogenesis,reducing lipid deposition,and decreasing ectopic ossification.Mechanistically,the piezoelectric nanofilms reduced tissue inflammation mainly via inhibiting the nuclear factor(NF)-κB signaling pathway that is mediated by interleukin(IL)-17A secreted from CD3^(+)T cells,and thus to reduce proinflammatory factors,such as IL-1βand IL-6,inducible nitric oxide synthase,monocyte chemoattractant protein-1,and tumor necrosis factor-α.These findings indicate the potential of piezoelectric stimulation in immunomodulation,and in promoting tendon regeneration via IL-17A/NF-κB-mediated pathway.展开更多
基金supported by the National Science Foundation of China(No.82405004,82474253)the Natural Science Foundation postdoctoral project of Chongqing(CSTB2022NSCQ-BHX0709)+2 种基金Chongqing Wanzhou District doctoral“through train”scientific research project(wzstc-20220124)Natural Science Foundation of Chongqing,China(No.Cstc2021jcyj-msxmX0996)Chongqing Wanzhou District Science and Health Joint Medical Research Project(wzstc-kw2023032)。
文摘Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.
文摘Background The IL-23/Th17 pathway plays an important role in the development of chronic in?ammatory diseases and autoimmune diseases.However,the role of the IL-23/Th17 axis in the regulation of virus myocarditis is still largely unknown.We aim to determine the role of IL-23/Th17 axis in virus myocartidis.Methods and Results Balb/c male mice were peritoneally injected with 100TICD50 Coxsackie virus B3 to establish virus myocarditis(VMC),mice injected with PBS peritoneally were taken as the controls.0,1,2,3,4 and 6 weeks After injection,IL-23,L-17 and RORγt mRNA in the myocardium of VMC were assessed by Semi-quantitative RT-PCR,and IL-23 protein from plasm was evaluated by ELISA.Flow cytometric analysis was used to evaluate the frequencies of Th17 subsets in CD4,To investigated whether the IL-23 is important during IL-23/Th-17 pathway challenge,we isolated CD4+T cells and cultured with rIL-23 in vitro,and examined the Th17 cells.Results show that,comparing with the controls,IL-23,IL-17 and RORγt mRNA was steadly expressed in the myocardiums of infected mice from 1 week after virus injection.Conclusions IL-23/Th-17 pathway may therefore play an essential role in VMC.Comparative studies are required to reveal further the roles of these cytokines in the pathogenesis of?these immune-related diseases.
基金supported by the National Natural Science Founda-tion of China(31870967 to Wei Liu and 81701841 to Wenbo Wang)the National Key R&D Program of China(2018YFC1105800 to Wei Liu)+1 种基金supported by the Shanghai Pujiang Program(23PJD047)the on-job postdoctoral program.
文摘Tendon injuries are often exacerbated by persistent inflammation,which hampers tissue regeneration.In this study,we developed a noninvasive,wirelessly controlled,and self-powered piezoelectric nanofilm fabricated by coaxial electrospinning of polycaprolactone(PCL)and tetragonal barium titanate nanoparticles(BTO),and investigated its roles in modulating inflammation and repairing Achilles tendon defects as well as the mechanism in a rat model.In vitro study and in vivo study upon subcutaneous implantation showed that the piezoelectric PCL/BTO nanofilms could inhibit M1 macrophage polarization and reduce the secretion of inflammatory factors.Moreover,when bridging an Achilles tendon defect,the nanofilms could promote tenogenic gene expression including collagen deposition,and collagen remodeling,facilitate functional tendon recovery and significantly reduce tissue inflammation by suppressing M1 macrophage polarization and promoting M2 polarization.Moreover,the piezoelectric stimulation could also enhance tendon regeneration by inhibiting angiogenesis,reducing lipid deposition,and decreasing ectopic ossification.Mechanistically,the piezoelectric nanofilms reduced tissue inflammation mainly via inhibiting the nuclear factor(NF)-κB signaling pathway that is mediated by interleukin(IL)-17A secreted from CD3^(+)T cells,and thus to reduce proinflammatory factors,such as IL-1βand IL-6,inducible nitric oxide synthase,monocyte chemoattractant protein-1,and tumor necrosis factor-α.These findings indicate the potential of piezoelectric stimulation in immunomodulation,and in promoting tendon regeneration via IL-17A/NF-κB-mediated pathway.
