Cyclic peptides,with their unique structures and versatile biological activities,hold great potential for combating skin aging issues such as wrinkles,laxity,and pigmentation.However,traditional discovery methods rely...Cyclic peptides,with their unique structures and versatile biological activities,hold great potential for combating skin aging issues such as wrinkles,laxity,and pigmentation.However,traditional discovery methods relying on iterative synthesis and screening are labor-intensive and resource-intensive.Here,we present an integrated platform combining automated rapid cyclopeptide synthesis,virtual screening,and biological activity assessment,enabling the transformation of designed cyclic peptide sequences into chemical entities within minutes with high crude purity.Using ADCP docking with the ADFR suite,we identified a series of novel cyclic peptides targeting JAK1,Keap1,and TGF-βproteins.Among these,MKC1 demonstrated optimal anti-aging efficacy,as evidenced by its reactive oxygen species(ROS)scavenging activity(20%)and significant upregulation of type I collagen genes(Col1a1a:156%,Col1a1b:87%,Col1a2:103%)and elastin(Elna:132%)at a concentration of 0.001%.This study establishes a robust foundation for the discovery and development of cyclic peptides as anti-aging active compounds.展开更多
Objective:Cassiae Semen(CS,Juemingzi in Chinese)has been used for thousands of years in ancient Chinese history for relieving constipation,improving liver function as well as preventing myopia.Here we aimed to elucida...Objective:Cassiae Semen(CS,Juemingzi in Chinese)has been used for thousands of years in ancient Chinese history for relieving constipation,improving liver function as well as preventing myopia.Here we aimed to elucidate the anti-steatosis effect and underlying mechanism of CS against non-alcoholic fatty liver disease(NAFLD).Methods:High-performance liquid chromatography(HPLC)was used to identify the major components of CS water extract.Mice were fed with a high-fat and sugar-water(HFSW)diet to induce hepatic steatosis and then treated with CS.The anti-NAFLD effect was determined by measuring serum biomarkers and histopathology staining.Additionally,the effects of CS on cell viability and lipid metabolism in oleic acid and palmitic acid(OAPA)-treated HepG2 cells were measured.The expression of essential genes and proteins involved in lipid metabolism and autophagy signalings were measured to uncover the underlying mechanism.Results:Five compounds,including aurantio-obtusin,rubrofusarin gentiobioside,cassiaside C,emodin and rhein were simultaneously identified in CS extract.CS not only improved the diet-induced hepatic steatosis in vivo,as indicated by decreased number and size of lipid droplets,hepatic and serum triglycerides(TG)levels,but also markedly attenuated the OAPA-induced lipid accumulation in hepatocytes.These lipid-lowering effects induced by CS were largely dependent on the inhibition of fatty acid synthase(FASN)and the activation of autophagy-related signaling,including AMP-activated protein kinase(AMPK),light chain 3-II(LC3-II)/LC3-1 and autophagy-related gene5(ATG5).Conclusion:Our study suggested that CS effectively protected liver steatosis via decreasing FASN-related fatty acid synthesis and activating AMPK-mediated autophagy,which might become a promising therapeutic strategy for relieving NAFLD.展开更多
Objective:Hepatic fibrosis has been widely considered as a conjoint consequence of almost all chronic liver diseases.Chuanxiong Rhizoma(Chuanxiong in Chinese,CX)is a traditional Chinese herbal product to prevent cereb...Objective:Hepatic fibrosis has been widely considered as a conjoint consequence of almost all chronic liver diseases.Chuanxiong Rhizoma(Chuanxiong in Chinese,CX)is a traditional Chinese herbal product to prevent cerebrovascular,gynecologic and hepatic diseases.Our previous study found that CX extracts significantly reduced collagen contraction force of hepatic stellate cells(HSCs).Here,this study aimed to compare the protection of different CX extracts on bile duct ligation(BDL)-induced liver fibrosis and investigate plausible underlying mechanisms.Methods:The active compounds of CX extracts were identified by high performance liquid chromatography(HPLC).Network pharmacology was used to determine potential targets of CX against hepatic fibrosis.Bile duct hyperplasia and liver fibrosis were evaluated by serologic testing and histopathological evaluation.The expression of targets of interest was determined by quantitative real-time PCR(qPCR)and Western blot.Results:Different CX extracts were identified by tetramethylpyrazine,ferulic acid and senkyunolide A.Based on the network pharmacological analysis,42 overlap targets were obtained via merging the candidates targets of CX and liver fibrosis.Different aqueous,alkaloid and phthalide extracts of CX(CX_(AE),CX_(AL) and CXP_(HL))significantly inhibited diffuse severe bile duct hyperplasia and thus suppressed hepatic fibrosis by decreasing CCCTC binding factor(CTCF)-c-MYC-long non-coding RNA H19(H19)pathway in the BDL-induced mouse model.Meanwhile,CX extracts,especially CX_(AL) and CX_(PHL) also suppressed CTCF-c-MYC-H19 pathway and inhibited ductular reaction in cholangiocytes stimulated with taurocholate acid(TCA),lithocholic acid(LCA)and transforming growth factor beta(TGF-β),as illustrated by decreased bile duct proliferation markers.Conclusion:Our data supported that different CX extracts,especially CX_(AL) and CX_(PHL) significantly alleviated hepatic fibrosis and bile duct hyperplasia via inhibiting CTCF-c-MYC-H19 pathway,providing novel insights into the anti-fibrotic mechanism of CX.展开更多
Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoh...Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases.However,current treatment options are limited,highlighting the urgent need for the development of new therapies.As a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver fibrosis.Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still controversial.This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic diseases.The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted.Finally,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed.In summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.展开更多
基金supported by the National Natural Science Foundation of China(22208290)the Guangzhou Muke Biotechnology Co.,Ltd.
文摘Cyclic peptides,with their unique structures and versatile biological activities,hold great potential for combating skin aging issues such as wrinkles,laxity,and pigmentation.However,traditional discovery methods relying on iterative synthesis and screening are labor-intensive and resource-intensive.Here,we present an integrated platform combining automated rapid cyclopeptide synthesis,virtual screening,and biological activity assessment,enabling the transformation of designed cyclic peptide sequences into chemical entities within minutes with high crude purity.Using ADCP docking with the ADFR suite,we identified a series of novel cyclic peptides targeting JAK1,Keap1,and TGF-βproteins.Among these,MKC1 demonstrated optimal anti-aging efficacy,as evidenced by its reactive oxygen species(ROS)scavenging activity(20%)and significant upregulation of type I collagen genes(Col1a1a:156%,Col1a1b:87%,Col1a2:103%)and elastin(Elna:132%)at a concentration of 0.001%.This study establishes a robust foundation for the discovery and development of cyclic peptides as anti-aging active compounds.
基金supported by the Beijing Municipal Science&Technology Commission(No.7212174 to XL)National Natural Science Foundation of China(No.82004045 to XL)+2 种基金Beijing Nova Program of Science&Technology(No.Z191100001119088 to XL)the Young Talents Promotion Project of China Association of Traditional Chinese Medicine(No.2020-QNRC2-01 to XL)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202006 to XL)。
文摘Objective:Cassiae Semen(CS,Juemingzi in Chinese)has been used for thousands of years in ancient Chinese history for relieving constipation,improving liver function as well as preventing myopia.Here we aimed to elucidate the anti-steatosis effect and underlying mechanism of CS against non-alcoholic fatty liver disease(NAFLD).Methods:High-performance liquid chromatography(HPLC)was used to identify the major components of CS water extract.Mice were fed with a high-fat and sugar-water(HFSW)diet to induce hepatic steatosis and then treated with CS.The anti-NAFLD effect was determined by measuring serum biomarkers and histopathology staining.Additionally,the effects of CS on cell viability and lipid metabolism in oleic acid and palmitic acid(OAPA)-treated HepG2 cells were measured.The expression of essential genes and proteins involved in lipid metabolism and autophagy signalings were measured to uncover the underlying mechanism.Results:Five compounds,including aurantio-obtusin,rubrofusarin gentiobioside,cassiaside C,emodin and rhein were simultaneously identified in CS extract.CS not only improved the diet-induced hepatic steatosis in vivo,as indicated by decreased number and size of lipid droplets,hepatic and serum triglycerides(TG)levels,but also markedly attenuated the OAPA-induced lipid accumulation in hepatocytes.These lipid-lowering effects induced by CS were largely dependent on the inhibition of fatty acid synthase(FASN)and the activation of autophagy-related signaling,including AMP-activated protein kinase(AMPK),light chain 3-II(LC3-II)/LC3-1 and autophagy-related gene5(ATG5).Conclusion:Our study suggested that CS effectively protected liver steatosis via decreasing FASN-related fatty acid synthesis and activating AMPK-mediated autophagy,which might become a promising therapeutic strategy for relieving NAFLD.
基金supported by the Beijing Municipal Science&Technology Commission(No.7212174)the National High-Level Talents Special Support Program to XL+1 种基金National Key Research and Development Program on Modernization of Traditional Chinese Medicine(No.2022YFC3502100)National Natural Science Foundation of China(No.82004045 and No.82274186).
文摘Objective:Hepatic fibrosis has been widely considered as a conjoint consequence of almost all chronic liver diseases.Chuanxiong Rhizoma(Chuanxiong in Chinese,CX)is a traditional Chinese herbal product to prevent cerebrovascular,gynecologic and hepatic diseases.Our previous study found that CX extracts significantly reduced collagen contraction force of hepatic stellate cells(HSCs).Here,this study aimed to compare the protection of different CX extracts on bile duct ligation(BDL)-induced liver fibrosis and investigate plausible underlying mechanisms.Methods:The active compounds of CX extracts were identified by high performance liquid chromatography(HPLC).Network pharmacology was used to determine potential targets of CX against hepatic fibrosis.Bile duct hyperplasia and liver fibrosis were evaluated by serologic testing and histopathological evaluation.The expression of targets of interest was determined by quantitative real-time PCR(qPCR)and Western blot.Results:Different CX extracts were identified by tetramethylpyrazine,ferulic acid and senkyunolide A.Based on the network pharmacological analysis,42 overlap targets were obtained via merging the candidates targets of CX and liver fibrosis.Different aqueous,alkaloid and phthalide extracts of CX(CX_(AE),CX_(AL) and CXP_(HL))significantly inhibited diffuse severe bile duct hyperplasia and thus suppressed hepatic fibrosis by decreasing CCCTC binding factor(CTCF)-c-MYC-long non-coding RNA H19(H19)pathway in the BDL-induced mouse model.Meanwhile,CX extracts,especially CX_(AL) and CX_(PHL) also suppressed CTCF-c-MYC-H19 pathway and inhibited ductular reaction in cholangiocytes stimulated with taurocholate acid(TCA),lithocholic acid(LCA)and transforming growth factor beta(TGF-β),as illustrated by decreased bile duct proliferation markers.Conclusion:Our data supported that different CX extracts,especially CX_(AL) and CX_(PHL) significantly alleviated hepatic fibrosis and bile duct hyperplasia via inhibiting CTCF-c-MYC-H19 pathway,providing novel insights into the anti-fibrotic mechanism of CX.
基金supported by the National Key Research and Development Program on Modernization of Traditional Chinese Medicine(Grant No.2022YFC3502104,China)supports from VA Merit Award 5 I01 BX005730+2 种基金National Institutes of Health Grant R01 R01DK-057543 to Huiping Zhou(USA)National High-Level Talents Special Support Program to Xiaojiaoyang Li(China)Fundamental Research Funds for the Central Universities(Grant No.2023-JYBJBZD-046 to Xiaojiaoyang Li,China)。
文摘Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases.However,current treatment options are limited,highlighting the urgent need for the development of new therapies.As a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver fibrosis.Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still controversial.This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic diseases.The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted.Finally,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed.In summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.
