Hepatocellular carcinoma(HCC)is one of most common and deadliest malignancies.Celastrol(Cel),a natural product derived from the Tripterygium wilfordii plant,has been extensively researched for its potential effectiven...Hepatocellular carcinoma(HCC)is one of most common and deadliest malignancies.Celastrol(Cel),a natural product derived from the Tripterygium wilfordii plant,has been extensively researched for its potential effectiveness in fighting cancer.However,its clinical application has been hindered by the unclear mechanism of action.Here,we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and antitumor capacity by developing a Cel-based liposomes in HCC.We demonstrated that Cel selectively targets the voltage-dependent anion channel 2(VDAC2).Cel directly binds to the cysteine residues of VDAC2,and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore(mPTP)function.We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells.Moreover,coencapsulation of Cel into alkyl glucoside-modified liposomes(AGCL)improved its antitumor efficacy and minimized its side effects.AGCL has been shown to effectively suppress the proliferation of tumor cells.In a xenograft nude mice experiment,AGCL significantly inhibited tumor growth and promoted apoptosis.Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death,while the Cel liposomes enhance its targetability and reduces side effects.Overall,Cel shows promise as a therapeutic agent for HCC.展开更多
Background:Aristolochic acids(AAs),a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants,are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma.Recen...Background:Aristolochic acids(AAs),a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants,are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma.Recently,accumulating evidence suggests that exposure to AAs could also induce hepatotoxicity and even hepatocellular carcinoma,though the mechanisms are poorly defined.Methods:Here,we aimed to dissect the underlying cellular and molecular mechanisms of aristolochic acid I(AAI)-induced hepatotoxicity by using advanced single-cell RNA sequencing(scRNA-seq)and proteomics techniques.We established the first single-cell atlas of mouse livers in response to AAI.Results:In hepatocytes,our results indicated that AAI activated NF-κB and STAT3 signaling pathways,which may contribute to the inflammatory response and apoptosis.In liver sinusoidal endothelial cells(LSECs),AAI activated multiple oxidative stress and inflammatory associated signaling pathways and induced apoptosis.Importantly,AAI induced infiltration of cytotoxic T cells and activation of proinflammatory macrophage and neutrophil cells in the liver to produce inflammatory cytokines to aggravate inflammation.Conclusions:Collectively,our study provides novel knowledge of AAs-induced molecular characteristics of hepatotoxicity at a singlecell level and suggests future treatment options for AAs associated hepatotoxicity.展开更多
Skipped dienes are of great importance but remain challenging to synthesize because of the presence of a sp hybrid carbon between the two alkenes.Herein,we have developed the first nickel-catalyzed regio-,(E)-stereo-a...Skipped dienes are of great importance but remain challenging to synthesize because of the presence of a sp hybrid carbon between the two alkenes.Herein,we have developed the first nickel-catalyzed regio-,(E)-stereo-and linear-selective ring-opening/cross-coupling reaction of vinylaziridines with organoboronic acids under mild conditions to construct various skipped aminodienes.The reaction exhibits wide functional-group compatibility,and could be adapted for the introduction of skipped aminodiene functionality into bioactive molecules.展开更多
基金support from the National Natural Science Foundation of China(Grants No.82304827,82074098,81841001)the Fundamental Research Funds for the Central public welfare research institutes(ZZ13-ZD-07),the National Key Research and Development Programof China(2020YFA0908000,2022YFC2303600)+7 种基金the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No:ZYYCXTD-C-202002)The Shenzhen Medical Research Fund of Shenzhen Medical Academy of Research and Translation(B2302051)the Fundamental Research Funds for the Central Public Welfare Research Institutes(Grants No.ZZ13-YQ-108)the Shenzhen Science and Technology Innovation Commission(Grants No.JCYJ20210324115800001)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases),the Distinguished Expert Project of Sichuan Province Tianfu Scholar(CW202002)Supported by Shenzhen Governmental Sustainable Development Fund(KCXFZ20201221173612034)Supported by Shenzhen key Laboratory of Kidney Diseases(ZDSYS201504301616234)Supported by Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(NO.SZGSP001).
文摘Hepatocellular carcinoma(HCC)is one of most common and deadliest malignancies.Celastrol(Cel),a natural product derived from the Tripterygium wilfordii plant,has been extensively researched for its potential effectiveness in fighting cancer.However,its clinical application has been hindered by the unclear mechanism of action.Here,we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and antitumor capacity by developing a Cel-based liposomes in HCC.We demonstrated that Cel selectively targets the voltage-dependent anion channel 2(VDAC2).Cel directly binds to the cysteine residues of VDAC2,and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore(mPTP)function.We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells.Moreover,coencapsulation of Cel into alkyl glucoside-modified liposomes(AGCL)improved its antitumor efficacy and minimized its side effects.AGCL has been shown to effectively suppress the proliferation of tumor cells.In a xenograft nude mice experiment,AGCL significantly inhibited tumor growth and promoted apoptosis.Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death,while the Cel liposomes enhance its targetability and reduces side effects.Overall,Cel shows promise as a therapeutic agent for HCC.
基金supported by the National Key Research and Development Program of China(Grant No.2020YFA0908000)the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(Grant No.ZYYCXTD-C-202002)+3 种基金the National Natural Science Foundation of China(Grants No.82074098 and 81841001)the Fundamental Research Funds for the Central Public Welfare Research Institutes(Grants No.ZXKT18003,ZZ14-YQ-050,ZZ14-ND-010,ZZ15-ND-10,ZZ14-FL-002,ZZ14-YQ-059,and ZZ15-YQ-063)the Shenzhen Science and Technology Innovation Commission(Grants No.JCYJ20210324115800001 and JCYJ20210324114014039)the National Key R&D Program of China Key Projects for International Cooperation on Science,Technology and Innovation(Grant No.2020YFE0205100).
文摘Background:Aristolochic acids(AAs),a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants,are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma.Recently,accumulating evidence suggests that exposure to AAs could also induce hepatotoxicity and even hepatocellular carcinoma,though the mechanisms are poorly defined.Methods:Here,we aimed to dissect the underlying cellular and molecular mechanisms of aristolochic acid I(AAI)-induced hepatotoxicity by using advanced single-cell RNA sequencing(scRNA-seq)and proteomics techniques.We established the first single-cell atlas of mouse livers in response to AAI.Results:In hepatocytes,our results indicated that AAI activated NF-κB and STAT3 signaling pathways,which may contribute to the inflammatory response and apoptosis.In liver sinusoidal endothelial cells(LSECs),AAI activated multiple oxidative stress and inflammatory associated signaling pathways and induced apoptosis.Importantly,AAI induced infiltration of cytotoxic T cells and activation of proinflammatory macrophage and neutrophil cells in the liver to produce inflammatory cytokines to aggravate inflammation.Conclusions:Collectively,our study provides novel knowledge of AAs-induced molecular characteristics of hepatotoxicity at a singlecell level and suggests future treatment options for AAs associated hepatotoxicity.
基金the funding support of this work by the National Natural Science Foundation of China(Nos.21831005 and 21991112)National Key R&D Program of China(No.2018YFE0126800).
文摘Skipped dienes are of great importance but remain challenging to synthesize because of the presence of a sp hybrid carbon between the two alkenes.Herein,we have developed the first nickel-catalyzed regio-,(E)-stereo-and linear-selective ring-opening/cross-coupling reaction of vinylaziridines with organoboronic acids under mild conditions to construct various skipped aminodienes.The reaction exhibits wide functional-group compatibility,and could be adapted for the introduction of skipped aminodiene functionality into bioactive molecules.
