Dear Editor,Physical exercise has been shown to be associated with reduced cancer incidence and cancer-associated mortality[1,2],but the underlying mechanisms are obscure.Immunometabolic regulation has emerged as one ...Dear Editor,Physical exercise has been shown to be associated with reduced cancer incidence and cancer-associated mortality[1,2],but the underlying mechanisms are obscure.Immunometabolic regulation has emerged as one of the most prominent mechanisms explaining the effects of exercise on cancer[1,2].Physical exercise primarily lowers blood cholesterol and triglycerides,and protects against cardiovascular diseases[3].However,whether physical exercise can modulate cholesterol metabolism in tumor cells is currently unknown.展开更多
Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechani...Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the cholesterol synthesis,selected as the potential targets,were confirmed by the molecular docking,the overexpression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.展开更多
Panax ginseng C.A.Mey.is an important plant species used in traditional Chinese medicine,whose primary active ingredient is a ginsenoside.Ginsenoside biosynthesis is not only regulated by transcription factors but als...Panax ginseng C.A.Mey.is an important plant species used in traditional Chinese medicine,whose primary active ingredient is a ginsenoside.Ginsenoside biosynthesis is not only regulated by transcription factors but also controlled by a variety of structural genes.Nonetheless,the molecular mechanism underlying ginsenoside biosynthesis has always been a topic in the discussion of ginseng secondary metabolites.Squalene epoxidase(SQE)is a key enzyme in the mevalonic acid pathway,which affects the biosynthesis of secondary metabolites such as terpenoid.Using ginseng transcriptome,expression,and ginsenoside content databases,this study employed bioinformatic methods to systematically analyze the genes encoding SQE in ginseng.We first selected six PgSQE candidates that were closely involved in ginsenoside biosynthesis and then identified PgSQE08-01 to be highly associated with ginsenoside biosynthesis.Next,we constructed the overexpression vector pCAMBIA3301-PgSQE08-01 and the RNAi vector pART27-PgSQE08-01 and transformed ginseng adventitious roots using Agrobacterium rhizogenes,to obtain positive hairy-root clones.Thereafter,quantitative reverse transcriptionpolymerase chain reaction and high-performance liquid chromatography were used to determine the expression of relevant genes and ginsenoside content,respectively.Then,we focused on the function of PgSQE08-01 gene,which was noted to be involved in ginsenoside biosynthesis.Thus,these findings not only provided a molecular basis for the identification of important functional genes in ginseng but also enriched genetic resources for the biosynthesis of ginsenosides using synthetic biology.展开更多
Lesion mimic mutants(LMMs) are advantageous materials for studying programmed cell death(PCD).Although some rice LMM genes have been cloned, the diversity of functions of these genes indicates that the mechanism of ce...Lesion mimic mutants(LMMs) are advantageous materials for studying programmed cell death(PCD).Although some rice LMM genes have been cloned, the diversity of functions of these genes indicates that the mechanism of cell death regulation in LMMs needs further study. In this study, we identified a rice light-dependent leaf lesion mimic mutant 4(llm4) that showed abnormal chloroplast structure, photoinhibition, reduced photosynthetic protein levels, massive accumulation of reactive oxygen species(ROS), and PCD. Map-based cloning and complementation testing revealed that LLM4 encodes zeaxanthin epoxidase(ZEP), an enzyme involved in the xanthophyll cycle, which functions in plant photoprotection,ROS scavenging, and carotenoid and abscisic acid(ABA) biosynthesis. The ABA content was decreased,and the contents of 24 carotenoids differed between the llm4 mutant and the wild type(WT). The llm4mutant showed reduced dormancy and greater sensitive to ABA than the WT. We concluded that the mutation of LLM4 resulted in the failure of xanthophyll cycle, in turn causing ROS accumulation. The excessive ROS accumulation damaged chloroplast structure and induced PCD, leading eventually to the formation of lesion mimics.展开更多
Background:Lung squamous cell carcinoma(Lusc)lacks effective targeted therapies and has a poor prognosis.Disruption of squalene epoxidase(SQLE)has been implicated in metabolic disorders and cancer.However,the role of ...Background:Lung squamous cell carcinoma(Lusc)lacks effective targeted therapies and has a poor prognosis.Disruption of squalene epoxidase(SQLE)has been implicated in metabolic disorders and cancer.However,the role of SQLE as a monooxygenase involved in oxidativestressremainsunclear.Methods:We analyzed the expression and prognosis of lung adenocarcinoma(LUAD)and LUSC samples from GEO and TCGA databases.The proliferative activity of the tumors after intervention of SQLE was verified by cell and animal experiments.JC-1 assay,flow cytometry,and Western blot were used to show changes in apoptosis after intervention of sQLE.Flow cytometry and fluorescence assay of ROs levels were used to indicate oxidative stress status.Results:We investigated the unique role of SQLE expression in the diagnosis and prognosis prediction of LUSC.Knockdown of SQLE or treatment with the SQLE inhibitor terbinafine can suppress the proliferation of LUsC cells by inducing apoptosis and reactive oxygen species accumulation.However,depletion of SQLE also results in the impairment of lipid peroxidation and ferroptosis resistance such as upregulation of glutathione peroxidase 4.Therefore,prevention of SQLE in synergy with glutathione peroxidase 4 inhibitor RSL3 effectively mitigates the proliferation and growth of LUSC.Conclusion:Our study indicates that the low expression of sQLE employs adaptive survival through regulating the balance of apoptosis and ferroptosis resistance.In future,the combinational therapy of targeting sQLE and ferroptosis could be a promising approach in treating LUSC.展开更多
基金This work was supported by the National Natural Science Foundation of China(82172511)the Natural Science Foundation of Jiangsu Province(BK20210068)+4 种基金the Sanming Project of Medicine in Shenzhen(SZSM201612078)the Health Shanghai Initiative Special Fund[Medical-Sports Integration(JKSHZX-2022-02)]the Top Talent Support Program for Young-and Middle-aged People of Wuxi Municipal Health Commission(HB2020003)the Mega-project of Wuxi Commission of Health(Z202216)the High-end Medical Expert Team of the 2019 Taihu Talent Plan(2019-THRCTD-1)
文摘Dear Editor,Physical exercise has been shown to be associated with reduced cancer incidence and cancer-associated mortality[1,2],but the underlying mechanisms are obscure.Immunometabolic regulation has emerged as one of the most prominent mechanisms explaining the effects of exercise on cancer[1,2].Physical exercise primarily lowers blood cholesterol and triglycerides,and protects against cardiovascular diseases[3].However,whether physical exercise can modulate cholesterol metabolism in tumor cells is currently unknown.
基金supported by the National Natural Science Foundation of China(Grant No.:82204753),the Scientific Research Staring Foundation for the New Teachers of Beijing University of Chinese Medicine(Grant No.:2020-JYB-XJSJJ-009),and Special Scientific Research for Traditional Chinese Medicine of State Administration of Traditional Chinese Medicine of China(Grant No.:201507004).The funders had no role in the study design,data collection,data analysis,interpretation,or writing of the report.
文摘Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the cholesterol synthesis,selected as the potential targets,were confirmed by the molecular docking,the overexpression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.
基金This work was supported by an award from the Department of Science and Technology of Jilin Province(20210402043GH and 20210204063YY).
文摘Panax ginseng C.A.Mey.is an important plant species used in traditional Chinese medicine,whose primary active ingredient is a ginsenoside.Ginsenoside biosynthesis is not only regulated by transcription factors but also controlled by a variety of structural genes.Nonetheless,the molecular mechanism underlying ginsenoside biosynthesis has always been a topic in the discussion of ginseng secondary metabolites.Squalene epoxidase(SQE)is a key enzyme in the mevalonic acid pathway,which affects the biosynthesis of secondary metabolites such as terpenoid.Using ginseng transcriptome,expression,and ginsenoside content databases,this study employed bioinformatic methods to systematically analyze the genes encoding SQE in ginseng.We first selected six PgSQE candidates that were closely involved in ginsenoside biosynthesis and then identified PgSQE08-01 to be highly associated with ginsenoside biosynthesis.Next,we constructed the overexpression vector pCAMBIA3301-PgSQE08-01 and the RNAi vector pART27-PgSQE08-01 and transformed ginseng adventitious roots using Agrobacterium rhizogenes,to obtain positive hairy-root clones.Thereafter,quantitative reverse transcriptionpolymerase chain reaction and high-performance liquid chromatography were used to determine the expression of relevant genes and ginsenoside content,respectively.Then,we focused on the function of PgSQE08-01 gene,which was noted to be involved in ginsenoside biosynthesis.Thus,these findings not only provided a molecular basis for the identification of important functional genes in ginseng but also enriched genetic resources for the biosynthesis of ginsenosides using synthetic biology.
基金the financial support of the National Natural Science Foundation of China (32060454, 32272109)Hainan Yazhou Bay Seed Laboratory (B21HJ0215)+1 种基金National Natural Science Foundation of China (32072048, U2004204)Specific Research Fund of The Innovation Platform for Academicians of Hainan Province。
文摘Lesion mimic mutants(LMMs) are advantageous materials for studying programmed cell death(PCD).Although some rice LMM genes have been cloned, the diversity of functions of these genes indicates that the mechanism of cell death regulation in LMMs needs further study. In this study, we identified a rice light-dependent leaf lesion mimic mutant 4(llm4) that showed abnormal chloroplast structure, photoinhibition, reduced photosynthetic protein levels, massive accumulation of reactive oxygen species(ROS), and PCD. Map-based cloning and complementation testing revealed that LLM4 encodes zeaxanthin epoxidase(ZEP), an enzyme involved in the xanthophyll cycle, which functions in plant photoprotection,ROS scavenging, and carotenoid and abscisic acid(ABA) biosynthesis. The ABA content was decreased,and the contents of 24 carotenoids differed between the llm4 mutant and the wild type(WT). The llm4mutant showed reduced dormancy and greater sensitive to ABA than the WT. We concluded that the mutation of LLM4 resulted in the failure of xanthophyll cycle, in turn causing ROS accumulation. The excessive ROS accumulation damaged chloroplast structure and induced PCD, leading eventually to the formation of lesion mimics.
基金the National Natural Science Foundation of China(Grant No.92159302,W.L.)Science and Technology Project of Sichuan(Grant No.2022ZDZX0018,W.L.)+6 种基金1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(Grant No.ZYGD22009,W.L.)National Key R&D program of China(Grant No.2022YFC2505000)NSFC general program(Grant No.82272796)NSFC special program(Grant No.82241229)CAMS Innovation Fund for Medical Sciences(Grant No.CIFMS 2022-I2M-1-009)CAMS Key Laboratory of Translational Research on Lung Cancer(Grant No.2018PT31035)the Aiyou foundation(Grant No.KY201701).
文摘Background:Lung squamous cell carcinoma(Lusc)lacks effective targeted therapies and has a poor prognosis.Disruption of squalene epoxidase(SQLE)has been implicated in metabolic disorders and cancer.However,the role of SQLE as a monooxygenase involved in oxidativestressremainsunclear.Methods:We analyzed the expression and prognosis of lung adenocarcinoma(LUAD)and LUSC samples from GEO and TCGA databases.The proliferative activity of the tumors after intervention of SQLE was verified by cell and animal experiments.JC-1 assay,flow cytometry,and Western blot were used to show changes in apoptosis after intervention of sQLE.Flow cytometry and fluorescence assay of ROs levels were used to indicate oxidative stress status.Results:We investigated the unique role of SQLE expression in the diagnosis and prognosis prediction of LUSC.Knockdown of SQLE or treatment with the SQLE inhibitor terbinafine can suppress the proliferation of LUsC cells by inducing apoptosis and reactive oxygen species accumulation.However,depletion of SQLE also results in the impairment of lipid peroxidation and ferroptosis resistance such as upregulation of glutathione peroxidase 4.Therefore,prevention of SQLE in synergy with glutathione peroxidase 4 inhibitor RSL3 effectively mitigates the proliferation and growth of LUSC.Conclusion:Our study indicates that the low expression of sQLE employs adaptive survival through regulating the balance of apoptosis and ferroptosis resistance.In future,the combinational therapy of targeting sQLE and ferroptosis could be a promising approach in treating LUSC.
