HMOX1 is an important functional candidate gene for chicken blue egg in view of its role in biosynthesis of biliverdin for blue egg coloration. To elucidate molecular mechanism of blue egg formation, this study detect...HMOX1 is an important functional candidate gene for chicken blue egg in view of its role in biosynthesis of biliverdin for blue egg coloration. To elucidate molecular mechanism of blue egg formation, this study detected expression of HMOX1 in blue-shelled chickens and brown-shelled chickens. Expression and alternative splicing of HMOX1 were detected by Northern blot, expression traits of HO-1 protein in shell glands of blue- （n=4） and brown-shelled （n=4） chickens were analyzed by immunohistochemistry. 3＇ UTR of HMOX1 was cloned using 3＇RACE. Results showed that the expression of HMOX1 at mRNA level had no significant difference between two groups of chickens, but at protein level HO-1 protein was highly expressed in blue-shelled chickens. Immunohistochemistry analysis showed that HO-1 protein expression was predominately located in villus epithelial cell of shell gland. Length of HMOX1 3＇ UTR were 586 bp. In 3＇ UTR we found a SNP of rs13866562 showing significant association with blue egg phenotype. Further miRNA prediction showed that it might influence interaction of some miRNAs and target sequences. The data suggested that blue egg is relevant to high expression of HO-1 in villus epithelial cell of shell gland. Further experimental validation for biological relevance of miRNAs is dispensable to elucidate reason for differential expressions of HO-1 protein.展开更多
Background:Gallbladder cancer(GBC)is the most common malignant tumor of biliary tract.Isoliquiritigenin(ISL)is a natural compound with chalcone structure extracted from the roots of licorice and other plants.Relevant ...Background:Gallbladder cancer(GBC)is the most common malignant tumor of biliary tract.Isoliquiritigenin(ISL)is a natural compound with chalcone structure extracted from the roots of licorice and other plants.Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors.However,the research of ISL against GBC has not been reported,which needs to be further investigated.Methods:The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test,RNA-sequencing,quantitative real-time polymerase chain reaction,reactive oxygen species(ROS)detection,lipid peroxidation detection,ferrous ion detection,glutathione disulphide/glutathione(GSSG/GSH)detection,lentivirus transfection,nude mice tumorigenesis experiment and immunohistochemistry.Results:ISL significantly inhibited the proliferation of GBC cells in vitro.The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC,and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis.Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells.Moreover,ISL significantly reversed the iron content,ROS level,lipid peroxidation level and GSSG/GSH ratio of GBC cells.Finally,ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4.Conclusion:ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and downregulating GPX4 in vitro and in vivo.This evidence may provide a new direction for the treatment of GBC.展开更多
Most deaths from the COVID-19 pandemic are due to acute respiratory distress syndrome(ARDS)-related respiratory failure.Cytokine storms and oxidative stress are the major players in ARDS development during respiratory...Most deaths from the COVID-19 pandemic are due to acute respiratory distress syndrome(ARDS)-related respiratory failure.Cytokine storms and oxidative stress are the major players in ARDS development during respiratory virus infections.However,it is still unknown how oxidative stress is regulated by viral and host factors in response to SARS-CoV-2 infection.Here,we found that activation of NRF2/HMOX1 significantly suppressed SARS-CoV-2 replication in multiple cell types by producing the metabolite biliverdin,whereas SARS-CoV-2 impaired the NRF2/HMOX1 axis through the action of the nonstructural viral protein NSP14.Mechanistically,NSP14 interacts with the catalytic domain of the NAD-dependent deacetylase Sirtuin 1(SIRT1)and inhibits its ability to activate the NRF2/HMOX1 pathway.Furthermore,both genetic and pharmaceutical evidence corroborated the novel antiviral activity of SIRT1 against SARS-CoV-2.Therefore,our findings reveal a novel mechanism by which SARS-CoV-2 dysregulates the host antioxidant defense system and emphasize the vital role played by the SIRT1/NRF2 axis in host defense against SARS-CoV-2.展开更多
Arsenic,a naturally occurring toxic element,manifests in various chemical forms and is widespread in the environment.Exposure to arsenic is a well-established risk factor for an elevated incidence of various cancers a...Arsenic,a naturally occurring toxic element,manifests in various chemical forms and is widespread in the environment.Exposure to arsenic is a well-established risk factor for an elevated incidence of various cancers and chronic diseases.The crux of arsenic-mediated toxicity lies in its ability to induce oxidative stress,characterized by an unsettling imbalance between oxidants and antioxidants,accompanied by the rampant generation of reactive oxygen species and free radicals.In response to this oxidative turmoil,cells deploy their defensemechanisms,prominently featuring the redox-sensitive transcription factor known as nuclear factor erythroid 2-related factor 2(NRF2).NRF2 stands as a primary guardian against the oxidative harm wrought by arsenic.When oxidative stress activates NRF2,it orchestrates a symphony of downstream antioxidant genes,leading to the activation of pivotal antioxidant enzymes like glutathione-S-transferase,heme oxygenase-1,and NAD(P)H:quinone oxidoreductase 1.This comprehensive review embarks on the intricate and diverse ways by which various arsenicals influence the NRF2 antioxidant pathway and its downstream targets,shedding light on their roles in defending against arsenic exposure toxic effects.It offers valuable insights into targeting NRF2 as a strategy for safeguarding against or treating the harmful and carcinogenic consequences of arsenic exposure.展开更多
文摘目的:检测Cd2+处理的He La细胞模型中HMOX1的表达变化,初步探索调控HMOX1转录的启动子的活化区域.方法:通过RT-PCR和Western Blot检测HMOX1m RNA与蛋白水平变化;通过系列报告基因检测初步鉴定HMOX1启动子的活化区域.结果:Cd2+处理的He La细胞模型中,和对照组0h相比,各处理组HMOX1 m RNA与蛋白水平变化显著上调,差异有统计学意义(P<0.05);报告基因检测HMOX1-577-+92启动子片段荧光素酶相对活性显著低于其他组,差异有统计学意义(P<0.05),HMOX1-120-+92启动子片段荧光素酶相对活性也显著降低,差异有统计学意义(P<0.05).结论:Cd2+处理He La细胞模型中,HMOX1 m RNA与蛋白水平显著上调;HMOX1启动子-577^-470片段内存在抑制性转录因子结合位点,-692^-577和-272^-120片段内存在激活性转录因子结合位点.
基金Supported by the Northwest Scientific Startup Foundation for Doctor(Z109021112)the National Nature Science Foundation(31072024)Lueyang Chicken Breeding Project of Northwest A&F University(Z109021127)
文摘HMOX1 is an important functional candidate gene for chicken blue egg in view of its role in biosynthesis of biliverdin for blue egg coloration. To elucidate molecular mechanism of blue egg formation, this study detected expression of HMOX1 in blue-shelled chickens and brown-shelled chickens. Expression and alternative splicing of HMOX1 were detected by Northern blot, expression traits of HO-1 protein in shell glands of blue- （n=4） and brown-shelled （n=4） chickens were analyzed by immunohistochemistry. 3＇ UTR of HMOX1 was cloned using 3＇RACE. Results showed that the expression of HMOX1 at mRNA level had no significant difference between two groups of chickens, but at protein level HO-1 protein was highly expressed in blue-shelled chickens. Immunohistochemistry analysis showed that HO-1 protein expression was predominately located in villus epithelial cell of shell gland. Length of HMOX1 3＇ UTR were 586 bp. In 3＇ UTR we found a SNP of rs13866562 showing significant association with blue egg phenotype. Further miRNA prediction showed that it might influence interaction of some miRNAs and target sequences. The data suggested that blue egg is relevant to high expression of HO-1 in villus epithelial cell of shell gland. Further experimental validation for biological relevance of miRNAs is dispensable to elucidate reason for differential expressions of HO-1 protein.
基金supported by grants from the National Natural Science Foundation of China(Nos.3213000192,81874181,and 31620103910)the Science and Technology Commission of Shanghai Municipality(No.20JC1419101).
文摘Background:Gallbladder cancer(GBC)is the most common malignant tumor of biliary tract.Isoliquiritigenin(ISL)is a natural compound with chalcone structure extracted from the roots of licorice and other plants.Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors.However,the research of ISL against GBC has not been reported,which needs to be further investigated.Methods:The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test,RNA-sequencing,quantitative real-time polymerase chain reaction,reactive oxygen species(ROS)detection,lipid peroxidation detection,ferrous ion detection,glutathione disulphide/glutathione(GSSG/GSH)detection,lentivirus transfection,nude mice tumorigenesis experiment and immunohistochemistry.Results:ISL significantly inhibited the proliferation of GBC cells in vitro.The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC,and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis.Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells.Moreover,ISL significantly reversed the iron content,ROS level,lipid peroxidation level and GSSG/GSH ratio of GBC cells.Finally,ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4.Conclusion:ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and downregulating GPX4 in vitro and in vivo.This evidence may provide a new direction for the treatment of GBC.
基金National Institute of Health(NIH)grants(AI069120,AI158154 and AI149718)the UCLA AIDS Institute and UCLA David Geffen School of Medicine-Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award Program.
文摘Most deaths from the COVID-19 pandemic are due to acute respiratory distress syndrome(ARDS)-related respiratory failure.Cytokine storms and oxidative stress are the major players in ARDS development during respiratory virus infections.However,it is still unknown how oxidative stress is regulated by viral and host factors in response to SARS-CoV-2 infection.Here,we found that activation of NRF2/HMOX1 significantly suppressed SARS-CoV-2 replication in multiple cell types by producing the metabolite biliverdin,whereas SARS-CoV-2 impaired the NRF2/HMOX1 axis through the action of the nonstructural viral protein NSP14.Mechanistically,NSP14 interacts with the catalytic domain of the NAD-dependent deacetylase Sirtuin 1(SIRT1)and inhibits its ability to activate the NRF2/HMOX1 pathway.Furthermore,both genetic and pharmaceutical evidence corroborated the novel antiviral activity of SIRT1 against SARS-CoV-2.Therefore,our findings reveal a novel mechanism by which SARS-CoV-2 dysregulates the host antioxidant defense system and emphasize the vital role played by the SIRT1/NRF2 axis in host defense against SARS-CoV-2.
基金supported by the Natural Sciences and Engineering Research Council of Canada(NSERC)Discovery Grant[RGPIN 250139]to A.O.S.E.
文摘Arsenic,a naturally occurring toxic element,manifests in various chemical forms and is widespread in the environment.Exposure to arsenic is a well-established risk factor for an elevated incidence of various cancers and chronic diseases.The crux of arsenic-mediated toxicity lies in its ability to induce oxidative stress,characterized by an unsettling imbalance between oxidants and antioxidants,accompanied by the rampant generation of reactive oxygen species and free radicals.In response to this oxidative turmoil,cells deploy their defensemechanisms,prominently featuring the redox-sensitive transcription factor known as nuclear factor erythroid 2-related factor 2(NRF2).NRF2 stands as a primary guardian against the oxidative harm wrought by arsenic.When oxidative stress activates NRF2,it orchestrates a symphony of downstream antioxidant genes,leading to the activation of pivotal antioxidant enzymes like glutathione-S-transferase,heme oxygenase-1,and NAD(P)H:quinone oxidoreductase 1.This comprehensive review embarks on the intricate and diverse ways by which various arsenicals influence the NRF2 antioxidant pathway and its downstream targets,shedding light on their roles in defending against arsenic exposure toxic effects.It offers valuable insights into targeting NRF2 as a strategy for safeguarding against or treating the harmful and carcinogenic consequences of arsenic exposure.
