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
The significance of the heme-metabolizing enzyme heme oxygenase-1(HMOx1)in the pathogenesis of colorectal cancer(CRC)has not been fully explored.HMOx1 cytoprotection is imperative to limit oxidative stress.However,its...The significance of the heme-metabolizing enzyme heme oxygenase-1(HMOx1)in the pathogenesis of colorectal cancer(CRC)has not been fully explored.HMOx1 cytoprotection is imperative to limit oxidative stress.However,its roles in preventing carcinogenesis in response to high levels of heme are not thoroughly understood.This study re-views various mechanisms associated with the paradoxical role of HMOx1,which is advantageous for tumor growth,refractoriness,and survival of cancer cells amid oxidative stress in heme-induced CRC.The alternate role of HMOx1 promotes cell proliferation and metastasis through immune modulation and angiogenesis.Inhibiting HMOx1 has been found to reverse tumor promotion.Thus,HMOx1 acts as a conditional tumor promoter in CRC pathogenesis.展开更多
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
Accumulating studies have demonstrated that hyperbaric oxygen(HBO)treatment alleviates spinal cord injury(SCI).However,the underlying mechanism by which HBO alleviates SCI remains to be elucidated.In this study,we per...Accumulating studies have demonstrated that hyperbaric oxygen(HBO)treatment alleviates spinal cord injury(SCI).However,the underlying mechanism by which HBO alleviates SCI remains to be elucidated.In this study,we performed genome-wide transcriptional profiling of the spinal cord between SCI mice and mice that received HBO treatment by high-throughput RNA sequencing at 1 week after SCI.We also compared genome-wide transcriptional profiles from SCI mice and sham-operated mice.We found 76 differentially co-expressed genes in sham-operated mice,SCI mice,and HBO-treated SCI mice.Using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis,we identified the biological characteristics of these differentially expressed genes from the perspectives of cell component,biological process,and molecular function.We also found enriched functional pathways including ferroptosis,calcium signaling pathway,serotonergic synapse,hypoxia-inducible factor-1 signaling pathway,cholinergic synapse,and neuroactive ligand-receptor interaction.We performed quantitative reverse transcription-polymerase chain reaction and validated that HBO treatment decreased the expression of Hspb1(heat shock protein beta 1),Hmox1(heme oxygenase 1),Ftl1(ferritin light polypeptide 1),Tnc(tenascin C)and Igfbp3(insulin-like growth factor binding protein 3)and increased the expression of Slc5a7(solute carrier family 5 choline transporter member 7)after SCI.These results revealed the genome-wide transcriptional profile of the injured spinal cord after HBO treatment.Our findings contribute to a better understanding of the mechanism by which HBO treats SCI and may provide new targets for SCI intervention.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
Background:Now that the epidemic of new coronavirus pneumonia(corona virus disease 2019)is spreading all over the world,Jinhuaqinggan granules in the Chinese treatment plan has been proved to be an effective Chinese p...Background:Now that the epidemic of new coronavirus pneumonia(corona virus disease 2019)is spreading all over the world,Jinhuaqinggan granules in the Chinese treatment plan has been proved to be an effective Chinese patent medicine for the treatment of corona virus disease 2019.Methods:This study aims to clarify the possible therapeutic mechanism governing the efficacy of Jinhuaqinggan granules in the treatment of corona virus disease 2019,through using network pharmacology and molecular docking.During the analysis,227 active components were obtained and screened by using the ADME method.Furthermore,282 Jinhuaqinggan granule targets and 56 common targets with corona virus disease 2019 were gathered from various databases.Then the protein-protein interaction network of Jinhuaqinggan granules and corona virus disease 2019 targets were constructed and 6 core targets were selected through network topology analysis.In addition,A total of 262 biological function annotation entries(P<0.01)and 101 pathways(P<0.01)were obtained by gene ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis.Results:Molecular docking showed that quercetin,luteolin,kaempferol,wogonin and naringin had an affinity for SARS-CoV-23CL hydrolase and angiotensin-converting enzyme 2.Conclusion:corona virus disease 2019 can be prevented by the primary targets of Jinhuaqinggan granules.The most important bioactive components in Jinhuaqinggan granules-quercetin,naringenin,luteolin and wogonin-can play antiviral effect,anti-inflammatory storm,regulate immunity by regulating signal transducers and activators of transcription 1,interleukin 4,interferon-γ,heme oxygenase 1 and acting on the lipopolysaccharide response,toll-like receptor signaling pathway,mitogen-activated protein kinase signaling pathway,etc.展开更多
Osteoarthritis(OA)is a chronic progressive osteoarthropathy in the elderly.Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in early OA.However,the specific mechanism of osteoclast...Osteoarthritis(OA)is a chronic progressive osteoarthropathy in the elderly.Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in early OA.However,the specific mechanism of osteoclast differentiation in OA remains unclear.In our study,gene expression profiles related to OA disease progression and osteoclast activation were screened from the Gene Expression Omnibus(GEO)repository.GEO2R and Funrich analysis tools were employed to find differentially expressed genes(DEGs).Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses demonstrated that chemical carcinogenesis,reactive oxygen species(ROS),and response to oxidative stress were mainly involved in osteoclast differentiation in OA subchondral bone.Furthermore,fourteen DEGs that are associated with oxidative stress were identified.The first ranked differential gene,heme oxygenase 1(HMOX1),was selected for further validation.Related results showed that osteoclast activation in the pathogenesis of OA subchondral bone is accompanied by the downregulation of HMOX1.Carnosol was revealed to inhibit osteoclastogenesis by targeting HMOX1 and upregulating the expression of antioxidant protein in vitro.Meanwhile,carnosol was found to alleviate the severity of OA by inhibiting the activation of subchondral osteoclasts in vivo.Our research indicated that the activation of osteoclasts due to subchondral bone redox dysplasia may serve as a significant pathway for the advancement of OA.Targeting HMOX1 in subchondral osteoclasts may offer novel insights for the treatment of early OA.展开更多
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.
文摘The significance of the heme-metabolizing enzyme heme oxygenase-1(HMOx1)in the pathogenesis of colorectal cancer(CRC)has not been fully explored.HMOx1 cytoprotection is imperative to limit oxidative stress.However,its roles in preventing carcinogenesis in response to high levels of heme are not thoroughly understood.This study re-views various mechanisms associated with the paradoxical role of HMOx1,which is advantageous for tumor growth,refractoriness,and survival of cancer cells amid oxidative stress in heme-induced CRC.The alternate role of HMOx1 promotes cell proliferation and metastasis through immune modulation and angiogenesis.Inhibiting HMOx1 has been found to reverse tumor promotion.Thus,HMOx1 acts as a conditional tumor promoter in CRC pathogenesis.
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.
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 Natural Science Foundation of Beijing, No.7202055(to XHL)
文摘Accumulating studies have demonstrated that hyperbaric oxygen(HBO)treatment alleviates spinal cord injury(SCI).However,the underlying mechanism by which HBO alleviates SCI remains to be elucidated.In this study,we performed genome-wide transcriptional profiling of the spinal cord between SCI mice and mice that received HBO treatment by high-throughput RNA sequencing at 1 week after SCI.We also compared genome-wide transcriptional profiles from SCI mice and sham-operated mice.We found 76 differentially co-expressed genes in sham-operated mice,SCI mice,and HBO-treated SCI mice.Using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis,we identified the biological characteristics of these differentially expressed genes from the perspectives of cell component,biological process,and molecular function.We also found enriched functional pathways including ferroptosis,calcium signaling pathway,serotonergic synapse,hypoxia-inducible factor-1 signaling pathway,cholinergic synapse,and neuroactive ligand-receptor interaction.We performed quantitative reverse transcription-polymerase chain reaction and validated that HBO treatment decreased the expression of Hspb1(heat shock protein beta 1),Hmox1(heme oxygenase 1),Ftl1(ferritin light polypeptide 1),Tnc(tenascin C)and Igfbp3(insulin-like growth factor binding protein 3)and increased the expression of Slc5a7(solute carrier family 5 choline transporter member 7)after SCI.These results revealed the genome-wide transcriptional profile of the injured spinal cord after HBO treatment.Our findings contribute to a better understanding of the mechanism by which HBO treats SCI and may provide new targets for SCI intervention.
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 Hebei University Talent Cultivation Project(No.521000981330)2019 Hebei University Undergraduate Innovation and Entrepreneurship Training Project(No.S201910075030).
文摘Background:Now that the epidemic of new coronavirus pneumonia(corona virus disease 2019)is spreading all over the world,Jinhuaqinggan granules in the Chinese treatment plan has been proved to be an effective Chinese patent medicine for the treatment of corona virus disease 2019.Methods:This study aims to clarify the possible therapeutic mechanism governing the efficacy of Jinhuaqinggan granules in the treatment of corona virus disease 2019,through using network pharmacology and molecular docking.During the analysis,227 active components were obtained and screened by using the ADME method.Furthermore,282 Jinhuaqinggan granule targets and 56 common targets with corona virus disease 2019 were gathered from various databases.Then the protein-protein interaction network of Jinhuaqinggan granules and corona virus disease 2019 targets were constructed and 6 core targets were selected through network topology analysis.In addition,A total of 262 biological function annotation entries(P<0.01)and 101 pathways(P<0.01)were obtained by gene ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis.Results:Molecular docking showed that quercetin,luteolin,kaempferol,wogonin and naringin had an affinity for SARS-CoV-23CL hydrolase and angiotensin-converting enzyme 2.Conclusion:corona virus disease 2019 can be prevented by the primary targets of Jinhuaqinggan granules.The most important bioactive components in Jinhuaqinggan granules-quercetin,naringenin,luteolin and wogonin-can play antiviral effect,anti-inflammatory storm,regulate immunity by regulating signal transducers and activators of transcription 1,interleukin 4,interferon-γ,heme oxygenase 1 and acting on the lipopolysaccharide response,toll-like receptor signaling pathway,mitogen-activated protein kinase signaling pathway,etc.
基金supported by the National Natural Science Foundation of China(Nos.82272157,82072425,and 82072498)the Natural Science Foundation of Jiangsu Province(No.BE2021650)+3 种基金the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions,the Program of Suzhou Health Commission(Nos.GSWS2022002 and GSWS2020121)the Jiangsu Medical Research Project(No.ZD2022014)the National and Local Engineering Laboratory of New Functional Polymer Materials(No.SDGC2205)the Special Project of Diagnosis and Treatment Technology for Key Clinical Diseases in Suzhou(No.LCZX202003),China.
文摘Osteoarthritis(OA)is a chronic progressive osteoarthropathy in the elderly.Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in early OA.However,the specific mechanism of osteoclast differentiation in OA remains unclear.In our study,gene expression profiles related to OA disease progression and osteoclast activation were screened from the Gene Expression Omnibus(GEO)repository.GEO2R and Funrich analysis tools were employed to find differentially expressed genes(DEGs).Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses demonstrated that chemical carcinogenesis,reactive oxygen species(ROS),and response to oxidative stress were mainly involved in osteoclast differentiation in OA subchondral bone.Furthermore,fourteen DEGs that are associated with oxidative stress were identified.The first ranked differential gene,heme oxygenase 1(HMOX1),was selected for further validation.Related results showed that osteoclast activation in the pathogenesis of OA subchondral bone is accompanied by the downregulation of HMOX1.Carnosol was revealed to inhibit osteoclastogenesis by targeting HMOX1 and upregulating the expression of antioxidant protein in vitro.Meanwhile,carnosol was found to alleviate the severity of OA by inhibiting the activation of subchondral osteoclasts in vivo.Our research indicated that the activation of osteoclasts due to subchondral bone redox dysplasia may serve as a significant pathway for the advancement of OA.Targeting HMOX1 in subchondral osteoclasts may offer novel insights for the treatment of early OA.
