Western urbanization theory has crucial influence on the course of China' s urban and rural construction.Social economy and the scientific distribution of population are the key of the layout of urban and rural co...Western urbanization theory has crucial influence on the course of China' s urban and rural construction.Social economy and the scientific distribution of population are the key of the layout of urban and rural construction and an important factor in facilitating the innovative development of urban and rural construction.The continuous improvement of the environment of social resources as well as the quality of life is the focus of China' s urban and rural construction.As western urbanization theory just probes into this specific issue,it offers referential value in urging us to take the path of sustainable development in urban and rural construction.展开更多
Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in ...Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.展开更多
OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a pote...OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.展开更多
OBJECTIVE Cytochrome P450(CYP)2J2 is highly expressed in many kinds of human tumors and promotes tumor cell growth via regulating the metabolism of arachidonic acids.The purposes of this study were toidentify the new ...OBJECTIVE Cytochrome P450(CYP)2J2 is highly expressed in many kinds of human tumors and promotes tumor cell growth via regulating the metabolism of arachidonic acids.The purposes of this study were toidentify the new inhibitor of CYP2J2 from natural compounds and evaluate its potential to inhibit hepatoma carcinoma cells.METHODS Total fifty natural products were screened for the inhibitory potency against the activity of CYP2J2-mediated astemizole O-demethylation via LCMS/MS analysis.Enzyme kinetic and molecular docking studies were also carried out.RESULTS Our data found that plumbagin potently inhibited CYP2J2 with IC50value at 3.42,3.37 and 1.17μmol·L-1in rat liver microsomes,human liver microsomes(HLMs)and recombinant CYP2J2(rC YP2J2),respectively.Further enzyme kinetic studies showed that plumbagin was a mixed-type inhibitor of CYP2J2 in HLMs and r CYP2J2 with Kivalues of 1.88and 0.92μmol·L-1,respectively.Docking data presented that plumbagin interacted with CYP2J2 mainly through GLU222 and ALA223,which were crucial residues for substrates binding.At the same time,plumbagin showed cytotoxicity effects on hepatic carcinoma cell lines,such as HepG 2 and SMMC-7721,with IC50values at 11.55±1.06and(13.15±1.11)μmol·L-1,respectively.CONCLUSION These results indicated that plumbagin was a potent CYP2J2 inhibitor and potential anticancer agent.Further studies are needed to cover the mechanism of its antitumor activity.展开更多
OBJECTIVE Cytochrome P450(CYP)3A accounts for nearly 30%of total CYP enzymes in human liver and participates in the metabolism of over 50%of clinical drugs.CYP3A also plays an important role in the chemical metabolism...OBJECTIVE Cytochrome P450(CYP)3A accounts for nearly 30%of total CYP enzymes in human liver and participates in the metabolism of over 50%of clinical drugs.CYP3A also plays an important role in the chemical metabolism,toxicity,and carcinogenicity.New animal models are needed to investigate CYP3A functions.METHODS The CRISPR-Cas9 technology was used to generate Cyp3a1/2 double knockout rat model.The absence of Cyp3a1/2 expression was evaluated through PCR and immunostaining.Metabolic studies of the CYP3A substrates midazolam and nifedipine both in vitro and in vivo were conducted to verify that CYP3A1/2 was functional y inactive in KO rats.In addition,compensatory up-regulation of other P450 genes in Cyp3a1/2 KO rats was detected.RESULTS The Cyp3a1/2 double KO rats were viable and fertile,and had no obvious physiological abnormities.Compared with the wild-type(WT)rat,Cyp3a1/2 expression was completely absent in the liver of the KO rat.In vitro and in vivo metabolic studies of the CYP3A1/2 substrates indicated that CYP3A1/2 was functionally inactive in double KO rats.CONCLUSION The Cyp3a1/2 double KO rat model was successfully generated and characterized.The Cyp3a1/2 KO rats as a novel rodent animal model will be a valuable tool for the study of the physiological and pharmacological roles of CYP3A,and determining whether the absence of CYP3A results in non-CYP mediated metabolism or metabolism by other CYP isoforms.展开更多
基金supported by the project of Humanities and Social Sciences granted by the Ministry of Education in China entitled"Analysison the Protection and Utilization of the Drainage System of Traditional Villages under the Background of New Type of Urbanization"
文摘Western urbanization theory has crucial influence on the course of China' s urban and rural construction.Social economy and the scientific distribution of population are the key of the layout of urban and rural construction and an important factor in facilitating the innovative development of urban and rural construction.The continuous improvement of the environment of social resources as well as the quality of life is the focus of China' s urban and rural construction.As western urbanization theory just probes into this specific issue,it offers referential value in urging us to take the path of sustainable development in urban and rural construction.
基金This work was supported by the National Natural Science Foundation(82172594 and 82373046)the Hunan Graduate Research Innovation Project(CX20230318),China.
文摘Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.
基金supported by National Natural Science Foundation of China(81402482,91313303)
文摘OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
基金The project supported by National Natural Science Foundation of China(81301908)the Science and Technology Commission of Shanghai Municipality(15140904700,13ZR1412600 and 14DZ2270100)
文摘OBJECTIVE Cytochrome P450(CYP)2J2 is highly expressed in many kinds of human tumors and promotes tumor cell growth via regulating the metabolism of arachidonic acids.The purposes of this study were toidentify the new inhibitor of CYP2J2 from natural compounds and evaluate its potential to inhibit hepatoma carcinoma cells.METHODS Total fifty natural products were screened for the inhibitory potency against the activity of CYP2J2-mediated astemizole O-demethylation via LCMS/MS analysis.Enzyme kinetic and molecular docking studies were also carried out.RESULTS Our data found that plumbagin potently inhibited CYP2J2 with IC50value at 3.42,3.37 and 1.17μmol·L-1in rat liver microsomes,human liver microsomes(HLMs)and recombinant CYP2J2(rC YP2J2),respectively.Further enzyme kinetic studies showed that plumbagin was a mixed-type inhibitor of CYP2J2 in HLMs and r CYP2J2 with Kivalues of 1.88and 0.92μmol·L-1,respectively.Docking data presented that plumbagin interacted with CYP2J2 mainly through GLU222 and ALA223,which were crucial residues for substrates binding.At the same time,plumbagin showed cytotoxicity effects on hepatic carcinoma cell lines,such as HepG 2 and SMMC-7721,with IC50values at 11.55±1.06and(13.15±1.11)μmol·L-1,respectively.CONCLUSION These results indicated that plumbagin was a potent CYP2J2 inhibitor and potential anticancer agent.Further studies are needed to cover the mechanism of its antitumor activity.
基金The project supported by National Natural Science Foundation of China(81301908)the Science and Technology Commission of Shanghai Municipality(15140904700,13ZR1412600,14DZ2270100)
文摘OBJECTIVE Cytochrome P450(CYP)3A accounts for nearly 30%of total CYP enzymes in human liver and participates in the metabolism of over 50%of clinical drugs.CYP3A also plays an important role in the chemical metabolism,toxicity,and carcinogenicity.New animal models are needed to investigate CYP3A functions.METHODS The CRISPR-Cas9 technology was used to generate Cyp3a1/2 double knockout rat model.The absence of Cyp3a1/2 expression was evaluated through PCR and immunostaining.Metabolic studies of the CYP3A substrates midazolam and nifedipine both in vitro and in vivo were conducted to verify that CYP3A1/2 was functional y inactive in KO rats.In addition,compensatory up-regulation of other P450 genes in Cyp3a1/2 KO rats was detected.RESULTS The Cyp3a1/2 double KO rats were viable and fertile,and had no obvious physiological abnormities.Compared with the wild-type(WT)rat,Cyp3a1/2 expression was completely absent in the liver of the KO rat.In vitro and in vivo metabolic studies of the CYP3A1/2 substrates indicated that CYP3A1/2 was functionally inactive in double KO rats.CONCLUSION The Cyp3a1/2 double KO rat model was successfully generated and characterized.The Cyp3a1/2 KO rats as a novel rodent animal model will be a valuable tool for the study of the physiological and pharmacological roles of CYP3A,and determining whether the absence of CYP3A results in non-CYP mediated metabolism or metabolism by other CYP isoforms.
