Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulator...Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.展开更多
This study aims to thoroughly investigate the axial power peaking factors (PPF) within the low-enriched uranium (LEU) core of the Ghana Research Reactor-1 (GHARR-1). This study uses advanced simulation tools, like the...This study aims to thoroughly investigate the axial power peaking factors (PPF) within the low-enriched uranium (LEU) core of the Ghana Research Reactor-1 (GHARR-1). This study uses advanced simulation tools, like the MCNPX code for analysing neutron behavior and the PARET/ANL code for understanding power variations, to get a clearer picture of the reactor’s performance. The analysis covers the initial six years of GHARR-1’s operation and includes projections for its whole 60-year lifespan. We closely observed the patterns of both the highest and average PPFs at 21 axial nodes, with measurements taken every ten years. The findings of this study reveal important patterns in power distribution within the core, which are essential for improving the safety regulations and fuel management techniques of the reactor. We provide a meticulous approach, extensive data, and an analysis of the findings, highlighting the significance of continuous monitoring and analysis for proactive management of nuclear reactors. The findings of this study not only enhance our comprehension of nuclear reactor safety but also carry significant ramifications for sustainable energy progress in Ghana and the wider global context. Nuclear engineering is essential in tackling global concerns, such as the demand for clean and dependable energy sources. Research on optimising nuclear reactors, particularly in terms of safety and efficiency, is crucial for the ongoing advancement and acceptance of nuclear energy.展开更多
Objective To analyze the association of variants of hepatocyte nuclear factor-1α （HNF-1α） gene with type 2 diabetes in Chinese population. Methods In 152 unrelated type 2 diabetes patients and 93 unrelated control...Objective To analyze the association of variants of hepatocyte nuclear factor-1α （HNF-1α） gene with type 2 diabetes in Chinese population. Methods In 152 unrelated type 2 diabetes patients and 93 unrelated controls, eleven single nucleotide polymorphisms （SNPs） were identified and genotyped. Statistical analyses were performed to investigate whether these SNPs were associated with diabetes status in our samples. Results In the individual SNP study, no SNP differed significantly in frequency between type 2 diabetes patients and controls. In the haplotype analysis, two haplotype blocks were identified. In haplotype block 1, no evidence was found between common HNF-1α haplotypes and type 2 diabetes. However, in haplotype block 2, a common haplotype GCGC formed by four tagging SNPs （tSNPs） was found to be associated with decreased risk of type 2 diabetes （odds ratio [OR] 0.6011, 95% confidence interval [CI] 0.4138-0.8732, P=0.0073, empirical P=0.0511, permutation test）. A similar trend was also observed in the diplotype analysis, indicating that the increasing copy number of the haplotype GCGC was associated with the decreased frequency of diabetes （P=0.0193）. Conclusion The results of this study provide evidence that the haplotype of HNF-1α decreases the risk of type 2 diabetes in Chinese individuals.展开更多
BACKGROUND Renal cysts and diabetes(RCAD)syndrome is an autosomal dominant diabetic renal disease.Precise molecular diagnosis of RCAD syndrome has proven valuable for understanding its mechanism and personalized thera...BACKGROUND Renal cysts and diabetes(RCAD)syndrome is an autosomal dominant diabetic renal disease.Precise molecular diagnosis of RCAD syndrome has proven valuable for understanding its mechanism and personalized therapy.CASE SUMMARY A RCAD patient and her family were studied to investigate potential responsible genes by the whole exome sequencing(WES).Candidate pathogenic variants were validated by Sanger sequencing.The clinical characteristics of RCAD patient were collected from medical records.Unlike those typical RCAD patients,we observed renal manifestation and prediabetes phenotype,but not reproductive organ phenotype and hypomagnesaemia.A novel 7-bp deletion mutation in exon 4 of the hepatocyte nuclear factor 1B,NM_000458:c.882_888del(p.V294fs),was identified by WES and confirmed by Sanger sequencing.CONCLUSION This novel mutation identified in a Chinese family with RCAD syndrome might be the molecular pathogenic basis of this disorder.展开更多
Aim In diabetic patients, metformin appears to provide cardiovascular protection that cannot be attribu- ted only to its antihyperglycemic effects. Metformin is also known as the AMP-activated protein kinase （AMPK） ...Aim In diabetic patients, metformin appears to provide cardiovascular protection that cannot be attribu- ted only to its antihyperglycemic effects. Metformin is also known as the AMP-activated protein kinase （AMPK） ac- tivator. Our previous study suggested that metformin inhibits transforming growth factor-β1 （TGF-β1） production in a mouse heart failure model of pressure overload. TGF-β1 is a key factor in cardiac fibrosis and is usually induced by Angiotensin Ⅱ （Ang Ⅱ ） in the pressure overload mouse models. This study investigated the effect of metformin on cardiac fibrosis and TGF-β production induced by AngII and the underlying mechanisms. Methods C57/BL6 wild-type and AMPKα2 knockout mice were used. AngII （3 mg · kg-1 · d-1） was infused subcutaneously into mice for 7 days. Adult mouse cardiac fibroblasts were isolated and treated with AngII （ 1 μmol · L-1） and/or met- formin （1 mmol · L-l）. Results In C57/BL6 mice, metformin inhibits AngII-induced cardiac fibrosis. In cardi-ac fibroblasts, metformin inhibits TGF-β1 expression and production induced by AngII. AMPK inhibitor, com- pound C, reversed the effects of metformin. In vivo, AMPKα2 deficiency further increases AngII-induced TGF-β1 production. In cardiac fibroblasts, metformin inhibited AngII induced hepatocyte nuclear factor4 （HNF4ot protein level increase and HNF4α binding with TGF-β1 promoter using chromatin immunoprecipitation assay. In vivo, AMPKα2 deficiency further increased AngII-induced HNF4α protein level. Using HNF4α adenovirus, overexpress- ing HNF4α led to a 1.5-fold increase in TGF-β1 mRNA expression. HNF4a siRNA blocked AngII induced TGF- β1 production. Luciferase reporter with deleted HNF4a binding sites showed decreased TGFbl transcriptional activ- ity induced by AngII. In AMPK or2-/- heart, the inhibition of metformin on HNF4a protein was attenuated. Con- clusion Metformin inhibits AngII induced cardiac fibrosis and TGF-β1 production through AMPK activation. The underlying mechanism is that AMPK activation inhibits AngII induced HNF4α and then decreases TGF-β1 expres- sion.展开更多
We present 2 cases of hepatocyte nuclear factor 1α (HNF1α)-mutated adenomatosis, discovered for reasons unrelated to this disease, and identified using immunohistochemical methods. These new tools may further our un...We present 2 cases of hepatocyte nuclear factor 1α (HNF1α)-mutated adenomatosis, discovered for reasons unrelated to this disease, and identified using immunohistochemical methods. These new tools may further our understanding of the link between adenomas/adenomatosis subtypes and their complications, and their association with other abnormalities.展开更多
Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkin...Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.展开更多
Objective:To observe the preventive and control effect of matrine on transforming growth factor(TCF- β1) and hepatocyte.growth factor(HCF) of liver fibrosis tissue in rals.Methods:A total of48 SD rats were randomly d...Objective:To observe the preventive and control effect of matrine on transforming growth factor(TCF- β1) and hepatocyte.growth factor(HCF) of liver fibrosis tissue in rals.Methods:A total of48 SD rats were randomly divided into A,B,C,D groups with 12 in each,group A as the normal control group and groups B.C,D as liver fibrosis models using composite modulus method with carbon tetrachloride(CCL_4).Group B was the model group,group C adopted γ— interferon lavage therapy in the second day of modeling,and group D adopted matrine lavage treatment,at 4 and8 weeks after treatment.Six rats were executed for detection of TGF- β1 and HGF,liver tissue histology and comparison fibrosis degree changes of rat liver tissue between groups.Results:Croups B,C,D showed a more significantly increased TCF- β1 at each time point compared with group A(P<0.05);Group B showed a more significantly increased TGF- β1 than groups C and D at weeks 4 and 8(P<0.05);group D showed a lowest level of TGF-β1,followed by groups C and B.HGF of group B decreased more significantly than A group at weeks 4 and 8(P<0.05);HGF of groups C and D was significantly elevated at 4 and 8 weeks than groups A and B(P<0.05),in which the group D showed the highest level of HGF.According to tissue histologic observation,rat liver tissue structure of group A was clear and normal,tissue structure of group B was destroyed with obvious fibrous tissue hyperplasia and fatty change of hepatic cells;groups C and D showed a slighter liver tissue damage,cell necrosis and connective tissue hyperplasia in collect abbacy than group B with a trend of obvious improvement.Conclusions:Matrine can reduce TGF- β1expression and enhance the activity of HGF,so as to realize the inhibition effect on liver fibrosis in rats.展开更多
AIM: To provide the expression profile of serine protease SNC19/matriptase and its inhibitor hepatocyte growth factor activator inhibitor type 1 (HAI-1) in normal and malignant tissues of gastrointestinal tract at mRN...AIM: To provide the expression profile of serine protease SNC19/matriptase and its inhibitor hepatocyte growth factor activator inhibitor type 1 (HAI-1) in normal and malignant tissues of gastrointestinal tract at mRNA level for further study on their correlations with tumor progression and metastasis. METHODS: Total RNAs were prepared from 37 samples of colorectal cancer tissues, 40 samples of gastric cancer tissues, and their adjacent normal tissues. The expression of SNC19/matriptase and HAM in these samples was detected by real-time fluorescent quantitative PCR using glyceraldehyde-3-phosphate dehydrogenase as internal standard, and the clinical significance for the correlation with clinicopathological parameters was evaluated. RESULTS: In gastric cancer tissues the expression of HAI-1 and SNC19/matriptase was significantly lower than that in the corresponding adjacent normal tissues (Z=-3.280, P= 0.006; Z=-4.651, P=0.000). HAI-1:SNC19/matriptase ratio showed no difference between normal and malignant tissues (P>0.05). Analysis of clinicopathological parameters showed decreased expression of HAM and HAI-1:SNC19/ matriptase ratio associated with stage Ⅲ/Ⅳ gastric tumors as compared to stage Ⅰ/Ⅱ ones (Z = -2.140, P= 0.031; Z= -2.155, P= 0.031), and with lymph node-positive gastric cancer tissues as compared to lymph node-negative ones (Z= -2.081, P= 0.036; Z= -2.686, P= 0.006). The expression of SNC19/matriptase had no relationship with stages and lymph node metastasis (P>0.05). The expression of HAM and HAM:SNC19/matriptase ratio increased in well-differentiated gastric cancer tissues, but there was no statistical significance (P>0.05). The difference of SNC19/matriptase expression was not significant in gastric cancer tissues of different histological differentiation status (P>0.05). In colorectal cancer tissues, the expression of HAI-1 and SNC19/matriptase was also markedly lower than that in their adjacent normal tissues (Z=-3.100, P=0.002; Z=-2.731, P=0.006), whereas HAI-1:SNC19/matriptase ratio showed no difference. Decreased expression of HAI-1 was associated with increased invasive depth and lymph node metastasis, but there was no statistical significance (P>0.05). The difference of SNC19/matriptase expression and HAI-1: SNC19/matriptase ratio was not significant in different stages and different lymph node metastasis status (P>0.05). The expression of SNC19/matriptase, HAI-1 or HAI-1: SNC19/matriptase ratio showed no difference in colorectal cancer tissues of different histological differentiation status (P>0.05). CONCLUSION: The expressions of SNC19/matriptase and its inhibitor HAI-1 are decreased in gastrointestinal cancer tissues compared to their normal counterparts, and the decreased expression of HAI-1 may correlate with invasion and lymph node metastasis. The possible mechanisms involved need to be further investigated.展开更多
Objective To study the influence of hepatocyte growth factor (HGF) antibody on the lung expression level of matrix metalloproteinases-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Methods Thirty male...Objective To study the influence of hepatocyte growth factor (HGF) antibody on the lung expression level of matrix metalloproteinases-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Methods Thirty male Wistar rats were randomly divided into 3 groups: control group, model group, and intervention group. Endotoxin was intratracheally infused in the model and intervention groups. HGF antibody was injected in the rats of the intervention group from day 1 to day 14, while the same volume of saline was injected in the control group. The rats were sacrificed on day 28 after endotoxin treatment. The amounts of MMP-9 mRNA and TIMP-1 mRNA were measured by reverse transcription-polymerase chain reaction, and protein expression levels of MMP-9 and TIMP-1 were measured by immunohistochemistry. Results In the model group, both mRNA and protein expression levels of TIMP-1 were significantly increased, the same as MMP-9. In the intervention group, the increase of TIMP-1 was remarkably reduced compared with the model group, while the mRNA and protein expression levels of MMP-9 were still increased. Conclusion HGF activity may accelerate the repair of lung injury through contrary regulating the expression levels of TIMP-1 and MMP-9.展开更多
We reported in this manuscript that TGF-β1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly in...We reported in this manuscript that TGF-β1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-β1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-β1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-β1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-β1-mediated gene expression and apoptosis.展开更多
基金the European Structural and Investment Funded Grant"Cardio Metabolic"(#KK.01.2.1.02.0321)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010)+2 种基金the European Regional Development Fund Grant,project"CRISPR/Cas9-CasMouse"(#KK.01.1.1.04.0085)the European Structural and Investment Funded Project of Centre of Competence in Molecular Diagnostics(#KK.01.2.2.03.0006)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010).
文摘Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
文摘This study aims to thoroughly investigate the axial power peaking factors (PPF) within the low-enriched uranium (LEU) core of the Ghana Research Reactor-1 (GHARR-1). This study uses advanced simulation tools, like the MCNPX code for analysing neutron behavior and the PARET/ANL code for understanding power variations, to get a clearer picture of the reactor’s performance. The analysis covers the initial six years of GHARR-1’s operation and includes projections for its whole 60-year lifespan. We closely observed the patterns of both the highest and average PPFs at 21 axial nodes, with measurements taken every ten years. The findings of this study reveal important patterns in power distribution within the core, which are essential for improving the safety regulations and fuel management techniques of the reactor. We provide a meticulous approach, extensive data, and an analysis of the findings, highlighting the significance of continuous monitoring and analysis for proactive management of nuclear reactors. The findings of this study not only enhance our comprehension of nuclear reactor safety but also carry significant ramifications for sustainable energy progress in Ghana and the wider global context. Nuclear engineering is essential in tackling global concerns, such as the demand for clean and dependable energy sources. Research on optimising nuclear reactors, particularly in terms of safety and efficiency, is crucial for the ongoing advancement and acceptance of nuclear energy.
基金This research was supported by the National 973 Program (2006 CB503901) the Major Project of Shanghai Science and Technology Development Foundation (02DJ14052-I)+1 种基金the Science and Technology Development Foundation of Shanghai Municipal Health Bureau (034043) the Young Doctor Training Project of Shanghai Municipal Health Bureau
文摘Objective To analyze the association of variants of hepatocyte nuclear factor-1α （HNF-1α） gene with type 2 diabetes in Chinese population. Methods In 152 unrelated type 2 diabetes patients and 93 unrelated controls, eleven single nucleotide polymorphisms （SNPs） were identified and genotyped. Statistical analyses were performed to investigate whether these SNPs were associated with diabetes status in our samples. Results In the individual SNP study, no SNP differed significantly in frequency between type 2 diabetes patients and controls. In the haplotype analysis, two haplotype blocks were identified. In haplotype block 1, no evidence was found between common HNF-1α haplotypes and type 2 diabetes. However, in haplotype block 2, a common haplotype GCGC formed by four tagging SNPs （tSNPs） was found to be associated with decreased risk of type 2 diabetes （odds ratio [OR] 0.6011, 95% confidence interval [CI] 0.4138-0.8732, P=0.0073, empirical P=0.0511, permutation test）. A similar trend was also observed in the diplotype analysis, indicating that the increasing copy number of the haplotype GCGC was associated with the decreased frequency of diabetes （P=0.0193）. Conclusion The results of this study provide evidence that the haplotype of HNF-1α decreases the risk of type 2 diabetes in Chinese individuals.
文摘BACKGROUND Renal cysts and diabetes(RCAD)syndrome is an autosomal dominant diabetic renal disease.Precise molecular diagnosis of RCAD syndrome has proven valuable for understanding its mechanism and personalized therapy.CASE SUMMARY A RCAD patient and her family were studied to investigate potential responsible genes by the whole exome sequencing(WES).Candidate pathogenic variants were validated by Sanger sequencing.The clinical characteristics of RCAD patient were collected from medical records.Unlike those typical RCAD patients,we observed renal manifestation and prediabetes phenotype,but not reproductive organ phenotype and hypomagnesaemia.A novel 7-bp deletion mutation in exon 4 of the hepatocyte nuclear factor 1B,NM_000458:c.882_888del(p.V294fs),was identified by WES and confirmed by Sanger sequencing.CONCLUSION This novel mutation identified in a Chinese family with RCAD syndrome might be the molecular pathogenic basis of this disorder.
文摘Aim In diabetic patients, metformin appears to provide cardiovascular protection that cannot be attribu- ted only to its antihyperglycemic effects. Metformin is also known as the AMP-activated protein kinase （AMPK） ac- tivator. Our previous study suggested that metformin inhibits transforming growth factor-β1 （TGF-β1） production in a mouse heart failure model of pressure overload. TGF-β1 is a key factor in cardiac fibrosis and is usually induced by Angiotensin Ⅱ （Ang Ⅱ ） in the pressure overload mouse models. This study investigated the effect of metformin on cardiac fibrosis and TGF-β production induced by AngII and the underlying mechanisms. Methods C57/BL6 wild-type and AMPKα2 knockout mice were used. AngII （3 mg · kg-1 · d-1） was infused subcutaneously into mice for 7 days. Adult mouse cardiac fibroblasts were isolated and treated with AngII （ 1 μmol · L-1） and/or met- formin （1 mmol · L-l）. Results In C57/BL6 mice, metformin inhibits AngII-induced cardiac fibrosis. In cardi-ac fibroblasts, metformin inhibits TGF-β1 expression and production induced by AngII. AMPK inhibitor, com- pound C, reversed the effects of metformin. In vivo, AMPKα2 deficiency further increases AngII-induced TGF-β1 production. In cardiac fibroblasts, metformin inhibited AngII induced hepatocyte nuclear factor4 （HNF4ot protein level increase and HNF4α binding with TGF-β1 promoter using chromatin immunoprecipitation assay. In vivo, AMPKα2 deficiency further increased AngII-induced HNF4α protein level. Using HNF4α adenovirus, overexpress- ing HNF4α led to a 1.5-fold increase in TGF-β1 mRNA expression. HNF4a siRNA blocked AngII induced TGF- β1 production. Luciferase reporter with deleted HNF4a binding sites showed decreased TGFbl transcriptional activ- ity induced by AngII. In AMPK or2-/- heart, the inhibition of metformin on HNF4a protein was attenuated. Con- clusion Metformin inhibits AngII induced cardiac fibrosis and TGF-β1 production through AMPK activation. The underlying mechanism is that AMPK activation inhibits AngII induced HNF4α and then decreases TGF-β1 expres- sion.
文摘We present 2 cases of hepatocyte nuclear factor 1α (HNF1α)-mutated adenomatosis, discovered for reasons unrelated to this disease, and identified using immunohistochemical methods. These new tools may further our understanding of the link between adenomas/adenomatosis subtypes and their complications, and their association with other abnormalities.
基金supported by the National Natural Science Foundation of China,No. 81971006 (to DSG)。
文摘Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.
基金supported by the Science and Technology Projectsof Technology Bureau of Taiyuan City(Graut No:11016203)
文摘Objective:To observe the preventive and control effect of matrine on transforming growth factor(TCF- β1) and hepatocyte.growth factor(HCF) of liver fibrosis tissue in rals.Methods:A total of48 SD rats were randomly divided into A,B,C,D groups with 12 in each,group A as the normal control group and groups B.C,D as liver fibrosis models using composite modulus method with carbon tetrachloride(CCL_4).Group B was the model group,group C adopted γ— interferon lavage therapy in the second day of modeling,and group D adopted matrine lavage treatment,at 4 and8 weeks after treatment.Six rats were executed for detection of TGF- β1 and HGF,liver tissue histology and comparison fibrosis degree changes of rat liver tissue between groups.Results:Croups B,C,D showed a more significantly increased TCF- β1 at each time point compared with group A(P<0.05);Group B showed a more significantly increased TGF- β1 than groups C and D at weeks 4 and 8(P<0.05);group D showed a lowest level of TGF-β1,followed by groups C and B.HGF of group B decreased more significantly than A group at weeks 4 and 8(P<0.05);HGF of groups C and D was significantly elevated at 4 and 8 weeks than groups A and B(P<0.05),in which the group D showed the highest level of HGF.According to tissue histologic observation,rat liver tissue structure of group A was clear and normal,tissue structure of group B was destroyed with obvious fibrous tissue hyperplasia and fatty change of hepatic cells;groups C and D showed a slighter liver tissue damage,cell necrosis and connective tissue hyperplasia in collect abbacy than group B with a trend of obvious improvement.Conclusions:Matrine can reduce TGF- β1expression and enhance the activity of HGF,so as to realize the inhibition effect on liver fibrosis in rats.
基金Supported by the National Natural Science Foundation of China,No. 30271450the Natural Science Foundation of Zhejiang Province,No. 300466
文摘AIM: To provide the expression profile of serine protease SNC19/matriptase and its inhibitor hepatocyte growth factor activator inhibitor type 1 (HAI-1) in normal and malignant tissues of gastrointestinal tract at mRNA level for further study on their correlations with tumor progression and metastasis. METHODS: Total RNAs were prepared from 37 samples of colorectal cancer tissues, 40 samples of gastric cancer tissues, and their adjacent normal tissues. The expression of SNC19/matriptase and HAM in these samples was detected by real-time fluorescent quantitative PCR using glyceraldehyde-3-phosphate dehydrogenase as internal standard, and the clinical significance for the correlation with clinicopathological parameters was evaluated. RESULTS: In gastric cancer tissues the expression of HAI-1 and SNC19/matriptase was significantly lower than that in the corresponding adjacent normal tissues (Z=-3.280, P= 0.006; Z=-4.651, P=0.000). HAI-1:SNC19/matriptase ratio showed no difference between normal and malignant tissues (P>0.05). Analysis of clinicopathological parameters showed decreased expression of HAM and HAI-1:SNC19/ matriptase ratio associated with stage Ⅲ/Ⅳ gastric tumors as compared to stage Ⅰ/Ⅱ ones (Z = -2.140, P= 0.031; Z= -2.155, P= 0.031), and with lymph node-positive gastric cancer tissues as compared to lymph node-negative ones (Z= -2.081, P= 0.036; Z= -2.686, P= 0.006). The expression of SNC19/matriptase had no relationship with stages and lymph node metastasis (P>0.05). The expression of HAM and HAM:SNC19/matriptase ratio increased in well-differentiated gastric cancer tissues, but there was no statistical significance (P>0.05). The difference of SNC19/matriptase expression was not significant in gastric cancer tissues of different histological differentiation status (P>0.05). In colorectal cancer tissues, the expression of HAI-1 and SNC19/matriptase was also markedly lower than that in their adjacent normal tissues (Z=-3.100, P=0.002; Z=-2.731, P=0.006), whereas HAI-1:SNC19/matriptase ratio showed no difference. Decreased expression of HAI-1 was associated with increased invasive depth and lymph node metastasis, but there was no statistical significance (P>0.05). The difference of SNC19/matriptase expression and HAI-1: SNC19/matriptase ratio was not significant in different stages and different lymph node metastasis status (P>0.05). The expression of SNC19/matriptase, HAI-1 or HAI-1: SNC19/matriptase ratio showed no difference in colorectal cancer tissues of different histological differentiation status (P>0.05). CONCLUSION: The expressions of SNC19/matriptase and its inhibitor HAI-1 are decreased in gastrointestinal cancer tissues compared to their normal counterparts, and the decreased expression of HAI-1 may correlate with invasion and lymph node metastasis. The possible mechanisms involved need to be further investigated.
文摘Objective To study the influence of hepatocyte growth factor (HGF) antibody on the lung expression level of matrix metalloproteinases-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Methods Thirty male Wistar rats were randomly divided into 3 groups: control group, model group, and intervention group. Endotoxin was intratracheally infused in the model and intervention groups. HGF antibody was injected in the rats of the intervention group from day 1 to day 14, while the same volume of saline was injected in the control group. The rats were sacrificed on day 28 after endotoxin treatment. The amounts of MMP-9 mRNA and TIMP-1 mRNA were measured by reverse transcription-polymerase chain reaction, and protein expression levels of MMP-9 and TIMP-1 were measured by immunohistochemistry. Results In the model group, both mRNA and protein expression levels of TIMP-1 were significantly increased, the same as MMP-9. In the intervention group, the increase of TIMP-1 was remarkably reduced compared with the model group, while the mRNA and protein expression levels of MMP-9 were still increased. Conclusion HGF activity may accelerate the repair of lung injury through contrary regulating the expression levels of TIMP-1 and MMP-9.
基金grants fromthe Chinese Academy of Sciences (No. KJ951-BI608), the National Natural Sciences FOundation ofChina (No. 39625007 and
文摘We reported in this manuscript that TGF-β1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-β1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-β1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-β1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-β1-mediated gene expression and apoptosis.
