AIM: To assess the predictive value of the insulinlike growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis. METHODS: Patients with: (1) biopsy...AIM: To assess the predictive value of the insulinlike growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis. METHODS: Patients with: (1) biopsy-proven compensated HCV cirrhosis; (2) available baseline frozen liver sample; (3) absence of detectable HCC; (4) regular screening for HCC; (5) informed consent for genetic analysis were studied. After DNA extraction from liver samples and bisulfite treatment, unbiased PCR and DHPLC analysis were performed for methylation analysis at the Igf2 locus. The predictive value of the Igf2 methylation profile for HCC wasassessed by Kaplan-Meier and Cox methods. RESULTS: Among 94 included patients, 20 developed an HCC during follow-up (6.9 ± 3.2 years). The methylation profile was hypomethylated, intermediate and hypermethylated in 13, 64 and 17 cases, respectively. In univariate analysis, two baseline parameters were associated with the occurrence of HCC: age (P = 0.01) and prothrombin (P = 0.04). The test of linear tendency between the three ordered levels of Igf2 methylation and probability of HCC occurrence was significant (Log Rank, P = 0.043; Breslow, P = 0.037; Tarone-Ware, P = 0.039). CONCLUSION: These results suggest that hypomethylation at the Igf2 locus in the liver could be predictive for HCC occurrence in HCV cirrhosis.展开更多
The mechanism of ester hydrolysis has been extensively studied; however, the precise function of active-site residues in promoting catalysis is nuclear. We describe here the structural models for the complex of a cata...The mechanism of ester hydrolysis has been extensively studied; however, the precise function of active-site residues in promoting catalysis is nuclear. We describe here the structural models for the complex of a catalytic sntibody Fv fragment with a phosphonate transition -state analogue, constructed by using gene cloning, sequencing and molecular modeling, mainly based on a known X-ray structure of a catalytic atibody. Hydrophobic and electrostatic analyses of the Fv/analog and Fv/substrate interaction suggest the hydrolysis mechanism: In L91 and Tyr H97 play important roles to stabilize the β-naphthyl group of hapten through r-stack; His H35 donates a pair of free electrons at the atom NEZ to an active water and let it to be a partial hydroxide, which attacks the carbon atom of the carbonyl group of the substrate. Both His H35 and Arg L96 can form hydrogen bonds and stabilize the Anoinc tetrahedral intermediate formed during turnover. This mechanism emphasizes that an active water bridge may be formed during hydrolysis process.展开更多
To investigate the effects of overall alkali of a traditional Chinese medicine “Tongbiling” (brucine and strychnine alkaloids in main) on the cytokines expression in Th1 and Th2 cells in the synovial fluid of patien...To investigate the effects of overall alkali of a traditional Chinese medicine “Tongbiling” (brucine and strychnine alkaloids in main) on the cytokines expression in Th1 and Th2 cells in the synovial fluid of patients with rheumatism arthritis and their signal pathway, the mononuclear cells in the synovial fluid (SFMC) of patients were isolated by Ficoll-Hypaque gradient centrifugation, and the CD3 + CD69 + and CD3 + HLA-DR antigen were analyzed by flow cytometry in comparison with those of the peripheral blood. The rest of cells were cultured after resuspension with RPMI 1640 culture medium. Phorbol 12,13-dibutyrate (PDB) and ionomycin were added successively into the culture with various concentration of overall alkali Tongbiling (TBL). After 4 h of cultivation, the expression of IFN-γ and IL-4 in CD3 + cells were analyzed by flow cytometry. The influence of overall alkali TBL (100?mg/L) on the intracellular calcium was investigated after Fluo-3/AM labeling and stimulation with PDB and ionomycin at 1, 2, 4 and 10?min, and the influence of TBL on the expression of CD3 + CD69 + cells were determined with stimulation of PDB for 24?h in the whole blood lymphocytes culture. It was found that the percentage of T cells bearing CD69 was significantly up-regulated (77%), while that of T cells bearing HLA-DR was 44% in the synovial mononucleated cells. After PDB and ionomycin stimulation, the expression of IFN-γ in CD3 + cells were up-regulated, but there was no change on the expression of IL-4 in CD3 + cells, indicating that ratio of Th1/Th2 was significantly increased and Th cells differentiate to Th1 cells in mainly. Four concentrations of overall alkaloid of TBL (200?mg/L, 100?mg/L, 50?mg/L, 25?mg/L) could down-regulated the expression of IFN-γ in CD3 + cells and the Th1/Th2 ratio obviously, but all the concentrations of the overall alkaloids had no effect on the expression of IL-4 in CD3 + cells. 100?mg/L concentration of the overall alkaloid did not down-regulate the intracellular calcium level. Each concentration of the overall alkaloid could down-regulated the expression CD69 obviously on the PDB-activated mouse T cells. It concluded from the above observations that the overall alkaloid of TBL could relieve the inflammatory and immune damages by suppressing the expression of Th1 type cytokines and Th1 cell differentiation, regulating the imbalance of Th1/Th2 cells and inhibiting the early activation of the T lymphocytes bearing CD69. There was no remarkable influence on the intracellular calcium signaling transduction pathway. The inhibitory effected on T cells to express IFN-γ might be due to the suppression of PKC-MAPK signaling pathway. From the standpoint of traditional Chinese medicine, this might be due to the regulation of “Yin” and “Yang” imbalance of joints to modify the pathological status in rheumatoid arthritis. This study provided an experimental basis for the application of overall alkaloids of TBL in the treatment of rheumatoid arthritis.展开更多
Alzheimer's disease(AD) is one of the most common types of dementia whose hallmarks include neurofibrillary tangles and senile plaques. The latter are mainly composed of amyloid-β proteins(Aβ), and it's sugg...Alzheimer's disease(AD) is one of the most common types of dementia whose hallmarks include neurofibrillary tangles and senile plaques. The latter are mainly composed of amyloid-β proteins(Aβ), and it's suggested that Aβ may be the causative factor in AD pathogenesis. Immunotherapy targeting Aβ for preventing aggregation of Aβ and mildly clearing amyloid plaques has been a hot topic since 1999. Although the first clinical trial of Aβ vaccine, AN-1792, failed in phase II, its results suggested some key points in the design of Aβ vaccines. Avoiding the possible toxic Aβ specific T cell response and inducing a Th2 type cellular immune response may be beneficial for Aβ immunotherapy. Many associations and research groups are working on Aβ vaccine and some progress has been made in recent years. In this review, we have provided a detailed summary of past Aβ vaccines, which have been sorted by the immunogen, and we also discuss some recent progress and future perspectives.展开更多
Transposable elements(TEs), originally discovered in maize as controlling elements, are the main components of most eukaryotic genomes. TEs have been regarded as deleterious genomic parasites due to their ability to u...Transposable elements(TEs), originally discovered in maize as controlling elements, are the main components of most eukaryotic genomes. TEs have been regarded as deleterious genomic parasites due to their ability to undergo massive amplification. However, TEs can regulate gene expression and alter phenotypes. Also, emerging findings demonstrate that TEs can establish and rewire gene regulatory networks by genetic and epigenetic mechanisms. In this review, we summarize the key roles of TEs in fine-tuning the regulation of gene expression leading to phenotypic plasticity in plants and humans, and the implications for adaption and natural selection.展开更多
Kynurenine aminotransferases （KATs） catalyze the transamination of kynurenine （KYN） pathway and endogenous KYNs have been suggested to highly correlate to abnormal brain diseases. HKAT3 is a key member of KAT fami...Kynurenine aminotransferases （KATs） catalyze the transamination of kynurenine （KYN） pathway and endogenous KYNs have been suggested to highly correlate to abnormal brain diseases. HKAT3 is a key member of KAT family, while the binding mechanism of KYN and cofactor with HKAT3 has not been determined yet. In this study, we focus on the structure-function relationship among KYN, cofactor and HKAT3. The binding models of KYN complex and KYN＆cofactor complex were ob- tained and were studied by molecular dynamics （MD） simulations. We identified several critical residues and influence of conformational changes in human kynurenine aminotransferase 3 （HKAT3） complexes. The cofactor may contribute largely not only to the catalysis, but also to the binding. In addition, a hypothesis is proposed that a strong hydrophobic interaction between Tyr159 and Lys280 may influence the binding mode and the binding region of the substrate and the cofactor. Our re- suits will be a good starting point for further determination of the biological role.展开更多
文摘AIM: To assess the predictive value of the insulinlike growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis. METHODS: Patients with: (1) biopsy-proven compensated HCV cirrhosis; (2) available baseline frozen liver sample; (3) absence of detectable HCC; (4) regular screening for HCC; (5) informed consent for genetic analysis were studied. After DNA extraction from liver samples and bisulfite treatment, unbiased PCR and DHPLC analysis were performed for methylation analysis at the Igf2 locus. The predictive value of the Igf2 methylation profile for HCC wasassessed by Kaplan-Meier and Cox methods. RESULTS: Among 94 included patients, 20 developed an HCC during follow-up (6.9 ± 3.2 years). The methylation profile was hypomethylated, intermediate and hypermethylated in 13, 64 and 17 cases, respectively. In univariate analysis, two baseline parameters were associated with the occurrence of HCC: age (P = 0.01) and prothrombin (P = 0.04). The test of linear tendency between the three ordered levels of Igf2 methylation and probability of HCC occurrence was significant (Log Rank, P = 0.043; Breslow, P = 0.037; Tarone-Ware, P = 0.039). CONCLUSION: These results suggest that hypomethylation at the Igf2 locus in the liver could be predictive for HCC occurrence in HCV cirrhosis.
文摘The mechanism of ester hydrolysis has been extensively studied; however, the precise function of active-site residues in promoting catalysis is nuclear. We describe here the structural models for the complex of a catalytic sntibody Fv fragment with a phosphonate transition -state analogue, constructed by using gene cloning, sequencing and molecular modeling, mainly based on a known X-ray structure of a catalytic atibody. Hydrophobic and electrostatic analyses of the Fv/analog and Fv/substrate interaction suggest the hydrolysis mechanism: In L91 and Tyr H97 play important roles to stabilize the β-naphthyl group of hapten through r-stack; His H35 donates a pair of free electrons at the atom NEZ to an active water and let it to be a partial hydroxide, which attacks the carbon atom of the carbonyl group of the substrate. Both His H35 and Arg L96 can form hydrogen bonds and stabilize the Anoinc tetrahedral intermediate formed during turnover. This mechanism emphasizes that an active water bridge may be formed during hydrolysis process.
文摘To investigate the effects of overall alkali of a traditional Chinese medicine “Tongbiling” (brucine and strychnine alkaloids in main) on the cytokines expression in Th1 and Th2 cells in the synovial fluid of patients with rheumatism arthritis and their signal pathway, the mononuclear cells in the synovial fluid (SFMC) of patients were isolated by Ficoll-Hypaque gradient centrifugation, and the CD3 + CD69 + and CD3 + HLA-DR antigen were analyzed by flow cytometry in comparison with those of the peripheral blood. The rest of cells were cultured after resuspension with RPMI 1640 culture medium. Phorbol 12,13-dibutyrate (PDB) and ionomycin were added successively into the culture with various concentration of overall alkali Tongbiling (TBL). After 4 h of cultivation, the expression of IFN-γ and IL-4 in CD3 + cells were analyzed by flow cytometry. The influence of overall alkali TBL (100?mg/L) on the intracellular calcium was investigated after Fluo-3/AM labeling and stimulation with PDB and ionomycin at 1, 2, 4 and 10?min, and the influence of TBL on the expression of CD3 + CD69 + cells were determined with stimulation of PDB for 24?h in the whole blood lymphocytes culture. It was found that the percentage of T cells bearing CD69 was significantly up-regulated (77%), while that of T cells bearing HLA-DR was 44% in the synovial mononucleated cells. After PDB and ionomycin stimulation, the expression of IFN-γ in CD3 + cells were up-regulated, but there was no change on the expression of IL-4 in CD3 + cells, indicating that ratio of Th1/Th2 was significantly increased and Th cells differentiate to Th1 cells in mainly. Four concentrations of overall alkaloid of TBL (200?mg/L, 100?mg/L, 50?mg/L, 25?mg/L) could down-regulated the expression of IFN-γ in CD3 + cells and the Th1/Th2 ratio obviously, but all the concentrations of the overall alkaloids had no effect on the expression of IL-4 in CD3 + cells. 100?mg/L concentration of the overall alkaloid did not down-regulate the intracellular calcium level. Each concentration of the overall alkaloid could down-regulated the expression CD69 obviously on the PDB-activated mouse T cells. It concluded from the above observations that the overall alkaloid of TBL could relieve the inflammatory and immune damages by suppressing the expression of Th1 type cytokines and Th1 cell differentiation, regulating the imbalance of Th1/Th2 cells and inhibiting the early activation of the T lymphocytes bearing CD69. There was no remarkable influence on the intracellular calcium signaling transduction pathway. The inhibitory effected on T cells to express IFN-γ might be due to the suppression of PKC-MAPK signaling pathway. From the standpoint of traditional Chinese medicine, this might be due to the regulation of “Yin” and “Yang” imbalance of joints to modify the pathological status in rheumatoid arthritis. This study provided an experimental basis for the application of overall alkaloids of TBL in the treatment of rheumatoid arthritis.
基金supported by the National Basic Research Program of China(2013CB910700,2012CB821600)the National Natural Science Foundation of China(21472109,21102082)the Research Project of Chinese Ministry of Education(113005A)
文摘Alzheimer's disease(AD) is one of the most common types of dementia whose hallmarks include neurofibrillary tangles and senile plaques. The latter are mainly composed of amyloid-β proteins(Aβ), and it's suggested that Aβ may be the causative factor in AD pathogenesis. Immunotherapy targeting Aβ for preventing aggregation of Aβ and mildly clearing amyloid plaques has been a hot topic since 1999. Although the first clinical trial of Aβ vaccine, AN-1792, failed in phase II, its results suggested some key points in the design of Aβ vaccines. Avoiding the possible toxic Aβ specific T cell response and inducing a Th2 type cellular immune response may be beneficial for Aβ immunotherapy. Many associations and research groups are working on Aβ vaccine and some progress has been made in recent years. In this review, we have provided a detailed summary of past Aβ vaccines, which have been sorted by the immunogen, and we also discuss some recent progress and future perspectives.
基金supported by the National Natural Science Foundation of China(3121010390131123007)+2 种基金the National Basic Research Program of China(2013CB835200)the State Key Laboratory of Plant Genomics(2015B0129-01)Liya Wei was supported by the China Postdoctoral Science Foundation(2015M570170)
文摘Transposable elements(TEs), originally discovered in maize as controlling elements, are the main components of most eukaryotic genomes. TEs have been regarded as deleterious genomic parasites due to their ability to undergo massive amplification. However, TEs can regulate gene expression and alter phenotypes. Also, emerging findings demonstrate that TEs can establish and rewire gene regulatory networks by genetic and epigenetic mechanisms. In this review, we summarize the key roles of TEs in fine-tuning the regulation of gene expression leading to phenotypic plasticity in plants and humans, and the implications for adaption and natural selection.
基金supported by the National Natural Science Foundation of ChinaSpecialized Research Fund for the Doctoral Program of Higher EducationSpecialized Fund for the Basic Research of Jilin University (20903045, 20573042, 20070183046,200810018)
文摘Kynurenine aminotransferases （KATs） catalyze the transamination of kynurenine （KYN） pathway and endogenous KYNs have been suggested to highly correlate to abnormal brain diseases. HKAT3 is a key member of KAT family, while the binding mechanism of KYN and cofactor with HKAT3 has not been determined yet. In this study, we focus on the structure-function relationship among KYN, cofactor and HKAT3. The binding models of KYN complex and KYN＆cofactor complex were ob- tained and were studied by molecular dynamics （MD） simulations. We identified several critical residues and influence of conformational changes in human kynurenine aminotransferase 3 （HKAT3） complexes. The cofactor may contribute largely not only to the catalysis, but also to the binding. In addition, a hypothesis is proposed that a strong hydrophobic interaction between Tyr159 and Lys280 may influence the binding mode and the binding region of the substrate and the cofactor. Our re- suits will be a good starting point for further determination of the biological role.
