Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C

INTRODUCTION The goal of therapy for chronic hepatitis C (CHC) is the eradication of the hepatitis C virus (HCV)[1]. In the recent decade, anti-viral therapy against HCV has been markedly improved, especially treatment with ribavirin and peg- interferon (…     

Effect of transforming growth factor-β1 on human intrahepatic cholangiocarcinoma cell growth

INTRODUCTION Intrahepatic cholangiocarcinoma (ICC) is the second most common form of primary liver cancer after hepatocellular carcinoma. Despite advances in diagnosis and treatment, the prognosis of ICC has not yet been resolved[1-3]. When compared with …     

Connection between inflammation and carcinogenesis in gastrointestinal tract: Focus on TGF-β signaling

Inflammation is a primary defense process against various extracellular stimuli,such as viruses,pathogens,foods,and environmental pollutants.When cells respond to stimuli for short periods of time,it results in acute or physiological inflammation.However,if the stimulation is sustained for longer time or a pathological state occurs,it is known as chronic or pathological inflammation.Several studies have shown that tumorigenesis in the gastrointestinal (GI) tract is closely associated with chronic inflammati...     

Gastric cancer cells induce human CD4~+ Foxp3~+ regulatory T cells through the production of TGF-β1

AIM: To elucidate the molecular and cellular features responsible for the increase of regulatory T cells (Tregs) in gastric cancer. METHODS: The frequencies of CD4 + Foxp3 + Tregs and the level of transforming growth factor-β1 (TGF-β1) were analyzed from 56 patients with gastric cancer byflow cytometry and enzyme-linked immunosorbent assay respectively. Foxp3 gene expression was analyzed by real-time polymerase chain reaction. The gastric cancer microenvironment was modeled by establishing the coculture of ...     

Increased ΤGF-β3 in primary biliary cirrhosis: An abnormality related to pathogenesis?

AIM: To investigate the transforming growth factor-β (TGF-β) isoforms in the peripheral and hepatic venous blood of primary biliary cirrhosis (PBC) patients. METHODS: We examined TGF-β1, TGF-β2 and TGF-β3 (enzyme-linked immunosorbent assay), in 27 stage Ⅳ PBC patients (27 peripheral and 15 hepatic vein sera), 35 early (Ⅰ-Ⅱ) PBC and 60 healthy controls. As disease controls 28 hepatitis C virus (HCV) cirrhosis (28 peripheral and 17 hepatic vein serum), 44 chronic HCV hepatitis and 38 HCV-related hepatocellula...     

转化生长因子β_1基因标签单核苷酸多态性与新疆汉族原发性高血压相关性研究

Objective Essential hypertension (EH) was a complex disease resulted from the interaction of cumulative effect of multiple genetic and environment factors. The relationship between the genetic polymorphisms in the transforming growth factor-β_1 ( TGF-β_1 ), the blood levels and EH have been investigated, but the conclusions were different. Therefore, we investigate the relationship between the tagging single nucleotide polymorphisms (tSNPs) ( rs1800469, rs2241716, rs11466345, rs2241715,rs4803455) in TGF-β_1 gene, blood levels and EH in the Han nationality population in Xinjiang, to clarity the pattern of linkage disequilibrium (LD) and the feature of the structure of haplotype. Methods Based on the case-control study,we selected 732 (365 EH patients,367 controls) Han Chinese population from the Boertonggu countryside of Shawan region in the Xinjiang Uygur Autonomous Region of China by random cluster sampling. After questionnaire and physical examination, we collected blood samples, and the blood levels of TGF-β_1, were quantified using sandwich ELISA. The polymorphisms of TGF-β_1 gene in the study groups were detected with SNaPshot system. The case-control study in a large group was carried out separately for each of the tSNP and followed up by haplotypes analyses to determine the relation between tSNPs of TGF-β_1 gene and EH in the Han population. Results ( 1 ) The frequencies of alleles A, G of rs11466345 of TGF-β_1, gene in EH group and control group were as follows: 69.7%, 30. 3% ,74.4%,25.6%, respectively. It was demonstrated that the G allele of the rs11466345 polymorphism occurred at a significantly higher frequency in EH patients than in healthy controls (30. 3% vs. 25. 6%, P <0. 05). The rs11466345G-allele carriers had a significantly increased risk of EH compared to rs11466345A -allele carrier ( OR = 1. 261 ; P <0. 05). The frequencies of genotypes and alleles of the other tSNPs of TGF-β_1 gene had no difference between EH patients and controls ( P > 0. 05 ). (2) Except the site of rs11466345, the other tSNPs were in strong LD, and no statistical differences were observed in haplotypes distribution in the followup study between case-control groups (P >0. 05). (3) There were no difference of TGF-β_1 levels between the different genotypes and alleles in tSNPs of TGF-β_1 gene ( P > 0. 05 ). Conclusions ( 1 ) These results suggested that TGF-β_1 gene rs11466345 G allele was likely to be a genetic susceptibility factor for EH in the Xinjiang Han population, the other tSNPs perhaps had no association with EH of in the study groups. (2) Except rs11466345, the other tSNPs were in strong LD, and the haplotypes reconsreucted by tSNPs might not be associated with EH in the Han nationality populations. (3) There was no association between the tSNP of TGF-β_1 gene and TGF-β_1 blood levels in the Xinjiang Han nationality population.     

Hypermethylation of TGF-β1 gene promoter in gastric cancer

AIM:To examine transforming growth factor-β1(TGF-β1)promoter methylation in gastric cancer and to determine if Helicobacter pylori(H.pylori)or interleukin(IL)-1β could induce TGF-β1 hypermethylation in vitro.METHODS:We examined the frequency and extent of TGF-β1 promoter methylation using methylationspecific PCR in the gastric tissues from 47 gastric cancer patients and 39 non-gastric cancer subjects.H.pylori infection was confirmed by a positive result from either a serological test,histological analysis or C13urea breath test.GES-1 and MKN-45 cells co-cultured with H.pylori or treated with IL-1β for 12,24 and 48 h in vitro tested the effects of H.pylori or IL-1β on TGF-1β.RESULTS:Twenty-four/forty-seven(51%)cases of gastric cancer(GC)tissues showed TGF-β1 promoter methylation,15/47(31.9%)cases of matched noncancerous gastric mucosa tissues from the GC patients,and 11/39(28%)case of the normal gastric mucosa tissues from non-GC subjects showed TGF-β1 promoter methylation(51%vs 28%,P<0.05).Significantly higher levels of methylation of TGF-β1 were found in the tumor tissues than in non-tumor tissues from GC patients(0.24±0.06 vs 0.17±0.04,P<0.05)and normal gastric tissues from non-GC subjects(0.24±0.06 vs 0.15±0.03,P<0.05).TGF-β1 methylation was found in 48.3% of H.pylori-positive gastric mucosal tissues whereas only 23.1% of H.pylori-negative gastric mucosal tissues showed TGF-β1 methylation(48.3%vs 23.1%,P<0.05).IL-1β appeared to induce a dose-dependent methylation of TGF-β1 and the strongest methylation was observed in GES-1 cells treated with 2.5 ng/mL of IL-1β for 48 h.Further studies showed that pre-treatment of GES-1 cells with 20ng/mL IL-1RA for 1 h could partially abolish the effect of IL-1β on TGF-β1 methylation.Infection of GES-1cells by H.pylori was not found to induce significant TGF-β1 promoter methylation.CONCLUSION:Our data revealed that TGF-1 promoter is methylated in GC patients.IL-1β may be an important mediator for H.pylori induced gene methylation during GC     

转化生长因子β_1基因标签单核苷酸多态性与新疆汉族原发性高血压相关性研究

Objective Essential hypertension (EH) was a complex disease resulted from the interaction of cumulative effect of multiple genetic and environment factors. The relationship between the genetic polymorphisms in the transforming growth factor-β_1 ( TGF-β_1 ), the blood levels and EH have been investigated, but the conclusions were different. Therefore, we investigate the relationship between the tagging single nucleotide polymorphisms (tSNPs) ( rs1800469, rs2241716, rs11466345, rs2241715,rs4803455) in TGF-β_1 gene, blood levels and EH in the Han nationality population in Xinjiang, to clarity the pattern of linkage disequilibrium (LD) and the feature of the structure of haplotype. Methods Based on the case-control study,we selected 732 (365 EH patients,367 controls) Han Chinese population from the Boertonggu countryside of Shawan region in the Xinjiang Uygur Autonomous Region of China by random cluster sampling. After questionnaire and physical examination, we collected blood samples, and the blood levels of TGF-β_1, were quantified using sandwich ELISA. The polymorphisms of TGF-β_1 gene in the study groups were detected with SNaPshot system. The case-control study in a large group was carried out separately for each of the tSNP and followed up by haplotypes analyses to determine the relation between tSNPs of TGF-β_1 gene and EH in the Han population. Results ( 1 ) The frequencies of alleles A, G of rs11466345 of TGF-β_1, gene in EH group and control group were as follows: 69.7%, 30. 3% ,74.4%,25.6%, respectively. It was demonstrated that the G allele of the rs11466345 polymorphism occurred at a significantly higher frequency in EH patients than in healthy controls (30. 3% vs. 25. 6%, P <0. 05). The rs11466345G-allele carriers had a significantly increased risk of EH compared to rs11466345A -allele carrier ( OR = 1. 261 ; P <0. 05). The frequencies of genotypes and alleles of the other tSNPs of TGF-β_1 gene had no difference between EH patients and controls ( P > 0. 05 ). (2) Except the site of rs11466345, the other tSNPs were in strong LD, and no statistical differences were observed in haplotypes distribution in the followup study between case-control groups (P >0. 05). (3) There were no difference of TGF-β_1 levels between the different genotypes and alleles in tSNPs of TGF-β_1 gene ( P > 0. 05 ). Conclusions ( 1 ) These results suggested that TGF-β_1 gene rs11466345 G allele was likely to be a genetic susceptibility factor for EH in the Xinjiang Han population, the other tSNPs perhaps had no association with EH of in the study groups. (2) Except rs11466345, the other tSNPs were in strong LD, and the haplotypes reconsreucted by tSNPs might not be associated with EH in the Han nationality populations. (3) There was no association between the tSNP of TGF-β_1 gene and TGF-β_1 blood levels in the Xinjiang Han nationality population.     

Paclitaxel ameliorates fibrosis in hepatic stellate cells via inhibition of TGF-β/Smad activity

AIM: To investigated if paclitaxel can attenuate hepatic fi brosis in rat hepatic stellate cells (RHSCs). METHODS: RHSCs were cultured in vitro and randomly assigned to four groups: normal control group (treated only with Dulbecco's Modified Eagle's Medium), Taxol group (200 nmol/L paclitaxel was added to the cell culture), transforming growth factor (TGF)-β group (5 ng/mL recombinant human TGF-β1 was added to the cell culture), and TGF-β + Taxol group. TGF-β signaling cascade and status of various extracel...     

Effect of IL-10 on the expression of HSC growth factors in hepatic fibrosis rat

AIM: To study the effect of IL-10 on the expression of growth factors - transforming growth factor-β1(TGF-β1), epidermal growth factor (EGF), hepatocyte growth factor (HGF)and platelet-derived growth factor (PDGF) of hepatic stellate cells (HSCs) of hepatic fibrosis rat and the anti-fibrogenic role of exogenous IL-10. METHODS: Hepatic fibrosis was induced by CCl4 administration intra-peritoneally. Sixty clean male Sprague-Dawley (SD) rats were randomly divided into three groups: normal control group (GN, 8 rats), hepatic fibrosis model group (GC, 28 rats) and IL-10 treated group (GI, 24 rats). At the beginning of the 7th and 11th wk, rats in each group were routinely perfused with pronase E and type IV collag-enase through a portal vein catheter and the suspension obtained from the liver was spun by centrifugation with 11% Nycodenz density gradient to isolate HSCs. Histological examination was used to determine the degree of hepatic fibrosis. RT-PCR was employed to analyze mRNA expression from freshly isolated cells. Immunocytochemistry was performed to detect protein expression in primary cultured HSCs. RESULTS: Rat hepatic fibrosis was developed with the increase of injection frequency of CCl4, and HSCs were successfully isolated. At the 7th and 11th wk, TGF-β1, EGF, and HGF mRNA in GC increased obviously compared with GN (P= 0.001/0.042, 0.001/0.001, 0.001/0.001) and GI (P=0.001/0.007, 0.002/0.001, 0.001/0.001). For TGF-β1, no difference was observed between GI and GN. For EGF, mRNA level in GI increased compared with GN during the 7th wk (P=0.005) and 11th wk (P=0.049). For HGF, mRNA level in GI decreased compared with GN at the 7th wk (P=0.001) and 11th wk (P=0.021). Between these two time points, TGF-β1 expression at the 7th wk was higher than that of the 11th wk (P=0.049), but for EGF, the former was lower than the latter (P=0.022). As for PDGF mRNA, there was no significant difference between these groups, but difference seemed to exist in protein levels. Results by immunocytochemistry of TGF-β1 and EGF were paralleled with the above findings. CONCLUSION: The expression of TGF-β1, EGF and HGF increased in HSC of hepatic fibrosis rat and decreased after treatment with IL-10. IL-10 plays an anti-fibrogenic role by suppressing growth factors expression.     

依那普利对高糖诱导的大鼠肾小球系膜细胞产生TGF-β1、LN及CTGF表达的影响

目的 观察依那普利(Enalapril,Ena)对高糖诱导的大鼠肾小球系膜细胞(GMCs)转化生长因子-β1(TGF-β1)、层黏连蛋白(LN)及结缔组织生长因子(CTGF)表达的影响.方法 大鼠GMCs分别培养于正常浓度葡萄糖(5.5 mmol/L)、高浓度葡萄糖(20 mmol/L)及高糖和不同浓度(10~(-7)mol/L、10~(-6)mol/L、10~(-5)mol/L)的Ena中,同时设空白对照.分别采用放射免疫法、酶联免疫吸附实验(ELISA)检测不同时间(24、48、72 h)细胞培养上清液中TGF-β1、LN含量,采用逆转录聚合酶链反应(RT-PCR)检测72 h细胞CTGF mRNA的表达.结果 与空白对照组比较,正常糖组和高糖组TGF-β1分泌增加、LN合成增多、CTGF表达上调(P<0.001),高糖组更明显(P<0.001).与高糖组比较,高、中、低浓度的Ena干预均可逆转上述变化.结论 高糖可致GMCs分泌TGF-β1增加、合成LN增多、CTGF表达上调,Ena可减少细胞外基质(ECM)积聚,下调CTGF表达,从而有利于延缓糖尿病肾病肾小球硬化(GS)的进展.     

Growth factor- and cytokine-driven pathways governing liver stemness and differentiation

Liver is unique in its capacity to regenerate in response to injury or tissue loss. Hepatocytes and other liver cells are able to proliferate and repopulate the liver. However, when this response is impaired, the contribution of hepatic progenitors becomes very relevant. Here, we present an update of recent studies on growth factors and cytokine-driven intracellular pathways that govern liver stem/pro-genitor cell expansion and differentiation, and the rel-evance of these signals in liver development, regen...