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Wen S.-L.,Regenerative Medicine Research Center | Wen S.-L.,University of Sichuan | Gao J.-H.,University of Sichuan | Yang W.-J.,West China Hospital | And 5 more authors.
Journal of Gastroenterology and Hepatology (Australia) | Year: 2014

Background and Aim: The epithelial-mesenchymal transition (EMT) of hepatocytes is a key step for hepatic fibrosis and cirrhosis. Long-term administration of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, can ameliorate hepatic fibrosis. This research aimed to examine the effect of celecoxib on the EMT of hepatocytes during the development of liver cirrhosis. Methods: Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). Thirty-six rats were randomly assigned to control, TAA, and TAA+celecoxib groups. Hepatic expressions of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), COX-2, prostaglandin E2 (PGE2), matrix metalloproteinase (MMP)-2 and -9, transforming growth factor-β1 (TGF-β1), Phospho-Smad2/3, Snail1, α-smooth muscle actin (α-SMA), vimentin, collagen I, fibroblast-specific protein (FSP-1), E-cadherin and N-cadherin were quantitated. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and Ishak's scoring system. Results: Exposed to TAA treatment, hepatocytes underwent the process of EMT during hepatic fibrosis. Compared with those in TAA group, celecoxib significantly downregulated the hepatic expressions of TNF-α, IL-6, COX-2, PGE2, MMP-2, MMP-9, TGF-β1, Phospho-Smad2/3, Snail1, α-SMA, FSP-1, and vimentin while greatly restoring the levels of E-cadherin. The fibrotic areas and collagen I levels of TAA+celecoxib group were much lower than those in TAA group. Conclusions: Celecoxib could ameliorate hepatic fibrosis and cirrhosis in TAA-rat model through suppression of the mesenchymal biomarkers in the hepatocytes while restoring the levels of their epithelial biomarkers. The inhibitory effect of celecoxib on the EMT of hepatocytes is associated with reduction of intrahepatic inflammation, preservation of normal basement matrix, and inhibition of TGF-β1/Smad pathway. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd. Source


Li X.,Regenerative Medicine Research Center | Chen Y.,Regenerative Medicine Research Center | Liu J.,Regenerative Medicine Research Center | Yang G.,University of Sichuan | And 7 more authors.
Experimental Biology and Medicine | Year: 2012

Dyslipidemia caused by 'Western-diet pattern' is a strong risk factor for the onset of diabetes. This study aimed to disclose the relationship between the serum metabolite changes induced by habitual intake of high-fat and high-cholesterol (HFHC) diet and the development of impaired glucose tolerance (IGT) and insulin resistance through animal models of Macaca mulatta. Sixteen M. mulatta (six months old) were fed a control diet or a HFHC diet for 18 months. The diet effect on serum metabolic profiles was investigated by longitudinal research. Islet function was assessed by intravenous glucose tolerance and hyperinsulinemic - euglycemic clamp test. Metabonomics were determined by 1H proton nuclear magnetic resonance spectroscopy. Prolonged diet-dependent hyperlipidemia facilitated visceral fat accumulation in liver and skeletal muscle and disorder of glucose homeostasis in juvenile monkeys. Glucose disappearance rate (KGlu) and insulin response to the glucose challenge effects in HFHC monkeys were significantly lower than in control monkeys. Otherwise, serum trimethylamine-N-oxide (TMAO), lactate and leucine/isoleucine were significantly higher in HFHC monkeys. Sphingomyelin and choline were the most positively correlated with KGlu (R2 = 0.778), as well as negative correlation (R2 = 0.64) with total cholesterol. The HFHC diet induced visceral fat, abnormal lipid metabolism and IGT prior to weight gain and body fat content increase in juvenile monkeys. We suggest that increased serum metabolites, such as TMAO, lactate, branched-chain amino acids and decreased sphingomyelin and choline, may serve as possible predictors for the evaluation of IGT and insulin resistance risks in the prediabetic state. © 2008 Society for Experimental Biology and Medicine. Source


Liu J.,Regenerative Medicine Research Center | Liu S.,Regenerative Medicine Research Center | Chen Y.,Regenerative Medicine Research Center | Zhao X.,University of Sichuan | And 2 more authors.
International Journal of Nanomedicine | Year: 2015

Islet transplantation is considered to be a curative treatment for type 1 diabetes mellitus. However, disruption of the extracellular matrix (ECM) leads to β-cell destruction and graft dysfunction. In this study, we developed a functionalized self-assembling peptide, KLD-F, with ECM mimic motifs derived from fibronectin and collagen IV, and evaluated its effect on β-cell function and proliferation. Atomic force microscopy and rheological results showed that KLD-F could self-assemble into a nanofibrous scaffold and change into a hydrogel in physiological saline condition. In a three-dimensional cell culture model, KLD-F improved ECM remodeling and cell-cell adhesion of INS-1 β-cells by upregulation of E-cadherin, fibronectin, and collagen IV. KLD-F also enhanced glucose-stimulated insulin secretion and expression of β-cell function genes, including Glut2, Ins1, MafA, and Pdx-1 in INS-1 cells. Moreover, KLD-F promoted proliferation of INS-1 β-cells and upregulated Ki67 expression by mediating cell cycle progression. In addition, KLD-F improved β-cell function and proliferation via an integrin/focal adhesion kinase/extracellular signal-regulated kinase/cyclin D pathway. This study highlights the fact that the β-cell-ECM interaction reestablished with this functionalized self-assembling peptide is a promising method to improve the therapeutic efficacy of islet transplantation. © 2015 Liu et al. Source


Wang X.-L.,Qingdao University | He S.,Maternal and Child Health Hospital | Zhai H.-L.,Regenerative Medicine Research Center
International Journal of Clinical and Experimental Medicine | Year: 2015

Objective: The influence of β2-microglobulin (β2-MG) on the prognosis of non-Hodgkin’s lymphoma (NHL) remains controversial. This study performed meta-analyses to evaluate the prognostic value of β2-MG on the overall survival (OS) of NHL. Methods: Through a search of relevant literature in PubMed, EMbase, Science Direct, OVID and Wanfang databases from 1980-2013, the hazard ratios (HRs) of OS between the normal β2-MG group and the increased β2-MG group were retrieved, and the results were combined using a fixed effect model and a random effect model. Subgroup analyses were performed based on univariate and multivariate analysis results, and sensitivity analyses were performed to estimate the changes of the combined HRs. In addition, funnel plots and fail-safe numbers were used to estimate publication bias. Results: A total of 17 qualified publications were included, with a cumulative total of 2,479 cases. The result of heterogeneity examination showed that there was heterogeneity among all studies (P < 0.001, I2 = 87%). In the random effect model, the combined HR was 2.71 (95% confidence interval [CI]: 1.91-3.85). The result of the total effect examination was statistically significant (Z = 5.59, P < 0.001). Conclusion: The increased β2-MG level was an independent risk factor for the prognosis of NHL. © 2015, Int J Clin Exp Med. All rights reserved. Source


Hu X.J.,University of Sichuan | Wu X.,Regenerative Medicine Research Center | Huang Y.,Chinese Academy of Sciences | Tong Q.,Regenerative Medicine Research Center | And 2 more authors.
Molecular Medicine Reports | Year: 2014

Berberine is a natural isoquinoline alkaloid, the majority of which is extracted from Huang Lian and other medicinal herbs. Numerous studies have revealed that berberine exhibits anticancer activity, however the mechanisms underlying this effect remain elusive. To examine these mechanisms, we analyzed the effects of berberine on a panel of DNA repair deficient chicken B lymphocyte (DT40) clones. Our results revealed that DT40 cells deficient in Rev3 (Rev3-/-), a translesion DNA synthesis (TLS) gene, were hypersensitive to berberine. Following berberine treatment, cell cycle analysis identified that G2/M arrest was increased in Rev3-/- cells. Furthermore, compared with wild-type cells (WT), berberine also induced a significant increase in double-strand breaks (DSBs) in Rev3 -/- cells, as revealed by chromosomal aberration (CA) analysis. These results suggest that berberine is able to induce DNA damage, and that the Rev3 associated DNA repair pathway participates in the processes that aid its repair. Source

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