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[Effect of microRNA-34a/SIRT1/p53 signal pathway on notoginsenoside R₁ delaying vascular endothelial cell senescence].
Lai, XH, Lei, Y, Yang, J, Xiu, CK
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. 2018;(3):577-584
Abstract
This study aimed to investigate the effect of notoginsenoside R₁ in delaying H₂O₂-induced vascular endothelial cell senescence through microRNA-34a/SIRT1/p53 signal pathway. In this study, human umbilical vein endothelial cells(HUVECs) were selected as the study object; the aging model induced by hydrogen peroxide(H₂O₂) was established, with resveratrol as the positive drug. HUVECs were randomly divided into four groups, youth group, senescence model group, notoginsenoside R₁ group and resveratrol group. Notoginsenoside R₁ group and resveratrol group were modeled with 100 μmoL·L⁻¹ H₂O₂ for 4 h after 24 h treatment with notoginsenoside R₁(30 μmoL·L⁻¹) and resveratrol(10 μmoL·L⁻¹) respectively. At the end, each group was cultured with complete medium for 24 h. The degree of cellular senescence was detected by senescence-associated β-galactosidase(SA-β-Gal) staining kit, the cell viability was detected by cell counting kit-8, the cell cycle distribution was analyzed by flow cytometry, and the cellular SOD activity was detected by WST-1 method in each group. The expressions of SIRT1, p53, p21 and p16 proteins in HUVECs were detected by Western blot. In addition, the mRNA expressions of miRNA-34a, SIRT1 and p53 in HUVECs were assayed by Real-time PCR. These results indicated that notoginsenoside R₁ significantly reduced the positive staining rate of senescent cells, enhanced the cell proliferation capacity and intracellular SOD activity, decreased the proportion of cells in G₀/G₁ phase, and increased the percentage of cells in S phase simultaneously compared with the senescence model group. Moreover, notoginsenoside R₁ decreased the mRNA expressions of miRNA-34a and p53 and the protein expression of p53, p21 and p16.At the same time, notoginsenoside R₁ increased the protein and mRNA expressions of SIRT1. The differences in these results between the senescence model group and the notoginsenoside R₁ group were statistically significant(P<0.05). However, there was not statistically significant difference in these results between the notoginsenoside R₁ group and the resveratrol group. In conclusion, the senescence of endothelial cells induced by H₂O₂ can be used as a model for studying aging. Notoginsenoside R₁ has an obvious anti-aging effect on vascular endothelial cells in this study. The possible mechanism is that notoginsenoside R₁ can delay the senescence process of vascular endothelial cells induced by H₂O₂ by regulating microRNA-34a/SIRT1/p53 signal pathway.
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Ursodeoxycholic acid improves liver function via phenylalanine/tyrosine pathway and microbiome remodelling in patients with liver dysfunction.
Kim, DJ, Yoon, S, Ji, SC, Yang, J, Kim, YK, Lee, S, Yu, KS, Jang, IJ, Chung, JY, Cho, JY
Scientific reports. 2018;(1):11874
Abstract
Ursodeoxycholic acid (UDCA) is a metabolic by-product of intestinal bacteria, showing hepatoprotective effects. However, its underlying molecular mechanisms remain unclear. The purpose of this study was to elucidate the action mechanisms underlying the protective effects of UDCA and vitamin E against liver dysfunction using metabolomics and metagenomic analysis. In this study, we analysed blood and urine samples from patients with obesity and liver dysfunction. Nine patients were randomly assigned to receive UDCA (300 mg twice daily), and 10 subjects received vitamin E (400 IU twice daily) for 8 weeks. UDCA significantly improved the liver function scores after 4 weeks of treatment and effectively reduced hepatic deoxycholic acid and serum microRNA-122 levels. To better understand its protective mechanism, a global metabolomics study was conducted, and we found that UDCA regulated uremic toxins (hippuric acid, p-cresol sulphate, and indole-derived metabolites), antioxidants (ascorbate sulphate and N-acetyl-L-cysteine), and the phenylalanine/tyrosine pathway. Furthermore, microbiome involvement, particularly of Lactobacillus and Bifidobacterium, was demonstrated through metagenomic analysis of bacteria-derived extracellular vesicles. Meanwhile, vitamin E treatment did not result in such alterations, except that it reduced uremic toxins and liver dysfunction. Our findings suggested that both treatments were effective in improving liver function, albeit via different mechanisms.
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Circ-ZNF609 promotes migration of colorectal cancer by inhibiting Gli1 expression via microRNA-150.
Wu, L, Xia, J, Yang, J, Shi, Y, Xia, H, Xiang, X, Yu, X
Journal of B.U.ON. : official journal of the Balkan Union of Oncology. 2018;(5):1343-1349
Abstract
PURPOSE To investigate the effect of circular (circ)-ZNF609 on the pathogenesis of colorectal cancer and its underlying mechanism. METHODS 24 cases of postoperative colorectal cancer tissues and 36 cases of mucosa tissues were selected as experimental group and control group, respectively. Circ-ZNF609 expression in colorectal cancer tissues and mucosa tissues were detected by quantitative real-time PCR (qRT-PCR). For in vitro experiments, subcellular localization of Circ-ZNF609 in nuclear and cytoplasmic HCT116 cells was assessed. MicroRNA-150 was found to bind to Circ-ZNF609 by dual luciferase reporter assay. Furthermore, migration ability of transfected HCT116 cells was assessed by Transwell assay. Additionally, mRNA and protein levels of glioma-associated oncogene 1 (Gli1) in HCT116 cells were detected by qRT-PCR and Western blot, respectively. RESULTS Higher expressions of Circ-ZNF609 and Gli1 were found in colorectal cancer tissues compared to paracancerous tissues. MicroRNA-150 was downregulated in colorectal cancer tissues. Pearson correlation analysis showed that Circ-ZNF609 was positively correlated with Gli1, and microRNA-150 was negatively correlated with Circ-ZNF609 and Gli1. Dual luciferase reporter assay confirmed that microRNA-150 was bound with cytoplasmic Circ-ZNF609. Furthermore, downregulated Circ-ZNF609 inhibited migration of HCT116 cells. In addition, knockdown of Circ-ZNF609 or overexpression of microRNA-150 inhibited cell migration, which was reversed by co-transfection with microRNA-150 inhibitor and Circ-ZNF609 siRNA. CONCLUSIONS Circ-ZNF609 regulates Gli1 expression via microRNA-150, thus affecting the migration of colorectal cancer.
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An rs13293512 polymorphism in the promoter of let-7 is associated with a reduced risk of ischemic stroke.
Zhang, L, Yang, J, Xue, Q, Yang, D, Lu, Y, Guang, X, Zhang, W, Ba, R, Zhu, H, Ma, X
Journal of thrombosis and thrombolysis. 2016;(4):610-5
Abstract
The expression of let-7 family members was differentiated in ischemic stroke (IS), functioning as an important regulating molecular in the pathophysiology of stroke. We hypothesized that genetic polymorphism in the promoters of let-7 family may be associated with the risk of IS. To test this hypothesis, we investigated the association of the rs10877887 and rs13293512 in the promoters of let-7 family with the susceptibility to IS. A hospital-based case-control study was performed. The rs10877887 genotype was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay, and the rs13293512 genotype was determined by using a TaqMan assay. We found that the rs13293512CC genotype was associated with a reduced risk of IS (CC vs. TT: adjusted OR = 0.43, 95 % CI 0.26-0.71; dominant model: adjusted OR = 0.70, 95 % CI 0.49-0.98; recessive model: adjusted OR = 0.45, 95 % CI, 0.28-0.73). Stratification analysis showed that the rs10877887TT carriers had a higher level of total cholesterol compared to rs10877887TC/CC carriers (P = 0.03). Combined analysis showed that the rs10877887TC/CC and rs13293512TC/CC genotypes had a reduced risk of IS risk (adjusted OR = 0.58, 95 % CI 0.36-0.95). Our findings suggest that the rs13293512 polymorphism may be a protective factor for the development of IS.
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MicroRNA MIR21 and T Cells in Colorectal Cancer.
Mima, K, Nishihara, R, Nowak, JA, Kim, SA, Song, M, Inamura, K, Sukawa, Y, Masuda, A, Yang, J, Dou, R, et al
Cancer immunology research. 2016;(1):33-40
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Abstract
The complex interactions between colorectal neoplasia and immune cells in the tumor microenvironment remain to be elucidated. Experimental evidence suggests that microRNA MIR21 (miR-21) suppresses antitumor T-cell-mediated immunity. Thus, we hypothesized that tumor MIR21 expression might be inversely associated with T-cell density in colorectal carcinoma tissue. Using 538 rectal and colon cancer cases from the Nurses' Health Study and the Health Professionals Follow-up Study, we measured tumor MIR21 expression by a quantitative reverse-transcription PCR assay. Densities of CD3(+), CD8(+), CD45RO (PTPRC)(+), and FOXP3(+) cells in tumor tissue were determined by tissue microarray immunohistochemistry and computer-assisted image analysis. Ordinal logistic regression analysis was conducted to assess the association of MIR21 expression (ordinal quartiles as a predictor variable) with T-cell density (ordinal quartiles as an outcome variable), adjusting for tumor molecular features, including microsatellite instability; CpG island methylator phenotype; KRAS, BRAF, and PIK3CA mutations; and LINE-1 methylation. We adjusted the two-sided α level to 0.012 for multiple hypothesis testing. Tumor MIR21 expression was inversely associated with densities of CD3(+) and CD45RO(+) cells (Ptrend < 0.0005). The multivariate odds ratio of the highest versus lowest quartile of MIR21 for a unit increase in quartile categories of CD3(+) or CD45RO(+) cells was 0.44 [95% confidence interval (CI), 0.28 to 0.68] or 0.41 (95% CI, 0.26-0.64), respectively. Our data support a possible role of tumor epigenetic deregulation by noncoding RNA in suppressing the antitumor T-cell-mediated adaptive immune response and suggest MIR21 as a potential target for immunotherapy and prevention in colorectal cancer.
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MicroRNA MIR21 (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival.
Mima, K, Nishihara, R, Yang, J, Dou, R, Masugi, Y, Shi, Y, da Silva, A, Cao, Y, Song, M, Nowak, J, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;(15):3841-8
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Abstract
PURPOSE Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2; a target of aspirin) produces inflammatory mediator prostaglandin E2 (PGE2), and contributes to colorectal neoplasia development. PTGS2-driven inflammatory responses can induce tumor expression of microRNA MIR21 (miR-21) that can increase local PGE2 level by downregulating PGE2-metabolizing enzymes. We hypothesized that the prognostic association of tumor MIR21 expression level in colorectal carcinoma might depend on inflammatory tumor microenvironment and be stronger in tumors expressing high-level PTGS2. EXPERIMENTAL DESIGN Utilizing 765 rectal and colon cancer specimens in the Nurses' Health Study and the Health Professionals Follow-up Study, we measured MIR21 expression by quantitative reverse transcription PCR, and PTGS2 expression by immunohistochemistry. Cox proportional hazards regression model was used to assess statistical interaction between MIR21 and PTGS2 in colorectal cancer-specific survival analysis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. RESULTS Tumor MIR21 expression level was associated with higher colorectal cancer-specific mortality (Ptrend = 0.029), and there was a statistically significant interaction between MIR21 and PTGS2 (Pinteraction = 0.0004). The association between MIR21 expression and colorectal cancer-specific mortality was statistically significant in PTGS2-high cancers (multivariable hazard ratio of the highest vs. lowest quartile of MIR21, 2.28; 95% confidence interval, 1.42-3.67; Ptrend = 0.0004) but not in PTGS2-absent/low cancers (Ptrend = 0.22). CONCLUSIONS MIR21 expression level in colorectal carcinoma is associated with worse clinical outcome, and this association is stronger in carcinomas expressing high-level PTGS2, suggesting complex roles of immunity and inflammation in tumor progression. Clin Cancer Res; 22(15); 3841-8. ©2016 AACR.