miR-373 Suppresses Cell Proliferation and Apoptosis via Regulation of SIRT1/PGC-1α/NRF2 Axis in Pancreatic Cancer.

OBJECTIVE: Our study aimed to investigate function and mechanism of miR-373 in proliferation and apoptosis of pancreatic cancer (PC) cells by regulating NAD+-dependent histone deacetylase sirtulin 1 (SIRT1). MATERIALS AND METHODS: This experimental study included two PC cell lines AsPC-1 and PANC-1 in which expression levels of miR-373 and SIRT1 were manipulated. The level of miR-373 was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) method. Expression levels of SIRT1, BCL-2, BAX, cleaved CASPASE-8/9/3, PARP, PGC-1α, NRF2, eNOS and iNOS were examined via RT-qPCR and western blotting, respectively. The binding sites of miR-373 on the SIRT1 were examined via dual-luciferase assay. Cell proliferation and apoptosis were examined by MTT assay, colony formation assay, Annexin-V/PI staining and TUNEL assay. The oxidative metabolic changes were monitored by reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) detection. RESULTS: miR-373 could specifically target the 3'-UTR of SIRT1 and reduce its expression in PC cells. Either elevated expression of miR-373 or partial loss of SIRT1 inhibited cell proliferation and induced cell apoptosis. Accumulation of BAX and cleaved CASPASE-8/9/3, inhibition of PGC-1α/NRF2 pathway, increase oxidative stress and reduction of BCL-2 as well as uncleaved PARP were found in the presence of miR-373 or the absence of SIRT1. Overexpression of SIRT1 could reduce anti-proliferative and pro-apoptotic effects of miR-373. CONCLUSION: Overall, this study concluded that miR-373-dependent SIRT1 inhibition displays anti-proliferative and proapoptotic roles in PC cells via PGC-1α/NRF2 pathway, which highlights miR-373 as a potential target for PC treatment.

Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice.

ATP-binding cassette transporter A1 (ABCA1), which promotes cholesterol efflux from cells and inhibits inflammatory responses, is highly expressed in the kidney. Research has shown that exendin-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, promotes ABCA1 expression in multiple tissues and organs; however, the mechanisms underlying exendin-4 induction of ABCA1 expression in glomerular endothelial cells are not fully understood. In this study we investigated the effect of exendin-4 on ABCA1 in glomerular endothelial cells of diabetic kidney disease (DKD) and the possible mechanism. We observed a marked increase in glomerular lipid deposits in tissues of patients with DKD and diabetic apolipoprotein E knock-out (apoE-/-) mice by Oil Red O staining and biochemical analysis of cholesterol. We found significantly decreased ABCA1 expression in glomerular endothelial cells of diabetic apoE-/- mice and increased renal lipid, cholesterol, and inflammatory cytokine levels. Exendin-4 decreased renal cholesterol accumulation and inflammation and increased cholesterol efflux by up-regulating ABCA1. In human glomerular endothelial cells, GLP-1R-mediated signaling pathways (e.g. Ca2+/calmodulin-dependent protein kinase, cAMP/PKA, PI3K/AKT, and ERK1/2) were involved in cholesterol efflux and inflammatory responses by regulating ABCA1 expression. We propose that exendin-4 increases ABCA1 expression in glomerular endothelial cells, which plays an important role in alleviating renal lipid accumulation, inflammation, and proteinuria in mice with type 2 diabetes.

Charlson comorbidity index helps predict the risk of mortality for patients with type 2 diabetic nephropathy.

Our intent is to examine the predictive role of Charlson comorbidity index (CCI) on mortality of patients with type 2 diabetic nephropathy (DN). Based on the CCI score, the severity of comorbidity was categorized into three grades: mild, with CCI scores of 1-2; moderate, with CCI scores of 3-4; and severe, with CCI scores ≥5. Factors influencing mortality and differences between groups stratified by CCI were determined by logistical regression analysis and one-way analysis of variance (ANOVA). The impact of CCI on mortality was assessed by the Kaplan-Meier analysis. A total of 533 patients with type 2 DN were enrolled in this study, all of them had comorbidity (CCI score >1), and 44.7% (238/533) died. The mortality increased with CCI scores: 21.0% (50/238) patients with CCI scores of 1-2, 56.7% (135/238) patients with CCI scores of 3-4, and 22.3% (53/238) patients with CCI scores ≥5. Logistical regression analysis showed that CCI scores, hemoglobin, and serum albumin were the potential predictors of mortality (P<0.05). One-way ANOVA analysis showed that DN patients with higher CCI scores had lower levels of hemoglobulin, higher levels of serum creatinine, and higher mortality rates than those with lower CCI scores. The Kaplan-Meier curves showed that survival time decreased when the CCI scores and mortality rates went up. In conclusion, CCI provides a simple, readily applicable, and valid method for classifying comorbidities and predicting the mortality of type 2 DN. An increased awareness of the potential comorbidities in type 2 DN patients may provide insights into this complicated disease and improve the outcomes by identifying and treating patients earlier and more effectively.

XPD Lys751Gln and Asp312Asn polymorphisms and gastric cancer susceptibility: a meta-analysis of case-control studies.

BACKGROUND: Published data regarding the association between xeroderma pigmentosum group D (XPD) Lys751Gln and Asp312Asn polymorphisms and gastric cancer susceptibility havew been inconclusive. This meta-analysis was therefore performed toobtain a more precise estimation of any relationship. MATERIALS AND METHODS: A comprehensive literature search was conducted to identify all case-control studies of Lys751Gln and Asp312Asn polymorphisms and susceptibility to gastric cancer. Summary odds ratios (ORs) and its 95% confidence intervals (95% CIs) were calculated using a random-effects model with the software STATA (version10.0). RESULTS: A total of 12 case-control studies including 3,147 cases and 4,736 controls were included. Overall, no significant associations were found in some models (for Lys751Gln: Lys/Gln vs Lys/Lys: OR=1.144, 95% CI=0.851-1.541, Gln/Gln vs Lys/Lys: OR=1.215, 95% CI = 0.740-1.955, dominant model: OR=1.137, 95% CI=0.818-1.582; recessive model: OR=1.123, 95% CI=0.765-1.650; for Asp312Asn: Asp/Asn vs Asp/Asp: OR=1.180, 95% CI=0.646-2.154, dominant model: OR=1.380, 95% CI = 0.812-2.346), but significantly elevated susceptibility was found for Asp312Asn polymorphism in some models (Asn/Asn vs Asp/Asp: OR=2.045, 95% CI=1.254-3.335, recessive model: OR=1.805, 95% CI =1.219-2.672 ), for the additive model, the XPD Lys751Gln and Asp312Asn polymorphisms were not significantly associated with gastric cancer susceptibility. In stratified analyses, significantly elevated susceptibility was found for some models in the Chinese population. CONCLUSION: This meta-analysis suggested the XPD Asp312Asn polymorphism might be a potential biomarker of gastric cancer susceptibility in overall population, while both XPD Lys751Gln and Asp312Asn polymorphisms might be risk factors of gastric cancer susceptibility in Chinese.

Association between the XRCC3 T241M polymorphism and head and neck cancer susceptibility: a meta-analysis of case-control studies.

BACKGROUND: To evaluate the role of the X-ray repair cross complementing group 3 (XRCC3) T241M polymorphism in head and neck cancer susceptibility. MATERIALS AND METHODS: We performed a meta-analysis of all available studies, which included 3,191 cases and 5,090 controls. RESULTS: Overall, a significant risk effect of the T241M polymorphism was not found under homologous contrast (MM vs TT: OR=1.293, 95% CI=0.926-1.805; TM vs TT: OR=1.148 95% CI=0.930-1.418) and recessive models (MM vs TT+TM): OR=1.170, 95% CI=0.905- 1.512, but a significantly increased risk was observed under a dominant model (MM+TM vs TT): OR=1.243, 95% CI=1.001-1.544. In stratified analyses, there were no significant associations for Asians or Caucasians. CONCLUSION: Our meta-analysis suggested the XRCC3 241M allele (MM+TM) might act as a head and neck cancer risk factor among all subjects, and the effect of T241M polymorphism on head and neck susceptibility should be studied with a larger, stratified population.

Anti-proliferative and pro-apoptotic effect of carvacrol on human hepatocellular carcinoma cell line HepG-2.

Carvacrol is one of the members of monoterpene phenol and is present in the volatile oils of Thymus vulgaris, Carum copticum, origanum and oregano. It is a safe food additive commonly used in our daily life, and few studies have indicated that carvacrol has anti-hepatocarcinogenic activities. The rationale of the study was to examine whether carvacrol affects apoptosis of human hepatoma HepG2 cells. In this study, we showed that carvacrol inhibited HepG2 cell growth by inducing apoptosis as evidenced by Hoechst 33258 stain and Flow cytometric (FCM) analysis. Incubation of HepG2 cells with carvacrol for 24 h induced apoptosis by the activation of caspase-3, cleavage of PARP and decreased Bcl-2 gene expression. These results demonstrated that a significant fraction of carvacrol treated cells died by an apoptotic pathway in HepG2 cells. Moreover, carvacrol selectively altered the phosphorylation state of members of the MAPK superfamily, decreasing phosphorylation of ERK1/2 significantly in a dose-dependent manner, and activated phosphorylation of p38 but not affecting JNK MAPK phosphorylation. These results suggest that carvacrol may induce apoptosis by direct activation of the mitochondrial pathway, and the mitogen-activated protein kinase pathway may play an important role in the antitumor effect of carvacrol. These results have identified, for the first time, the biological activity of carvacrol in HepG2 cells and should lead to further development of carvacrol for liver disease therapy.