BackgroundGlioblastoma is the most common type of primary brain tumors. Cisplatin is a commonly used chemotherapeutic agent for Glioblastoma patients. Despite a consistent rate of initial responses, cisplatin treatment often develops chemoresistance, leading to therapeutic failure. Cellular resistance to cisplatin is of great concern and understanding the molecular mechanisms is an utter need.MethodsGlioblastoma cell line U251 cells were exposed to increasing doses of cisplatin for 6 months to establish cisplatin-resistant cell line U251R. The differential miRNA expression profiles in U251 and U251R cell lines were identified by microarray analysis and confirmed by Q-PCR. MiRNA mimics were transfected into U251R cells, and cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis.ResultsU251R cells showed 3.1-fold increase in cisplatin resistance compared to its parental U251 cells. Microarray analysis identified Let-7b and other miRNAs significantly down-regulated in U251R cells compared to U251 cells. Transfection of Let-7b mimics greatly re-sensitized U251R cells to cisplatin, while transfection of other miRNAs has no effect or slightly effect. Cyclin D1 is predicted as a target of Let-7b through bioinformatics analysis. Over-expression of Let-7b mimics suppressed cyclin D1 protein expression and inhibited cyclin D1-3’-UTR luciferase activity. Knockdown of cyclin D1 expression significantly increased cisplatin-induced G1 arrest and apoptosis.ConclusionsCollectively, our results indicated that cisplatin treatment leads to Let-7b suppression, which in turn up-regulates cyclin D1 expression. Let-7b may serve as a marker of cisplatin resistance, and can enhance the therapeutic benefit of cisplatin in glioblastoma cells.

This study investigated the interaction among valsartan (VAL), TGF-β pathways, and long non-coding RNA (lncRNA) cardiac hypertrophy-related factor (CHRF) in doxorubicin (DOX)-induced heart failure (HF), and explored their roles in DOX-induced HF progression. HF mice models in vivo were constructed by DOX induction. The expression of CHRF and TGF-β1 in hearts was detected, along with cardiac function, caspase-3 activity, and cell apoptosis. Primary myocardial cells were pretreated with VAL, followed by DOX induction in vitro for functional studies, including the detection of cell apoptosis with terminal deoxynucleotidyl transferase dUTP nick-end labeling and the expression of proteins associated with TGF-β1 pathways. HF models were established in vivo and in vitro. Expression of CHRF and TGF-β1 was up-regulated, and cell apoptosis and caspase-3 activity were increased in the hearts and cells of the HF models. VAL supplementation alleviated the cardiac dysfunction and injury in the HF process. Moreover, overexpressed CHRF up-regulated TGF-β1, promoted myocardial cell apoptosis, and reversed VAL's cardiac protective effect, while interference of CHRF (si-CHRF) did the opposite. Down-regulation of CHRF reversed the increased expression of TGF-β1 and the downstream proteins induced by pcDNA-TGF-β1 in HL-1 cells, while overexpression of CHRF reversed the VAL's cardiac protective effect in vivo. In conclusion, VAL regulates TGF-β pathways through lncRNA CHRF to improve DOX-induced HF.

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Dan-Shen-Yin (DSY) is a well-known traditional Chinese formula which is widely used in clinical practice for the treatment of coronary heart disease (CHD) and has produced a favorable effect in China. The present study was designed to examine whether or not acute oral DSY can protect the heart against myocardial infarction in acute myocardial ischemic rats. If so, we would then investigate the anti-inflammatory and anti-oxidant mechanisms involved. The left anterior descending coronary artery was occluded to induce myocardial ischemia in the hearts of Sprague-Dawley rats. At the end of the 3-h ischemic period (or 24 h for infarction size), we measured the myocardial infarction size, inflammatory factors and the activities of anti-oxidative enzymes. DSY reduced the infarction size and the serum levels of C-reactive protein, interleukin-6, tumour necrosis factor-α and malondialdehyde and increased the activities of superoxide dismutase and the serum levels of glutathione. The results show that DSY exerts significant cardioprotective effects against acute ischemic myocardial injury in rats, possibly through its anti-inflammatory and anti-oxidant properties, and may thus be used as a potential therapeutic reagent for the treatment of CHD.

Guizhi Gancao Decoction (GGD) is a well-known traditional Chinese herbal medicine for the treatment of various cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury and arrhythmia. However, the mechanism by which GGD contributes to the amelioration of cardiac injury remains unclear. The aim of this study was to investigate the potential protective role of GGD against myocardial I/R injury and its possible mechanism. Consistent with the effect of the positive drug (Trimetazidine, TMZ), we subsequently validated that GGD could ameliorate myocardial I/R injury as evidenced by histopathological examination and triphenyltetrazolium chloride (TTC) staining. Moreover, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated that GGD suppressed myocardial apoptosis, which may be related to the upregulation of Bcl-2, PPARα, and PPARγ and downregulation of Bax, caspase-3, and caspase-9. Pretreatment with GGD attenuated the levels of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin- (IL-) 6, and IL-1β in serum by inhibiting Toll-like receptor 4 (TLR4)/NF-κB signaling pathway. These results indicated that GGD exhibits cardioprotective effects on myocardial I/R injury through inhibition of the TLR4/NF-κB signaling pathway, which led to reduced inflammatory response and the subsequent cardiomyocyte apoptosis.