Trimetazidine enhances myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice through directly activating Akt and promoting the binding of HSF1 to VEGF-A promoter.

Latest clinical research shows that trimetazidine therapy during the perioperative period relieves endothelial dysfunction in patients with unstable angina induced by percutaneous coronary intervention. In this study we investigated the effects of TMZ on myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery. TAC mice were administered trimetazidine (2.8 mg/100 µL, i.g.) for 28 consecutive days. We showed that trimetazidine administration significantly increased blood vessel density in the left ventricular myocardium and abrogated cardiac dysfunction in TAC mice. Co-administration of a specific HSF1 inhibitor KRIBB11 (1.25 mg/100 µL, i.h.) abrogated the angiogenesis-promoting effects of trimetazidine in TAC mice. Using luciferase reporter and electrophoretic mobility shift assays we demonstrated that the transcription factor HSF1 bound to the promoter region of VEGF-A, and the transcriptional activity of HSF1 was enhanced upon trimetazidine treatment. In molecular docking analysis we found that trimetazidine directly bound to Akt via a hydrogen bond with Asp292 and a pi-pi bond with Trp80. In norepinephrine-treated HUVECs, we showed that trimetazidine significantly increased the phosphorylation of Akt and the synergistic nuclear translocation of Akt and HSF1, as well as the binding of Akt and HSF1 in the nucleus. These results suggest that trimetazidine enhances myocardial angiogenesis through a direct interaction with Akt and promotion of nuclear translocation of HSF1, and that trimetazidine may be used for the treatment of myocardial angiogenic disorders in hypertensive patients.

Comparative efficacy and tolerability of front-line treatments for newly diagnosed chronic-phase chronic myeloid leukemia: an update network meta-analysis.

BACKGROUND: Recent years have witnessed the rapid evolution of therapies in chronic-phase chronic myeloid leukemia (CP-CML). To assess the efficacy and tolerability of all reported front-line treatments for patients with newly diagnosed CML, a multiple-treatments meta-analysis was performed, which accounted for both direct and indirect comparisons among those treatments. METHODS: Primary outcomes were the percentage of patients achieving major molecular response (MMR) and complete cytogenetic response (CCyR) within 12 months. Secondary outcomes included the percentage of progression to accelerated phase (AP), serious adverse effects (AEs), overall discontinuation and discontinuation for drug-related AEs. Direct pairwise meta-analysis and indirect multi-comparison meta-analysis among those treatments in each outcome were both conducted. The surface under the cumulative ranking curve (SUCRA) was calculated for all treatments in each outcome. Cluster analysis demonstrated the division of treatments into distinct groupings according to efficacy and tolerability profiles. RESULTS: A total of 21 randomized controlled trials (RCTs, including 10,187 patients) comparing 15 different interventions for CP-CML patients were included in this study. SUCRA analysis suggested that all tyrosine kinase inhibitors (TKIs) are highly effective in newly diagnosed CP-CML when compared to traditional drugs. Newer TKIs and higher-dose imatinib generally resulted in faster cytogenetic and molecular responses when compared with standard-dose imatinib and traditional drugs. Furthermore, traditional drugs, higher-dose imatinib and newer TKIs demonstrated lower acceptability than standard-dose imatinib. One cluster of interventions, which included nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID), demonstrated higher efficacy and tolerability than other treatments. CONCLUSIONS: Nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID) prove to be the most recommended front-line treatments of the greatest efficacy and tolerability for CP-CML patients. High-dose therapies are recommended only for patients in accelerated phase/blast phase or with suboptimal CML-CP response, and management of adverse events should be carried out to avoid compromising the clinical efficacy.

Prognostic and Clinicopathological Significance of MiR-155 in Hematologic Malignancies: A Systematic Review and Meta-analysis.

Background: Aberrant miR-155 expression has been reported in various types of hematologic malignancies. However, the prognostic and clinicopathological value of miR-155 remains unclear. Here, we performed this systemic review and meta-analysis to comprehensively evaluate the prognostic and clinicopathological significance of miR-155 expression in hematologic malignancies. Methods: We systematically searched the PubMed, EMBASE, ISI Web of Science, Cochrane library databases and OVID to identify eligible studies published from Jan 1, 2008 to Aug 1, 2018. The pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to detect the prognostic and clinicopathological role of miR-155 in hematologic malignancies. Results: A total of 18 studies including 2316 patients were enrolled in the present meta-analysis, indicating significant association between elevated miR-155 expression and poor overall survival (OS) in 2114 patients (pooled HR = 1.72, 95%CI [1.50-1.97], p<0.001). Elevated miR-155 expression level was related to shorter event free survival (EFS, pooled HR = 1.55, 95%CI [0.94-2.57], P=0.002), disease free survival (DFS, pooled HR = 1.38, 95%CI [1.13-1.68], P=0.001), progress free survival (PFS, pooled HR = 1.58, 95%CI [1.06-2.35], p<0.001) and treatment free survival (TFS, pooled HR = 1.67, 95%CI [1.16-2.39], P=0.006). Additionally, overexpression of miR-155 was found to be significantly related to FLT3/ITD presence (OR=4.751, 95%CI [3.229-6.990], P<0.001), more WT1 mutation (OR=2.090, 95%CI [1.240-3.522], P=0.006) and less CEBPA mutation (OR=0.477, 95%CI [0.286-0.794], P=0.004) in 552 AML patients. Conclusion: MiR-155 expression was found to be associated with several leukemia-related phenotype and poor prognosis in hematologic malignancies. Therefore, miR-155 overexpression might be a convinced unfavorable prognostic indicator that helps the clinical decision-making process.