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OBJECTIVE: To investigate the effect of miRNA-182 on cardiomyocyte apoptosis of heart failure (HF). MATERIALS AND METHODS: HF model in rats was established by rapid ventricular pacing. AAV-miRNA-182 (adeno-associated virus) vector was constructed to upregulate miRNA-182 level and its negative control AAV-NC was prepared. Rats undergoing rapid pacing (pacing group) and sham operation (sham group) were injected with AAV-miRNA-182 or AAV-NC, respectively. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was conducted to determine the miRNA-182 level in rats. Cardiac function test was carried out after the HF model establishment. Western blot was performed to examine the protein levels of human programmed cell death4 (PDCD4) and phosphoacidic cluster sorting protein (PACS2) in rats. Finally, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP Nick End Labeling (TUNEL) assay was performed to evaluate the apoptotic rate of cardiomyocytes. RESULTS: HF model in rats was successfully established by rapid pacing. Injection of AAV-miRNA-182 markedly upregulated miRNA-182 level in rats. Compared with rats in the sham group, left ventricle ejection fraction (LVEF; 81.8% ± 2.4% vs. 64.3% ± 2.2%, p<0.05) and left ventricular fractional shortening (LVFS; 44.7% ± 2.4% vs. 29.1% ± 0.9%, p<0.05) markedly decreased in the pacing + NC group, whereas heart rate (HR) and left ventricular end-diastolic pressure (LVEDP) increased. Compared with rats in the pacing + NC group, HR [(441.6 ± 22) /min vs. (368.4 ± 27)/min, p<0.05] and LVEDP [(34.8 ± 11.4) mmHg vs. (19.4 ± 10.3) mmHg, p<0.05] were reduced in the pacing + miRNA-182 group. The protein levels of PDCD4 and PACS2 were downregulated in the pacing + miRNA-182 group relative to the pacing + NC group. Rapid pacing stimulation induced cardiac structural remodeling and cardiomyocyte apoptosis, which were alleviated by injection of AAV-miRNA-182. CONCLUSIONS: MiRNA-182 inhibits cardiomyocyte apoptosis induced by non-ischemic HF via downregulating PDCD4 and PACS2. [ABSTRACT FROM AUTHOR]

Background: The identification of novel therapeutic candidates from natural products for the development of chemoresistant glioblastoma multiforme (GBM) treatment has been a highly significant and effective strategy.Purpose: Sesquiterpenes are a class of naturally occurring 15-carbon isoprenoid compounds, and several types of sesquiterpenes have the ability to induce growth inhibition and apoptosis in a variety of cancer cell lines. In the present study, 56 sesquiterpenes of five types, namely, eudesmane-type (I) (1-24), eremophilane-type (II) (25-32), cadinane-type (III) (33-41), guaiane-type (IV) (42-49), and oplopanone-type (V) (50-56), were screened for their antiglioma activity, structure-activity relationship analysis (SAR), and underlying mechanism based on patient-derived recurrent GBM strains, patient-derived GBM cell sphere, GBM organoid (GBO) models, and temozolomide (TMZ)-resistant GBM cell lines.Results: We found that compound 12 (oxyphyllanene B, OLB) showed the most potent antiglioma activity, and we confirmed that OLB could induce apoptosis in a time- and dose-dependent manner in TMZ-resistant GBM cells and GBOs. SAR announced that the presence of an α, β-unsaturated carbonyl moiety was likely to enhance cytotoxic activities. Mechanistic studies demonstrated that OLB induced abnormal changes in ER and mitochondria-associated membrane (MAM) networks, which triggered ER stress, mitochondrial dysfunction, and apoptosis. Furthermore, our findings suggested that OLB-triggered PACS2 activation might form a committed step to disrupt ER-mitochondria communication and showed for the first time that the expression levels of PACS2 might positively correlate with the progression and chemotherapy resistance of glioma.Conclusion: Our results indicated that OLB might be a promising candidate for treating TMZ-resistant GBM cells by activating PACS2, which triggered a crucial event to promote the disruption of ER-mitochondria communication and overcome chemotherapy resistance of GBM. [ABSTRACT FROM AUTHOR]