ABHD15 promotes cell viability, glycolysis, and inhibits apoptosis in cardiomyocytes under hypoxia.

BACKGROUND AND AIMS: Myocardial infarction (MI) has been an important heart disease affecting human health. The aim of this study was to investigate the regulatory effect of abhydrolase domain containing 15 (ABHD15) on hypoxic cardiomyocytes. METHODS AND RESULTS: Hypoxic cardiomyocytes are commonly used as an vitro model for the study of MI. We found that cardiomyocyte viability was decreased under hypoxia, but cell glucose uptake, insulin receptor phosphorylation level and apoptosis were increased. Interestingly, ABHD15 expression was up-regulated in hypoxia-induced cardiomyocytes. Then, we identified the function of ABHD15 in hypoxic cardiomyocytes by using ABHD15 overexpression vector or short interfering RNA (siRNA) against ABHD15. The results showed that overexpression of ABHD15 promoted hypoxic cardiomyocyte viability, glucose uptake and IR phosphorylation (p-IR), and inhibited cell apoptosis. However, knockdown of ABHD15 attenuated hypoxic cardiomyocyte viability, glucose uptake and IR phosphorylation, and promoted apoptosis. Moreover, we found that ABHD15 promoted glucose transporter 4 (GLUT4) expression, translocation and enhance rate-limiting enzyme activation of glycolysis, thereby affecting glucose uptake. Furthermore, our study suggested that ABHD15 may affect the viability and apoptosis of hypoxic cardiomyocytes through IR/Ras/Raf/ERK/MEK and IR/PI3K/AKT/Bcl2/Bad/caspase9 signaling pathways, respectively. When the phosphorylation of IR, Raf or ERK was blocked by inhibitors, the protective effect of overexpressing ABHD15 on the viability of hypoxic cardiomyocytes was eliminated. Furthermore, inhibiting the phosphorylation of IR, AKT or Bcl2 abolished the inhibitory effect of overexpressing ABHD15 on hypoxic cardiomyocyte apoptosis. CONCLUSION: ABHD15 regulated myocardial cell viability, glycolysis, and apoptosis under hypoxia, providing a novel potential therapeutic strategy for MI.

Ginkgolide B ameliorates myocardial ischemia reperfusion injury in rats via inhibiting endoplasmic reticulum stress.

PURPOSE: Ginkgolide B (GB) is a terpene lactone component found in Ginkgo biloba, which has a protective role on ischemia reperfusion (I/R) injury. This study was aimed at exploring the protective mechanism of GB on the myocardial I/R. PATIENTS AND METHODS: Myocardial I/R model was established on Sprague Dawley rats. The levels of cardiac troponin I, cardiac troponin T, lactic dehydrogenase, and myoglobin were determined by a 200FR NEO automatic biochemical analyzer. Histological examination was performed through HE and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining. The expression levels of p-PERK, p-IRE1α, ATF6, p-AKT, and mTOR were detected by Western blot. RESULTS: The results exhibited that GB treatment suppressed the high levels of cardiac troponin I, cardiac troponin T, lactic dehydrogenase, and myoglobin and ameliorated the damaged and irregularly arranged myocardial cells induced by I/R injury significantly, indicating that GB could ameliorate myocardial I/R injury. Moreover, the high expression levels of endoplasmic reticulum (ER) stress key proteins caused by I/R injury were suppressed significantly by GB treatment, including p-PERK, p-IRE1α, and ATF6. GB treatment also decreased the number of apoptotic cells compared with I/R group. In addition, activation of ER stress by Tunicamycin treatment could counteract the protective effects of GB on I/R injury, suggesting that GB ameliorated myocardial I/R injury through inhibition of ER stress-induced apoptosis. Finally, the decreased p-AKT and p-mTOR expressions caused by I/R injury were upregulated by GB and inhibition of PI3K/AKT/mTOR pathway by LY294002 abolished the protective effects of GB on I/R injury, indicating that GB activated PI3K/AKT/mTOR pathway during I/R injury. CONCLUSION: GB protected against myocardial I/R injury through inhibiting ER stress-induced apoptosis via PI3K/AKT/mTOR signaling pathway.

White Matter Microstructural Similarity and Diversity of Functional Constipation and Constipation-predominant Irritable Bowel Syndrome.

BACKGROUND/AIMS: The Rome III criteria separated chronic constipation into functional constipation (FC) and constipation-predominant irritable bowel syndrome (IBS-C), but some researchers questioned the partitioning and treated both as distinct parts of a continuum. The study aims to explore the similarity and diversity of brain white matter between FC and IBS-C. METHODS: The voxel-wise analysis of the diffusion parameters was used to quantify the white matter changes of female brains in 18 FC patients and 20 IBS-C patients compared with a comparison group with 19 healthy controls by tract-based spatial statistics. The correlations between diffusive parameters and clinical symptoms were evaluated using a Pearson's correlation. RESULTS: In comparison to healthy controls, FC patients showed a decrease of fractional anisotropy (FA) and an increase of radial diffusivity (RD) in multiple major fibers encompassing the corpus callosum (CC, P = 0.001 at peak), external capsule (P = 0.002 at peak), corona radiata (CR, P = 0.001 at peak), and superior longitudinal fasciculus (SLF, P = 0.002 at peak). In contrast, IBS-C patients showed FA and RD aberrations in the CC (P = 0.048 at peak). Moreover, the direct comparison between FC and IBS-C showed only RD differences in the CR and SLF. In addition, FA and RD in the CC were significantly associated with abdominal pain for all patients, whereas FA in CR (P = 0.016) and SLF (P = 0.040) were significantly associated with the length of time per attempt and incomplete evacuation separately for FC patients. CONCLUSION: These results may improve our understanding of the pathophysiological mechanisms underlying different types of constipation.

WITHDRAWN: Schisandrin B suppresses NLRP3 inflammasome activation to alleviate myocardial ischemia reperfusion injury via maintaining mitochondrial autophagy.

This article has been retracted at the request of the authors. The Editor in Chief has agreed to retract this article and the publisher supports the decision. The authors have indicated that their initial results were not reproducible when conducted by their colleagues. They indicated that the levels of autophagy were significantly different in the MI/R mice model in the respective results. The authors of this article would like to apologize to all affected parties. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Barbaloin pretreatment attenuates myocardial ischemia-reperfusion injury via activation of AMPK.

Myocardial ischemia/reperfusion (MI/R) injury is a major cause of cardiac dysfunction during cardiovascular surgery and heart transplantation and characterized by hyperactive oxidative stress and inflammatory response. Barbaloin (BAR) is the main medicinal composition of the Chinese traditional medicine aloe vera. BAR has strong anti-oxidant, anti-inflammatory and anti-tumor properties. However, the effect of BAR on MI/R-induced myocardial injury is not explored. This study aims to investigate whether BAR provides cardio-protection against MI/R injury and the underlying mechanisms. BAR (20 mg/kg/d) or vehicle was intragastrically administered to Sprague-Dawley rats for 5 days before MI/R operation. BAR pretreatment conferred cardio-protective effects against MI/R injury by improving hemodynamic function and limiting infarction size. Moreover, BAR pretreatment effectively inhibited I/R-induced myocardial oxidative stress and inflammatory response. Furthermore, BAR pretreatment activated adenosine monophosphate-activated protein kinase (AMPK) signaling in MI/R hearts. AMPK inhibitor compound C inhibited BAR-induced AMPK activation, and blunted BAR-mediated anti-oxidative, anti-inflammatory effects and cardio-protection. Taken together our study has identified a novel function of BAR and provided a molecular basis for BAR potential applications in the treatment of MI/R injury and other ischemic disorders.

Vitexin alleviates ox-LDL-mediated endothelial injury by inducing autophagy via AMPK signaling activation.

Endothelial cell injury plays a crucial role in the development and pathogenesis of cardiovascular disease. Vitexin is a natural flavonoid characterized by anti-oxidative and anti-inflammatory properties. The purpose of this study was to investigate the effects of vitexin on ox-LDL-induced endothelial dysfunction and to explore the underlying molecular mechanisms. In the present study, vitexin was found to play a protective role against ox-LDL-induced endothelial injury. Vitexin significantly promoted cell viability and inhibited apoptosis in ox-LDL-treated HUVECs. The up-regulation of cleaved Caspase-3, cleaved Caspase-9 and Bax induced by ox-LDL were inhibited by treatment with vitexin; meanwhile, the down-regulation of Bcl-2 was suppressed by vitexin. Pretreatment with vitexin was found to inhibit the ox-LDL-induced overexpression of IL-1ß, IL-6, TNF-α, E-selectin, ICAM1 and VCAM1. Moreover, vitexin reduced ox-LDL-induced oxidative stress by inhibiting the production of ROS and MDA, and by promoting the expression of SOD. Furthermore, we had shown that vitexin protected against the ox-LDL induced cell injury by activating autophagy. The protective effects of vitexin in ox-LDL-treated HUVECs were all reversed following treatment with the autophagy inhibitor 3-MA. In addition, we found that vitexin increased the expression of p-AMPK and decreased the expression of p-mTOR. The combination of the AMPK inhibitor Compound C plus vitexin significantly reversed the effects of vitexin in ox-LDL-treated HUVECs, such as the inhibition of autophagy, reduction in cell viability, increase in apoptosis and ROS production. In conclusion, these data suggest that vitexin ameliorates ox-LDL-mediated endothelial injury by inducing autophagy via AMPK signaling.