GSK-3α aggravates inflammation, metabolic derangement, and cardiac injury post-ischemia/reperfusion.

Reperfusion after acute myocardial infarction further exaggerates cardiac injury and adverse remodeling. Irrespective of cardiac cell types, loss of specifically the α isoform of the protein kinase GSK-3 is protective in chronic cardiac diseases. However, the role of GSK-3α in clinically relevant ischemia/reperfusion (I/R)-induced cardiac injury is unknown. Here, we challenged cardiomyocyte-specific conditional GSK-3α knockout (cKO) and littermate control mice with I/R injury and investigated the underlying molecular mechanism using an in vitro GSK-3α gain-of-function model in AC16 cardiomyocytes post-hypoxia/reoxygenation (H/R). Analysis revealed a significantly lower percentage of infarct area in the cKO vs. control hearts post-I/R. Consistent with in vivo findings, GSK-3α overexpression promoted AC16 cardiomyocyte death post-H/R which was accompanied by an induction of reactive oxygen species (ROS) generation. Consistently, GSK-3α gain-of-function caused mitochondrial dysfunction by significantly suppressing mitochondrial membrane potential. Transcriptomic analysis of GSK-3α overexpressing cardiomyocytes challenged with hypoxia or H/R revealed that NOD-like receptor (NLR), TNF, NF-κB, IL-17, and mitogen-activated protein kinase (MAPK) signaling pathways were among the most upregulated pathways. Glutathione and fatty acid metabolism were among the top downregulated pathways post-H/R. Together, these observations suggest that loss of cardiomyocyte-GSK-3α attenuates cardiac injury post-I/R potentially through limiting the myocardial inflammation, mitochondrial dysfunction, and metabolic derangement. Therefore, selective inhibition of GSK-3α may provide beneficial effects in I/R-induced cardiac injury and remodeling. KEY MESSAGES: GSK-3α promotes cardiac injury post-ischemia/reperfusion (I/R). GSK-3α regulates inflammatory and metabolic pathways post-hypoxia/reoxygenation (H/R). GSK-3α overexpression upregulates NOD-like receptor (NLR), TNF, NF-kB, IL-17, and MAPK signaling pathways in cardiomyocytes post-H/R. GSK-3α downregulates glutathione and fatty acid metabolic pathways in cardiomyocytes post-H/R.

Arum palaestinum delays hepatocellular carcinoma proliferation through the PI3K-AKT-mTOR signaling pathway and exhibits anticoagulant effects with antimicrobial properties.

Background: Arum palaestinum Boiss (AP) is a wild plant in Palestine whose leaves have a long history as food and medicine in Middle Eastern countries. The current study aimed to evaluate the biological characteristics of AP flower extract, including its antimicrobial and coagulation cascade activities and its effects on anticancer molecular pathways. Methods: The antimicrobial activity of the aqueous extract of AP flowers was assessed using a microdilution assay against eight pathogens. The coagulation properties were assessed by prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) tests using standard hematological methods. The biological effects of AP on hepatocellular carcinoma were measured by assessing the impact of AP on cell cycle, proliferation (CFSE), apoptosis (annexin-v+/PI), and tumorigenicity (αFP and HBsAg), as well as its effects on the PI3K-AKT-mTOR molecular signaling pathway. Results: The antimicrobial screening results revealed that the aqueous extract of AP had potent antibacterial effects against P. vulgaris and E. faecium compared to ampicillin, with MIC values of 6.25, 6.25, and 18 µg/mL, respectively. Moreover, the AP aqueous extract exerted anticoagulant activity, with significant prolonged results in the aPTT and TT tests (25 µg/mL and 50 µg/mL, respectively) and slightly prolonged results in the PT test (50 µg/mL). The anticancer results indicated a delay in the cell cycle through decreased cell proliferation rates following incubation with AP fractions. The effect of the aqueous fraction was most evident in a delay in the S phase. The aqueous and DMSO fractions maintained the cells in the G2-M phase, similar to the DOX, while the flower extract in methanol accelerated the cells in the G2-M phase, suggesting that AF flower extracts may have anti-cancer properties. The aqueous extract of AP 1) reduced secretions of HCC αFP by 1.55-fold and 3.3-fold at the 50 and 100 µg/mL concentrations, respectively (p = 0.0008); 2) decreased phosphorylation in the PI3K-AKT-mTOR signaling pathway (p < 0.05); and 3) shifted cells from necrosis to apoptosis by 50% and 70% at the 50 and 100 µg/mL concentrations, respectively (p < 0.05). Conclusion: The results of this study showed the activities of the bioactive components for the treatment of infectious diseases and blood coagulation disorders, which could also be a potential therapeutic approach for delaying HCC tumorigenicity.