PGE2 synthesis and signaling in the liver physiology and pathophysiology: An update.

The liver plays a central role in systemic metabolism and drug degradation. However, it is highly susceptible to damage due to various factors, including metabolic imbalances, excessive alcohol consumption, viral infections, and drug influences. These factors often result in conditions such as fatty liver, hepatitis, and acute or chronic liver injury. Failure to address these injuries could promptly lead to the development of liver cirrhosis and potentially hepatocellular carcinoma (HCC). Prostaglandin E2 (PGE2) is a metabolite of arachidonic acid that belongs to the class of polyunsaturated fatty acids (PUFA) and is synthesized via the cyclooxygenase (COX) pathway. By binding to its G protein coupled receptors (i.e., EP1, EP2, EP3 and EP4), PGE2 has a wide range of physiological and pathophysiology effects, including pain, inflammation, fever, cardiovascular homeostasis, etc. Recently, emerging studies showed that PGE2 plays an indispensable role in liver health and disease. This review focus on the research progress of the role of PGE2 synthase and its receptors in liver physiological and pathophysiological processes and discuss the possibility of developing liver protective drugs targeting the COXs/PGESs/PGE2/EPs axis.

Procyanidin B2 mitigates endothelial endoplasmic reticulum stress through a PPARδ-Dependent mechanism.

Hyperglycemia-induced endothelial endoplasmic reticulum (ER) stress is implicated in the pathophysiology of diabetes and its vascular complications. Procyanidins are enriched in many plant foods and have been demonstrated to exert several beneficial effects on diabetes, cardiovascular and other metabolic diseases. In the present study, we investigated the effect of procyanidin B2 (PCB2), the most widely distributed natural procyanidin, on ER stress evoked by high glucose in endothelial cells (ECs) and the underlying mechanisms. We showed that PCB2 mitigated the high glucose-activated ER stress pathways (PERK, IRE1α and ATF6) in human vascular ECs. In addition, we found that PCB2 attenuated endothelial ER stress via the activation of peroxisome proliferator-activated receptor δ (PPARδ). We demonstrated that PCB2 directly bound to and activated PPARδ. Conversely, GSK0660, a selective PPARδ antagonist, attenuated the suppressive effect of PCB2 on the ER stress signal pathway. Functionally, PCB2 ameliorated the high glucose-impaired endothelium-dependent relaxation in mouse aortas. The protective effect of PCB2 on vasodilation was abolished in the aortas pretreated with GSK0660 or those from the EC-specific PPARδ knockout mice. Moreover, the protective effects of PCB2 on ER stress and endothelial dysfunction required the inter-dependent actions of PPARδ and AMPK. Collectively, we demonstrated that PCB2 mitigated ER stress and ameliorated vasodilation via a PPARδ-mediated mechanism beyond its classic action as a scavenger of free radicals. These findings further highlighted the novel roles of procyanidins in intervening the ER stress and metabolic disorders related to endothelial dysfunction.