Quercetin ameliorated cardiac injury via reducing inflammatory actions and the glycerophospholipid metabolism dysregulation in a diabetic cardiomyopathy mouse model

Figure 1. Eicosanoid biosynthesis and GPCR-mediated signalling pathways. Prostanoid receptors mediate the biological effects of PG, LT, and TX and include receptors for PGE2, PGF2α, PGI2, PGD2, and TXA2, as well as LTB4, LTC4, LTD4, and LTE4. These receptors are predominantly integral membrane proteins characterized by a seven-transmembrane (heptahelical) structure and belong to the family of G protein-coupled receptors (GPCRs). Prostanoid receptors display considerable diversity in their G-protein coupling profiles, which leads to distinct downstream physiological responses. Activation of Gq-coupled receptors result in increased intracellular levels of IP3 and Ca2+, whereas receptors coupled to Gs proteins stimulate cAMP production. In contrast, Gi-coupled receptors inhibit adenylate cyclase activity, leading to reduced intracellular cAMP levels. Prostaglandin E2 (PGE2); Prostaglandin F2α (PGF2α); Prostaglandin I2 (PGI2); Prostaglandin D2 (PGD2); Thromboxane A2 (TXA2); Leukotriene B4 (LTB4); Leukotriene C4 (LTC4); Leukotriene D4 (LTD4); Leukotriene E4 (LTE4); Cyclic adenosine monophosphate (cAMP); Inositol trisphosphate (IP3); Calcium ion (Ca2+); Stimulatory G-protein (GS);…

Figure 2. Schematic representation of the main molecular pathways involved in cardiac dysfunction in various pathological conditions. In the presence of anoxia and treatment with doxorubicin, marked activation of the PGD2/CRTH2 axis is observed in cardiomyocytes, resulting in oxidative stress accumulation and apoptosis induction. In inflammation and HF models, the increased expression of PGE2 and its interaction with EP3 and EP4 receptors determine different responses: both EP3 inhibition and EP4 activation could promote PLN protein phosphorylation, improving intracellular calcium regulation and reducing left ventricular inflammation, thus contributing to improved contractile function. On the contrary, both EP3 up-regulation and EP4 down-regulation could promote ATP-dependent pathway inhibition, determining ROS production and the reduction of scavenger enzymes; this, in turn, could induce chemokines overexpression and activation. In essential hypertension, increased systemic biosynthesis of TxA2 is associated with oxidative stress, increased blood pressure, and cardiac fibrosis development. A selective reduction in TXA2 synthesis, achieved by administering low-dose aspirin, can limit the…

Figure 3. Natural derivatives with cardioprotective potential in cardiomyopathy. Polyphenols, flavonoids, terpenoids, omega-3 fatty acids, vitamins, and alkaloids exert multiple biological effects through antioxidant, anti-inflammatory, anti-fibrotic, anti-hypertrophic, anti-thrombotic, and mitochondrial protective mechanisms. These compounds contribute to the modulation of myocardial remodelling, inflammatory signalling, cardiomyocyte survival, and cardiac function preservation. Eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA); DanQi Pill (DQP); epigallocatechin gallate (EGCG).

Figure 4. Natural compounds targeting eicosanoid-associated signalling pathways in cardiomyopathy. DanQi Pill (DQP), a formulation derived from Salvia Miltiorrhiza and Panax Notoginseng, has been reported to downregulate the expression of COX-1, COX-2, LTB4, and its receptor (LTB4R), as well as phospholipase A2 (PLA2). This modulation contributes to restoring the physiological balance between prostacyclin (PGI2) and thromboxane A2 (TXA2), reflected in the normalization of the P/T ratio. In addition, supplementation with vitamins D and E has been shown to significantly decrease myocardial levels of oxidative stress markers such as 8-iso-prostane and 8-iso-prostaglandin F2α. Furthermore, natural compounds including curcumin, oleuropein, and Boswellia-derived constituents act as dual inhibitors of both cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) in in vitro and preclinical models. The modulation of these pathways exerts beneficial effects, including anti-atherosclerotic, antioxidant, and anti-inflammatory activities, thereby promoting the preservation of myocardial function. DanQi Pill (DQP); Cyclooxygenases-1 (COX-1); Cyclooxygenases-2(COX-2); Leukotriene B4 (LTB4); Phospholipase A2…