Phospholipase iPLA2ß averts ferroptosis by eliminating a redox lipid death signal.

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2ß (iPLA2ß, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2ß averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2ß expression and a PD-relevant phenotype. Thus, iPLA2ß is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

Naoxintong Capsule Activates the Nrf2/HO-1 Signaling Pathway and Suppresses the p38α Signaling Pathway Via Estrogen Receptors to Ameliorate Heart Remodeling in Female Mice With Postmenopausal Hypertension.

ABSTRACT: Limited treatments are available for alleviating heart remodeling in postmenopausal hypertension. The cardioprotective effect of naoxintong (NXT) has been widely accepted. This study aimed to explore the effects of NXT on pathological heart remodeling in a postmenopausal hypertension mouse model in vivo and H9c2 cardiomyocytes in vitro. In vivo, ovariectomy combined with chronic angiotensin II infusion was used to establish the postmenopausal hypertension animal model. NXT significantly ameliorated cardiac remodeling as indicated by a reduced ratio of heart weight/body weight and left ventricle weight/body weight, left ventricular wall thickness, diameter of cardiomyocytes, and collagen deposition in the heart. NXT also significantly increased the expression of estrogen receptors (ERs) and downregulated the expression of nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2). In vitro, NXT treatment greatly suppressed angiotensin II-induced cardiac hypertrophy, cardiac fibrosis, and excessive oxidative stress as proven by reducing the diameter of H9c2 cardiomyocytes, expression of hypertrophy and fibrosis markers, intracellular reactive oxygen species, and oxidative enzymes. Mechanistically, NXT significantly upregulated the expression of ERs, which activated the Nrf2/HO-1 signaling pathway and inhibited the phosphorylation of the p38α pathway. Collectively, the results indicated that NXT administration might attenuate cardiac remodeling through upregulating the expression of ERs, which activated the Nrf2/HO-1 signaling pathway, inhibited the phosphorylation of the p38α signaling pathway, and reduced oxidative stress.

Caffeine ameliorates high energy diet-induced hepatic steatosis: sirtuin 3 acts as a bridge in the lipid metabolism pathway.

The beneficial effect of caffeine-containing food on non-alcoholic fatty liver disease (NAFLD) has been widely reported. The aim of this study was to explore the effect of caffeine on hepatic steatosis. C57BL/6 mice were randomly assigned to a normal diet or a high energy diet (HED). Caffeine was given to HED mice by oral gavage. Body weights, lipids in the liver and liver damage were measured. Meanwhile, cAMP, SIRT3 or AMPK inhibitors were treated respectively before incubation with caffeine in oleate-treated HepG2 cells. SIRT3 was further silenced by siRNA to confirm the results. Caffeine significantly decreased the mass of fat tissues, lipids, ALT and AST levels in the liver of HED-treated mice. Caffeine increased the transformation of ADP to ATP and activated the cAMP/CREB/SIRT3/AMPK/ACC pathway in the liver. Nile red staining demonstrated that suppression of cAMP, SIRT3 or AMPK in oleate-treated HepG2 cells counteracted the effect of caffeine. Moreover, knocking down SIRT3 could down-regulate AMPK and ACC phosphorylation by caffeine. These results demonstrate that caffeine could improve HED-induced hepatic steatosis by promoting lipid metabolism via the cAMP/CREB/SIRT3/AMPK/ACC pathway. SIRT3 functioned as a molecular bridge connecting caffeine and lipid metabolism.