Phospholipase iPLA2β 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 Ca^{2+} -independent phospholipase A2β (iPLA2β, 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, iPLA_{2}β 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 (fPD^{R747W}) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9^{R748W/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 Snca^{A53T} mice, with decreased iPLA2β expression and a PD-relevant phenotype. Thus, iPLA_{2}β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis

Sezgisel Yeme

Eating behavior is an action in response to physiological, psychological and social cues. The physical hunger state of the individual, the mood she is in and the social environment she lives in affect her eating attitudes and behaviors. Intuitive eating is a new understanding of nutrition as an alternative to diet programs that tell individuals what, when and how much they should eat. In this understanding of nutrition, only the body will guide the individual. The hunger and satiety signals created by the body direct it to the most appropriate food at the most appropriate time. Although diet programs that have been applied for years to lose weight show effectiveness in the short term, they have resulted in weight gain in the long term. In contrast to traditional weight loss methods, intuitive eating is thought to be a new intervention in the prevention and treatment of obesity. Intuitive eating has both physiological and psychological effects on human health. In terms of physiological health, intuitive eating has been associated with lower body mass index, blood pressure, and cholesterol levels, while insufficient studies have yet found it to be associated with higher levels of physical activity. In terms of psychological health, many eating pathology indices were found to be negatively associated with body image disorders and psychological distress, and positively with improved psychological health. There are studies that include the positive effects of intuitive eating without diet logic on health. Future studies are expected to shed light on the unexplored aspects of the effects of intuitive eating. In this review, literature information about the physiological and psychological effects of intuitive eating will be summarized. Keywords: Intiutive Eating, Physiological Health, Psychological Healt

Attitudes of Doctors Working in Abant Izzet Baysal University Health Research and Application Center on Cardiopulmonary Resuscitation.

OBJECTIVE: We aimed to evaluate the attitudes of doctors about cardiopulmonary resuscitation (CPR) in this research. METHODS: Overall, 234 doctors who were working in Abant İzzet Baysal University Health Research and Application Center and who accepted to participate in this research were included. Research data were obtained by a questionnaire containing questions about demographic characteristics of doctors and their knowledge about CPR. Questionnaires were applied between 27.02.2012 and 04.06.2012. The chi-square test was used for categorical variables. A value of p<0.05 was considered statistically significant. RESULTS: It was determined that 90% of the participants included in the study applied and/or observed CPR, and 62% of participants did not attend any CPR course. In addition, 64.1% of the doctors were found to be aware of guidelines prepared every 5 years. Although 65.2% of the doctors who attended a course previously gave a correct answer for the question about the number of cardiac compressions during adult CPR, 47.6% of the doctors who did not attend a course gave the correct answer (p=0.014). Additionally, 71.9% of participants who attended a course previously and 51.7% of participants who did not replied correctly to the question 'What should be done immediately after defibrillation during CPR?' And also the results for the question about how many joules is necessary to begin defibrillation with a monophasic defibrillator were statistically significant according to the attendance for a CPR course (p<0.005). CONCLUSION: In this study, we have identified the lack of knowledge of the doctors about resuscitation

The effect of phthalocyanine's periphery on the biological activities of carbazole-containing metal phthalocyanines

This study reports the synthesis and characterization of two new mono- and di-substituted phthalonitriles namely 4-((9H-carbazol-3-yl)oxy)-5-chlorophthalonitrile and 4,5-bis((9H-carbazol-3-yl)oxy)phthalonitrile, respectively. Cyclotetramerization of the new phthalonitriles in the presence of zinc(ii) acetate resulted in related zinc(ii) phthalocyanines. To study the effect of the position and number of substituents on the biological properties of the phthalocyanines, peripherally or non-peripherally tetra-substituted zinc(ii) phthalocyanines bearing (9H-carbazol-3-yl)oxy groups, as well as axially di-substituted silicon phthalocyanines containing the same groups, were prepared. Since gold nanoparticles are well-known as efficient drug delivery agents, the surface of these metal nanoparticles was functionalized with all the compounds. This modification also improved the solubility of the phthalocyanines in aqueous media. In this study, the antioxidant, DNA cleavage, and toxic/phototoxic activities of the resultant nanoconjugates were examined. With a combination of metal ion and substituent (nature, number, and position) effects, the silicon(iv) phthalocyanine exhibited the highest biological properties

Normoxic versus Hyperoxic Resuscitation in Pediatric Asphyxia Cardiac Arrest: Effects on Oxidative Stress

Objective: To determine the effects of normoxic vs. hyperoxic resuscitation on oxidative stress in a model of pediatric asphyxial cardiac arrest.Design: Prospective, interventional study.Setting: University research laboratory.Subjects: Postnatal day 16-18 rats (n = 5 per group).Interventions: Rats underwent asphyxial cardiac arrest for 9 min. Rats were randomized to receive 100% oxygen, room air, or 100% oxygen with polynitroxyl albumin (10 mL[middle dot]kg-1 intravenously, 0 and 30 min after resuscitation) for 1 hr from the start of cardiopulmonary resuscitation. Shams recovered in 100% oxygen or room air after surgery.Measurements and Main Results: Physiological variables were recorded at baseline to 1 hr after resuscitation. At 6 hrs after asphyxial cardiac arrest, levels of reduced glutathione and protein-thiols (fluorescent assay), activities of total superoxide dismutase and mitochondrial manganese superoxide dismutase (cytochrome c reduction method), manganese superoxide dismutase expression (Western blot), and lipid peroxidation (4-hydroxynonenal Michael adducts) were evaluated in brain tissue homogenates. Hippocampal 3-nitrotyrosine levels were determined by immunohistochemistry 72 hrs after asphyxial cardiac arrest. Survival did not differ among groups. At 1 hr after resuscitation, Pao2, pH, and mean arterial pressure were decreased in room air vs. 100% oxygen rats (59 +/- 3 vs. 465 +/- 46 mm Hg, 7.36 +/- 0.05 vs. 7.42 +/- 0.03, 35 +/- 4 vs. 45 +/- 5 mm Hg; p \u3c .05). Rats resuscitated with 100% oxygen had decreased hippocampal reduced glutathione levels vs. sham (15.3 +/- 0.4 vs. 20.9 +/- 4.1 nmol[middle dot]mg protein-1; p \u3c .01). Hippocampal manganese superoxide dismutase activity was significantly increased in 100% oxygen rats vs. sham (14 +/- 2.4 vs. 9.5 +/- 1.6 units[middle dot]mg protein-1, p \u3c .01), with no difference in protein expression of manganese superoxide dismutase. Room air and 100% oxygen plus polynitroxyl albumin groups had hippocampal reduced glutathione and manganese superoxide dismutase activity levels comparable with sham. Protein thiol levels were unchanged across groups. Compared with all other groups, rats receiving 100% oxygen had increased immunopositivity for 3-nitrotyrosine in the hippocampus and increased lipid peroxidation in the cortex.Conclusions: Resuscitation with 100% oxygen leads to increased oxidative stress in a model that mimics pediatric cardiac arrest. This may be prevented by using room air or giving an antioxidant with 100% oxygen resuscitation

Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1.

Ferroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. Here, we identify conjugated linoleates including α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, to mice limits tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a potential approach to ferroptosis, complementary to GPX4 inhibition

Resolving the paradox of ferroptotic cell death: Ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis

Hydroperoxy-eicosatetraenoyl-phosphatidylethanolamine (HpETE-PE) is a ferroptotic cell death signal. HpETE-PE is produced by the 15-Lipoxygenase (15LOX)/Phosphatidylethanolamine Binding Protein-1 (PEBP1) complex or via an Fe-catalyzed non-enzymatic radical reaction. Ferrostatin-1 (Fer-1), a common ferroptosis inhibitor, is a lipophilic radical scavenger but a poor 15LOX inhibitor arguing against 15LOX having a role in ferroptosis. In the current work, we demonstrate that Fer-1 does not affect 15LOX alone, however, it effectively inhibits HpETE-PE production by the 15LOX/PEBP1 complex. Computational molecular modeling shows that Fer-1 binds to the 15LOX/PEBP1 complex at three sites and could disrupt the catalytically required allosteric motions of the 15LOX/PEBP1 complex. Using nine ferroptosis cell/tissue models, we show that HpETE-PE is produced by the 15LOX/PEBP1 complex and resolve the long-existing Fer-1 anti-ferroptotic paradox