Cardiac Lipid Peroxidation Research Articles

Puerarin reduces susceptibility to ventricular arrhythmias and inhibits ferroptosis via Sirt1/Nrf2 signaling in high-fat-diet rats.

Obesity is a significant risk factor for cardiac arrhythmias, and the ferroptosis is closely related to cardiac arrhythmias. This study aimed to investigate whether puerarin (Pue), a natural isoflavone, could reduce the susceptibility to ventricular arrhythmias (VAs) associated with obesity and inhibit ferroptosis, with a particular focus on the Sirt1/Nrf2 signaling pathway. Male rats were randomly divided into three groups: normal chow diet (NC), high-fat diet (HFD), and HFD with Pue treatment (100 mg/kg, HFD+Pue). After 16 weeks, electrophysiological, structural, and molecular analysis were performed. Compared to the NC group, HFD rats exhibited prolonged QT interval and Tpeak-Tend interval, amplified transmural dispersion of ventricular repolarization, and increased susceptibility to VAs. Pue treatment significantly ameliorated these electrophysiological abnormalities and reduced VAs susceptibility. HFD rats showed cardiac hypertrophy, fibrosis, and inflammation, which were alleviated by Pue application. Cardiac lipid peroxidation, iron deposition, mitochondrial abnormality, and ferroptosis marker induction were observed in HFD rats. Further, treatment with Pue improved these alterations. Additionally, molecular docking analysis confirmed the interaction of Pue with Sirt1 and Nrf2. Furthermore, Pue treatment upregulated Sirt1 and Nrf2 expression in HFD rats, thereby reducing reactive oxygen species (ROS) generation and ferroptosis. Moreover, Pue protected cardiomyocytes against palmitic acid (PA)-induced injury by inhibiting ferroptosis via the Sirt1/Nrf2 pathway in H9c2 cells. Overall, our study shows for the first time that Pue reduces susceptibility to VAs and inhibits ferroptosis in HFD rats by modulating the Sirt1/Nrf2 signaling pathway, offering a potential therapeutic strategy for obesity-related cardiac arrhythmias.

Identification of STAT3 and MYC as critical ferroptosis-related biomarkers in septic cardiomyopathy: a bioinformatics and experimental study.

Ferroptosis is the well-known mechanism of septic cardiomyopathy (SCM). Bioinformatics analysis was employed to identify ferroptosis-related SCM differentially expressed genes (DEG). DEGs' functional enrichment was explored. Weighted gene co-expression network analysis (WGCNA) was employed to form gene clusters. The identified hub genes, signal transducer and activator of transcription 3 (STAT3) and myelocytomatosis (MYC) were further evaluated by generating receiver operator characteristic (ROC) curves and a nomogram prediction model. Additionally, survival rate, cardiac damage markers, and cardiac function and ferroptosis markers were evaluated in septic mouse model. STAT3 and MYC levels were measured in SCM heart tissue via immunohistochemical (IHC) staining, real-time polymerase chain reaction (qPCR) and western blot analysis. Analysis identified 225 DEGs and revealed 22 intersected genes. Of the 7 hub genes, STAT3 and MYC showed enrichment in septic heart tissue and a strong predicative ability based on AUC values. Cardiac damage, iron metabolism, and lipid peroxidation occurred in the SCM model. By experiments, STAT3 and MYC expression was increased in the SCM model. Impairment was reversed with a ferroptosis inhibitor, Fer-1. As conclusion, STAT3 and MYC are related with ferroptosis and may serve as potential SCM predictor indicators. KEY MESSAGES: Septic cardiomyopathy (SCM) often leads to high mortality in septic patients, and the diagnostic criteria still remains unclear. Ferroptosis as the pathogenic mechanism of SCM could help predict its progression and clinical outcomes. STAT3 and MYC are related with ferroptosis and may serve as potential SCM predictor biomarkers.

Can Alpha-Pinene Prevent Methotrexate-Induced Cardiac and Hepatic Damage?

The effects of alpha-pinene (AP), a monoterpenoid, known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, on methotrexate (MTX)-induced cardiac and hepatic damage were investigated in this study. Male Sprague-Dawley rats were divided into Control, Vehicle, AP, MTX, and AP+MTX groups (n=7). AP (50 mg/kg/day, 14 days) was applied subcutaneously in the AP and AP+MTX groups. MTX (20 mg/kg) was injected three days before sacrification. Serum CK-MB, troponin T, ALT, and AST levels, as well as cardiac and hepatic MDA, GSH, caspase-3, and p53 levels, were measured by ELISA. Histological changes in tissues were evaluated by scoring in terms of tissue damage and cellular degeneration parameters after hematoxylin-eosin staining. MTX caused significant increase in serum CK-MB, troponin T, ALT, and AST levels, hepatic and cardiac lipid peroxidation, GSH depletion, and caspase-3 level. However, tissue levels of p53 did not change significantly. MTX-induced histological deterioration was observed in both tissues. These MTX-induced changes were significantly reduced in the AP+MTX group. Present results show that MTX-induced cardiac and hepatic damage is prevented by AP pretreatment. This protection can be attributed to the antioxidant and anti-apoptotic properties of AP. Considering the importance of MTX in cancer treatment, AP appears to have highly promising potential as a cardioprotective and hepatoprotective agent in anti-tumoral therapy.

Pseudocannabinoid H4CBD Reduces Cardiac Damage Indicator 4HNE in OLETF (Otsuka Long Evans Tokushima Fatty) Rats

Cardiovascular disease (CVD) is a leading cause of death globally and MetS is an associated precursor of CVD. Of the 6 known cluster factor conditions of MetS, obesity, and poor glucose tolerance are known to contribute to high lipid peroxidation, which can contribute to the generation of damaging free radical species and a pro-oxidant system. Cannabidiol (CBD) is a known antioxidant and a growing understanding of CBD analogs and pseudocannabinoids, like H4CBD, implicate similar antioxidant effects. However, little is known about the effects of CBD analogs on MetS-associated cardiac tissue damage. To better understand these effects during extreme metabolic dysfunction, 41-weeks-old animals were assigned into three groups, (n=8/group): (1) one-lean-strain control, Long Evans Tokushima Otsuka (LETO), (2) untreated OLETF, and (3) OLETF + H4CBD (200 mg/kg/day x 4 weeks). Our hypothesis focuses on the prospect that ongoing treatment with H4CBD in a MetS model using Otsuka Long-Evans Tokushima Fatty (OLETF) rats will reduce indicators of lipid peroxidation including 4-hydroxynonenal (4HNE), a toxic end product of lipid peroxidation. After the 4-week treatment, cardiac tissue was analyzed for 4-hydroxynonenal (4HNE) protein expression. We found that H4CBD decreased cardiac 4HNE protein expression in treated OLETF rats by 68% (p<0.05) compared to OLETF control, which indicates H4CBD attenuated cardiac lipid peroxidation overall. Although the 4-week treatment of H4CBD was not suffcient to ameliorate MetS-associated hypertension, the reduction of 4HNE suggests that the attenuation of cardiac damage is independent of arterial pressure. These data indicate that H4CBD and its derivatives hold promise for therapeutic use in managing CVD and related metabolic syndrome-associated pathologies. Undergraduate Research Training Initiative for Student Enhancement (U-RISE), Center for Medical Cannabis Research. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cirbp suppression compromises DHODH-mediated ferroptosis defense and attenuates hypothermic cardioprotection in an aged donor transplantation model.

Hypothermia is commonly used to protect donor hearts during transplantation. However, patients transplanted with aged donor hearts still have severe myocardial injury and decreased survival rates, but the underlying mechanism remains unknown. Because aged hearts are not considered suitable for donation, the number of patients awaiting heart transplants is increasing. In this study, we examined whether hypothermic cardioprotection was attenuated in aged donor hearts during transplantation and evaluated potential therapeutic targets. Using a rat heart transplantation model, we found that hypothermic cardioprotection was impaired in aged donor hearts but preserved in young donor hearts. RNA-Seq showed that cold-inducible RNA-binding protein (Cirbp) expression was decreased in aged donor hearts, and these hearts showed severe ferroptosis after transplantation. The young donor hearts from Cirbp-KO rats exhibited attenuated hypothermic cardioprotection, but Cirbp overexpression in aged donor hearts ameliorated hypothermic cardioprotection. Cardiac proteomes revealed that dihydroorotate dehydrogenase (DHODH) expression was significantly decreased in Cirbp-KO donor hearts during transplantation. Consequently, DHODH-mediated ubiquinone reduction was compromised, thereby exacerbating cardiac lipid peroxidation and triggering ferroptosis after transplantation. A cardioplegic solution supplemented with CIRBP agonists improved hypothermic cardioprotection in aged donor hearts, indicating that this method has the potential to broaden the indications for using aged donor hearts in transplantation.

In-silico and in-vivo comparative evaluation of the cardioprotective potential of Yellow turmeric and White turmeric in Mn-induced cardiac oxidative stress

IntroductionThe effect of the ethanol extracts of Curcuma longa Linn (yellow turmeric) and Curcuma zedoaria Rosc (white turmeric) on cardiac oxidative stress in rats exposed to manganese was evaluated in this study. MethodsWe divided 60 Wistar rats into 12 groups (n = 5) with some administered different concentrations of yellow or white turmeric extract. The animals except the control groups were exposed to manganese on days 1,3, and 7. All the animals were sacrificed on the 8th day and the hearts were harvested for biochemical assays. Ferric-reducing antioxidant power (FRAP) and the levels of cardiac superoxide dismutase, reduced glutathione, nitric oxide, and lipid peroxidation in rats were determined. Additionally, in silico studies were performed to further compare the cardioprotective potential of the two species of turmeric. ResultsThe results showed that rats treated with manganese alone had decreased levels of FRAP, superoxide dismutase, and glutathione but increased levels of nitric oxide and lipid peroxidation were observed. The Mn-induced oxidative stress was ameliorated in animals co-treated with yellow or white turmeric. The yellow turmeric showed better activity than white turmeric. In the in-silico evaluation, phytocompounds from yellow turmeric had higher binding energy against Nuclear factor erythroid 2-related factor 2 (NRF2) protein than the ones from white turmeric. Bioactive compounds from white turmeric did not violate any of Lipinski's rules of five or three, despite having lower binding energy. ConclusionThese findings suggest that ethanol extract of yellow and white turmeric may have the potential to ameliorate manganese-induced cardiac oxidative stress.

Elevated levels of alcohol dehydrogenase aggravate ethanol-evoked cardiac remodeling and contractile anomalies through FKBP5-yap-mediated regulation of ferroptosis and ER stress

Alcohol intake provokes severe organ injuries including alcoholic cardiomyopathy with hallmarks of cardiac remodeling and contractile defects. This study examined the toxicity of facilitated ethanol metabolism in alcoholism-evoked changes in myocardial morphology and contractile function, insulin signaling and various cell death domains using cardiac-selective overexpression of alcohol dehydrogenase (ADH). WT and ADH mice were offered an alcohol liquid diet for 12 weeks prior to assessment of cardiac geometry, function, ER stress, apoptosis and ferroptosis. Alcohol intake provoked pronounced glucose intolerance, cardiac remodeling and contractile anomalies with apoptosis, ER stress, and ferroptosis, the effects were accentuated by ADH with the exception of global glucose intolerance. Hearts from alcohol ingesting mice displayed dampened insulin-stimulated phosphorylation of insulin receptor (tyr1146) and IRS-1 (tyrosine) along with elevated IRS-1 serine phosphorylation, the effect was augmented by ADH. Alcohol challenge dampened phosphorylation of Akt and GSK-3β, and increased phosphorylation of c-Jun and JNK, the effects were accentuated by ADH. Alcohol challenge promoted ER stress, FK506 binding protein 5 (FKBP5), YAP, apoptosis and ferroptosis, the effects were exaggerated by ADH. Using a short-term ethanol challenge model (3 g/kg, i.p., twice in three days), we found that inhibition of FKBP5-YAP signaling or facilitated ethanol detoxification by Alda-1 alleviated ethanol cardiotoxicity. In vitro study revealed that the ethanol metabolite acetaldehyde evoked cardiac contractile anomalies, lipid peroxidation, and apoptosis, the effects of which were mitigated by Alda-1, inhibition of ER stress, FKBP5 and YAP. These data suggest that facilitated ethanol metabolism via ADH exacerbates alcohol-evoked myocardial remodeling, functional defects, and insulin insensitivity possibly through a FKBP5-YAP-associated regulation of ER stress and ferroptosis.

The New Nano-Resuscitation Solution (TPP-MR) Attenuated Myocardial Injury in Hemorrhagic Shock Rats by Inhibiting Ferroptosis.

Hemorrhagic shock was a leading cause of death worldwide, with myocardial injury being a primary affected organ. As commonly used solutions in fluid resuscitation, acetated Ringer's (AR) and Lactate Ringer's solution (LR) were far from perfect for their adverse reactions such as lactic acidosis and electrolyte imbalances. In previous studies, TPP@PAMAM-MR (TPP-MR), a novel nanocrystal resuscitation fluid has been found to protect against myocardial injury in septic rats. However, its role in myocardial injury in rats with hemorrhagic shock and underlying mechanism is unclear. The hemorrhagic shock rats and hypoxia-treated cardiomyocytes (H9C2) were utilized to investigate the impact of TPP-MR on cardiac function, mitochondrial function, and lipid peroxidation. The expressions of ferritin-related proteins glutathione peroxidase 4 (GPX4), Acyl CoA Synthase Long Chain Family Member 4 (ACSL4), and Cyclooxygenase-2(COX2) were analyzed through Western blotting to explore the mechanism of TPP-MR on hemorrhagic myocardial injury. TPP-MR, a novel nanocrystalline resuscitation fluid, was synthesized using TPP@PAMAM@MA as a substitute for L-malic acid. We found that TPP-MR resuscitation significantly reduced myocardial injury reflected by enhancing cardiac output, elevating mean arterial pressure (MAP), and improving perfusion. Moreover, TPP-MR substantially prolonged hemorrhagic shock rats' survival time and survival rate. Further investigations indicated that TPP-MR improved the mitochondrial function of myocardial cells, mitigated the production of oxidative stress agents (ROS) and increased the glutathione (GSH) content. Additionally, TPP-MR inhibited the expression of the ferroptosis-associated GPX4 protein, ACSL4 and COX2, thereby enhancing the antioxidant capacity. The results showed that TPP-MR had a protective effect on myocardial injury in rats with hemorrhagic shock, and its mechanism might be related to improving the mitochondrial function of myocardial cells and inhibiting the process of ferroptosis.

Psidium guajava L.: Chemical composition and protective effects of a leaf extract against ethanol-induced cardiotoxicity

It has been previously reported that a leaf extract of Psidium guajava L. (GV.E) can impart numerous health benefits that were attributed to its antioxidant and anti-inflammatory effects. Ethanol (EtOH, alcohol) misuse is a global health burden, with profound effects on the younger population. The toxic effects of EtOH, that are largely attributed to oxidative stress, target a variety of organs including the heart. The current study tested the protective effects of two different doses of GV.E (1 and 2 g/kg/d) on EtOH-induced cardiac injury in 8-10 (post-pubertal) weeks-old male rats. The plant metabolites of the extract were profiled using HPLC-PDA-ESI-MS, and fifty-one metabolites, mostly polyphenols, were tentatively identified. Importantly, the EtOH-induced increase in heart weight and heart coefficient (heart/body weight ratio) were mitigated by the GV.E at both tested doses. Additionally, the EtOH-induced increase in the selective heart injury marker; creatine kinase-m b, and the non-selective tissue injury marker, lactate dehydrogenase, were attenuated by the GV.E (1 g/kg/d). The EtOH-induced increase in serum aspartate aminotransferase and c-reactive protein were normalized by GV.E (2 g/kg/d). Cardiac lipid peroxidation, nitrates, and nitrites (markers of oxidative stress) were reduced by GV.E. However, cardiac reduced glutathione was not affected by EtOH, which could be due to upregulation of the body's defense mechanisms. GV.E also caused a suppression of the cardiac mRNA expression of two inflammatory cytokines; interleukin-6 and tumor necrosis factor (TNF)-α, which were upregulated by EtOH, with a normalization of TNF-α by GV.E (1 g/kg/d). Taken together, these results indicate that GV.E exerts cardio-protective effects against EtOH-induced cardiac damage in male rats.

Yttrium chloride induces ferroptosis in cardiomyocytes via iron accumulation and triggers cardiac lipid peroxidation and inflammation that cause heart adverse events in mice

The growing presence of yttrium (Y) in the environment raises concern regarding its safety and toxicity. However, limited toxicological data are available to determine cardiotoxicity of Y and its underlying mechanisms. In the present study, yttrium chloride (YCl3) intervention with different doses was performed in male Kunming mice for the toxicological evaluation of Y in the heart. After 28 days of intragastric administration, 500 mg/kg·bw YCl3 induces iron accumulation in cardiomyocytes, and triggers ferroptosis through the glutathione peroxidase 4 (GPX4)/glutathione (GSH)/system Xc− axis via the inhibition of Nrf2 signaling pathway. This process led to cardiac lipid peroxidation and inflammatory response. Further RNA sequencing transcriptome analysis found that many genes involved in ferroptosis and lipid metabolism-related pathways were enriched. The ferroptosis induced by YCl3 in cardiomyocytes ultimately caused cardiac injury and dysfunction in mice. Our findings assist in the elucidation of the potential subacute cardiotoxicity of Y3+ and its underlying mechanisms.

Protective effects of β-caryophyllene on mitochondrial damage and cardiac hypertrophy pathways in isoproterenol-induced myocardial infarcted rats

The cardiac mitochondrial damage and cardiac hypertrophy pathways are intimately associated with the pathology of myocardial infarction (MI). The protective effects of β-caryophyllene on mitochondrial damage and cardiac hypertrophy pathways in isoproterenol-induced myocardial infarcted rats were investigated. Isoproterenol (100 mg/kg body weight) was administered to induce MI. The ST-segment, QT interval, and T wave were widened, and the QRS complex and P wave were shortened in the electrocardiogram (ECG) and the serum cardiac diagnostic markers and heart mitochondrial lipid peroxidation products, calcium ions, and reactive oxygen species (ROS) were elevated and the heart mitochondrial antioxidants, tricarboxylic acid cycle, and respiratory chain enzymes were lessened in isoproterenol-induced myocardial infarcted rats. The heart mitochondrial damage was noted in the transmission electron microscopic study. The whole heart weight was increased and the subunits of nicotinamide adenine dinucleotide phosphate – oxidase 2 (Nox 2) genes such as cybb and p22-phox and cardiac hypertrophy genes such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β -myosin heavy chain (β-MHC), and actin alpha skeletal muscle-1(ACTA-1) were highly expressed in the rat's heart by reverse transcription-polymerase chain reaction study. The β-caryophyllene (20 mg/kg body weight) pre- and co-treatment orally, daily for 21 days reversed changes in ECG and lessened cardiac diagnostic markers, ROS, and whole heart weight and ameliorated mitochondrial damage and Nox/ANP/BNP/β-MHC/ACTA-1cardiac hypertrophy pathways in isoproterenol-induced myocardial infarcted rats. The observed effects might be due to the antioxidant, anti-mitochondrial damaging, and anti-cardiac hypertrophic mechanisms of β-caryophyllene.

Pomegranate peel extract protects against the development of diabetic cardiomyopathy in rats by inhibiting pyroptosis and downregulating LncRNA-MALAT1.

Background: Pyroptosis is an inflammatory programmed cell death accompanied by activation of inflammasomes and maturation of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Pyroptosis is closely linked to the development of diabetic cardiomyopathy (DC). Pomegranate peel extract (PPE) exhibits a cardioprotective effect due to its antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanisms of the protective effect of PPE on the myocardium in a rat model of DC and determine the underlying molecular mechanism. Methods: Type 1 diabetes (T1DM) was induced in rats by intraperitoneal injection of streptozotocin. The rats in the treated groups received (150mg/kg) PPE orally and daily for 8weeks. The effects on the survival rate, lipid profile, serum cardiac troponin-1, lipid peroxidation, and tissue fibrosis were assessed. Additionally, the expression of pyroptosis-related genes (NLRP3 and caspase-1) and lncRNA-MALAT1 in the heart tissue was determined. The PPE was analyzed using UPLC-MS/MS and NMR for characterizing the phytochemical content. Results: Prophylactic treatment with PPE significantly ameliorated cardiac hypertrophy in the diabetic rats and increased the survival rate. Moreover, prophylactic treatment with PPE in the diabetic rats significantly improved the lipid profile, decreased serum cardiac troponin-1, and decreased lipid peroxidation in the myocardial tissue. Histopathological examination of the cardiac tissues showed a marked reduction in fibrosis (decrease in collagen volume and number of TGF-β-positive cells) and preservation of normal myocardial structures in the diabetic rats treated with PPE. There was a significant decrease in the expression of pyroptosis-related genes (NLRP3 and caspase-1) and lncRNA-MALAT1 in the heart tissue of the diabetic rats treated with PPE. In addition, the concentration of IL-1β and caspase-1 significantly decreased in the heart tissue of the same group. The protective effect of PPE on diabetic cardiomyopathy could be due to the inhibition of pyroptosis and downregulation of lncRNA-MALAT1. The phytochemical analysis of the PPE indicated that the major compounds were hexahydroxydiphenic acid glucoside, caffeoylquinic acid, gluconic acid, citric acid, gallic acid, and punicalagin. Conclusion: PPE exhibited a cardioprotective potential in diabetic rats due to its unique antioxidant, anti-inflammatory, and antifibrotic properties and its ability to improve the lipid profile. The protective effect of PPE on DC could be due to the inhibition of the NLRP3/caspase-1/IL-1β signaling pathway and downregulation of lncRNA-MALAT1. PPE could be a promising therapy to protect against the development of DC, but further clinical studies are recommended.

The effect of dapagliflozin on myocardial ischemia–reperfusion injury in diabetic rats

The incidence of ischemic heart disease is 2-3 times higher in diabetic patients. However, the effect of dapagliflozin on ischemia-reperfusion myocardial injury in diabetic rats has not been studied. We examined the effects of dapagliflozin on myocardial IR injury in streptozotocin-nicotinamide-induced diabetic rats. Rats were divided into four groups (n = 7 in each group): control, control-dapagliflozin, diabetes, and diabetes-dapagliflozin. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water for 2 months. The hearts were perfused in a Langendorff's apparatus at 2 months and assessed before (baseline) and after myocardial IR for the following parameters: left ventricular developed pressure (LVDP), minimum and maximum rates of pressure change in the left ventricle (±dP/dt), endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) mRNA expressions, creatine kinase MB (CK-MB) and troponin imyocardial enzyme extravasation, and lactate dehydrogenase. The recovery of LVDP and±dP/dt in diabetic rats was lower than that in controls but near normal after dapagliflozin treatment. Diabetic rats had decreased eNOS expression and increased iNOS expression at baseline and after IR, whereas dapagliflozin normalized these parameters after IR. Compared with controls, cardiac NOx levels were initially lower in diabetic patients but higher after IR. Baseline MDA levels were higher in diabetic rats after IR, whereas cardiac NOx levels decreased after treatment with dapagliflozin. Dapagliflozin protects the diabetic rat heart from ischemia-reperfusion myocardial injury by regulating the expression of eNOS and iNOS and inhibiting cardiac lipid peroxidation.

Rutin and Hesperidin Alleviate Paclitaxel-Induced Nephrocardiotoxicity in Wistar Rats via Suppressing the Oxidative Stress and Enhancing the Antioxidant Defense Mechanisms.

Paclitaxel is a primary chemotherapy agent that displays antitumor activity against a variety of solid tumors. However, the clinical effectiveness of the drug is hampered by its nephrotoxic and cardiotoxic side effects. Thus, this investigation aimed at assessing the protective effects of rutin, hesperidin, and their combination to alleviate nephrotoxicity caused by paclitaxel (Taxol), cardiotoxicity in male Wistar rats, as well as oxidative stress. Rutin (10 mg/kg body weight), hesperidin (10 mg/kg body weight), and their mixture were given orally every other day for six weeks. Rats received intraperitoneal injections of paclitaxel twice weekly, on the second and fifth days of the week, at a dose of 2 mg/kg body weight. In paclitaxel-treated rats, the treatment of rutin and hesperidin decreased the elevated serum levels of creatinine, urea, and uric acid, indicating a recovery of kidney functions. The cardiac dysfunction in paclitaxel-treated rats that got rutin and hesperidin treatment also diminished, as shown by a substantial reduction in elevated CK-MB and LDH activity. Following paclitaxel administration, the severity of the kidney and the heart's histopathological findings and lesion scores were markedly decreased by rutin and hesperidin administration. Moreover, these treatments significantly reduced renal and cardiac lipid peroxidation while markedly increased GSH content and SOD and GPx activities. Thus, paclitaxel likely induces toxicity in the kidney and the heart by producing oxidative stress. The treatments likely countered renal and cardiac dysfunction and histopathological changes by suppressing oxidative stress and augmenting the antioxidant defenses. Rutin and hesperidin combination was most efficacious in rescuing renal and cardiac function as well as histological integrity in paclitaxel-administered rats.

PS-B11-1: ACETATE RESTORES CARDIAC METABOLIC FLEXIBILITY IN HIGH FAT DIET-INDUCED OBESITY THROUGH HDAC MODULATION

Objectives: Obesity remains a global epidemic and an independent risk factor for cardiovascular disease. Histone deacetylase (HDAC) activity has been implicated to increase adipogenic differentiation and consequent increase in adiposity, which are crucial features of obesity. Short chain fatty acids (SCFAs), which are potential HDAC inhibitors have been shown to be effective for glycemic/immune modulation. However, the involvement of HDAC or ANP/BNP in obesity-associated cardiac metabolic events is inconclusive. The present study hypothesized that cardiac metabolic inflexibility is dependent on cardiac ANP/BNP alteration and HDAC activity. We further sought to investigate the therapeutic potential of SCFA, acetate in high fat diet (HFD)-induced obese rat model. Methods: Adult male Wistar rats were assigned into groups (n = 6/group): Control, Obese, Sodium acetate (NaAc)-treated and Obese+ NaAc-treated groups received distilled water once daily (oral gavage), 40% HFD ad libitum, 200 mg/kg NaAc once daily (oral gavage) and 40% HFD+NaAc respectively. Results: The treatments lasted for 12 weeks. HFD resulted in increased food intake, body weight and cardiac mass. It also caused insulin resistance and enhanced Beta-cell function, increased fasting insulin, lactate, plasma and cardiac triglyceride, total cholesterol, glycogen content, lipid peroxidation, TNF-alpha, IL-6, HDAC and cardiac troponin T and gamma-glutamyl transferase and decreased plasma and cardiac GSH with unaltered cardiac ANP and BNP. However, these alterations were averted when treated with acetate. Conclusions: Taken together, these results indicate that obesity induces defective cardiac metabolic flexibility, which is accompanied by elevated level of HDAC and not ANP/BNP alteration. The results also suggest that acetate ameliorates obesity-induced cardiac metabolic inflexibility by suppression of HDAC and independent of ANP/BNP modulation.

The Preventive Effects of Naringin and Naringenin against Paclitaxel-Induced Nephrotoxicity and Cardiotoxicity in Male Wistar Rats.

This study assessed the preventive properties of naringin and naringenin on paclitaxel-induced nephrotoxicity and cardiotoxicity in adult male Wistar rats. Intraperitoneal injection of paclitaxel 2 mg/kg body weight, two days/week on the 2nd and 5th days of each week, with or without oral administration of naringin and/or naringenin 10 mg/kg body weight every other day, was continued for six weeks. Treatment of rats with naringin and/or naringenin significantly reversed elevated serum creatinine, urea, and uric acid levels caused by paclitaxel, reflecting improved kidney function. Similarly, heart dysfunction induced by paclitaxel was alleviated after treatment with naringin and/or naringenin, as evidenced by significant decreases in elevated CK-MB and LDH activities. After drug administration, histopathological findings and lesion scores in the kidneys and heart were markedly decreased by naringin and/or naringenin. Moreover, the treatments reversed renal and cardiac lipid peroxidation and the negative impacts on antioxidant defenses via raising GSH, SOD, and GPx. The preventive effects of naringin and naringenin were associated with suppressing oxidative stress and reestablishing antioxidant defenses. A combination of naringin and naringenin was the most efficacious in rescuing organ function and structure.

Cardioprotective Effects and in-silico Antioxidant Mechanism of L-Ergothioneine in Experimental Type-2 Diabetic Rats.

Diabetic cardiotoxicity is commonly associated with oxidative injury, inflammation, and endothelial dysfunction. L-ergothioneine (L-egt), a diet-derived amino acid, has been reported to decrease mortality and risk of cardiovascular injury, provides cytoprotection to tissues exposed to oxidative damage, and prevents diabetes-induced perturbation. This study investigated the cardioprotective effects of L-egt on diabetes-induced cardiovascular injuries and its probable mechanism of action. Twenty-four male Sprague-Dawley rats were divided into non-diabetic (n = 6) and diabetic groups (n = 18). Six weeks after the induction of diabetes, the diabetic rats were divided into three groups (n = 6) and administered distilled water, L-egt (35mg/kg), and losartan (20mg/kg) by oral gavage for six weeks. Blood glucose and mean arterial pressure (MAP) were recorded pre-and post-treatment, while biochemical, ELISA, and RT-qPCR analyses were conducted to determine inflammatory, injury-related and antioxidant biomarkers in cardiac tissue after euthanasia. Also, an in-silico study, including docking and molecular dynamic simulations of L-egt toward the Keap1- Nrf2 protein complex, was done to provide a basis for the molecular antioxidant mechanism of Legt. Administration of L-egt to diabetic animals reduced serum triglyceride, water intake, MAP, biomarkers of cardiac injury (CK-MB, CRP), lipid peroxidation, and inflammation. Also, Legt increased body weight, antioxidant enzymes, upregulated Nrf2, HO-1, NQO1 expression, and decreased Keap1 expression. The in-silico study showed that L-egt inhibits the Keap1-Nrf2 complex by binding to the active site of Nrf2 protein, thereby preventing its degradation. L-egt protects against diabetes-induced cardiovascular injury via the upregulation of the Keap1-Nrf2 pathway and its downstream cytoprotective antioxidants.

Impaired Myocardial Mitochondrial Function in an Experimental Model of Anaphylactic Shock.

Simple SummaryAnaphylactic shock (AS) is the most severe allergic hypersensitivity reaction. In the early stage of shock, AS was associated with hemodynamic impairments: severe failure in arterial blood pressure and cardiac dysfunction. Mitochondrial disorders are associated with a high incidence of acute or chronic cardiac dysfunctions. The aim of the study was to evaluate mitochondrial involvement in cardiac dysfunction at the early stage of AS. In control (CON) and sensitized Brown Norway rats, anaphylactic shock (AS) was induced with ovalbumin iv bolus injection. Aortic abdominal blood flow (ABF), mean blood arterial pressure (MAP), and lactatemia were assessed during 15 min. The myocardial mitochondrial defect in AS was assessed by mitochondrial respiration, oxidative stress production, total superoxide dismutase activity (SODs), and oxidative damage. An ultrastructural evaluation of myocardial mitochondria was also performed using electronic microscopy. AS was associated with a rapid and dramatic decrease in MAP, ABF, and severe hyperlactatemia 15 min after AS induction. Non-phosphorylating mitochondrial respiration and OXPHOS states involving mitochondrial complex II were significantly impaired in the AS group. Oxidative stress was observed with a significant increase in SODs activity after AS induction. Moreover, in the AS group we observed an increase in oxidative damage via lipid peroxidation. No modifications of the mitochondrial ultrastructure were shown at the early stage of AS. In this experimental model, AS was associated with a rapid and significant myocardial mitochondrial dysfunction with oxidative damage that could explain cardiac anaphylaxis dysfunction.Anaphylactic shock (AS) is associated with a profound vasodilation and cardiac dysfunction. The cellular mechanisms underlying AS-related cardiac dysfunction are unknown. We hypothesized that myocardial mitochondrial dysfunction may be associated with AS cardiac dysfunction. In controls and sensitized Brown Norway rats, shock was induced by ovalbumin i.v bolus, and abdominal aortic blood flow (ABF), systemic mean arterial pressure (MAP), and lactatemia were measured for 15 min. Myocardial mitochondrial function was assessed with the evaluation of mitochondrial respiration, oxidative stress production by reactive oxygen species (ROS), reactive nitrogen species (RNS), and the measurement of superoxide dismutases (SODs) activity. Oxidative damage was assessed by lipid peroxidation. The mitochondrial ultrastructure was assessed using transmission electronic microscopy. AS was associated with a dramatic drop in ABF and MAP combined with a severe hyperlactatemia 15 min after shock induction. CI-linked substrate state (197 ± 21 vs. 144 ± 21 pmol/s/mg, p < 0.05), OXPHOS activity by complexes I and II (411 ± 47 vs. 246 ± 33 pmol/s/mg, p < 0.05), and OXPHOS activity through complex II (316 ± 40 vs. 203 ± 28 pmol/s/mg, p < 0.05) were significantly impaired. ROS and RNS production was not significantly increased, but SODs activity was significantly higher in the AS group (11.15 ± 1.02 vs. 15.50 ± 1.40 U/mL/mg protein, p = 0.02). Finally, cardiac lipid peroxidation was significantly increased in the AS group (8.50 ± 0.67 vs. 12.17 ± 1.44 µM/mg protein, p < 0.05). No obvious changes were observed in the mitochondrial ultrastructure between CON and AS groups. Our experimental model of AS results in rapid and deleterious hemodynamic effects and was associated with a myocardial mitochondrial dysfunction with oxidative damage and without mitochondrial ultrastructural injury.

β-Caryophyllene Ameliorates Cyclophosphamide Induced Cardiac Injury: The Association of TLR4/NFκB and Nrf2/HO1/NQO1 Pathways.

Background: β-caryophyllene (BCP), a natural sesquiterpene, is extensively present in the essential oils of several plants. Cyclophosphamide (CYC) is an anticancer drug. However, its clinical usage is inadequate due to its cardiotoxicity. The aim of this study was to study the effects of BCP on cardiac injury induced by CYC exposure, and to identify the underlying mechanism of action. Methods: Five groups of Wistar rats were allocated. Group I (Normal), II (BCP), and III (CYC) acted as controls. Group IV, V (CYC + BCP) received BCP in two doses (100 and 200 mg/kg, orally, respectively) for 14 days after CYC challenge. CYC groups received 200 mg/kg, i.p. of the drug once on the first day of experiments. Results: CYC group displayed numerous ECG and histological irregularities and cardiac markers elevation. CYC induced lipid peroxidation and oxidative stress intensification, as well as inflammatory and apoptotic markers escalation. Treatment with BCP resulted in modified ECG traces and histological sections. BCP mitigated cardiac markers and lipid peroxidation whereas intensified antioxidant capacity. BCP activated Nrf2, with subsequent HO1 and NQO1 amplification. BCP diminished TLR4/NFκB pathway, which consequently lessened the inflammatory and apoptosis responses. Conclusion: BCP administration was associated with activated Nrf2/HO1/NQO1 and inhibited TLR4/NFκB pathways with subsequent enhanced anti-oxidative capacity and diminished inflammatory and apoptosis responses.

D-limonene (5 (one-methyl-four-[1-methylethenyl]) cyclohexane) diminishes CCl4-induced cardiac toxicity by alleviating oxidative stress, inflammatory and cardiac markers

ABSTRACT Background: The cardiovascular crisis is advancing rapidly throughout the world. A large number of studies have shown that plant polyphenols affect major mechanisms involved in cardiovascular events through their action on the antioxidant system, signaling, and transcription pathways. D-limonene, a monocyclic monoterpene obtained from citrus fruits, is reported to possess many pharmacological activities. Methods: The experiment was designed to determine the protective effect of D-limonene against cardiac injury induced by CCl4 in Wistar rats. Rats were treated with two doses of D-limonene against cardiac injury induced by CCl4. Serum toxicity markers, cardiac toxicity biomarker enzymes, inflammatory mediators, anti-oxidant armory, lipid peroxidation, lipid profile, and histology were done. Results: CCl4 intoxication resulted in a substantial rise in FFA, TC, TG, PL, LDL, VLDL, and a reduction in HDL, restoring these changes with the administration of D-limonene at a dosage of 200 mg/kg. CCl4 administration also resulted in lipid oxidation and decreased antioxidant activity. At the same time, D-limonene at a dosage of 200 mg/kg body weight inhibited LPO and restored in vivo antioxidant components to normal. CCl 4 intoxication also resulted in a significant increase in inflammatory markers like IL-6, TNF-α, high sensitivity Corticotropin Releasing Factor (Hs-CRF), and biomarkers of cardiac toxicity like alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase MB (CKMB), and Troponin I & troponin-t activities. D-limonene reversed all these changes to normal. Histology further confirmed our obtained results. Conclusion: These findings indicate that D-limonene can ameliorate cardiac injury at a 200 mg/kg body weight dosage. Henceforth, D-Limonene intervenes in mediating CCl4 induced toxicity by various signaling pathways.