Naringenin protects cardiac hypercholesterolemia-induced oxidative stress and subsequent necroptosis in rats

Chtourou, Yassine; Slima, Ahlem Ben; Makni, Mohamed; Gdoura, Radhouane; Fetoui, Hamadi

doi:10.1016/j.pharep.2015.04.002

Cited by 82 publications

(50 citation statements)

References 54 publications

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“…Here we demonstrate that the expression of major markers of necroptosis are not modulated in the heart of cholesterol-fed rats. However, in a similar model of hypercholesterolemia, cardiac expression of RIP3 mRNA was increased [42], although no other measures of necroptosis were assessed. Nevertheless, these findings demonstrate that the effect of hypercholesterolemia on cardiac necroptosis needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia downregulates autophagy in the rat heart

et al. 2017

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BackgroundWe have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart.MethodsMale Wistar rats were fed either normal chow (NORM; n = 9) or with 2% cholesterol and 0.25% cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41% increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot.ResultsIsolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments.ConclusionsThis is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the loss of cardioprotection reported in hypercholesterolemic animals.

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Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia downregulates autophagy in the rat heart

et al. 2017

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“…This may have been responsible for the diverse effects on the longer tail length observed in HN80 when compared to HN40. Furthermore, the antioxidant‐bioflavonoid: Naringenin has been reported to neutralize oxidative stress in neurons (Al‐Rejaie et al ., ) and hepatic cells (Chtourou et al ., ). Hence, Naringenin may have protected against HAART‐induced testicular toxicity by possibly decreasing oxidative stress.…”

Section: Discussionmentioning

confidence: 97%

Naringenin attenuates highly active antiretroviral therapy‐induced spermDNAfragmentations and testicular toxicity in Sprague‐Dawley rats

et al. 2017

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SUMMARYHighly active antiretroviral therapy has evolved over the years, leading to a boost in the quality of life in people living with HIV and AIDS. However, growing evidence has shown that highly active antiretroviral therapy has deleterious effects on the testes and the overall reproductive capacity. Therefore, this study is to determine the adjuvant potential of Naringenin on highly active antiretroviral therapy-induced perturbations in fertility of male Sprague-Dawley rats. Thirty adult male Sprague-Dawley rats were divided into six groups viz -Control; H: 30 mg/kg of highly active antiretroviral therapy (EFV, 600 mg + FTC, 200 mg + TDF, 300 mg); N40: Naringenin, 40 mg/kg; N80: Naringenin, 80 mg/kg; HN40: highly active antiretroviral therapy + Naringenin, 40 mg/kg; HN80: highly active antiretroviral therapy + Naringenin, 80 mg/kg. The rats were euthanized after 4 weeks. Results showed that there was a significant decrease in sperm count (p < 0.001), spermatozoa with normal morphology (p < 0.001) and progressive sperm motility (p < 0.05) of H compared to the control and the HN groups. Likewise, fragmentations increased (p < 0.05) in tail lengths of sperm DNA in H compared to control. HN40 and HN80 decreased tail lengths compared to H (p < 0.001). There was also a decrease in %tail DNA and tail moment in HN40 (p < 0.001) compared to H. Luteinizing hormone significantly increased (p < 0.05) in HN40, HN80, and N40 (p < 0.001) but decreased in H (p < 0.05) compared to control. The diameter of the seminiferous tubules also decreased (p < 0.05) in H compared to control, N80, and HN40. Likewise, the area of the seminiferous tubules in group H decreased (p < 0.05) compared to N80 and HN80. The seminiferous tubules epithelium increased (p < 0.05) in N40 and HN40 compared to H. This study establishes that highly active antiretroviral therapy has deleterious effects on the testicular microanatomy, sperm parameters, and sperm DNA of Sprague-Dawley rats, which may impair fertility but Naringenin is a potential complimentary adjuvant.

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“…There is evidence that phosphorylation of eNOS at serine 1117 is a crucial target for intervention to improve endothelial dysfunction (15). In addition, there is growing evidence that an overproduction of ROS, which is generally generated by a cellular disturbance in glucose or/and lipid metabolism leads to the degradation of NO (39)(40)(41). Superoxide rapidly reacts with NO to form the powerful oxidant peroxynitrite which causes the nitration of proteins leading to the impairing of the function of cellular proteins including eNOS protein (15).…”

Section: Discussionmentioning

confidence: 99%

Naringin ameliorates endothelial dysfunction in fructose-fed rats

et al. 2018

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Abstract. High fructose consumption is associated with metabolic disorders including hyperglycemia and dyslipidemia, in addition to endothelial dysfunction. Naringin, a flavonoid present in citrus fruit, has been reported to exhibit lipid lowering, antioxidant, and cardiovascular protective properties. Therefore, the present study investigated the effect of naringin on fructose-induced endothelial dysfunction in rats and its underlying mechanisms. Male Sprague-Dawley rats were given 10% fructose in drinking water for 12 weeks, whereas control rats were fed drinking water alone. Naringin (100 mg/kg) was orally administered to fructose fed rats during the last 4 weeks of the study. Following 12 weeks, blood samples were collected for measurement of blood glucose, serum lipid profile and total nitrate/nitrite (NOx). Vascular function was assessed by isometric tension recording. Aortic expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), and nitrotyrosine were evaluated by western blot analysis. Fructose feeding induced increased levels of blood glucose, total cholesterol, triglyceride, and low density lipoprotein. In rat aortae, fructose reduced acethycholine-induced vasorelaxation, without affecting sodium nitroprusside-induced vasorelaxation. Treatment of fructose-fed rats with naringin restored fructose-induced metabolic alterations and endothelial dysfunction. Fructose-fed rats also exhibited decreased serum NOx level, reduced eNOS and p-eNOS protein expression, and enhanced nitrotyrosine expression in aortae. These alterations were improved by naringin treatment. The results of the present study suggested that naringin treatment preserves endothelium-dependent relaxation in aortae from fructose fed rats. This effect is primarily mediated through an enhanced NO bioavailability via increased eNOS activity and decreased NO inactivated to peroxynitrite in aortae.

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Naringenin protects cardiac hypercholesterolemia-induced oxidative stress and subsequent necroptosis in rats

Abstract: Our results show that the co-administration of NGEN (50 mg/kg/bw) in HCD rats improved all the altered parameters and provided insight into a possible molecular mechanism underlying NGEN suppression of necroptosis pathway in the heart.

Cited by 82 publications

References 54 publications

Hypercholesterolemia downregulates autophagy in the rat heart

Hypercholesterolemia downregulates autophagy in the rat heart

Naringenin attenuates highly active antiretroviral therapy‐induced spermDNAfragmentations and testicular toxicity in Sprague‐Dawley rats

Naringin ameliorates endothelial dysfunction in fructose-fed rats

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