Chronic heart failure is the end stage of heart diseases caused by multiple causes. Myocardial cell injury is the key cause of cardiac function deterioration. Ferroptosis, an iron-dependent programmed death mode, is characterized by iron overload and excessive accumulation of lipid peroxides. Studies have demonstrated that inhibiting ferroptosis has a protective effect on myocardial cells. The theory of "harmful hyperactivity and responding inhibition" is an important rule developed by physicians to explain the generation and restriction of the five elements and the pathological imbalance of the human body, and can guide medication. Correlating with the nature, humans need to rely on the law of responding inhibition to maintain the harmony of five Zang-organs and the steady state of Fu-organs. The pathogenesis of ferroptosis in chronic heart failure highly coincides with the process of failing to "inhibition and hyperactivity becoming harmful". The initial factor of ferroptosis is the deficiency of heart Qi, which results in the inability to maintain the balance of cardiomyocyte redox system. The involvement of the five Zang-organs leads to the loss of distribution of body fluid and blood. As a result, the phlegm turbidity, blood stasis, and water retention in the meridians occur, which are manifested as the accumulation of iron and lipid peroxides, which is the aggravating factor of ferroptosis. The two factors interact with each other, leading to the spiral development and thus aggravating heart failure. According to the traditional Chinese medicine(TCM) pathogenesis of ferroptosis, the authors try to treat the chronic heart failure by stages in accordance with the general principle of restraining excess and alleviating hyperactivity. The early-stage treatment should "nourish heart Qi, regulate the five Zang-organs, so as to restrain excess". The middle-stage treatment should "active blood, resolve phlegm, dispel pathogen, and eliminate turbidity", so as to alleviate hyperactivity. The late-stage treatment should "warm Yang, replenish Qi, active blood, and excrete water". Following the characteristics of pathogenesis, the TCM intervention can reduce iron accumulation and promote the clearance of lipid peroxide, thus inhibiting ferroptosis and improving cardiac function.
Humans ; Ferroptosis ; Lipid Peroxides ; Medicine, Chinese Traditional ; Heart Failure/drug therapy* ; Chronic Disease ; Iron ; Water

Enhanced oxidative stress is a hallmark of cisplatin nephrotoxicity, and inhibition of poly(ADP-ribose) polymerase 1 (PARP1) attenuates oxidative stress during cisplatin nephrotoxicity; however, the precise mechanisms behind its action remain elusive. Here, using an in vitro model of cisplatin-induced injury to human kidney proximal tubular cells, we demonstrated that the protective effect of PARP1 inhibition on oxidative stress is associated with sirtuin 3 (SIRT3) activation. Exposure to 400 µM cisplatin for 8 hours in cells decreased activity and expression of manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase (GPX), and SIRT3, while it increased their lysine acetylation. However, treatment with 1 µM PJ34 hydrochloride, a potent PARP1 inhibitor, restored activity and/or expression in those antioxidant enzymes, decreased lysine acetylation of those enzymes, and improved SIRT3 expression and activity in the cisplatin-injured cells. Using transfection with SIRT3 double nickase plasmids, SIRT3-deficient cells given cisplatin did not show the ameliorable effect of PARP1 inhibition on lysine acetylation and activity of antioxidant enzymes, including MnSOD, catalase and GPX. Furthermore, SIRT3 deficiency in cisplatin-injured cells prevented PARP1 inhibition-induced increase in forkhead box O3a transcriptional activity, and upregulation of MnSOD and catalase. Finally, loss of SIRT3 in cisplatin-exposed cells removed the protective effect of PARP1 inhibition against oxidative stress, represented by the concentration of lipid hydroperoxide and 8-hydroxy-2'-deoxyguanosine; and necrotic cell death represented by a percentage of propidium iodide–positively stained cells. Taken together, these results indicate that PARP1 inhibition protects kidney proximal tubular cells against oxidative stress through SIRT3 activation during cisplatin nephrotoxicity.
Acetylation ; Catalase ; Cell Death ; Cisplatin* ; Deoxyribonuclease I ; Down-Regulation* ; Glutathione Peroxidase ; Humans ; In Vitro Techniques ; Kidney ; Lipid Peroxides ; Lysine ; Oxidative Stress* ; Plasmids ; Poly Adenosine Diphosphate Ribose* ; Poly(ADP-ribose) Polymerases* ; Propidium ; Sirtuin 3* ; Superoxide Dismutase ; Transfection ; Up-Regulation

Treatment with cisplatin for cancer therapy has a major side effect such as nephrotoxicity; however, the role of poly (ADP-ribose) polymerase 1 (PARP1) in necrosis in response to cisplatin nephrotoxicity remains to be defined. Here we report that cisplatin induces primary necrosis through PARP1 activation in kidney proximal tubular cells derived from human, pig and mouse. Treatment with high dose of cisplatin for 4 and 8 hours induced primary necrosis, as represented by the percentage of propidium iodide-positive cells and lactate dehydrogenase release. The primary necrosis was correlated with PARP1 activation during cisplatin injury. Treatment with PJ34, a potent PARP1 inhibitor, at 2 hours after injury attenuated primary necrosis after 8 hours of cisplatin injury as well as PARP1 activation. PARP1 inhibition also reduced the release of lactate dehydrogenase and high mobility group box protein 1 from kidney proximal tubular cells at 8 hours after cisplatin injury. Oxidative stress was increased by treatment with cisplatin for 8 hours as shown by 8-hydroxy-2'-deoxyguanosine and lipid hydroperoxide assays, but PARP1 inhibition at 2 hours after injury reduced the oxidative damage. These data demonstrate that cisplatin-induced PARP1 activation contributes to primary necrosis through oxidative stress in kidney proximal tubular cells, resulting in the induction of cisplatin nephrotoxicity and inflammation.
Animals ; Cisplatin* ; Humans ; Inflammation ; Kidney* ; L-Lactate Dehydrogenase ; Lipid Peroxides ; Mice ; Necrosis* ; Oxidative Stress ; Poly(ADP-ribose) Polymerases* ; Propidium

The effects of toluene in dimethylformamide (DMF)-induced hepatotoxicity were investigated with respect to the induction of cytochrome P-450 (CYP) and the activities of related enzymes. The rats were treated intraperitoneally with the organic solvents in olive oil (Single treatment groups: 450 [D1], 900 [D2], 1,800 [D3] mg DMF, and 346 mg toluene [T] per kg of body weight; Combined treatment groups: D1+T, D2+T, and D3+T) once a day for three days, while the control group received just the olive oil. Each group consisted of 4 rats. The activities of the xenobiotic metabolic enzymes and the hepatic morphology were assessed. The immunoblots indicated that the expression of CYP2E1 was considerably enhanced depending on the dosage of DMF and the CYP2E1 blot densities were significantly increased after treatment with both DMF and toluene, compared to treatment with DMF alone. The activities of glutathione-S-transferase and glutathione peroxidase were either decreased or remained unaltered after treatment with DMF and toluene, whereas the lipid peroxide levels were increased with increasing dosage of DMF and toluene. The liver tissue in the D3 group (1,800 mg/kg of DMF) showed signs of microvacuolation in the central vein region and a large necrotic zone around the central vein, in rats treated with both DMF (1,800 mg/kg) and toluene (D3T). These results suggest that the expression of CYP2E1 is induced by DMF and enhanced by toluene. These changes may have facilitated the accelerated formation of N-methylformamide (NMF) from toluene, and the generated NMF may directly induce liver damage.
Animals ; Body Weight ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System ; Dimethylformamide* ; Formamides ; Glutathione Peroxidase ; Lipid Peroxides ; Liver ; Olea ; Plant Oils ; Rats* ; Solvents ; Toluene* ; Veins ; Olive Oil

Polyphenol-rich grape seeds have a beneficial effect on human health. The present study was performed to investigate the effects of grape seeds on antioxidant activities in rats. Male Sprague-Dawley rats were randomly divided into a control diet group (C), a high-fat diet group (HF), a 5% grape seed-supplemented control diet group (G), and a 5% grape seed-supplemented high-fat diet group (HG). Dietary supplementation with grape seeds reduced serum concentrations of lipid peroxides compared with those in the C and HF groups. The hepatic level of lipid peroxides decreased significantly in the grape seed groups compared with that in the C and HF groups. Superoxide dismutase activity in the G group increased significantly compared with that in the C group. Catalase activity tended to be higher by feeding grape seeds. The grape seed diet increased glutathione peroxidase activity in the C group. Glutathione-S-transferase activity increased significantly in the G group compared with that in the C group. Hepatic content of total glutathione increased significantly in the HG group but decreased significantly in the HF group. The ratio of reduced glutathione and oxidized glutathione increased by feeding the grape seed diet. Total vitamin A concentration was significantly higher in HG group than in other groups. Liver tocopherol content of the G and HG groups was significantly higher than that of the control groups. These results suggest that dietary supplementation with grape seeds is beneficial for suppressing lipid peroxidation in high fat-fed rats.
Animals ; Catalase ; Diet ; Diet, High-Fat ; Dietary Supplements ; Glutathione ; Glutathione Disulfide ; Glutathione Peroxidase ; Humans ; Lipid Peroxidation ; Lipid Peroxides ; Liver ; Male ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Seeds ; Superoxide Dismutase ; Tocopherols ; Vitamin A ; Vitis

Dietary fatty acids are under intense research to identify anti-atherogenic mechanisms, so we investigated green tea powder (GT) as a protector against atherogenesis originating from lipid peroxidation such as 4-hydroxynonemal (4-HNE) and malondialdehyde (MDA) in different dietary fatty acid-treated apo E KO mice. Growth rate and dietary efficiency were lower in apo E KO mice with or without LA compared to wild type. Plasma total cholesterol (TC) and triacylglycerol (TG) did not correspond to values in other tissues, but TG in heart tissue decreased significantly by GT after linoleic acid (LA) or docosahexaenoic acid (DHA) was administered. LA induced apoptosis as evidenced by changes in aorta morphology and immunohistochemistry. Lipid peroxides (LPO) was increased in apo E KO mice with or without LA corresponding to the accumulation of 4-HNE or MDA in the proximal aorta above the atria. GT consumption tended to reduce the primary causal mechanism of atherogenic phenomena such as oxidizability in both LA and DHA treated atherogenic mice. A high polyunsaturated fatty acids (PUFA) diet involved the changes on stress-induced apoptotic signaling by increasing caspase 3, cytochrome c, and nuclear factor-kappaB in the heart tissue, but decreasing the bcl-2 protein. However, GT remarkably reduced the expression of apoptotic signaling, in contrast to the PUFA diet. Therefore, the potential of GT as an anti-atherosclerotic dietary antioxidant was tested in this study.
Animals ; Aorta ; Apolipoproteins E ; Apoptosis ; Atherosclerosis ; Caspase 3 ; Cholesterol ; Cytochromes c ; Diet ; Fatty Acids ; Fatty Acids, Unsaturated ; Heart ; Immunohistochemistry ; Linoleic Acid ; Lipid Peroxidation ; Lipid Peroxides ; Malondialdehyde ; Mice ; Plasma ; Tea ; Triglycerides

This study was performed to examine the combined effects of gamma linolenic acid and isoflavone supplementation on menopausal symptoms and serum lipids in 73 postmenopausal women. A total subjects were randomly assigned to isoflavone (30 mg) + gamma-linolenic acid (110 mg) group or placebo group. We measured menopausal symptoms by modified Kupperman Index (KI) and oxidized LDL, lipid peroxides, blood components and anthropometric parameters before and after the 12 week intervention period. After the 12 weeks of supplementation, supplement group and placebo group showed a significant reduction of modified kupperman index (p < 0.001). Isoflavone (30 mg) + gamma-linolenic acid (110 mg) supplement group showed a significant reduction of oxidized LDL cholesterol concentration (p = 0.006) whereas placebo group did not show significant change. Isoflavone and gamma-linolenic acid consumption did not significantly affect plasma concentrations of total, LDL, HDL cholesterol, triglyceride, apo A1, B and blood components. The result of present study demonstrated the supplementation of 30 mg isoflavone and 110 mg gamma-linolenic acid per day for 12 weeks may protect LDL cholesterol from oxidative stress.
Apolipoprotein A-I ; Cholesterol, HDL ; Cholesterol, LDL ; Female ; gamma-Linolenic Acid ; Humans ; Lipid Peroxides ; Lipoproteins, LDL ; Oxidative Stress ; Plasma

PURPOSE:To investigate the change in the antioxidant vitamin levels in maternal uterine venous plasma (MUVP), amniotic fluid (AF), and chorioamnion after vitamin C and E supplementation during pregnancy. METHODS:Thirty pregnant women who were scheduled for elective cesarean section between 37 and 39 gestational weeks were randomized in this study. Fifteen women were given a daily oral dose of vitamin C 1,000 mg and vitamin E 400 IU from 33~34 gestational weeks to delivery. The other fifteen women were not given, as a control group. Maternal uterine venous blood, AF, and chorioamnion were obtained after cesarean section. Lipid peroxides and oxygen-radical absorbance capacity value were measured by thiobarbituric acid reaction and Cao's method respectively. Ascorbic acid, uric acid, beta-carotene, retinol, alpha-tocopherol, and gamma-tocopherol were measured by high performance liquid chromatography. The tissue sections of chorioamnion were stained with hematoxylin-eosin and Masson-trichrome stain, and immunohistochemical stain for collagen type IV was also performed. RESULTS:The lipid peroxide levels in MUVP of the study group were significantly lower than those of the control group but in contrast, ORAC (Oxygen-radical absorbance capacity) values were lower in the control group. The alpha-tocopherol levels in MUVP, AF, and chorioamnion study group were significantly higher than those of the control group. Amniotic membrane and subepithelial stromal tissue in the study group were thicker than those in the control group. And subchorionic type IV collagen of placenta tissue in the study group was more stained than that of the control group. CONCLUSION:Maternal vitamin C and E supplementation may be beneficial in the prevention of diseases caused by oxidative stress such as preeclampsia and PROM and in increasing fibrin and type IV collagen in chorioamnion.
alpha-Tocopherol ; Amnion ; Amniotic Fluid ; Ascorbic Acid ; beta Carotene ; Cesarean Section ; Chromatography, Liquid ; Collagen Type IV ; Female ; Fibrin ; gamma-Tocopherol ; Humans ; Lipid Peroxides ; Oxidative Stress ; Placenta ; Plasma ; Pre-Eclampsia ; Pregnancy ; Pregnant Women ; Thiobarbiturates ; Uric Acid ; Vitamin A ; Vitamin E ; Vitamins

OBJECTIVETo investigate the acting mechanism of Buxu Huayu Qutan Decoction (BHQD) for impacting the anti-oxidative capacity in aged patients with stable angina pectoris of coronary heart disease (AP-CHD).

METHODSForty patients of AP-CHD, Chinese medicine diagnosed as Xiong-bi, were equally assigned to the treatment group and the control group. Superoxide dismutase (SOD) activity and lipid peroxide (LPO) contents in blood, and mRNA expression of manganese-containing superoxide dismutase (MnSOD) in peripheral mononuclear cells were determined before and after treatment by biochemical and molecular biologic techniques.

RESULTSNo significant change of plasma SOD and LPO was found in the control group after treatment (P >0.05), while the plasma SOD activity increased and LPO content lowered in the treatment group significantly (P<0.01). Moreover, mRNA expression of MnSOD in the treatment group after treatment was obviously higher than that in the control group (P <0.01).

CONCLUSIONSThe acting mechanism of BHQD for AP-CHD treatment might partially due to its effects in inducing gene expression of MnSOD in mononuclear cells, enhancing SOD activity, decreasing LPO content, maintaining oxidation/antioxidation equilibrium in myocardial cells, blocking the chain reaction of lipid peroxidation, intervening the production and enhancing the scavenging of oxygen free radicals.

Aged ; Angina Pectoris ; drug therapy ; metabolism ; Coronary Disease ; drug therapy ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Humans ; Lipid Peroxidation ; Lipid Peroxides ; blood ; Male ; Middle Aged ; Oxidative Stress ; Phytotherapy ; Superoxide Dismutase ; metabolism

Hyperglycemia in the diabetic state increases oxidative stress and antioxidant therapy can be strongly correlated with decreased risks for diabetic complications. The purpose of this study is to determine antioxidant effect of garlic and aged black garlic in animal model of type 2 diabetes. The antioxidant activity of garlic and aged black garlic was measured as the activity in scavenging free radicals by the trolox equivalent antioxidant capacity (TEAC) assay. Three week-old db/db mice were fed AIN-93G diet or diet containing 5% freeze-dried garlic or aged black garlic for 7 weeks after 1 week of adaptation. Hepatic levels of lipid peroxides and activities of antioxidant enzymes were measured. TEAC values of garlic and aged black garlic were 13.3 +/- 0.5 and 59.2 +/- 0.8 micromol/g wet weight, respectively. Consumption of aged black garlic significantly decreased hepatic thiobarbituric acid reactive substances (TBARS) level compared with the garlic group which showed lower TBARS level than control group (p<0.05). Activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) of garlic and aged black garlic group were significantly elevated compared to the control group. Catalase (CAT) activity of aged black garlic group was increased compared with the control group. These results show that aged black garlic exerts stronger antioxidant activity than garlic in vitro and in vivo, suggesting garlic and aged black garlic, to a greater extent, could be useful in preventing diabetic complications.
Aged ; Animals ; Antioxidants ; Catalase ; Chromans ; Diabetes Complications ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Diet ; Free Radicals ; Garlic ; Glutathione Peroxidase ; Humans ; Hyperglycemia ; Lipid Peroxides ; Mice ; Models, Animal ; Oxidative Stress ; Superoxide Dismutase ; Thiobarbiturates ; Thiobarbituric Acid Reactive Substances