Modulatory Effects of Curcumin on Redox Status,Mitochondrial Function,and Caspace‐3 Expression During Atrazin‐Induced Toxicity

Atrazine is currently the most widely used herbicide in agriculture with lots of adverse effects on human health. Curcumin is a polyphenol known for its antioxidant, anti‐inflammatory, and anticancer properties. In the present study, the protective effect of curcumin on atrazin‐intoxicated rats is evaluated. Toxicity was induced by oral administration of atrazine (400 mg/kg/day) for 3 weeks. Curcumin at a dose of 400 mg/kg/day was given simultaneously by oral route. Redox status, mitochondrial function, 8‐hydroxydeoxyguanosine (8‐OHdG) level by immunoassay, and caspace‐3 expression by immunohistochemistry were evaluated. Curcumin showed significant cardiac protection with improvement of redox status, mitochondrial function, 8‐OHdG level, caspase‐3 immunoreactivity, and cardiac muscle degeneration. From this current study, it can be concluded that administration of curcumin improved atrazine‐induced cardiotoxicity through its modulatory effect on redox status, mitochondrial function, and caspase‐3 expression.     

Dose‐dependent actions of curcumin in experimentally induced myocardial necrosis: a biochemical,histopathological, and electron microscopic evidence

Curcumin, an active component of turmeric, is a well‐known antioxidant due to its reactive oxygen species (ROS) scavenging property. However, some in vitro studies have suggested that curcumin induces generation of ROS at higher doses and thus exerts pro‐oxidant effect. We demonstrate, for the first time, the dose‐dependent effects of curcumin in isoprenaline‐induced model of myocardial necrosis in rats. The animals were assigned to control, isoprenaline and three curcumin treatment groups. Curcumin (100, 200, and 400 mg/kg) and vehicle (dimethyl sulfoxide) were administrated orally for 15 days and isoprenaline (85 mg/kg, s.c.) was given to curcumin treated and isoprenaline group on 13th and 14th day, respectively. Thereafter, on 15th day, the animals were sacrificed for biochemical analysis along with histopathological and ultrastructural examination. There was an increase in glutathione, superoxide dismutase (SOD), creatine kinase‐MB (CK‐MB) and lactate dehydrogenase (LDH) levels, decrease in thiobarbituric acid reactive substances (TBARS), and preservation of myocardial architecture in the curcumin (100 and 200 mg/kg) treated groups. However, at 400 mg/kg dose there was ineffectual protection against isoprenaline‐induced myocardial damage. Instead, there was significant lipid peroxidation as evident by increased levels of TBARS (93.87 ± 9.93, p < 0.0001) and decrease in CK‐MB (206.32 ± 13.54, p < 0.0001) and LDH (134.26 ± 9.13, p < 0.01) as compared to the two lower doses. Hence, it can be concluded that curcumin augments endogenous antioxidant system at lower doses but mediates ROS induction at higher concentration leading to myocardial damage. Copyright © 2009 John Wiley & Sons, Ltd.     

Protective Effects of Curcumin against Sodium Fluoride-Induced Toxicity in Rat Kidneys

In the present study, the protective effect of curcumin against sodium fluoride-induced nephrotoxicity was evaluated in rats. Renal injury was induced by daily administration of 600 ppm sodium fluoride in drinking water for 1 week. One week before the administration of fluoride, the animals selected as study group were given curcumin (10 and 20 mg/kg body weight, intraperitoneally). After 1 week, lipid peroxidation level, activities of superoxide dismutase, catalase, and level of glutathione in kidney homogenate were measured. Blood serum samples were examined for creatinine, serum urea, and blood urea nitrogen levels. Another group of rats received vitamin C (10 mg/kg) as standard antioxidant. The results show that curcumin and vitamin C treatment prior to fluoride administration normalized the levels of serum creatinine, serum urea, and blood urea nitrogen. Moreover, curcumin and vitamin C administrations prevented the antioxidant enzyme decreasing and lipid peroxidation levels imbalance. In conclusion, curcumin treatment at the doses of 10 and 20 mg/kg (intraperitoneally) showed significant nephroprotective effects.     

Regulation of expression of antioxidant enzymes by vitamin E and curcumin in <Emphasis Type="SmallCaps">l</Emphasis>-thyroxine-induced oxidative stress in rat renal cortex

The present study investigates the antioxidative effects of vitamin E and curcumin against l-thyroxine (T₄)-induced oxidative stress in renal cortex of adult male rats. Rats were made hyperthyroid by administration of l-thyroxine (0.0012%) in their drinking water for 30 days. Vitamin E (200 mg/kg body weight/day) and curcumin (30 mg/kg body weight/day) were supplemented singly or in combination orally for 30 days along with l-thyroxine treatment. The elevated level of oxidative stress parameters (lipid peroxidation and protein carbonylation) and decline level of small antioxidant molecules (reduced glutathione and ascorbic acid) in renal cortex of T₄-treated rats were restored back by supplementation of vitamin E or/and curcumin. Increased superoxide dismutase and catalase activities in kidney cortex of T₄-treated rats were ameliorated in response to vitamin E or/and curcumin treatment. The elevated translated product of Cu/Zn-SOD, Mn-SOD and catalase in T₄-treated rats were differentially reduced by the administration of vitamin E and curcumin independently or in combination. Cu/Zn-SOD expression was ameliorated by both vitamin E and curcumin independently or in combination, whereas Mn-SOD expression was ameliorated by the supplementation of vitamin E or curcumin independently. However, the expression of catalase was alleviated by only supplementation of vitamin E to T₄-treated rats. The results suggest that both vitamin E and curcumin may play an important role in protecting T₄-induced oxidative stress in rat renal cortex by differentially modulating the activities of antioxidant enzymes and oxidative stress parameters.     

Nimbolide prevents myocardial damage by regulating cardiac biomarkers,antioxidant level,and apoptosis signaling against doxorubicin‐induced cardiotoxicity in rats

The current work planned to assess the protecting properties of nimbolide against doxorubicin (DOX)‐treated myocardial damage. Myocardial damage was produced with 2.5 mg/kg of DOX given on alternative days (14 days). Thiobarbituric acid reactive substances (TBARS) levels of a lipid peroxidative marker were elevated, whereas reduced body weight, heart weight, blood pressure indices and reduced levels of antioxidants like glutathione‐S‐transferase, superoxide dismutase, catalase, glutathione peroxidase, glutathione, and glutathione reductase were observed in the heart tissue of DOX‐treated animals. DOX‐treated animals showed augmented levels of cardiac markers likes monocyte chemotactic protein‐1, interferon‐gamma, aspartate transferase, creatine kinase, lactate dehydrogenase, creatine kinase‐muscle/brain, heart‐type fatty acid‐binding protein, glycogen phosphorylase isoenzyme BB, transforming growth factor‐β, brain natriuretic peptide, myoglobin, and cTnI in serum. Histopathological assessment confirmed the DOX‐induced cardiotoxicity. Furthermore, DOX‐induced rats showed augmented inflammatory mediators (nuclear factor‐κB [NF‐kB], tumor necrosis factor‐α [TNF‐α], and interleukin‐1β [IL‐1β]) and increased PI3K/Akt signaling proteins (PI3K, p‐Bad/Bad, caspase‐3, and p‐Akt), whereas decreased oxidative markers (HO‐1 and NQO‐1) and p‐PTEN were observed. Nimbolide‐supplemented rats showed reduced activity/levels of cardiac markers and TBARS levels in serum and heart tissue. Levels of enzymatic and nonenzymatic antioxidants were augmented in the heart tissue of nimbolide‐supplemented rats. Nimbolide influence decreased apoptosis, inflammation, and enhanced antioxidant markers through the modulation of p‐Bad/Bad, caspase‐3, PI3K, p‐Akt, TNF‐α, NF‐kB, IL‐1β, HO‐1, NQO‐1, and p‐PTEN markers. The histopathological explanations were observed to be in line with biochemical analysis. Therefore, the finding of current work was that nimbolide has a defensive effect on the myocardium against DOX‐induced cardiac tissue damage.     

Protective effect of curcumin nanoparticles against cardiotoxicity induced by doxorubicin in rat

The present study designed to investigate the protective effect of curcumin nanoparticles (CUR-NPs) on the cardiotoxicity induced by doxorubicin. Rats were divided into four groups; control, rats treated daily with CUR-NPs (50 mg/kg) for 14 days, rats treated with an acute dose of doxorubicin (20 mg/kg) and rats treated daily with CUR-NPs for 14 days injected with doxorubicin on the 10th day. After electrocardiogram (ECG) recording from rats at different groups, rat decapitation was carried out and the heart of each rat was excised out to measure the oxidative stress parameters; lipid peroxidation (MDA), nitric oxide (NO) and reduced glutathione (GSH) and the activities of Na,K,ATPase and acetylcholinesterase (AchE). In addition, the levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) were determined in the cardiac tissues. Lactate dehydrogenase (LDH) activity was measured in the serum. The ECG recordings indicated that daily pretreatment with CUR- NPs has prevented the tachycardia (i.e. increase in heart rate) and ameliorated the changes in ST wave and QRS complex induced by doxorubicin. In addition, CUR-NPs prevented doxorubicin induced significant increase in MDA, NO, DA, AchE and LDH and doxorubicin induced significant decrease in GSH, NE, 5-HT and Na,K,ATPase. According to the present findings, it could be concluded that CUR-NPs have a protective effect against cardiotoxicity induced by doxorubicin. This may shed more light on the importance of CUR-NPs pretreatment before the application of doxorubicin therapy.     

Protective effect of Piper longum L. on oxidative stress induced injury and cellular abnormality in adriamycin induced cardiotoxicity in rats

Effect of methanolic extract of fruits of P. longum (PLM) on the biochemical changes, tissue peroxidative damage and abnormal antioxidant levels in adriamycin (ADR) induced cardiotoxicity in Wistar rats was investigated. PLM was administered to Wistar albino rats in two different doses, by gastric gavage (250 mg/kg and 500 mg/kg) for 21 days followed by ip ADR (15 mg/kg) on 21st day. ADR administration showed significant decrease in the activities of marker enzymes aspartate transaminase, alanine transaminase, lactate dehydrogenase and creatine kinase in heart with a concomitant increase in their activities in serum. A significant increase in lipid peroxide levels in heart of ADR treated rats was also observed. Pretreatment with PLM ameliorated the effect of ADR on lipid peroxide formation and restored activities of marker enzymes. Activities of myocardial antioxidant enzymes like catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase along with reduced glutathione were significantly lowered due to cardiotoxicity in rats administered with ADR. PLM pretreatment augmented these endogenous antioxidants. Histopathological studies of heart revealed degenerative changes and cellular infiltrations in rats administered with ADR and pretreatment with PLM reduced the intensity of such lesions. The results indicate that PLM administration offers significant protection against ADR induced oxidative stress and reduces the cardiotoxicity by virtue of its antioxidant activity.     

Protective effect of CardiPro against doxorubicin-induced cardiotoxicity in mice

The effect of CardiPro, a polyherbal formulation, with an antioxidant property, has been studied on doxorubicin (DXR)-induced cardiotoxicity in mice. CardiPro (150 mg/kg b.w., twice daily was administered orally for 7 weeks along with four equal injections (each containing 4.0 mg/kg b.w., DXR) intraperitoneally, once weekly (cumulative dose 16 mg/kg). After a 3-week post DXR treatment period, cardiotoxicity was assessed by noting mortality, volume of ascites, liver congestion, changes in heart weight, myocardial lipid peroxidation, antioxidant enzymes and histology of heart. DXR-treated animals showed higher mortality (50%) and more ascites. Myocardial SOD and glutathione peroxidase activity were decreased and lipid peroxidation was increased. Histology of heart of DXR-treated animals showed loss of myofibrils and focal cytoplasmic vacuolization. CardiPro significantly protected the mice from DXR-induced cardiotoxic effects as evidenced by lower mortality (25%), less ascites, myocardial lipid peroxidation, normalization of antioxidant enzymes and minimal damage to the heart histologically. Our data confirm the earlier reports that DXR cardiotoxicity is associated with the free radical-induced tissue damage. Administration of CardiPro, with an antioxidant property, protected the DXR-induced cardiotoxicity in mice.     

Loperamide‐induced cardiotoxicity in rats: Evidence from cardiac and oxidative stress biomarkers

At therapeutic dose, loperamide is a safe over‐the‐counter antidiarrheal drug but could induce cardiotoxic effect at a supratherapeutic dose. In this study, we use cardiac and oxidative biomarkers to evaluate loperamide‐induced cardiotoxicity in rats. Rats were orally gavaged with 1.5, 3, or 6 mg/kg body weight (BW) of loperamide hydrochloride for 7 days. The results after 7 days administration of loperamide, revealed dose‐dependent increase (P < 0.05) in aspartate aminotransferase, lactate dehydrogenase, creatine kinase‐MB, and serum concentration of cardiac troponin I, total homocysteine, and nitric oxide. A 50% decrease in antioxidant enzymes activity was observed at 6 mg/kg BW. Furthermore, malondialdehyde and fragmented DNA also increased significantly in the heart of the treatment groups. Loperamide provoked cardiotoxicity through oxidative stress, lipid peroxidation, and DNA fragmentation in rats. This study has provided a possible biochemical explanation for the reported cardiotoxicity induced by loperamide overdose.     

Piperine,a Natural Bioenhancer,Nullifies the Antidiabetic and Antioxidant Activities of Curcumin in Streptozotocin-Diabetic Rats

Knowing that curcumin has low bioavailability when administered orally, and that piperine has bioenhancer activity by inhibition of hepatic and intestinal biotransformation processes, the aim of this study was to investigate the antidiabetic and antioxidant activities of curcumin (90 mg/kg) and piperine (20 or 40 mg/kg), alone or co-administered, incorporated in yoghurt, in streptozotocin (STZ)-diabetic rats. The treatment for 45 days of STZ-diabetic rats with curcumin-enriched yoghurt improved all parameters altered in this experimental model of diabetes: the body weight was increased in association with the weight of skeletal muscles and white adipose tissues; the progressive increase in the glycemia levels was avoided, as well as in the glycosuria, urinary urea, dyslipidemia, and markers of liver (alanine and aspartate aminotransferases and alkaline phosphatase) and kidney (urinary protein) dysfunction; the hepatic oxidative stress was decreased, since the activities of the antioxidant enzymes superoxide dismutase, catalase and gluthatione peroxidase were increased, and the levels of malondialdehyde and protein carbonyl groups were reduced. The dose of 20 mg/kg piperine also showed antidiabetic and antioxidant activities. The treatment of STZ-diabetic rats with both curcumin and 20 mg/kg piperine in yoghurt did not change the antidiabetic and antioxidant activities of curcumin; notably, the treatment with both curcumin and 40 mg/kg piperine abrogated the beneficial effects of curcumin. In addition, the alanine aminotransferase levels were further increased in diabetic rats treated with curcumin and 40 mg/kg piperine in comparison with untreated diabetic rats. These findings support that the co-administration of curcumin with a bioenhancer did not bring any advantage to the curcumin effects, at least about the antidiabetic and antioxidant activities, which could be related to changes on its biotransformation.     

Alpha lipoic acid prevents doxorubicin‐induced nephrotoxicity by mitigation of oxidative stress,inflammation, and apoptosis in rats

This study aimed to evaluate the protective effects of alpha lipoic acid (ALA) against doxorubicin (DOX)‐induced nephrotoxicity in rats. A single dose of DOX (7.5 mg/kg i.v.) induced nephrotoxicity evidenced by significant elevations in kidney weight, kidney/body weight ratio, serum urea, creatinine, tumor necrosis factor alpha, and renal contents of malondialdehyde, nitric oxide, cyclooxygenase‐2, and caspase‐3. Also, it causes significant reduction in final body weight, serum albumin, renal contents of reduced glutathione and superoxide dismutase activity. Histopathological changes in the kidney tissue confirmed the nephrotoxic effect. In contrast, pretreatment with ALA (50 mg/kg, orally) for 14 days before DOX and for 7 days after DOX administration mitigated renal toxicity evidenced by greater improvement in the examined oxidative stress, inflammation, and apoptosis parameters. In conclusion, ALA had promising protective effects against DOX‐induced nephrotoxicity that might be attributed to its antioxidant, anti‐inflammatory, and antiapoptoic activities.     

Protective effects of thymol on altered plasma lipid peroxidation and nonenzymic antioxidants in isoproterenol-induced myocardial infarcted rats

This study evaluates the protective effects of thymol on altered plasma lipid peroxidation products and nonenzymic antioxidants in isoproterenol (ISO)‐induced myocardial infarcted rats. Male albino Wistar rats were pre and cotreated with thymol (7.5 mg/kg body weight) daily for 7 days. ISO (100 mg/kg body weight) was subcutaneously injected into rats on 6th and 7th day to induce myocardial infarction (MI). Increased activity/levels of serum creatine kinase‐MB (CK‐MB), plasma thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes with decreased levels of plasma reduced glutathione (GSH), vitamin C, and vitamin E were observed in ISO‐induced myocardial infarcted rats. Pre and cotreatment with thymol (7.5 mg/kg body weight) showed normalized activity of serum CK‐MB and near normalized levels of plasma lipid peroxidation products, reduced GSH, vitamin C, and vitamin E in myocardial infarcted rats. Furthermore, the in vitro study on reducing power of thymol confirmed its potent antioxidant action. Thus, thymol protects ISO‐induced MI in rats by its antilipid peroxidation and antioxidant properties. © 2012 Wiley Periodicals, Inc. J Biochem Mol Toxicol 26:368–373, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21431     

Preventive Effects of Zingerone on Altered Lipid Peroxides and Nonenzymatic Antioxidants in the Circulation of Isoproterenol‐Induced Myocardial Infarcted Rats

The present study was designed to evaluate the preventive effects of zingerone on circulatory lipid peroxides and nonenzymatic antioxidants in isoproterenol‐induced myocardial infarcted rats. Rats were pretreated with zingerone (6 mg/kg body weight) daily for a period of 14 days and were then induced myocardial infarction with isoproterenol (100 mg/kg body weight) on 15th and 16th day. Increased intensities of serum lactate dehydrogenase isoenzymes 1 and 2 bands enhanced plasma lipid peroxidation products and lowered nonenzymatic antioxidant system were noted in isoproterenol‐induced rats. Pretreatment with zingerone daily for 14 days revealed significant preventive effects on the electrophoretic and biochemical parameters evaluated in isoproterenol‐induced rats. Furthermore, the in vitro study confirmed the potent antioxidant activity of zingerone. The results of our study showed that zingerone protected the rat's heart against isoproterenol‐induced myocardial infarction by its antioxidant effect.     

Yellow Wine Polyphenolic Compounds prevents Doxorubicin‐induced cardiotoxicity through activation of the Nrf2 signalling pathway

Doxorubicin (DOX) is considered as the major culprit in chemotherapy‐induced cardiotoxicity. Yellow wine polyphenolic compounds (YWPC), which are full of polyphenols, have beneficial effects on cardiovascular disease. However, their role in DOX‐induced cardiotoxicity is poorly understood. Due to their antioxidant property, we have been suggested that YWPC could prevent DOX‐induced cardiotoxicity. In this study, we found that YWPC treatment (30 mg/kg/day) significantly improved DOX‐induced cardiac hypertrophy and cardiac dysfunction. YWPC alleviated DOX‐induced increase in oxidative stress levels, reduction in endogenous antioxidant enzyme activities and inflammatory response. Besides, administration of YWPC could prevent DOX‐induced mitochondria‐mediated cardiac apoptosis. Mechanistically, we found that YWPC attenuated DOX‐induced reactive oxygen species (ROS) and down‐regulation of transforming growth factor beta 1 (TGF‐β1)/smad3 pathway by promoting nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) nucleus translocation in cultured H9C2 cardiomyocytes. Additionally, YWPC against DOX‐induced TGF‐β1 up‐regulation were abolished by Nrf2 knockdown. Further studies revealed that YWPC could inhibit DOX‐induced cardiac fibrosis through inhibiting TGF‐β/smad3‐mediated ECM synthesis. Collectively, our results revealed that YWPC might be effective in mitigating DOX‐induced cardiotoxicity by Nrf2‐dependent down‐regulation of the TGF‐β/smad3 pathway.     

Curcumin treatment modulates collagen metabolism in isoprot3erenol induced myoxardial necrosis in rats

This study was carried out to evaluate whether curcumin, a potent antioxidant, had any specific role in the synthesis and degradation of collagen in rat heart with mocardial necrosis, induced by isoproterenol.HCI (ISO). Myocardial necrosis was induced by administration of ISO (30 mg/100 g body weight subcutaneously twice at an interval of 24 h) and studies on collagen metabolism were carried out with curcumin (200 mg/kg) pre-and co-treatment with ISO. The incorporation of ₁₄C-proline into collagen was studied as an index of collagen synthesis. The heart weight /body weight ratio,heart RNA/DNA ratio and protein were found to increase significantly in ISO administered animals. Curcumin pre- and co-treatment with ISO reversed these changes and attenuated the development of cardiac hypertrophy two weeks after the second dose of ISO. Increased fractional synthesis rate and enhanced degradation of newly synthesized collagen were observed in ISO administered animals. Curcumin pre- and co-treatment with ISO was noticed to decrease the degree of degradation of the existing collagen matrix and collagen synthesis, two weeks after the second dose of ISO. The observed effects could be due to free radical scavenging capacity and inhibition of lysosomal enzyme release by curcumin.     

Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced oxidative cardiac injury

Cyclophosphamide (CP), one of the most widely prescribed antineoplastic drugs could cause a lethal cardiotoxicity. The present study is aimed at evaluating the role of DL-alpha-lipoic acid (LA) in oxidative cardiac damage induced by CP. Adult male Wistar rats were divided into four treatment groups. Two groups received single intraperitoneal injection of CP (200 mg/kg BW) to induce cardiotoxicity, one of these groups received LA treatment (25 mg/kg BW for 10 days). A vehicle treated control group and a LA drug control were also included. Cardiotoxicity, evident from increased activities of serum creatine phosphokinase, lactate dehydrogenase, aspartate transaminase and alanine transaminase in CP administered rats, was reversed by LA treatment. CP administered rats showed abnormal levels of enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase) and non-enzymic antioxidants (glutathione, vitamin C and vitamin E) along with high malondialdehyde levels. However, normalized lipid peroxidation and antioxidant defenses were reported in the LA treated rats. These findings highlight the efficacy of LA as a cytoprotectant in CP induced cardiotoxicity.     

Effect of lupeol isolated from Crataeva nurvala Buch.-Ham. stem bark extract against free radical induced nephrotoxicity in rats

Lupeol, isolated from Crataeva nurvala stem bark in doses 40 and 80 mg/kg body weight, po, for 10 days, decreased the concentration of blood urea nitrogen, creatinine and lipid peroxidation and increased glutathione and catalase activities in cisplatin (5 mg/kg body weight, ip) induced nephrotoxicity in rats. The increased glutathione and catalase activities are indicative of antioxidant properties of lupeol.