Mechanism Involved in Fortification by Berberine in CDDP-Induced Nephrotoxicity.

BACKGROUND: The activation of Nrf2/HO-1 pathway has been shown to protect against cisplatin- induced nephrotoxicity by reducing oxidative stress. Berberine (Ber), an isoquinoline alkaloid, has demonstrated antioxidant, anti-inflammatory and anti-apoptotic activities in various experimental models. AIM: To check the effect of Ber on cisplatin-induced nephrotoxicity and to explore the involved mechanism. METHODS: Adult male Wistar rats were divided into 6 groups: Normal, cisplatin-control, treatment groups and per se group. Normal saline and Ber (20, 40 and 80 mg/kg; p.o.) was administered to rats for 10 days. A single intraperitoneal injection of cisplatin (8 mg/kg) was injected on 7th day to induced nephrotoxicity. On 10th day, rats were sacrificed, the kidney was removed and stored for the estimation of various parameters. RESULTS: As compared to cisplatin-control group, Ber pretreatment improved renal function system and preserved renal architecture. It also diminished oxidative stress by upregulating the expression of Nrf2/HO-1 proteins. In addition, Ber attenuated the cisplatin mediated inflammation and apoptosis. Furthermore, it also reduced the phosphorylation of p38/JNK and PARP/Beclin-1 expression in the kidney. CONCLUSION: Ber attenuated renal injury by activating Nrf2/HO-1 and inhibiting JNK/p38MAPKs/ PARP/Beclin-1 expression which prevented oxidative stress, inflammation, apoptosis and autophagy in renal tissue.

Therapeutic Potential and Molecular Mechanisms of Emblica officinalis Gaertn in Countering Nephrotoxicity in Rats Induced by the Chemotherapeutic Agent Cisplatin.

Emblica officinalis Gaertn. belonging to family Euphorbiaceae is commonly known as Indian gooseberry or "Amla" in India. It is used as a 'rejuvenating herb' in traditional system of Indian medicine. It has been shown to possess antioxidant, anti-inflammatory and anti-apoptotic effects. Thus, on the basis of its biological effects, the present study was undertaken to evaluate the protective effect of the dried fruit extract of the E. Officinalis (EO) in cisplatin-induced nephrotoxicity in rats and also to evaluate the mechanism of its nephroprotection. The study was done on male albino Wistar rats. They were divided into six groups (n = 6) viz. control, cisplatin-control, cisplatin and EO (150, 300, and 600 mg/kg; p.o. respectively in different groups) and EO only (600 mg/kg; p.o. only). EO was administered orally to the rats for a period of 10 days and on the 7th day, a single injection of cisplatin (8 mg/kg; i.p.) was administered to the cisplatin-control and EO treatment groups. The rats were sacrificed on the 10th day. Cisplatin-control rats had deranged renal function parameters and the kidney histology confirmed the presence of acute tubular necrosis. Furthermore, there were increased oxidative stress, apoptosis and inflammation along with higher expression of MAPK pathway proteins in the rat kidney from the cisplatin-control group. Contrary to this, EO (600 mg/kg) significantly normalized renal function, bolstered antioxidant status and ameliorated histological alterations. The inflammation and apoptosis were markedly lower in comparison to cisplatin-control rats. Furthermore, EO (600 mg/kg) inhibited MAPK phosphorylation which was instrumental in preserving renal function and morphology. In conclusion, the results of our study demonstrated that EO attenuated cisplatin-induced nephrotoxicity in rats through suppression of MAPK induced inflammation and apoptosis.

Thymoquinone Protects against Myocardial Ischemic Injury by Mitigating Oxidative Stress and Inflammation.

The present study was aimed at investigating the cardioprotective activity of thymoquinone (TMQ), an active principle of the herb, Nigella sativa, which is used for the management of various diseases. The present study examined the cardioprotective effect of TMQ in isoproterenol- (ISP-) induced myocardial infarction in rats. Myocardial infarction was induced by two subcutaneous injections of ISP (85 mg/kg) at an interval of 24 hr. TMQ (20 mg/kg) was administered orally for 21 days. ISP-treated rats showed depletion of antioxidants and marker enzymes from myocardium along with lipid peroxidation and enhanced levels of proinflammatory cytokines. ISP also induced histopathological alterations in myocardium. Treatment with TMQ prevented the depletion of endogenous antioxidants and myocyte injury marker enzymes and inhibited lipid peroxidation as well as reducing the levels of proinflammatory cytokines. TMQ pretreatment also reduced myonecrosis, edema, and infiltration of inflammatory cells and showed preservation of cardiomyocytes histoarchitecture. The present study results demonstrate that TMQ exerts cardioprotective effect by mitigating oxidative stress, augmenting endogenous antioxidants, and maintaining structural integrity. The results of the present study indicate that TMQ may serve as an excellent agent alone or as adjuvant to prevent the onset and progression of myocardial injury.

Glycyrrhiza glabra protects from myocardial ischemia-reperfusion injury by improving hemodynamic, biochemical, histopathological and ventricular function.

Present study evaluated the cardioprotective effect of Glycyrrhiza glabra against ischemia-reperfusion injury (I-R) induced by ligation of left anterior descending coronary artery (LADCA) in rats. Ligation of LADCA for 45 min followed by 60 min of reperfusion has induced significant (p<0.05) heart dysfunction evidenced by significant (p<0.05) decrease in mean arterial pressure (MAP), heart rate (HR), contractility; (+)LVdP/dtmax and relaxation; (-)LVdP/dtmax along with increased left ventricular end diastolic pressure (LVEDP). Ligation induced I-R injury also significantly (p<0.05) decreased myocyte injury enzymes, creatine phosphokinase-MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH) as well as antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Furthermore, I-R injury also induced lipid peroxidation evidenced by significant (p<0.05) increase in malondialdehyde (MDA) formation and histological perturbations concomitant to depletion of glutathione (GSH) from heart. However, pretreatment with G. glabra significantly (p<0.05) prevented the depletion of the antioxidant enzymes; SOD, CAT, GSH-Px and myocyte injury marker enzymes; CK-MB isoenzyme and LDH. Pretreatment with G. glabra also prevented GSH depletion and inhibited lipid peroxidation in heart. In addition to improving biochemical indices of myocardial function, G. glabra also significantly (p<0.05) reinstated MAP, HR, (±)LVdP/dtmax and attenuated abrupt rise in LVEDP. Histopathological preservation evidenced by reduced infiltration of cells and myonecrosis depicted the myocardial salvaging effect of G. glabra. Taken together, results of the present study clearly suggest the cardioprotective potential of G. glabra against myocardial infarction by amelioration of oxidative stress and favorable modulation of cardiac function.

Crocus sativus L. (saffron) attenuates isoproterenol-induced myocardial injury via preserving cardiac functions and strengthening antioxidant defense system.

Saffron (dried stigmas of Crocus sativus L.), a naturally derived plant product, has long been used as a traditional ancient medicine against various human diseases. The aim of the series of experiments was to systematically determine whether saffron exerts cardioprotection in isoproterenol-induced myocardial damage. Male Wistar rats (150-175 g) were divided into five groups: control, isoproterenol (ISO) and three saffron (200, 400 and 800 mg/kg) treatment groups. Aqueous extract of saffron or vehicle was administered orally to rats for four weeks. On days 28 and 29, the animals in ISO and saffron treatment groups were administered ISO (85 mg/kg, s.c.) at an interval of 24 h. On day 30, after recording hemodynamics and left ventricular functions, animals were sacrificed for biochemical, histopathological and electromicroscopical examinations. Isoproterenol challenged animals showed depressed hemodynamics and left ventricular functions as evident by decreased left ventricular rate of peak positive and negative pressure change and elevated left ventricular end-diastolic pressure. Structural and ultrastructural studies further confirmed the damage which was reconfirmed by increased thiobarbituric acid reactive substances (p<0.001) and decreased creatine kinase-MB and lactate dehydrogenase (p<0.001). In addition, significant reduction in superoxide dismutase and catalase (p<0.001) was observed in ISO group. Our results suggested that saffron at all the doses exerted significant cardioprotective effect by preserving hemodynamics and left ventricular functions, maintaining structural integrity and augmenting antioxidant status. Among the different doses used, saffron at 400mg/kg dose exhibited maximum protective effects which could be due to maintenance of the redox status of the cell reinforcing its role as an antioxidant.

Cardioprotection by Inula racemosa Hook in experimental model of myocardial ischemic reperfusion injury.

To evaluate the cardioprotective potential of Inula racemosa in myocardial ischemic-reperfusion injury, Wistar male albino rats were randomly divided into four groups. The group I and II animals were administered saline orally {(sham, ischemia- reperfusion (I-R) control group)} and animals of group III and group IV received I. racemosa extract (100 mg/kg) for 30 days. On the 30th day, animals of I-R control and I. racemosa treated groups were underwent 45 min of ligation of left anterior descending coronary artery and were thereafter re-perfused for 60 min. In the I-R control group, a significant decrease of mean arterial pressure (MAP), heart rate (HR), contractility, (+)LVdP/dt and relaxation, (-)LVdP/dt and an increase of left ventricular end diastolic pressure (LVEDP) were observed. Subsequent to haemodynamic impairment and left ventricular contractile dysfunction, a significant decline was observed in endogenous myocardial antioxidants; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH). Increased lipid peroxidation characterized by malonaldialdehyde (MDA) formation along with depletion of cardiomyocytes specific enzymes, creatine phosphokinase-MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH) in I-R control group compared to sham group revealed I-R injury of heart. However, treatment with I. racemosa significantly restored the myocardial antioxidant status evidenced by increased SOD, CAT, GPx and GSH and prevented leakage of cardio-specific enzymes; CK-MB and LDH and favorably modulated the altered MAP, HR, (+)LVdP/dt, (-)LVdP/dt and LVEDP as compared to I-R control. Furthermore, I-R induced lipid peroxidation was significantly inhibited by I. racemosa treatment. These beneficial cardioprotective effects translated into significant improvement in cardiac function. In conclusion, our study has demonstrated that the cardioprotective effect of I. racemosa likely resulted to improved antioxidant status, haemodynamic and left ventricular contractile function subsequent to suppression of oxidative stress.