Irbesartan suppresses cardiac toxicity induced by doxorubicin via regulating the p38-MAPK/NF-κB and TGF-ß1 pathways.

Doxorubicin (DOX) so far continues to be one of the most potent and effective anticancer drugs. Therefore, it is still needed to search for a safe and effective therapy that can opposite DOX-induced cardiotoxicity. Irbesartan (IRB), an angiotensin II receptor blocker, has a wide-ranging variety of biological activities. The present study was designed to explore the possible protective effects of IRB against DOX-induced cardiotoxicity and the underlying mechanisms. Rats were divided into four groups: control, IRB (40 mg/kg, orally/daily) for 3 weeks, DOX (2.5 mg/kg, intraperitoneally/ three times weekly) for 2 weeks to obtain cumulative dose of 15 mg/kg, and finally IRB + DOX group. IRB inhibited cardiotoxicity induced by DOX which was evident by ECG changes, alterations of cardiac enzymes and histopathological changes. IRB improved DOX-induced alterations in oxidative/nitrosative status by decreasing lipid peroxidation and nitric oxide (NO) content in addition to increasing the antioxidant capacity. In addition, DOX triggers the cardiac expression of tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB) where IRB diminished DOX-induced alterations in theses parameters. Moreover, DOX significantly increase the expression levels of caspase-3 and transforming growth factor-beta 1 (TGF-ß1), while IRB exhibited anti-apoptotic and anti-fibrotic effects where it abolished these elevations. Meanwhile, DOX-induced activation of p38-mitogen activated protein kinase (p38-MAPK) which was inhibited by IRB. Collectively, these results proposed that IRB afforded a significant protection against DOX-induced cardiac damage by means of antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic remodeling mechanisms. These mechanisms are possibly mediated, at least in part, by alterations of TGF-ß1/p38-MAPK/NF-κB signaling.

Effects of Nigella sativa oil and thymoquinone on oxidative stress and neuropathy in streptozotocin-induced diabetic rats.

We examined whether Nigella sativa (NS) oil and its active constituent thymoquinone (TQ) attenuate oxidative stress in the heart and brain in an experimental model of diabetes mellitus using streptozotocin (STZ). Oxidative stress was assessed by measuring cardiac and brain nitric oxide (NO), lipid peroxide levels, glutathione (GSH) and antioxidant enzyme activities, i.e. glutathione-S-transferase (GST) and catalase. Cardiac metabolic damage was estimated by measuring cardiac creatine kinase muscle and brain types (CK-MB). Brain monoamine levels were also evaluated. STZ diabetes induced a significant increase in heart and brain NO and malondialdehyde concentrations compared with the control group. These changes were attenuated by posttreatment of rats with NS oil and TQ. STZ diabetes induced oxidative stress via a significant decrease in GST, GSH and catalase. These lowered levels were improved by either NS oil or TQ administration. Serum CK-MB was decreased in the diabetic rats, which recovered with NS oil and TQ administration. During the course of diabetes, there was a marked increase in norepinephrine and dopamine concentrations and a marked decrease in serotonin concentration compared to the control group. These findings were partly reversed by oral administration of either NS oil or TQ. It is concluded that NS and TQ correct STZ-diabetes-induced alterations in CK-MB and brain monoamines due to their antioxidant properties.

Synthesis and biological evaluation of novel imidazolone derivatives as potential COX-2 inhibitors.

Three novel series of 2-(substituted phenyl)-4-(substituted arylidene)-imidazolone-5-(4H)-ones were derived from the corresponding oxazolones by condensation with different arylamines. Eleven of the synthesized compounds were selected and evaluated for their effect on carrageenan-induced rat paw edema. Compound 4b had the same efficacy as the reference standard (indomethacin), and compounds 3b, 3c, 4a, 4d and 9a showed good to excellent activities, with other compounds only weakly active. The potent compounds were evaluated for their inhibitory activities against COX-2-catalyzed PGE(2) production, with 4a, 4b and 3c showing strong inhibitory activity.

Thymoquinone is a potent superoxide anion scavenger.

The antioxidant and pro-oxidant effects of thymoquinone (TQ), a natural main constituent of the volatile oil of Nigella saliva seeds, and a synthetic structurally-related tert-butylhydroquinone (TBHQ), were examined in vitro. Both TQ and TBHQ efficiently inhibited iron-dependent microsomal lipid peroxidation in a concentration-dependent manner with median inhibitory concentration (IC50) values of 16.8 and 14.9 microM, respectively. TBHQ was stronger than TQ as a scavenger of 2,2'-diphenyl-p-picrylhydrazyl radical (DPPH) (IC50 = 5 microM, 200 times more active than TQ) and as a scavenger of hydroxyl radical (OH*) with an IC50 of 4.6 microM (approximately 10 times more active than TQ). TQ was more active than TBHQ as a superoxide anion scavenger with IC50 of 3.35 microM compared to 18.1 microM for TBHQ. Only TBHQ significantly promoted DNA damage in the bleomycin-Fe(III) system. The results suggest that both TQ and TBHQ have strong antioxidant potentials through scavenging ability of different free radicals. Moreover, the data indicate that TQ is acting mainly as a potent superoxide anion scavenger.

Effects of benzo[a]pyrene on tissue activities of metabolizing enzymes and antioxidant system in normal and protein-malnourished rats.

The effects of benzo[a]pyrene (B[a]P) on some drug-metabolizing and antioxidant systems in liver, lung, and stomach were investigated in normal and protein malnutrition (PM) rats. PM significantly inhibited tissue glutathione (GSH) content and increased hepatic lipid peroxidation. Cytochrome P450 isoform CYP1A1 was significantly increased in various tissues (42-73%). Also, lung glutathione S-transferase (GST) activity was significantly decreased (19%) in PM rats. On the other hand, B[a]P significantly induced tissue GSH of control and PM rats. Also, hepatic lipid peroxidation were significantly increased in control rats treated with B[a]P. Superoxide dismutase (SOD) activity was decreased by B[a]P treatment in PM rat stomach. B[a]P significantly induced both quinone reductase (QR) (in all tissues) and hepatic GST of control and PM rats. GST activity in PM rat liver was significantly higher than that of control rat liver after B[a]P treatment. Also, B[a]P induced hepatic CYP1A1 by 32-fold and 27-fold (P < or = 0.05) in control and PM rats, respectively. Stomach and hepatic UDP-glucuronosyltransferase activities were significantly decreased (34%) and increased (74%), respectively by B[a]P in PM rats. The results suggest that PM status has a modifying effect on the response of some antioxidant and metabolizing systems to a well-known carcinogen risk.

Goitrogenic activity of p-coumaric acid in rats.

The effects of three natural phenolic acids (caffeic, ferulic, and p-coumaric) on the rat thyroid gland were examined in a 3-week oral-treatment study. Forty male Wistar albino rats, divided into groups of 10 rats each and fed iodine-rich diet, were administered by gastrointestinal tube saline (control), caffeic acid, ferulic acid, or p-coumaric acid at a dose level of 0.25 micromol/kg/day for 3 weeks. The mean absolute and relative thyroid weights in caffeic, ferulic, or p-coumaric acid groups were significantly increased to 127 and 132%, 146 and 153%, or 189 and 201% compared to control value, respectively. Histological examination of the thyroids of p-coumaric acid group revealed marked hypertrophy and/or hyperplasia of the follicles. Caffeic or ferulic groups showed slight to moderate thyroid gland enlargement. Thyroid lesions in p-coumaric acid group were associated with significant increases in cellular proliferation as indicated by [(3)H]thymidine incorporation. In addition, the goitrogenic effect of p-coumaric acid was further confirmed by significant decreases (50%) in serum tri-iodothyronine (T(3)) and thyroxine (T(4)), and a parallel increase (90%) in serum thyroid stimulating hormone (TSH) compared to control group. These results indicate that administration of p-coumaric acid at relatively high doses induces goiter in rats.