Beneficial actions of esculentin-2CHa(GA30) on high sucrose-induced oxidative stress in Drosophila melanogaster.

Hyperglycaemia-induced oxidative stress plays a critical role in the development of diabetes and its complications. This study investigated actions of esculentin-2CHa(GA30) on high sucrose-induced oxidative stress in adult Drosophila melanogaster. Adult flies were exposed to diets containing graded concentrations of sucrose in the presence or absence of esculentin-2CHa(GA30) (5.0-10 µmol/kg diet) for 7 days. Effects of high sucrose diet and/or esculentin-2CHa(GA30) on survival and longevity of flies, and markers of oxidative stress, antioxidant status and glucose were assessed. High-sucrose diet (15-30%) and esculentin-2CHa(GA30) (5-10 µmol/kg diet) enhanced the percentage of surviving flies by 33.5%-46.2% (P < 0.01) and 7.4%-26.9% (P < 0.01) respectively. Concentration-dependent reduction in total thiol (19.3-51.3%, P < 0.01), reduced glutathione (22.6-54.9%, P < 0.05-0.01), catalase activity (36.8-57.3%, P < 0.05-0.01) and elevated glucose concentration (1.8-2.9-fold, P < 0.001) were observed in high sucrose-fed flies. Esculentin-2CHa(GA30) alone did not affect levels of total thiol, reduced glutathione, glucose and catalase activity. Improved survival (1.2-1.3-fold, P < 0.05-0.01) and longevity (1.3-fold) were observed in flies treated with the peptide (5.0 and 7.5 µmol/kg diet). Feeding on sucrose and esculentin-2CHa(1-30) (5.0 and 7.0 µmol/kg diet) for 7 days increased total thiol (2 - 3-fold, P < 0.001) and reduced glutathione (1.6-1.8-fold, P < 0.05) levels. Reduced catalase activity (21.4-36.4%, P < 0.01) and reduced glucose level (38.6-49.4%, P < 0.01) were observed in peptide-treated flies. Esculentin-2CHa(1-30) inhibited sucrose-induced generation of hydrogen peroxide (7.5-13.7%, P < 0.05) and nitric oxide (22.3-42.9%, P < 0.01) in adult flies. Overall, findings from this study offered further insights into the anti-oxidative properties of esculentin-2CHa(GA30).

Luteolin-Supplemented diets ameliorates Bisphenol A-Induced toxicity in Drosophila melanogaster.

Bisphenol A (BPA) is an industrial chemical used in the production of various plastic materials. It is associated with reproductive, immunological and neurological disorders. Luteolin, a flavonoid found in fruits and vegetables, possesses anti-oxidative, anti-inflammatory and free radical scavenging properties. Here, we carried out studies to ascertain if Luteolin would ameliorate BPA-induced toxicity in Drosophila melanogaster. Firstly, flies were treated separately with Luteolin (0, 50, 100, 150 and 300 mg/kg diet) and BPA (0, 0.01, 0.05 and 0.1 mM) for 28 days survival assessments. Consequently, Luteolin (150 and 300 mg/kg diet) and/or BPA (0.05 mM) were exposed to D. melanogaster for 7 days for the evaluation of nitric oxide level, eclosion rate, viability assay, histology of fat body, antioxidant (Glutathione-S-transferase, catalase and total thiol), oxidative stress (hydrogen peroxide) and behavioural (negative geotaxis and acetylcholinesterase) markers. The results showed that BPA induced antioxidant-oxidative stress imbalance and behavioural deficit in flies. Luteolin increased survival rate and augmented antioxidant markers in flies. Importantly, Luteolin ameliorated BPA-induced degeneration in the fat body around the rostral, thorax and abdominal regions, oxidative stress, behavioural deficit, reduction in cell viability and eclosion rate of D. melanogaster (p < 0.05). Overall, this study offered further insights on the antioxidative and chemopreventive properties of Luteolin against BPA-induced toxicity.

First-line antituberculosis drugs disrupt endocrine balance and induce ovarian and uterine oxidative stress in rats.

BACKGROUND: The first-line antituberculosis (anti-TB) drugs, isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA), are effective in the treatment of pulmonary tuberculosis. However, the toxicity of these drugs in the clinical setting limits their use. Here, we evaluated the effects of anti-TB drugs on the reproductive system in female rats. METHODS: Thirty-five female Wistar rats were assigned into five groups of seven animals each. The control group received normal saline, whereas others received INH (5 mg/kg), RIF (10 mg/kg), EMB (15 mg/kg), and PZA (15 mg/kg) through gavage thrice a week for 8 consecutive weeks. RESULTS: Administration of anti-TB drugs significantly (p<0.05) reduced uterine and ovarian weight, as well as the relative weight of the uterus when compared with controls. In addition, anti-TB drugs increased the activities of alanine aminotransferase as well as the level of total bilirubin. Treatment with INH, RIF, and PZA significantly (p<0.05) reduced the levels of follicle-stimulating and luteinizing hormones, estrogen, and prolactin. The INH, RIF, EMB, and PZA caused significant (p<0.05) increases in uterine malondialdehyde (MDA) levels by 281%, 214%, 273% and 190%, respectively, whereas INH and EMB increased the ovarian malondialdehyde by 111% and 129%, respectively. These drugs significantly (p<0.05) decreased the activities of ovarian glutathione-S-transferase and uterine glutathione peroxidase, superoxide dismutase, and catalase. Histology revealed the erosion of uterine mucosa, debris in the lumen of the uterus, congestion, and underdeveloped follicles in ovaries. CONCLUSIONS: The first-line anti-TB drugs elicited reproductive toxicity in the uterus and ovaries of rats through mechanisms that involved oxidative stress.

Chemoprotective effect of Vernonia amygdalina Del. (Astereacea) against 2-acetylaminofluorene-induced hepatotoxicity in rats.

Natural products possessing antioxidant properties play a very crucial role in ameliorating deleterious effects of reactive oxygen species. This study investigated the chemoprotective properties of methanolic extract of Vernonia amygdalina (MEVA) in an experimental model of hepatic oxidative damage induced by 2-acetylaminofluorene (2-AAF). Rats were divided into six groups. Groups 1 and 2 received saline and dimethyl sulfoxide, respectively, and served as controls. Group 3 received MEVA at a dose of 250 mg/kg, while groups 5 and 6 were pretreated for 14 days with MEVA at 250 mg/kg and 500 mg/kg doses before coadministration with 2-AAF at 100 mg/kg for another 7 days. 2-AAF was administered to group 4 for the last 7 days. Animals were killed 24 h after the last administration of 2-AAF. 2-AAF significantly (p < 0.05) induced marked hepatic damage as revealed by increased activities of serum enzymes such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transferase and bilirubin concentration. 2-AAF also elicited decrease in the activities of antioxidant enzymes such as superoxide dismutase, catalase, glutathione-S-transferase, and glutathione peroxidase, depletion of reduced glutathione, and increase in malondialdehyde levels. The activities of glucose-6-phosphatase and 5'-nucleotidase were also depleted. MEVA at 250 mg/kg and 500 mg/kg significantly (p < 0.05) ameliorated the oxidative damage, functional impairments, and histopathological changes associated with 2-AAF toxicity by reducing the activities of serum enzymes, upregulating the antioxidant defense enzymes and glutathione with decrease in malondialdehyde level. In this study, the revealed ameliorative and hepatoprotective effects of MEVA against 2-AAF-induced toxicity may be due to its antioxidant and free-radical scavenging activities, thus suggesting its usefulness as a possible chemoprophylactic agent.

Modulation of paracetamol-induced hepatotoxicity by phosphodiesterase isozyme inhibition in rats: a preliminary study.

BACKGROUND: Altered regulation of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) is present in liver cirrhosis. Several experimental studies have shown that selective modulation of NO metabolism in the liver reduces intrahepatic resistance and portal pressure in cirrhosis. This preliminary study investigated whether selective inhibition of phosphodiesterase-5 (PDE-5), which prevents the conversion of cGMP to 5'-GMP, as well as non-selective inhibition of PDE isozymes could ameliorate hepatic toxicity induced by paracetamol (PCM). METHODS: PCM (250 mg/kg, i.p.) was administered to induce hepatotoxicity. Control rats received physiological saline (10 mL/kg, p.o.), while sildenafil (a selective PDE-5 inhibitor) and aminophylline (a non-selective PDE inhibitor) were administered separately at 10 mg/kg p.o. to PCM-treated rats. RESULTS: PCM hepatotoxicity, characterized by elevation of aspartate and alanine aminotransferases, hepatic degeneration, and centrilobular necrosis, was attenuated by both PDE inhibitors. Sildenafil and aminophylline significantly (p<0.05) reduced plasma aspartate aminotransferase activity by 49.6% and 39.8%, respectively, with moderate increase in alanine aminotransferase activity by 26.1% and 20.4%, respectively, in PCM-treated rats. Decreases in total protein and albumin induced by PCM were significantly (p<0.05) prevented by 30.0% and 22.2%, respectively, following sildenafil administration, while aminophylline decreased these proteins by 14.0% and 25.9%, respectively. Sildenafil and aminophylline significantly (p<0.05) reduced lipid peroxidation by 30.7% and 19.7%, respectively, while moderately increasing glutathione (GSH) in the PCM-treated rats. Both drugs did not significantly alter the total cholesterol and triglyceride levels. CONCLUSIONS: These preliminary data suggest that pharmacological inhibition of PDE isozymes may be a useful strategy in protecting against PCM hepatic toxicity.

Celecoxib, a selective cyclooxygenase-2 inhibitor, lowers plasma cholesterol and attenuates hepatic lipid peroxidation during carbon-tetrachloride-associated hepatotoxicity in rats.

Cyclooxygenase-2 (COX-2) expression and prostaglandin production are suggested to play important, complex roles in the pathogenesis of various liver diseases. Studies on the effects of COX-2 inhibitors on the progression of liver fibrosis present controversial results, and the proposed therapeutic potential of these agents in chronic liver disease is predicated largely on their effectiveness in modulating hepatic stellate cell activation in vitro. This study investigated the modulatory effect of celecoxib, a selective COX-2 inhibitor, in CCl(4)-mediated hepatotoxicity in rats. Thirty Wistar albino rats, weighing 120-180 g, were assigned into five groups of 6 rats/group. Groups 1 and 2 received saline (10 mL/kg) and CCl(4) (80 mg/kg), respectively. Group 3 was given celecoxib (5.7 mg/kg), whereas groups 4 and 5 were pretreated with 2.9 and 5.7 mg/kg/day of celecoxib, respectively, 1 hour before CCl(4) treatment. Plasma aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities increased significantly by 118.5, 150.0, and 51.3%, respectively, with an accompanying decrease (P < 0.05) in total protein and albumin after CCl(4) treatment. Hepatotoxicity was associated with a significant increase in plasma cholesterol, hepatic lipid peroxidation (LPO), and severe hepatic necrosis with marked fatty and cellular (i.e., mononuclear cells) infiltration. Although celecoxib neither reduced CCl(4)-induced increases in marker enzymes of hepatotoxicity nor significantly attenuated hepatic necrosis, it, however, was effective in reducing elevated cholesterol by 16.5 and 20.8% and LPO by 12.9 and 35.5% at 2.9 and 5.7 mg/kg, respectively. Data suggest that COX-2 inhibitors may be effective in controlling hypercholesterolemia and peroxidative changes associated with liver injury.

Modulatory effect of methanolic extract of Vernonia amygdalina (MEVA) on tert-butyl hydroperoxide-induced erythrocyte haemolysis.

Reactive oxygen species (ROS) have been implicated in the aetiology of several pathological and degenerative diseases. The protective effect of natural products possessing antioxidant properties has played a crucial role in ameliorating these deleterious effects. This study investigated the chemoprotective properties of the methanolic extract of Vernonia amygdalina (MEVA) in an experimental model of tert-butyl hydroperoxide (t-BHP)-induced human erythrocyte lysis in vitro. Haemolysis was induced by incubating erythrocytes with t-BHP (2 and 3 mM) in vitro. Samples of erythrocyte suspensions were removed at different intervals over a 6-h period, and the degree of haemolysis was measured. The anti-haemolytic effect of MEVA at 25-150 µg ml(-1) concentrations on the samples were assessed and compared with Triton X-100. Administration of t-BHP at 2- and 3-mM concentrations significantly (p < 0.05) induced erythrocyte lysis by 37.5% and 31.4%, respectively. The addition of MEVA, however, reduced t-BHP-induced erythrocyte lysis significantly (p < 0.05) by 39.3%, 48.4%, 67.3% and 73.4% at 25, 50, 100 and 150 µg ml(-1) concentrations, respectively. MEVA likewise protected against t-BHP-induced lipid peroxidation significantly (p < 0.05) at 100 and 150 µg ml(-1) by the fourth hour and non-significantly (p > 0.05) at all concentrations by the sixth hour. The reduced glutathione level was, however, increased with the administration of t-BHP, while a delayed addition of MEVA had no protective effect on the t-BHP-induced cell lysis. These findings therefore suggest that MEVA may have protective antioxidant properties, making it suitable for incorporation into food and drug products.

Pharmacologic inhibition of the renin-angiotensin system did not attenuate hepatic toxicity induced by carbon tetrachloride in rats.

The renin-angiotensin system (RAS) subserves vital physiological functions and also implicated in certain pathological states. Modulation of this system has been proposed in recent studies to be a promising strategy in treating liver fibrosis. We investigated the effect of the pharmacologic inhibition of RAS with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in CCl(4)-induced liver injury with a view to ascertaining the chemopreventive benefit. Fifty-six Wistar albino rats were divided into eight experimental groups of seven rats/group. Groups 1-4 received normal saline (10 ml/kg), enalapril (0.6 mg/kg), losartan (1.4 mg/kg) and CCl(4) (80 mg/kg), respectively. Groups 5-8 were pretreated with enalapril (0.3 mg/kg), enalapril (0.6 mg/kg), losartan (0.7 mg/kg) and losartan (1.4 mg/kg) 1 hour before CCl(4) administration. Experiment lasted 11 days and dosing was via oral route. Rats were killed 24 hours after the last treatment. Serum activities of alkaline phosphatase, aspartate and alanine aminotransferases increased significantly (p < 0.05) by 46.0%, 90.6% and 122.3%, respectively, with severe hepatic centrilobular necrosis, fatty infiltration and increase in liver weight (p < 0.05) in the CCl(4)-treated rats. Enalapril (0.6 mg/kg) and losartan (1.4 mg/kg) significantly (p < 0.05) increased aspartate aminotransferase activity by 37.0% and 94.7% and produced mild centrilobular and periportal hepatic necrosis, respectively, with enalapril significantly (p < 0.05) increasing liver weight. Serum total cholesterol, triglyceride, albumin and total protein did not change significantly in these rats. Also, glutathione, malondialdehyde and uric acid levels were not significantly altered. Enalapril and losartan failed to attenuate liver injury associated with CCl(4) treatment. Although both drugs did not significantly alter serum biochemistry in the CCl(4)-treated rats, they however produced slight elevations in biomarkers of liver function and appear to worsen liver histopathology. Overall, the chemopreventive benefits of RAS inhibitors in liver disease remain doubtful and should be used with caution during hepatic dysfunction.

Hepatoprotective effects of Vernonia amygdalina (astereaceae) in rats treated with carbon tetrachloride.

The possible modulatory effect of methanolic extract of Vernonia amygdalina (MEVA), a plant widely consumed in the tropics and used locally in the treatment of fever, jaundice, stomach disorders and diabetes on the toxicity of CCl(4), was investigated in male rats. Oral administration of CCl(4) at a dose of 1.2g/kg body weight 3 times a week for 3 weeks significantly induced marked hepatic injury as revealed by increased activity of the serum enzymes ALT, AST, SALP and gamma-GT. Methanolic extract of V. amygdalina administered 5 times a week for 2 weeks before CCl(4) treatment at 250 and 500 mg/kg doses of the extract ameliorated the increase in the activities of these enzymes. Likewise the methanolic extract of V. amygdalina reduced the CCl(4)-induced increase in the concentrations of cholesterol, triglyceride and phospholipid by 37.8%, 30.6% and 8.5%, respectively, and a reduction in the cholesterol/phospholipids ratio. These parameters were however increased at 750 mg/kg extract pretreatment. CCl(4)-induced lipid peroxidation was likewise attenuated by 57.2% at 500 mg/kg dose of the methanolic extract of V. amygdalina. Similarly, administration of the extract increased the activities of the antioxidant enzymes: superoxide dismutase, glutathione S-transferase and reduced glutathione concentration significantly at 500 mg/kg (P<0.05) and catalase activity at 500-1000 mg/kg doses. These results suggest that methanolic extract of V. amygdalina leaves posseses protective effect against CCl(4)-induced hepatotoxicity by the antioxidant mechanism of action.