Attenuation of oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits by allicin.

Allicin, the active substance of garlic, exerts a broad spectrum of pharmacological activities and is considered to have potential therapeutic applications. The present study was designed to investigate the possible beneficial effects of allicin against oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits. Male New Zealand white rabbits were used in this study. Rabbits randomly received 1 of the following treatments: normal chow diet for 4 weeks, 1% high cholesterol diet (HCD), HCD plus allicin (10 mg/kg/day), or HCD plus atorvastatin (10 mg/kg/day). Blood samples were collected at the end of experimental diets for measurement of serum total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD). In addition, the aorta was removed for measurement of vascular reactivity, histopathological changes, intima/media (I/M) ratio, and immunohistochemical staining of both tumor necrosis-alpha (TNF-α) and nuclear factor (NF)-κB. HCD induced significant increases in serum TC, TGs, low-density lipoprotein cholesterol (LDL-C), CRP, and MDA. Moreover, HCD caused significant decrease in serum GSH and SOD. In addition, aortic relaxation response to acetylcholine (ACh) was impaired. Immunohistochemical staining of aortic specimens from HCD-fed rabbits revealed high expression levels of both TNF-α and the oxidant-induced transcription factor, NF-κB. Allicin supplementation significantly decreased serum MDA and CRP, increased serum HDL-C, GSH, and SOD levels while nonsignificantly affecting HCD-induced elevations in serum TC and LDL-C. Additionally, allicin significantly protected against HCD-induced attenuation of rabbit aortic endothelium-dependent relaxation to ACh and elevation in I/M ratio. This effect was confirmed by histopathological examination of the aorta. Moreover, allicin has substantially beneficial effects on aortic expression of TNF-α and NF-κB compared with HCD-fed rabbits. In conclusion, these findings demonstrate that allicin may be useful in reducing oxidative stress, inflammation, vascular dysfunction, and the aortic pathology in hypercholesterolemic rabbits.

Cardioprotective effect of grape-seed proanthocyanidins on doxorubicin-induced cardiac toxicity in rats.

CONTEXT: Doxorubicin (Dox) is an anthracycline antibiotic used as anticancer agent. However, its use is limited due to its cardiotoxicity which is mainly attributed to accumulation of reactive oxygen species. OBJECTIVE: This study was conducted to assess whether the antioxidant, proanthocyanidins (Pro) can ameliorate Dox-induced cardiotoxicity in rats. MATERIALS AND METHODS: Male Sprague-Dawely rats were divided into four groups. Group I was control. Group II received Pro (70 mg/kg, orally) once daily for 10 days. Group III received doxorubicin 15 mg/kg i.p. as a single dose on the 7th day and Group IV animals were treated with Pro once daily for 10 days and Dox on the 7th day. The parameters of study were serum biomarkers, cardiac tissue antioxidant status, ECG, and effect on aconitine-induced cardiotoxicity. RESULTS: Cardiac toxicity of doxorubicin was manifested as a significant increase in heart rate, elevation of the ST segment, prolongation of the QT interval and an increase in T wave amplitude. In addition, Dox enhanced aconitine-induced cardiotoxicity by a significant decrease in the aconitine dose producing ventricular tachycardia (VT). Administration of Pro significantly suppressed Dox-induced ECG changes and normalized the aconitine dose producing VT. The toxicity of Dox was also confirmed biochemically by significant elevation of serum CK-MB and LDH activities as well as myocardial MDA and GSH contents and decrease in serum catalase and myocardial SOD activities. Administration of Pro significantly suppressed these biochemical changes. DISCUSSION AND CONCLUSION: These results suggest that proanthocyanidins might be a potential cardioprotective agent against Dox-induced cardiotoxicity due to its antioxidant properties.

Amelioration of doxorubicin-induced cardiotoxicity by deferiprone in rats.

The therapeutic usefulness of doxorubicin (Dox), an anthracycline antibiotic used as an anticancer agent, is limited by its cardiotoxicity. Dox-induced cardiotoxicity is mainly attributed to accumulation of reactive oxygen species and interaction of Dox with cellular iron metabolism. The present study investigated the effects of the iron chelator deferiprone (Def) against Dox-induced cardiotoxicity in rats. Dox (15 mg/kg) was injected intraperitoneally as a single dose, and Def (10 mg/kg) was administered orally for 10 days. Dox showed cardiotoxicity as evidenced by increased heart rate, elevated ST segment, prolonged QTc interval, and increased T wave amplitude. In addition, Dox enhanced aconitine cardiotoxicity by decreasing its dose, producing ventricular tachycardia. Administration of Def significantly attenuated Dox-induced electrocardiographic changes. Cardiotoxicity of Dox was confirmed biochemically by a significant elevation in serum creatine kinase-MB and lactate dehydrogenase activities as well as by myocardial malondialdehyde and reduced glutathione contents. Moreover, Dox caused a significant decrease in myocardial superoxide dismutase activity. Administration of Def significantly attenuated the biochemical changes. These results suggest that Def might be a potential cardioprotective agent against Dox-induced cardiotoxicity.

Antioxidant and anti-inflammatory effects of flavocoxid in high-cholesterol-fed rabbits.

Flavocoxid is a mixed extract containing baicalin and catechin, and it acts as a dual balanced inhibitor of cyclooxygenase-1 (COX-1) and COX-2 peroxidase enzyme activities with a significant inhibition of 5-lipoxygenase (5-LOX) enzyme activity in vitro. Flavocoxid downregulates gene or protein expression of several inflammatory markers and exerts also strong antioxidant activity in several experimental models. Inflammation and oxidative stress contribute in the pathogenesis of atherosclerosis. In the present study, an experimental rabbit model of hypercholesterolemia was developed and the effects of flavocoxid were evaluated. Rabbits were divided into four groups-normal control, high-cholesterol-diet (HCD)-fed group, HCD plus flavocoxid (20 mg/kg/day), or HCD plus atorvastatin (10 mg/kg/day). Blood samples were collected at the end of the experiment for measuring serum total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD). In addition, the aorta was removed for measurement of antioxidant status, vascular reactivity, and intima/media (I/M) ratio. Elevated levels of serum TC, TGs, LDL-C, and CRP were measured in HCD group. Moreover, HCD caused a significant increase in serum and aortic MDA concomitantly with a reduction in serum and aortic GSH and SOD. Immunohistochemical staining of aortic specimens from HCD-fed rabbits revealed high expression levels of both tumor necrosis factor-alpha (TNF-α) and nuclear factor (NF)-κB. Rabbits in flavocoxid group showed significantly lower levels of serum CRP, serum, and aortic MDA and higher levels of serum HDL-C, serum, and aortic GSH and SOD compared to HCD group. HCD-induced elevations in serum TC and LDL-C did not significantly affected by flavocoxid treatment. Additionally, flavocoxid significantly enhanced rabbit aortic endothelium-dependent relaxation to acetylcholine and decreased the elevated I/M ratio. This effect was confirmed by histopathological examination of the aorta. Moreover, flavocoxid effectively suppresses the release of inflammatory markers. In conclusion, these findings demonstrated that flavocoxid would be useful in preventing oxidative stress, inflammation, and vascular dysfunction induced by HCD.

Protective effects of methyl palmitate against silica-induced pulmonary fibrosis in rats.

Silicosis is one of the most prevalent chronic occupational pulmonary diseases worldwide. The present study aimed to investigate the effects of methyl palmitate on silica-induced lung fibrosis in rats and explore the possible mechanisms. Male Sprague-Dawley rats were divided into 3 groups: group I served as control and group II served as positive control where rats were intranasally instilled with a single dose of silica suspension (50mg in 0.1ml saline/rat). Rats of group III received methyl palmitate (300mg/kg, I.P. three times per week at alternating days) for 60days after instillation of silica. At the end of the treatment period, animals were sacrificed then biochemical parameters and histopathology were assessed. Treatment with methyl palmitate attenuated silica-induced lung inflammation and fibrosis, as it significantly decreased lactate dehydrogenase (LDH) activity and the accumulation of the inflammatory cells in the bronchoalveolar lavage fluid (BALF). Methyl palmitate significantly reduced collagen deposition as indicated by a decrease in lung hydroxyproline content and marked attenuation in silica-induced lung fibrosis in histopathological results. In addition, methyl palmitate significantly increased superoxide dismutase (SOD) and reduced glutathione (GSH) activities with a significant decrease in the lung malondialdehyde (MDA) content. Methyl palmitate also reduced silica mediated overproduction of pulmonary nitrite/nitrate (NO2(-)/NO3(-)). Importantly, methyl palmitate decreased the level of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in the lung. Taken together, these results demonstrate the potent protective effects of methyl palmitate against silica-induced lung fibrosis. This effect can be attributed to methyl palmitate's ability to counteract the inflammatory cells' infiltration and hence reactive oxygen species (ROS) generation and regulate cytokine effects.

Sensitization of TRAIL-induced apoptosis in human hepatocellular carcinoma HepG2 cells by phytochemicals.

AIMS: The present study investigated and compared the potential chemosensitizing effect of indole-3-carbinol (I3C) and epigallocatechin-3-gallate (EGCG) on TRAIL-induced apoptosis in human hepatocellular carcinoma (HCC) HepG2 cells as well as the possible mechanisms underlying these modulatory effects, particularly their effects on TRAIL death receptors (DR), Bcl-2 and c-FLIP proteins expression. MAIN METHODS: HepG2 cells were treated with different concentrations of TRAIL ranging from 3 to 400ng/ml for 24h. For studying the modulatory effects of the phytochemicals on TRAIL-induced apoptosis, I3C and EGCG were used at concentrations that inhibit only 5% of the cells which were found to be 110µM and 70µg/ml, respectively. KEY FINDINGS: It was found that 24h pre-treatment of HepG2 cells with either 110µM I3C or 70µg/ml EGCG significantly enhanced TRAIL cytotoxicity. EGCG induced more reduction in IC50 of TRAIL compared to I3C. Nevertheless, I3C was more efficient than EGCG in enhancing TRAIL cytotoxicity at higher concentrations of TRAIL. Both I3C and EGCG significantly increased caspase-3 activity, DNA fragmentation percentage, DR4 and DR5 protein expression as well as decreased Bcl-2 protein expression when compared to control groups. SIGNIFICANCE: Both I3C and EGCG chemosensitized HCC HepG2 cells to TRAIL-induced apoptosis. These modulatory effects were partially attributed to the up-regulation of caspase-3 activity and DR4 and DR5 expression, as well as down-regulation of Bcl-2 expression. Only EGCG was able to induce a significant decrease in c-FLIP expression level.

Comparative evaluation of anti-inflammatory properties of thymoquinone and curcumin using an asthmatic murine model.

This study was designed to compare the inhibitory effects of thymoquinone (TQ) and curcumin (CMN) on the biological changes associating asthma. TQ appeared to exhibit greater inhibitory effects on the aggregation of inflammatory cells in bronchoalveolar lavage (BAL) fluid and in lung tissues. We also measured the effects of the two agents on serum IgE and the changes in the mRNA levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and transforming growth factor-ß1 (TGF-ß1). Serum IgE was significantly decreased by TQ and CMN with TQ being more potent. Also, TQ showed superior inhibitory effects on iNOS and TGF-ß1. Meanwhile, CMN was more potent in inhibiting mRNA expression of TNF-α. These results suggest that TQ is more potent in inhibiting the inflammatory changes associating asthma. On the other hand, CMN was a less potent inhibitor of all measured parameters, despite its superior inhibitory effect on TNF-α mRNA levels.

Effect of bosentan (ETA/ETB receptor antagonist) on metabolic changes during stress and diabetes.

Elevated plasma ET-1 levels have been reported in several conditions such as stress and diabetes. ET-1 is found to cause insulin resistance and to stimulate liver glycogenolysis. The question arises whether ET-1 has a role in the metabolic changes occurring in such conditions. To test this, we studied the possible effect of the endothelin receptor antagonist, bosentan (50 and 100 mg kg(-1)) on serum glucose and insulin levels as well as on liver glycogen contents in normoglycemic stressed animals. In addition, the effect of bosentan on serum glucose and insulin levels in both mild and severely diabetic rats and its effect on insulin-induced hypoglycemia were also determined. Restraining water immersion stress was used as a model for severe stress reported to elevate plasma ET-1 level. Mild diabetes was induced in rats by intraperitoneal injection of a low dose of streptozotocin (38 mg kg(-1)) while severe diabetes was induced by intraperitoneal injection of a higher dose of streptozotocin (45 mg kg(-1)). Bosentan partially prevented stress-induced both hyperglycemia and decrease in glycogen content while it completely blocked the stress-induced decrease in insulin level in normoglycemic stressed rats. Bosentan also decreased serum glucose level without any effect on insulin secretion in mild diabetic rats and potentiated the hypoglycemic action of insulin.