Ghada M. Suddek

Protective effects of propolis and thymoquinone on development of atherosclerosis in cholesterol-fed rabbits

Hypercholesterolemia, cholesterol-enriched diet and oxidative stress have been shown to increase serum total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) levels resulting in development of atherosclerosis. Antioxidants play an important role in inhibiting and scavenging free radicals, thus providing protection to humans against infectious and degenerative diseases. The present study was undertaken to examine the possible protective effects of propolis (a resinous hive product collected by honeybees from various plant sources) and thymoquinone (TQ, active constituent of Nigella. Sativa seeds oil) on serum lipid levels and early atherosclerotic lesions in hypercholestrolemic rabbits. New Zealand rabbits were fed on either standard chow or atherogenic diet during four weeks and concomitantly received either propolis or TQ. At the end of experiment period, serum samples were collected to determine lipid profile, kidney functions and antioxidant status. Tissues from aorta, pulmonary artery and kidney were taken for histopathological examination. The cholesterol-enriched diet induced a significant increase in serum TC, triglycerides, LDL-C, thiobarbituric acid-reactive substances concentrations and a significant decrease in high density lipoprotein-cholesterol and in reduced glutathione levels compared to control group. Administration of propolis or TQ with cholesterol-enriched diet significantly (p < 0.05) reduced TC, LDL-C, triglycerides and thiobarbituric acid-reactive substances concentrations, while increased high density lipoprotein-cholesterol concentration, as well as glutathione content compared to high cholesterol (HC) control group. Kidney function parameters were significantly affected by cholesterol diet and both propolis and TQ counterregulated the cholesterol-induced changes. Histopathologically, early athersclerotic changes were observed in HC control group represented by endothelial damage and thickened foam cells while propolis or TQ provided protection against the HC-induced damage. In conclusion, the present study suggests the potential beneficial effects of both propolis and TQ in diminishing the risk of atherosclerosis via antioxidant mechanism.

Synthesis of N-benzenesulfonamide-1H-pyrazoles bearing arylsulfonyl moiety: novel celecoxib analogs as potent anti-inflammatory agents.

The reaction of arylsulfones 11a-d with hydrazonoyl chloride derivative 13 furnished celecoxib analogs 4-(3-acetyl-5-aryl-4-(arylsulfonyl)-1H-pyrazol-1-yl)benzenesulfonamides 15a-d, respectively. Oximes 16a, b and hydrazones 17a, b were prepared by reacting sulfones 11a, b with hydroxyl amine and phenyl hydrazine, respectively. The anti-inflammatory activity of the synthesized compounds showed that, 5-(4-bromophenyl)-4-(phenylsulfonyl)pyrazole 15c and 5-(4-bromophenyl)-4-(4-tolylsulfonyl)pyrazole 15d exhibited excellent anti-inflammatory activity with ED50 = 68 ± 2.2 and 51 ± 0.7 μM/kg, respectively, higher than that of celecoxib (ED50 = 86 ± 1.1 μM/kg) after 3 h with acceptable ulcer index. In addition, the LD50 of 15c and 15d is 7.1 mM/kg for each, and 9.8 mM/kg for celecoxib. Compound 15d appeared selectivity index (COX-2/COX-1) almost the half of celecoxib while 15c is non-selective for COX-2. Compound 15c with ED50 = 80 ± 2.8 μM/kg showed a significant analgesic activity when compared with celecoxib (ED50 = 70 ± 3.9 μM/kg) after 2 h whereas 15b (ED50 = 50 ± 1.2 μM/kg) and 15d (ED50 = 69 ± 2.7 μM/kg) seemed to be more potent than celecoxib (ED50 = 156 ± 4.8 μM/kg) but with a shorter duration (0.5 h).

Celecoxib, a Selective Cyclooxygenase-2 Inhibitor, Attenuates Renal Injury in a Rat Model of Cisplatin-Induced Nephrotoxicity

Background: Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of tumors. Nevertheless, nephrotoxicity has restricted its clinical use. Recent studies have strongly suggested that inflammatory mechanisms may play an important role in the pathogenesis of cisplatin nephrotoxicity. Celecoxib, a selective cyclooxygenase-2 inhibitor used as anti-inflammatory, may therefore have a protective effect on cisplatin-induced renal injury. Methods: In the present study, rats were injected intraperitoneally with a single dose of cisplatin (7 mg/kg) and/or celecoxib (30 mg/kg) for 5 days. Results: Nephrotoxicity manifested biochemically by elevations in serum creatinine, blood urea nitrogen, and proteinuria, and an increase in kidney weight as a percentage of total body weight. In addition, a marked decrease in serum albumin was observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde level and glutathione content, which were increased and depleted, respectively. Administration of celecoxib with cisplatin attenuated cisplatin-induced changes in kidney function parameters and oxidative stress markers. Histopathological examination of the kidney confirmed these results. Conclusion: In conclusion, this study indicates that celecoxib may be a promising drug for clinical use as a nephroprotectant against cisplatin-induced nephrotoxicity.

Levocetirizine ameliorates high fructose diet-induced insulin resistance, vascular dysfunction and hepatic steatosis in rats

This study investigates the possible protective effects of levocetirizine against fructose-induced insulin resistance, hepatic steatosis and vascular dysfunction, in comparison to pioglitazone, a standard insulin sensitizer. Male Sprague Dawley rats (150-200 g) were divided into 4 groups. Three groups were fed on high fructose diets (HFD) containing 60% w/w fructose, while the fourth control group was fed on standard laboratory food for 8 weeks. AUCOGTT, AUCITT, fasting glucose, HOMA-IR, hepatic glutathione (GSH) and malondialdehyde (MDA) levels, serum total cholesterol, LDL-C, C-reactive protein (CRP) level and lactate dehydrogenase (LDH) activity and liver steatosis scores were significantly higher in HFD group compared to control group. Moreover, body weight gain, food intake, feeding efficiency, HOMA-β, Emax and pEC50 of acetylcholine-induced relaxations of aortic rings and hepatic superoxide dismutase (SOD) activity were significantly lower in HFD group than in control group. Treatment with levocetirizine caused significant decreases in AUCOGTT, AUCITT, HOMA-IR, hepatic GSH and MDA levels and serum CRP level and LDH activity and significant increases in hepatic SOD activity and HOMA-β when compared with the HFD group. Although levocetirizine failed to alter TC and LDL-C levels, it produced a significant increase in HDL-C level relative to control group. Levocetirizine was also able to improve acetylcholine-induced relaxations of aortic rings, indicating a protective effect against insulin resistance-induced endothelial damage comparable to that offered by pioglitazone. Moreover, levocetirizine substantially attenuated insulin resistance-associated liver macrovesicular steatosis. These findings demonstrate that levocetirizine ameliorates insulin resistance, improves glucose tolerance and attenuates insulin resistance-linked hepatic steatosis and vascular damage.

Thymoquinone-induced relaxation of isolated rat pulmonary artery

AIM OF THE STUDY The effect of thymoquinone (TQ), the main constituent of the volatile oil of black seed (Nigella sativa L. family Ranunculaceae), on the isolated rat pulmonary arterial rings was investigated. MATERIALS AND METHODS Isolated rat pulmonary arterial rings were precontracted with phenylephrine and concentration-response curves to TQ were constructed. The effects of different receptors antagonists or enzyme inhibitors were examined. RESULTS TQ caused a concentration-dependent decrease in the tension of the pulmonary arterial rings precontracted by phenylephrine. The effects of TQ were not influenced by pretreatment of the rings with propranolol (a non-selective beta-blocker), atropine (a non-selective blocker for muscarinic receptors), theophylline (an adenosine receptor antagonist), indomethacin (a cyclooxygenase inhibitor), L-NAME (a NO synthase inhibitor), methylene blue (an inhibitor of soluble guanylyl cyclase) and nifedipine (a Ca(2+) channel blocker). The effects of TQ were significantly potentiated by bosentan (an ET(A)/ET(B) receptor antagonist). The effects of TQ were slightly abolished by pretreatment of the rings with glibenclamide (a non-selective blocker of ATP-sensitive K+ channels). TQ totally abolished the pressor effects of serotonin and phenylephrine on the isolated rat pulmonary arterial rings. CONCLUSION The results of the present study suggest that TQ-induced relaxation of the precontracted pulmonary artery is probably mediated, at least in part, by activation of ATP-sensitive potassium channels and possibly by non-competitive blocking of serotonin, alpha1 and endothelin receptors.

Agmatine ameliorates atherosclerosis progression and endothelial dysfunction in high cholesterol-fed rabbits.

The aim of this work was to explore possible effects of agmatine, an endogenous inhibitor of inducible nitric oxide synthase (iNOS), against hypercholesterolemia‐induced lipid profile changes and endothelial dysfunction.

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.

Allicin enhances chemotherapeutic response and ameliorates tamoxifen-induced liver injury in experimental animals

Abstract Context: Tamoxifen (TAM) is widely used for treatment of hormone-dependent breast cancer; however, it may be accompanied with hepatic injury. Allicin is the most abundant thiosulfinate molecule from garlic with the potential to provide beneficial effects on various diseases. Objective: To elucidate the effect of commercially available allicin on both antitumor activity and liver injury of TAM. Materials and methods: The cytotoxicity of TAM and/or allicin was evaluated in vitro using cultured Ehrlich ascites carcinoma (EAC) cells and in vivo against murine tumor (solid) model of EAC. TAM induced liver injury in rats by intraperitoneally (i.p.) injection at a dose of 45 mg/kg, for 7 successive days. Results: TAM at a dose of 3 µM (IC50) significantly decreased percent survival of EAC to 52%. TAM combination with allicin (5 or 10 µM) showed a significant cytotoxic effect compared with the TAM-treated group as manifested by a decrease in percent survival of EAC to 35% and 29%, respectively. Allicin (10 mg/kg, orally) enhanced the efficacy of TAM (1 mg/kg, i.p.) in mice as manifested by a significant increase in solid tumor growth inhibition by 82% compared with 70% in the TAM group. In rats, TAM intoxication resulted in a significant decline in SOD, GSH, and total protein with significant elevation in TBARS, ALT and AST, ALP, LDH, total bilirubin, γGT, and TNF-α levels. These changes are abrogated by allicin treatment. Discussion and conclusion: The results suggest the beneficial role of allicin as an adjuvant to TAM in cancer treatment by alleviating liver injury.

Modulation of cyclophosphamide-induced early lung injury by allicin.

Abstract Context: Cyclophosphamide (CP) causes lung injury in rats through its ability to generate free radicals with subsequent epithelial and endothelial cell damage. Objective: This study was conducted to assess whether allicin can ameliorate CP-induced early lung injury in rats. Materials and methods: Male Sprague Dawely rats were divided into four groups. Group I was the control group. Group II received allicin (50 mg/kg/d, p.o.) for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.). Group IV received allicin for seven consecutive days, before and after CP injection (150 mg/kg, i.p.). The parameters of study were serum biomarkers, lung tissue antioxidant profile and histopathological changes in lung tissue. Results: A single intraperitoneal injection of CP markedly altered the levels of several biomarkers in lung homogenates. Significant increases in lung content of lipid hydroperoxides were seen that paralleled the decreased levels of total reduced glutathione. Superoxide dismutase activity (SOD) was significantly increased. CP increased the level of serum biomarkers; total protein, lactate dehydrogenase (LDH) and tumor necrosis factor-alpha (TNF-α). Pretreatment of rats daily with oral allicin seven days prior to and seven days after CP inject significantly inhibited the development of lung injury, prevented the alterations in lung and serum biomarkers associated with inflammatory reactions, with less lipid peroxidation (LP) and restoration of antioxidants. Moreover, allicin attenuated the secretion of proinflammatory cytokine, TNF-α expression in rat serum. In addition, allicin effectively blunted CP-induced histopathological changes in lung tissue. Discussion and conclusion: Our results suggest that allicin is efficient in blunting CP-induced pulmonary damage.

Sulforaphane improves dysregulated metabolic profile and inhibits leptin-induced VSMC proliferation: Implications toward suppression of neointima formation after arterial injury in western diet-fed obese mice.

Sulforaphane (SFN), a dietary phase-2 enzyme inducer that mitigates cellular oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) activation, is known to exhibit beneficial effects in the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, a major event in atherosclerosis and restenosis after angioplasty. In particular, SFN attenuates the mitogenic and pro-inflammatory actions of platelet-derived growth factor (PDGF) and tumor necrosis factor-α (TNFα), respectively, in VSMCs. Nevertheless, the vasoprotective role of SFN has not been examined in the setting of obesity characterized by hyperleptinemia and insulin resistance. Using the mouse model of western diet-induced obesity, the present study demonstrates for the first time that subcutaneous delivery of SFN (0.5mg/Kg/day) for~3weeks significantly attenuates neointima formation in the injured femoral artery [↓ (decrease) neointima/media ratio by~60%; n=5-8]. This was associated with significant improvements in metabolic parameters, including ↓ weight gain by~52%, ↓ plasma leptin by~42%, ↓ plasma insulin by~63%, insulin resistance [↓ homeostasis model assessment of insulin resistance (HOMA-IR) index by~73%], glucose tolerance (↓ AUCGTT by~24%), and plasma lipid profile (e.g., ↓ triglycerides). Under in vitro conditions, SFN significantly decreased leptin-induced VSMC proliferation by~23% (n=5) with associated diminutions in leptin-induced cyclin D1 expression and the phosphorylation of p70S6kinase and ribosomal S6 protein (n=3-4). The present findings reveal that, in addition to improving systemic metabolic parameters, SFN inhibits leptin-induced VSMC proliferative signaling that may contribute in part to the suppression of injury-induced neointima formation in diet-induced obesity.