Tariq Al-Qirim

Effects of antioxidant vitamins on glutathione depletion and lipid peroxidation induced by restraint stress in the rat liver.

AbstractBackground and aim: Stress as a cofactor has been reported to affect the progression and severity of several diseases. The influence of stress on the liver is of interest from the clinical point of view because stress plays a potential role in aggravating liver diseases in general and hepatic inflammation in particular, probably through generation of reactive oxygen species. The present study was undertaken to investigate the potential of the antioxidant vitamins A (retinol), E (tocopherol) and C (ascorbic acid) individually and in combination (vitamin E + C) to modulate restraint stress-induced oxidative changes. These effects were determined by measuring changes in hepatic levels of free radical scavenging enzymes such as superoxide dismutase (SOD), glutathione-S-transferase (GST) and catalase, as well as levels of total glutathione (GSH), malondialdehyde (MDA), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Methods: Immobilisation was achieved by placing the animals in wire mesh cages of their size. The rats were orally administered vitamins A, E and C individually and in combination (E + C) prior to and after 6 hours of immobilisation stress exposure. The hepatic levels of SOD, GST, catalase, GSH and MDA were determined by spectrophotometric methods. Liver SOD activity was assayed by monitoring the amount of enzyme required to inhibit autoxidation of pyrogallol by 50%. Hepatic GST was monitored by following the increase in absorbance at 340nm of CDNB-GSH conjugate generated due to GST catalysis between GSH and CDNB. Catalase activity in liver tissues was determined using peroxidase as the substrate. Lipid peroxidation was measured by determining the level of thiobarbituric acid reactive substances. ALT and AST were determined by commercial kits. Results: Six hours of immobilisation stress caused a decrease in liver levels of SOD (p = 0.001), catalase (p = 0.031), GST (p = 0.021) and GSH (0.013), while levels of MDA (p = 0.0015), AST (p = 0.05) and ALT (p = 0.046) were increased compared with non-stressed control rats. Both pre-vitamin stress and post-vitamin stress treatments either alone or in combination were associated with increased normalisation of these parameters towards control values, with post-vitamin treatment being the more effective of the two. Vitamins E and C individually were found to be more effective in restoring the endogenous antioxidant system than vitamin A. The combined vitamin (E + C) post-stress treatment was found to be effective but not additive in combating hepatic oxidative stress. The beneficial effects of these vitamin treatments were also reflected in reversions of altered AST and ALT levels towards their control values. Conclusion: Vitamins E or C alone or in combination can be given as prophylactic/therapeutic supplements for combating scavenging free radicals generated in liver tissue. This approach may reduce oxidative stress caused by diseases such as cirrhosis.

Effect of khat, its constituents and restraint stress on free radical metabolism of rats.

The leaves of khat (Catha edulis) are found to have stimulating and pleasurable effect and are chewed habitually by people of East Africa and Arabian Peninsula. Due to various toxic and psychostimulative effect of khat the present study was undertaken to evaluate the effect of intragastric khat alone or its major constituents flavonoids/alkaloids administration and before and after 4 h of immobilization stress in terms of alteration of free radical scavenging/metabolizing enzymes, uric acid and glucose in rats. Oral khat, alkaloid administration or 4 h restraint stress resulted in the decrease of the circulating levels of superoxide dismutase, catalase, glutathione-S-transferase and glucose with enhanced uric acid concentrations as compared with control rats. Oral treatment with flavonoid fraction of khat was found to enhance the activities of GST and catalase but showed no effect on SOD while the level of glucose was decreased and uric acid increased. The levels of these biochemical parameters were more altered in post stress khat/alkaloid treated rats than pre stress khat/alkaloid treated rats. The alteration in the levels of SOD, GST, catalase and uric acid in the pre stress khat treated rats were comparable with that of khat alone, except the level of glucose which was further decreased in pre stress khat treated rats. The flavonoid fraction of khat reduced the stress induced oxidative stress in terms of above mentioned biochemical parameters. The present study suggests that khat alone or khat/alkaloid consumption preceding stress may significantly decrease the levels of free radical metabolizing/scavenging enzymes and glucose leading to enhanced free radical concentration and toxicity of khat, which could be due to its alkaloid fraction as flavonoids were found to show antioxidant properties for oxidative stress generated during restraint stress.

Modulation of restraint stress induced oxidative changes in rats by antioxidant vitamins

In the present study we examined immobilization stress-induced antioxidant defense changes in rat plasma and also observed the antioxidant effects of pre and post vitamins A, E and C administration (15 mg/Kg of body weight) individually and in combination (vit E + C) on these alterations.Following immobilization stress the circulating activities of superoxide dismutase, catalase and glutathione-S-transferase were decreased, while the level of thiobarbituric acid reactive substances (TBARS) was increased as compared to non-stressed control rats. Post treatment with individual vitamins A, E and C (after exposure to stress) resulted in a less marked alteration of plasma TBARS levels and activities of SOD, GST and catalase as compared to pre vitamin stress or stress alone treatments. Both pre and post vitamin treatments were effective in preventing stress induced derangement of free radical metabolism with a relative dominance by latter. The combined treatment with vitamin E and C did not show any additive antioxidant effect on restraint stress induced altered free radical metabolism, rather a predominant effect similar to vitamin E alone was observed. The prevention of oxidative stress generated in response to restraint stress by the vitamins can be summarized as: vitamin (E + C) i.e. vit E > vit C > vit A, thus combined vitamin (E + C) treatment though showed maximum preventive effect, but was similar to vitamin E treatment alone, in terms of the circulating activities of SOD, GST, catalase and TBARS levels.

Synthesis and anti-hyperlipidemic evaluation of N‑(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide derivatives in Triton WR-1339-induced hyperlipidemic rats.

The lipid-lowering activity of a series of novel N-(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide derivatives has been studied in Triton WR-1339-induced hyperlipidemia in rats. The test animals were divided into four groups: control, hyperlipidemic, compound + 4% DMSO [C1: N-(2-benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (1), C2: N-(3-benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (2), C3: N-(4-benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (3)]-treated and bezafibrate (BF)-treated. At a dose of 15 mg/Kg body weight, compounds 2, 3 and BF significantly reduced elevated plasma triglycerodes levels after 12 h. Moreover, high density lipoprotein-cholesterol levels were significantly increased in all treated groups after 12 h compared to the hyperlipidemic control group, except for C1 which was inactive. In sum, it may be stated that the results of the present study demonstrated new properties of some N-(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide derivatives as potent lipid lowering agents and these beneficial activities may contribute to their cardioprotective and antiatherosclerotic role.

The hypolipidemic activity of novel benzofuran-2- carboxamide derivatives in Triton WR-1339-induced hyperlipidemic rats: a comparison with bezafibrate

Using Triton WR-1339-induced hyperlipidemic rats as an experimental model, we investigated whether compound 4 [N-(9,10-dihydro-9,10-dioxoanthracen-2-yl)bezofuran-2-carboxamide] and compound 5 [N-(4-benzoylphenyl)benzofuran-2-carboxamide], two novel anti-hyperlipidemic agents, have any effect on plasma triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol levels (HDL-C) levels. The tested animals were divided into control (CG), hyperlipidemic (HG), and compounds 4, 5, and bezafibrate (BF) treated groups. At a dose of 15 mg/kg body weight, compounds 4, 5, and BF significantly reduced elevated plasma TG levels after 7 and 24 h. Furthermore, HDL-C levels were remarkably increased in all treated groups after 7 and 24 h compared to the hyperlipidemic control group. However, only compounds 4 and 5 treated groups clearly showed a significant reduction in plasma total cholesterol levels after 7 and 24 h. It is therefore reasonable to assume that compounds 4 and 5 may have promising potential in the treatment of hyperlipidemia and atherosclerosis.

In Vivo Antihyperlipidemic Activity of a New Series of N‐(Benzoylphenyl) and N‐(Acetylphenyl)‐1‐benzofuran‐2‐carboxamides in Rats

A new series of N‐(benzoylphenyl) and N‐(acetylphenyl)‐1‐benzofuran‐2‐carboxamides (3a–3d and 4a′–4c′) were synthesized. Compounds (3a, 3b, and 4a′–4c′) were tested in vivo using Triton‐WR‐1339‐induced hyperlipidemic rats as an experimental model for their hypolipidemic activity. The tested animals were divided into eight groups: control, hyperlipidemic, 3a, 3b, 4a′, 4b′, 4c′, and bezafibrate. At a dose of 15 mg/kg, the elevated plasma triglyceride (TG) levels were significantly reduced in compounds 3b (p <0.0001) and 4c′ (p <0.05) after 12 and 24 h compared to the normal control group. Furthermore, high‐density lipoprotein‐cholesterol levels were remarkably increased in compounds 3b (p <0.001) and 4c′ (p <0.05). Meanwhile, compound 4b′ slightly reduced the TG levels after 12 and 24 h. The present study demonstrated new properties of the novel series of benzofuran‐2‐carboxamides 3b and 4c′ as potent lipid‐lowering agents. It is, therefore, reasonable to assume that compounds 3b and 4c′ may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases.

Antihyperlipidemic Properties of Novel N-(Benzoylphenyl)-5-substituted-1H-indole-2-carboxamides in Triton WR-1339-Induced Hyperlipidemic Rats

In the search for new potential antihyperlipidemic agents, the present study focuses on the synthesis of novel N-(benzoylphenyl)-5-substituted-1H-indole-2-carboxamides (compounds 8-12, 15, 16, 18) and investigating their antihyperlipidemic activity using Triton WR-1339-induced hyperlipidemic rats as an experimental model. Hyperlipidemia was developed by intraperitoneal injection of Triton WR-1339 (250 mg/kg body weight). The tested animals were divided into normal control (NCG), hyperlipidemic (HG), compound 8, 9, 15, 16, 18- and bezafibrate treated groups. At a dose of 15 mg/kg body weight, compounds 9, 16, 18 and bezafibrate (100 mg/kg) significantly (p < 0.0001) reduced elevated plasma triglycerides levels after 12 h compared to the hyperlipidemic control group. However, only the group treated with compounds 9, 16 and 18 showed an obviously significant (p < 0.001) reduction in plasma total cholesterol levels after 12 h compared to the hyperlipidemic control group. Moreover, high density lipoprotein-cholesterol levels were significantly (p < 0.0001) increased in all treated groups after 12 h compared to the hyperlipidemic control group, except for compounds 8 and 15 which revealed inactive. It is therefore reasonable to assume that compounds 9, 16 and 18 may have potential in the treatment of hyperlipidemia.

Pharmacological evaluation of novel indole-2-carboxamides as potent lipid-lowering agents in Triton-WR-1339-induced hyperlipidemic rats.

The lipid-lowering effects of two novel antihyperlipidemic agents, BMI2C [N-(4-benzoylphenyl)- 5-methoxy-1H-indole-2-carboxamide] and DDMI2C [N-(9,10-dihydro-9,10-dioxoanthracen- 2-yl)-5-methoxy-1H-indole-2-carboxamide], were studied using hyperlipidemic rats as an experimental model; hyperlipidemia was developed by intraperitoneal injection of Triton WR-1339 (200 mg/kg body weight). At a dose of 15 mg/kg body weight, BMI2C and DDMI2C signifi cantly reduced elevated plasma triglyceride levels after 7 and 24 h. Furthermore, BMI2C and DDMI2C significantly reduced elevated plasma total cholesterol levels after 24 h. Interestingly, high-density lipoprotein-cholesterol levels were significantly increased in all treated groups. These findings indicate that the two studied novel compounds have a promising potential in the treatment of hyperlipidemia and atherosclerosis

Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα).

The oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has made it an attractive target for anticancer drug design. In this work, we describe our efforts to optimize the lead PI3Kα inhibitor 2-hydroxy-1,2-diphenylethanone (benzoin). A series of 2-oxo-1,2-diphenylethyl benzoate analogs were identified as potential PI3Kα inhibitors. Docking studies confirmed that the aromatic interaction is mediating ligand/protein complex formation and identified Lys802 and Val851 as H-bonding key residues. Our biological data in human colon carcinoma HCT116 showed that the structure analogs inhibited cell proliferation and induced apoptosis.

Synthesis and Pharmacological Evaluation of Novel Substituted and Unsubstituted N-(Benzoylphenyl)-1H-indole-2-carboxamides as Potent Antihypertriglyceridemic Agents

The N-(benzoylphenyl)-1H-indole-2-carboxamide derivatives 1 - 6 were synthesized, and the lipid-lowering effects of two of these novel compounds were studied using hyperlipidemic rats as an experimental model. Treatment of ethyl-1H-indole-2-carboxylate with aminobenzophenones in the presence of sodium ethoxide and DMF, followed by purifi cation using column chromatography, gave the target compounds in good yields. The tested animals were divided into control, hyperlipidemic, compounds 2-, 3- and bezafibrate-treated groups. At a dose of 15 mg/kg body weight, compounds 2, 3 and bezafibrate significantly reduced the elevated plasma triglyceride levels after 7 and 24 h. Furthermore, the high-density lipoprotein- cholesterol levels were remarkably increased in all treated groups after 7 and 24 h compared to the hyperlipidemic control group. However, only compounds 2- and 3-treated groups obviously showed a significant reduction in plasma total cholesterol levels after 24 h. It is therefore reasonable to assume that 2 and 3 may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases.