Rehab Kamel

Synthesis and biological evaluation of some thio containing pyrrolo [2,3-d]pyrimidine derivatives for their anti-inflammatory and anti-microbial activities.

The pyrroles Ia-c were used as precursor for the preparation of pyrrolo [2, 3-d] pyrimidine-2 and/or 4 thione derivatives IIa-f. A series of 8-Aryl-pyrrolo [2, 3-d] thiazolo[3,2-a]pyrimidine VI and VII were prepared. Alkylation of the thione compounds in basic medium afforded the pyrrolo [2, 3-d] pyrimidine IV. Also, some 2-amino pyrrolo [2, 3-d]pyrimidines V were obtained. Some newly synthesized compounds were examined for their in vitro anti-inflammatory. Also, all new compounds were examined for their in vivo anti-microbial activity. Several derivatives, showed a promising anti-inflammatory activity in compared to ibuprofen. In this paper, we examine and discuss the structure-activity relationships and anti-inflammatory activities of these compounds.

Effect of thymoquinone on hepatorenal dysfunction and alteration of CYP3A1 and spermidine/spermine N‐1‐acetyl‐transferase gene expression induced by renal ischaemia–reperfusion in rats

Objectives  Renal ischaemia–reperfusion (I/R) is a well‐characterised model of acute renal failure that causes both local and remote organ injury. The aim of this work was to investigate the effect of thymoquinone, the main constituent of the volatile oil extracted from Nigella sativa seeds, on renal and hepatic changes after renal ischaemia–reperfusion.

New condensed pyrroles of potential biological interest: Syntheses and structure–activity relationship studies

The Pyrrole derivatives Ia-d were prepared and utilized for the preparation of pyrrolo[2,3-d]pyrimidine derivatives IIa-c, III, IVa-e, V and VIIIa-c; pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidine VI and pyrrolo[4,3e][1,2,4]triazolo[1,5-c]pyrimidine derivative derivatives VIIa-c. These some newly synthesized compounds were examined for their in vitro antimicrobial activity and in vivo anti-inflammatory. Result indicated that these compounds showed promising anti-inflammatory activity in comparison to ibuprofen (the standard anti-inflammatory drug). The structure-activity relationships (SAR) and anti-inflammatory activities of these compounds are also discussed in this paper.

Evaluation of the anti-inflammatory activity of some pyrrolo[2,3-d]pyrimidine derivatives

A series of novel pyrrolo[2,3-d]pyrimidine and fused pyrrolo[2,3-d]pyrimidine derivatives were synthesized and their structures were characterized by elemental analysis, 1H NMR, IR, and mass spectroscopy. Their in vivo anti-inflammatory activities were evaluated, and the results indicated that some of the title compounds compounds showed significant activities. These compounds are 2b ((7-(4-Methoxyphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine), 7b (4-(2-(Benzyl)hydrazinyl)-7-(4-methoxyphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d] pyrimidine), 7d (4-(2-(Benzyl)hydrazinyl)-7-(4-methoxyphenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine), and 9b (4-(3,5-Dimethyl-4H-pyrazol-1-yl)-7-(4-Methoxyphenyl)-5,6-diphenyl-4,7dihydro-3H-pyrrolo[2,3-d]pyrimidine).

Synthesis of New Pyrroles of Potential Anti‐Inflammatory Activity

We herein disclose a series of novel pyrrole derivatives 1–4 and pyrrolo[2,3‐d]pyrimidine derivatives 6–11 as novel potent anti‐inflammatory compounds. The structures were confirmed by IR, 1H‐NMR, and MS. Some newly synthesized compounds were examined for their in‐vivo anti‐inflammatory activity. Several derivatives showed a promising anti‐inflammatory activity compared to ibuprofen. In this paper, we examine and discuss the structure–activity relationships and anti‐inflammatory activities of these compounds.

Protective effect of artichoke leaf extract against paracetamol-induced hepatotoxicity in rats

Abstract Context: Paracetamol overdose is a predominant cause of hepatotoxicity in both humans and experimental animals. Objective: In this study, we investigated the protective effect of aqueous artichoke leaf extract (ALE) against paracetamol-induced liver injury in rats using N-acetylcysteine (NAC) as a reference drug. Materials and methods: Rats were divided into five groups: negative control, paracetamol (2 g/kg, single oral dose), ALE (1.5 g/kg, orally for 14 d), ALE + paracetamol, and NAC (100 mg/kg) + paracetamol. Indices of liver damage (serum alanine aminotransferase and aspartate aminotransferase) were measured. Liver homogenates were analyzed for oxidative stress biomarkers (MDA, malondialdehyde; SOD activity, superoxide dismutase activity; NO, nitric oxide; GSH content, reduced glutathione), glutathione cycling (GR, glutathione reductase), and utilization (GST, glutathione-S-transferase). Apoptosis was assessed using the comet assay. Results: Paracetamol caused marked liver damage as noted by significant increased activities of serum aminotransferases (p < 0.05) as well as a significant increase in hepatic MDA and NO levels (p < 0.001) compared with the negative control group. GSH content, GR, GST, and SOD activities were decreased significantly (p < 0.001). Comet assay parameters (tail length, percentage of tailed cells, percentage of migrated DNA, and tail moment) were increased (p < 0.05), indicating apoptosis. Histopathological examination showed necrotic areas. Pre-treatment with ALE replenished hepatic GSH, reversed oxidative stress parameters, DNA damage, and necrosis induced by paracetamol. Discussion and conclusion: These results suggest that ALE may protect from paracetamol-induced liver toxicity via its antioxidant and anti-apoptotic properties.

Effect of rosuvastatin on cholestasis‐induced hepatic injury in rat livers

Recent studies reported that 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase inhibitors have pleotropic effects independent of their lipid‐lowering properties. The present study was undertaken to determine whether treatment with rosuvastatin (RO) would be beneficial in a rat model of bile duct ligation (BDL). Animals were divided into three groups: a sham group (group I), a BDL group treated with vehicle (group II), and a BDL group treated with RO (10 mg/kg) (group III). Serum levels of total bilirubin, γ‐glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase decreased significantly in group III when compared to group II. Lipid peroxides and NO levels of group III were found to be significantly lower than those of group II. Antioxidant enzymes (superoxide dismutase, glutathione‐S‐transferase, and catalase) activity in liver tissues markedly decreased in group II, whereas treatment with RO preserved antioxidant enzyme activity. DT‐diaphorase activity in group II was significantly higher than that in group III. The histopathological results showed multiple numbers of newly formed bile ductules with inflammatory cells infiltration in group II. These pathological changes were improved in group III. Our data indicate that RO ameliorates hepatic injury, inflammation, lipid peroxidation and increases antioxidant enzymes activity in rats subjected to BDL. RO may have a beneficial effect on treatment of cholestatic liver diseases.

Attenuating effects of coenzyme Q10 and amlodipine in ulcerative colitis model in rats

Abstract Context: Ulcerative colitis is a chronic inflammatory bowel disease. Recent studies reported a pivotal role of elevated intracellular calcium in this disorder. Coenzyme Q10 (CoQ10) and amlodipine are known to maintain cellular energy, decrease intracellular calcium concentration in addition to their antioxidant and anti-inflammatory properties. Objective: The aim of this study was to evaluate the possible protective effects of CoQ10, amlodipine and their combination on ulcerative colitis. Materials and methods: Colitis was induced in rats by intracolonic injection of 3% acetic acid. CoQ10 (10 mg/kg), amlodipine (3 mg/kg) and their combination were administered for 8 consecutive days before induction of colitis. Results: Our results showed that administration of CoQ10, amlodipine and their combination decreased colon tissue malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), prostaglandin E2 (PGE2), myeloperoxidase (MPO) and heat shock protein (HSP70) levels induced by intracolonic injection of acetic acid and restored many of the colon structure in histological examination. On the other hand, they increased superoxide dismutase (SOD) activity, adenosine-5′-triphosphate (ATP) and interleukin-10 (IL-10) colonic contents. Discussion and conclusion: Administration of either CoQ10 or amlodipine was found to protect against acetic acid-induced colitis. Moreover, their combination was more effective than individual administration of either of them. The protective effect of CoQ10 and amlodipine may be in part via their antioxidant, anti-inflammatory and energy restoration properties.

Immunomodulatory effect of candesartan on indomethacin-induced gastric ulcer in rats

Non steroidal anti-inflammatory drugs (NSAIDs) induce gastric mucosal lesions in part by induction of oxidative stress as well as the activation of inflammatory cells and the production of proinflammatory cytokines. In this study, we examined the protective effect of candesartan (2 and 5 mg/kg) on indomethacin-induced gastric mucosa damage. Pretreatment with candesartan for 10 days reduced significantly the ulcer index induced by indomethacin injection. The preventive index of 2 mg/kg (76.74%) was higher than that of 5 mg/kg (65.11%). Both doses of candesartan were able to reduce significantly the stomach malondialdehyde content compared to indomethacin-treated group. Myeloperoxidase, tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant gastric levels were significantly reduced by 2 mg/kg of candesartan more than 5 mg/kg. The Th1 cytokine interferon γ was also significantly reduced by both doses of candesartan compared to indomethacin injected group. On the other hand, indomethacin significant decreased the anti-inflammatory cytokine IL-10 gastric level. Pretreatment with candesartan (2 and 5 mg/kg) reversed this effect. In conclusion, the present study indicates that pretreatment with candesartan, can protect against the stomach injury induced by indomethacin through its antioxidant and immunomodulatory effects.

The growth inhibitory effect of gambogic acid on pancreatic cancer cells

Pancreatic cancer, the fourth most common cause of cancer-related deaths, is one of the most aggressive and devastating human malignancies with increasing incidence worldwide. To date, surgical resection is the only potentially curative therapy available for pancreatic cancer patients. Early diagnosis of pancreatic tumors is difficult, and hence, nearly 80% of patients cannot receive surgical resection. Natural products have always been a vital source for novel compounds for cancer treatment. The naturally occurring prenylated xanthone, gambogic acid, has been previously shown to exert potent anticancer, anti-inflammatory, apoptotic, antiangiogenic, and antioxidant activities. However, to our knowledge, there have been no specific studies showing its effect on the whole-genome expression in pancreatic cancer cells. Here, the anticancer activity of gambogic acid toward a panel of pancreatic cancer cells with different differentiation stages has been evaluated. Additionally, a whole-genome transcription profiling study was performed in order to identify possible candidate players modulating the antitumor effect of gambogic acid on pancreatic cancer cells. Expression analysis results showed that the pancreatic adenocarcinoma signaling pathway was specifically affected upon gambogic acid treatment. Moreover, the growth inhibitory effect of gambogic acid on pancreatic cancer cells was modulated through up-regulation of DDIT3, DUSP1, and DUSP5 and down-regulation of ALDOA, TOP2A, and ATG4B. The present work is a starting point for the generation of hypotheses on significantly regulated candidate key player genes and for a detailed dissection of the potential role of each individual gene for the activity of gambogic acid on pancreatic cancer.