Ibrahim A. Maghrabi

Diosmin Protects against Ethanol-Induced Gastric Injury in Rats: Novel Anti-Ulcer Actions

Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels along with nuclear factor kappa B (NF-κB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase-3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses.

Camel’s milk ameliorates TNBS-induced colitis in rats via downregulation of inflammatory cytokines and oxidative stress

Current treatment strategies for inflammatory bowel diseases (IBD) are associated with several adverse effects, and thus, the search for effective agents with minimal side effects merits attention. Camels milk (CM) is endowed with antioxidant/anti-inflammatory features and has been reported to protect against diabetes and hepatic injury, however, its effects on IBD have not been previously explored. In the current study, we aimed to investigate the potential alleviating effects of CM against TNBS-induced colitis in rats. CM (10 ml/kg b.i.d. by oral gavage) effectively suppressed the severity of colon injury as evidenced by amelioration of macroscopic damage, colon weight/length ratio, histopathological alterations, leukocyte influx and myeloperoxidase activity. Administration of CM mitigated the colonic levels of TNF-α and IL-10 cytokines. The attenuation of CM to colon injury was also associated with suppression of oxidative stress via reduction of lipid peroxides and nitric oxide along with boosting the antioxidant defenses through restoration of colon glutathione and total anti-oxidant capacity. In addition, caspases-3 activity, an apoptotic marker, was inhibited. Together, our study highlights evidences for the promising alleviating effects of CM in colitis. Thus, CM may be an interesting complementary approach for the management of IBD.

Design, synthesis, anti-schistosomal activity and molecular docking of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives.

Schistosomiasis remains one of the most prevalent parasitic infections and has significant public health consequences. Praziquantel (PZQ) is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Herein we report a series of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives, which were synthesized, characterized and tested as anti-schistosomal agents in vitro. Among all tested compounds, compounds 4a, 5b, and 7b at different tested concentrations (50, 100, and 200 μg/mL) showed the highest schistosomicidal activity. Among those 3 compounds, compound 7b was the most potent anti-schistosomal one. Moreover, all tested compound, at 50 μg/mL concentration, significantly reduced oviposition of adult worms in vitro. Furthermore, both compound 4a and 7b, as well as compound 6a, completely diminished egg deposition. To clarify the possible mechanism by which novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives act as anti-schistosomal agents, molecular docking of all new compounds was carried out using Molsoft ICM pro 3.5-0a to investigate the binding affinity and binding mode to thioredoxin glutathione reductase enzyme (TGR), a potential drug target for anti-schistosomal agents. The docking results revealed moderate to high affinity of the new compounds towards TGR. Compound 7b scored the highest binding energy (-101.13 kcal/mol) against TGR crystal structure forming eight hydrogen bonds with the amino acid residues at the binding site of the receptor. This result indicates that compound 7b could exert its effect through inhibition of TGR, which is a vital enzyme for schistosome survival.

Development of insulin loaded mesoporous silica injectable particles layered by chitosan as a controlled release delivery system

The present work investigated the possibility of using mesoporous silica nanoparticles coated with low molecular weight chitosan as an injectable controlled release carrier of insulin. Insulin was totally encapsulated in particles. Surface tension measurements indicated that insulin was absorbed into mesoporous silica pores and interacted with chitosan. The stability of the encapsulated insulin was confirmed by different analytical methods such as RP-HPLC, FTIR and CD. Furthermore, the thermal stability using DSC was in the favor of the encapsulated insulin compared to free insulin. In vivo results indicated that insulin release was prolonged after loading into mesoporous silica nanoparticles. Such particles could be a potential carrier to control the release of insulin.

Sensitization of Hepatocellular Carcinoma Cells to Apo2L/TRAIL by a Novel Akt/NF-κB Signalling Inhibitor

Hepatocellular carcinoma (HCC) cells are intrinsically resistant to tumour necrosis factor‐related apoptosis ligand (Apo2L/TRAIL), in part, due to the compensatory activation of nuclear factor‐kappaB (NF‐κB). To broaden the clinical utilization of Apo2L/TRAIL in HCC, OSU‐A9, a potent indole‐3‐carbinol‐derived Akt/NF‐κB signalling inhibitor was used to overcome the intrinsic resistance. The antitumour effects of OSU‐A9, Apo2L/TRAIL and the therapeutic combination were assessed by MTT assay, caspase activation and PARP cleavage, and the synergistic interactions were determined by Calcusyn analysis. NF‐κB reporter gene and RT‐PCR were tested for the activation of NF‐κB and the expression of death receptors (DR)4 and 5. OSU‐A9 could sensitize HCC cells to Apo2L/TRAIL with high potency through down‐regulation of Akt/NF‐κB signalling. OSU‐A9 dose‐dependently reduced Akt phosphorylation and the expression and nuclear localization of RelA/p65, accompanied by parallel decreases in the expression of NF‐κB target products, including Bcl‐xL, Mcl‐1, cIAP1, cIAP2 and survivin. Moreover, OSU‐A9 increased DR5 expression through a reactive oxygen species (ROS)‐dependent mechanism. Concertedly, these mechanisms underlie the synergistic interaction between OSU‐A9 and Apo2L/TRAIL in mediating apoptotic death in HCC cells. The ability of OSU‐A9 to accentuate Apo2L/TRAIL‐induced apoptosis by inactivating Akt/NF‐κB signalling might foster a promising therapeutic strategy for HCC.

Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000ft above the sea level). Iron supplementation (2mg elemental iron/kg, once daily for 15days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25mg/kg, once daily for the last 7days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures.

Clozapine-carboxylic acid plasticized co-amorphous dispersions: Preparation, characterization and solution stability evaluation.

Abstract This study addressed the possibility of forming of co-amorphous systems between clozapine (CZ) and various carboxylic acid plasticizers (CAPs). The aim was to improve the solubility and oral bioavailability of clozapine. Co-amorphous dispersions were prepared using modified solvent evaporation methodology at drug/plasticizer stoichiometric ratios of 1:1, 1:1.5 and 1:2. Solid state characterization was performed using differential scanning calorimetry, X-ray diffraction and infra red spectroscopy. Highly soluble homogeneous co-amorphous dispersions were formed between clozapine and CAPs via hydrogen bonding. The co-amorphous dispersions formed with tartaric acid (1:2) showed the highest dissolution percentage (> 95 % in 20 minutes) compared to pure crystalline CZ (56 %). Highly stable solutions were obtained from co-amorphous CZ-citric and CZ-tartaric acid at 1:1.5 molar ratio. The prepared dispersions suggest the possibility of peroral or sublingual administration of highly soluble clozapine at a reduced dose with the great chance to bypass the first pass metabolism.

Nicotine Mediates Hypochlorous Acid-Induced Nuclear Protein Damage in Mammalian Cells

Activated neutrophils secrete hypochlorous acid (HOCl) into the extracellular space of inflamed tissues. Because of short diffusion distance in biological fluids, HOCl-damaging effect is restricted to the extracellular compartment. The current study aimed at investigating the ability of nicotine, a component of tobacco and electronic cigarettes, to mediate HOCl-induced intracellular damage. We report, for the first time, that HOCl reacts with nicotine to produce nicotine chloramine (Nic-Cl). Nic-Cl caused dose-dependent damage to proliferating cell nuclear antigen (PCNA), a nuclear protein, in cultured mammalian lung and kidney cells. Vitamin C, vitamin E analogue (Trolox), glutathione, and N-acetyl-l-cysteine inhibited the Nic-Cl-induced PCNA damage, implicating oxidation in PCNA damage. These findings point out the ability of nicotine to mediate HOCl-induced intracellular damage and suggest antioxidants as protective measures. The results also raise the possibility that Nic-Cl can be created in the inflamed tissues of tobacco and electronic cigarette smokers and may contribute to smoking-related diseases.

Chitosan/lecithin liposomal nanovesicles as an oral insulin delivery system

Abstract In the present work, insulin–chitosan polyelectrolyte complexes associated to lecithin liposomes were investigated as a new carrier for oral delivery of insulin. The preparation was characterized in terms of particle size, zeta potential and encapsulation efficiency. Surface tension measurements revealed that insulin–chitosan polyelectrolyte complexes have some degree of hydrophobicity and should be added to lecithin liposomal dispersion and not the vice versa to prevent their adsorption on the surface. Stability of insulin was enhanced when it was associated to liposomes. Significant reduction of blood glucose levels was noticed after oral administration of liposomal preparation to streptozotocin diabetic rats compared to control. The hypoglycemic activity was more prolonged compared to subcutaneously administered insulin.

Design, synthesis, and anti-inflammatory evaluation of novel diphenylthiazole-thiazolidinone hybrids.

A series of diphenylthiazole–thiazolidinone hybrids was synthesized and evaluated in vitro and in vivo as anti‐inflammatory/analgesic agents. The inhibition of cyclooxygenase (COX) enzymes was suggested as a molecular mechanism for the hybrids to exert their anti‐inflammatory action. Of these compounds, 13b, 14, and 15b showed the most potent COX inhibitory activity with IC50 values between 2.03 and 12.27 µM, but with different selectivity profiles. All compounds were further evaluated in vivo for their anti‐inflammatory/analgesic activities using three animal models. Interestingly, the results of the COX assay were in agreement with those of in vivo assays where the most potent COX inhibitors, 13b, 14, and 15b, exhibited the highest anti‐inflammatory/analgesic activities compared to diclofenac. On the contrary, compounds 11 and 12 were the least potent ligands in vitro and in vivo as well.