Mona K. Tawfik

Evaluation of the antifibrotic effect of fenofibrate and rosiglitazone on bleomycin-induced pulmonary fibrosis in rats

Idiopathic pulmonary fibrosis is the most prevalent chronic fibrosing lung disease. Peroxisome proliferator-activated receptors-gamma agonists provide potential therapy for fibrotic diseases of the lung. Peroxisome proliferator-activated receptors-alpha agonists may be helpful in the treatment of lung inflammatory diseases, however their therapeutic potential on the fibro-proliferative process and extracellular matrix accumulation in idiopathic pulmonary fibrosis has been less well studied. So, the present study was conducted to evaluate the anti-fibrotic effects of fenofibrate (peroxisome proliferator-activated receptors-alpha agonist) alone and in combination with rosiglitazone (peroxisome proliferator-activated receptors-gamma agonist) on lung injury induced by bleomycin administration. Oral administration of either rosiglitazone (5 mg/kg/d) or fenofibrate (100 mg/kg/d) for 14 days, attenuated the severity of bleomycin-induced lung injury and fibrosis through decreasing lung water contents, lung fibrotic grading, lung hydroxyproline contents and lung transforming growth factor-beta1 levels; with no significant difference between them. Combined low doses of rosiglitazone (1 mg/kg/d) and fenofibrate (30 mg/kg/d) provided more benefits than full separate doses of each on the deleterious effects accompanied bleomycin administration. These findings suggested the potential use of peroxisome proliferator-activated receptors-alpha ligands as anti-fibrotic agents in lung fibrosis. Additionally, the concurrent administration of fenofibrate and rosiglitazone in low doses has synergistic effect and enhanced the beneficial effects afforded by either fenofibrate or rosiglitazone.

Design and Optimization of Self-Nanoemulsifying Delivery System to Enhance Quercetin Hepatoprotective Activity in Paracetamol-Induced Hepatotoxicity

The present study aimed to develop optimized quercetin (QT)-loaded self-nanoemulsifying drug delivery system (SNEDDS) that offers protective effect against liver damage. Solubility study of QT in different oils, surfactants, and cosurfactants was performed. Ternary phase mixtures of the selected components were constructed to select a suitable range for each component. Experimental mixture design was utilized to optimize SNEDDSs that possess smaller globule size with enhanced emulsification and dissolution rates. QT SNEDDS was compared with QT suspension control and silymarin. In vivo evaluation and histopatholgical study of the selected QT SNEDDSs were achieved after administration of paracetamol over dosage to albino rats. Two optimized formulations were selected; one based on Sefsol and the other based on linoleic acid as an oily phase, Tween(®) 80 and polyethylene glycol 400 as surfactant and cosurfactant, respectively. Both Sefsol and linoleic-acid-optimized SNEDDS formulation showed no symptoms associated with toxicity and offered protective effect against paracetamol-induced hepatotoxicity by scavenging free radicals, attenuating lipid peroxidation, and enhancing the activity of antioxidants. The histopatholgical observations revealed that the inflammatory infiltrations induced by paracetamol were significantly ameliorated.

Coenzyme Q10 enhances the anticonvulsant effect of phenytoin in pilocarpine-induced seizures in rats and ameliorates phenytoin-induced cognitive impairment and oxidative stress

Conventional antiepileptic drugs fail to adequately control seizures and predispose to cognitive impairment and oxidative stress with chronic usage in a significant proportion of patients with epilepsy. Coenzyme Q10 (CoQ10), an antioxidant compound, exhibits a wide range of therapeutic effects that are attributed to its potent antioxidant capacity. To evaluate the neuroprotective effects of CoQ10 in rats against the observed oxidative stress during seizures induced by pilocarpine, and to study its interactions with the conventional antiepileptic drug phenytoin, two experiments were performed. Experiment 1 was conducted to test the effect of phenytoin, CoQ10, or both on seizure severity and oxidative markers in the pilocarpine model of epilepsy. Experiment 2 was conducted to test the effect of 2 weeks of chronic treatment with phenytoin, CoQ10, or both on oxidative markers and behavioral tests in rats. Overall, CoQ10 reduced the severity of pilocarpine-induced seizures and the severity of oxidative stress. Moreover, it potentiated the antiepileptic effects afforded by phenytoin treatment, with the potential safety and efficacy in ameliorating oxidative stress and cognitive impairment caused by chronic phenytoin therapy. Our findings strongly suggest that CoQ10 can be considered a safe and effective adjuvant to phenytoin therapy in epilepsy both to ameliorate seizure severity and to protect against seizure-induced oxidative damage by reducing the cognitive impairment and oxidative stress associated with chronic use of phenytoin.

Bioactive Brominated Metabolites from the Red Sea Sponge Pseudoceratina arabica

Chemical investigation of the Red Sea sponge Pseudoceratina arabica has led to the isolation and identification of seven brominated compounds including two new bromotyramine derivatives, hydroxymolokaiamine (2) and molokaiakitamide (6), and a new brominated phenolic compound, ceratinophenol A (5), together with the known compounds molokaiamine (1), ceratinamine (3), 5-bromo-2,3-dihydroxy-6-methoxybenzaldehyde (4), and psammaplysin-A (7). Biological evaluation of these metabolites indicated that molokaiamine and molokaiakitamide possess significant parasympatholytic effects on isolated rabbit heart and jejunum. This finding has important implications for further biological investigation of this class of compounds. Moreover, these compounds showed weak antibacterial and antifungal activities.

Combination of coenzyme Q10 with methotrexate suppresses Freund's complete adjuvant-induced synovial inflammation with reduced hepatotoxicity in rats: Effect on oxidative stress and inflammation

Methotrexate (MTX) is a cornerstone disease modifying anti-rheumatic drug. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Coenzyme Q10 (CoQ10) is an antioxidant and anti-inflammatory compound, possessing both anti-arthritic and hepatoprotective potential. The present study was carried out to evaluate the effect of CoQ10 (10mg/kg) alone and in combination with MTX (2mg/kg) on the progression of adjuvant-induced arthritis in rats, and to elucidate the potential properties of CoQ10 in ameliorating MTX-induced liver damage in rats. Rats were assigned to; normal, arthritic, MTX treated, CoQ10 treated or a combination of MTX and CoQ10. CoQ10 administration potentiated the antiarthritic effect of MTX. Moreover, the combination therapy was effective in attenuating the severity of MTX-induced liver damage displayed by the improvement in hepatospecific serum markers and confirmed by the histo-pathological evaluation. Additionally, it attenuated the hepatic oxidative stress and the intensity of inflammatory mediators associated with MTX administration as evident by the regulation of oxidant/anti-oxidant balance and the inhibitory effects on TNF-α and IL-6 levels. These results revealed that CoQ10 can serve as a useful adjuvant and promote the safe use of MTX in the management of arthritis, not only by potentiating the antiarthritic effect of MTX, but also by alleviating MTX-induced hepatocellular injury.

Effect of mononuclear cells versus pioglitazone on streptozotocin-induced diabetic nephropathy in rats

BACKGROUNDnDiabetic nephropathy is a serious diabetic complication that leads to end stage renal disease. Cell therapies with human embryonic and specific adult stem cells have emerged as an alternative management for various diseases.nnnMETHODSnTo test this hypothesis, the present study was conducted to compare effect of MNCs treatment (iv injection once in the tail vein for diabetic rats in a dose of 150 x 10(6) MNCs cells/rat) versus pioglitazone (10 mg/kg, for eight weeks) on improving the renal structure and function changes and reducing laminin deposition associated with STZ-induced diabetic nephropathy in rats.nnnRESULTSnTreatment with pioglitazone orMNCs, demonstrated a significant improvement in the STZ-induced renal functional and structural changes in comparison with diabetic control group. Additionally, our histopathological and immunohistochemical studies confirm these results. Meanwhile, MNCs treated group exhibited more improvement in all studied parameters as compared to pioglitazone treated group.nnnCONCLUSIONnThese data indicate that MNCs treatment was superior to pioglitazone in controlling hyperglycemia, improving the renal structure and function changes and reducing renal laminin expression associated with STZ-induced diabetic nephropathy in rats.

Exenatide suppresses 1,2-dimethylhydrazine-induced colon cancer in diabetic mice: Effect on tumor angiogenesis and cell proliferation.

Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20mg/kg/week,s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20μg/kg) group: mice received exenatide (10 or 20μg/kg/day,s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD34) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20μg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH-induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.

Metformin enhancing the antitumor efficacy of carboplatin against Ehrlich solid carcinoma grown in diabetic mice: Effect on IGF-1 and tumoral expression of IGF-1 receptors

&NA; Diabetes has been listed as a risk factor for various types of cancer. Cancer cell development can be promoted by increased levels of IGF‐1 and hyperinsulinemia that are associated with diabetes type II. Metformin is an anti‐diabetic agent and its potential antitumor impact has become the objective of numerous studies. In this vein, we hypothesize that using metformin in diabetes type II mice may synergistic with carboplatin for reducing the risk of cancer. Therefore, the study aimed to evaluate the in vivo antitumor activity of metformin against solid EAC tumor growth in female diabetic mice and its potential pro‐apoptotic and anti‐proliferative effects with clarification of its inconclusive biological mechanisms. Mice were assigned into nine groups; normal control, diabetic control, diabetic plus EAC control, EAC control, and treated groups received carboplatin and/or metformin (100, 200 mg/kg). Metformin administration especially with high dose potentiated the antitumor activity of carboplatin displayed by increased pro‐apoptotic activators “caspase‐3 and bax” and reduced anti‐apoptotic protein bcl‐2. This was confirmed by the histopathological scores. Moreover, the combination therapy was effective in attenuating the expression of the pro‐angiogenic mediator “VEGF” and the microvessel density as revealed by the CD34. Additionally, this combination down‐regulated the high levels of the mutagenic element “IGF‐1” and its receptor expression, and attenuated the intensity of inflammatory mediators. In conclusion, it was found that metformin therapy could enhance apoptotic marker, and suppress the neovascularization and proliferation process. This clarified the ability of metformin to support carboplatin activity in reducing tumor progression in type II diabetes. HighlightsThe study tests the effect of metformin against solid EAC tumor in diabetic mice.Metformin potentiated the antitumor effect of carboplatin by activating apoptosis.Additionally, metformin inhibits the angiogenic and mutagenic markers.Metformin serves as an adjuvant to classic chemotherapeutics in diabetic patients.

5-HT7 receptor antagonism (SB-269970) attenuates bleomycin-induced pulmonary fibrosis in rats via downregulating oxidative burden and inflammatory cascades and ameliorating collagen deposition: Comparison to terguride

ABSTRACT The neurotransmitter 5‐hydroxytryptamine (5‐HT) is involved in regulation of local tissue inflammation and repair through a set of receptors (5‐HT1‐7 receptors), which are expressed in the lung. Considering the protective importance of 5‐HT receptor antagonists against development of pulmonary fibrosis, we evaluated whether 5‐HT7 receptor antagonist (SB‐269970) modulates lung inflammatory and fibrogenic processes in comparison with 5‐HT2A/B receptor antagonist (terguride), in bleomycin (BLM)‐induced idiopathic pulmonary fibrosis (IPF) model. IPF model induced by a single dose of intra‐tracheal BLM instillation (5 mg/kg), and rats were treated with intraperitoneal injection of SB‐269970 (1 mg/kg day) or terguride (1.2 mg/kg/d). The experiment was carried out on two separate sets of rats that were killed at day 7th and day 21st to evaluate the endpoint of the IPF inflammatory and fibrogenic phases, respectively. During the inflammatory phase 5‐HT2A/B and 5‐HT7 receptor antagonists attenuated the BLM‐induced increase in the lung fluid content, the inflammatory cytokines levels and oxidative stress burden. In the fibrogenic phase, both SB‐269970 and terguride reduced the serotonin concentrations in lung homogenates and significantly protected against IPF fibrogenic phase by attenuating collagen deposition and mRNA expression of both transforming growth factor‐&bgr;1 (TGF‐ &bgr;1), and procollagen type | (PINP). 5‐hydroxytryptamine 5‐HT7 receptor antagonist showed more benefits than 5‐HT2A/B receptor antagonist on the deleterious effects accompanied BLM instillation. The present study showed involvement of 5‐HT7 receptor in the pathophysiology of BLM‐induced IPF in rats and identified it as a potential therapeutic target in lung fibrotic disorders.

Effects of adenosine receptor antagonists in MPTP mouse model of Parkinson’s disease: mitochondrial DNA integrity

Introduction In Parkinson’s disease (PD), compelling data indicate a functional link between adenosine/dopamine receptors and the progression of the neurodegenerative process. The present study was carried out to evaluate the effect of the non-selective adenosine receptor (ADR) antagonist caffeine, as well as the selective antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an ADRsA1 antagonist, and ((E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione) (KW-6002), an ADRsA2A antagonist, on the prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in mice. Material and methods Mice were allocated to five groups: group I – control group; group II: MPTP group, received four injections of MPTP (20 mg/kg, i.p.) at 2 h intervals; groups III, IV, V: received MPTP and i.p. caffeine (20 mg/kg/day) or DPCPX (5 mg/kg/day) or KW-6002 (10 mg/kg/day) starting one week before MPTP injection and continuing for 2 weeks. Results Therapy with caffeine or KW-6002 not only led to the reversibility of movement dysfunction and increased the concentrations of dopamine and ATP levels (p < 0.05), but also, ameliorates the dopaminergic neuron loss and restored the mtDNA and nDNA integrity (p < 0.05). Furthermore, in passive avoidance test, caffeine and DPCPX significantly (p < 0.05) reversed the MPTP-induced memory deficits, whereas the specific ADRsA2A antagonist did not. Conclusions The current results provide evidence that blockade of both ADRsA1 and ADRsA2A has therapeutic implications in alleviating MPTP-induced motor and cognitive dysfunction and might be a promising candidate for treatment of PD.