Olmesartan attenuates type 2 diabetes-associated liver injury: Cross-talk of AGE/RAGE/JNK, STAT3/SCOS3 and RAS signaling pathways.

Olmesartan (OLM), an angiotensin receptor blocker, was tested against diabetes/insulin resistance (IR) models associated with renal/cardiovascular complications. Methods: we tested its potential role against diabetes-induced hepatic hitches using an IR/type2 diabetic (IR/D) model induced by high fat/high fructose diet for 7 weeks â€‹+ â€‹a single sub-diabetogenic dose of streptozotocin (35mg/kg; i.p). IR/D rats were orally treated with OLM (10 â€‹mg/kg), pioglitazone (PIO; 5 or 10 â€‹mg/kg) or their combinations for 4 consecutive weeks. OLM alone opposed the detrimental effects of IR/D; it significantly improved metabolic parameters, liver function, and abated hepatic oxidative stress, and inflammatory cytokine interleukin-6 (IL-6) and its upstream mediator nuclear factor kappa B. Consequently, OLM turned off the downstream cue p-Jak2/STAT3/SOCS3. Moreover, it suppressed the elevated AGE/RAGE/p-JNK pathway and increased the PPARγ/adiponectin cue to signify its anti-inflammatory and anti-oxidant capacity (GSH, MDA). Nevertheless, co-administration of OLM to PIO showed a synergistic improvement in all the aforementioned parameters in a dose dependent manner. Additionally, OLM with PIO10 provoked a surge in hepatic PPARγ and adiponectin (5 and 6 folds) with a sharp decrease of about 85% in the NF-κB/IL-6/p-STAT3/SCOS3 pathway. These effects were confirmed by the histopathological study. In conclusion, OLM and its combination with PIO enhanced insulin sensitivity and guarded against hepatic complications associated with type 2 diabetes probably via modulating various inter-related pathways; namely, metabolic alteration, renin-angiotensin system, inflammatory trajectories, as well as oxidative stress. This study manifests the potential synergistic effects of OLM as an adjuvant therapy to the conventional antidiabetic therapies.

Fingolimod interrupts the cross talk between estrogen metabolism and sphingolipid metabolism within prostate cancer cells.

Sphingolipids are critical regulators of tumor microenvironments and play an important role in estrogen-dependent cancers. Estrogen and estrogen metabolites were found to be involved in prostate cancer. Fingolimod (FTY720) is a sphingokinase-1 (SphK1) inhibitor with anticancer properties against various tumor cell types. Herein, we investigated the interference of FTY720 with the cross talk between sphingolipid metabolism and estrogen metabolism within prostate cancer cells. FTY720 showed cytotoxic antiproliferative effects against androgen-dependent and -independent prostate cancer cells with IC50 ranging from 3.0 ±â€¯0.3 to 6.8 ±â€¯1.7 µM. Exposure of prostate cancer cells to FTY720 resulted in a dramatic decrease in the concentration of estradiol, estrone, 4-hydroxyestradiol and 16α-hydroxyestrone compared to control cells. However, FTY720 significantly increased the concentration of 2-methoxyestrone and 2-methoxyestradiol within prostate cancer cells. This was mirrored by significant downregulating of the expression of estrogen and catechol estrogen-synthesizing enzymes (CYP19, CYP1A1 and CYP1B1) within prostate cancer cells. On the other hand, FTY720 significantly upregulated the expression of catechol estrogen-detoxifying enzyme (COMT). Additionally, FTY720 abolished estrogen-stimulated expression of ERα and basal expression of ERß within prostate cancer cells. Furthermore, FTY720 suppressed the expression of the ER-downstream regulated genes, CXCR4 and cyclin D1. Reciprocally, it was found that estradiol and catechol estrogens significantly induced the expression of SphK1 while methoxylated catechol estrogen suppressed its expression within prostate cancer cells in a dose-dependent manner. Current research has highlighted the hazardous influence of the estrogenic component to prostate cancer. We found that fingolimod (FTY720) could modulate the estrogenic micromilieu and interrupt its cross talk with sphingolipid metabolism.

Nimesulide improves the symptomatic and disease modifying effects of leflunomide in collagen induced arthritis.

Nimesulide is a COX-2 inhibitor used for symptomatic relief of rheumatoid arthritis. Leflunomide is an anti-pyrimidine used to manage the progression of rheumatoid arthritis. Herein we studied the influence of nimesulide and leflunomide combination in terms of disease symptoms and progression using collagen-induced arthritis model in mice, as a model for rheumatoid arthritis. Collagen induced arthritis was induced by immunization with type II collagen. Assessment of joint stiffness and articular hyperalgesia were evaluated using a locomotor activity cage and the Hargreaves method, respectively. Disease progression was assessed via arthritic index scoring, X-ray imaging, myeloperoxidase enzyme activity and histopathologic examination. Nimesulide induced only transient symptomatic alleviation on the top of decreased leucocytic infiltration compared to arthritis group. However, nimesulide alone failed to induce any significant improvement in the radiological or pathological disease progression. Leflunomide alone moderately alleviates the symptoms of arthritis and moderately retarded the radiological and pathological disease progression. Combination of nimesulide and leflunomide significantly improved symptomatic (analgesia and joint stiffness) and arthritic disease progression (radiological, pathological and Myeloperoxidase enzyme activity) in collagen induced arthritis animal model.

Hepatoprotective effects of Astragalus kahiricus root extract against ethanol-induced liver apoptosis in rats.

The hepatoprotective activity of the ethanol extract of Astragalus kahiricus (Fabaceae) roots against ethanol-induced liver apoptosis was evaluated and it showed very promising hepatoprotective actions through different mechanisms. The extract counteracted the ethanol-induced liver enzymes leakage and glutathione depletion. In addition, it demonstrated anti-apoptotic effects against caspase-3 activation and DNA fragmentation that were confirmed by liver histopathological examination. Moreover, the phytochemical study of this extract led to the isolation of four cycloartane-type triterpenes identified as astrasieversianin II (1), astramembrannin II (2), astrasieversianin XIV (3), and cycloastragenol (4). The structures of these isolates were established by HRESI-MS and 1D and 2D NMR experiments. The antimicrobial, antimalarial, and cytotoxic activities of the isolates were further evaluated, but none of them showed any activity.

Nimesulide improves the disease modifying anti-rheumatic profile of methotrexate in mice with collagen-induced arthritis.

Methotrexate is a disease modifying anti-rheumatic drug that is widely used for the treatment of rheumatoid arthritis. Nimesulide is a non-steroidal anti-inflammatory drug which is frequently used as adjuvant therapy for symptomatic alleviation of rheumatoid arthritis. In this study, we have evaluated the potential influence of nimesulide on the disease modifying anti-rheumatic properties of methotrexate using the collagen-induced arthritis model. Mice were immunized with collagen type II for the induction of arthritis and treated with methotrexate (2.5mg/kg) twice a week, nimesulide (20mg/kg) every other day or a combination of both drugs. Treatment started one week after the onset of arthritis until day 40. An arthritic index was used to compare the severity of arthritis between different treatments. In addition, articular hyperalgesia, joint stiffness, radiological deterioration and intra-articular leucocytic infiltration were evaluated. Methotrexate alone showed modest but significant analgesic and anti-inflammatory effects, and the effects of nimesulide were comparable. On the other hand, nimesulide significantly improved the disease modifying anti-rheumatic profile of methotrexate in terms of arthritic index and joint mobility. Furthermore, although nimesulide failed to show any radiological evidence of articular protection, it significantly improved methotrexate-induced joint protection as judged by X-ray analysis.

Novel 3-(p-substituted phenyl)-6-bromo-4(3H)-quinazolinone derivatives of promising antiinflammatory and analgesic properties.

A new series of the title compounds incorporated into diverse N and O heterocyclic moieties of pharmacoavailability as anti-inflammatory or analgesic agents, were synthesized starting with 6-bromo-2-phenyl-4H-3,1-benzoxazin-4-one (I) by its fusion with p-aminoacetophenone to give the intermediate compound, 6-bromo-2-phenyl-3-(4-acetylphenyl)-4(3H)quinazolinone (II). The one pot reaction of II with the appropriate aromatic aldehydes and anhyd. ammonium acetate in the presence of either ethyl cyanoacetate or malononitrile afforded the corresponding 2(1H)-pyridone derivatives III or 2(1H)- iminopyridine derivatives IV, respectively, while its reaction with malononitrile and aromatic aldehydes in piperdine gave the 2-aminopyrans V. Also reaction of the acetyl derivative II with different aromatic aldehydes afforded the corresponding 1,3-propen-1-one derivatives VI which underwent cyclization with hydrazines to give the corresponding pyrazoline derivatives VII and with urea or thiourea to give the pyrimidones or pyrimidinethiones VIII. Some representative examples of the new compounds showed promising anti-inflammatory and analgesic activities in experimental animals.

Synthesis of novel tetrahydronaphthalen-2-yl heterocycles for analgesic, anti-inflammatory and antipyretic evaluation.

Condensation of 2-acetyltetralin with ethylcyanoacetate and/or malononitrile and some aldehydes in the presence of excess of ammonium acetate afforded the respective hydroxycyanopyridines or aminocyanopyridines 1a-f and 2a-f. Treatment of 2-acetyltetralin with some sulfonylhydrazides yielded the hydrazone derivatives 3a-d, respectively, which upon treatment with thioglycolic acid gave the corresponding thiazole derivatives 4a-d, respectively. Compounds 4a-d underwent cyclocondensation with different arylidene derivatives to give the corresponding pyrane derivatives 5a-d. Upon the reaction of compounds 4a-d with some secondary amines and paraformaldehyde the corresponding Mannich bases 6a,c, 7b,d and 8a,d were obtained. Compounds 1c, 1d, 1e, 2e, 3a and 3d were evaluated as analgesic, anti-iflammatory and antipyretic agents.

Effect of rosiglitazone and nateglinide on serum glucose and lipid profile alone or in combination with the biguanide metformin in diabetic rats.

UNLABELLED: This study was designed to investigate the effect of 1 month treatment with nateglinide, rosiglitazone, metformin and their different combinations on streptozotocin (STZ) diabetic rats. METHODS: Diabetes was induced by a single intraperitoneal injection of STZ at a dose 55 mg kg(-1). The plasma glucose, total lipid, cholesterol, triglyceride and protein components were measured before and 15 and 30 days after the administration of the antidiabetic agents. RESULTS: After the treatment, a significant reduction was observed in fasting blood glucose levels in all groups. Rosiglitazone or metformin were found to exhibit a hypolipidaemic effect in diabetic rats when administered alone or in combination. In comparison, nateglinide, when used alone, resulted in a significant increase in cholesterol and total lipid levels. This effect was masked when nateglinide was administered concurrently with metformin and hypolipidaemic effect was noticed. CONCLUSIONS: Results from this study suggest that compared with nateglinide, rosiglitazone has a more favorable effect on the lipid profile in STZ-induced diabetes in rats.

Studies on the glycemic and lipidemic effect of monopril and losartan in normal and diabetic rats.

The effects of the angiotensin-converting enzyme (ACE) inhibitor monopril and the angiotensin II receptor blocker losartan on serum glucose, protein levels and some serum lipid components were compared in normal and diabetic rats receiving oral antidiabetic drugs 'repaglinide or gliclazide'. The two antihypertensive agents, when administered concurrently with oral hypoglycemic agents 'repaglinide or gliclazide' in normal and diabetic rats exerted a significant hypoglycemic effect. Serum protein levels were mainly unaffected by the two antihypertensive drugs. Monopril and losartan exhibit a hypolipidemic effect in normal and diabetic rats when administered in combination with oral hypoglycemic agents 'gliclazide or repaglinide'. Monopril or losartan when used alone exerted insignificant effect in high density lipoprotein (HDL) in normal rats, while in combination with gliclazide or repaglinide caused a significant increase in HDL in normal rats. Concomitantly, monopril or losartan, when administered alone or in combination with repaglinide or gliclazide in diabetic rats exerted a significant increase in serum HDL. On the other hand, all the investigated drugs showed a significant decrease in serum low density lipoprotein (LDL) in normal and diabetic rats.

Evaluation of the anti-inflammatory and anti-nociceptive effects of different antidepressants in the rat.

The present study was designed to compare the anti-inflammatory and anti-nociceptive effects of different classes of antidepressant drugs on the carrageenan paw oedema and tail-electric stimulation assays in the rat. Drugs were intraperitoneally administered 30 min prior to carrageenan or nociceptive testing. The non-selective noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors imipramine, amitriptyline and clomipramine displayed anti-inflammatory activity in the carrageenan model of paw inflammation. The maximal degree of oedema inhibitions seen with these agents were 28.8, 41.5 and 46.8% for 5, 10 and 20 mg kg(-1) amitriptyline, 26.2, 38.2 and 51.4% for 3.75, 7.5 and 15 mg kg(-1) imipramine and 51.2 and 54.1% for 16 and 32 mg kg(-1) clomipramine, respectively. The heterocyclic agent trazodone significantly inhibited paw oedema by 46 and 41% at 1 and 2h after dosing at the highest dose (40 mg kg(-1)) examined. Fluoxetine, a selective 5-HT reuptake inhibitor (SSRI) caused dose-related reduction of paw oedema, with 20.7% inhibition at the dose of 10 mg kg(-1). In contrast, sertraline, another SSRI caused dose-dependent enhancement of paw oedema. All antidepressant drugs in the study showed anti-nociceptive properties in the tail-electric stimulation assay with amitriptyline and trazodone being the most effective in this respect. Taken together, data in the present study confirm anti-inflammatory and anti-nociceptive effect for some antidepressant drugs and indicate that SSRIs differently affects inflammation.