Protective effect of atorvastatin on oxidative stress in streptozotocin-induced diabetic rats independently their lipid-lowering effects.

In the present study, we investigate the effects of atorvastatin on the lipid profile, oxidative stress, and liver enzyme markers, and its protective activity against diabetic complications, in streptozotocin (STZ)-induced diabetic rats. Fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), and high-density lipoprotein (HDL) levels, as well as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme activities, were measured 7 weeks after the administration of STZ and atorvastatin. Thiobarbituric acid reactive substances (TBARS), non-protein associated sulfhydryl (NP-SH), total sulfhydryl (T-SH), and nitric oxide (NO) levels were measured to evaluate oxidative stress. Atorvastatin was found to inhibit ALT and AST activities and to reduce FBG levels in rats with STZ-induced diabetes. Moreover, atorvastatin treatment significantly reduced lipid peroxidation in kidney, heart, and eye tissues (P < 0.001, for all), and resulted in a significant increase in NP-SH levels in brain tissues (P < 0.001). Total NO and nitrate levels increased significantly after atorvastatin treatment (P < 0.01). Our results revealed that atorvastatin has a protective effect against STZ-induced oxidative damage by reducing TBARS levels and increasing NP-SH levels, has a hepatoprotective effect by decreasing ALT and AST activities. It also shows the antihyperglycemic activity by lowering FBG levels.

Synthesis and characterization of celecoxib derivatives as possible anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV agents.

A series of novel N-(3-substituted aryl/alkyl-4-oxo-1,3-thiazolidin-2-ylidene)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamides 2a-e were synthesized by the addition of ethyl a-bromoacetate and anhydrous sodium acetate in dry ethanol to N-(substituted aryl/alkylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]benzene sulfonamides 1a-e, which were synthesized by the reaction of alkyl/aryl isothiocyanates with celecoxib. The structures of the isolated products were determined by spectral methods and their anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV NS5B RNA-dependent RNA polymerase (RdRp) activities evaluated. The compounds were also tested for gastric toxicity and selected compound 1a was screened for its anticancer activity against 60 human tumor cell lines. These investigations revealed that compound 1a exhibited anti-inflammatory and analgesic activities and further did not cause tissue damage in liver, kidney, colon and brain compared to untreated controls or celecoxib. Compounds 1c and 1d displayed modest inhibition of HCV NS5B RdRp activity. In conclusion, N-(ethylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (1a) may have the potential to be developed into a therapeutic agent.

Investigation of antioxidant properties of some 6-(alpha-aminobenzyl)thiazolo[3,2-b]-1,2,4-triazole-5-ol compounds.

Promising antiinflammatory activity together with low ulcerogenic properties of some Michael addition products of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones which have been synthesized in our previous study, prompted us to investigate their antioxidant properties. Since compound Ib has both antioxidant and antiinflammatory activities beside the lowest ulcerogenic incidence, it was selected for investigation of its inhibitory effect on various cyclooxygenase ezymes. It was found that while it did not inhibit cyclooxygenase-1 (COX-1) enzyme, there was a small inhibitory effect (17%) on COX-2 enzyme. We concluded that the diminished harmful effects on the stomach of this novel antiinflammatory compound were related to its antioxidant properties since it is ineffective on COX-1 enzyme. In conclusion, the compounds having both antioxidant and antiinflammatory activities with a lack of COX-1 enzyme inhibitory effect may improve the gastrointestinal safety profile of such compounds.

Synthesis and characterization of some new 2(3H)-benzoxazolones with analgesic and antiinflammatory activities.

The synthesis, characterization and pharmacological activities of a new series of (6-difluorobenzoyl)-5-methyl-3-benzoylmethyl-2(3H)-benzoxazolone and 5-methyl-3-(2-hydroxyl-2-phenylethyl)-2(3H)-benzoxazolone are described. Antiinflammatory activity was investigated by the carrageenin-induced paw oedema test and analgesic activity by acetic acid writhing and hot plate tests in mice. Among the synthesized compounds, compound 3e 6-(2,5-difluorobenzoyl)-3-(4-bromobenzoylmethyl-2(3H)-benzoxazolone was found to be the most promising compound for analgesic activity. Reduced compounds (4a-4d) displayed considerable anti-inflammatory activity compared to the other derivatives.

Novel 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines: synthesis, characterization, and evaluation of analgesic/anti-inflammatory, antioxidant activities.

In this study, the synthesis of a new series of 3,6-disubstituted-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine 1a-4c compounds derived from 4-amino-3-substituted-1,2,4-triazole-5-thiones 1-4 is described. All of the synthesized compounds were screened for their possible analgesic / anti-inflammatory, antioxidant activities and gastric toxicity. The compound 2c was found to have both significant analgesic and consistent anti-inflammatory activity without inducing any gastric lesions along with minimal lipid peroxidation. A deep insight into the structures of the active compounds revealed that the compounds carrying an electron withdrawing group (a chloride or fluoride) on the phenyl ring at 6-position of the condensed heterocyclic derivatives exhibited noticeable higher activity.

Effects of benzo(a)pyrene and ethanol on oxidative stress of brain, lung tissues and lung morphology in rats.

Ethanol and benzo(a)pyrene cause lipid peroxidation either by producing the reactive oxygen species or decreasing the activities of antioxidant enzymes that lead to cellular damage and cellular dysfunction. In this study, we investigated both physiological and histological changes in lung and physiological changes in brain after the administration of benzo(a)pyrene and ethanol both separately and together. Male Sprague Dawley rats were divided into four groups, each containing seven rats as follows: Group I (control), group II (benzo(a)pyrene, [B(a)P]), group III ([B(a)P] + ethanol (EtOH)) and group IV (EtOH). Superoxide dismutase (SOD) activity, levels of glutathione(GSH), malondialdehyde (MDA) as well as histological examinations were evaluated to demonstrate the damages in lung and brain tissues following the administration of [B(a)P] and EtOH. SOD activities of lung and brain tissues in group II and group III decreased significantly, compared to that in group I and group IV, respectively. GSH levels of both the lung and brain tissues in the experimental groups were lower when compared to the control group. MDA levels of lung tissues in group II and III were significantly higher than that in the control group. Moreover, MDA levels in the brain tissues of all the experimental groups were higher than that in the control group, but these values were only significantly higher in group II and IV. In the second study group, [B(a)P] administration resulted in lung damage. On the other hand, lung tissue of the third experimental group showed moderate damage, and lung tissues of the fourth group was less severely damaged. [B(a)P] and EtOH administration alone or together caused changes in the GSH, MDA levels and SOD enzyme activity in the lung and brain tissues. We also noted that [B(a)P] and EtOH caused different degrees of histological changes.

A Guidance Manual for the Toxicity Assessment of Traditional Herbal Medicines.

Herbal remedies have been used for thousands of years in worldwide traditional medicines for their potential health benefits. Although they are generally presumed safe unless a significant risk has been identified in humans, increasing number of case reports notify acute or chronic intoxications resulting from their use. This study aims to produce a scientific guide for the evaluation of traditional herbal medicines (THMs) in terms of their toxicity risks based on the published regulatory documents. For this purpose recommended in vitro and in vivo toxicity tests on medicinal products for human use issued by the international regulatory bodies are overviewed and they are then adopted to be used for the toxicity assessment of THMs. Accordingly, based on compilation of these issued regulations, the following tests are recommended for the toxicity assessment of THMs; in vitrocytotoxicity, genotoxicity, acute and repeated dose toxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance tests, toxicokinetic studies, and additional toxicity tests including safety pharmacology, immunotoxicity and antigenicity, endocrine system toxicity, gastro-intestinal toxicity, renal and hepatotoxicity, and drug interaction studies. This study describes and discusses the applicability of these tests for the risk assessment in THMs.

Protective effects of thiazolo[3,2-b]-1 ,2,4-triazoles on ethanol-induced oxidative stress in mouse brain and liver.

A series of 3-[1-(4-(2-methylpropyl) phenyl) ethyl]-1 ,2,4-triazole-5-thione (I) and its bicyclic condensed derivatives 6-benzylidenethiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones (IIa-IIf) were investigated for the prevention of ethanol-induced oxidative stress in liver and brain of mice. Administration of ethanol (0.1 mL/mice, p.o.) resulted in a drop of total thiol groups (T-SH) and non-protein thiol groups (NP-SH), and an increase in thiobarbituric acid reactive substances (TBARS) in both liver and brain tissue of mice (p < 0.001). Among the compounds investigated (at a dose of 200 mg/kg, p.o.), I and IId ameliorated the peroxidative injury in these tissues effectively. Compounds IIa, IIc and IIe improved the peroxidative tissue injury only in brain. These findings suggest that certain condensed thiazolo-triazole compounds may contribute to the control of ethanol-induced oxidative stress in an organ selective manner.

Evaluation of hepatoprotective effect of Gentiana olivieri herbs on subacute administration and isolation of active principle.

Hepatoprotective effect of Gentiana olivieri Griseb. (Gentianaceae) flowering herbs on subacute administration were studied using in vivo models in rats. For the activity assessment on carbon tetrachloride-induced hepatic damage following biochemical parameters were evaluated; plasma and hepatic tissue malondialdehyde formation, and liver tissue glutathione level, as well as plasma transaminase enzyme levels (aspartate transferase and alanine transferase). Results of biochemical tests were also confirmed by histopathological examination. Through bioassay-guided fractionation procedures isoorientin, a known C-glycosylflavone, was isolated from the ethyl acetate fraction as the active antihepatotoxic constituent by silica gel column chromatography. Isoorientin exhibited significant hepatoprotective effect at 15 mg/kg b.w. dose.

Synthesis of some 1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones with potential analgesic and antiinflammatory activities.

Starting from 3-substituted-1,2,4-triazole-5-thiones (la-h), eight new 5-carbomethoxy-2-substituted-7H-1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones (2a-h) were synthesized and characterized by spectral and elementary analysis. The obtained compounds were submitted to preliminary pharmacological assay to evaluate their antiinflammatory and analgesic activities as well as gastrointestinal irritation liability and acute toxicity. Among the compounds studied, compounds 2c, 2d, 2e and 2h showed most remarkable antiinflammatory activity in the carrageenan and serotonin induced edema and in the inhibition of castor oil-induced diarrhea tests. The analgesic activity of these active compounds correlated with their antiinflammatory activities in the inhibition of acetic acid-induced writhing test. In gastric ulceration studies, the compounds were found safety at low dose levels (10 and 20 mg/kg).

Influence of dihydropyridine calcium antagonist nitrendipine on benzo(a)pyrene-induced oxidative stress.

The aim of this study was to investigate the influence of nitrendipine (NIT), a dihydropyridine derived calcium channel antagonist, on polycyclic aromatic hydrocarbon benzo(a)pyrene (BAP)-induced oxidative stress. Male Sprague Dawley rats (155-220 g) were divided into four groups: Control (corn oil, i.p.); BAP (200 mg/kg, i.p.), BAP + NIT (200 mg/kg, i.p. + 50 mg/kg, i.p.), and NIT (50 mg/kg, i.p.) groups. Twenty-four hours after the injection of BAP, the rats were sacrificed and blood samples, liver, lung, and brain tissues were removed to determine serum alanine transaminase (ALT), aspartate transferase (AST), and gamma-glutamyltransferase (GGT) activities and tissue thiobarbituric acid reactive substances (TBARS), glutathione (GSH), and superoxide dismutase (SOD) levels. BAP significantly elevated serum ALT and TBARS levels in all tissues. However, NIT pre-treatment protected against increasing TBARS levels in lung and brain tissues. In addition, NIT pre-treatment significantly increased SOD levels in lung and liver tissues, as well as GSH levels in the lungs, compared to the BAP group. Thus, in conclusion, further studies are required to confirm the protective effects of calcium channel blockers, especially in liver tissue.

Synthesis of 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines as novel analgesic/anti-inflammatory compounds.

In this study, a new class of 4-amino-3-substituted-1,2,4-triazole-5-thiones (1-4) and their corresponding condensed derivatives 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (1a-4c) were synthesized and evaluated for their analgesic/anti-inflammatory activities. All synthesized compounds were also tested for their gastric toxicity and antioxidant activity on acute administration. Most of the compounds showed significant activity in both carrageenan-induced oedema and acetic acid-induced writhing tests besides negligible gastrointestinal toxicity. The compounds showing less ulcerogenic effect also showed less lipid peroxidation (LPO) level. Most promising results were obtained with the compounds that placed a fluoro or a chloride on the phenyl ring at the sixth position of the fused ring.

1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones, 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones: synthesis, analgesic-anti-inflammatory and antimicrobial activities.

Acetic acid hydrazide containing 5-methyl-2-benzoxazolinone (4) was synthesized by the condensation of 2-(5-methyl-2-benzoxazolinone-3-yl)acetate with hydrazine hydrate. Thiosemicarbazide derivatives (5a-5d) were afforded by the reaction of corresponding compound 4 with substituted isothiocyanates. The cyclization of compounds 5a-5d in the presence of triethylamine resulted in the formation of compounds 6a-6d containing 1,2,4-triazole ring. On the other hand, the treatment of compounds 5a-5d with orthophosphoric acid caused the conversion of side chain of compounds 5a-5d into 1,3,4-thiadiazole ring: thus, compounds 7a-7c were obtained. The treatment of compound 4 with aromatic aldehydes resulted in the formation of arylidene hydrazides as cis-trans conformers (8a-8e). The structures of the compounds were elucidated by spectral and elemental analysis. While most compounds were exhibiting high activity in the analgesic-anti-inflammatory field, most of them were found to be inactive against bacteria and fungi.