Does combined peroxisome proliferator-activated receptors-agonist and pravastatin therapy attenuate the onset of diabetes-induced experimental nephropathy?

To investigate the combined effects of rosiglitazone and pravastatin on renal functions in early streptozotocin induced diabetic nephropathy [DN]. This study was carried out at King Khalid University Hospital Animal House, Riyadh, Saudi Arabia from August 2013 to February 2014. Fifty male Wistar rats were assigned to normal control rats and diabetic rats that received saline, rosiglitazone, pravastatin, or rosiglitazone+pravastatin for 2 months. Their weight range was 230-250 gm, and age range was from 18-20 weeks. At the end of experiment, creatinine clearance, and urinary albumin to creatinine ratio [ACR] were measured. Blood samples were analyzed for transferrin, glycosylated hemoglobin [HbA1c], lipid profile, tumor necrosis factor-alpha [TNF-alpha], intercellular adhesion molecule-1 [ICAM-1], and lipid peroxide. Rosiglitazone treatment increased creatinine clearance and plasma transferrin, and decreased urinary ACR, HbA1c, plasma TNF- alpha, ICAM-1, and serum lipid peroxide levels without affecting the altered lipid profile. Pravastatin treatment produced similar results and normalized the lipid alteration. The combination of rosiglitazone and pravastatin was more effective in attenuating the diabetes-induced nephropathy compared with treatment with either drug alone. The combination strategy of rosiglitazone and pravastatin may provide a potential synergistic renoprotective effect against DN by improving renal functions and reducing indices of DN

Polimorfismo Gly482Ser del gen coactivador-1a dl receptor activado de proliferación de los peroxisomas y en individuos de la ciudad de Maracaibo estado Zulia Venezuela: estudio preliminar / Gly482Ser polymorphism of the coactivator-1a of the activated receptor of peroxisone y proliferation in individuals from Maracaibo Venezuela

El objetivo de este estudio fue determinar la asociación entre el polimorfismo Gly482Ser del gen PGC-1 con resistencia a la insulina y la diabetes mellitus tipo 2 en individuos de la ciudad de Maracaibo. Se estudiaron 64 individuos no diabético (36 sin resistencia a la insulina, 28 resistentes a la insulina) y 13 diabéticos tipo 2. Se realizó una historia clínica nutricional que incluyó la evaluación de parámetros antropométricos. Se midieron los niveles de glicemia e insulina basal, colesterol total, HDL-C y LDL-C. El polimorfismo Gly482Ser fue detectado empleando la reacción en cadena de la polimerasa y polimorfismo de restricción de fragmentos largos. Se encontró que las frecuencias alélicas para A y G resultaron 0,36 y 0,64 respectivamente. La población se encontró en equilibrio genético de Hardy Weinberg. Al asociar los genotipos del polimorfismo Gly482Ser con la resistencia a la insulina y la diabetes mellitus tipo 2, no se encontró asociación estadística significativa (OR=1,320, p=0,74; OR=2, p=0,47 respectivamente). Sin embargo, los individuos diabéticos con genotipo AA presentaron valores de LDL-C más elevados (p<0,05) que los individuos con el genotipo GG y GA. Los diabéticos con el genotipo GA mostraron concentraciones significativamente elevadas de triglicéridos (>150 mg/dL) comparados con los del genotipo GG. De acuerdo a los resultados obtenidos, el polimorfismo Gly482Ser del gen PGC-1 podría contribuir al riesgo cardiovascular en los individuos diabéticos tipo 2, mientras que en los individuos resistentes a la insulina este polimorfismo no estuvo asociado a factores de riesgo cardiovascular.

The aim of this study was to determine the association of the Gly482Ser polymorphism of the PGC-1 gene with insulin resistance and type 2 diabetes mellitus in subjects from the city of Maracaibo. The study was performed on 64 no-diabetic subjects (36 without insulin resistance and 28 with insulin resistance) and 13 with type 2 diabetes. A clinical and nutritional history was carried out and the evaluation of anthropometric parameters was included. Fasting serum glucose, fasting serum insulin, total cholesterol, HDL-C and LDL-C, were measured. The Gly482Ser polymorphism was detected by PCR-RFLP. It was found that the allelic frequencies for A and G were 0.36 and 0.64, respectively. The population was found in genetic equilibrium of Hardy Weinberg. The genotypes of the polymorphism Gly482Ser were not associated with insulin resistance and type 2 diabetes mellitus (OR=1.320, p=0.74; OR = 2, p=0.47 respectively). Nevertheless, the diabetic subjects with the genotype AA presented values of LDL-C higher (p<0.05) than the individuals with the genotypes GG and GA. The diabetics with the genotype GA showed significantly higher concentrations of triglycerides (>150 mg/dL) compared with the genotype GG. According to the results, the polymorphism Gly482Ser of the PGC-1 gene would be able to contribute to the cardiovascular risk in type 2 diabetics, while in the insulin resistant individuals, this polymorphism was not associated with cardiovascular risk factors.

Estudo para participação do receptor nuclear PPARy na resposta do hospedeiro frente à infecção por Mycobacterium bovis, BCG / Study for involvement of nuclear receptor PPARy in front of the host response to infection by Mycobacterium bovis, BCG

Os macrófagos são os principais agentes de defesa contra patógenos intracelulares e têm importante papel no metabolismo de lipídios e processos inflamatórios. Vários estudos demonstraram a participação de macrófagos “espumoso” durante a infecção intracelular por microbactérias, mas seu significado funcional é pouco entendido. Nosso laboratório tem mostrado que os corpúsculos lipídicos são organelas dinâmicas e funcionalmente ativas, que funcionam com sítios de sinalização em leocócitos para regulação do metabolismo lipídico e síntese de mediadores inflamatórios. Os mecanismos que regulam o acúmulo intracelular de lipídios, bem como a ativação de fatores transcricionais envolvidos no metabolismo lipídico de macrófagos, durante processos infecciosos, e seu signficado na patofisiologia e no curso de doenças desencadeadas por patógenos intracelulares não são completamente entendidos. Os Receptores Ativados por Proliferadores de Peroxissomos (PPARs) atuam em vários processos inflamatórios e imunoregulatórios devido à propriedade de regular a expressão de vários genes, estando desta maneira implicados na patofisiologia da aterosclerose, inflamação, diabetes e resposta imune. O papel do PPARy na resposta do hospedeiro frente à patógenos ainda não se encontra esclarecido. Assim nosso objetivo foi caracterizar o envolvimento do receptor nuclear PPARy na resposta do hospedeiro frente a infecções pelo patógeno intracelular Mycobacterium bovis, BCG. Em paralelo, investigamos o papel do receptor Toll-like 2 (TLR2) e outras moléculas sinalizadoras com CD14, CD11b/CD18, CD36, dectina-1 além de lipid rafts na resposta inflamatória durante a infecção por BCG. Nossos resultados demonstram que a infecção de macrófagos peritoneais de camundongos por M. bovis, BCG in vitro induziu aumento da expressão de PPARy, o qual foi acompanhado pela indução da formação de corpúsculos lipídicos, bem como aumento da produção de mediadores inflamatórios como PGE2 e citocinas. A expressão de PPARy e a produção de corpúsculos lipídicos e mediadores inflamatórios foram drasticamente inibidas em camundongos deficientes para o receptor TLR2, sugerindo um papel importante do TLR2 neste fenômeno. Demonstramos também que ativação de macrófagos in vitro pro agonistas de TLR2 (M. smegmatis, Pam3cys e zimosan) não foi capaz de induzir formação de corpúsculos lipídicos, sugerindo que ativação de TLR2, embora essencial para induzir expressão de PPARy ou formação de corpúsculos lipídicos na infecção, não é suficiente para desencadear vias de formação de corpúsculos lipídicos, indicando que outros co-fatores podem esta envolvidos. Nós verificamos de maneira significativa o envolvimento de CD14, CD11b, CD36, lipid raffs e dectina-1, na formação de corpúsculos lipídicos e produção de mediadores inflamatórios. Além disso, a neutralização do CD36 levou à inibição da expressão de PPARy induzida por BCG. Desta maneira sugerimos que a infecção por BCG altera significativamente os níveis de expressão de PPARy de maneira dependente de TLR2 e CD36 e que receptores nucleares ativados por lipídios podem modular a formação de corpúsculos lipídicos, síntese de PGE2, e a função de macrófagos durante infecções micobacterianas. O estudo da regulação e ativação de PPARy durante infecções por patógenos intracelulares poderá trazer contribuições sobre os mecanismos básicos de interação e escape na resposta patógeno-hospedeiro e poderá contribuir para a identificação de novos alvos terapêuticos para a tuberculose.

Modulação da ativação dos receptores ativados por proliferadores de peroxissoma (PPAR) e dos receptores X hepáticos (LXR) por LN´O IND. 2´ / Modulation of activity of peroxissome prolifetor-activated (PPAR) and liver X receptors(LXR) by LN´O IND. 2´

A atividade dos receptores ativados por proliferadores de peroxissoma (PPAR) e receptor X hepático (LXR) são regulados por ácidos graxos. Entretanto, o papel do LNO2, um produto endógeno da nitração do ácido linoléico por espécies reativas derivadas de óxido nítrico (•NO), na via de sinalização que regula a ativação destes receptores ainda não está elucidada. Assim, considerando a propriedade do LNO2 como doador de NO, nós investigamos a participação da via de sinalização p21Ras/Raf/ERK na ativação de PPAR e LXR por LNO2. Os resultados obtidos demonstraram que LNO2, na concentração de 0.01µM, foi um potente ativador de PPAR quando comparado ao ligante natural ácido linoléico, o qual apresentou ativação equivalente do PPAR na concentração de 0.01µM. O LN02, contudo não teve efeito na ativação de LXR. LNO2 foi um potente ativador de p21Ras quando comparado ao ácido linoléico. A ativação de Ras ocorreu após 5 minutos de incubação com LNO2 em células parentais. Entretanto, em células transfectadas com p21RasC118S, o LNO2 não foi capaz de ativar Ras. A ativação de Ras e PP AR foi dependente da liberação de NO a partir de LN02, o que foi evidenciado na presença de C-PTIO, um seqüestrador de NO. LNO2 ativou ERK, mas não demonstrou efeito relevante na ativação de p38 MAP kinase...

comparative study between influence of rosiglitazone; a peroxisome proliferator-activated receptor gamma [PPARS] agonist, and corticosteroids on experimentally induced asthma in guinea pigs

Dugs used currently to treat asthma have limitations partly due to their undesired effects. PPARgamma agonists including rosiglitazone may offer additional therapeutic advantages to current treatment. The aim of the present study was to assess the anti-inflammatory potential of a PPARi agonist, rosiglitazone, locally delivered by means of nebulization in a guinea pig model of asthma, in comparison with that of the corticosteroid budesonide. Five groups of guinea pigs were used, five animals each. The first group was Sham -sensitized guinea pigs; the other four groups were sensitized by ovalbumin [OVA] by allergen solution containing 100 micrograms OVA and 100 mg Al [OH]3 per ml saline. 0.5 ml was injected intraperitoneally, while another 0.5 ml of the solution was divided over seven intracutaneous injection sites. The second group was OVA-sensitized and exposed to inhalation of saline. The third, fourth and fifth group were OVA albumin-sensetized. The third group was treated with vehicle inhalation, The fourth group was treated with rosiglitazone and the fifth group was treated with budesonide. Animals in the last 3 groups were exposed to allergen provocation procedure [Ag challenge] from weeks 4 to 5 after OVA sensitization. Assessment of asthma was done by studying the effect of rosiglitazone and budesonide on airway hyper responsiveness [AHR] to acetylcholine [Ach], inflammatory cellular changes in bronchoalveolar lavage and histopathological changes. The effect of rosiglitazone and budesonide pretreatment on histamine induced contraction of isolated OVA sensitized guinea pig tracheal spiral strips was also investigated. In addition, the direct effect of rosiglitazone and budesonide incubation on histamine induced contraction of isolated guinea pig tracheal spiral strips was examined. The results revealed that one week pre-treatment with rosiglitazone [20 minutes inhalation in a dose of 300 microg/ Kg/ day] and budesonide [20 minutes inhalation in a dose of 2mg/ Kg/ day] resulted in significant reduction in airway hyperreactivity to inhaled Ach, inflammatory cellular content in bronchoalveolar lavage fluid [BALF] and improvement in histopathological changes of asthmatic lung. There was no significant difference between both drugs as regard improvement of AHR, reduction in thickness of the interalveolar septum, decrease in total leucocytic count [TLC], count of lymphocytes and macrophages. However, budesonide caused significant reduction in eosinophils and macrophages count in comparison to rosiglitazone. In addition, rosiglitazone had a direct relaxant effect on airway smooth muscle. The results provided evidence for the therapeutic potential of inhaled PPARi agonist, rosiglitazone, in the treatment of airway asthmatic inflammation. In addition PPARgamma agonists had a direct relaxant effect on the isolated tracheal smooth muscle

effect of peroxisome proliferator - activated gamma agonist on resistin in obese rats with type 2 diabetes

Adipocytes are highly differentiated cells and numerous genes are expressed significantly in fat cells, resistin is an adipocytokine highly expressed in murine adipose tissue. Peroxisome proliferator-activated gamma agonists [PPAR] down-regulate resistin gene expression in adipose tissue. The aim of the present work is to clarify the effect of peroxisome proliferator-activated gamma agonist [rosiglitazone] on resistin in obese rats and obese rats with type 2 diabetes. Forty eight white albino male rats of 150-250gm average weight were randomly divided into group 1: Control group [n=8], group 2: [n=8] rats received rosiglitazone, group 3s [n=32] obese rats, this group subdivided into group 3a: Obese rats recieved the drug [n=8]. Group 3b: Obese rats after induction of type 2 diabetes, Group 3c: Obese rats with diabetes and rosiglitazone [n=8]. At the time of scarification blood was collected and samples from central fat and peripheral fat was taken. The following parameters were assessed, serum glucose, triglycerides, cholesterol, insulin, serum resistin and resistin in fats. The results of the present work showed that serum glucose, insulin, triglycerides and cholesterol were significantly higher in [group 3, group 3b] compared to the control while their levels decreased after administration of the drug [Group 3c]. As regard resistin level in serum, central fat and peripheral fat were significantly higher in [group 3 and group 3b] compared to the control however its level significantly decrease after rosiglitazone administration. Also significant correlation were found between serum resistin and serum glucose, serum triglycerides and body mass index in all studied groups. Conclusion resistin seems to play an important role in development of type 2 diabetes particularly on top of obesity and its response to [PPAR] agonist may be used to relive insulin resistance in type 2 diabetes

Rosiglitazone Activates AMPK and Improves Non-Alcoholic Fatty Liver Disease in OLETF Rats / 당뇨병

BACKGROUND: Insulin resistance is very common in patients with nonalcoholic fatty liver disease (NAFLD). Glitazones improve insulin sensitivity by acting as a selective agonist of the peroxisome proliferators -activated receptor gamma (PPAR gamma), and were shown to activate AMP-activated protein kinase (AMPK) in skeletal muscle and the liver. Glitazones were also shown to reduce hepatic lipogenesis. The aim of this study was to investigate whether the protective mechanism of rosiglitazone on NAFLD is associated with AMPK activation. METHODS: Twelve OLETF rats were divided into 2 groups (control, treatment, n = 6 each). LETO rats served as controls. At 35 weeks of age, treatment group received rosiglitazone 4 mg/kg daily for 3 days. Fasting plasma glucose, insulin, free fatty acid, lactate and triglycerides were measured. Liver tissues from each group were processed for histological and hepatic triglyceride content analysis and western blotting. RESULTS: Fasting plasma glucose, insulin and triglycerides levels were significantly lower in treatment group than in control group. Histologic examination disclosed decreased hepatic steatosis in treatment group. Hepatic triglyceride content was also decreased in treatment group. Sterol regulatory binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) expression were increased and AMPK phosphorylation was reduced in OLETF rats compared with LETO rats, and these changes were reversed by rosiglitazone treatment. CONCLUSION: Rosiglitazone reduced hepatic steatosis in OLETF rats, and activated AMPK in the liver. These results suggest the role of AMPK activation in the protective action of rosiglitazone on NAFLD.

The Effects of Dietary Interventions on mRNA Expression of Peroxisome Proliferator Activated Receptor Isoforms (PPAR Isoforms)in Rat Skeletal Muscle

We determined the effects of dietary manipulations on messenger RNA of peroxisome proliferators activated receptor isoforms (i.e., PPAR alpha, beta/delta, gamma)in red vastus lateralis muscle of rats. Total 16 male Sprague-Dawley rats were used, and animals were divided into one of two dietary conditions :either chow diet group (CHOW ;n =8 )in which animals were fed with standard rodent chow (61.8% carbohydrate, 15.7% fat, 22.5% protein )or high fat diet group (FAT n =8 ) in which animals were fed 24.3% carbohydrate, 52.8% fat, 22.9% protein. At the end of the 8 weeks of experimental pe-riod, red vastus lateralis muscle was dissected out from all animals, and PPAR alpha, beta/delta, gamma mRNA expression was deter-mined. There was no significant difference in body mass (BM )between CHOW and FAT. As expected, blood glucose and free fatty acid (FFA )concentration was higher in FAT than CHOW (p <0.05 ), and lactate concentration was significan-tly lower in FAT compared to CHOW (p <0.05 ). Insulin concentration tended to higher in FAT than CHOW (67.2 +/- 21.9 vs. 27.0 +/-5.2 pmol/L ), but it did not reach to the statistical significance. Gene expression of PPAR alpha was not signifi-cantly different between CHOW and FAT. It was not also significantly different in PPAR beta/delta. Interestingly, expression of mRNA in PPAR gamma however, was markedly depressed in FAT compared to CHOW (approximately 3 fold higher in CHOW ; p <0.05 ). Results obtained from present study implies that PPAR gamma (as compensatory function of PPAR alpha is expressed ) possibly exerts another major tuning roles in fatty acid transport, utilization, as well as biosynthesis in skeletal muscle cells. The situations and conditions that can be postulated for this implication need to be further examined.

Human peroxisome proliferator-activated receptor 2 [PPAR 2] pro 12 Ala polymorphism: a possible association with risk of diabetic nephropathy in type 2 diabetes

Mutations of the nuclear receptors PPAR-gamma confer an extreme phenotype of partial lipodystrophy, early-onset severe insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and hepatic steatosis. The association between the Pro 12 Ala polymorphism in PPAR-gamma and obesity, insulin sensitivity, and type 2 diabetes was studied. It appears that the Ala 12 allele confers modest protection against the onset of type 2 diabetes and is also associated with an increased BMI in overweight individuals. This study was conducted to investigate an association between Pro 12 Ala polymorphism and the incidence of diabetic nephropathy in obese patients with long-lasting type 2 diabetes. The study was carried on sixty patients with type 2 diabetes mellitus, they were divided to 2 groups, group 1 included 30 patients with diabetic nephropathy and group 2 include 30 patients without diabetic nephropathy. Thirty healthy subjects of matched age and sex were included as controls [group 3]. Pro 12 Ala polymorphism was statistically significant more frequent in the diabetic group without nephropathy [group 2] in comparison to diabetic patients with nephropathy [group 1] p<0.0001, and the control group [group 3], p<0.0001. but there was no significant difference between the diabetic nephropathy group [group 1] and control group [group 3]. PPAR gamma receptor polymorphism was positive in 7 patients [23.33%] and negative in 23 patients [76.67%] of the diabetic nephropathy group [group 1]. In the diabetic group without diabetic nephropathy, it was positive in 24 patients [80%], negative in 6 patients [20%]. On the other hand, patient with diabetic nephropathy [group 1] associated with hypertension [21 patients] were all negative regarding PPAR gamma Pro 12 Ala polymorphism. Whereas, those without hypertension only 2 out of 9 patient were negative and the remaining 7 cases were positive regarding polymorphism. There were no significant differences between the two diabetic groups of patients regarding BMI, lipid profile and duration of diabetes. There was also no association between PPAR polymorphism and duration of diabetes, BMI and any of the biochemical parameters measured. In conclusion, the presence of the Ala allele of the PPAR gamma Pro 12 Ala polymorphism seems to be associated with a decreased risk of diabetic nephropathy in patients with type 2 diabetes. This association needs to be confirmed in other patient populations. More basic studies will be required to uncover the molecular mechanisms underlying the association between PPAR gamma Pro 12 Ala polymorphism and diabetic nephropathy risk

PPAR-gamma agonists: antioxidant and metabolic effects in fructose induced insulin resistant rats

The aim of the present study was to investigate oxidative stress in fructose induced model of insulin resistance in albino rats via measuring plasma superoxide dismutase enzyme [SOD enzyme]. Additionally, the present work compared the effects of two different insulin sensitizers, pioglitazone and rosiglitazone, on plasma glucose, plasma insulin, SOD enzyme, lipid profile, blood pressure and vascular reactivity in fructose induced model of insulin resistance in albino rats. The results revealed 20.38%* reduction of the superoxide dismutase enzyme in insulin resistant rats compared with the control. However, after giving PPAR-y agonists, pioglitazone and Rosiglitazone for 4 weeks, there was significant rise in SOD enzyme by 44.6 l%* in the former group compared to the latter, where there was significant rise by only 32.21%*. These PPAR-y agonists, also showed significant improvement in glycemic control, insulin resistance index, systolic blood pressure and specially lipid profile. The results of the present work indicate that these two agents have a promising place in the treatment of insulin resistance syndrome in humans not only due to their metabolic effects, but also due to their antioxidant action. In vitro experiments also revealed that pretreatment with pioglitazone and rosiglitazone were associated with blunting in aortic ring contractile response towards phenylephrine and enhanced endothelial dependent relaxation response to acetylcholine, compared to insulin resistant untreated group. Both drugs produced significant increase of effective concentration 50 [EC50] of phenylephrine by 60.7%* and 32.4%* respectively. Similarly, both drugs produced significant increase acetylcholine induced relaxation by 549%* and 40.8%* respectively when compared to insulin resistant group. However, pioglitazone proved to be more potent. These results are in accordance with the lowering of elevated systolic blood pressure in vivo experiments produced by both drugs

A peroxisome proliferator response elements regulatory system in xenopus oocytes and its application / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a kind of ligand-activated transcription factors binding to peroxisome proliferator response element (PPRE), a specific recognition site. It is thought to play a critical role in glucose and lipid metabolism and in inflammation control. The aim of this study was to establish a new cellular model for the quick screening of lipid-lowering drugs, which may be effective as PPAR-gamma ligands on the PPRE-mediated pathway regulatory system.</p><p><b>METHODS</b>Two plasmids were constructed: pXOE-PPARgamma, in which the human PPARgamma gene was in the downstream of TFIIIA gene promoter, and pLXRN-PPRE-d2EGFP, in which the enhanced green fluorescent protein (EGFP) gene was subcloned into PPRE. The xenopus oocytes were injected with these two plasmids, and consequently treated with prostaglandin E1, pioglitazone, and different kinds of lipid-lowering drugs. After 3 days, the oocytes were observed under a fluorescence microscope. To confirm the drug action,we injected pXOE-PPARgamma plasmid into the oocytes, which then treated with prostaglandin E1 and Hawthorn flavonoids. The mass of expressed lipoprotein lipase (LPL) in the cells was determined by enzyme labeling linked immunosorbent assay (ELISA).</p><p><b>RESULTS</b>The expression of EGFP was only induced by prostagalandin E1, pioglitazone, Hawthorn flavonoids. A concentration-response relationship was seen between expressed EGFP and Hawthorn flavonoids. The levels of LPL in both Hawthorn flavonoids groups and PPARgamma ligand prostagalandin E1 group injected with pXOE-PPARgamma plasmid increased significantly (< 0.001) compared with controls, and a concentration-response relationship was observed between LPL mass and Hawthorn flavonoids.</p><p><b>CONCLUSIONS</b>It is possible to establish a PPRE regulatory EGFP reporter system in xenopus oocytes to monitor the activity of PPARgamma ligand. Hawthorn flavonoids can increase the expression of gene downsteam of PPRE by effect on the PPRE pathway regulatory system.</p>

Role of rosiglitazone and pravastalin in freund's adjuvant arthritis and mixed-type hypersensitivity in rats

Recent studies have shown that peroxisome proliferator- activated receptor- gamma [PPAR gamma] may participate in control of inflammation, especially in modulating the production of inflammatory mediators. Similarly, the cholesterol lowering drugs, statins, have been found to exhibit anti-inflammatory properties that are beyond their lipid lowering effects. The present study was conducted to investigate the effect of a PPAR gamma agonist [rosiglitazone] and a statin [pravastatin] on immunologically mediated chronic inflammation. Two models were chosen, namely, Freund's adjuvant arthritis [FA] and mixed- type hypersensitivity [MH] in rats. The effect of these drugs was assessed on the basis of biochemical markers in blood and / or inflammatory exudate. The investigated drugs were given orally daily during the course of inflammation development. The results of the present study demonstrated that, in either model, rosiglitazone and pravastatin reduced the elevated serum and exudate [local] leukotriene B[4] [LTB[4]] and interleukine-6 [IL-6] levels. The anti-inflammatory effect of these drugs was also accompanied by reduction or normalization of elevated systemic and or local levels of lipid peroxide [LP], superoxide dismutase [SOD], and reduced glutathione [GSH]. It could be concluded that long-term treatment with rosiglitazone or pravastatin confers a good anti-inflammatory activity against arthritis in rat, leading to improvement of the oxidative stress induced by the arthritic insult. The reparative effect of these drugs could be mediated via reduction of LTB[4] and IL-6

Study of the potential role of candesartan, selenium, or rosiglitazone in the amelioration of cyclosporine-induced nephrotoxicity in rats

The clinical utility of cyclosporine A [CsA] as an immunosuppressive agent has been significantly limited by the frequent occurrence of chronic nephropathy. This study was designed to investigate the possible role of candesartan or selenium in the amelioration of CsA-induced chronic nephropathy in rats. Furthermore, to delineate the possible, if any, modulatory role of rosiglitazone in this pathological status. Fifty male albino rats weighing 180-220 g were used in the present study. Rats were divided into five groups, each of ten rats. Group I, injected subcutaneously [SC] by olive oil and received also 2% gum acacia daily through a gastric tube. Group II injected with CsA SC daily for 6 weeks and received also 2% gum acacia orally daily for 6 weeks. Group III, IV, and V received the same dose of CsA concomitantly with candesartan, selenium, or rosiglitazone respectively through a gastric tube daily for 6 weeks. Administration of CsA to rats for six weeks resulted in significant high levels of plasma renin activity, serum urea, and creatinine. It also, caused a significant decrease in creatinine clearance, renal contents of glutathione [GSH], glutathione peroxidase [GPx], superoxide dismutase [SOD], catalase, and accompanied by high levels of malondialdehyde [MDA], proteinuria, and urinary N-acetyl-beta-D-glucosaminidase [NAG] activity. The histopathological studies revealed arteriolopathy and fibrosis. Concomitant administration of candesartan or rosiglitazone with CsA significantly reduced proteinuria and attenuated glomerulosclerosis. Also, they improved the renal function as evidenced by significantly lower concentrations of serum creatinine, serum urea, urinary NAG activity and improved natriuresis and creatinine clearance. These beneficial effects were accompanied by significant increase in renal contents of GSH, GPx, SOD, and catalase with reduced levels of MDA. Furthermore, concomitant administration of selenium with CsA significantly reduced proteinuria and glomerulosclerosis, improved creatinine clearance, and lowered concentrations of serum creatinine, urea nitrogen, and urinary NAG activity. Also, concomitant administration of selenium elevated GSH level, GPx activity, and reduced MDA level significantly. The results of the present study demonstrated that concomitant administration of candesartan, selenium, or rosiglitazone with CsA attenuates its structural and functional changes in a rat model of chronic CsA-induced nephropathy. Our findings provide a potential rationale for the use of candesartan or rosiglitazone alone or combined with selenium in future clinical studies

Probing the possible interaction between montelukast or rosiglitazone and combined bisphosphonate-NSAIDs therapy on rat stomach

Gastric ulceration associated with the use of nonsteroidal anti-inflammatory drugs [NSAIDs] is mostly observed in elderly women, the same sector of society most likely to be receiving therapy for osteoporosis. Alendronate sodium, an aminobisphosphonate, is a selective inhibitor of osteoclast-mediated bone resorption. It is used for treatment and prevention of postmenopausal osteoporosis. It can cause irritation and inflammation of the upper gastrointestinal mucosa. This study was designed to delineate the effects of combined alendronate-indomethacin therapy on gastric mucosa of rats and the possible modulatory effects of montelukast or rosiglitazone. Fifty six adult male albino rats weighing 200-250g were used in this study and divided into seven groups, each of eight animals as follows: group I used as control untreated animals and received 1 ml of 0.9% saline, the vehicle, orally daily for six days, group II used as control treated animals and received alendronate only, group III used as control treated animals and received alendronate combined with indomethacin, group IV received montelukast before alendronate administration, group V received montelukast before combined administration of alendronate-indomethacin, group VI received rosiglitazone before alendronate administration, and group VII received rosiglitazone before combined administration of alendronate and indomethacin. Alendronate treatment produced a significant increase in gastric acidity, ulcer index, gastric myeloperoxidase [MPO] activity and malondialdehyde [MDA] levels in the stomach accompanied by a significant reduction in glutathione levels. The combined alendronate-indomethacin administration produced further significant deleterious changes on the previous studied parameters when compared with the alendronate-treated group. The previous changes in biochemical parameters were accompanied by histopathological changes evidenced by epithelial ulceration, dilatation of gastric glands, and infiltration by inflammatory cells. The gastric mucosal damage was more pronounced by the combined use of alendronate with indomethacin. Montelukast or rosiglitazone therapy produced a significant reduction in gastric acidity, ulcer index, gastric MPO activity, and MDA levels in the stomach accompanied by a significant increase in glutathione levels, both in alendronate-treated group and in alendronate-indomethacin combined group. Moreover, both drugs reduced the histopathological changes. The results of the present study demonstrated that alendronate-indomethacin combined therapy induced gastric damage more significant than alendronate alone and that the use of either montelukast or rosiglitazone can reduce these hazardous effects in rat gastric mucosa. Further studies on humans are needed to evaluate the clinical use of the studied drugs in patients using alendronate alone or in combination with NSAIDs

Rastreamento molecular do gene do receptor ativado por proliferadores de peroxissoma gama (PPAR`gama´) em pacientes com diabetes melito do tipo 2 / Molecular scanning of the peroxisome proliferator-activated receptors gamma (PPAR`gamma´) gene in patients with Type 2 diabetes mellitus

No presente estudo utilizaram-se as técnicas do polimorfismo conformacional de fita simples (PCR-SSCP) e sequenciamento na prospecção e caracterização de polimorfismos no gene do Peroxisome Proliferator-Activated Receptors Gamma (PPAR`gama´) em pacientes com diabetes melito do tipo 2 (DM2). Foi possível, portanto, caracterizar cinco polimorfismos, sendo um destes localizado em região intrônica (IVS3+21A>T) e quatro em região codificadora (exon B: 34C>G; exon 1: 90C>A e 159C>T e exon 6: 161C>T) no gene do PPAR`gama´. As regiões referentes aos polimorfismos 34C>G e 161C>T foram amplificadas pela técnica da PCR e analisadas por restrição enzimática...

comparative study of the effect of peroxisome proliferator - activated receptor gamma [PPAR - gamma] ligands and angiotensin converting enzyme [ACE] inhibitors on experimental colitis in rats

Peroxisome proliferator - activated receplor-gamma [PPAR- gamma], a member of the nuclear hormone receptor superfamily originally shown to play a critical role in adipocyte differentiation and glucose homeostasis, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. In addition, increasing evidence supports an association between inflammation and angiotensin converting enzyme [ACE]. The aim of this study was to investigate the efficacy of ACE inhibitors [captopril and enalapril] and a PPAR- gamma ligand [rosiglitazone] on acetic acid-induced colitis in rats. Colitis was induced by intracolonic injection of 2 ml of 3% acetic acid. One hundred adult male albino rats were studied in this work. The animals were divided into two main groups, each of fifty rats: group I, of long duration of inflammation and treatment [Three weeks] and group II, of short duration of inflammation and treatment [two days]. Each group was subdivided into five subgroups, each of ten rats namely; control, acetic acid untreated, captopril, enalapril and rosiglitazone-treated rats. The investigated drugs were given two days after induction of colitis and continued daily for three weeks in group I, and for two days before and two days after induction of colitis in group II. Intracolonic injection of acetic acid in rats produced significant inflammation, assessed by the ulcer index score, weight of the colon and the colonic tissue level of myeloperoxidase enzyme in acetic acid untreated rats of both groups. These parameters were significantly improved by administration of captopril, enalapril and rosiglitazone. The effect of rosiglitazone was more potent than captopril and enalapril in both groups. Furthermore, the colonic tissue level of glutathione reductase enzyme was significantly reduced in acetic acid untreated rats of both groups. This reduction was significantly inhibited by the three investigated drugs in both groups, with better results with rosiglitazone than captopril and enalapril - treated rats in both groups. Rosiglitazone, captopril and enalapril also significantly improved the tissue level of lipid peroxides which was significantly elevated in acetic acid - untreated rats of both groups. However, the efficacy of rosiglitazone in reducing the lipid peroxides level was more significant than captopril and enalapril in both groups. this study provides an evidence that the PPAR- gamma ligand, rosiglitazone and the two ACE inhibitors, captopril and enalapril confer a good anti-inflammatory activity against acetic acid-induced colitis in rats. This leads to improvement of oxidative stress induced by the inflammatory insult, with the better results being with rosiglitazone than with captopril and enalapril

PPAR gamma--the master of thrifty genes / 中国医学科学院学报

Peroxisome proliferation is a cellular response to many chemical compounds affects including natural and modified fatty acids, phthalate and adipate ester plasticizers, leukotriene antagonists, acetylsalicylic acid and certain pathophysiological conditions including dramatic change of cellular morphology and enzymatic activity. Peroxisome proliferation phenomenon is seen primarily in liver and kidney. Hormones and nutritional factor can regulate peroxisome proliferation response. Sustained peroxisome proliferation can lead to hepatocarcinogenesis. The three types of peroxisome proliferator activated receptor, termed PPAR alpha, PPAR beta, and PPAR gamma, expressed in specific tissue, are consisted of a specific a nuclear receptor superfamily. After more than 10 years world wide research, the function of PPAR is clarified, as PPAR gamma, the master of thrifty genes, controls the expression of genes relative to adipogenesis, diabetes mellitus and obesity. The receptor is involved in transcriptional control of numerous cellular processes including cell cycle control, inflammation, immunoregulation and carcinogenesis.

Avances en la genética molecular de la obesidad / Advances in the molecular genetics of the obesity

In the last decade, specially after the discovery of leptin, several neuropeptides that regulate energy intake and expenditure have been described in animal models. This has partially unvelied the underlying mechanisms that regulate body composition and weight and therefore a promise of a more effective treatment of obesity and its comorbidities is ad portas

Aspectos genéticos de la obesidad humana / Genetic conditions of human obesity

La obesidad está asociada con distintas complicaciones metabólicas como la diabetes, la hipertensión y la hiperlipidemia. No obstante, no todos los individuos obesos presentan estas complicaciones, lo que sugiere que la obesidad es una condición heterogénia. La obesidad es la resultante de una compleja interacción entre factores genéticos y ambientales. Los resultados aportados por la epidemiología genética han sido muy útiles para demostrar que, a nivel poblacional, los factores genéticos tienen importancia en la etiología de la obesidad humana. A nivel individual, es bien conocido que no todos los sujetos son igualmente susceptibles a las consecuencias adversas de la obesidad y que hay diferencias inter-individuales en la respuesta al estimulo ambiental. Este artículo presenta una breve revisión respecto de la contribución de siete genes candidatos en esta compleja enfermedad

Nutrición molecular, papel del sistema PPAR en el metabolismo lipídico y su importancia en obesidad y diabetes mellitus / Molecular nutrition: regulation of lipid metabolism by peroxisome proliferator activated receptors, PPAR: their relatioship to obesity and diabetes mellitus

PPARs are transcription factors belonging to the super family of hormonal receptors. Their activity is regulated by fibrates, thiazolidinediones, certain anti inflammatory drugs and fatty acid derivatives, present in food. PPAR isoforms play a central role in lipid homeostasis, regulating anabolic (PPARg) and catabolic (PPARa) pathways of lipid metabolism. Additionally, these receptors participate in glucose homeostasis, influence cellular proliferation and differentiation and participate in inflammatory processes. The effects of PPARs on oxidative substrate partitioning suggests that they have a relevant role in the development of obesity and insulin resistance