La activación de receptor activado por proliferadores peroxisómicos Beta/ Delta mejora la resistencia a insulina inducida porIL-6 en células hepáticas / No disponible

Introducción: La resistencia a la insulina precede y predice la presencia de diabetes mellitustipo 2, condición que supone un notable incremento del riesgo cardiovascular. La interleucina-6es uno de los mediadores que relacionan la inflamación crónica observada en estados de obesidad con la resistencia a la insulina a través de la activación de STAT3 (signal transducer and activator of transcription 3), con el consiguiente aumento de SOCS3 (suppressor of cytokinesignaling 3) en el hígado. El objetivo de este estudio ha sido evaluar si un agonista del receptor activado por proliferadores peroxisómicos (PPAR) / , GW501516, es capaz de evitar la activación de la vía de senalización IL-6/STAT3/SOCS3 y la resistencia a la insulina en células hepáticas. Material y métodos: Células HepG2 humanas se estimularon con IL-6 (20 ng/ml) en presenciao en ausencia de GW501516 (10 M). También analizamos el hígado de ratones salvajes y con deficiencia PPAR / . Los niveles de ARNm y proteínas se analizaron mediante las técnicas deRT-PCR y Western-Blot, respectivamente. Resultados: GW501516 evitó la fosforilación en Tyr705 y en Ser727 de STAT3 y el aumento deSOCS3 inducidas por la IL-6. Asimismo, el tratamiento con este fármaco evitó la activación por la IL-6 de la ERK1/2, una serina-treonina cinasa implicada en la fosforilación de STAT3 enSer727. Cabe destacar que el hígado de ratones deficientes en PPAR / mostró un aumento (..) (AU)

Introduction: Insulin resistance precedes and predicts the development of type 2 diabetes mellitus, a disease which increases the risk of cardiovascular events. Interleukin (IL)-6 is one of the mediators linking obesity-derived chronic inflammation with insulin resistance through activation of STAT3, with subsequent up regulation of suppressor of cytokine signaling 3 (SOCS3)in liver. The aim of this study was to evaluate whether peroxisome proliferator-activated receptor (PPAR) / agonist GW501516 prevented activation of the IL-6/STAT3/SOCS3 pathway and insulin resistance in hepatic cells. Material and methods: Human HepG2 cells were stimulated for 10 min with IL-6 (20 ng/mL)in the presence or in the absence of 10 M GW501516, then mRNA and protein levels were analyzed by RT-PCR or Western-Blot, respectively. In addition, we also analyzed protein levels from PPAR / null mice and wild-type mice livers. Results: GW501516 prevented IL-6-induced STAT3 phosphorylation on Tyr705 and Ser727 and avoided the increase in SOCS3 caused by this cytokine. In addition, this drug also preventedIL-6-dependent ERK1/2 phosphorylation, a serine-threonine protein kinase involved in STAT3phosphorylation on Ser727. Interestingly, livers from PPAR / null mice showed increased phosphorylations on Tyr 705 and Ser727 of STAT3 as well as phosphorylated ERK1/2 levels. Finally, all (..) (AU)

Tratamiento de enfermedades metabólicas mediante la modulación del PPARg / Treating metabolic diseases through PPAR modulation

La diabetes mellitus de tipo 2 (DM2), la obesidad, la hipertensión y la dislipemia son procesos fisiopatológicos que configuran el síndrome metabólico y que suelen caracterizarse por la presencia de resistencia a la insulina. Como consecuencia, uno de los objetivos terapéuticos prioritarios en el tratamiento del síndrome metabólico consiste en mejorar esta resistencia a la insulina. El receptor activado por proliferadores peroxisómicos g (PPARg) es un receptor nuclear que desempeña un papel crucial en la homeostasis de los lípidos y de la glucosa. Las tiazolidinedionas (TZD) son agonistas de PPARg que se utilizan clínicamente para el tratamiento de la resistencia a la insulina e hiperglucemia, que además presentan una cierta actividad antiinflamatoria potencialmente útil en el tratamiento y prevención de la arteriosclerosis. No obstante, los numerosos efectos secundarios que presentan las TZD han impulsado el desarrollo de nuevos fármacos moduladores de PPARg. En esta revisión se analizan algunos de los distintos compuestos con capacidad para modular la actividad de PPARg, incluyendo las TZD, y sus potenciales beneficios para la terapia de enfermedades metabólicas (AU)

Metabolic syndrome and related disorders, such as obesity, type 2 diabetes mellitus, hypertension and dyslipidemia, are characterized by a progressive resistance of glucose metabolism to the action of insulin, termed insulin resistance. Consequently, improving insulin resistance is a major therapeutic goal. Peroxisome proliferator-activated receptor g (PPARg) is a nuclear receptor, which plays a key role in lipid and glucose homeostasis. The PPARg agonists, thiazolidinediones (TZD), are powerful drugs that are clinically used to treat insulin resistance and hyperglycemia. Moreover, these compounds have additional lipid-independent anti-inflammatory effects, suggesting that they might also be useful for the treatment and prevention of atherosclerosis. However, given the numerous side effects observed with TZD treatment, novel classes of PPARg modulators have been designed and developed. The present review will focus on the different compounds that have been shown to bind and modulate PPARg activity, especially TZD, and the potential benefits of pharmacological modulation of PPARg to treat human metabolic disease (AU)

PPAR-gamma, hipertensión arterial y riñón / PPAR-Gamma, arterial hypertesnion and the kidney

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Evaluation of the carcinogenic potential of clofibrate in the neonatal mouse.

This study was conducted in support of the International Life Sciences Institute (ILSI) alternative carcinogenicity models initiative to evaluate the carcinogenic potential of clofibrate, a nongenotoxic peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to neonatal mice. Male and female neonatal CD-1 mice were dosed with clofibrate at doses of 100, 250, and 500 mg/kg or with the positive control, diethylnitrosamine (DEN), at 2 mg/kg by oral gavage on days 9 and 16 post birth and observed for approximately 1 year for the development of tumors. Plasma levels of clofibric acid after the second administration increased with dose, but were not dose proportional. Clofibrate administered by gavage on litter days 9 and 16 to neonatal mice at doses of 100, 250, or 500 mg/kg did not produce a carcinogenic effect. The positive control DEN did produce tumors in the liver and lung (single and multiple adenomas and carcinomas) and harderian gland (adenoma) of both sexes. Non-neoplastic lesions related to DEN treatment were confined to myocardial degeneration/fibrosis and testicular interstitial hyperplasia in males, and to glomerulonephrosis and gastritis in both sexes.

Gene expression profiling of the PPAR-alpha agonist ciprofibrate in the cynomolgus monkey liver.

Fibrates, such as ciprofibrate, fenofibrate, and clofibrate, are peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists that have been in clinical use for many decades for treatment of dyslipidemia. When mice and rats are given PPARalpha agonists, these drugs cause hepatic peroxisome proliferation, hypertrophy, hyperplasia, and eventually hepatocarcinogenesis. Importantly, primates are relatively refractory to these effects; however, the mechanisms for the species differences are not clearly understood. Cynomolgus monkeys were exposed to ciprofibrate at various dose levels for either 4 or 15 days, and the liver transcriptional profiles were examined using Affymetrix human GeneChips. Strong upregulation of many genes relating to fatty acid metabolism and mitochondrial oxidative phosphorylation was observed; this reflects the known pharmacology and activity of the fibrates. In addition, (1) many genes related to ribosome and proteasome biosynthesis were upregulated, (2) a large number of genes downregulated were in the complement and coagulation cascades, (3) a number of key regulatory genes, including members of the JUN, MYC, and NFkappaB families were downregulated, which appears to be in contrast to the rodent, where JUN and MYC are reported to upregulated after PPARalpha agonist treatment, (4) no transcriptional signal for DNA damage or oxidative stress was observed, and (5) transcriptional signals consistent with an anti-proliferative and a pro-apoptotic effect were seen. We also compared the primate data to literature reports of hepatic transcriptional profiling in PPARalpha-treated rodents, which showed that the magnitude of induction in beta-oxidation pathways was substantially greater in the rodent than the primate.

Effects of HCFC-123 exposure to maternal and infant rhesus monkeys on hepatic biochemistry, lactational parameters and postnatal growth.

Peroxisome proliferators are a class of nongenotoxic rodent hepatocarcinogens that cause peroxisome proliferation and liver tumors when administered to rats and mice; but other species, including guinea pigs, dogs, and primates are less sensitive or refractory to the induction of peroxisome proliferation. Therefore, rodent peroxisome proliferators are not believed to pose a hepatocarcinogenic hazard to humans. Some peroxisome proliferators produce developmental toxicity in rats that is expressed as suppressed postnatal growth. To evaluate the relevance of the rat developmental effect to primates, groups of 4 lactating female Rhesus monkeys and their infants were exposed for 6 h/day, 7 days/week for 3 weeks to air or 1000 ppm HCFC-123. Animals were evaluated for clinical signs, body weights, clinical pathology parameters, and biochemical and pathological evaluations of liver biopsy samples. The effect of HCFC-123 exposure on milk quality (protein and fat concentration) was evaluated. The concentrations of HCFC-123 and the major metabolite, trifluoroacetic acid (TFA), were measured in the blood of the mothers and infants and in the milk. Exposure of monkeys to 1000 ppm HCFC-123 did not result in exposure-related clinical observations, or changes in body weight, appetence and behavior. There were no exposure-related effects on serum triglycerides, cholesterol, or glucose levels. HCFC-123 and TFA were present in milk, although maternal HCFC-123 exposure did not affect milk protein and fat content. In general, HCFC-123 was not detected in maternal or infant blood. TFA was detected in the majority of the mothers and TFA levels in infants ranged from 2 to 6 times higher than levels in the corresponding maternal blood. A pharmacokinetic analysis in a maternal animal indicated a peak concentration of TFA at approximately 1 h post-exposure, with a half-life of approximately 20 h. Liver microsomal P450 and peroxisome oxidase activities showed exposure-related decreases in CYP4A1 and CYP2E1 and acyl-CoA oxidase for animals exposed to HCFC-123. Microscopic evaluation of maternal liver from HCFC-123 exposed animals revealed mild to moderate centrilobular hepatocyte vacuolation, trace to mild centrilobular necrosis, and trace to mild subacute inflammation. The histopathological damage and altered hepatic biochemical activities produced by HCFC-123 in monkeys are not consistent with the HCFC-123 peroxisome proliferation response observed in rat livers. These findings demonstrate that HCFC-123 is not a peroxisome proliferator in adult Rhesus monkeys and postnatal exposure to HCFC-123 does not affect body weight of nursing infant monkeys.

Toxicity of ammonium perfluorooctanoate in male cynomolgus monkeys after oral dosing for 6 months.

Ammonium perfluorooctanoate (APFO) is a processing aid in the production of fluoropolymers that has been shown to have a long half-life in human blood. To understand the potential toxicological response of primates, groups of male cynomolgus monkeys were given daily po (capsule) doses of either 0, 3, 10, or 30 (reduced to 20) mg/kg/day for 26 weeks. Two monkeys from each of the control and 10 mg/kg/day dose groups were observed for 90 days after the last dose. Clinical observations, clinical chemistry, determination of key hormones, gross and microscopic pathology, cell proliferation, peroxisomal proliferation, bile-acid determination, and serum and liver perfluorooctanoate (PFOA) concentrations were monitored. Toxicity, including weight loss and reduced food consumption, was noted early in the study at the 30 mg/kg/day dose; therefore, the dose was reduced to 20 mg/kg/day. The same signs of toxicity developed in 3 monkeys at 20 mg/kg/day, after which treatment of these monkeys was discontinued. One 30/20 mg/kg/day monkey developed the signs of toxicity noted above and a possible dosing injury, and this monkey was sacrificed in extremis on Day 29. A 3 mg/kg/day dose-group monkey was sacrificed in extremis on Day 137 for reasons not clearly related to APFO treatment. Dose-dependent increases in liver weight as a result of mitochondrial proliferation occurred in all APFO-treated groups. Histopathologic evidence of liver injury was not observed at either 3 or 10 mg/kg/day. Evidence of liver damage was seen in the monkey sacrificed in moribund condition at the highest dose. Body weights were decreased at 30/20 mg/kg. PFOA concentrations in serum and liver were highly variable, were not linearly proportional to dose, and cleared to background levels within 90 days after the last dose. A no observable effect level was not established in this study, and the low dose of 3 mg/kg/day was considered the lowest observable effect level based on increased liver weight and uncertainty as to the etiology leading to the moribund sacrifice of one low-dose monkey on Day 137. Other than those noted above, there were no APFO-related macroscopic or microscopic changes, changes in clinical chemistry, hormones, or urinalysis, or hematological effects. In particular, effects that have been associated with the development of pancreatic and testicular toxicity in rats were not observed in this study.

Weight-of-evidence versus strength-of-evidence in toxicologic hazard identification: Di(2-ethylhexyl)phthalate (DEHP).

Toxicokinetic and mode of action data for DEHP reduce the concern for its potential carcinogenic hazard to human health. Chronic, high dose ingestion of DEHP and related peroxisome proliferators (PP) by mice and rats precipitate the following: activation of peroxisome proliferator activated receptor (PPARalpha) and its binding to peroxisome proliferator response elements (PPREs) within promoters of PP-responsive genes, peroxisome proliferation, increased microsomal fatty acid oxidation, increased hepatic hydrogen peroxide, hepatomegaly, hyperplasia and subsequent neoplasia. Neither peroxisome proliferation nor increased liver cancer occur in patients treated with pharmacologic doses of PP. Species differences in endogenous PPARalpha expression and differential activity of the peroxisome proliferator response element (PPRE) contribute to the failure of humans to respond in a manner qualitatively similar to that of rats or mice. Where it can be demonstrated that a mechanism for rodent tumor formation has no relevance for humans, then a substance which elicits a carcinogenic response in the test species via that mechanism should not be classified as anything other than an animal carcinogen. Systemic noncarcinogenic endpoints are available for definition of a DEHP reference dose. Considerable difficulty is encountered in the revision of promulgated regulations and in public risk communication when a material is no longer considered a carcinogenic hazard to humans.