RESUMEN
Thermogenic brown and brite adipocytes convert chemical energy from nutrients into heat. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to control fat mass such as in obesity or cachexia. The peroxisome proliferator-activated receptor (PPAR) family plays key roles in the maintenance of adipose tissue and in the regulation of thermogenic activity. Activation of these receptors induce browning of white adipocyte. The purpose of this work was to characterize the role of carnosic acid (CA), a compound used in traditional medicine, in the control of brown/brite adipocyte formation and function. We used human multipotent adipose-derived stem (hMADS) cells differentiated into white or brite adipocytes. The expression of key marker genes was determined using RT-qPCR and western blotting. We show here that CA inhibits the browning of white adipocytes and favors decreased gene expression of thermogenic markers. CA treatment does not affect ß-adrenergic response. Importantly, the effects of CA are fully reversible. We used transactivation assays to show that CA has a PPARα/γ antagonistic action. Our data pinpoint CA as a drug able to control PPAR activity through an antagonistic effect. These observations shed some light on the development of natural PPAR antagonists and their potential effects on thermogenic response.
Asunto(s)
Abietanos/farmacología , Adipocitos Marrones/metabolismo , Adipocitos Blancos/metabolismo , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Rosmarinus/química , Adipocitos Beige/efectos de los fármacos , Adipocitos Beige/metabolismo , Adipocitos Marrones/efectos de los fármacos , Adipocitos Blancos/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Lipólisis/efectos de los fármacos , Ratones , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Rosiglitazona/farmacología , Termogénesis/efectos de los fármacos , Termogénesis/genéticaRESUMEN
Cancers are caused by the defects in apoptosis process which leads to uncontrolled proliferation, therefore, most attractive drug target discovery strategy is to find ligands which have the ability to activate or regulate the apoptotic machinery. Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors their over expression is observed in many tumours and contributes to chemotherapy resistance. The goal of this study to scrutinized antitumor phytochemicals from Alysicarpus bupleurifolius, Piper nigrum and Plumeria obtuse and potential energy values render from interactions between active site residues and ligands. The potential phytochemicals with significant binding affinity are ursolic acid, cis-4-decenoic acid and p-coumaric acid respectively most effective compounds in high throughput virtual screening belongs to Plumeria obtuse against PPARs associated with tumour development and progression. This modern drug designing modeling in silico approach, therefore, identifies the potential leads against over expressed tumours.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Evaluación Preclínica de Medicamentos/métodos , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Fitoquímicos/aislamiento & purificación , Antineoplásicos Fitogénicos/metabolismo , Antineoplásicos Fitogénicos/farmacología , Simulación del Acoplamiento Molecular/métodos , Receptores Activados del Proliferador del Peroxisoma/química , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Fitoquímicos/metabolismo , Fitoquímicos/farmacología , Unión Proteica/fisiología , Estructura Secundaria de Proteína , Estructura Terciaria de ProteínaRESUMEN
OBJECTIVE: To investigate the protective/ameliorative effects of vitamin E on di-2-(ethylhexyl) phthalate (DEHP)-induced reproductive toxicity, particularly in testicular toxicity in male rats, emphasizing peroxisome proliferator-activated receptor (PPAR)-dependent mechanism. METHODS: Sprague-Dawley females were exposed by oral route to DEHP alone or associated with vitamin E from gestation day (GD) 12.5 to postnatal day (PND) 3 according to the following treatment regimens: vehicle control (corn oil), vitamin E (200 mg/kg)+corn oil, DEHP (500 mg/kg)+corn oil, and DEHP (500 mg/kg)+vitamin E (200 mg/kg)+corn oil. Variables including litter size, sex ratio, pup weight, post-implantation losses, and the number of viable pups were also assessed. Three male pups per litter were randomly selected and necropsied to measure paired testes weight, apoptosis, and gene expression on PND 3. To evaluate the long-term protective effects of vitamin E, three randomly selected males were necropsied to measure testis histology on PND 70. RESULTS: Supplementation of vitamin E (200 mg/kg) reduced malformations, increased testes weight and prevented the maternal bodyweight loss induced by DEHP. Litter size, sex ratio, and number of viable pups were unaffected, but vitamin E co-administration declined testicular cell apoptosis, decreased the PPARs expression, and protected testis histology. CONCLUSIONS: Vitamin E cotreatment showed protective effects against DEHP-induced testicular toxicity, including reproductive malformations, testicular weight, apoptosis and histology, and the mechanisms maybe associated with PPARs.
Asunto(s)
Suplementos Dietéticos , Dietilhexil Ftalato/toxicidad , Disruptores Endocrinos/toxicidad , Infertilidad Masculina/prevención & control , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal , Vitamina E/uso terapéutico , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Dietilhexil Ftalato/administración & dosificación , Dietilhexil Ftalato/antagonistas & inhibidores , Disruptores Endocrinos/administración & dosificación , Disruptores Endocrinos/química , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Lactancia , Masculino , Exposición Materna/efectos adversos , Tamaño de los Órganos/efectos de los fármacos , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Embarazo , Sustancias Protectoras/uso terapéutico , Distribución Aleatoria , Ratas Sprague-Dawley , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patologíaRESUMEN
Maternal folic acid supplementation can alter DNA methylation and gene expression in the developing fetus, which may confer disease susceptibility later in life. We determined which gestation period and organ were most sensitive to the modifying effect of folic acid supplementation during pregnancy on DNA methylation and gene expression in the offspring. Pregnant rats were randomized to a control diet throughout pregnancy; folic acid supplementation at 2.5× the control during the 1st, 2nd or 3rd week of gestation only; or folic acid supplementation throughout pregnancy. The brain, liver, kidney and colon from newborn pups were analyzed for folate concentrations, global DNA methylation and gene expression of the Igf2, Er-α, Gr, Ppar-α and Ppar-γ genes. Folic acid supplementation during the 2nd or 3rd week gestation or throughout pregnancy significantly increased brain folate concentrations (P<.001), while only folic acid supplementation throughout pregnancy significantly increased liver folate concentrations (P=.005), in newborn pups. Brain global DNA methylation incrementally decreased from early to late gestational folic acid supplementation and was the lowest with folic acid supplementation throughout pregnancy (P=.026). Folic acid supplementation in late gestation or throughout pregnancy significantly decreased Er-α, Gr and Ppar-α gene expression in the liver (P<.05). The kidney and colon were resistant to the effect of folic acid supplementation. Maternal folic acid supplementation affects tissue folate concentrations, DNA methylation and gene expression in the offspring in a gestation-period-dependent and organ-specific manner.
Asunto(s)
Metilación de ADN , Suplementos Dietéticos , Desarrollo Fetal , Ácido Fólico/administración & dosificación , Regulación del Desarrollo de la Expresión Génica , Fenómenos Fisiologicos Nutricionales Maternos , Animales , Animales Recién Nacidos , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Ácido Fólico/sangre , Ácido Fólico/metabolismo , Ácido Fólico/uso terapéutico , Factor II del Crecimiento Similar a la Insulina/agonistas , Factor II del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , Hígado/metabolismo , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Defectos del Tubo Neural/sangre , Defectos del Tubo Neural/metabolismo , Defectos del Tubo Neural/prevención & control , Neuronas/citología , Neuronas/metabolismo , Especificidad de Órganos , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Embarazo , Distribución Aleatoria , Ratas Sprague-Dawley , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismoRESUMEN
Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as 'cytokine storm'. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-1-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.
Asunto(s)
Antivirales/uso terapéutico , Citocinas/antagonistas & inhibidores , Factores Inmunológicos/uso terapéutico , Inmunomodulación , Gripe Humana/tratamiento farmacológico , Orthomyxoviridae/efectos de los fármacos , Corticoesteroides/uso terapéutico , Antioxidantes/uso terapéutico , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Citocinas/genética , Citocinas/inmunología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Indoles/uso terapéutico , Gripe Humana/genética , Gripe Humana/inmunología , Gripe Humana/virología , Orthomyxoviridae/inmunología , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/genética , Receptores Activados del Proliferador del Peroxisoma/inmunología , Preparaciones de Plantas/uso terapéutico , Receptores de Lisoesfingolípidos/uso terapéuticoRESUMEN
Peroxisome proliferator-activated receptors (PPARs) are nuclear transcriptional factors closely related to glucose and lipid metabolism, insulin sensitivity. Activation of PPARs targets treated type 2 diabetes, obesity, hypertension and other metabolic diseases by insulin resistance. Recently, a variety of active ingredients of traditional Chinese medicines (TCMs) have been proved to activate PPARs targets for improving insulin resistance, which has attracted widespread attention at home and abroad. In this paper, we reviewed the pathological mechanisms between insulin resistance and PPARs, and summarized the active ingredients of TCMs improved insulin resistance based on PPARs targets. This paper may provide some theoretical guidance for the development of new drugs and TCMs.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Enfermedades Metabólicas/tratamiento farmacológico , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Animales , Humanos , Resistencia a la Insulina , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , Receptores Activados del Proliferador del Peroxisoma/genéticaRESUMEN
The increasing epidemic of diabetes mellitus around the globe is increasing the risk of various other chronic diseases i.e. coronary artery diseases, myocardial infarction, hypertension, dyslipidemia and number of other complicated disorders. Diabetes mellitus is clinically characterized by a marked increase in blood glucose levels and is associated with mild hyperlipidemia. Although the prevalence of this health ailment is increasing dramatically, various therapeutic compounds have been developed to treat this disease that is available in the market as synthetic, formulated and combined forms. Recently, various compounds have come through preclinical studies and shown the therapeutic efficacy of using multiple/ specific drug targets. Recent research approaches have been based on receptors targeting, islet cell transplantation, gene expression profiling, glucagon-like peptide-1, dipeptidyl peptidase IV inhibitors, insulin therapy, modulators of peroxisome proliferator-activated receptors (PPAR), glucagon receptor antagonists, insulin analogues, sensitizers and combination therapies. Furthermore various, latest findings claimed to identifying new anti-diabetic regimens with novel mechanism of action are being developed. This review provides an update on the use of approaches to the development of preventive and therapeutic strategies against diabetes and recent patents that could develop into novel therapeutics available to the clinical success for the management of the disease.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Patentes como Asunto , Animales , Glucemia/biosíntesis , Diabetes Mellitus/etiología , Diabetes Mellitus/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Péptido 1 Similar al Glucagón/farmacología , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Hipoglucemiantes/farmacología , Insulina/uso terapéutico , Trasplante de Islotes Pancreáticos , Terapia Molecular Dirigida , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidoresRESUMEN
For thousands of years, natural medicines have played an important role in treating and preventing human diseases worldwide. Natural products offer large structural diversity, and modern techniques for separation, structure elucidation, screening and combinatorial synthesis have led to revitalization of plant products as sources of new drugs. The number of people with cardiometabolic syndrome is increasing worldwide. This is expected to increase the prevalence of potentially harmful distortions of lipid distribution and thus intensify the need for appropriate intervention. With increasing evidence of the pathophysiological importance of the dyslipidaemia associated with type 2 diabetes mellitus, hypertension and insulin resistance, a more aggressive approach to lipid management is required. Nuclear receptors are an attractive and promising target for drug development. Functioning as transcription factors and thereby controlling cellular processes at the level of gene expression, modulation of nuclear receptor activity produces selective alterations in downstream gene expression. These characteristics, combined with their involvement in significant diseases, make nuclear receptors a key target for the development of disease-specific therapy. This review examines natural product libraries as a rich source of ligands for nuclear receptors and their potential as promising therapeutic agents for clinical practice. Continual evolution in drug discovery from plants remains an important source of new pharmaceuticals. Furthermore, by uncovering the regulatory mechanisms and transcriptional targets of the PPARs and other related receptors, it will be possible to provide a comprehensive insight into the pathogenesis of metabolic disease and, at the same time, offer valuable information for rational drug design, ultimately leading to a reduction in the chronic microvascular complications of cardiometabolic syndrome.
Asunto(s)
Síndrome Metabólico/tratamiento farmacológico , Receptores Activados del Proliferador del Peroxisoma/fisiología , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Descubrimiento de Drogas/tendencias , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Ligandos , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Plantas Medicinales/química , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidoresRESUMEN
Insulin resistance is the major cause in Non Insulin Dependent Diabetes Mellitus (NIDDM). In this review insulin production from beta-cells and action of insulin is briefly described. Any intervention either in the production or action of insulin has been the leading cause of NIDDM. Therapeutic intervention to deal with the defective action of insulin at various receptor or target tissues has been outlined. Structure-activity relationship of a large number of thiazolidinediones, oxazolidinediones, isoxazolidinediones, biguanides, tetrazole derivatives, pyrazoles and pyrazolones, oxathiadiazole oxide, hydroxyurea and carboxylic acid derivatives have been described. The probable mechanism of action of these novel compounds through Peroxisome Proliferator-Activated Receptors that ameliorate the insulin resistance, has been described. Finally the clinical candidates at various stages of clinical evaluation have been compiled.