RESUMEN
The Peroxisome proliferator-activated receptors (PPARs) are key regulators of metabolic events in our body. Owing to their implication in maintenance of homeostasis, both PPAR agonists and antagonists assume therapeutic significance. Understanding the molecular mechanisms of each of the PPAR isotypes in the healthy body and during disease is crucial to exploiting their full therapeutic potential. This article is an attempt to present a rational analysis of the multifaceted therapeutic effects and underlying mechanisms of isotype-specific PPAR agonists, dual PPAR agonists, pan PPAR agonists as well as PPAR antagonists. A holistic understanding of the mechanistic dimensions of these key metabolic regulators will guide future efforts to identify novel molecules in the realm of metabolic, inflammatory and immunotherapeutic diseases.
Asunto(s)
Receptores Activados del Proliferador del Peroxisoma , Animales , Apoptosis , Diabetes Mellitus/fisiopatología , Homeostasis , Humanos , Metabolismo de los Lípidos , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/metabolismoRESUMEN
Peroxisome Proliferator Activated Receptors (PPARs) are transcription factors that regulate processes such as lipid and glucose metabolism. Synthetic PPAR ligands, designed as therapeutics for metabolic disease, provide a tool to assess the relationship between PPAR activity and pancreas development in vivo, an area that remains poorly characterized. Here, we aim to assess the effects of PPAR agonists and antagonists on gene expression, embryonic morphology and pancreas development in transgenic zebrafish embryos. To evaluate developmental perturbations, we assessed gross body and pancreas morphology at 4 days post fertilization (dpf) in response to developmental exposures with PPARα, PPARγ, and PPARß/δ agonists and antagonists at 0, 0.01, 0.1, 1, and 10 µM concentrations. All ligand exposures, with the exception of the PPARα agonist, resulted in significantly altered fish length and yolk sac area. PPARγ agonist and antagonist had higher incidence of darkened yolk sac and craniofacial deformities, whereas PPARα antagonist had higher incidence of pericardial edema and death. Significantly reduced endocrine pancreas area was observed in both PPARγ ligands and PPARα agonist exposed embryos, some of which also exhibited aberrant endocrine pancreas morphology. Both PPARß/δ ligands caused reduced exocrine pancreas length and novel aberrant phenotype, and disrupted gene expression of pancreatic targets pdx1, gcga, and try. Lipid staining was performed at 8 dpf and revealed altered lipid accumulation consistent with isoform function. These data indicate chronic exposure to synthetic ligands may induce morphological and pancreatic defects in zebrafish embryos.
Asunto(s)
Páncreas/anomalías , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Anomalías Múltiples , Animales , Animales Modificados Genéticamente , Anomalías Craneofaciales , Embrión no Mamífero , Desarrollo Embrionario , Femenino , Expresión Génica , Metabolismo de los Lípidos , Masculino , Transducción de Señal , Saco Vitelino/anomalías , Pez Cebra/anomalías , Pez Cebra/genéticaRESUMEN
Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.
Asunto(s)
Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores de Cannabinoides/metabolismo , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Animales , Moduladores de Receptores de Cannabinoides/farmacología , Inhibidores Enzimáticos/farmacología , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidoresRESUMEN
Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligand-activated nuclear receptors. The PPAR family consists of three subtypes encoded by three separate genes: PPARα (NR1C1), PPARß/δ (NR1C2), and PPARγ (NR1C3). PPARs are critical regulators of metabolism and exhibit tissue and cell type-specific expression patterns and functions. Specific PPAR ligands have been proposed as potential therapies for a variety of diseases such as metabolic syndrome, cancer, neurogenerative disorders, diabetes, cardiovascular diseases, endometriosis, and retinopathies. In this review, we focus on the knowledge of PPAR function in angiogenesis, a complex process that plays important roles in numerous pathological conditions for which therapeutic use of PPAR modulation has been suggested.
Asunto(s)
Artritis Reumatoide/metabolismo , Enfermedades Cardiovasculares/metabolismo , Endometriosis/metabolismo , Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Enfermedades Placentarias/metabolismo , Enfermedades de la Retina/metabolismo , Animales , Células Endoteliales/metabolismo , Femenino , Humanos , Ligandos , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Embarazo , Transducción de SeñalRESUMEN
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
The reduced activation of PPARs has a positive impact on cancer cell growth and viability in multiple preclinical tumor models, suggesting a new therapeutic potential for PPAR antagonists. In the present study, the benzothiazole amides 2a-g were synthesized and their activities on PPARs were investigated. Transactivation assay showed a moderate activity of the novel compounds as PPARα antagonists. Notably, in cellular assays they exhibited cytotoxicity in pancreatic, colorectal and paraganglioma cancer cells overexpressing PPARα. In particular, compound 2b showed the most remarkable inhibition of viability (greater than 90%) in two paraganglioma cell lines, with IC50 values in the low micromolar range. In addition, 2b markedly impaired colony formation capacity in the same cells. Taken together, these results show a relevant anti-proliferative potential of compound 2b, which appears particularly effective in paraganglioma, a rare tumor poorly responsive to chemotherapy.
Asunto(s)
Amidas/farmacología , Antineoplásicos/farmacología , Benzotiazoles/farmacología , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Amidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzotiazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Relación Estructura-ActividadRESUMEN
We herein report a novel mechanism of action of statin preparations using a new drug discovery method. Milk fat globule-EGF factor 8 protein (MFG-E8) was identified from the secretory component of mouse embryonic fibroblast (MEF) as a cell adhesion-promoting factor effective for screening active cellular agents of human induced pluripotent stem cells (hiPSCs) in vitro using electrochemical impedance. Our analyses showed that atorvastatin did not cause death in myocardial cells differentiated from hiPSCs but reduced the pluripotent cell survival in vitro when using serum- and albumin-free media, and inhibited the ability to form teratomas in mice. This result could have been already the cytopathic effect of atorvastatin, and complete elimination of hiPSCs was confirmed in the xenotransplantation assay. The administration of atorvastatin to hiPSCs caused the expression of hypoxia inducible factor (HIF)1α mRNA to be unchanged at 6 hr and downregulated at 24 hr. In addition, the inhibition of the survival of hiPSCs was confirmed by HIF1α-peroxisome proliferator-activated receptor (PPAR) axis inhibition. These results suggest that the addition of atorvastatin to hiPSC cultures reduces the survival of pluripotent cells by suppressing the HIF1α-PPAR axis. In summary, the HIF1α-PPAR axis has an important role in maintaining the survival of pluripotent hiPSCs.
Asunto(s)
Atorvastatina/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Ratones , Ratones SCIDRESUMEN
Palmitoleic acid (PM, 16:1n-7) has anti-inflammatory properties that could be linked to higher expression of PPARα, an inhibitor of NFκB. Macrophages play a major role in the pathogenesis of chronic inflammation, however, the effects of PM on macrophages are underexplored. Thus, we aimed to investigate the effects of PM in activated macrophages as well the role of PPARα. Primary macrophages were isolated from C57BL/6 wild type (WT) and PPARα knockout (KO) mice, cultured under standard conditions and exposed to lipopolysaccharides LPS (2.5 µg/ml) and PM 600 µmol/L conjugated with albumin for 24 hours. The stimulation with LPS increased the production of interleukin (IL)-6 and IL-1ß while PM decreased the production of IL-6 in WT macrophages. In KO macrophages, LPS increased the production of tumour necrosis factor (TNF)-α and IL-6 and PM decreased the production of TNFα. The expression of inflammatory markers such NFκB and IL1ß were increased by LPS and decreased by PM in both WT and KO macrophages. PM reduced the expression of MyD88 and caspase-1 in KO macrophages, and the expression of TLR4 and HIF-1α in both WT and KO macrophages, although LPS had no effect. CD86, an inflammatory macrophage marker, was reduced by PM independently of genotype. PM increased PPARγ and reduced PPARß gene expression in macrophages of both genotypes, and increased ACOX-1 expression in KO macrophages. In conclusion, PM promotes anti-inflammatory effects in macrophages exposed to LPS through inhibition of inflammasome pathway, which was independent of PPARα, PPARÏ and AMPK, thus the molecular mechanisms of anti-inflammatory response caused by PM is still unclear.
Asunto(s)
Ácidos Grasos Monoinsaturados/farmacología , Mediadores de Inflamación/antagonistas & inhibidores , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Animales , Células Cultivadas , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismoRESUMEN
PPARγ-dependent gene expression during adipogenesis is facilitated by ADP-ribosyltransferase D-type 1 (ARTD1; PARP1)-catalyzed poly-ADP-ribose (PAR) formation. Adipogenesis is accompanied by a dynamic modulation of the chromatin landscape at PPARγ target genes by ligand-dependent co-factor exchange. However, how endogenous PPARγ ligands, which have a low affinity for the receptor and are present at low levels in the cell, can induce sufficient co-factor exchange is unknown. Moreover, the significance of PAR formation in PPARγ-regulated adipose tissue function is also unknown. Here, we show that inhibition of PAR formation in mice on a high-fat diet reduces weight gain and cell size of adipocytes, as well as PPARγ target gene expression in white adipose tissue. Mechanistically, topoisomerase II activity induces ARTD1 recruitment to PPARγ target genes, and ARTD1 automodification enhances ligand binding to PPARγ, thus promoting sufficient transcriptional co-factor exchange in adipocytes. Thus, ARTD1-mediated PAR formation during adipogenesis is necessary to adequately convey the low signal of endogenous PPARγ ligand to effective gene expression. These results uncover a new regulatory mechanism of ARTD1-induced ADP-ribosylation and highlight its importance for nuclear factor-regulated gene expression.
Asunto(s)
Adipogénesis/genética , PPAR gamma/metabolismo , Poli Adenosina Difosfato Ribosa/biosíntesis , Poli(ADP-Ribosa) Polimerasas/metabolismo , Activación Transcripcional , Tejido Adiposo Blanco/efectos de los fármacos , Animales , Línea Celular , Tamaño de la Célula/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/metabolismo , Dieta Alta en Grasa , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1 , Elementos de Respuesta , Aumento de Peso/efectos de los fármacosRESUMEN
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
Hypertension is an important component of metabolic syndrome. Adulthood hypertension and metabolic syndrome can be programmed in response to nutritional insults in early life. Peroxisome proliferator-activated receptors (PPARs) serve as a nutrient-sensing signaling linking nutritional programming to hypertension and metabolic syndrome. All three members of PPARs, PPARα, PPARß/δ, and PPARγ, are expressed in the kidney and involved in blood pressure control. This review provides an overview of potential clinical applications of targeting on the PPARs in the kidney to prevent programmed hypertension and metabolic syndrome, with an emphasis on the following areas: mechanistic insights to interpret programmed hypertension; the link between the PPARs, nutritional insults, and programmed hypertension and metabolic syndrome; the impact of PPAR signaling pathway in a maternal high-fructose model; and current experimental studies on early intervention by PPAR modulators to prevent programmed hypertension and metabolic syndrome. Animal studies employing a reprogramming strategy via targeting PPARs to prevent hypertension have demonstrated interesting results. It is critical that the observed effects on developmental reprogramming in animal models are replicated in human studies, to halt the globally-growing epidemic of metabolic syndrome-related diseases.
Asunto(s)
Carbohidratos de la Dieta/efectos adversos , Hipertensión/genética , Síndrome Metabólico/genética , Receptores Activados del Proliferador del Peroxisoma/genética , Efectos Tardíos de la Exposición Prenatal/genética , Animales , Antihipertensivos/uso terapéutico , Femenino , Fructosa/efectos adversos , Regulación de la Expresión Génica , Humanos , Hipertensión/etiología , Hipertensión/patología , Hipertensión/prevención & control , Riñón/metabolismo , Riñón/patología , Exposición Materna , Síndrome Metabólico/etiología , Síndrome Metabólico/patología , Síndrome Metabólico/prevención & control , Estado Nutricional , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/prevención & control , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transducción de SeñalRESUMEN
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
Resveratrol, a modulator of several signaling proteins, can exert off-target effects involving the peroxisome proliferator-activated receptor (PPAR) transcription factors. However, evidence for the direct interaction between this polyphenol and PPARs is lacking. Here, we addressed the hypothesis that resveratrol and its metabolites control aspects of PPAR transcriptional activity through direct interaction with PPARs. Bioaffinity chromatographic studies with the immobilized ligand-binding domains (LBDs) of PPARγ and PPARα and isothermal titration calorimetry allowed the binding affinities of resveratrol, resveratrol 3-O-glucuronide, resveratrol 4-O-glucuronide, and resveratrol 3-O-sulfate to both PPAR-LBDs to be determined. Interaction of resveratrol, resveratrol 3-O-glucuronide, and resveratrol 4-O-glucuronide with PPARγ-LBD occurred with binding affinities of 1.4, 1.1, and 0.8 µM, respectively, although only resveratrol bound to the PPARα-LBD with a binding affinity of 2.7 µM. Subsequently, X-ray crystallographic studies were carried out to characterize resveratrol binding to the PPARγ-LBD at the molecular level. The electron density map from the crystal structure of the complex between PPARγ-LBD and resveratrol revealed the presence of one molecule of resveratrol bound to the LBD of PPARγ, with the ligand occupying a position close to that of other known PPARγ ligands. Transactivation assays were also performed in HepG2 cells, with the results showing that resveratrol was not a PPAR agonist but instead was able to displace rosiglitazone from PPARγ and Wy-14643 from PPARα with IC50 values of (27.4±1.8) µM and (31.7±2.5) µM, respectively. We propose that resveratrol acts as a PPAR antagonist through its direct interaction with PPARγ and PPARα.
Asunto(s)
Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Estilbenos/metabolismo , Estilbenos/farmacología , Sitios de Unión , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Modelos Moleculares , Receptores Activados del Proliferador del Peroxisoma/química , Pirimidinas/farmacología , Resveratrol , Rosiglitazona , Relación Estructura-Actividad , Tiazolidinedionas/farmacología , Células Tumorales CultivadasRESUMEN
We investigated the adipogenic activity of cultured human periosteal-derived cells and studied perioxisome proliferator-activated receptor (PPAR) ligand-mediated differentiation of cultured human periosteal-derived cells into osteoblasts. Periosteal-derived cells expressed adipogenic markers, including CCAAT/enhancer binding protein α (C/EBP- α), C/EBP-δ, aP2, leptin, LPL, and PPARγ. Lipid vesicles were formed in the cytoplasm of periosteal-derived cells. Thus, periosteal-derived cells have potential adipogenic activity. The PPARα and PPARγ agonists, WY14643 and pioglitazone, respectively, did not modulate alkaline phosphatase (ALP) activity in periosteal-derived cells during induced osteoblastic differentiation, however, the PPARα and PPARγ antagonists, GW6471 and T0070907, respectively, both decreased ALP activity in these cells. WY14643 did not affect, whereas pioglitazone enhanced, alizarin red-positive mineralization and calcium content in the periosteal-derived cells. GW6471 and T0070907 both decreased mineralization and calcium content. By RT-PCR, pioglitazone significantly increased ALP expression in periosteal-derived cells between culture day 3 and 2 weeks. Pioglitazone increased Runx2 expression after 3 days, which declined thereafter, but did not alter osteocalcin expression. Both of GW6471 and T0070907 decreased ALP mRNA expression. These results suggest that pioglitazone enhances osteoblastic differentiation of periosteal-derived cells by increasing Runx2 and ALP mRNA expression, and increasing mineralization. GW6471 and T0070907 inhibit osteoblastic differentiation of the periosteal-derived cells by decreasing ALP expression and mineralization in the periosteal-derived cells. In conclusion, although further study will be needed to clarify the mechanisms of PPAR-regulated osteogenesis, our results suggest that PPARγ agonist stimulates osteoblastic differentiation of cultured human periosteal-derived cells and PPARα and PPARγ antagonists inhibit osteoblastic differentiation in these cells.
Asunto(s)
Osteoblastos/citología , Periostio/citología , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Benzamidas/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Osteoblastos/efectos de los fármacos , Oxazoles/farmacología , PPAR alfa/agonistas , PPAR alfa/antagonistas & inhibidores , PPAR gamma/agonistas , PPAR gamma/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Pioglitazona , Piridinas/farmacología , Pirimidinas/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tiazolidinedionas/farmacología , Tirosina/análogos & derivados , Tirosina/farmacologíaRESUMEN
In order to identify new leads for the treatment of type 2 diabetes, polyenic molecules A and B derived from nipecotic acid and dienol derivatives C have been prepared and their effect on PPARs transcriptional activity evaluated and compared to that of rosiglitazone, WY14,643 and GW501516. Among the synthesized compounds, dienol 39 is the most active, increasing WY14,643 PPARα response and demonstrating partial agonist properties on rosiglitazone PPARγ.
Asunto(s)
Alquenos/síntesis química , Alquenos/farmacología , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Alquenos/química , Técnicas de Química Sintética , Humanos , Receptores Activados del Proliferador del Peroxisoma/genética , Activación Transcripcional/efectos de los fármacosRESUMEN
Lipid lowering is established as a proven intervention to reduce atherosclerosis and its complications. Statins form the basis of care but are not able to treat all aspects of dyslipidaemia. Many novel therapeutic compounds are being developed. These include additional therapeutics for low-density lipoprotein cholesterol, for example, thyroid mimetics (thyroid receptor beta-agonists), antisense oligonucleotides or microsomal transfer protein inhibitors (MTPI); triglycerides, for example, novel peroxosimal proliferator activating receptors agonists, MTPIs, diacylglycerol acyl transferase-1 inhibitors and high-density lipoprotein cholesterol (HDL-C), for example, mimetic peptides; HDL delipidation strategies and cholesterol ester transfer protein inhibitors and modulators of inflammation, for example, phospholipase inhibitors. Gene therapy for specific rare disorders, for example, lipoprotein lipase deficiency using alipogene tiparvovec is also in clinical trials. Lipid-lowering drugs are likely to prove a fast-developing area for novel treatments as possible synergies exist between new and established compounds for the treatment of atherosclerosis.
Asunto(s)
Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Acetil-CoA C-Acetiltransferasa/antagonistas & inhibidores , Proteínas Portadoras/antagonistas & inhibidores , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , HDL-Colesterol/efectos de los fármacos , Combinación de Medicamentos , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Terapia Genética/métodos , Humanos , Lipotrópicos/uso terapéutico , Oligonucleótidos Antisentido/uso terapéutico , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Proproteína Convertasas/antagonistas & inhibidores , Triglicéridos/antagonistas & inhibidoresRESUMEN
AIMS: To investigate the effect of atorvastatin on cardiac aging in rats. MATERIALS: Ninety 20-month-old Wistar rats were administered oral atorvastatin (AVT; 10 or 1 mg·kg(-1)·day(-1)) or saline for 4 months. At the end of the experiment, age-related changes in hearts were measured. RESULTS: Compared with young rats, obvious increases were found in the aging rats in left ventricle thickness, diameter of cardiocytes, collagen deposition, the ratio of type I/type III collagen, ß-galactosidase and malondialdehyde (MDA), and obvious decreases were found in superoxide dismutase (SOD), catalase (CAT) and nitric oxide synthase (NOS). The treatment with AVT led to significant decreases in the thickness of the left ventricle, diameter of cardiocytes, collagen deposition, I/III collagen ratio, MDA, ß-galactosidase and increases in the activity of SOD, CAT and NOS. Some aging-related inflammatory cytokines like interleukin (IL)-1ß, tumour necrosis factor (TNF)-α and matrix metalloproteinase (MMP)-9 were found to be overexpressed in the aging rats. AVT treatment could inhibit the expression of IL-1ß, TNF-α and MMP-9 on both the mRNA and protein levels, and increase the expression of peroxisome proliferator-activated receptors (PPAR-α/ß/δ/γ). Pretreatment with PPAR inhibitors attenuated the inhibitory effect of AVT on the expression of inflammatory cytokines. CONCLUSION: AVT may retard the cardiac aging process by upregulating PPARs.
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Envejecimiento/efectos de los fármacos , Corazón/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Miocardio/metabolismo , Receptores Activados del Proliferador del Peroxisoma/biosíntesis , Pirroles/farmacología , Envejecimiento/metabolismo , Envejecimiento/fisiología , Animales , Anticolesterolemiantes/farmacología , Atorvastatina , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Corazón/fisiología , Mediadores de Inflamación/metabolismo , Oxidorreductasas/biosíntesis , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Ratas , Ratas Wistar , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVE: To observe the selective regulation of peroxisome proliferator-activated receptors (PPAR) on fatty acid binding protein-4 (FABP4) in human syncytiotrophoblasts. METHODS: Cultivate normal human syncytiotrophoblast cells, and put in the specific antagonists and agonists of PPAR each subtypes receptors, then observe the different expression of FABP4 mRNA and protein. RESULTS: Pretreated the human syncytiotrophoblast cells with the agonists (GW7647, GW0742) and antagonists (GW6471, GSK0660) of PPARα and PPARß receptors, the expression of the FABP4 was not significantly change (P > 0.05). However pretreated with PPAR γ agonists (rosiglitazone, 1×10(-9), 1×10(-8), 1×10(-7) and 1×10(-6) mol/L), the expression of FABP4 mRNA and protein could be dose dependent-promoted significantly (mRNA: 1.27 ± 0.12, 1.45 ± 0.14, 1.57 ± 0.14, 1.72 ± 0.12, protein:1.10 ± 0.08, 1.37 ± 0.09, 1.60 ± 0.13, 1.79 ± 0.14; P < 0.05), furthermore, the promotion can be dose dependent-reversed by specific antagonists GW9662 (mRNA:0.92 ± 0.06, 0.77 ± 0.06, 0.64 ± 0.05, 0.55 ± 0.05, protein:0.91 ± 0.03, 0.78 ± 0.06, 0.70 ± 0.07, 0.55 ± 0.06; P < 0.05). CONCLUSIONS: In normal human syncytiotrophoblast cells, FABP4 is a target factor of PPARγ. PPARγ regulated the expression of FABP4 mRNA and protein selectively. And the regulation will not be influenced by the other two PPAR subtypes.
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Proteínas de Unión a Ácidos Grasos/metabolismo , Regulación de la Expresión Génica , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Trofoblastos/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Proteínas de Unión a Ácidos Grasos/genética , Humanos , PPAR alfa/agonistas , PPAR alfa/antagonistas & inhibidores , PPAR alfa/metabolismo , PPAR gamma/agonistas , PPAR gamma/antagonistas & inhibidores , PPAR gamma/metabolismo , PPAR-beta/agonistas , PPAR-beta/antagonistas & inhibidores , PPAR-beta/metabolismo , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rosiglitazona , Tiazolidinedionas/farmacología , Trofoblastos/efectos de los fármacosRESUMEN
BACKGROUND: Colorectal cancer (CRC) ranks as the second-leading cause of cancer-related death worldwide with metastases being the main cause of cancer-related death. Here, we investigated the genomic and transcriptomic alterations in matching adjacent normal tissues, primary tumors, and metastatic tumors of CRC patients. METHODS: We performed whole genome sequencing (WGS), multi-region whole exome sequencing (WES), simultaneous single-cell RNA-Seq, and single-cell targeted cDNA Sanger sequencing on matching adjacent normal tissues, primary tumors, and metastatic tumors from 12 metastatic colorectal cancer patients (n=84 for genomes, n=81 for exomes, n=9120 for single cells). Patient-derived tumor organoids were used to estimate the anti-tumor effects of a PPAR inhibitor, and self-renewal and differentiation ability of stem cell-like tumor cells. RESULTS: We found that the PPAR signaling pathway was prevalently and aberrantly activated in CRC tumors. Blocking of PPAR pathway both suppressed the growth and promoted the apoptosis of CRC organoids in vitro, indicating that aberrant activation of the PPAR signaling pathway plays a critical role in CRC tumorigenesis. Using matched samples from the same patient, distinct origins of the metastasized tumors between lymph node and liver were revealed, which was further verified by both copy number variation and mitochondrial mutation profiles at single-cell resolution. By combining single-cell RNA-Seq and single-cell point mutation identification by targeted cDNA Sanger sequencing, we revealed important phenotypic differences between cancer cells with and without critical point mutations (KRAS and TP53) in the same patient in vivo at single-cell resolution. CONCLUSIONS: Our data provides deep insights into how driver mutations interfere with the transcriptomic state of cancer cells in vivo at a single-cell resolution. Our findings offer novel knowledge on metastatic mechanisms as well as potential markers and therapeutic targets for CRC diagnosis and therapy. The high-precision single-cell RNA-seq dataset of matched adjacent normal tissues, primary tumors, and metastases from CRCs may serve as a rich resource for further studies.
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Neoplasias Colorrectales , Metástasis de la Neoplasia , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Variaciones en el Número de Copia de ADN , ADN Complementario , Genómica , Humanos , Mutación , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Receptores Activados del Proliferador del Peroxisoma/genética , TranscriptomaRESUMEN
Docking-based virtual screening of large compound libraries has been widely applied to lead discovery in structure-based drug design. However, subsequent lead optimizations often rely on other types of computational methods, such as de novo design methods. We have developed an automatic method, namely automatic tailoring and transplanting (AutoT&T), which can effectively utilize the outcomes of virtual screening in lead optimization. This method detects suitable fragments on virtual screening hits and then transplants them onto a lead compound to generate new ligand molecules. Binding affinities, synthetic feasibilities, and drug-likeness properties are considered in the selection of final designs. In this study, our AutoT&T program was tested on three different target proteins, including p38 MAP kinase, PPAR-α, and Mcl-1. In the first two cases, AutoT&T was able to produce molecules identical or similar to known inhibitors with better potency than the given lead compound. In the third case, we demonstrated how to apply AutoT&T to design novel ligand molecules from scratch. Compared to the solutions generated by other two de novo design methods, i.e., LUDI and EA-Inventor, the solutions generated by AutoT&T were structurally more diverse and more promising in terms of binding scores in all three cases. AutoT&T also completed the assigned jobs more efficiently than LUDI and EA-Inventor by several folds. Our AutoT&T method has certain technical advantages over de novo design methods. Importantly, it expands the application of virtual screening from lead discovery to lead optimization and thus may serve as a valuable tool for many researchers.