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1.
Gene ; 775: 145441, 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33482280

RESUMEN

Exercise training with anti-inflammatory effects can improve insulin sensitivity in muscle tissue. This study investigated the effects of eight-week swimming exercises on lipid profile, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and peroxisome proliferator-activated receptor gamma (PPAR-γ) in gastrocnemius muscle of rats fed with high-fat diet (HFD). Thirty-two healthy male Wistar rats (8 weeks, 200 ± 20 g) were randomly divided into four groups (n = 8 each group): the control (C), aerobic exercise (E), HFD, and HFD + aerobic exercise (HFD & E). The exercise training protocol consisted of swimming 60 min/day, 5 days/week for eight weeks. Serum levels of glucose, insulin, and lipid profile were measured at end of the study. Protein expressions of TLR4, TNF-α, and IL-6 were determined by immunohistochemical method. Gene expression of TLR4/MyD88, TNF-α, IL-6, and PPAR-γ was evaluated by a real-time polymerase chain reaction in gastrocnemius muscle. HFD fed rats showed higher levels of cholesterol and LDL-c that were similar in weight gain. Meanwhile, the HFD group had a higher gene expression of TLR4, MyD88, TNF-α, IL-6, and lower gene expression of PPAR-γ compared to the control group (p < 0.05). Muscle protein expression of TLR4, TNF-α, IL-6 was lower in the E and HFD&E groups (especially when compared to HFD group, P < 0.05). We also showed a decrease in TLR4/MyD88 mRNA and an increase in PPAR-γ mRNA in gastrocnemius of E and HFD&E groups (compared to HFD group, p < 0.05). Insulin resistance in HFD&E groups show a significant decrease compared to the HFD group (p < 0.05). It seems that swimming aerobic exercise for eight weeks controlled the destructive effects of HFD on muscle inflammatory pathways along with the down-regulation of the TLR4/MyD88, inflammatory cytokine, and up-regulation PPAR-γ mRNA. It appears that the down-regulation in the expression of TLR4/MyD88 mRNA reduces the muscle pro-inflammatory cytokines, such as IL-6 and TNF-α, whose action may be caused by the adaptation of swimming aerobic exercise (an increase of PPAR-γ). Therefore, local and systemic inflammatory changes due to HFD and obesity may be affected by metabolic adaptations of aerobic exercise training, which requires further studies.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina/inmunología , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/métodos , Natación/fisiología , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Músculo Esquelético/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
2.
Environ Pollut ; 271: 116331, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33383419

RESUMEN

Tributyltin (TBT), a bioaccumulative and persistent environmental pollutant, has been proposed as a metabolism disruptor and obesogen through targeting peroxisome proliferator-activated receptor gamma (PPARγ) receptor pathway. However, it remains unknown whether this biological effect occurs in macrophage, a cell type which cooperates closely with hepatocytes and adipocytes to regulate lipid metabolism. This study for the first time investigated the effect of TBT on PPARγ pathway in macrophages. Our results indicated that nanomolar levels of TBT was able to strongly activate PPARγ in human macrophages. TBT treatment also markedly increased the intracellular lipid accumulation, and enhanced the expression of lipid metabolism-related genes in macrophages, while these effects were all significantly down-regulated in PPARγ-deficient macrophages, confirming the involvement of PPARγ in TBT-induced lipogenesis. Next, a mouse model that C57BL/6 mice were orally exposed to TBT with the doses (250 and 500 µg/kg body weight) lower than NOAEL (no observed adverse effect level) was used to further investigate the in vivo mechanisms. And the in vivo results were consistent with cellular assays, confirming the induction of PPARγ and the increased expression of lipogenesis-regulating and lipid metabolism-related genes by TBT in vivo. In conclusion, this study not only provided the first evidence that TBT stimulated lipogenesis, activated PPARγ and related genes in human macrophages, but also provided insight into the mechanism of TBT-induced metabolism disturbance and obesity through targeting PPARγ via both in vitro cellular assays and in vivo animal models.


Asunto(s)
Lipogénesis , PPAR gamma , Animales , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , PPAR gamma/genética , PPAR gamma/metabolismo , Compuestos de Trialquiltina
3.
Life Sci ; 266: 118882, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33310046

RESUMEN

AIMS: Cilostazol (Cilo), a phosphodiesterase-III inhibitor, has signified its efficacy against different ischemia/reperfusion (IS/RE) models. Nevertheless, it has not fully illuminated its potential effect against intestinal IS/RE-induced lung injury. Consequently, the study was fashioned to evaluate the feasible mechanism of action of Cilo against intestinal IS/RE-induced lung injury. MAIN METHODS: Wistar rats were treated with Cilo (0.1 g/kg, p.o.) or with a vehicle for 14 days prior to IS/RE, induced by clamping of the superior mesenteric artery for 30 min with subsequent clamp removal for 2 h. KEY FINDINGS: The mechanistic study disclosed that Cilo protected the two studied organs, viz., lung, and intestine partially by intensifying the expression/content of PPAR-γ accompanied by reducing the expression/content of NF-қB-p65 and STAT3. In addition to normalizing MDA, iNOS, and NOx, the Cilo antioxidant power was confirmed by intensifying tissues content of the total antioxidant capacity. With regard to the anti-inflammatory effect, Cilo reduced the effects of TNF-α, IL-6, and ICAM-1, which were reflected in MPO activity. Furthermore, Cilo had an anti-apoptotic attribute demonstrated by enhancing Bcl-2 content and lessening caspase-3 level. SIGNIFICANCE: Cilo provided conceivable protective mechanisms to modulate events concomitant with mesenteric IS/RE partly by modulating oxidative stress, inflammation, and apoptosis feasibly via the participation of PPAR-γ, STAT3, and NF-κB p65 signaling pathways.


Asunto(s)
Cilostazol/farmacología , Enfermedades Pulmonares/prevención & control , Isquemia Mesentérica/complicaciones , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Daño por Reperfusión/complicaciones , Factor de Transcripción STAT3/metabolismo , Animales , Broncodilatadores/farmacología , Regulación de la Expresión Génica , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/patología , Masculino , FN-kappa B/genética , Estrés Oxidativo , PPAR gamma/genética , Ratas , Ratas Wistar , Factor de Transcripción STAT3/genética , Transducción de Señal
4.
Gene ; 771: 145340, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33333224

RESUMEN

Diabetic patients are always at a higher risk of ischemic diseases like coronary artery diseases. One such ischemic carotid artery disease is Moyamoya disease (MMD) associated with diabetes Type I and II, but the causality was unclear. Ring Finger Protein 213 (RNF213) is the major susceptible gene for MMD. To understand the association between diabetes mellitus and MMD we chose the major players from both of the anomalies: insulin and RNF213. But before establishing the role of RNF213 in the insulin-regulating pathway we had to understand the involvement of RNF213 within different biological systems. For this, we have adopted a preliminary computational approach to find the prominent interactions of RNF213. Our first objective was to construct an interactome for RNF213. We have analyzed several curated databases and adapted a list of RNF213 interacting partners to develop its interactome. Then to understand the involvement of this interactome in biological functions we have analyzed major biological pathways, biological processes, and prominent clusters related to this interactome through a computational approach. Then to develop a pathway that might give clues for RNF213 involvement in the insulin regulatory pathway we have validated the intercluster and intracluster predictions and identified a regulatory pathway for RNF213. RNF213 interactome was observed to be involved in adaptive immunity with 4 major clusters; one of the clusters involved TNFα. The immune system involves several pathways, and therefore at this point, we have chosen an event-based strategy to obtain an explicit target. Immunity is mediated by pro-inflammatory cytokines like TNFα. TNFα-mediated inflammation, obesity, and insulin resistance are associated. Therefore we chose to explore the role of RNF213 in TNFα-mediated inflammation in macrophages and inflammation-mediated insulin-resistance in adipocytes. We have observed an enhancement of RNF213 gene expression by LPS mediated pro-inflammatory stimuli and suppression by PPARγ-mediated anti-inflammatory, insulin-sensitizing stimuli in macrophages, and also in adipocytes. Administration of the pro-inflammatory cytokine TNFα was able to impede the reduction in RNF213 expression during adipogenesis and this effect was observed to be mediated by PTP1B. Inactivation of PTP1B abolished RNF213 expression which in turn enhanced the adipogenesis process through enhanced PPARγ. Constitutive expression of RNF213 suppressed the adipocyte differentiation by the inhibition of PPARγ. We could show the regulation of RNF213 by TNFα/PTP1B pathway and PPARγ. The constitutive expression of RNF213 during adipogenesis appears to be an adipostatic measure that obese patients acquire to inhibit further adipogenesis. This is verified in silico by analyzing the gene expression data obtained from the Gene Expression Omnibus database, which showed a higher expression of RNF213 in adipose tissue samples of obese people. Overall this study gives new insights into the TNFα-mediated pathway in adipogenesis and suggests the role of RNF213 in adipogenesis via this pathway.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Inflamación/metabolismo , Resistencia a la Insulina/genética , Enfermedad de Moyamoya/metabolismo , PPAR gamma/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Células 3T3-L1 , Adenosina Trifosfatasas/genética , Adipogénesis , Animales , Biología Computacional/métodos , Humanos , Inflamación/genética , Lipopolisacáridos/efectos adversos , Ratones , Enfermedad de Moyamoya/genética , Obesidad/genética , Obesidad/metabolismo , Mapas de Interacción de Proteínas , Células RAW 264.7 , Transducción de Señal , Factor de Necrosis Tumoral alfa/farmacología , Ubiquitina-Proteína Ligasas/genética
5.
Gene ; 764: 145100, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-32877748

RESUMEN

Adipocyte differentiation is an essential part of adipose tissue development, and is closely related to obesity and obesity-related diseases. In this study, we found that the expression of PPARγ, RUVBL2 and Adiponectin were concurrently obviously increased in the 5th-7th day of 3T3-L1 cell differentiation. PPARγ overexpression or the PPARγ activator facilitated Adiponectin trafficking and secretion and upregulated RUVBL2 expression as well as AS160 phosphorylation during adipogenic differentiation of 3T3-L1 cells. Consistently RUVBL2 overexpression also enhanced the polymerization and secretion of Adiponectin, in contrast, RUVBL2 knockdown reduced Adiponectin secretion. Further, PPARγ significantly enhanced RUVBL2 promoter activity and transcription. The progressive deletions and mutations of RUVBL2 promoter for PPARγ binding sites suggested that the PPARγ binding motif situated at -804/-781 bp is an essential component required for RUVBL2 promoter activity. Chromatin immunoprecipitation (ChIP) assays determined that PPARγ can directly interact with the RUVBL2 promoter DNA. Taken together, these data suggest that PPARγ promotes the expression, polymerization and secretion of Adiponectin by activating RUVBL2 transcriptionally, which accelerates 3T3-L1 cell differentiation.


Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/genética , Adipocitos/fisiología , Adipogénesis/genética , Adiponectina/metabolismo , ADN Helicasas/genética , PPAR gamma/metabolismo , Células 3T3-L1 , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Animales , Sitios de Unión/genética , Diferenciación Celular/genética , Inmunoprecipitación de Cromatina , Clonación Molecular , ADN Helicasas/metabolismo , Ratones , Mutación , Regiones Promotoras Genéticas/genética , Multimerización de Proteína/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Activación Transcripcional , Regulación hacia Arriba
6.
Gene ; 766: 145155, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32950634

RESUMEN

Expression of browning genes are lower in both humans and animals with type 2 diabetes (T2D). This study aims at determining effects of long-term nitrate administration on protein and mRNA levels of uncoupling protein 1 (UCP1), peroxisome proliferator activated receptor gamma (PPAR-γ), and PPAR-γ coactivator 1 alpha (PGC1-α) in epididymal adipose tissue (eAT) of rats with T2D. Male Wistar rats were divided into 4 groups (n = 6/group): Control, diabetes, control + nitrate (CN), and diabetes + nitrate (DN). T2D was induced using high fat diet combined with a low-dose of streptozotocin (30 mg/kg body weight). Sodium nitrate was administrated at a dose of 100 mg/L for 6 months in nitrate-treated rats. Fasting serum glucose and insulin concentrations were measured at months 0 (i.e. at start of the protocol), 3, and 6. At month 6, protein and mRNA levels of UCP1, PPAR-γ, and PGC1-α were measured in eAT samples. In addition, tissue concentration of cyclic guanosine monophosphate (cGMP) was measured and histological analyses were done at month 6. In rats with T2D, 6-month administration of nitrate decreased serum glucose and insulin concentrations by 13% and 23%, respectively and increased cGMP level by 85%. Rats with T2D had lower mRNA and protein levels of PPAR-γ (62%, P < 0.0001 and 18%, P = 0.0472), PGC1-α (49%, P = 0.0019 and 21%, P = 0.0482), and UCP1 (35%, P = 0.0613 and 30%, P = 0.0031) in eAT; 6-month nitrate administration restored these decreased levels to near control values. In addition, nitrate increased adipocyte density by 193% and decreased adipocyte area by 53% in rats with T2D. In conclusion, long-term low-dose nitrate administration increased mRNA and protein expressions of browning genes in white adipose tissue of male rats with T2D; these findings partly explain favorable metabolic effects of nitrate administration in diabetes.


Asunto(s)
Adipocitos Marrones/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Epidídimo/efectos de los fármacos , Nitratos/administración & dosificación , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Epidídimo/metabolismo , Glucosa/metabolismo , Insulina/sangre , Masculino , PPAR gamma/genética , PPAR gamma/metabolismo , ARN Mensajero/genética , Ratas , Ratas Wistar , Estreptozocina/farmacología
7.
PLoS One ; 15(12): e0242640, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33373386

RESUMEN

To examine the differential mechanobiological responses of specific resident tendon cells, we developed an in vivo model of whole-body irradiation followed by injection of either tendon stem/progenitor cells (TSCs) expressing green fluorescent protein (GFP-TSCs) or mature tenocytes expressing GFP (GFP-TNCs) into the patellar tendons of wild type C57 mice. Injected mice were subjected to short term (3 weeks) treadmill running, specifically moderate treadmill running (MTR) and intensive treadmill running (ITR). In MTR mice, both GFP-TSC and GFP-TNC injected tendons maintained normal cell morphology with elevated expression of tendon related markers collagen I and tenomodulin. In ITR mice injected with GFP-TNCs, cells also maintained an elongated shape similar to the shape found in normal/untreated control mice, as well as elevated expression of tendon related markers. However, ITR mice injected with GFP-TSCs showed abnormal changes, such as cell morphology transitioning to a round shape, elevated chondrogenic differentiation, and increased gene expression of non-tenocyte related genes LPL, Runx-2, and SOX-9. Increased gene expression data was supported by immunostaining showing elevated expression of SOX-9, Runx-2, and PPARγ. This study provides evidence that while MTR maintains tendon homeostasis by promoting the differentiation of TSCs into TNCs, ITR causes the onset of tendinopathy development by inducing non-tenocyte differentiation of TSCs, which may eventually lead to the formation of non-tendinous tissues in tendon tissue after long term mechanical overloading conditions on the tendon.


Asunto(s)
Condrocitos/citología , Células Madre/citología , Tendinopatía/patología , Tendones/patología , Tenocitos/citología , Animales , Biomarcadores/metabolismo , Diferenciación Celular , Forma de la Célula , Rastreo Celular , Condrocitos/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Prueba de Esfuerzo , Femenino , Regulación de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , PPAR gamma/genética , PPAR gamma/metabolismo , Condicionamiento Físico Animal/efectos adversos , Carrera , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Células Madre/metabolismo , Tendinopatía/etiología , Tendinopatía/genética , Tendinopatía/metabolismo , Tendones/metabolismo , Tenocitos/metabolismo
8.
PLoS One ; 15(12): e0240873, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33382706

RESUMEN

BACKGROUND: Sorghum bicolor (SB) is rich in protective phytoconstituents with health benefits and regarded as a promising source of natural anti-diabetic substance. However, its comprehensive bioactive compound(s) and mechanism(s) against type-2 diabetes mellitus (T2DM) have not been exposed. Hence, we implemented network pharmacology to identify its key compounds and mechanism(s) against T2DM. METHODS: Compounds in SB were explored through GC-MS and screened by Lipinski's rule. Genes associated with the selected compounds or T2DM were extracted from public databases, and the overlapping genes between SB-compound related genes and T2DM target genes were identified using Venn diagram. Then, the networking between selected compounds and overlapping genes was constructed, visualized, and analyzed by RStudio. Finally, affinity between compounds and genes was evaluated via molecular docking. RESULTS: GC-MS analysis of SB detected a total of 20 compounds which were accepted by the Lipinski's rule. A total number of 16 compounds-related genes and T2DM-related genes (4,763) were identified, and 81 overlapping genes between them were selected. Gene set enrichment analysis exhibited that the mechanisms of SB against T2DM were associated with 12 signaling pathways, and the key mechanism might be to control blood glucose level by activating PPAR signaling pathway. Furthermore, the highest affinities were noted between four main compounds and six genes (FABP3-Propyleneglyco monoleate, FABP4-25-Oxo-27-norcholesterol, NR1H3-Campesterol, PPARA-ß-sitosterol, PPARD-ß-sitosterol, and PPARG-ß-sitosterol). CONCLUSION: Our study overall suggests that the four key compounds detected in SB might ameliorate T2DM severity by activating the PPAR signaling pathway.


Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Hipoglucemiantes/química , Fitoquímicos/química , Sorghum/química , Esteroles/química , Sitios de Unión , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteína 3 de Unión a Ácidos Grasos/antagonistas & inhibidores , Proteína 3 de Unión a Ácidos Grasos/genética , Proteína 3 de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/farmacología , Receptores X del Hígado/antagonistas & inhibidores , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Simulación del Acoplamiento Molecular , PPAR alfa/antagonistas & inhibidores , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR delta/antagonistas & inhibidores , PPAR delta/genética , PPAR delta/metabolismo , PPAR gamma/antagonistas & inhibidores , PPAR gamma/genética , PPAR gamma/metabolismo , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Extractos Vegetales/química , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Transducción de Señal , Esteroles/aislamiento & purificación , Esteroles/farmacología , Relación Estructura-Actividad
9.
J Med Chem ; 63(24): 16012-16027, 2020 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-33325691

RESUMEN

Following our report that A3 adenosine receptor (AR) antagonist 1 exhibited a polypharmacological profile as a dual modulator of peroxisome proliferator-activated receptor (PPAR)γ/δ, we discovered a new template, 1'-homologated adenosine analogues 4a-4t, as dual PPARγ/δ modulators without AR binding. Removal of binding affinity to A3AR was achieved by 1'-homologation, and PPARγ/δ dual modulation was derived from the structural similarity between the target nucleosides and PPAR modulator drug, rosiglitazone. All the final nucleosides were devoid of AR-binding affinity and exhibited high binding affinities to PPARγ/δ but lacked PPARα binding. 2-Cl derivatives exhibited dual receptor-binding affinity to PPARγ/δ, which was absent for the corresponding 2-H derivatives. 2-Propynyl substitution prevented PPARδ-binding affinity but preserved PPARγ affinity, indicating that the C2 position defines a pharmacophore for selective PPARγ ligand designs. PPARγ/δ dual modulators functioning as both PPARγ partial agonists and PPARδ antagonists promoted adiponectin production, suggesting their therapeutic potential against hypoadiponectinemia-associated cancer and metabolic diseases.


Asunto(s)
Adenosina/química , Adenosina/farmacología , Adiponectina/metabolismo , Descubrimiento de Drogas , Obesidad/tratamiento farmacológico , PPAR alfa/antagonistas & inhibidores , PPAR gamma/agonistas , Animales , Sitios de Unión , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Simulación de Dinámica Molecular , Obesidad/metabolismo , Obesidad/patología , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Unión Proteica , Relación Estructura-Actividad
10.
Proc Natl Acad Sci U S A ; 117(52): 33295-33304, 2020 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-33318171

RESUMEN

Adipocytes have been implicated in breast tumor growth and stemness maintenance through secreted factors. However, the mechanisms by which these cytokines are regulated during diet-induced obesity and contribute to breast tumorigenesis remain largely unknown. Here we show that transcription cofactor TAZ in adipocytes is directly up-regulated by the free fatty acid/PPARγ axis upon dietary fat stimulation. TAZ knockdown alters the expression profile of a series of secreted proteins and attenuates the tumor-supporting function of adipocytes. Moreover, we identify Resistin, an adipose-derived hormone, as a functional downstream target of TAZ, which facilitates tumorigenesis, and its expression correlated with adipocyitc TAZ in triple-negative breast cancer samples. Further, Adiponectin-cre-mediated TAZ knockout in adipocytes mitigates breast tumor growth. Taken together, our findings highlight how diet-induced TAZ expression in adipocytes promotes tumorigenesis, suggesting promising cancer therapeutic targets.


Asunto(s)
Adipocitos/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinogénesis/patología , Resistina/metabolismo , Transactivadores/metabolismo , Adipocitos/metabolismo , Adiposidad , Animales , Neoplasias de la Mama/genética , Carcinogénesis/metabolismo , Proliferación Celular , Dieta , Ácidos Grasos/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Obesidad/patología , PPAR gamma/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
11.
Yakugaku Zasshi ; 140(11): 1351-1363, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-33132271

RESUMEN

Epidemiological studies have shown that coffee consumption may be associated with a lower risk of developing several chronic disorders. To elucidate the molecular mechanism of the effects of coffee, we analyzed molecular response upon exposure to coffee extract using cellular and animal models of these diseases. As obesity is recognized as a major risk factor for these chronic diseases, we investigated the effect of coffee on adipogenesis using mouse preadipocyte 3T3-L1 cells. We found that coffee induced proteasomal degradation of IRS-1, leading to reduction of PPARγ expression, a master transcription factor for adipogenesis. Reduction in weight as well as in IRS-1 expression was detected in the fat tissues of the high fat-diet-fed mice when reared with 60% coffee for 7 weeks. As for Alzheimer's disease, we analyzed the effect of coffee on amyloid ß (Aß) production in human neuronal SH-SY5Y cells. We found a 20% reduction in Aß production when treated with 2.5% coffee for 2 d. This reduction was due to proteasomal degradation of BACE1 (ß-secretase), which was activated by protein kinase A. In addition, coffee ameliorates LPS-induced inflammatory responses in RAW264.7 macrophages by reducing NFκB activity and Nrf2 activation. Roasted coffee prevents selenite-induced cataractogenesis by ameliorating antioxidant loss. Pyrocatechol, a component of roasted coffee, also reduced Aß production and exhibits anti-inflammatory effects by a similar mechanism as coffee. Our results suggest that roasting coffee beans to generate pyrocatechol is necessary for the preventive effects of coffee intake on the chronic diseases.


Asunto(s)
Enfermedad de Alzheimer/prevención & control , Catarata/prevención & control , Enfermedad Crónica/prevención & control , Café , Ingestión de Líquidos/fisiología , Adipogénesis , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Catecoles , Células Cultivadas , Café/química , Modelos Animales de Enfermedad , Manipulación de Alimentos , Calor , Humanos , Proteínas Sustrato del Receptor de Insulina/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Células RAW 264.7
12.
J Oleo Sci ; 69(10): 1287-1295, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33028753

RESUMEN

Policosanol, a mixture of long-chain alcohols found in animal and plant waxes, has several biological effects including lipid-lowering that have been extensively studied. However, its bioavailability is low. To investigate the effect of nanoemulsified rice bran wax policosanol (NPOL) on plasma homocysteine, heart and liver histology in hyperlipidemic rats, high-fat diet containing 2.5% cholesterol was used to induce hyperlipidemia in Sprague Dawley rats. The hyperlipidemic rats were treated with NPOL and rice bran wax policosanol (POL) in comparison with normal diet (ND), high-cholesterol diet (HCD) and simvastatin-treated rats. Plasma homocysteine, heart and liver histology, and hepatic mRNA expression of peroxisome proliferator-activated receptor gamma (PPARG) were evaluated. The NPOL group, similar to the simvastatin group, showed reduced plasma homocysteine, preserved heart and liver histology, and down-regulated hepatic PPARG mRNA in comparison to the control group, and was better than the POL group. The results suggest that the modest effect of NPOL on homocysteine and preservation of heart and liver histology could be through the regulation of PPARG expression on a background of increased assimilation of rice bran wax policosanol.


Asunto(s)
Cardiotónicos , Alcoholes Grasos/farmacología , Alcoholes Grasos/uso terapéutico , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Hígado/metabolismo , Hígado/patología , Miocardio/metabolismo , Miocardio/patología , Oryza/química , PPAR gamma/genética , PPAR gamma/metabolismo , Fitoterapia , Ceras/química , Animales , Dieta Alta en Grasa/efectos adversos , Expresión Génica/efectos de los fármacos , Homocisteína/sangre , Hiperlipidemias/etiología , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley
13.
Nat Commun ; 11(1): 4448, 2020 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-32895370

RESUMEN

Substance abuse disorders are linked to alteration of circadian rhythms, although the molecular and neuronal pathways implicated have not been fully elucidated. Addictive drugs, such as cocaine, induce a rapid increase of dopamine levels in the brain. Here, we show that acute administration of cocaine triggers reprogramming in circadian gene expression in the striatum, an area involved in psychomotor and rewarding effects of drugs. This process involves the activation of peroxisome protein activator receptor gamma (PPARγ), a nuclear receptor involved in inflammatory responses. PPARγ reprogramming is altered in mice with cell-specific ablation of the dopamine D2 receptor (D2R) in the striatal medium spiny neurons (MSNs) (iMSN-D2RKO). Administration of a specific PPARγ agonist in iMSN-D2RKO mice elicits substantial rescue of cocaine-dependent control of circadian genes. These findings have potential implications for development of strategies to treat substance abuse disorders.


Asunto(s)
Relojes Circadianos/efectos de los fármacos , Trastornos Relacionados con Cocaína/fisiopatología , Cocaína/efectos adversos , Núcleo Accumbens/efectos de los fármacos , PPAR gamma/metabolismo , Receptores de Dopamina D2/metabolismo , Administración Oral , Animales , Relojes Circadianos/fisiología , Cocaína/administración & dosificación , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Dopamina/metabolismo , Inyecciones Intraperitoneales , Locomoción/fisiología , Masculino , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Núcleo Accumbens/fisiopatología , PPAR gamma/agonistas , Pioglitazona/administración & dosificación , Receptores de Dopamina D2/genética , Recompensa , Transducción de Señal
14.
PLoS One ; 15(9): e0239547, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32970728

RESUMEN

Obesity is a common disease over the world and is tightly associated with diabetes mellitus, cardiovascular and cancer disease. Although our previous study showed that the synthetic vanadium-protein (V-P) complex had a better effect on antioxidant and antidiabetic, the relative molecular mechanisms are still entirely unknown. Hence, we investigated the effect of the synthetic V-P complex on adipocyte differentiation (adipogenesis) using human preadipocytes to clarify its molecular mechanisms of action. The primary human preadipocytes were cultured with and without V-P complex during adipocyte differentiation. The cell proliferation, lipid accumulation, and the protein expression of transcription factors and related enzymes were determined for the differentiated human preadipocytes. In this study, the 20 µg/mL of V-P complex reduced the lipid and triglyceride (TG) content by 74.47 and 57.39% (p < 0.05), respectively, and down-regulated the protein expressions of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), sterol regulatory element-binding protein 1 (SREBP-1) and fatty acid synthase (FAS). Additionally, the V-P complex significantly up-regulated the protein levels of total ß-catenin (t-ß-catenin), nuclear ß-catenin (n-ß-catenin), phosphorylated adenosine monophosphate-activated protein kinase alpha (p-AMPKα) and liver kinase B1 (p-LKB1). These showed that the inhibitory effect of V-P complex on human adipogenesis was mediated by activating Wnt/ß-catenin and LKB1/AMPK-dependent signaling pathway. Therefore, the synthetic V-P complex could be considered as a candidate for prevention and treatment of obesity.


Asunto(s)
Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Vanadio/metabolismo , Células 3T3-L1 , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Proteína alfa Potenciadora de Unión a CCAAT/genética , Diferenciación Celular/efectos de los fármacos , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/fisiología , Ratones , Obesidad/metabolismo , PPAR gamma/metabolismo , Fosforilación , Transducción de Señal/efectos de los fármacos , Triglicéridos/metabolismo , beta Catenina/metabolismo
15.
Am J Chin Med ; 48(6): 1409-1433, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32907360

RESUMEN

Scutellaria baicalensis (SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice. Next, the optimized dose of SB (400[Formula: see text]mg/kg) was co-administered with MF (50, 100, and 200[Formula: see text]mg/kg) in a similar animal model to find the effective combinations of SB and MF. Metabolic markers were determined in serum and tissues using different assays, histology, gene expression, and gut microbial population. The SB and MF co-treatment significantly decreased the body, liver, and VAT weights. The outcome of OGTT was improved, and the fasting insulin, HbA1c, TG, TC, LDL-c, AST, and ALT were decreased, while HDL-c was significantly increased. Histological analyses revealed maintained the integrity of liver, adipose tissue, and intestine prevented lipid accumulation in the liver and intestine and combated neuronal damage in the brain. Importantly, controlled the expression of PPAR[Formula: see text], and IL-6 genes in the liver, and expression of BDNF, Glut1, Glut3, and Glut4 genes in the brain. Treatment-specific gut microbial segregation was observed in the PCA chart. Our findings indicate that SB and MF co-treatment is an effective therapeutic approach for HFFD-induced metabolic dysregulation which is operated through the gut-liver-brain axis.


Asunto(s)
Encéfalo/metabolismo , Microbioma Gastrointestinal , Hígado/metabolismo , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/metabolismo , Metformina/administración & dosificación , Metformina/farmacología , Fitoterapia , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Dieta de Carga de Carbohidratos/efectos adversos , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Quimioterapia Combinada , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/microbiología , Ratones Endogámicos C57BL , PPAR gamma/genética , PPAR gamma/metabolismo
16.
Mol Pharmacol ; 98(5): 634-647, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32892155

RESUMEN

Long-term administration of some antiepileptic drugs often increases blood lipid levels. In this study, we investigated its molecular mechanism by focusing on the nuclear receptors constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα), which are key transcription factors for enzyme induction and lipid metabolism, respectively, in the liver. Treatment of mice with the CAR activator phenobarbital, an antiepileptic drug, increased plasma triglyceride levels and decreased the hepatic expression of PPARα target genes related to lipid metabolism. The increase in PPARα target gene expression induced by fenofibrate, a PPARα ligand, was inhibited by cotreatment with phenobarbital. CAR suppressed PPARα-dependent gene transcription in HepG2 cells but not in COS-1 cells. The mRNA level of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), a coactivator for both CAR and PPARα, in COS-1 cells was much lower than in HepG2 cells. In reporter assays with COS-1 cells overexpressing PGC1α, CAR suppressed PPARα-dependent gene transcription, depending on the coactivator-binding motif. In mammalian two-hybrid assays, CAR attenuated the interaction between PGC1α and PPARα Chemical inhibition of PGC1α prevented phenobarbital-dependent increases in plasma triglyceride levels and the inhibition of PPARα target gene expression. These results suggest that CAR inhibits the interaction between PPARα and PGC1α, attenuating PPARα-dependent lipid metabolism. This might explain the antiepileptic drug-induced elevation of blood triglyceride levels. SIGNIFICANCE STATEMENT: Constitutive active/androstane receptor activated by antiepileptic drugs inhibits the peroxisome proliferator-activated receptor α-dependent transcription of genes related to lipid metabolism and upregulates blood triglyceride levels. The molecular mechanism of this inhibition involves competition between these nuclear receptors for coactivator peroxisome proliferator-activated receptor γ coactivator-1α binding.


Asunto(s)
Anticonvulsivantes/farmacología , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Triglicéridos/sangre , Animales , Línea Celular Tumoral , Inducción Enzimática/efectos de los fármacos , Fenofibrato/farmacología , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fenobarbital/farmacología , Factores de Transcripción/metabolismo , Activación Transcripcional/efectos de los fármacos
17.
Ann Agric Environ Med ; 27(3): 407-412, 2020 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-32955223

RESUMEN

INTRODUCTION AND OBJECTIVE: The biochemical and anthropometric consequences of metabolic disorders exert an enormous effect on the functioning of people worldwide. The aim of this study is to assess relationships between biochemical and anthropometric parameters associated with metabolic syndrome, and the presence of the PPAR-γ rs1801282, the FTO rs9939609, and the MC4R rs17782313 polymorphisms in women aged 45-60. MATERIAL AND METHODS: The study included 425 women, aged 45-59 years, from the general population of the West Pomeranian Province in north-west Poland. The research procedure involved a structured interview, anthropometric and blood pressure measurements, biochemical analysis of serum, and genetic analysis. RESULTS: The carriers of the A/A genotype of the FTO polymorphism had higher LDL levels than their counterparts with the T/T genotype (p = 0.01). The carriers of the T/T genotype of the MC4R polymorphism had lower non-HDL levels than those with the C/C and C/T genotypes (p = 0.019). Weight was related to the C/C and the C/G + G/G genotypes of the PPAR-γ gene polymorphism (p = 0.046). The model of inheritance for the MC4R polymorphism had a significant effect on TG (p = 0.039) and non-HDL (p = 0.05) levels. CONCLUSIONS: The genotypes analyzed in the study had only a slight direct effect on the biochemical and anthropometric abnormalities typical of metabolic disorders. Nonetheless, the risk alleles (A allele of the FTO rs9939609 and the C allele of the MC4R rs17782313) were found to be related to lipid metabolism disorders in 45-60-year-old women.


Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Antropometría , Predisposición Genética a la Enfermedad , Síndrome Metabólico/genética , PPAR gamma/genética , Receptor de Melanocortina Tipo 4/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Femenino , Humanos , Persona de Mediana Edad , PPAR gamma/metabolismo , Polonia , Polimorfismo de Nucleótido Simple , Receptor de Melanocortina Tipo 4/metabolismo
18.
Life Sci ; 261: 118363, 2020 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-32861797

RESUMEN

AIM: Dexamethasone (DXM) is a synthetic glucocorticoid whose effects in early and terminal adipogenesis have been addressed. In this study, we evaluated if DXM affects adipocyte precursor cells (APCs), priming them for further adipogenic differentiation. For this purpose, we analyzed APCs number and competency after DXM treatment. MATERIALS AND METHODS: Adult male rats were injected for 2 or 7 days with either DXM (30 µg/kg of weight, sc.) or vehicle. Stromal vascular fraction (SVF) cells from retroperitoneal adipose tissue (RPAT) were isolated to quantify APCs by flow cytometry (CD34+/CD45-/CD31-). Also, expression of competency markers (PPARγ2 and Zfp423) was assessed. Additionally, SVF cells from control rats were incubated with DXM (0.25 µM) alone or combined with a mineralocorticoid receptor (MR) antagonist (Spironolactone 10 µM) and/or a glucocorticoid receptor (GR) antagonist (RU486 1 µM) to assess APCs competency and adipocyte differentiation. KEY FINDINGS: APCs from 2 days DXM-treated rats showed increased expression of PPARγ2 and Zfp423 (competency markers), but did not affect APCs percentage by FACS analysis (CD34+/CD45-/CD31-). Additionally, we found that DXM treatment in SVF also increased APCs competency in vitro, predisposing APCs to further adipocyte differentiation. These effects on APCs were abrogated only when both, MR and GR, were blocked. SIGNIFICANCE: Overall, our results suggest that DXM primes APCs for differentiation mainly by enhancing Zfp423 and PPARγ2 expressions. Also, we showed that the inhibition of MR and GR was necessary for the complete abolishment of DXM effects.


Asunto(s)
Adipocitos/citología , Adipogénesis , Dexametasona/farmacología , Células Madre/citología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Tejido Adiposo/citología , Animales , Biomarcadores/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , PPAR gamma/genética , PPAR gamma/metabolismo , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Espacio Retroperitoneal , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Factores de Transcripción/metabolismo
19.
Nat Commun ; 11(1): 4150, 2020 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-32811819

RESUMEN

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.


Asunto(s)
Adipocitos/metabolismo , Envejecimiento/fisiología , Autofagia/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Enfermedades Metabólicas/metabolismo , Adipocitos/patología , Adipogénesis/genética , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Adiposidad/genética , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagia/fisiología , Hígado Graso/genética , Hígado Graso/metabolismo , Técnicas de Inactivación de Genes , Glucosa/genética , Glucosa/metabolismo , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Metabolismo de los Lípidos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/metabolismo , Coactivador 1 de Receptor Nuclear/metabolismo , Coactivador 2 del Receptor Nuclear/metabolismo , PPAR gamma/metabolismo
20.
PLoS One ; 15(8): e0237976, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32822399

RESUMEN

Environmental exposure to arsenite (As3+) has a strong association with the development of human urothelial cancer (UC) and is the 5th most common cancer in men and the 12th most common cancer in women. Muscle invasive urothelial cancer (MIUC) are grouped into basal or luminal molecular subtypes based on their gene expression profile. The basal subtype is more aggressive and can be associated with squamous differentiation, characterized by high expression of keratins (KRT1, 5, 6, 14, and 16) and epidermal growth factor receptor (EGFR) within the tumors. The luminal subtype is less aggressive and is predominately characterized by elevated gene expression of peroxisome proliferator-activated receptor- gamma (PPARγ) and forkhead box protein A1 (FOXA1). We have previously shown that As3+-transformed urothelial cells (As-T) exhibit a basal subtype of UC expressing genes associated with squamous differentiation. We hypothesized that the molecular subtype of the As-T cells could be altered by inducing the expression of PPARγ and/or inhibiting the proliferation of the cells. Non-transformed and As-T cells were treated with Troglitazone (TG, PPARG agonist, 10 µM), PD153035 (PD, an EGFR inhibitor, 1 µM) or a combination of TG and PD for 3 days. The results obtained demonstrate that treatment of the As-T cells with TG upregulated the expression of PPARγ and FOXA1 whereas treatment with PD decreased the expression of some of the basal keratins. However, a combined treatment of TG and PD resulted in a consistent decrease of several proteins associated with the basal subtype of bladder cancers (KRT1, KRT14, KRT16, P63, and TFAP2A). Our data suggests that activation of PPARγ while inhibiting cell proliferation facilitates the regulation of genes involved in maintaining the luminal subtype of UC. In vivo animal studies are needed to address the efficacy of using PPARγ agonists and/or proliferation inhibitors to reduce tumor grade/stage of MIUC.


Asunto(s)
Arsenitos/farmacología , Proliferación Celular/efectos de los fármacos , PPAR gamma/metabolismo , Troglitazona/farmacología , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Factor Nuclear 3-alfa del Hepatocito/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Queratinas/genética , Queratinas/metabolismo , Ratones , Ratones Desnudos , PPAR gamma/agonistas , Quinazolinas/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcriptoma/efectos de los fármacos , Trasplante Heterólogo , Regulación hacia Arriba/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología
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