Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
bioRxiv ; 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38746132

RESUMEN

Clear cell renal cell carcinomas (ccRCC) are largely driven by HIF2α and are avid consumers of glutamine. However, inhibitors of glutaminase1 (GLS1), the first step in glutaminolysis, have not shown benefit in phase III trials, and HIF2α inhibition, recently FDA-approved for treatment of ccRCC, shows great but incomplete benefits, underscoring the need to better understand the roles of glutamine and HIF2α in ccRCC. Here, we report that glutamine deprivation rapidly redistributes GLS1 into isolated clusters within mitochondria across diverse cell types, excluding ccRCC. GLS1 clustering is rapid (1-3 hours) and reversible, is specifically driven by the level of intracellular glutamate, and is mediated by mitochondrial fission. Clustered GLS1 has markedly enhanced glutaminase activity and promotes cell death under glutamine-deprived conditions. We further show that HIF2α prevents GLS1 clustering, independently of its transcriptional activity, thereby protecting ccRCC cells from cell death induced by glutamine deprivation. Reversing this protection, by genetic expression of GLS1 mutants that constitutively cluster, enhances ccRCC cell death in culture and suppresses ccRCC growth in vivo . These finding provide multiple insights into cellular glutamine handling, including a novel metabolic pathway by which HIF2α promotes ccRCC, and reveals a potential therapeutic avenue to synergize with HIF2α inhibition in the treatment of ccRCC.

2.
Cancer Res ; 84(10): 1570-1582, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38417134

RESUMEN

Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis. In support of this hypothesis, ccRCC cells acquire exogenous cholesterol through the high-density lipoprotein receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we showed that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is also essential for ccRCC cell survival. Development of an HSD3B7 enzymatic assay and screening for small-molecule inhibitors uncovered the compound celastrol as a potent HSD3B7 inhibitor with low micromolar activity. Repressing HSD3B7 expression genetically or treating ccRCC cells with celastrol resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target. SIGNIFICANCE: The bile acid biosynthetic enzyme HSD3B7 is essential for ccRCC cell survival and can be targeted to induce accumulation of cholesterol-derived oxysterols and apoptotic cell death.


Asunto(s)
Ácidos y Sales Biliares , Carcinoma de Células Renales , Colesterol , Homeostasis , Neoplasias Renales , Humanos , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Ácidos y Sales Biliares/metabolismo , Colesterol/metabolismo , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/genética , Animales , Ratones , Triterpenos Pentacíclicos , Línea Celular Tumoral , Apoptosis , Proliferación Celular , Triterpenos/farmacología , Carcinogénesis/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Nat Rev Nephrol ; 20(4): 233-250, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38253811

RESUMEN

Kidney cancer is the seventh leading cause of cancer in the world, and its incidence is on the rise. Renal cell carcinoma (RCC) is the most common form and is a heterogeneous disease comprising three major subtypes that vary in their histology, clinical course and driver mutations. These subtypes include clear cell RCC, papillary RCC and chromophobe RCC. Molecular analyses of hereditary and sporadic forms of RCC have revealed that this complex and deadly disease is characterized by metabolic pathway alterations in cancer cells that lead to deregulated oxygen and nutrient sensing, as well as impaired tricarboxylic acid cycle activity. These metabolic changes facilitate tumour growth and survival. Specifically, studies of the metabolic features of RCC have led to the discovery of oncometabolites - fumarate and succinate - that can promote tumorigenesis, moonlighting functions of enzymes, and substrate auxotrophy owing to the disruption of pathways that enable the production of arginine and cholesterol. These metabolic alterations within RCC can be exploited to identify new therapeutic targets and interventions, in combination with novel approaches that minimize the systemic toxicity of metabolic inhibitors and reduce the risk of drug resistance owing to metabolic plasticity.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Redes y Vías Metabólicas , Carcinogénesis
4.
bioRxiv ; 2023 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-37745397

RESUMEN

Nuclear speckles are membrane-less bodies within the cell nucleus enriched in RNA biogenesis, processing, and export factors. In this study we investigated speckle phenotype variation in human cancer, finding a reproducible speckle signature, based on RNA expression of speckle-resident proteins, across >20 cancer types. Of these, clear cell renal cell carcinoma (ccRCC) exhibited a clear correlation between the presence of this speckle expression signature, imaging-based speckle phenotype, and clinical outcomes. ccRCC is typified by hyperactivation of the HIF-2α transcription factor, and we demonstrate here that HIF-2α drives physical association of a select subset of its target genes with nuclear speckles. Disruption of HIF-2α-driven speckle association via deletion of its speckle targeting motifs (STMs)-defined in this study-led to defective induction of speckle-associating HIF-2α target genes without impacting non-speckle-associating HIF-2α target genes. We further identify the RNA export complex, TREX, as being specifically altered in speckle signature, and knockdown of key TREX component, ALYREF, also compromises speckle-associated gene expression. By integrating tissue culture functional studies with tumor genomic and imaging analysis, we show that HIF-2α gene regulatory programs are impacted by specific manipulation of speckle phenotype and by abrogation of speckle targeting abilities of HIF-2α. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of a specific subset of HIF-2α-regulated target genes that, in turn, influence patient outcomes. We also identify STMs in other transcription factors, suggesting that DNA-speckle targeting may be a general mechanism of gene regulation.

5.
J Med Chem ; 65(3): 2374-2387, 2022 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-35084860

RESUMEN

In the present report, we describe the synthesis and structure-activity relationships of novel "four-arm" dihydropyrazoline compounds designed as peripherally restricted antagonists of cannabinoid-1 receptor (CB1R). A series of racemic 3,4-diarylpyrazolines were synthesized and evaluated initially in CB1 receptor binding assays. The novel compounds, designed to limit brain penetrance and decreased lipophilicity, showed high affinity for CB1R and potent in vitro CB1R antagonist activities. Promising compounds with potent CB1R activity were evaluated in tissue distribution studies. Compounds 6a, 6f, and 7c showed limited brain penetrance attesting to its peripheral restriction. The 4S-enantiomer of these compounds further showed a stereoselective affinity for the CB1 receptor and behaved as inverse agonists. In vivo studies on food intake and body weight reduction in diet-induced obese (DIO) mice showed that these compounds could serve as potential leads for the development of selective CB1R antagonists with improved potency and peripheral restriction.


Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Antagonistas de Receptores de Cannabinoides/uso terapéutico , Obesidad/tratamiento farmacológico , Pirazoles/uso terapéutico , Receptor Cannabinoide CB1/metabolismo , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/metabolismo , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Antagonistas de Receptores de Cannabinoides/síntesis química , Antagonistas de Receptores de Cannabinoides/metabolismo , Dieta Alta en Grasa , Agonismo Inverso de Drogas , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
6.
J Clin Invest ; 131(20)2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34651582

RESUMEN

Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.


Asunto(s)
Apolipoproteína L1/genética , Enfermedades Renales/etiología , Proteínas de la Membrana/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Podocitos/patología , Animales , Apolipoproteína L1/fisiología , Humanos , Ratones
7.
Clin Transl Med ; 11(7): e471, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34323400

RESUMEN

Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1 R system and inducible nitric oxide synthase (iNOS) for dual-target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS-PF patient-derived lung fibroblasts, and bleomycin-induced PF in pale ear mice (HPS1ep/ep ). We found overexpression of CB1 R and iNOS in fibrotic lungs of HPSPF patients and bleomycin-infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin-induced PF. Simultaneous targeting of CB1 R and iNOS by MRI-1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI-1867 treatment abrogated bleomycin-induced increases in lung levels of the profibrotic interleukin-11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1 R inhibition. Dual inhibition of CB1 R and iNOS is an effective antifibrotic strategy for HPSPF.


Asunto(s)
Síndrome de Hermanski-Pudlak/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fibrosis Pulmonar/patología , Receptor Cannabinoide CB1/metabolismo , Adulto , Animales , Antifibróticos/farmacología , Antifibróticos/uso terapéutico , Ácidos Araquidónicos/metabolismo , Bleomicina/efectos adversos , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Endocannabinoides/metabolismo , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Síndrome de Hermanski-Pudlak/complicaciones , Síndrome de Hermanski-Pudlak/metabolismo , Humanos , Interleucina-11/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/genética , Alcamidas Poliinsaturadas/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/tratamiento farmacológico , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/genética , Factor de Crecimiento Transformador beta1/metabolismo
8.
ACS Pharmacol Transl Sci ; 4(3): 1175-1187, 2021 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-34151207

RESUMEN

Seven-transmembrane receptors signal via G-protein- and ß-arrestin-dependent pathways. We describe a peripheral CB1R antagonist (MRI-1891) highly biased toward inhibiting CB1R-induced ß-arrestin-2 (ßArr2) recruitment over G-protein activation. In obese wild-type and ßArr2-knockout (KO) mice, MRI-1891 treatment reduces food intake and body weight without eliciting anxiety even at a high dose causing partial brain CB1R occupancy. By contrast, the unbiased global CB1R antagonist rimonabant elicits anxiety in both strains, indicating no ßArr2 involvement. Interestingly, obesity-induced muscle insulin resistance is improved by MRI-1891 in wild-type but not in ßArr2-KO mice. In C2C12 myoblasts, CB1R activation suppresses insulin-induced akt-2 phosphorylation, preventable by MRI-1891, ßArr2 knockdown or overexpression of CB1R-interacting protein. MRI-1891, but not rimonabant, interacts with nonpolar residues on the N-terminal loop, including F108, and on transmembrane helix-1, including S123, a combination that facilitates ßArr2 bias. Thus, CB1R promotes muscle insulin resistance via ßArr2 signaling, selectively mitigated by a biased CB1R antagonist at reduced risk of central nervous system (CNS) side effects.

9.
Adv Exp Med Biol ; 1311: 39-56, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34014533

RESUMEN

The study of cancer cell metabolism has traditionally focused on glycolysis and glutaminolysis. However, lipidomic technologies have matured considerably over the last decade and broadened our understanding of how lipid metabolism is relevant to cancer biology [1-3]. Studies now suggest that the reprogramming of cellular lipid metabolism contributes directly to malignant transformation and progression [4, 5]. For example, de novo lipid synthesis can supply proliferating tumor cells with phospholipid components that comprise the plasma and organelle membranes of new daughter cells [6, 7]. Moreover, the upregulation of mitochondrial ß-oxidation can support tumor cell energetics and redox homeostasis [8], while lipid-derived messengers can regulate major signaling pathways or coordinate immunosuppressive mechanisms [9-11]. Lipid metabolism has, therefore, become implicated in a variety of oncogenic processes, including metastatic colonization, drug resistance, and cell differentiation [10, 12-16]. However, whether we can safely and effectively modulate the underlying mechanisms of lipid metabolism for cancer therapy is still an open question.


Asunto(s)
Metabolismo de los Lípidos , Neoplasias , Transformación Celular Neoplásica , Glucólisis , Humanos , Lipidómica
10.
Sci Rep ; 11(1): 3706, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33580091

RESUMEN

Signaling through integral membrane G protein-coupled receptors (GPCRs) is influenced by lipid composition of cell membranes. By using novel high affinity ligands of human cannabinoid receptor CB2, we demonstrate that cholesterol increases basal activation levels of the receptor and alters the pharmacological categorization of these ligands. Our results revealed that (2-(6-chloro-2-((2,2,3,3-tetramethylcyclopropane-1-carbonyl)imino)benzo[d]thiazol-3(2H)-yl)ethyl acetate ligand (MRI-2646) acts as a partial agonist of CB2 in membranes devoid of cholesterol and as a neutral antagonist or a partial inverse agonist in cholesterol-containing membranes. The differential effects of a specific ligand on activation of CB2 in different types of membranes may have implications for screening of drug candidates in a search of modulators of GPCR activity. MD simulation suggests that cholesterol exerts an allosteric effect on the intracellular regions of the receptor that interact with the G-protein complex thereby altering the recruitment of G protein.


Asunto(s)
Colesterol/metabolismo , Receptor Cannabinoide CB2/metabolismo , Escherichia coli , Células HEK293 , Humanos , Simulación de Dinámica Molecular , Receptor Cannabinoide CB2/aislamiento & purificación
11.
Am J Respir Cell Mol Biol ; 62(2): 178-190, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31419911

RESUMEN

ATP-binding cassette (ABC) transporters are evolutionarily conserved membrane proteins that pump a variety of endogenous substrates across cell membranes. Certain subfamilies are known to interact with pharmaceutical compounds, potentially influencing drug delivery and treatment efficacy. However, the role of drug resistance-associated ABC transporters has not been examined in idiopathic pulmonary fibrosis (IPF) or its animal model: the bleomycin (BLM)-induced murine model. Here, we investigate the expression of two ABC transporters, P-gp (permeability glycoprotein) and BCRP (breast cancer resistance protein), in human IPF lung tissue and two different BLM-induced mouse models of pulmonary fibrosis. We obtained human IPF specimens from patients during lung transplantation and administered BLM to male C57BL/6J mice either by oropharyngeal aspiration (1 U/kg) or subcutaneous osmotic infusion (100 U/kg over 7 d). We report that P-gp and BCRP expression in lungs of patients with IPF was comparable to controls. However, murine lungs expressed increased levels of P-gp and BCRP after oropharyngeal and subcutaneous BLM administration. We localized this upregulation to multiple pulmonary cell types, including alveolar fibroblasts, endothelial cells, and type 2 epithelial cells. Functionally, this effect reduced murine lung exposure to nintedanib, a U.S. Food and Drug Administration-approved IPF therapy known to be a P-gp substrate. The study reveals a discrepancy between IPF pathophysiology and the common animal model of lung fibrosis. BLM-induced drug efflux in the murine lungs may present an uncontrolled confounding variable in the preclinical study of IPF drug candidates, and these findings will facilitate disease model validation and enhance new drug discoveries that will ultimately improve patient outcomes.


Asunto(s)
Bleomicina/farmacología , Células Endoteliales/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Femenino , Fibroblastos/metabolismo , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas de Neoplasias/efectos de los fármacos , Proteínas de Neoplasias/metabolismo
12.
Cell Metab ; 29(6): 1320-1333.e8, 2019 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-31105045

RESUMEN

Endocannabinoids acting on the cannabinoid-1 receptor (CB1R) or ghrelin acting on its receptor (GHS-R1A) both promote alcohol-seeking behavior, but an interaction between the two signaling systems has not been explored. Here, we report that the peripheral CB1R inverse agonist JD5037 reduces ethanol drinking in wild-type mice but not in mice lacking CB1R, ghrelin peptide or GHS-R1A. JD5037 treatment of alcohol-drinking mice inhibits the formation of biologically active octanoyl-ghrelin without affecting its inactive precursor desacyl-ghrelin. In ghrelin-producing stomach cells, JD5037 reduced the level of the substrate octanoyl-carnitine generated from palmitoyl-carnitine by increasing fatty acid ß-oxidation. Blocking gastric vagal afferents abrogated the ability of either CB1R or GHS-R1A blockade to reduce ethanol drinking. We conclude that blocking CB1R in ghrelin-producing cells reduces alcohol drinking by inhibiting the formation of active ghrelin and its signaling via gastric vagal afferents. Thus, peripheral CB1R blockade may have therapeutic potential in the treatment of alcoholism.


Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Encéfalo/fisiología , Intestinos/fisiología , Receptor Cannabinoide CB1/genética , Aciltransferasas/genética , Aciltransferasas/fisiología , Consumo de Bebidas Alcohólicas/fisiopatología , Alcoholismo/genética , Alcoholismo/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Células Cultivadas , Eliminación de Gen , Ghrelina/metabolismo , Ghrelina/fisiología , Intestinos/efectos de los fármacos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Receptores de Ghrelina/genética , Receptores de Ghrelina/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sulfonamidas/farmacología
13.
Cell ; 176(3): 459-467.e13, 2019 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-30639103

RESUMEN

The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.


Asunto(s)
Receptor Cannabinoide CB2/metabolismo , Receptor Cannabinoide CB2/ultraestructura , Animales , Antagonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Diseño de Fármacos , Endocannabinoides , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Unión Proteica , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB2/química , Receptores de Cannabinoides/química , Receptores de Cannabinoides/metabolismo , Receptores de Cannabinoides/ultraestructura , Receptores Acoplados a Proteínas G/metabolismo , Células Sf9 , Relación Estructura-Actividad
14.
Adv Exp Med Biol ; 1063: 33-55, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29946774

RESUMEN

KEY POINTS: The study of cancer cell metabolism has traditionally focused on glycolysis and glutaminolysis. However, lipidomic technologies have matured considerably over the last decade and broadened our understanding of how lipid metabolism is relevant to cancer biology [1­3]. Studies now suggest that the reprogramming of cellular lipid metabolism contributes directly to malignant transformation and progression [4, 5]. For example, de novo lipid synthesis can supply proliferating tumor cells with phospholipid components that comprise the plasma and organelle membranes of new daughter cells [6, 7]. Moreover, the upregulation of mitochondrial ß-oxidation can support tumor cell energetics and redox homeostasis [8], while lipid-derived messengers can regulate major signaling pathways or coordinate immunosuppressive mechanisms [9­11]. Lipid metabolism has therefore become implicated in a variety of oncogenic processes, including metastatic colonization, drug resistance, and cell differentiation [10, 12­16]. However, whether we can safely and effectively modulate the underlying mechanisms for cancer therapy is still an open question.


Asunto(s)
Metabolismo de los Lípidos/fisiología , Neoplasias/metabolismo , Animales , Humanos
15.
Artículo en Inglés | MEDLINE | ID: mdl-29790591

RESUMEN

Cannabinoid-1 receptor (CB1 R) antagonists/inverse agonists have great potential in the treatment of metabolic disorders like dyslipidemia, type 2 diabetes, and nonalcoholic steatohepatitis. Cannabinoid-1 receptor inverse agonists have also been reported to be effective in mitigating fibrotic disorders in murine models. Inducible nitric oxide synthase is another promising target implicated in fibrotic and inflammatory disorders. We have disclosed MRI-1867 as a potent and selective, peripherally acting dual-target inhibitor of the CB1 R and inducible nitric oxide synthase (iNOS). Herein, we report the synthesis of [13 C6 ]-MRI-1867 as a racemate from commercially available chlorobenzene-13 C6 as the starting, stable-isotope label reagent. The racemic [13 C6 ]-MRI-1867 was further processed to the stable-isotope-labeled enantiopure compounds using chiral chromatography. Both racemic [13 C6 ]-MRI-1867 and S-13 C6 -MRI-1867 will be used to quantitate unlabeled S-MRI-1867 during clinical drug metabolism and pharmacokinetics studies and will be used as a liquid chromatography-tandem mass spectrometry bioanalytical standard.

16.
Diabetes Obes Metab ; 20(3): 698-708, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29106063

RESUMEN

AIMS: To determine the specific role of podocyte-expressed cannabinoid-1 receptor (CB1 R) in the development of diabetic nephropathy (DN), relative to CB1 R in other renal cell types. MATERIAL AND METHODS: We developed a mouse model with a podocyte-specific deletion of CB1 R (pCB1Rko) and challenged this model with streptozotocin (STZ)-induced type-1 DN. We also assessed the podocyte response to high glucose in vitro and its effects on CB1 R activation. RESULTS: High glucose exposure for 48 hours led to an increase in CB1 R gene expression (CNR1) and endocannabinoid production in cultured human podocytes. This was associated with podocyte injury, reflected by decreased podocin and nephrin expression. These changes could be prevented by Cnr1-silencing, thus identifying CB1R as a key player in podocyte injury. After 12 weeks of chronic hyperglycaemia, STZ-treated pCB1Rko mice showed elevated blood glucose similar to that of their wild-type littermates. However, they displayed less albuminuria and less podocyte loss than STZ-treated wild-type mice. Unexpectedly, pCB1Rko mice also have milder tubular dysfunction, fibrosis and reduction of cortical microcirculation compared to wild-type controls, which is mediated, in part, by podocyte-derived endocannabinoids acting via CB1 R on proximal tubular cells. CONCLUSIONS: Activation of CB1 R in podocytes contributes to both glomerular and tubular dysfunction in type-1 DN, which highlights the therapeutic potential of peripheral CB1 R blockade.


Asunto(s)
Nefropatías Diabéticas/fisiopatología , Glomérulos Renales/fisiología , Túbulos Renales Proximales/fisiología , Podocitos/metabolismo , Receptores de Cannabinoides/deficiencia , Animales , Arginasa/metabolismo , Hipoxia de la Célula/fisiología , Células Cultivadas , Diabetes Mellitus Experimental/fisiopatología , Glucosa/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Riñón/irrigación sanguínea , Proteínas de la Membrana/metabolismo , Ratones , Microcirculación/fisiología , Estrés Oxidativo/fisiología , Receptor Cannabinoide CB1/deficiencia , Receptor Cannabinoide CB1/metabolismo
17.
J Multidiscip Healthc ; 10: 429-435, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29255363

RESUMEN

PURPOSE: Research examining the utilization of evidence-based practice (EBP) specifically among rehabilitation clinicians is limited. The objective of this study was to examine how various rehabilitative clinicians including physical therapists, occupational therapists, rehabilitation counselors, and physiatrists are gaining access to literature and whether they are able to implement the available research into practice. METHODS: A total of 21 total clinicians were interviewed via telephone. Using NVivo, a qualitative analysis of the responses was performed. RESULTS: There were similarities found with respect to the information-seeking behaviors and translation of research across the different clinician types. Lack of time was reported to be a barrier for both access to literature and implementation of research across all clinician types. The majority of clinicians who reported having difficulty with utilizing the published literature indicated that the literature was not applicable to their practice, the research was not specific enough to be put into practice, or the research found was too outdated to be relevant. In addition, having a supportive work environment aided in the search and utilization of research through providing resources central to assisting clinicians in gaining access to health information. CONCLUSION: Our study identified several barriers that affect EBP for rehabilitation clinicians. The findings suggest the need for researchers to ensure that their work is applicable and specific to clinical practice for implementation to occur.

18.
Mol Metab ; 6(11): 1517-1528, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-29107297

RESUMEN

OBJECTIVE: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-α, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB1R in KCs in obesity-induced hepatic insulin resistance. METHODS: We used intravenously administered ß-D-glucan-encapsulated siRNA to knock-down CB1R gene expression selectively in KCs. RESULTS: We demonstrate that a robust knock-down of the expression of Cnr1, the gene encoding CB1R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin-induced Akt phosphorylation. CONCLUSION: These findings suggest that CB1R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro-inflammatory mechanism.


Asunto(s)
Resistencia a la Insulina , Macrófagos del Hígado/metabolismo , Obesidad/metabolismo , Receptor Cannabinoide CB1/metabolismo , Animales , Dieta Alta en Grasa , Hígado Graso/metabolismo , Hepatocitos/metabolismo , Insulina/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Receptor Cannabinoide CB1/genética , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo
19.
J Med Internet Res ; 19(5): e159, 2017 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-28490418

RESUMEN

BACKGROUND: In order to meet the challenges of caring for an injured person, caregivers need access to health information. However, caregivers often feel that they lack adequate information. Previous studies of caregivers have primarily focused on either their time and emotional burdens or their health outcomes, but the information needs of caregivers have not been thoroughly investigated. OBJECTIVE: The purpose of this investigation was to identify the preferred sources of health information for caregivers supporting individuals with injuries and to explore how access to this information could be improved. METHODS: A total of 32 caregivers participated in semistructured interviews, which were used in order to develop a more in-depth understanding of these caregivers' information needs. Digital audio recordings of the interviews were used for analysis purposes. These audio recordings were analyzed using a thematic analysis or qualitative content analysis. All of participant's interviews were then coded using the qualitative analysis program, Nvivo 10 for Mac (QSR International). RESULTS: The caregivers endorsed similar behaviors and preferences when seeking and accessing health information. Medical professionals were the preferred source of information, while ease of access made the Internet the most common avenue to obtain information. The challenges faced by participants were frequently a result of limited support. In describing an ideal health system, participants expressed interest in a comprehensive care website offering support network resources, instructive services about the injury and caregiving, and injury-specific materials. CONCLUSIONS: According to the participants, an ideal health information system would include a comprehensive care website that offered supportive network resources, instructive services about the injury and caregiving, and materials specific to the type of patient injury.


Asunto(s)
Lesiones Traumáticas del Encéfalo/psicología , Quemaduras/psicología , Cuidadores/psicología , Conducta en la Búsqueda de Información/ética , Traumatismos de la Médula Espinal/psicología , Adolescente , Adulto , Lesiones Traumáticas del Encéfalo/terapia , Quemaduras/terapia , Estudios de Evaluación como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Traumatismos de la Médula Espinal/terapia , Adulto Joven
20.
J Labelled Comp Radiopharm ; 60(10): 460-465, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28545167

RESUMEN

JD5037 (1) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB1 R) receptor. Peripheral CB1 receptor antagonists/inverse agonists have great potential in the treatment of metabolic disorders like type 2 diabetes, obesity, and nonalcoholic steatohepatitis. We report the synthesis of octadeuterated [2 H8 ]-JD5037 (S, S) (8) along with its (S, R) diastereomer (13) from commercially available L-valine-d8 starting material. The [2 H8 ]-JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC-MS/MS bioanalytical standard.


Asunto(s)
Deuterio/química , Pirazoles/química , Pirazoles/síntesis química , Sulfonamidas/química , Sulfonamidas/síntesis química , Amidas/química , Técnicas de Química Sintética , Modelos Moleculares , Conformación Molecular , Pirazoles/metabolismo , Receptor Cannabinoide CB1/metabolismo , Sulfonamidas/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA