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1.
Nanomedicine (Lond) ; 19(3): 231-254, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38284384

RESUMEN

Aim: To synthesize HER2 aptamer-conjugated iron oxide nanoparticles with a coating of poly(2-(dimethylamino) ethyl methacrylate)-poly(2-methacryloyloxyethylphosphorylcholine) block copolymer (IONPPPs). Methods: Characterization covered molecular structure, chemical composition, thermal stability, magnetic characteristics, aptamer interaction, crystalline nature and microscopic features. Subsequent investigations focused on IONPPPs for in vitro cancer cell identification. Results: Results demonstrated high biocompatibility of the diblock copolymer with no significant toxicity up to 150 µg/ml. The facile coating process yielded the IONPP complex, featuring a 13.27 nm metal core and a 3.10 nm polymer coating. Functionalized with a HER2-targeting DNA aptamer, IONPPP enhanced recognition in HER2-amplified SKBR3 cells via magnetization separation. Conclusion: These findings underscore IONPPP's potential in cancer research and clinical applications, showcasing diagnostic efficacy and HER2 protein targeting in a proof-of-concept approach.


Asunto(s)
Neoplasias de la Mama , Nanopartículas , Nylons , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Polímeros/química , Metacrilatos/química , Nanopartículas Magnéticas de Óxido de Hierro , Nanopartículas/química
2.
Proc Natl Acad Sci U S A ; 120(4): e2211933120, 2023 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-36656866

RESUMEN

Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP.


Asunto(s)
Tracto Gastrointestinal , Glucosa , Hígado , Metformina , Animales , Humanos , Ratones , Células CACO-2 , Diabetes Mellitus Tipo 2 , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Hígado/metabolismo , Metformina/farmacología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tracto Gastrointestinal/metabolismo
3.
Cancers (Basel) ; 14(20)2022 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-36291837

RESUMEN

Neoadjuvant chemotherapy (NACT) is offered to patients with operable or inoperable breast cancer (BC) to downstage the disease. Clinical responses to NACT may vary depending on a few known clinical and biological features, but the diversity of responses to NACT is not fully understood. In this study, 80 women had their metabolite profiles of pre-treatment sera analyzed for potential NACT response biomarker candidates in combination with immunohistochemical parameters using Nuclear Magnetic Resonance (NMR). Sixty-four percent of the patients were resistant to chemotherapy. NMR, hormonal receptors (HR), human epidermal growth factor receptor 2 (HER2), and the nuclear protein Ki67 were combined through machine learning (ML) to predict the response to NACT. Metabolites such as leucine, formate, valine, and proline, along with hormone receptor status, were discriminants of response to NACT. The glyoxylate and dicarboxylate metabolism was found to be involved in the resistance to NACT. We obtained an accuracy in excess of 80% for the prediction of response to NACT combining metabolomic and tumor profile data. Our results suggest that NMR data can substantially enhance the prediction of response to NACT when used in combination with already known response prediction factors.

4.
Virulence ; 13(1): 1031-1048, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35734825

RESUMEN

The ongoing COVID-19 pandemic caused a significant loss of human lives and a worldwide decline in quality of life. Treatment of COVID-19 patients is challenging, and specific treatments to reduce COVID-19 aggravation and mortality are still necessary. Here, we describe the discovery of a novel class of epiandrosterone steroidal compounds with cationic amphiphilic properties that present antiviral activity against SARS-CoV-2 in the low micromolar range. Compounds were identified in screening campaigns using a cytopathic effect-based assay in Vero CCL81 cells, followed by hit compound validation and characterization. Compounds LNB167 and LNB169 were selected due to their ability to reduce the levels of infectious viral progeny and viral RNA levels in Vero CCL81, HEK293, and HuH7.5 cell lines. Mechanistic studies in Vero CCL81 cells indicated that LNB167 and LNB169 inhibited the initial phase of viral replication through mechanisms involving modulation of membrane lipids and cholesterol in host cells. Selection of viral variants resistant to steroidal compound treatment revealed single mutations on transmembrane, lipid membrane-interacting Spike and Envelope proteins. Finally, in vivo testing using the hACE2 transgenic mouse model indicated that SARS-CoV-2 infection could not be ameliorated by LNB167 treatment. We conclude that anti-SARS-CoV-2 activities of steroidal compounds LNB167 and LNB169 are likely host-targeted, consistent with the properties of cationic amphiphilic compounds that modulate host cell lipid biology. Although effective in vitro, protective effects were cell-type specific and did not translate to protection in vivo, indicating that subversion of lipid membrane physiology is an important, yet complex mechanism involved in SARS-CoV-2 replication and pathogenesis.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Animales , Antivirales/farmacología , Chlorocebus aethiops , Células HEK293 , Humanos , Lípidos , Ratones , Pandemias , Calidad de Vida , Células Vero , Replicación Viral
5.
J Org Chem ; 87(12): 7610-7617, 2022 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-35171607

RESUMEN

Ellipticine was synthesized in six steps and 20% global yield starting from the readily available 2,5-dimethoxy isoquinoline. Unprecedented regioselective control of the nucleophilic attack on the isoquinoline-5,8-dione is first described. Investigation of the possible pathways of this transformation through density functional theory calculations reveals unexpected N-oxide assistance in cascade tautomerizations, which was crucial for directing the nucleophilic attack and hastening the overall process. Using this strategy, we prepared the aniline-isoquinolinedione adduct and submitted it to an intramolecular double C-H cross-coupling activation to furnish ellipticinequinone, which gave ellipticine after a MeLi addition/BH3 reduction sequence.


Asunto(s)
Elipticinas , Isoquinolinas
6.
Nat Commun ; 12(1): 4049, 2021 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-34193873

RESUMEN

Xyloglucans are highly substituted and recalcitrant polysaccharides found in the primary cell walls of vascular plants, acting as a barrier against pathogens. Here, we reveal that the diverse and economically relevant Xanthomonas bacteria are endowed with a xyloglucan depolymerization machinery that is linked to pathogenesis. Using the citrus canker pathogen as a model organism, we show that this system encompasses distinctive glycoside hydrolases, a modular xyloglucan acetylesterase and specific membrane transporters, demonstrating that plant-associated bacteria employ distinct molecular strategies from commensal gut bacteria to cope with xyloglucans. Notably, the sugars released by this system elicit the expression of several key virulence factors, including the type III secretion system, a membrane-embedded apparatus to deliver effector proteins into the host cells. Together, these findings shed light on the molecular mechanisms underpinning the intricate enzymatic machinery of Xanthomonas to depolymerize xyloglucans and uncover a role for this system in signaling pathways driving pathogenesis.


Asunto(s)
Pared Celular/metabolismo , Citrus/microbiología , Glucanos/metabolismo , Glicósido Hidrolasas/metabolismo , Factores de Virulencia/genética , Xanthomonas/metabolismo , Xilanos/metabolismo , Proteínas Bacterianas/metabolismo , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/microbiología , Activación Transcripcional , Sistemas de Secreción Tipo III/metabolismo , Factores de Virulencia/metabolismo , Xanthomonas/genética , Xanthomonas/patogenicidad
7.
ACS Appl Bio Mater ; 4(6): 5240-5250, 2021 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-35007006

RESUMEN

Wound healing materials to prevent blood loss are crucial during emergency medical treatment because uncontrolled bleeding can lead to patient death. Herein, bioabsorbable fibrous architectures of thrombin-loaded poly(ethylene oxide)-PEO/thrombin-are conceptualized and accomplished via electrospinning for faster wound clotting. Membranes with average fiber diameters ranging from 188 to 264 nm are achieved, where the active thrombin is entrapped within the nanofibers. The results of in vitro and in vivo wound healing activity tests revealed that when the nanofibers with thrombin-loaded capacity are in contact with the wound, the presence of water in the skin or blood catalyzes the degradation of the membranes, thus releasing thrombin. Thrombin then accelerates the wound clotting process. In contrast to other hemostatic materials, PEO/thrombin nanofibers do not require mechanical removal after application, and the viscoelastic nature of such biomaterials enables their conformation to a variety of wound topographies. Remarkably, PEO/thrombin membranes are promising functional materials and their use is a powerful strategy for hemostatic treatment, ranging from simple first aid and sealing to a wound to small surgical procedures.


Asunto(s)
Quitosano , Hemostáticos , Nanofibras , Óxido de Etileno , Hemostáticos/farmacología , Humanos , Polietilenglicoles , Trombina
8.
Nat Commun, v. 12, 4049, jun. 2021
Artículo en Inglés | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-3884

RESUMEN

Xyloglucans are highly substituted and recalcitrant polysaccharides found in the primary cell walls of vascular plants, acting as a barrier against pathogens. Here, we reveal that the diverse and economically relevant Xanthomonas bacteria are endowed with a xyloglucan depolymerization machinery that is linked to pathogenesis. Using the citrus canker pathogen as a model organism, we show that this system encompasses distinctive glycoside hydrolases, a modular xyloglucan acetylesterase and specific membrane transporters, demonstrating that plant-associated bacteria employ distinct molecular strategies from commensal gut bacteria to cope with xyloglucans. Notably, the sugars released by this system elicit the expression of several key virulence factors, including the type III secretion system, a membrane-embedded apparatus to deliver effector proteins into the host cells. Together, these findings shed light on the molecular mechanisms underpinning the intricate enzymatic machinery of Xanthomonas to depolymerize xyloglucans and uncover a role for this system in signaling pathways driving pathogenesis.

9.
ACS Infect Dis ; 6(8): 2192-2201, 2020 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-32603583

RESUMEN

Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria, and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, they have been underexplored to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind to MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that considerably differs from other DHFR antifolates, thus opening perspectives for the development of relevant MtDHFR inhibitors.


Asunto(s)
Antagonistas del Ácido Fólico , Mycobacterium tuberculosis , Tuberculosis , Diseño de Fármacos , Antagonistas del Ácido Fólico/farmacología , Humanos , Tetrahidrofolato Deshidrogenasa/genética , Tuberculosis/tratamiento farmacológico
10.
Oncogene ; 39(3): 690-702, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31541193

RESUMEN

Many types of cancers have a well-established dependence on glutamine metabolism to support survival and growth, a process linked to glutaminase 1 (GLS) isoforms. Conversely, GLS2 variants often have tumor-suppressing activity. Triple-negative (TN) breast cancer (testing negative for estrogen, progesterone, and Her2 receptors) has elevated GLS protein levels and reportedly depends on exogenous glutamine and GLS activity for survival. Despite having high GLS levels, we verified that several breast cancer cells (including TN cells) express endogenous GLS2, defying its role as a bona fide tumor suppressor. Moreover, ectopic GLS2 expression rescued cell proliferation, TCA anaplerosis, redox balance, and mitochondrial function after GLS inhibition by the small molecule currently in clinical trials CB-839 or GLS knockdown of GLS-dependent cell lines. In several cell lines, GLS2 knockdown decreased cell proliferation and glutamine-linked metabolic phenotypes. Strikingly, long-term treatment of TN cells with another GLS-exclusive inhibitor bis-2'-(5-phenylacetamide-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) selected for a drug-resistant population with increased endogenous GLS2 and restored proliferative capacity. GLS2 was linked to enhanced in vitro cell migration and invasion, mesenchymal markers (through the ERK-ZEB1-vimentin axis under certain conditions) and in vivo lung metastasis. Of concern, GLS2 amplification or overexpression is linked to an overall, disease-free and distant metastasis-free worse survival prognosis in breast cancer. Altogether, these data establish an unforeseen role of GLS2 in sustaining tumor proliferation and underlying metastasis in breast cancer and provide an initial framework for exploring GLS2 as a novel therapeutic target.


Asunto(s)
Neoplasias de la Mama/patología , Carcinogénesis/patología , Glutaminasa/metabolismo , Neoplasias Pulmonares/secundario , Adulto , Anciano , Anciano de 80 o más Años , Bencenoacetamidas/farmacología , Bencenoacetamidas/uso terapéutico , Mama/patología , Mama/cirugía , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Glutaminasa/antagonistas & inhibidores , Humanos , Persona de Mediana Edad , Pronóstico , Sulfuros/farmacología , Sulfuros/uso terapéutico , Tiadiazoles/farmacología , Tiadiazoles/uso terapéutico
11.
Pest Manag Sci ; 75(5): 1295-1303, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30350447

RESUMEN

BACKGROUND: Moniliophthora perniciosa (Stahel) Aime & Phillips-Mora is the causal agent of witches' broom disease (WBD) of cocoa (Theobroma cacao L.) and a threat to the chocolate industry. The membrane-bound enzyme alternative oxidase (AOX) is critical for M. perniciosa virulence and resistance to fungicides, which has also been observed in other phytopathogens. Notably AOX is an escape mechanism from strobilurins and other respiration inhibitors, making AOX a promising target for controlling WBD and other fungal diseases. RESULTS: We present the first study aimed at developing novel fungal AOX inhibitors. N-Phenylbenzamide (NPD) derivatives were screened in the model yeast Pichia pastoris through oxygen consumption and growth measurements. The most promising AOX inhibitor (NPD 7j-41) was further characterized and displayed better activity than the classical AOX inhibitor SHAM in vitro against filamentous fugal phytopathogens, such as M. perniciosa, Sclerotinia sclerotiorum and Venturia pirina. We demonstrate that 7j-41 inhibits M. perniciosa spore germination and prevents WBD symptom appearance in infected plants. Finally, a structural model of P. pastoris AOX was created and used in ligand structure-activity relationships analyses. CONCLUSION: We present novel fungal AOX inhibitors with antifungal activity against relevant phytopathogens. We envisage the development of novel antifungal agents to secure food production. © 2018 Society of Chemical Industry.


Asunto(s)
Agaricales/efectos de los fármacos , Agaricales/fisiología , Benzamidas/síntesis química , Benzamidas/farmacología , Cacao/microbiología , Proteínas Mitocondriales/antagonistas & inhibidores , Oxidorreductasas/antagonistas & inhibidores , Enfermedades de las Plantas/microbiología , Proteínas de Plantas/antagonistas & inhibidores , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Benzamidas/química , Técnicas de Química Sintética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Relación Estructura-Actividad
16.
Sci Rep ; 5: 12698, 2015 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-26237540

RESUMEN

Hypoxia-inducible transcription factors (HIF) form heterodimeric complexes that mediate cell responses to hypoxia. The oxygen-dependent stability and activity of the HIF-α subunits is traditionally associated to post-translational modifications such as hydroxylation, acetylation, ubiquitination, and phosphorylation. Here we report novel evidence showing that unsaturated fatty acids are naturally occurring, non-covalent structural ligands of HIF-3α, thus providing the initial framework for exploring its exceptional role as a lipid sensor under hypoxia.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Ácido Linoleico/metabolismo , Neoplasias/metabolismo , Ácido Oléico/metabolismo , Proteínas Reguladoras de la Apoptosis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/química , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Clonación Molecular , Cristalografía por Rayos X , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Humanos , Ligandos , Ácido Linoleico/química , Modelos Moleculares , Monoglicéridos/química , Monoglicéridos/metabolismo , Neoplasias/genética , Neoplasias/patología , Ácido Oléico/química , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Represoras , Transducción de Señal , Ácidos Esteáricos/química , Ácidos Esteáricos/metabolismo , Análisis de Matrices Tisulares
17.
Am J Physiol Heart Circ Physiol ; 300(3): H902-12, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21148763

RESUMEN

We studied the implication of focal adhesion kinase (FAK) in cardiac mitochondrial biogenesis induced by mechanical stress. Prolonged stretching (2-12 h) of neonatal rat ventricular myocytes (NRVM) upregulated the main components of mitochondrial transcription cascade [peroxisome proliferator-activated receptor coactivator-1 (PGC-1α), nuclear respiratory factor (NRF-1), and mitochondrial transcription factor A]. Concomitantly, prolonged stretching enhanced mitochondrial biogenesis [copy number of mitochondrial DNA (mtDNA), content of the subunit IV of cytochrome oxidase, and mitochondrial staining-green fluorescence intensity of Mitotracker green] and induced the hypertrophic growth (cell size and atrial natriuretic peptide transcripts) of NRVM. Furthermore, the stretching of NRVM enhanced phosphorylation, nuclear localization, and association of FAK with PGC-1α. Recombinant FAK COOH-terminal, but not the NH(2)-terminal or kinase domain, precipitated PGC-1α from nuclear extracts of NRVM. Depletion of FAK by RNA interference suppressed the upregulation of PGC-1α and NRF-1 and markedly attenuated the enhanced mitochondrial biogenesis and hypertrophic growth of stretched NRVM. In the context of energy metabolism, FAK depletion became manifest by a reduction of ATP levels in stretched NRVM. Complementary studies in adult mice left ventricle demonstrated that pressure overload upregulated PGC-1α, NRF-1, and mtDNA. In vivo FAK silencing transiently attenuated the upregulation of PGC-1α, NRF-1, and mtDNA, as well as the left ventricular hypertrophy induced by pressure overload. In conclusion, activation of FAK signaling seems to be important for conferring enhanced mitochondrial biogenesis coupled to the hypertrophic growth of cardiomyocytes in response to mechanical stress, via control of mitochondrial transcription cascade.


Asunto(s)
Quinasa 1 de Adhesión Focal/metabolismo , Mitocondrias Cardíacas/enzimología , Miocitos Cardíacos/enzimología , Estrés Mecánico , Animales , Animales Recién Nacidos , Células Cultivadas , ADN Mitocondrial/metabolismo , ADN Mitocondrial/fisiología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/fisiología , Complejo IV de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/fisiología , Ratones , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/fisiología , Miocitos Cardíacos/fisiología , Factor 1 Relacionado con NF-E2/metabolismo , Factor 1 Relacionado con NF-E2/fisiología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/fisiología , Ratas , Ratas Wistar , Factores de Transcripción/metabolismo , Factores de Transcripción/fisiología , Regulación hacia Arriba
18.
PLoS One ; 5(5): e10666, 2010 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-20498724

RESUMEN

BACKGROUND: The aim of the present study was to evaluate the protective effects of the 4-anilinoquinazoline derivative PD153035 on cardiac ischemia/reperfusion and mitochondrial function. METHODOLOGY/PRINCIPAL FINDINGS: Perfused rat hearts and cardiac HL-1 cells were used to determine cardioprotective effects of PD153035. Isolated rat heart mitochondria were studied to uncover mechanisms of cardioprotection. Nanomolar doses of PD153035 strongly protect against heart and cardiomyocyte damage induced by ischemia/reperfusion and cyanide/aglycemia. PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition. The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state. Interestingly, PD153035 activated K(+) transport in isolated mitochondria, in a manner prevented by ATP and 5-hydroxydecanoate, inhibitors of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)). 5-Hydroxydecanoate also inhibited the cardioprotective effect of PD153035 in cardiac HL-1 cells, demonstrating that this protection is dependent on mitoK(ATP) activation. CONCLUSIONS/SIGNIFICANCE: We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation.


Asunto(s)
Cardiotónicos/farmacología , Activación del Canal Iónico/efectos de los fármacos , Canales de Potasio/metabolismo , Quinazolinas/farmacología , Adenosina Trifosfato/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Calcio/metabolismo , Respiración de la Célula/efectos de los fármacos , Cianuros/toxicidad , Pruebas de Función Cardíaca , Técnicas In Vitro , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/enzimología , Miocardio/patología , Permeabilidad/efectos de los fármacos , Fosforilación/efectos de los fármacos , Potasio/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar
19.
PLoS One ; 4(12): e8472, 2009 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-20041152

RESUMEN

BACKGROUND: The activation of the members of the myocyte enhancer factor-2 family (MEF2A, B, C and D) of transcription factors promotes cardiac hypertrophy and failure. However, the role of its individual components in the pathogenesis of cardiac hypertrophy remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated whether MEF2C plays a role in mediating the left ventricular hypertrophy by pressure overload in mice. The knockdown of myocardial MEF2C induced by specific small interfering RNA (siRNA) has been shown to attenuate hypertrophy, interstitial fibrosis and the rise of ANP levels in aortic banded mice. We detected that the depletion of MEF2C also results in lowered levels of both PGC-1alpha and mitochondrial DNA in the overloaded left ventricle, associated with enhanced AMP:ATP ratio. Additionally, MEF2C depletion was accompanied by defective activation of S6K in response to pressure overload. Treatment with the amino acid leucine stimulated S6K and suppressed the attenuation of left ventricular hypertrophy and fibrosis in the aforementioned aortic banded mice. CONCLUSION/SIGNIFICANCE: These findings represent new evidences that MEF2C depletion attenuates the hypertrophic responses to mechanical stress and highlight the potential of MEF2C to be a target for new therapies to cardiac hypertrophy and failure.


Asunto(s)
Silenciador del Gen , Hipertrofia Ventricular Izquierda/enzimología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Factores Reguladores Miogénicos/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Transducción de Señal , Animales , Células Cultivadas , ADN Mitocondrial/genética , Hemodinámica , Hipertrofia Ventricular Izquierda/fisiopatología , Factores de Transcripción MEF2 , Ratones , Miocardio/enzimología , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Factores Reguladores Miogénicos/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Serina-Treonina Quinasas TOR , Presión Ventricular/fisiología
20.
Diabetes ; 58(12): 2910-9, 2009 12.
Artículo en Inglés | MEDLINE | ID: mdl-19696185

RESUMEN

OBJECTIVE: In obesity, an increased macrophage infiltration in adipose tissue occurs, contributing to low-grade inflammation and insulin resistance. Epidermal growth factor receptor (EGFR) mediates both chemotaxis and proliferation in monocytes and macrophages. However, the role of EGFR inhibitors in this subclinical inflammation has not yet been investigated. We investigated, herein, in vivo efficacy and associated molecular mechanisms by which PD153035, an EGFR tyrosine kinase inhibitor, improved diabetes control and insulin action. RESEARCH DESIGN AND METHODS: The effect of PD153035 was investigated on insulin sensitivity, insulin signaling, and c-Jun NH(2)-terminal kinase (JNK) and nuclear factor (NF)-kappaB activity in tissues of high-fat diet (HFD)-fed mice and also on infiltration and the activation state of adipose tissue macrophages (ATMs) in these mice. RESULTS: PD153035 treatment for 1 day decreased the protein expression of inducible nitric oxide synthase, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 in the stroma vascular fraction, suggesting that this drug reduces the M1 proinflammatory state in ATMs, as an initial effect, in turn reducing the circulating levels of TNF-alpha and IL-6, and initiating an improvement in insulin signaling and sensitivity. After 14 days of drug administration, there was a marked improvement in glucose tolerance; a reduction in insulin resistance; a reduction in macrophage infiltration in adipose tissue and in TNF-alpha, IL-6, and free fatty acids; accompanied by an improvement in insulin signaling in liver, muscle, and adipose tissue; and also a decrease in insulin receptor substrate-1 Ser(307) phosphorylation in JNK and inhibitor of NF-kappaB kinase (IKKbeta) activation in these tissues. CONCLUSIONS: Treatment with PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice.


Asunto(s)
Glucemia/efectos de los fármacos , Grasas de la Dieta/administración & dosificación , Inhibidores Enzimáticos/farmacología , Receptores ErbB/antagonistas & inhibidores , Hipoglucemiantes/metabolismo , Insulina/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Quinazolinas/farmacología , Adiponectina/sangre , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Tejido Adiposo/ultraestructura , Animales , Glucemia/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/sangre , Immunoblotting , Inmunoprecipitación , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Insulina/sangre , Proteínas Sustrato del Receptor de Insulina/efectos de los fármacos , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina , Interleucina-6/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Leptina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Macrófagos/efectos de los fármacos , Masculino , Ratones , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Subunidad p50 de NF-kappa B/efectos de los fármacos , Subunidad p50 de NF-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo
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