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1.
Am J Physiol Cell Physiol ; 327(3): C698-C715, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38946422

RESUMEN

Type 2 diabetes (T2D) constitutes a major public health problem, and despite prevention efforts, this pandemic disease is one of the deadliest diseases in the world. In 2022, 6.7 million patients with T2D died prematurely from vascular complications. Indeed, diabetes increases the risk of myocardial infarction or stroke eightfold. The identification of the molecular factors involved in the occurrence of cardiovascular complications and their prevention are therefore major axes. Our hypothesis is that factors brought into play during physiological aging appear prematurely with diabetes progression. Our study focused on the aging of the extracellular matrix (ECM), a major element in the maintenance of vascular homeostasis. We characterized the morphological and functional aspects of aorta, with a focus on the collagen and elastic fibers of diabetic mice aged from 6 mo to nondiabetic mice aged 6 mo and 20 mo. The comparison with the two nondiabetic models (young and old) highlighted an exacerbated activity of proteases, which could explain a disturbance in the collagen accumulation and an excessive degradation of elastic fibers. Moreover, the generation of circulating elastin-derived peptides reflects premature aging of the ECM. These extracellular elements contribute to the appearance of vascular rigidity, often the origin of pathologies such as hypertension and atherosclerosis. In conclusion, we show that diabetic mice aged 6 mo present the same characteristics of ECM wear as those observed in mice aged 20 mo. This accelerated aortic wall remodeling could then explain the early onset of cardiovascular diseases and, therefore, the premature death of patients with T2D.NEW & NOTEWORTHY Aortic elastic fibers of young (6-mo old) individuals with diabetes degrade prematurely and exhibit an appearance like that found in aged (20-mo old) nondiabetic mice. Exacerbated elastolysis and elastin-derived peptide production are characteristic elements, contributing to early aortic wall rigidity and hypertension development. Therefore, limiting this early aging could be a judicious therapeutic approach to reduce cardiovascular complications and premature death in patients with diabetes.


Asunto(s)
Aorta , Tejido Elástico , Matriz Extracelular , Síndrome Metabólico , Ratones Endogámicos C57BL , Rigidez Vascular , Animales , Tejido Elástico/metabolismo , Tejido Elástico/patología , Rigidez Vascular/fisiología , Ratones , Aorta/metabolismo , Aorta/patología , Aorta/fisiopatología , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Masculino , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Síndrome Metabólico/fisiopatología , Elastina/metabolismo , Colágeno/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Envejecimiento/patología , Envejecimiento/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Envejecimiento Prematuro/metabolismo , Envejecimiento Prematuro/patología , Envejecimiento Prematuro/fisiopatología
2.
J Physiol Biochem ; 80(2): 363-379, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38393636

RESUMEN

The insulin receptor (IR) plays an important role in insulin signal transduction, the defect of which is believed to be the root cause of type 2 diabetes. In 3T3-L1 adipocytes as in other cell types, the mature IR is a heterotetrameric cell surface glycoprotein composed of two α subunits and two ß subunits. Our objective in our study, is to understand how the desialylation of N-glycan chains, induced by elastin-derived peptides, plays a major role in the function of the IR. Using the 3T3-L1 adipocyte line, we show that removal of the sialic acid from N-glycan chains (N893 and N908), induced by the elastin receptor complex (ERC) and elastin derived-peptides (EDPs), leads to a decrease in the autophosphorylation activity of the insulin receptor. We demonstrate by molecular dynamics approaches that the absence of sialic acids on one of these two sites is sufficient to generate local and general modifications of the structure of the IR. Biochemical approaches highlight a decrease in the interaction between insulin and its receptor when ERC sialidase activity is induced by EDPs. Therefore, desialylation by EDPs is synonymous with a decrease of IR sensitivity in adipocytes and could thus be a potential source of insulin resistance associated with diabetic conditions.


Asunto(s)
Células 3T3-L1 , Adipocitos , Elastina , Insulina , Receptor de Insulina , Receptores de Superficie Celular , Ácidos Siálicos , Animales , Receptor de Insulina/metabolismo , Ratones , Adipocitos/metabolismo , Insulina/metabolismo , Elastina/metabolismo , Ácidos Siálicos/metabolismo , Fosforilación , Resistencia a la Insulina , Simulación de Dinámica Molecular , Péptidos/metabolismo , Péptidos/farmacología , Péptidos/química , Ácido N-Acetilneuramínico/metabolismo , Transducción de Señal
3.
Cell Biosci ; 11(1): 206, 2021 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-34903296

RESUMEN

BACKGROUND: Vascular aging is associated with remodeling of elastin, one of the main extracellular matrix component of the arterial wall, and production of elastin-derived peptides (EDP). These extracellular matrix degradation products have been shown to trigger biological activities through the elastin receptor complex (ERC) and data from the last decade have brought significant insights on the critical role played by its NEU1 subunit in the biological effects mediated by EDP and the ERC in vascular and metabolic diseases. RESULTS: Using a proteomic approach, we previously identified new potential interaction partners of membrane NEU1. Here, we validated the interaction between NEU1 and the ß2 integrin in human monocytes and show that binding of EDP to the ERC leads to desialylation of ß2 integrin through NEU1. A similar action mechanism was identified in human umbilical vein endothelial cells (HUVEC) for intercellular cell adhesion molecule-1 (ICAM-1). Importantly, these effects were associated with a significant increase in monocyte adhesion to endothelial cells and monocyte transendothelial migration. CONCLUSIONS: These results demonstrate that membrane NEU1 sialidase interacts and modulates the sialylation levels of the ß2 integrin and ICAM-1 through the ERC in monocytes and endothelial cells, respectively, and suggest that EDP and the ERC, through this newly identified common mode of action governed by NEU1, may be important regulators of circulating monocyte recruitment to inflamed vascular sites. Moreover, by its ability to interact with and to modulate the sialylation of key membrane glycoproteins through NEU1, new biological functions are anticipated for EDP and the ERC in elastin remodeling-associated disorders.

4.
Sci Rep ; 11(1): 22278, 2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34782679

RESUMEN

Numerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann-Whitney statistical test determined the significant data (p < 5%) between groups. The APL-KO mice developed inflammation, which was associated with significant remodeling of visceral WAT, such as neutrophil elastase and cathepsin S expressions. In vitro, cathepsin S activity was detected in conditioned medium prepared from adipose tissue of the APL-KO mice, and cathepsin S activity induced high fragmentations of elastic fiber of wild-type aorta, suggesting that the WAT secretome could play a major role in vascular stiffening. In vivo, remodeling of the extracellular matrix (ECM), such as collagen accumulation and elastolysis, was observed in the aortic walls of the APL-KO mice, with the latter associated with high cathepsin S activity. In addition, pulse wave velocity (PWV) and AHT were increased in the APL-KO mice. The latter could explain aortic wall remodeling in the APL-KO mice. The absence of apelin expression, particularly in WAT, modified the adipocyte secretome and facilitated remodeling of the ECM of the aortic wall. Thus, elastolysis of elastic fibers and collagen accumulation contributed to vascular stiffening and AHT. Therefore, apelin expression could be a major element to preserve vascular homeostasis.


Asunto(s)
Aorta/metabolismo , Aorta/fisiopatología , Apelina/deficiencia , Matriz Extracelular/metabolismo , Rigidez Vascular/genética , Animales , Apelina/genética , Apelina/metabolismo , Biomarcadores , Presión Sanguínea , Expresión Génica , Inmunohistoquímica , Ratones , Ratones Noqueados , Elastasa Pancreática/genética , Elastasa Pancreática/metabolismo
5.
Cell Mol Life Sci ; 76(4): 791-807, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30498996

RESUMEN

In addition to its critical role in lysosomes for catabolism of sialoglycoconjugates, NEU1 is expressed at the plasma membrane and regulates a myriad of receptors by desialylation, playing a key role in many pathophysiological processes. Here, we developed a proteomic approach dedicated to the purification and identification by LC-MS/MS of plasma membrane NEU1 interaction partners in human macrophages. Already known interaction partners were identified as well as several new candidates such as the class B scavenger receptor CD36. Interaction between NEU1 and CD36 was confirmed by complementary approaches. We showed that elastin-derived peptides (EDP) desialylate CD36 and that this effect was blocked by the V14 peptide, which blocks the interaction between bioactive EDP and the elastin receptor complex (ERC). Importantly, EDP also increased the uptake of oxidized LDL by macrophages that is blocked by both the V14 peptide and the sialidase inhibitor 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA). These results demonstrate, for the first time, that binding of EDP to the ERC indirectly modulates CD36 sialylation level and regulates oxidized LDL uptake through this sialidase. These effects could contribute to the previously reported proatherogenic role of EDP and add a new dimension in the regulation of biological processes through NEU1.


Asunto(s)
Aterosclerosis , Antígenos CD36/metabolismo , Neuraminidasa/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Antígenos CD36/genética , Células COS , Membrana Celular/metabolismo , Chlorocebus aethiops , Elastina/química , Humanos , Lipoproteínas LDL/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Ácido N-Acetilneuramínico/farmacología , Neuraminidasa/genética , Péptidos/metabolismo , Péptidos/farmacología , Unión Proteica , Proteómica/métodos , Interferencia de ARN , Células THP-1
6.
Diabetes ; 67(8): 1604-1615, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29802129

RESUMEN

Affecting more than 30% of the Western population, nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including nonalcoholic steatohepatitis (NASH), cancer, hypertension, and atherosclerosis. Insulin resistance and obesity are described as potential causes of NAFLD. However, we surmised that factors such as extracellular matrix remodeling of large blood vessels, skin, or lungs may also participate in the progression of liver diseases. We studied the effects of elastin-derived peptides (EDPs), biomarkers of aging, on NAFLD progression. We evaluated the consequences of EDP accumulation in mice and of elastin receptor complex (ERC) activation on lipid storage in hepatocytes, inflammation, and fibrosis development. The accumulation of EDPs induces hepatic lipogenesis (i.e., SREBP1c and ACC), inflammation (i.e., Kupffer cells, IL-1ß, and TGF-ß), and fibrosis (collagen and elastin expression). These effects are induced by inhibition of the LKB1-AMPK pathway by ERC activation. In addition, pharmacological inhibitors of EDPs demonstrate that this EDP-driven lipogenesis and fibrosis relies on engagement of the ERC. Our data reveal a major role of EDPs in the development of NASH, and they provide new clues for understanding the relationship between NAFLD and vascular aging.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Elastina/metabolismo , Regulación de la Expresión Génica , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fragmentos de Péptidos/metabolismo , Receptores de Superficie Celular/agonistas , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Índice de Masa Corporal , Células Cultivadas , Estudios de Cohortes , Dieta Alta en Grasa/efectos adversos , Progresión de la Enfermedad , Elastina/sangre , Elastina/genética , Matriz Extracelular/inmunología , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Humanos , Lipogénesis , Hígado/inmunología , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Obesidad Mórbida/complicaciones , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/genética , Prueba de Estudio Conceptual , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Transducción de Señal
7.
Sci Rep ; 6: 38363, 2016 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-27917893

RESUMEN

Neuraminidase 1 (NEU1) is a lysosomal sialidase catalyzing the removal of terminal sialic acids from sialyloconjugates. A plasma membrane-bound NEU1 modulating a plethora of receptors by desialylation, has been consistently documented from the last ten years. Despite a growing interest of the scientific community to NEU1, its membrane organization is not understood and current structural and biochemical data cannot account for such membrane localization. By combining molecular biology and biochemical analyses with structural biophysics and computational approaches, we identified here two regions in human NEU1 - segments 139-159 (TM1) and 316-333 (TM2) - as potential transmembrane (TM) domains. In membrane mimicking environments, the corresponding peptides form stable α-helices and TM2 is suited for self-association. This was confirmed with full-size NEU1 by co-immunoprecipitations from membrane preparations and split-ubiquitin yeast two hybrids. The TM2 region was shown to be critical for dimerization since introduction of point mutations within TM2 leads to disruption of NEU1 dimerization and decrease of sialidase activity in membrane. In conclusion, these results bring new insights in the molecular organization of membrane-bound NEU1 and demonstrate, for the first time, the presence of two potential TM domains that may anchor NEU1 in the membrane, control its dimerization and sialidase activity.


Asunto(s)
Membrana Celular/química , Neuraminidasa/química , Fosfatidilcolinas/química , Ácidos Siálicos/química , Ubiquitina/química , Secuencia de Aminoácidos , Animales , Sitios de Unión , Células COS , Membrana Celular/enzimología , Sistema Libre de Células/química , Sistema Libre de Células/metabolismo , Chlorocebus aethiops , Escherichia coli/química , Expresión Génica , Humanos , Modelos Moleculares , Neuraminidasa/genética , Neuraminidasa/metabolismo , Fosfatidilcolinas/metabolismo , Plásmidos/química , Plásmidos/metabolismo , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ácidos Siálicos/metabolismo , Homología Estructural de Proteína , Especificidad por Sustrato , Ubiquitina/genética , Ubiquitina/metabolismo
8.
Sci Rep ; 6: 35666, 2016 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-27759083

RESUMEN

Sialic acids (SA) are monosaccharides that can be located at the terminal position of glycan chains on a wide range of proteins. The post-translational modifications, such as N-glycan chains, are fundamental to protein functions. Indeed, the hydrolysis of SA by specific enzymes such as neuraminidases can lead to drastic modifications of protein behavior. However, the relationship between desialylation of N-glycan chains and possible alterations of receptor function remains unexplored. Thus, the aim of the present study is to establish the impact of SA removal from N-glycan chains on their conformational behavior. We therefore undertook an in silico investigation using molecular dynamics to predict the structure of an isolated glycan chain. We performed, for the first time, 3 independent 500 ns simulations on bi-antennary and tri-antennary glycan chains displaying or lacking SA. We show that desialylation alters both the preferential conformation and the flexibility of the glycan chain. This study suggests that the behavior of glycan chains induced by presence or absence of SA may explain the changes in the protein function.


Asunto(s)
Simulación de Dinámica Molecular , Polisacáridos/química , Polisacáridos/metabolismo , Ácidos Siálicos/química , Ácidos Siálicos/metabolismo , Conformación Molecular
9.
Cardiovasc Res ; 110(3): 298-308, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27009176

RESUMEN

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and represent a major problem of public health. Over the years, life expectancy has considerably increased throughout the world, and the prevalence of CVD is inevitably rising with the growing ageing of the population. The normal process of ageing is associated with progressive deterioration in structure and function of the vasculature, commonly called vascular ageing. At the vascular level, extracellular matrix (ECM) ageing leads to molecular alterations in long half-life proteins, such as elastin and collagen, and have critical effects on vascular diseases. This review highlights ECM alterations occurring during vascular ageing with a specific focus on elastin fragmentation and also the contribution of elastin-derived peptides (EDP) in age-related vascular complications. Moreover, current and new pharmacological strategies aiming at minimizing elastin degradation, EDP generation, and associated biological effects are discussed. These strategies may be of major relevance for preventing and/or delaying vascular ageing and its complications.


Asunto(s)
Envejecimiento/metabolismo , Arterias/metabolismo , Elastina/metabolismo , Matriz Extracelular/metabolismo , Fragmentos de Péptidos/metabolismo , Enfermedades Vasculares/metabolismo , Envejecimiento/patología , Animales , Arterias/efectos de los fármacos , Arterias/patología , Fármacos Cardiovasculares/uso terapéutico , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/patología , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Humanos , Terapia Molecular Dirigida , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/metabolismo , Elastasa Pancreática/antagonistas & inhibidores , Elastasa Pancreática/metabolismo , Proteolisis , Inhibidores de Serina Proteinasa/uso terapéutico , Transducción de Señal/efectos de los fármacos , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/patología
10.
J Clin Endocrinol Metab ; 101(4): 1615-26, 2016 04.
Artículo en Inglés | MEDLINE | ID: mdl-26829440

RESUMEN

CONTEXT: Obesity alters adipose tissue's metabolic and endocrine functions and causes a chronic local and systemic low-grade inflammatory state to develop, generating obesity-associated complications. In the last decade, many entities contributing to and regulating this inflammatory state have been identified, among which are microRNAs. OBJECTIVE: This study aimed to identify microRNA regulated in inflamed adipocytes and adipose tissue, and its effect on adipocyte biology. DESIGN AND RESULTS: We screened the expression profile of TNFα-treated adipocytes (a major pro-inflammatory protein expressed in obese adipose tissue), and identified miR-155 as the most responsive microRNA. The involvement of TNFα on the basal miR-155 expression was confirmed in the adipose tissue of Tnfa−/− mice where miR-155 was significantly reduced. Also, mice overexpressing p65 or invalidated for p65 in adipose tissue respectively increased and decreased miR-155 expression, in line with the involvement of the nuclear factor κB (NF-κB) pathway in miR-155 induction. miR-155 expression was higher in obese subjects' adipose tissue than in that of normal-weight subjects, and correlated with TNFα expression and body mass index. Gain and loss of function of miR-155 showed its effect on adipocyte function, probably via its ability to target PPARγ mRNA 3'UTR. Interestingly, miR-155 overexpression also resulted in an increased inflammatory state in adipocytes. CONCLUSION: Altogether, these data are evidence of a proinflammatory loop mediated by NF-κB and miR-155 that could participate in the amplification of inflammatory status in adipocytes.


Asunto(s)
Adipocitos/patología , Tejido Adiposo/patología , Inflamación/etiología , MicroARNs/genética , Obesidad/complicaciones , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Adulto , Animales , Células Cultivadas , Humanos , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal
11.
Arterioscler Thromb Vasc Biol ; 34(12): 2570-8, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25341794

RESUMEN

OBJECTIVE: Elastin is the major structural extracellular matrix component of the arterial wall that provides the elastic recoil properties and resilience essential for proper vascular function. Elastin-derived peptides (EDP) originating from elastin fragmentation during vascular remodeling have been shown to play an important role in cell physiology and development of cardiovascular diseases. However, their involvement in thrombosis has been unexplored to date. In this study, we investigated the effects of EDP on (1) platelet aggregation and related signaling and (2) thrombus formation. We also characterized the mechanism by which EDP regulate thrombosis. APPROACH AND RESULTS: We show that EDP, derived from organo-alkaline hydrolysate of bovine insoluble elastin (kappa-elastin), decrease human platelet aggregation in whole blood induced by weak and strong agonists, such as ADP, epinephrine, arachidonic acid, collagen, TRAP, and U46619. In a mouse whole blood perfusion assay over a collagen matrix, kappa-elastin and VGVAPG, the canonical peptide recognizing the elastin receptor complex, significantly decrease thrombus formation under arterial shear conditions. We confirmed these results in vivo by demonstrating that both kappa-elastin and VGVAPG significantly prolonged the time for complete arteriole occlusion in a mouse model of thrombosis and increased tail bleeding times. Finally, we demonstrate that the regulatory role of EDP on thrombosis relies on platelets that express a functional elastin receptor complex and on the ability of EDP to disrupt plasma von Willebrand factor interaction with collagen. CONCLUSIONS: These results highlight the complex nature of the mechanisms governing thrombus formation and reveal an unsuspected regulatory role for circulating EDP in thrombosis.


Asunto(s)
Elastina/fisiología , Trombosis/etiología , Animales , Plaquetas/fisiología , Catepsina A/sangre , Bovinos , Colágeno/sangre , Elastina/sangre , Elastina/química , Humanos , Ratones , Neuraminidasa/sangre , Oligopéptidos/sangre , Oligopéptidos/química , Oligopéptidos/fisiología , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/química , Fragmentos de Péptidos/fisiología , Agregación Plaquetaria/fisiología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Proteolisis , Receptores de Superficie Celular/sangre , Transducción de Señal , Trombosis/sangre , Remodelación Vascular/fisiología , Factor de von Willebrand/metabolismo
12.
Adipocyte ; 3(3): 180-9, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-25068084

RESUMEN

Tumor necrosis factor α (TNFα) is a well-known mediator of inflammation in the context of obesity in adipose tissue. Its action appears to be directly linked to perturbations of the insulin pathway, leading to the development of insulin resistance. Visfatin has been suspected to be linked to insulin sensitivity, but the mechanism involved is still partly unknown. The aim of this study was to evaluate the role of visfatin in the impairment of the insulin pathway by TNFα activity in 3T3-L1 adipocytes and to unveil the mechanisms involved in such impairment. We demonstrated in 3T3-L1 adipocytes that visfatin was involved in TNFα-mediated insulin resistance in adipocytes. Indeed, after TNFα treatment in 3T3-L1 cells, visfatin was downregulated, leading to decreased nicotinamide adenine dinucleotide (NAD(+)) concentrations in cells. This decrease was followed by a decrease in Sirt1 activity, which was linked to an increase in PTP1B expression. The modulation of PTP1B by visfatin was likely responsible for the observed decreases in glucose uptake and Akt phosphorylation in 3T3-L1 adipocytes. Here, we demonstrated a complete pathway involving visfatin, NAD(+), Sirt1, and PTP1B that led to the perturbation of insulin signaling by TNFα in 3T3-L1 adipocytes.

13.
Diabetes ; 62(11): 3807-16, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23919962

RESUMEN

Although it has long been established that the extracellular matrix acts as a mechanical support, its degradation products, which mainly accumulate during aging, have also been demonstrated to play an important role in cell physiology and the development of cardiovascular and metabolic diseases. In the current study, we show that elastin-derived peptides (EDPs) may be involved in the development of insulin resistance (IRES) in mice. In chow-fed mice, acute or chronic intravenous injections of EDPs induced hyperglycemic effects associated with glucose uptake reduction and IRES in skeletal muscle, liver, and adipose tissue. Based on in vivo, in vitro, and in silico approaches, we propose that this IRES is due to interaction between the insulin receptor (IR) and the neuraminidase-1 subunit of the elastin receptor complex triggered by EDPs. This interplay was correlated with decreased sialic acid levels on the ß-chain of the IR and reduction of IR signaling. In conclusion, this is the first study to demonstrate that EDPs, which mainly accumulate with aging, may be involved in the insidious development of IRES.


Asunto(s)
Elastina/metabolismo , Resistencia a la Insulina/fisiología , Fragmentos de Péptidos/farmacología , Animales , Metabolismo Energético/efectos de los fármacos , Hiperglucemia/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Ácido N-Acetilneuramínico/análogos & derivados , Ácido N-Acetilneuramínico/farmacología , Neuraminidasa/metabolismo , Oligopéptidos/farmacología , Receptor de Insulina/metabolismo , Receptores de Superficie Celular/metabolismo
14.
Metallomics ; 5(5): 524-31, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23503329

RESUMEN

The white adipose tissue plays a major role in the development of obesity and associated metabolic complications by producing a variety of pro and anti-inflammatory adipokines. Recently, studies in humans or in animals have shown a beneficial effect of certain trace elements such as zinc on insulin resistance and adipokine secretion. The aim of our study was to test the effect of a zinc-nickel-cobalt solution (ZnNiCo) on adipocyte function and to identify potential health effects of this solution in the context of obesity and associated disorders. No impact of ZnNiCo on adipogenesis was observed in 3T3-L1 cells. Gene expression in murine and human adipocytes was examined in the presence of ZnNiCo using whole genome microarrays. This transcriptomic analysis indicated that ZnNiCo affected the expression levels of genes in adipocytes under basal conditions or incubated with TNF-α and showed a down regulation of several inflammatory genes belonging to the cytokine and chemokine families (P < 0.01). These data were confirmed in mice fed with a high fat diet supplemented with ZnNiCo (P < 0.05). A modulation of NF-κB activation (evaluated by ELISA; P < 0.05) by ZnNiCo could explain at least in part these observations. The trace elements present in ZnNiCo are able to modulate the expression level of several inflammation related transcripts in adipocytes. These studies suggest that ZnNiCo could play a role in the prevention of inflammation in adipose tissue in obesity.


Asunto(s)
Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Oligoelementos/farmacología , Células 3T3-L1 , Adipocitos/patología , Adipogénesis/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Quimiocinas/genética , Quimiocinas/metabolismo , Dieta Alta en Grasa , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/genética , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Elementos de Respuesta/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Soluciones , Transcriptoma/genética , Factor de Necrosis Tumoral alfa/farmacología
15.
Biochimie ; 95(6): 1233-8, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23376875

RESUMEN

We have developed an innovative soluble galenic form to overcome the low absorption of trans-Resveratrol (t-Res) as a dry powder. We present here data on pharmacokinetics, bioavailability, and toxicity of t-Res in human volunteers treated with this soluble form, plus additional data on biological effects in rodents. Fifteen healthy volunteers of both sexes received 40 mg of t-Res in two forms, the soluble formulation (caplets) and the original powder (capsules), in a crossover design. Blood samples were collected at 15 min, 30 min, and every hour for 5 h. Plasma concentrations of t-Res and its metabolites were analyzed by liquid chromatography and mass spectrometry. The single dose (40 mg) of the soluble t-Res was well absorbed and elicited biologically efficient blood levels (0.1-6 µM) for several hours, despite metabolization into glucuronide and sulfate conjugates coupled to renal elimination. In contrast, t-Res administered as a dry powder barely elicited efficient blood levels for a short duration. The new formulation led to 8.8-fold higher t-Res levels in plasma versus the powder. t-Res metabolism was not modified and neither intolerance nor toxicity were observed during the study and the following week. The soluble formulation elicited a robust anti-inflammatory effect in various tissues of mice fed a high-fat diet, while dry powder t-Res was almost inactive. Our data suggest that significant improvements in t-Res bioavailability and efficiency can be obtained by this soluble galenic form, also allowing lower doses. The use of t-Res in human therapy is thus greatly facilitated and the toxicity risk is reduced.


Asunto(s)
Antioxidantes/administración & dosificación , Antioxidantes/farmacocinética , Estilbenos/administración & dosificación , Estilbenos/farmacocinética , Administración Oral , Adulto , Anciano , Animales , Disponibilidad Biológica , Cápsulas , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Polvos , Resveratrol
16.
Mol Nutr Food Res ; 56(12): 1771-82, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23065818

RESUMEN

SCOPE: Obesity is strongly associated with low-grade inflammation, notably due to an overproduction of proinflammatory markers by adipose tissue and adipocytes as well as a vitamin D deficiency. Whether these problems are interrelated has not been clearly established. METHODS AND RESULTS: In the present report, decreases in the levels of inflammatory markers such as IL-6, MCP-1, and IL-1ß (mRNA and protein level) in human adipocytes and in 3T3-L1 adipocytes were observed after 1,25-dihydroxyvitamin D3 (1,25-(OH)(2) D(3) ) treatment. Such treatment also decreased the expression of the TNF-α-mediated proinflammatory marker in 3T3-L1 and human adipocytes. A similar effect was observed in adipocyte-macrophage co-culture systems in which 1,25-(OH)(2) D(3) decreased proinflammatory marker expression under basal and TNF-α-stimulated conditions. The involvement of VDR and NF-κB was confirmed in these regulations. Incubation with 1,25-(OH)(2) D(3) also resulted in the dephosphorylation of p38, which is linked to the transcriptional induction of several Dusp family members. Functional consequences of the 1,25-(OH)(2) D(3) treatment on glucose uptake and AKT phosphorylation were observed. CONCLUSION: The improvement of both proinflammatory status and glucose uptake in adipocytes under 1,25-(OH)(2) D(3) effect suggests that low-grade inflammation could be linked to vitamin D deficiency. This observation offers new perspectives in the context of obesity and associated physiopathological disorders.


Asunto(s)
Adipocitos/citología , Glucosa/metabolismo , Inflamación/metabolismo , Vitamina D/farmacología , Vitaminas/farmacología , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Biomarcadores/sangre , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Técnicas de Cocultivo , Regulación hacia Abajo , Humanos , Resistencia a la Insulina , Interleucina-1beta/sangre , Interleucina-1beta/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
17.
Mol Nutr Food Res ; 56(5): 725-32, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22648619

RESUMEN

SCOPE: Adipose tissue is infiltrated by an increasing number of macrophages during the development of obesity. These immune cells are suspected to be a major source of TNF-α that interferes with adipocyte function. Because lycopene possesses anti-inflammatory properties, we hypothesize that lycopene could reduce the production of TNF-α by macrophages and thus interfere in the cross-talk between macrophages and adipocytes. METHODS AND RESULTS: We demonstrated that physiological concentrations of lycopene were able to attenuate the lipopolysaccharide (LPS)-mediated induction of TNF-α in RAW 264.7 macrophages, at both the mRNA and protein levels. The molecular mechanism was studied. It appeared that the LPS-activation of both JNK and NF-κB signaling pathways was modulated by lycopene. The anti-inflammatory effects of lycopene on macrophages were accompanied by a decrease in LPS-stimulated macrophage migration in the presence of lycopene. Furthermore, lycopene decreased macrophage conditioned medium-induced proinflammatory cytokine, acute phase protein, and chemokine mRNA expression in 3T3-L1 adipocytes. CONCLUSION: These data indicate that lycopene displayed an anti-inflammatory effect on macrophages that beneficially impacted adipocyte function. Thus, these results suggest that lycopene could block the vicious cycle that occurs between adipocytes and macrophages in adipose tissue during obesity.


Asunto(s)
Adipocitos/efectos de los fármacos , Antiinflamatorios no Esteroideos/farmacología , Carotenoides/farmacología , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Células 3T3-L1/efectos de los fármacos , Adipocitos/metabolismo , Animales , Biomarcadores/metabolismo , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Quimiocinas/genética , Medios de Cultivo Condicionados/farmacología , Citocinas/genética , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Lipopolisacáridos/toxicidad , Licopeno , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Factor de Necrosis Tumoral alfa/genética
18.
Toxicol In Vitro ; 24(5): 1441-9, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20406675

RESUMEN

Enterocytes regulate gut maintenance and defence by secreting and responding to inflammatory mediators and by modulating the intestinal epithelial permeability. In order to develop an in vitro model of the acute phase of intestinal inflammation, Caco-2 cells were exposed to the inflammatory mediators IL-1beta, TNF-alpha, IFN-gamma and LPS, and the importance of several experimental parameters, i.e. cell differentiation, stimulus nature, concentration and combination on the inflammatory response was assessed by measuring the production of IL-6, IL-8, PGE-2 and NO and by evaluating the monolayer permeability. A maximal increase in IL-8, IL-6 and PGE-2 production and monolayer permeability was observed when using the cytokines simultaneously at their highest level, but this relied mainly on IL-1beta. The effects of TNF-alpha on IL-8 and IL-6 or NO production were stronger upon combination with IL-1beta or IFN-gamma, respectively, whereas cells were unaffected by the presence of LPS. Although NO production, induced by IFN-gamma-containing combinations, was observed only in differentiated cells, general inflammatory response was higher in proliferating cells. The use of a mixture of IL-1beta, TNF-alpha and IFN-gamma thus accurately mimics intestinal inflammatory processes, but cell differentiation and stimuli combination are important parameters to take into account for in vitro studies on intestinal inflammation.


Asunto(s)
Células CACO-2 , Enterocitos/metabolismo , Mediadores de Inflamación/metabolismo , Modelos Biológicos , Ácido Araquidónico/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dinoprostona/metabolismo , Humanos , Mediadores de Inflamación/farmacología , Interferón gamma/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Óxidos de Nitrógeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
19.
Neurobiol Learn Mem ; 94(1): 42-56, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20359541

RESUMEN

The cholinergic neuronal system, through its projections to the hippocampus, plays an important role in learning and memory. The aim of the study was to identify genes and networks in rat hippocampus with and without memory deficit. Genome-scale screening was used to analyze gene expression changes in rats submitted or not to intraparenchymal injection of 192 IgG-saporin and trained in spatial/object novelty tasks. Results showed learning processes were associated with significant expression of genes that could be grouped into several clusters of similar expression profiles and that are involved in biological functions, namely lipid metabolism, signal transduction, protein metabolism and modification, and transcription regulation. Memory loss following hippocampal cholinergic deafferentation was associated with significant expression of genes that did not show similar cluster organization. Only one cluster of genes could be identified; it included genes that would be involved in tissue remodeling. More important, most of the genes significantly altered in lesioned rats were down-regulated.


Asunto(s)
Expresión Génica , Hipocampo/metabolismo , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Análisis de Varianza , Animales , Anticuerpos Monoclonales , Conducta Exploratoria/fisiología , Perfilación de la Expresión Génica , Aprendizaje/fisiología , Masculino , Trastornos de la Memoria/inducido químicamente , Pruebas Neuropsicológicas , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Wistar , Reconocimiento en Psicología/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Inactivadoras de Ribosomas Tipo 1 , Saporinas , Percepción Espacial/fisiología , Factores de Tiempo
20.
Nutr Rev ; 67(7): 363-78, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19566597

RESUMEN

Inflammatory bowel diseases (IBD) arise from multiple causes, including environmental factors, gut microflora, immunity, and genetic predispositions. In the course of IBD, immune homeostasis and intestinal mucosa barrier integrity are impaired. Among natural preventive treatments that have been identified to date, polyphenols appear as promising candidates. They have been shown to protect against several diseases, including cardiovascular diseases and cancers, and they have anti-inflammatory properties in non-intestinal models. This paper will review the literature that has described to date some effects of polyphenols on intestinal inflammation. Studies, conducted using in vivo and in vitro models, provide evidence that pure polyphenolic compounds and natural polyphenolic plant extracts can modulate intestinal inflammation.


Asunto(s)
Antioxidantes/farmacología , Flavonoides/farmacología , Flavonoles/farmacología , Inflamación/prevención & control , Enfermedades Inflamatorias del Intestino/dietoterapia , Fenoles/farmacología , Animales , Humanos , Inflamación/dietoterapia , Inflamación/fisiopatología , Enfermedades Inflamatorias del Intestino/fisiopatología , Intestinos/efectos de los fármacos , Intestinos/fisiopatología , Ratones , Extractos Vegetales/farmacología , Polifenoles , Ratas
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