Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 62
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Immunity ; 53(3): 627-640.e5, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32562600

RESUMEN

Kupffer cells (KCs) are liver-resident macrophages that self-renew by proliferation in the adult independently from monocytes. However, how they are maintained during non-alcoholic steatohepatitis (NASH) remains ill defined. We found that a fraction of KCs derived from Ly-6C+ monocytes during NASH, underlying impaired KC self-renewal. Monocyte-derived KCs (MoKCs) gradually seeded the KC pool as disease progressed in a response to embryo-derived KC (EmKC) death. Those MoKCs were partly immature and exhibited a pro-inflammatory status compared to EmKCs. Yet, they engrafted the KC pool for the long term as they remained following disease regression while acquiring mature EmKC markers. While KCs as a whole favored hepatic triglyceride storage during NASH, EmKCs promoted it more efficiently than MoKCs, and the latter exacerbated liver damage, highlighting functional differences among KCs with different origins. Overall, our data reveal that KC homeostasis is impaired during NASH, altering the liver response to lipids, as well as KC ontogeny.


Asunto(s)
Autorrenovación de las Células/fisiología , Macrófagos del Hígado/fisiología , Metabolismo de los Lípidos/fisiología , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Animales , Proliferación Celular/fisiología , Lípidos/análisis , Hígado/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/metabolismo
2.
Basic Res Cardiol ; 118(1): 33, 2023 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-37639039

RESUMEN

While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.


Asunto(s)
Enfermedades Cardiovasculares , Humanos , Proteómica , HDL-Colesterol , Factores de Riesgo de Enfermedad Cardiaca , Metabolismo de los Lípidos
3.
FASEB J ; 36(5): e22274, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35416331

RESUMEN

Phosphatidylserine (PS) is a minor phospholipid constituent of high-density lipoprotein (HDL) that exhibits potent anti-inflammatory activity. It remains indeterminate whether PS incorporation can enhance anti-inflammatory effects of reconstituted HDL (rHDL). Human macrophages were treated with rHDL containing phosphatidylcholine alone (PC-rHDL) or PC and PS (PC/PS-rHDL). Interleukin (IL)-6 secretion and expression was more strongly inhibited by PC/PS-rHDL than PC-rHDL in both tumor necrosis factor (TNF)-α- and lipopolysaccharide (LPS)-stimulated macrophages. siRNA experiments revealed that the enhanced anti-inflammatory effects of PC/PS-rHDL required scavenger receptor class B type I (SR-BI). Furthermore, PC/PS-rHDL induced a greater increase in Akt1/2/3 phosphorylation than PC-rHDL. In addition, PC/PS but not PC-rHDL decreased the abundance of plasma membrane lipid rafts and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. Finally, when these rHDL formulations were administered to dyslipidemic low-density lipoprotein (LDL)-receptor knockout mice fed a high-cholesterol diet, circulating IL-6 levels were significantly reduced only in PC/PS-rHDL-treated mice. In parallel, enhanced Akt1/2/3 phosphorylation by PC/PS-rHDL was observed in the mouse aortic tissue using immunohistochemistry. We concluded that the incorporation of PS into rHDLs enhanced their anti-inflammatory activity by modulating Akt1/2/3- and p38 MAPK-mediated signaling through SR-BI in stimulated macrophages. These data identify PS as a potent anti-inflammatory component capable of enhancing therapeutic potential of rHDL-based therapy.


Asunto(s)
Lipoproteínas HDL , Fosfatidilserinas , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Espacio Intracelular/metabolismo , Lipoproteínas HDL/metabolismo , Macrófagos/metabolismo , Ratones , Fosfatidilserinas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
4.
Haematologica ; 107(6): 1347-1357, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-34647443

RESUMEN

Erdheim-Chester disease (ECD) is a rare, systemic, non-Langerhans cell histiocytosis neoplasm, which is characterized by the infiltration of CD63+ CD1a- histiocytes in multiple tissues. The BRAFV600E mutation is frequently present in individuals with ECD and has been detected in hematopoietic stem cells and immune cells from the myeloid and systemic compartments. Immune cells and pro-inflammatory cytokines are present in lesions, suggesting that ECD involves immune cell recruitment. Although a systemic cytokine T-helper-1-oriented signature has been reported in ECD, the immune cell network orchestrating the immune response in ECD has yet to be described. To address this issue, the phenotypes of circulating leukocytes were investigated in a large, single-center cohort of 78 patients with ECD and compared with those of a group of 21 control individuals. Major perturbations in the abundance of systemic immune cells were detected in patients with ECD, with decreases in circulating plasmacytoid, myeloid 1, and myeloid 2 dendritic cells, mostly in BRAFV600E carriers, in comparison with individuals in the control group. Similarly, marked decreases in blood Thelper, cytotoxic, and B-lymphocyte numbers were observed in patients with ECD, relative to the control group. Measurement of circulating immunoglobulin concentrations revealed an immunoglobulin G switch, from IgG1 to IgG4 subclasses, which are more frequently associated with the BRAF mutation. First-line therapies, including pegylated interferon-a and vemurafenib, were able to correct most of these alterations. This study reveals a profound disturbance in the systemic immune phenotype in patients with ECD, providing important new information, helping to understand the physiopathological mechanisms involved in this rare disease and improving the therapeutic management of patients.


Asunto(s)
Enfermedad de Erdheim-Chester , Citocinas/genética , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Enfermedad de Erdheim-Chester/genética , Humanos , Inmunoglobulina G , Fenotipo , Proteínas Proto-Oncogénicas B-raf/genética , Vemurafenib/uso terapéutico
5.
Nutr Metab Cardiovasc Dis ; 30(1): 33-39, 2020 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-31753791

RESUMEN

BACKGROUND AND AIMS: High-density lipoprotein (HDL) particles play atheroprotective roles by their ability to efflux cholesterol from foam cells and to protect low-density lipoproteins (LDLs) from oxidative damage in the arterial intima. We hypothesized that antioxidative properties of HDLs can be attenuated in the oxygen-rich prooxidative arterial environment, contributing to the development of atherosclerosis. To evaluate this hypothesis, we compared antioxidative activity of HDLs from arterial and venous plasmas. METHODS AND RESULTS: Arterial and venous blood samples were simultaneously obtained from 16 patients (age 68 ± 10 years; 75% males) presenting with ischemic or valvular heart disease. Major HDL subfractions and total HDLs were isolated by density gradient ultracentrifugation and their chemical composition and the capacity to protect LDLs from in vitro oxidation were evaluated. HDL-cholesterol, triglycerides and apolipoprotein (apo) B-100 levels were slightly but significantly reduced by -4 to -8% (p < 0.01) in the arterial vs. venous samples. Total mass of HDL subpopulations was similar and HDL subpopulations did not reveal marked compositional differences between the arterial and venous circulation. Potent antioxidative activity of the small, dense HDL3c subpopulation was significantly reduced in the particles of arterial origin vs. their counterparts from venous plasma (increase of +21% in the propagation rate of LDL oxidation, p < 0.05). Interestingly, antioxidative properties of venous HDLs were enhanced in statin-treated patients relative to untreated subjects. CONCLUSION: Antioxidative properties of small, dense HDLs from arterial plasma are attenuated as compared to the particles of venous origin, consistent with the development of atherosclerosis in the arterial wall.


Asunto(s)
Antioxidantes/análisis , Arterias , Aterosclerosis/sangre , Enfermedades de las Válvulas Cardíacas/sangre , Lipoproteínas HDL/sangre , Isquemia Miocárdica/sangre , Venas , Adulto , Anciano , Aterosclerosis/diagnóstico , Aterosclerosis/tratamiento farmacológico , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Enfermedades de las Válvulas Cardíacas/diagnóstico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/diagnóstico , Oxidación-Reducción , Estrés Oxidativo
6.
BMC Biol ; 17(1): 94, 2019 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-31775890

RESUMEN

BACKGROUND: Management of blood cholesterol is a major focus of efforts to prevent cardiovascular diseases. The objective of this study was to investigate how the gut microbiota affects host cholesterol homeostasis at the organism scale. RESULTS: We depleted the intestinal microbiota of hypercholesterolemic female Apoe-/- mice using broad-spectrum antibiotics. Measurement of plasma cholesterol levels as well as cholesterol synthesis and fluxes by complementary approaches showed that the intestinal microbiota strongly regulates plasma cholesterol level, hepatic cholesterol synthesis, and enterohepatic circulation. Moreover, transplant of the microbiota from humans harboring elevated plasma cholesterol levels to recipient mice induced a phenotype of high plasma cholesterol levels in association with a low hepatic cholesterol synthesis and high intestinal absorption pattern. Recipient mice phenotypes correlated with several specific bacterial phylotypes affiliated to Betaproteobacteria, Alistipes, Bacteroides, and Barnesiella taxa. CONCLUSIONS: These results indicate that the intestinal microbiota determines the circulating cholesterol level and may thus represent a novel therapeutic target in the management of dyslipidemia and cardiovascular diseases.


Asunto(s)
Colesterol/metabolismo , Dislipidemias/metabolismo , Microbioma Gastrointestinal/fisiología , Homeostasis , Intestinos/microbiología , Animales , Trasplante de Microbiota Fecal , Ratones , Ratones Endogámicos C57BL
7.
Arterioscler Thromb Vasc Biol ; 38(8): 1913-1925, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29930009

RESUMEN

Objective- Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues with lipid-laden histiocytes. Cardiovascular involvement is frequent in ECD and leads to a severe prognosis. The objective of this study was to determine whether an alteration of lipid metabolism participates in the lipid accumulation in histiocytes and the cardiovascular involvement in ECD. Approach and Results- An analysis of plasma lipid levels indicated that male ECD patients carrying the BRAFV600E (B-Raf proto-oncogene, serine/threonine kinase) mutation exhibited hypoalphalipoproteinemia, as demonstrated by low plasma HDL-C (high-density lipoprotein cholesterol) levels. Capacity of sera from male BRAFV600E ECD patients to mediate free cholesterol efflux from human macrophages was reduced compared with control individuals. Cardiovascular involvement was detected in 84% of the ECD patients, and we reported that the presence of the BRAFV600E mutation and hypoalphalipoproteinemia is an independent determinant of aortic infiltration in ECD. Phenotyping of blood CD14+ cells, the precursors of histiocytes, enabled the identification of a specific inflammatory signature associated with aortic infiltration which was partially affected by the HDL phenotype. Finally, the treatment with vemurafenib, an inhibitor of the BRAFV600E mutation, restored the defective sera cholesterol efflux capacity and reduced the aortic infiltration. Conclusions- Our findings indicate that hypoalphalipoproteinemia in male ECD patients carrying the BRAFV600E mutation favors the formation of lipid-laden histiocytes. In addition, we identified the BRAF status and the HDL phenotype as independent determinants of the aortic involvement in ECD with a potential role of HDL in modulating the infiltration of blood CD14+ cells into the aorta.


Asunto(s)
Aorta/metabolismo , Enfermedades de la Aorta/genética , HDL-Colesterol/sangre , Enfermedad de Erdheim-Chester/genética , Histiocitos/metabolismo , Hipoalfalipoproteinemias/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Aorta/efectos de los fármacos , Aorta/patología , Enfermedades de la Aorta/tratamiento farmacológico , Enfermedades de la Aorta/enzimología , Biomarcadores/sangre , Estudios de Casos y Controles , Enfermedad de Erdheim-Chester/sangre , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Femenino , Predisposición Genética a la Enfermedad , Histiocitos/efectos de los fármacos , Histiocitos/patología , Humanos , Hipoalfalipoproteinemias/sangre , Hipoalfalipoproteinemias/diagnóstico , Hipoalfalipoproteinemias/tratamiento farmacológico , Receptores de Lipopolisacáridos/sangre , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Factores de Riesgo , Factores Sexuales , Células THP-1 , Vemurafenib/uso terapéutico , Adulto Joven
8.
J Lipid Res ; 59(1): 25-34, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29150495

RESUMEN

The functional heterogeneity of HDL is attributed to its diverse bioactive components. We evaluated whether the vasodilatory effects of HDL differed across HDL subpopulations, reflecting their distinct molecular composition. The capacity of five major HDL subfractions to counteract the inhibitory effects of oxidized LDL on acetylcholine-induced vasodilation was tested in a rabbit aortic rings model. NO production, an essential pathway in endothelium-dependent vasorelaxation, was studied in simian vacuolating virus 40-transformed murine endothelial cells (SVECs). Small dense HDL3 subfractions displayed potent vasorelaxing activity (up to +31% vs. baseline, P < 0.05); in contrast, large light HDL2 did not induce aortic-ring relaxation when compared on a total protein basis. HDL3 particles were enriched with sphingosine-1-phosphate (S1P) (up to 3-fold vs. HDL2), with the highest content in HDL3b and -3c that concomitantly revealed the strongest vasorelaxing properties. NO generation was enhanced by HDL3c in SVECs (1.5-fold, P < 0.01), a phenomenon that was blocked by the S1P receptor antagonist, VPC 23019. S1P-enriched reconstituted HDL (rHDL) was a 1.8-fold (P < 0.01) more potent vasorelaxant than control rHDL in aortic rings. Small dense HDL3 particles displayed potent protective effects against oxidative stress-associated endothelium dysfunction, potentially reflecting their elevated content of S1P that might facilitate interaction with S1P receptors and ensuing NO generation.


Asunto(s)
Lipoproteínas HDL/química , Lipoproteínas HDL/farmacología , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Vasodilatación/efectos de los fármacos , Voluntarios Sanos , Humanos , Lipoproteínas HDL/sangre , Lisofosfolípidos/sangre , Esfingosina/sangre , Esfingosina/metabolismo
9.
Arterioscler Thromb Vasc Biol ; 36(2): 285-94, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26681758

RESUMEN

OBJECTIVES: Postprandial atherogenic lipoproteins, characterizing high-risk patients, correlate positively with cardiovascular events. Although the effect of niacin on fasting lipids is well established, its impact on atheroprotective reverse cholesterol transport (RCT) pathway and on functional features of circulating lipoproteins during the postprandial state remains indeterminate. APPROACH AND RESULTS: We evaluated RCT pathway during postprandial phase in dyslipidemic patients displaying a low high-density lipoprotein (HDL) cholesterol phenotype. Ten subjects on stable statin therapy received 1 g/20 mg extended-release niacin/laropiprant (ERN/LRPT) for 4 weeks followed by 2 g/40 mg ERN/LRPT for additional 8 weeks. At each experimental period, postprandial hypertriglyceridemia and major steps of RCT, including cholesterol efflux from human macrophages, cholesteryl ester transfer protein-mediated cholesteryl ester transfer, and hepatic HDL-cholesteryl ester selective uptake were evaluated. Equally, the capacity of postprandial HDL particles isolated from patients before and after ERN/LRPT treatment to mediate RCT to feces was evaluated in vivo in human apolipoprotein B/cholesteryl ester transfer protein double transgenic mouse model. Compared with baseline, ERN/LRPT significantly reduced postprandial hypertriglyceridemia (incremental area under the curve-triglyceride: -53%; P=0.02). Postprandial increase in endogenous plasma cholesteryl ester transfer protein activity was completely abolished after ERN/LRPT treatment. Despite a slight reduction in plasma cholesterol efflux capacity from human THP-1 macrophages, evaluation of global RCT efficacy by combining both ex vivo and in vivo approaches indicate that postprandial HDL particles formed under ERN/LRPT therapy displayed a greater capacity for HDL-mediated RCT to feces. CONCLUSIONS: ERN/LRPT treatment efficiently attenuates atherogenic postprandial lipemia and stimulates HDL-mediated cholesterol return to the liver and elimination into feces during postprandial phase, thus maintaining an efficient removal of cholesterol from the body.


Asunto(s)
Anticolesterolemiantes/uso terapéutico , Colesterol/sangre , Dislipidemias/tratamiento farmacológico , Indoles/uso terapéutico , Hígado/efectos de los fármacos , Macrófagos/efectos de los fármacos , Niacina/uso terapéutico , Periodo Posprandial , Anciano , Animales , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Transporte Biológico , Células CHO , Línea Celular Tumoral , Proteínas de Transferencia de Ésteres de Colesterol/genética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangre , Cricetulus , Combinación de Medicamentos , Dislipidemias/sangre , Dislipidemias/diagnóstico , Heces/química , Femenino , Humanos , Hígado/metabolismo , Macrófagos/metabolismo , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Factores de Tiempo , Transfección , Resultado del Tratamiento
10.
Biochim Biophys Acta ; 1851(9): 1254-61, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26037829

RESUMEN

BACKGROUND: Low plasma levels of high-density lipoprotein-cholesterol (HDL-C) are typical of acute myocardial infarction (MI) and predict risk of recurrent cardiovascular events. The potential relationships between modifications in the molecular composition and the functionality of HDL subpopulations in acute MI however remain indeterminate. METHODS AND RESULTS: ST segment elevation MI (STEMI) patients were recruited within 24h after diagnosis (n=16) and featured low HDL-C (-31%, p<0.05) and acute-phase inflammation (determined as marked elevations in C-reactive protein, serum amyloid A (SAA) and interleukin-6) as compared to age- and sex-matched controls (n=10). STEMI plasma HDL and its subpopulations (HDL2b, 2a, 3a, 3b, 3c) displayed attenuated cholesterol efflux capacity from THP-1 cells (up to -32%, p<0.01, on a unit phospholipid mass basis) vs. CONTROLS: Plasma HDL and small, dense HDL3b and 3c subpopulations from STEMI patients exhibited reduced anti-oxidative activity (up to -68%, p<0.05, on a unit HDL mass basis). HDL subpopulations in STEMI were enriched in two proinflammatory bioactive lipids, lysophosphatidylcholine (up to 3.0-fold, p<0.05) and phosphatidic acid (up to 8.4-fold, p<0.05), depleted in apolipoprotein A-I (up to -23%, p<0.05) and enriched in SAA (up to +10.2-fold, p<0.05); such changes were most marked in the HDL3b subfraction. In vitro HDL enrichment in both lysophosphatidylcholine and phosphatidic acid exerted deleterious effects on HDL functionality. CONCLUSIONS: In the early phase of STEMI, HDL particle subpopulations display marked, concomitant alterations in both lipidome and proteome which are implicated in impaired HDL functionality. Such modifications may act synergistically to confer novel deleterious biological activities to STEMI HDL. SIGNIFICANCE: Our present data highlight complex changes in the molecular composition and functionality of HDL particle subpopulations in the acute phase of STEMI, and for the first time, reveal that concomitant modifications in both the lipidome and proteome contribute to functional deficiencies in cholesterol efflux and antioxidative activities of HDL particles. These findings may provide new biomarkers and new insights in therapeutic strategy to reduce cardiovascular risk in this clinical setting where such net deficiency in HDL function, multiplied by low circulating HDL concentrations, can be expected to contribute to accelerated atherogenesis.


Asunto(s)
Lipoproteínas HDL3/sangre , Lisofosfatidilcolinas/sangre , Infarto del Miocardio/sangre , Ácidos Fosfatidicos/sangre , Proteína Amiloide A Sérica/metabolismo , Adulto , Anciano , Apolipoproteína A-I/química , Apolipoproteína A-I/deficiencia , Apolipoproteína A-I/metabolismo , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Línea Celular , Femenino , Humanos , Interleucina-6/sangre , Lipoproteínas HDL3/química , Lisofosfatidilcolinas/química , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Infarto del Miocardio/patología , Ácidos Fosfatidicos/química , Proteoma/química , Proteoma/metabolismo
11.
J Immunol ; 193(2): 817-26, 2014 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-24935924

RESUMEN

Scavenger receptor class B type I (SR-BI)-deficient mice display reduced survival to endotoxic shock and sepsis. The understanding of the mechanisms underlying SR-BI protection has been hampered by the large spectrum of SR-BI functions and ligands. It notably plays an important role in the liver in high-density lipoprotein metabolism, but it is also thought to participate in innate immunity as a pattern recognition receptor for bacterial endotoxins, such as LPS. In this study, we sought to determine the tissue-specific contribution of SR-BI in the hyperinflammatory response and high mortality rates observed in SR-BI(-/-) mice in endotoxicosis or sepsis. Restoring plasma levels of high-density lipoprotein, which are critical lipoproteins for LPS neutralization, did not improve acute outcomes of LPS injection in SR-BI(-/-) mice. Mice deficient for SR-BI in hepatocytes, endothelial cells, or myeloid cells were not more susceptible to LPS-induced death. However, if SR-BI ablation in hepatocytes led to a moderate increase in systemic inflammatory markers, SR-BI deficiency in myeloid cells was associated with an anti-inflammatory effect. Finally, mice deficient for SR-BI in the adrenal cortex, where the receptor provides lipoprotein-derived cholesterol, had impaired secretion of glucocorticoids in response to stress. When exposed to an endotoxin challenge, these mice exhibited an exacerbated systemic and local inflammatory response, reduced activation of atrophy genes in muscle, and high lethality rate. Furthermore, polymicrobial sepsis induced by cecal ligature and puncture resulted in early death of these animals. Our study clearly demonstrates that corticoadrenal SR-BI is a critical element of the hypothalamic-pituitary-adrenal axis to provide effective glucocorticoid-dependent host defense after an endotoxic shock or bacterial infection.


Asunto(s)
Corteza Suprarrenal/inmunología , Lipopolisacáridos/inmunología , Receptores Depuradores de Clase B/inmunología , Sepsis/inmunología , Choque Séptico/inmunología , Corteza Suprarrenal/metabolismo , Animales , LDL-Colesterol/sangre , LDL-Colesterol/inmunología , LDL-Colesterol/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Citometría de Flujo , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Hepatocitos/efectos de los fármacos , Hepatocitos/inmunología , Hepatocitos/metabolismo , Interleucina-10/sangre , Interleucina-10/inmunología , Interleucina-10/metabolismo , Interleucina-6/sangre , Interleucina-6/inmunología , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Fluorescente , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , Células Mieloides/efectos de los fármacos , Células Mieloides/inmunología , Células Mieloides/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptores Depuradores de Clase B/deficiencia , Receptores Depuradores de Clase B/genética , Sepsis/microbiología , Sepsis/mortalidad , Choque Séptico/microbiología , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Análisis de Supervivencia , Tasa de Supervivencia , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
12.
J Hepatol ; 62(4): 905-12, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25450212

RESUMEN

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning with fibrosis in severe cases, and high prevalence in obesity. We aimed at defining NASH signature in morbid obesity by mass spectrometry-based lipidomic analysis. METHODS: We analyzed systemic blood before and 12 months after bariatric surgery, along with portal blood and adipose tissue lipid efflux collected from obese women at the time of surgery (9 structural classes, 150 species). RESULTS: Increased concentrations of several glycerophosphocholines (PC), glycerophosphoethanolamines (PE), glycerophosphoinositols (PI), glycerophosphoglycerols (PG), lyso-glycerophosphocholines (LPC), and ceramides (Cer) were detected in systemic circulation of NASH subjects. Post-surgery weight loss (12 months) improved the levels of liver enzymes, as well as several lipids, but most PG and Cer species remained elevated. Analysis of lipids from hepatic portal system at the time of surgery revealed limited lipid alterations compared to systemic circulation, but PG and PE classes were found significantly increased in NASH subjects. We evaluated the contribution of visceral adipose tissue to lipid alterations in portal circulation by measuring adipose tissue lipid efflux ex vivo, and observed only minor alterations in NASH subjects. Interestingly, integration of clinical and lipidomic data (portal and systemic) led us to define a NASH signature in which lipids and clinical parameters are equal contributors. CONCLUSIONS: Circulatory (portal and systemic) phospholipid profiling and clinical data defines NASH signature in morbid obesity. We report weak contribution of visceral adipose tissue to NASH-related portal lipid alterations, suggesting possible contribution from other organs draining into hepatic portal system.


Asunto(s)
Tejido Adiposo , Ceramidas , Glicerofosfolípidos , Enfermedad del Hígado Graso no Alcohólico , Obesidad Mórbida , Complicaciones Posoperatorias/sangre , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Adulto , Cirugía Bariátrica/efectos adversos , Cirugía Bariátrica/métodos , Ceramidas/sangre , Ceramidas/metabolismo , Femenino , Estudios de Seguimiento , Francia , Glicerofosfolípidos/sangre , Glicerofosfolípidos/clasificación , Glicerofosfolípidos/metabolismo , Humanos , Hígado/metabolismo , Hígado/patología , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad Mórbida/sangre , Obesidad Mórbida/complicaciones , Obesidad Mórbida/cirugía , Sistema Porta/metabolismo , Periodo Posoperatorio
13.
Blood ; 122(15): 2714-22, 2013 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-23974197

RESUMEN

Chronic inflammatory diseases such as atherosclerosis are characterized by an accumulation of macrophages. To design therapies that would reduce macrophage burden during disease, understanding the cellular and molecular mechanisms that regulate macrophage removal from sites of resolving inflammation is critical. Although past studies have considered the local death of macrophages or the possibility that they emigrate out of inflammatory foci, methods to quantify death or emigration have never been employed. Here, we applied quantitative competition approaches and other methods to study resolution of thioglycollate-induced peritonitis, the model in which earlier work indicated that emigration to lymph nodes accounted for macrophage removal. We show that migration to lymph nodes occurred in a CC chemokine receptor 7-independent manner but, overall, had a quantitatively minor role in the removal of macrophages. Blocking migration did not significantly delay resolution. However, when macrophages resistant to death were competed against control macrophages, contraction of the macrophage pool was delayed in the apoptosis-resistant cells. These data refute the concept that macrophages are dominantly cleared through emigration and indicate that local death controls macrophage removal. This finding alters the emphasis on which cellular processes merit targeting in chronic diseases associated with accumulation of macrophages.


Asunto(s)
Apoptosis/inmunología , Macrófagos Peritoneales/citología , Macrófagos Peritoneales/inmunología , Peritonitis/inmunología , Enfermedad Aguda , Traslado Adoptivo , Animales , Movimiento Celular/inmunología , Femenino , Expresión Génica/inmunología , Inmunofenotipificación , Inflamación/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL
14.
Clin Sci (Lond) ; 128(9): 609-18, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25442240

RESUMEN

Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high-density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex- and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment-estimated insulin resistance): +93%, P< 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n=7) presented a reduced ß-cell function and insulin secretion compared with non-C282Y patients (n=11) (-58% and -73%, respectively, P< 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43±5; non-C282Y: 25±8; controls: 32±7%; P< 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23±5; non-C282Y: 39±10; controls: 26±4%; P< 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined.


Asunto(s)
Aterosclerosis/etiología , Glucemia/metabolismo , HDL-Colesterol/sangre , Antígenos de Histocompatibilidad Clase I/genética , Insulina/sangre , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/genética , Proteínas de la Membrana/genética , Mutación , Adulto , Anciano , Aterosclerosis/sangre , Aterosclerosis/genética , Biomarcadores/sangre , Estudios de Casos y Controles , Línea Celular , LDL-Colesterol/sangre , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Prueba de Tolerancia a la Glucosa , Proteína de la Hemocromatosis , Heterocigoto , Homocigoto , Humanos , Resistencia a la Insulina , Células Secretoras de Insulina/metabolismo , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/diagnóstico , Masculino , Persona de Mediana Edad , Fenotipo , Factores de Riesgo
15.
J Am Acad Dermatol ; 73(5): 809-20, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26365596

RESUMEN

BACKGROUND: Neutrophilic dermatoses refer to a group of cutaneous inflammatory disorders characterized by neutrophilic infiltration of the skin. Neutrophilic dermatoses have been reported in association with various conditions including autoimmune diseases, inflammatory bowel diseases, and neoplasia. In the later condition, myeloproliferative disorders and monoclonal gammopathy (monoclonal immunoglobulin [MIg]) are the most frequent. Only few data are available in case of neutrophilic dermatoses associated with MIg regarding the pathophysiology and the clinical outcome. OBJECTIVE: We sought to gain further insight into clinical and biological aspects of neutrophilic dermatoses associated with MIg. METHODS: We report a retrospective series of 26 patients with neutrophilic dermatoses associated with MIg focusing on clinical and biological aspects, with a study of a large panel of cytokines, chemokines, and adhesion molecules. RESULTS: This study reveals an association between MIg IgA isotype and neutrophilic dermatoses, and a specific inflammatory pattern including elevated interleukin 6, vascular endothelial growth factor, monocyte chemotactic protein-1, epidermal growth factor, and intercellular adhesion molecule-1. LIMITATIONS: This is a retrospective study from a single institution with a limited number of participants. CONCLUSION: Our data highlight a strong association between IgA isotype and neutrophilic dermatoses, and the existence of a specific inflammatory profile involving several molecules.


Asunto(s)
Inmunoglobulina A/inmunología , Isotipos de Inmunoglobulinas/inmunología , Paraproteinemias/complicaciones , Paraproteinemias/inmunología , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Moléculas de Adhesión Celular/sangre , Quimiocinas/sangre , Citocinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos , Paraproteinemias/diagnóstico , Estudios Retrospectivos , Enfermedades de la Piel/diagnóstico
16.
Arterioscler Thromb Vasc Biol ; 33(10): 2297-305, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23887641

RESUMEN

OBJECTIVE: Alterations of the chemokine receptor CX3CR1 gene were associated with a reduced risk of myocardial infarction in human and limited atherosclerosis in mice. In this study, we addressed whether CX3CR1 antagonists are potential therapeutic tools to limit acute and chronic inflammatory processes in atherosclerosis. APPROACH AND RESULTS: Treatment with F1, an amino terminus-modified CX3CR1 ligand endowed with CX3CR1 antagonist activity, reduced the extent of atherosclerotic lesions in both Apoe(-/-) and Ldlr(-/-) proatherogenic mouse models. Macrophage accumulation in the aortic sinus was reduced in F1-treated Apoe(-/-) mice but the macrophage density of the lesions was similar in F1-treated and control mice. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte adhesion, potentially limiting their recruitment. In addition, F1-treated Apoe(-/-) mice displayed reduced numbers of blood inflammatory monocytes, whereas resident monocyte numbers remained unchanged. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte survival. Finally, F1 treatment of Apoe(-/-) mice with advanced atherosclerosis led to smaller lesions than untreated mice but without reverting to the initial phenotype. CONCLUSIONS: The CX3CR1 antagonist F1 is a potent inhibitor of the progression of atherosclerotic lesions by means of its selective impact on inflammatory monocyte functions. Controlling monocyte trafficking and survival may be an alternative or complementary therapy to lipid-lowering drugs classically used in the treatment of atherosclerosis.


Asunto(s)
Antiinflamatorios/farmacología , Aorta/efectos de los fármacos , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Quimiocina CX3CL1/farmacología , Hipolipemiantes/farmacología , Péptidos/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Animales , Aorta/inmunología , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Receptor 1 de Quimiocinas CX3C , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Ligandos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/efectos de los fármacos , Monocitos/inmunología , Receptores de Quimiocina/metabolismo , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de Tiempo
17.
Panminerva Med ; 66(1): 18-26, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37851332

RESUMEN

BACKGROUND: Increased level of blood LDL-C has a causal and cumulative effect on advancing atherosclerotic cardiovascular diseases (ASCVD). European guidelines for treating high LDL-C levels have been recently updated. However, in France, several challenges (e.g., physician and patient awareness, healthcare management) limit the application of management guidelines. The aim of this study was to understand the current opinions and perceived unmet clinical needs in recognising and managing hypercholesterolemia as an ASCVD risk factor, and to explore consensus around factors that support the effective management of elevated LDL-C. METHODS: An expert group of cardiologists, endocrinologists, biology/genetics researchers, and a health technology assessments expert, from France was convened. The current management of hypercholesterolemia and barriers to achieving LDL-C goals in France were discussed and 44 statements were developed. Wider consensus was assessed by sending the statements as a 4-point Likert Scale questionnaire to cardiologists and endocrinologists across France. The consensus threshold was defined as ≥75%. RESULTS: A total of 101 responses were received. Consensus was very high (>90%) in 25 (57%) statements, high (≥75%) in 18 (41%) statements and was not achieved (<75%) only in 1 (2%) of statements. Overall, 43 statements achieved consensus. CONCLUSIONS: Based on consensus levels, key recommendations for improving current guidelines and approaches to care have been developed. Implementation of these recommendations will lead to better concordance with international treatment guidelines and increase levels of education for healthcare practitioners and patients. In turn, this will improve the available treatment pathways for cardiovascular diseases, potentially creating improved patient outcomes in the future.


Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Hipercolesterolemia , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/terapia , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/terapia , LDL-Colesterol , Consenso , Terapias en Investigación
18.
Microbiome ; 12(1): 50, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38468305

RESUMEN

BACKGROUND: Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the ß-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience. RESULTS: While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of ß-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the ß-lactamase activity of the microbiota. The level of ß-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools. CONCLUSIONS: In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous ß-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon. Video Abstract.


Asunto(s)
Microbioma Gastrointestinal , Resiliencia Psicológica , Adulto , Humanos , Microbioma Gastrointestinal/genética , beta-Lactamasas/genética , beta-Lactamas/farmacología , Voluntarios Sanos , Antibacterianos , Bacterias/genética , Heces/microbiología
19.
Arterioscler Thromb Vasc Biol ; 32(5): 1142-9, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22383704

RESUMEN

OBJECTIVE: Bcl-x is the most abundantly expressed member of the Bcl-2 gene family in macrophages, but its role in macrophage apoptosis during atherogenesis is unknown. METHODS AND RESULTS: We previously reported dual pro- and antiatherogenic effects of macrophage survival in early versus advanced atherosclerotic lesions, respectively, potentially reflecting growing impairment of efferocytosis during plaque progression. Here, we specifically inactivated Bcl-x in macrophages and evaluated its impact on atherosclerotic lesion formation in Apoe(-/-) mice at various stages of the disease. Bcl-x deficiency in macrophages increased their susceptibility to apoptosis, resulting in the depletion of tissue macrophages in vivo, including its major pool, Küppfer cells in the liver. We also observed increased cholesterol levels that were, however, not associated with any acceleration of early atherosclerotic plaque progression. This observation suggests that the atheroprotective effect of macrophage apoptosis at that stage of disease was counterbalanced by enhanced cholesterol levels. Bcl-x KO(mac)/Apoe(-/-) mice exhibited significantly larger advanced lesions than control mice. These lesions showed vulnerable traits. Such enhanced lesion size may occur as a result not only of apoptotic cell accumulation but also of elevated cholesterol levels. CONCLUSIONS: Modulation of macrophage resistance to apoptosis through targeted deletion of Bcl-x has a major impact on the entire macrophage cell population in the body, including Küpffer cells. Macrophage survival may, therefore, not only influence atherosclerotic plaque development and vulnerability but also cholesterol metabolism.


Asunto(s)
Apolipoproteínas E/metabolismo , Aterosclerosis/genética , ADN/genética , Regulación de la Expresión Génica , Proteína bcl-X/genética , Animales , Apolipoproteínas E/genética , Apoptosis , Aterosclerosis/metabolismo , Aterosclerosis/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis , Proteína bcl-X/biosíntesis
20.
Front Pediatr ; 11: 1120008, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37842027

RESUMEN

Sterilized donor milk (DM) is frequently used for feeding preterm infants. To date, the effect of different modes of DM sterilization on short-chain fatty acids (SCFAs) remains unknown. We aimed to quantify SCFAs in DM samples after two types of milk sterilization: the Holder pasteurization (HoP) and a high hydrostatic pressure (HP) processing. Eight pooled DM samples were sterilized by HoP (62.5°C for 30 min) or processed by HP (350 MPa at 38°C). Raw DM was used as control. Six SCFAs were quantified by gas chromatography/mass spectrometry. Compared to raw milk, both HoP and HP treatment did not significantly modulate the concentration of acetate, butyrate, propionate and isovalerate in DM. Valerate and isobutyrate were undetectable in DM samples. In conclusion, both HoP and HP processing preserved milk SCFAs at their initial levels in raw human milk.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA