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Stress ; 22(3): 347-357, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30741061


Ethanol consumption during pregnancy alters offspring hypothalamus-pituitary-adrenal (HPA) axis regulation. However, little is known about the outcomes of alcohol consumption confined to the periconceptional period. This study investigated the effects of periconceptional ethanol (PC:EtOH) exposure on corticosterone concentrations, response to restraint stress and gene expression of adrenal, hypothalamic, and hippocampal glucocorticoid-related pathways in rat offspring. Female Sprague-Dawley rats were treated with PC:EtOH (12.5% v/v EtOH liquid diet) or a control diet from four days before conception, until embryonic day 4. At 6 (adult) and 12-14 (aged) months of age, basal corticosterone concentrations were measured, while in a separate cohort of aged rats, blood pressure, heart rate, and plasma corticosterone concentrations were measured during a 30-minute restraint stress. Adrenal gland, hypothalamic and hippocampal tissue from aged rats were subjected to transcriptomic analysis. PC:EtOH exposure reduced basal plasma corticosterone concentrations in adult and aged female but not male offspring (p < .05). The corticosterone and pressor response were significantly reduced in aged PC:EtOH female offspring following restraint (p < .05). Expression of adrenal steroidogenesis genes (Mc2r, Cyp11a1, Cyp21a1, 11bhsd2, and Nr3c1) and hypothalamic genes (Crh, Crh-r1, Nr3c1, and Hsp90a1) was not affected by PC:EtOH. In aged female offspring exposed to PC:EtOH, adrenal mRNA expression of Hsp90a1 was significantly elevated, and within the hippocampus, mRNAs for glucocorticoid receptor (Nr3c1) and Hsp90a1 were increased (p < .05). This study supports the hypothesis that prenatal alcohol exposure programs sex-specific alterations in the HPA axis and provides the first evidence that the periconceptional period is a critical window for programing of this axis. Lay summary This study investigated the impact of alcohol consumption around the time of conception on offspring stress reactivity in a rat model. Offspring exposed to alcohol displayed altered cardiovascular responses to stress and had reduced circulating concentrations of the stress hormone corticosterone both under basal conditions and following a stressful challenge. This study also identified altered expression of key genes in an important part of the brain known to be involved in stress responsiveness; the hippocampus. If similar outcomes occur in humans, these results would suggest that alcohol consumption, even before a woman knows she is pregnant, may significantly impact stress-related outcomes in children.

Etanol/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Glándulas Suprarrenales/metabolismo , Consumo de Bebidas Alcohólicas , Animales , Corticosterona/sangre , Femenino , Expresión Génica , Glucocorticoides/farmacología , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/patología , Embarazo , ARN Mensajero , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/fisiopatología
Hum Vaccin Immunother ; 12(4): 1009-26, 2016 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-26618392


Millions of seasonal and pandemic influenza vaccine doses containing oil-in-water emulsion adjuvant have been administered in order to enhance and broaden immune responses and to facilitate antigen sparing. Despite the enactment of a Global Action Plan for Influenza Vaccines and a multi-fold increase in production capabilities over the past 10 years, worldwide capacity for pandemic influenza vaccine production is still limited. In developing countries, where routine influenza vaccination is not fully established, additional measures are needed to ensure adequate supply of pandemic influenza vaccines without dependence on the shipment of aid from other, potentially impacted first-world countries. Adaptation of influenza vaccine and adjuvant technologies by developing country influenza vaccine manufacturers may enable antigen sparing and corresponding increases in global influenza vaccine coverage capacity. Following on previously described work involving the technology transfer of oil-in-water emulsion adjuvant manufacturing to a Romanian vaccine manufacturing institute, we herein describe the preclinical evaluation of inactivated split virion H5N1 influenza vaccine with emulsion adjuvant, including immunogenicity, protection from virus challenge, antigen sparing capacity, and safety. In parallel with the evaluation of the bioactivity of the tech-transferred adjuvant, we also describe the impact of concurrent antigen manufacturing optimization activities. Depending on the vaccine antigen source and manufacturing process, inclusion of adjuvant was shown to enhance and broaden functional antibody titers in mouse and rabbit models, promote protection from homologous virus challenge in ferrets, and facilitate antigen sparing. Besides scientific findings, the operational lessons learned are delineated in order to facilitate adaptation of adjuvant technologies by other developing country institutes to enhance global pandemic influenza preparedness.

Adyuvantes Inmunológicos , Subtipo H5N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza , Transferencia de Tecnología , Evaluación Preclínica de Medicamentos , Emulsiones/química , Humanos , Subtipo H5N1 del Virus de la Influenza A/fisiología , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Aceites , Pandemias/prevención & control , Rumanía , Virión/fisiología , Inactivación de Virus
J Immunol ; 174(10): 6416-23, 2005 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-15879143


Current evidence indicates that the chronic inflammation observed in the intestines of patients with inflammatory bowel disease is due to an aberrant immune response to enteric flora. We have developed a lipid A-mimetic, CRX-526, which has antagonistic activity for TLR4 and can block the interaction of LPS with the immune system. CRX-526 can prevent the expression of proinflammatory genes stimulated by LPS in vitro. This antagonist activity of CRX-526 is directly related to its structure, particularly secondary fatty acyl chain length. In vivo, CRX-526 treatment blocks the ability of LPS to induce TNF-alpha release. Importantly, treatment with CRX-526 inhibits the development of moderate-to-severe disease in two mouse models of colonic inflammation: the dextran sodium sulfate model and multidrug resistance gene 1a-deficient mice. By blocking the interaction between enteric bacteria and the innate immune system, CRX-526 may be an effective therapeutic molecule for inflammatory bowel disease.

Adyuvantes Inmunológicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Glucosamina/análogos & derivados , Glucosamina/farmacología , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/prevención & control , Lípido A/análogos & derivados , Lípido A/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adyuvantes Inmunológicos/síntesis química , Animales , Caproatos/química , Células Cultivadas , Colitis/inducido químicamente , Colitis/genética , Colitis/inmunología , Colitis/prevención & control , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Femenino , Glucosamina/química , Células HeLa , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Noqueados , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Receptores Inmunológicos/metabolismo , Receptor Toll-Like 4 , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo