Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mil Med ; 185(9-10): e1499-e1505, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32514537

RESUMO

INTRODUCTION: Despite the rich history and progression of mental health assets and their utilization within the Marine Corps, the implementation of these assets has been varied and inconsistent. This article strives to take the lessons learned from the past and improve on them. The goal is to develop a consistent program focused on resiliency and retention, and propose an integrated organized structure across all the Marine Expeditionary Forces (MEF). MEANS AND METHODS: Review of the literature, current practices, and future recommendations. RESULTS: This article demonstrates that continuing to utilize mental health resources at the Regimental level with a focus on community mental health principles rather than the medical model allows for proximity to members and leadership of their primary command, immediate access to them as their Special Staff Officer, the ability to set the expectation of recovery, resiliency, and readiness, and the capability to implement simple principles of nonmedical recuperation and advisement. CONCLUSIONS: Improving on the organizational structure of mental health in the Marine Corps by placing a mental health Special Staff Officer at the MEF level and focusing on the principles of community mental health will shift the focus back to the primary and secondary prevention care efforts across all levels of the Marine Corps and provide clinical and leadership oversight as it relates to the philosophy, role, and implementation of organic mental health Officers.


Assuntos
Saúde Mental , Militares , Humanos , Estados Unidos
3.
Biochim Biophys Acta ; 1864(12): 1667-1677, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27596062

RESUMO

We report on the molecular interactions of the farnesoid X receptor (FXR) with prenylflavonoids, an emerging class of FXR modulators. FXR is an attractive therapeutic target for mitigating metabolic syndromes (MetS) because FXR activates the inhibitory nuclear receptor, small heterodimer partner (SHP), thereby inhibiting both gluconeogenesis and de novo lipogenesis. We and others have shown that xanthohumol (XN), the principal prenylflavonoid of the hop plant (Humulus lupulus L.), is a FXR agonist based on its ability to affect lipid and glucose metabolism in vivo and to induces FXR target genes in biliary carcinoma cells and HEK293 cells. However, studies are currently lacking to rationalize the molecular mechanisms of FXR modulation by prenylflavonoids. We addressed this deficiency and report the first systematic study of FXR prenylflavonoid interactions. We combined hydrogen deuterium exchange mass spectrometry (HDX-MS) with computational studies for dissecting molecular recognition and conformational impact of prenylflavonoid interactions on the ligand binding domain (LBD) of human FXR. Four prenylflavonoids were tested: xanthohumol, a prenylated chalcone, two prenylated flavonones, namely isoxanthohumol (IX) and 8-prenylnaringenin (8PN), and a semisynthetic prenylflavonoid derivative, tetrahydroxanthohumol (TX). Enhancement of the HDX protection profile data by in silico predicted models of FXR prenylflavonoid complexes resulted in mapping of the prenylflavonoid interactions within the canonical ligand binding pocket. Our findings provide a foundation for the exploration of the chemical scaffolds of prenylated chalcones and flavanones as leads for future structure activity studies of this important nuclear receptor with potential relevance for ameliorating lipid metabolic disorders associated with obesity and MetS.


Assuntos
Flavonoides/metabolismo , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Linhagem Celular Tumoral , Medição da Troca de Deutério , Flavonoides/química , Células HEK293 , Humanos , Cinética , Ligantes , Espectrometria de Massas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Propiofenonas/metabolismo , Conformação Proteica , Receptores Citoplasmáticos e Nucleares/agonistas , Espectrometria de Fluorescência
4.
Biochim Biophys Acta ; 1844(9): 1684-93, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24953769

RESUMO

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of transcription factors that plays a key role in the regulation of bile acids, lipid and glucose metabolisms. The regulative function of FXR is governed by conformational changes of the ligand binding domain (LBD) upon ligand binding. Although FXR is a highly researched potential therapeutic target, only a limited number of FXR-agonist complexes have been successfully crystallized and subsequently yielded high resolution structures. There is currently no structural information of any FXR-antagonist complexes publically available. We therefore explored the use of amide hydrogen/deuterium exchange (HDX) coupled with mass spectrometry for characterizing conformational changes in the FXR-LBD upon ligand binding. Ligand-specific deuterium incorporation profiles were obtained for three FXR ligand chemotypes: GW4064, a synthetic non-steroidal high affinity agonist; the bile acid chenodeoxycholic acid (CDCA), the endogenous low affinity agonist of FXR; and Z-guggulsterone (GG), an in vitro antagonist of the steroid chemotype. A comparison of the HDX profiles of their ligand-bound FXR-LBD complexes revealed a unique mode of interaction for GG. The conformational features of the FXR-LBD-antagonist interaction are discussed.


Assuntos
Hipolipemiantes/química , Pregnenodionas/química , Receptores Citoplasmáticos e Nucleares/química , Sequência de Aminoácidos , Ácido Quenodesoxicólico/química , Medição da Troca de Deutério , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Isoxazóis/química , Ligantes , Espectrometria de Massas/métodos , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Proteínas Recombinantes/química
5.
Biophys Chem ; 141(1): 1-10, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19167149

RESUMO

The retinoid X receptor (RXR) is a ligand-activated transcription factor that plays an important role in growth and development and the maintenance of cellular homeostasis. A thermodynamic ultraviolet circular dichroism, tryptophan fluorescence and ligand binding activity with guanidine as a chemical denaturant are consistent with a two step mechanism. The dimeric LBD equilibrates with a monomeric intermediate (DeltaG(0)(H(2)O) equal to 8.3 kcal/mol) that is in equilibrium with the unfolded state (DeltaG(0)(H(2)O) equal to 2.8 kcal/mol). The intermediate was characterized by analytical ultracentrifugation, spectroscopy, and collisional fluorescence quenching, which imply that the monomeric intermediate maintains a high degree, but not all, of native secondary structure. Although intrinsic fluorescence from native and intermediate suggests little change in tryptophan environments, fluorescence intensities from fluorescein reporter groups differ significantly between the two structures. Analysis of the collisional quenching results imply that the intermediate is characterized by tryptophans with increased accessibility to small solutes and less overall compactness than the native protein.


Assuntos
Receptores X de Retinoides/química , Receptores X de Retinoides/metabolismo , Acrilamida/farmacologia , Alitretinoína , Dicroísmo Circular , Relação Dose-Resposta a Droga , Fluoresceína/metabolismo , Corantes Fluorescentes/metabolismo , Humanos , Ligantes , Nitratos/farmacologia , Desnaturação Proteica/efeitos dos fármacos , Dobramento de Proteína , Multimerização Proteica , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Termodinâmica , Tretinoína/metabolismo , Triptofano , Ultracentrifugação
6.
Anal Chem ; 79(24): 9398-402, 2007 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17997524

RESUMO

Retinoid X receptors (RXRs) function as ligand-activated transcription factors and are obligatory components of a large number of nuclear receptor heterodimers. RXRs help regulate diverse physiological responses including the cancer prevention responses of cell proliferation, inflammation, cell differentiation, and apoptosis. Since RXRs represent important targets for cancer chemoprevention, an ultrafiltration mass spectrometry-based assay was developed to facilitate the discovery of potential chemoprevention agents that bind to human RXRalpha. Natural and synthetic ligands for RXRalpha including 9-cis-retinoic acid, docosahexaenoic acid, and LG100268 could be detected and identified in DMSO (dimethyl sulfoxide) or even complex matrixes such as extracts of marine bacteria. Specific binding of ligands to RXRalpha was demonstrated through competitive binding using ultrafiltration LC-MS/MS (liquid chromatography-tandem mass spectrometry), and ligands could be ranked in order of affinity for RXRalpha. Therefore, ultrafiltration LC-MS/MS is suitable for the screening of complex mixtures such as natural product extracts for the discovery of new ligands to RXRalpha.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Espectrometria de Massas/métodos , Receptores X de Retinoides/química , Quimioprevenção , Cromatografia Líquida , Humanos , Ligantes , Receptores X de Retinoides/metabolismo , Ultrafiltração
7.
J Am Soc Mass Spectrom ; 17(11): 1510-7, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16872832

RESUMO

Several different agonists of the retinoic X receptor alpha (hRXRalpha) were examined for their effects on the amide H/D exchange kinetics of the homodimeric protein using mass spectrometry. Some agonists, LG 100268, SR11246, and DHA, bind such that slower deuterium exchange-in occurs compared with 9-cis-retinoic acid (9-cis-RA), whereas others, fenretinide and methoprenic acid, result in poorer protection during binding and hence faster exchange-in. Protection against H/D exchange by different agonists and the inhibition of H/D exchange kinetics relative to 9-cis-RA varies markedly in different regions of the protein. Agonists LG 100268, SR11246, and DHA generally inhibit faster exchange processes in the ligand binding regions of hRXRalpha than does the native ligand 9-cis-RA. In at least half of these regions, the level of protection by 9-cis-RA lags behind the agonists even after 60 min. Methoprenic acid did not significantly protect hRXRalpha against amide hydrogen exchange. An efficient method is described for comparing the effects of different agonists on the protein structure of the agonist-RXRalpha complex.


Assuntos
Medição da Troca de Deutério/métodos , Hidrogênio/química , Conformação Proteica , Receptor X Retinoide alfa/química , Espectrometria de Massas por Ionização por Electrospray , Sequência de Aminoácidos , Humanos , Ligantes , Dados de Sequência Molecular
8.
Biochemistry ; 43(4): 909-17, 2004 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-14744134

RESUMO

Receptors for retinoic acid act as ligand activated transcription factors. The three-dimensional structure of the retinoid X receptor (RXR) ligand binding domain has been determined, but little information is available concerning the properties of the protein in solution. Hydrogen/deuterium exchange followed by electrospray ionization mass spectrometry was used to probe the solution conformation of the recombinant human RXRalpha homodimer ligand binding domain in the presence and absence of 9-cis-retinoic acid (9-cis-RA). Within the experimental time domain (0.25-180 min), about 20 amide hydrogens showed decreased exchange rates in the presence of saturating concentrations of 9-cis-RA as compared to those found for the homodimer in the absence of ligand. Most of the amides were located in peptides derived from regions of the protein shown by the X-ray structure to interact with the bound ligand: the amino termini of helices 3 and 9, the two beta sheets, helix 8, the H8-H9 loop, and the carboxyl terminus of helix 11. Unexpectedly, protection was also observed in peptides derived from helices 7, 10, 11, and the H7-H8 and H10-H11 loops, regions that are not directly in contact with bound 9-cis-RA. These results suggest that the binding of ligand results in additional effects on the conformation or dynamics of the homodimer in solution as compared to those observed for the X-ray structure. Overall, the change in deuterium exchange induced by the binding of 9-cis-RA correlated reasonably well with changes in hydrogen bonding, residue depth, and/or solvent accessibility predicted from the crystal structure.


Assuntos
Medição da Troca de Deutério , Receptores do Ácido Retinoico/química , Solventes/química , Espectrometria de Massas por Ionização por Electrospray , Termodinâmica , Fatores de Transcrição/química , Alitretinoína , Sequência de Aminoácidos , Cromatografia em Gel , Cristalografia por Raios X , Medição da Troca de Deutério/métodos , Dimerização , Humanos , Ligantes , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Conformação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Subunidades Proteicas/química , Receptores do Ácido Retinoico/agonistas , Proteínas Recombinantes de Fusão/agonistas , Proteínas Recombinantes de Fusão/química , Receptores X de Retinoides , Soluções , Espectrometria de Massas por Ionização por Electrospray/métodos , Fatores de Transcrição/agonistas , Tretinoína/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...