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1.
J Interferon Cytokine Res ; 36(4): 238-46, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26716812

RESUMO

As in bacterial infections and endotoxin shock, type I interferons (IFNs) also have complex and often opposing effects in various models of autoimmune disease. We have shown that type I IFN paradoxically inhibits autoimmune diabetes in the nonobese diabetic mouse (NOD) and biobreeding (BB) rat. We hypothesize that type I IFN activity differs by IFN subtype and interaction with IFN-gamma. We examined the structure-function relationship of the type I IFN molecule and the mechanism of its diabetes-sparing activity in the NOD mouse. While both recombinant human IFN-alpha A/D (bgl 11) (rHuIFN-alphaA/D) and ovine IFN-tauImod (ovIFN-tau) potently inhibited the development of diabetes (P < 0.01), neither recombinant human IFN-alpha B/D (rHuIFN-alphaB/D) nor recombinant human IFN-alpha consensus (CIFN) were efficacious. The activity of IFN subtypes correlate with their NH3-terminal amino acid sequences. All type I IFN save CIFN, which has no diabetes-sparing activity, inhibited the accessory cell function. IFN-tau administration decreased the expression of Fas and ICAM on total cells, class II MHC expression on B cells, and CD40L expression on T cells by 39%, 45%, 45%, and 60%, respectively. In addition, IFN-tau inhibited the development of diabetes in the NOD.IL4(null) but not the NOD.IFN-gamma(null) mice, suggesting a coordinated interaction between type I and type II IFNs to suppress diabetes development. Thus, the amino terminal portion of the type I IFN molecule influences its ability to inhibit the development of autoimmune diabetes in NOD mice. These data also support the contention that IFN-gamma may have a role in mediating the diabetes-sparing effect of high-dose type I IFNs by the inhibition of the IFN-gamma-inducible immune modulators, class II MHC, Fas, ICAM, and CD40L.


Assuntos
Diabetes Mellitus/terapia , Imunoterapia/métodos , Interferon-alfa/uso terapêutico , Animais , Células Cultivadas , Diabetes Mellitus/imunologia , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Interferon-alfa/química , Interferon gama/genética , Interleucina-4/genética , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Ratos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Ovinos , Relação Estrutura-Atividade
2.
J Nutr ; 140(6): 1192S-1204S, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20392880

RESUMO

The NIH sponsored a scientific workshop, "Soy Protein/Isoflavone Research: Challenges in Designing and Evaluating Intervention Studies," July 28-29, 2009. The workshop goal was to provide guidance for the next generation of soy protein/isoflavone human research. Session topics included population exposure to soy; the variability of the human response to soy; product composition; methods, tools, and resources available to estimate exposure and protocol adherence; and analytical methods to assess soy in foods and supplements and analytes in biologic fluids and other tissues. The intent of the workshop was to address the quality of soy studies, not the efficacy or safety of soy. Prior NIH workshops and an evidence-based review questioned the quality of data from human soy studies. If clinical studies are pursued, investigators need to ensure that the experimental designs are optimal and the studies properly executed. The workshop participants identified methodological issues that may confound study results and interpretation. Scientifically sound and useful options for dealing with these issues were discussed. The resulting guidance is presented in this document with a brief rationale. The guidance is specific to soy clinical research and does not address nonsoy-related factors that should also be considered in designing and reporting clinical studies. This guidance may be used by investigators, journal editors, study sponsors, and protocol reviewers for a variety of purposes, including designing and implementing trials, reporting results, and interpreting published epidemiological and clinical studies.


Assuntos
Ensaios Clínicos como Assunto/normas , Projetos de Pesquisa , Alimentos de Soja , Animais , Humanos , National Institutes of Health (U.S.) , Estados Unidos
3.
Genome Res ; 19(12): 2317-23, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19819907

RESUMO

The Human Microbiome Project (HMP), funded as an initiative of the NIH Roadmap for Biomedical Research (http://nihroadmap.nih.gov), is a multi-component community resource. The goals of the HMP are: (1) to take advantage of new, high-throughput technologies to characterize the human microbiome more fully by studying samples from multiple body sites from each of at least 250 "normal" volunteers; (2) to determine whether there are associations between changes in the microbiome and health/disease by studying several different medical conditions; and (3) to provide both a standardized data resource and new technological approaches to enable such studies to be undertaken broadly in the scientific community. The ethical, legal, and social implications of such research are being systematically studied as well. The ultimate objective of the HMP is to demonstrate that there are opportunities to improve human health through monitoring or manipulation of the human microbiome. The history and implementation of this new program are described here.


Assuntos
Bactérias , Trato Gastrointestinal/microbiologia , Metagenoma/genética , Boca/microbiologia , National Institutes of Health (U.S.) , Pele/microbiologia , Vagina/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Feminino , Humanos , Programas Nacionais de Saúde , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Estados Unidos
5.
Microb Pathog ; 45(5-6): 303-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18721871

RESUMO

Staphylococcal enterotoxin B (SEB) is a toxic shock-inducing agent produced by Staphylococcus aureus. The hallmark of SEB-induced lethal shock is acute vasodilation leading to severe hypotension. Animal studies reveal that approximately 70% of intravenously administered toxin localizes to renal proximal tubule epithelial cells (RPTEC). This evidence, together with the well-documented role of the kidney in regulation of vascular tone, suggests that molecular events induced in RPTEC by SEB may contribute to the blood pressure dysregulation seen in enterotoxic shock. In an attempt to elucidate these molecular mechanisms, differential display was performed on SEB-treated and untreated RPTEC, and 32 differentially expressed transcripts (DETs) were identified. One of the down-regulated DETs matched the sequence for Rnd3, which normally inhibits Rho protein function. Consistent with Rnd3 down-regulation, message for RhoA was shown to increase upon SEB exposure, and actin stress fiber formation was dramatically increased. Further, SEB-exposed cells showed both increased enzymatic activity of caspase-3 and an increase in the percentage of apoptotic cells. Taken together, these results support the hypothesis that RPTEC undergo apoptosis upon exposure to SEB. Furthermore, these data implicate the involvement of the Rho family proteins in the molecular signaling pathway induced by SEB in RPTEC.


Assuntos
Apoptose/efeitos dos fármacos , Enterotoxinas/farmacologia , Células Epiteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Fibras de Estresse/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/genética , Actinas/metabolismo , Adulto , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Masculino , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/química , Fibras de Estresse/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
6.
Autoimmunity ; 41(7): 543-53, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18608174

RESUMO

Interferon-alpha (IFN-alpha) inhibits the development of diabetes in animal models of autoimmune diabetes. However, the mechanism of the action is not fully understood and drug toxicity could limit its potential clinical utility. Interferon-tau (IFN-tau) is another type 1 interferon, which has less toxicity but may have different biologic activity than IFN-alpha. This study explores the effect of IFN-tau on the diabetic process in non-obese diabetic (NOD) mice. IFN-tau by intraperitoneal, subcutaneous, or oral routes of administration decreased the development of spontaneous diabetes in NOD mice. Islet inflammation was decreased 50%. IFN-tau administration to recipient mice prevented the development of passively transferred and cyclophosphamide accelerated diabetes. IFN-tau treatment also decreased anti-islet effector activity of NOD splenic cells. Immunoregulatory activity of splenic cells was augmented by IFN-tau administration as was the number of splenic CD25+CD4+ cells. Concanavalin A (Con A)-induced release of IFN-gamma was decreased in spleen cells from IFN-tau treated mice. In conclusion, IFN-tau inhibits spontaneous autoimmune diabetes and passively transferred diabetes in the NOD mouse. This diabetes sparing activity may be due to an induction of regulatory cells, possibly CD25+CD4+ T cells, which in turn inhibit anti-islet effector cell activity and the development of insulitis and diabetes. Due to the lower drug toxicity, IFN-tau could be a better drug candidate than IFN-alpha for experimental clinical trials.


Assuntos
Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Interferon Tipo I/uso terapêutico , Proteínas da Gravidez/uso terapêutico , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Ciclofosfamida/farmacologia , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Modelos Animais de Doenças , Feminino , Imunossupressores/farmacologia , Interferon Tipo I/administração & dosagem , Interferon Tipo I/farmacologia , Interferon gama/biossíntese , Ilhotas Pancreáticas/imunologia , Camundongos , Camundongos Endogâmicos NOD , Proteínas da Gravidez/administração & dosagem , Proteínas da Gravidez/farmacologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
7.
Health Aff (Millwood) ; 24(4): 991-3, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16012139

RESUMO

Health care opinion leaders concur that integration of complementary and alternative medicine (CAM) into the U.S. health care system must be based on strong supporting evidence of safety and efficacy. As others have pointed out, integration is under way, despite the lack of reliable, rigorous science supporting the use of most CAM treatments. We contend that optimal integration of CAM is a long-term endeavor--a marathon rather than a sprint. The evidence base does not now support its wholesale assimilation; market forces, although compelling, should not be the primary consideration in integration.


Assuntos
Terapias Complementares/tendências , Prestação Integrada de Cuidados de Saúde , Pesquisa Biomédica/métodos , Pesquisa Biomédica/normas , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências , Humanos , National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division , Segurança , Resultado do Tratamento , Estados Unidos
8.
Exp Biol Med (Maywood) ; 229(2): 194-202, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14734798

RESUMO

Interferon (IFN)-tau is a type I IFN that is responsible for the maternal recognition of pregnancy in ruminants. This protein also has classic IFN-like properties, including antiviral, antiproliferative, and immunomodulatory functions. Using IFN-tau as a model, we examined the structural basis for the activity of type I IFNs, focusing on amino acids within helix A and the first section of the AB loop, which have been proposed as a site for receptor interaction. Six amino-acid substitutions were made that replaced a residue in ovine IFN-tau1mod with the corresponding residue in human IFN-alphaA. Receptor binding was enhanced by a P26L mutation and was reduced by a conservative lysine-to-histidine substitution at residue 34. Alterations in the antiviral and antiproliferative activities of the IFN-tau mutants were not always correlated, but both functions were maintained or enhanced relative to the wild-type IFN-tau by the proline-to-leucine mutation at residue 26. In contrast, this mutation did not affect the low in vitro cytotoxicity that is characteristic of ovine IFN-tau1mod. Thus, the IFN-tau P26L mutant may have potential as an improved IFN-based therapeutic.


Assuntos
Interferon Tipo I/genética , Interferon Tipo I/farmacologia , Proteínas da Gravidez/genética , Proteínas da Gravidez/farmacologia , Substituição de Aminoácidos/genética , Animais , Antivirais/farmacologia , Bovinos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular , Humanos , Interferon Tipo I/química , Interferon Tipo I/metabolismo , Modelos Moleculares , Mutagênese Sítio-Dirigida , Fosforilação , Pichia/metabolismo , Proteínas da Gravidez/química , Proteínas da Gravidez/metabolismo , Estrutura Secundária de Proteína , Ensaio Radioligante , Receptores de Interferon/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Ovinos , Transativadores/metabolismo
9.
Infect Immun ; 70(4): 2178-86, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11895985

RESUMO

Staphylococcal enterotoxins (SE) are exoproteins produced by Staphylococcus aureus that act as superantigens and have been implicated as a leading cause of food-borne disease and toxic shock. Little is known about how these molecules penetrate the gut lining and gain access to both local and systemic immune tissues. To model movement in vitro of staphylococcal enterotoxins, we have employed a monolayer system composed of crypt-like human colonic T-84 cells. SEB and SEA showed comparable dose-dependent transcytosis in vitro, while toxic shock syndrome toxin (TSST-1) exhibited increased movement at lower doses. Synthetic peptides corresponding to specific regions of the SEB molecule were tested in vitro to identify the domain of the protein involved in the transcytosis of SE. A toxin peptide of particular interest contains the amino acid sequence KKKVTAQELD, which is highly conserved across all SE. At a toxin-to-peptide ratio of 1:10, movement of SEB across the monolayers was reduced by 85%. Antisera made against the SEB peptide recognized native SEB and also inhibited SEB transcytosis. Finally, the conserved 10-amino-acid peptide inhibited transcytosis of multiple staphylococcal enterotoxins, SEA, SEE, and TSST-1. These data demonstrate that this region of the staphylococcal enterotoxins plays a distinct role in toxin movement across epithelial cells. It has implications for the prevention of staphylococcal enterotoxin-mediated disease by design of a peptide vaccine that could reduce systemic exposure to oral or inhaled superantigens. Since the sequence identified is highly conserved, it allows for a single epitope blocking the transcytosis of multiple SE.


Assuntos
Enterotoxinas/imunologia , Epitopos , Animais , Transporte Biológico , Linhagem Celular , Enterotoxinas/química , Enterotoxinas/metabolismo , Humanos , Soros Imunes/imunologia , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
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