RESUMO
Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear as targeting histamine 1 receptor (H1R) or H2R is clinically ineffective. We hypothesized that histamine functioned instead through the other colon-expressed histamine receptor, H4R. In humans, UC patient biopsies exhibited increased H4R RNA and protein expression over control tissue, and immunohistochemistry showed that H4R was in proximity to immunopathogenic myeloperoxidase-positive neutrophils. To characterize this association further, we employed both the oxazolone (Ox)- and dextran sulfate sodium (DSS)-induced experimental colitis mouse models and also found upregulated H4R expression. Mast cell (MC)-derived histamine and H4R drove experimental colitis, as H4R-/- mice had lower symptom scores, neutrophil-recruitment mediators (colonic interleukin-6 (IL-6), CXCL1, CXCL2), and mucosal neutrophil infiltration than wild-type (WT) mice, as did MC-deficient KitW-sh/W-sh mice reconstituted with histidine decarboxylase-deficient (HDC-/-) bone marrow-derived MCs compared with WT-reconstituted mice; adaptive responses remained intact. Furthermore, Rag2-/- × H4R-/- mice had reduced survival, exacerbated colitis, and increased bacterial translocation than Rag2-/- mice, revealing an innate protective antibacterial role for H4R. Taken together, colonic MC-derived histamine initiates granulocyte infiltration into the colonic mucosa through H4R, suggesting alternative therapeutic targets beyond adaptive immunity for UC.
Assuntos
Colite Ulcerativa/imunologia , Colite/imunologia , Colo/imunologia , Histamina/metabolismo , Mucosa Intestinal/imunologia , Mastócitos/fisiologia , Receptores Histamínicos H4/metabolismo , Adolescente , Adulto , Idoso , Animais , Células Cultivadas , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Histidina Descarboxilase/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Infiltração de Neutrófilos , Oxazolona , Receptores Histamínicos H4/genética , Adulto JovemRESUMO
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized pathologically by eosinophil infiltration. In addition to loss of barrier integrity, a dominant T Helper 2-associated immune response and strong allergic connection, the esophagus tissue undergoes dramatic changes, with frequent presence of mucosal rings, strictures, linear furrows, and trachealization. Although the inflammatory mechanisms behind this disease are being increasingly well understood, the structural features remain unexplained. We examined the expression of key members of the Wnt-signaling pathway in biopsies from patients with EoE. This pathway has been shown to be critically important in regulating cellular homeostasis, growth, and differentiation and to be dysregulated in several disease conditions. Biopsies from adult EoE patients were collected by endoscopy and mRNA extracted. After cDNA synthesis, the relative gene expression from key upstream (secreted frizzled-related protein 1) and downstream (c-myc and Cyclin D1) molecules in the Wnt pathway, as well as several Wnt pathway members (Wnt1, Axin1, low-density lipoprotein receptor-related protein 6, glycogen synthase kinase 3 beta, and ß-catenin), were determined. Biopsies from patients with EoE displayed significantly higher expression of secreted frizzed-related protein 1 than controls, as well as reductions in Cyclin D1 and c-myc. In contrast, there were no differences in the Wnt pathway molecules. The levels of expression of Cyclin D1 and c-myc, as well as ß-catenin, in EoE patients showed strong correlations with the frequency of esophageal eosinophils. Our findings suggest that although there are no changes in the overall levels of key Wnt pathway genes in adult EoE, there is evidence for dysregulation of upstream and downstream regulators of Wnt signaling. Importantly, the associations with eosinophilia suggest that these may participate in the pathogenesis of this disease and be markers of disease severity.
Assuntos
Esofagite Eosinofílica/genética , Via de Sinalização Wnt/genética , Adulto , Proteína Axina/genética , Biópsia , Ciclina D1/genética , Esofagite Eosinofílica/patologia , Eosinófilos/patologia , Esofagoscopia , Esôfago/patologia , Feminino , Genes myc/genética , Marcadores Genéticos/genética , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Glicoproteínas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Estudos Prospectivos , RNA Mensageiro/análise , Proteína Wnt1/genética , beta Catenina/genéticaRESUMO
BACKGROUND: Anaphylaxis is a severe, potentially life-threatening reaction that can occur in response to common triggers, including food allergens (e.g., peanut), insect stings, and several medications. Activation of mast cells and basophils to release preformed mediators, such as histamine, is thought to be an important process that underlies reactions. Histamine can exert effects through four different receptors, termed H1R-H4R. Despite clinical use of both H1R and H2R blockers in the therapy for acute allergic reactions, there is little mechanistic evidence to support the necessity for blocking H2R, a receptor best characterized for its role in stomach acid production. METHODS: Here, we sought to define the necessity for histamine receptors in the pathology of anaphylaxis using H1R and H2R knockout (KO) mice, as well as a H1R/H2R double KO strain. RESULTS: In response to IgE-mediated systemic anaphylaxis, the symptoms and decreases in core body temperature observed in wild-type mice were reduced but not ablated in either H1R or H2R KO. In contrast, H1R/H2R KO were significantly protected and were indistinguishable from histamine-deficient mice. Intravenous injection of histamine was sufficient to elicit these responses, and similar to IgE-mediated anaphylaxis, loss of both H1R and H2R was necessary for complete protection. CONCLUSION: Our data demonstrate definitively that both H1R and H2R participate in the immediate systemic responses during histamine-associated pathophysiology and mechanistically support the utility of H2R-blocking therapeutics in alleviating symptoms of anaphylaxis.
Assuntos
Anafilaxia/metabolismo , Histamina/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Anafilaxia/genética , Anafilaxia/imunologia , Animais , Especificidade de Anticorpos/imunologia , Modelos Animais de Doenças , Histamina/sangue , Imunoglobulina E/administração & dosagem , Imunoglobulina E/imunologia , Camundongos , Camundongos Knockout , Ovalbumina/imunologia , Receptores Histamínicos H1/genética , Receptores Histamínicos H2/genéticaRESUMO
Previous work in our laboratories has demonstrated the effectiveness of peracetic acid for improving enzymatic digestibility of lignocellulosic materials. The use of dilute alkali solutions as a pre-pretreatment prior to peracetic acid lignin oxidation increased carbohydrate hydrolysis yields in a synergistic as opposed to additive manner. Deacetylation of xylan is easily achieved using dilute alkali solutions under mild conditions. In this article, we evaluate the effectiveness of peracetic acid combined with an alkaline pre-pretreatment through simultaneous saccharification and cofermentation (SSCF) of pretreated hybrid poplar wood and sugar cane bagasse. Respective ethanol yields of 92.8 and 91.9% of theoretical are achieved using 6% NaOH/15% peracetic acid-pretreated substrates and recombinant Zymomonas mobilis CP4/pZB5. Reduction of acetyl groups of the lignocellulosic materials is demonstrated following alkaline pre-pretreatments. Such processing may be helpful in reducing peracetic acid requirements. The influence of deacetylation is more significant in combined pretreatments using lower peracetic acid loadings.
Assuntos
Biomassa , Celulose/química , Lignina/química , Madeira , Cycadopsida , Fermentação , Hidrólise , Indicadores e Reagentes , Cinética , Ácido Peracético , Polissacarídeos/análise , Zymomonas/fisiologiaAssuntos
Diabetes Insípido/história , Animais , Diabetes Insípido/genética , Diabetes Insípido/fisiopatologia , Diurese , Feminino , História do Século XX , Doenças Hipotalâmicas/genética , Doenças Hipotalâmicas/história , Doenças Hipotalâmicas/fisiopatologia , Masculino , Ratos , Ratos Brattleboro , Vasopressinas/fisiologiaRESUMO
Aspen (Populus tremuloides) and black cottonwood (Populus trichocarpa) organosolv pulps produced in a wide range of solvent composition (between 30 and 70% by volume of methanol) and catalysts (H(2)SO(4) and H(3)PO(4)) such that the cooking liquor pH = 3 are easily digested by enzymes. The total yields of hydrolysis residues (pulps) are in the 40-60% range; the acid-catalyzed delignification followed by enzyme hydrolysis can generate 70-88% of the original six-carbon sugars contained in the wood. Glucomannan and arablnogalactan are dissolved into the pulping liquor in the pH range of 2-4.5. Lower pH (=3) leads to additional solubilization of six-carbon sugars. These sugars may be fermented directly. From the insoluble hydrolysis residues, 36-41% conversions of wood into fermentable sugars were obtained after enzyme hydrolysis; the starting feedstocks contain 50.8 and 46.6% hexosans, respectively, for aspen and black cotton-wood. The kinetics of enzymatic hydrolysis of cellulose can be formally treated as two simultaneous pseudo-first-order reactions in which fast and slow hydrolyses of cellulose occur. Correlations between the glucan digestibility and the effect of the pretreatment have been made. The higher residual xylan content reduces the amount of the rapidly hydrolyzable glucan fraction and lowers the glucan digestibility. The proposed simple kinetic treatment is very helpful in assessing the effect of the pretreatment on pulp enzyme hydrolyzability.
RESUMO
Tissues of rats and mice fed a nonessential metal in drinking water for life were analyzed for the essential metals chromium, copper, manganese and zinc. The study involved 505 rats and 843 mice. Livers, lungs, hearts, kidneys and spleens were pooled in groups according to age at death, averaging 5 for rats and 8 for mice, in order to provide adequate sample weight. Copper was significantly higher in livers of rats fed tin, germanium, niobium and zirconium than in controls. Similarly, niobium was associated with deposition of manganese in heart and zinc deposition in liver. Chromium levels were depressed in heart, kidney and spleen by germanium. In mice the greatest effects occurred when indium and rhodium were fed, all four essential trace metals exhibiting raised levels principally in kidney but also in heart and spleen. Chromium levels were raised in all organs but heart when hexavalent chromium was fed. From these data it is apparent that the ingestion of a nonessential metal can enhance the retention of an essential trace metal, perhaps thus avoiding toxicity from the nonessential one.