RESUMO
Dedicator of cytokinesis 3 (DOCK3) is an atypical member of the guanine nucleotide exchange factors (GEFs) and plays important roles in neurite outgrowth. DOCK3 forms a complex with Engulfment and cell motility protein 1 (Elmo1) and effectively activates Rac1 and actin dynamics. In this study, we screened 462,169 low-molecular-weight compounds and identified the hit compounds that stimulate the interaction between DOCK3 and Elmo1, and neurite outgrowth in vitro. Some of the derivatives from the hit compound stimulated neuroprotection and axon regeneration in a mouse model of optic nerve injury. Our findings suggest that the low-molecular-weight DOCK3 activators could be a potential therapeutic candidate for treating axonal injury and neurodegenerative diseases including glaucoma.
RESUMO
Oral immunotherapy (OIT) is a promising treatment of food allergy. To administer an appropriate oral dose of an allergenic component as OIT to individuals sensitized with a food allergen may prevent inducing food allergic inflammation in them. So we attempted to establish a mouse model to evaluate efficacy for oral administration of food allergen after sensitization. In BALB/c mice sensitized by injecting ovalbumin (OVA) with alum twice, OVA was administered before inducing inflammation by feeding the mice with egg white (EW) diet. Severe inflammatory responses, such as enteropathy, weight loss, IL-4 production, and increase of IgE antibody levels, were suppressed by administration with 4 mg of OVA 7 times before feeding EW diet. OVA administration alone induced a slight Th2 response, but no symptoms. The current study demonstrated that severe food allergic enteropathy could be prevented by pre-administration with appropriate dose of OVA to sensitized mice.
Assuntos
Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/prevenção & controle , Imunização , Enteropatias/complicações , Ovalbumina/administração & dosagem , Ovalbumina/farmacologia , Administração Oral , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/metabolismo , Imunoglobulina E/biossíntese , Interleucina-4/biossíntese , Camundongos , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND AND OBJECTIVE: The mechanism inducing either inflammation or tolerance to orally administered food allergens remains unclear. To investigate this we analyzed mouse models of food allergy (OVA23-3) and tolerance (DO11.10 [D10]), both of which express ovalbumin (OVA)-specific T-cell receptors. METHODS: OVA23-3, recombination activating gene (RAG)-2-deficient OVA23-3 (R23-3), D10, and RAG-2-deficient D10 (RD10) mice consumed a diet containing egg white (EW diet) for 2-28 days. Interleukin (IL)-4 production by CD4+ T cells was measured as a causative factor of enteropathy, and anti-IL-4 antibody was used to reveal the role of Foxp3+ OVA-specific Tregs (aiTreg) in this process. RESULTS: Unlike OVA23-3 and R23-3 mice, D10 and RD10 mice did not develop enteropathy and weight loss on the EW diet. On days 7-10, in EW-fed D10 and RD10 mice, splenic CD4+ T cells produced significantly more IL-4 than did those in the mesenteric lymph nodes (MLNs); this is in contrast to the excessive IL-4 response in the MLNs of EW-fed OVA23-3 and R23-3 mice. EW-fed R23-3 mice had few aiTregs, whereas EW-fed RD10 mice had them in both tissues. Intravenous injections of anti-IL-4 antibody recovered the percentage of aiTregs in the MLNs of R23-3 mice. On day 28, in EW-fed OVA23-3 and R23-3 mice, expression of Foxp3 on CD4+ T cells corresponded with recovery from inflammation, but recurrence of weight loss was observed on restarting the EW diet after receiving the control-diet for 1 month. No recurrence developed in D10 mice. CONCLUSIONS: Excessive IL-4 levels in the MLNs directly inhibited the induction of aiTregs and caused enteropathy. The aiTregs generated in the attenuation of T cell-dependent food allergic enteropathy may function differently than aiTregs induced in a tolerance model. Comparing the two models enables to investigate their aiTreg functions and to clarify differences between inflammation with subsequent desensitization versus tolerance.