Kyoko Oh-Oka

University of Yamanashi, Kōhu, Yamanashi, Japan

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Publications (7)21.18 Total impact

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    ABSTRACT: OBJECT Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (Trp) metabolism, is involved in tumor-derived immune suppression through depletion of Trp and accumulation of the metabolite kynurenine, resulting in inactivation of natural killer cells and generation of regulatory T cells (Tregs). It has been reported that high expression of IDO in cancer cells is associated with suppression of the antitumor immune response and is consistent with a poor prognosis. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model. METHODS Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-l-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated. RESULTS In the subcutaneous model, oral administration of 1-MT significantly suppressed tumor growth, and synergistic antitumor effects of 1-MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01). CONCLUSIONS These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO inhibition with standard TMZ treatment could be an encouraging therapeutic strategy for patients with malignant glioma.
    No preview · Article · Dec 2015 · Journal of Neurosurgery
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    ABSTRACT: Background: Maternal milk-borne transforming growth factor (TGF)-β plays a potential role in the development of the mucosal immune system in infants. However, it remains unclear what factors determine TGF-β levels in breast milk. We hypothesized that microbial pressures during pregnancy might affect the expression levels of TGF-β in colostrum. Objectives: This study compared TGF-β2 levels in colostrum of lactating women living in Japan and Nepal with contrasting hygiene statuses. Additionally, we identified environmental and intrinsic factors influencing TGF-β levels in colostrum. Methods: Breast milk samples and structured questionnaires were collected from 80 women living in Japan and 208 women living in Nepal. A robust regression model was used to identify factors associated with colostral TGF-β levels. Results: Analysis using the Mann-Whitney U test showed that TGF-β levels were significantly higher in Japanese women than in Nepalese women. Japanese women who consumed animal milk daily during pregnancy and had atopic dermatitis expressed lower levels of TGF-β in colostrum, as compared to Japanese women who did not. Among Nepalese women, large family size and higher birth order were associated with lower TGF-β levels and women who gave birth to infants with low birth weight had higher expression of TGF-β levels in milk than women who gave birth to infants with normal birth weight. Conclusion: The results suggest that induction of TGF-β levels in colostrum depends on differences in the ethnicity of lactating women. Consumption of animal protein and parturition characteristics may affect TGF-β levels in breast milk, and may explain differences in these levels in breast milk between countries.
    Full-text · Article · Jun 2014 · Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand
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    ABSTRACT: Background & Aims The circadian clock drives daily rhythms in behavior and physiology. A recent study suggests that intestinal permeability is also under control of the circadian clock. However, the precise mechanisms remain largely unknown. Because intestinal permeability depends on tight junction (TJ) that regulates the epithelial paracellular pathway, this study investigated whether the circadian clock regulates the expression levels of TJ proteins in the intestine. Methods The expression levels of TJ proteins in the large intestinal epithelium and colonic permeability were analyzed every 4, 6, or 12 hours between wild-type mice and mice with a mutation of a key clock gene Period2 (Per2; mPer2m/m). In addition, the susceptibility to dextran sodium sulfate (DSS)-induced colitis was compared between wild-type mice and mPer2m/m mice. Results The mRNA and protein expression levels of Occludin and Claudin-1 exhibited daily variations in the colonic epithelium in wild-type mice, whereas they were constitutively high in mPer2m/m mice. Colonic permeability in wild-type mice exhibited daily variations, which was inversely associated with the expression levels of Occludin and Claudin-1 proteins, whereas it was constitutively low in mPer2m/m mice. mPer2m/m mice were more resistant to the colonic injury induced by DSS than wild-type mice. Conclusions Occludin and Claudin-1 expressions in the large intestine are under the circadian control, which is associated with temporal regulation of colonic permeability and also susceptibility to colitis.
    Full-text · Article · May 2014 · PLoS ONE
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    Full-text · Article · Mar 2014 · Allergology International
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) recognizes environmental xenobiotics and is originally thought to be involved in the metabolism (detoxification) of the substances. Recently, AhR is highlighted as an important regulator of inflammation. Notably, accumulating evidence suggests that activation of the AhR suppresses inflammatory bowel diseases (IBDs). Therefore, non-toxic AhR activators become attractive drug candidates for IBD. This study identified 1,4-dihydroxy-2-naphthoic acid (DHNA), a precursor of menaquinone (vitamin K2) abundantly produced by Propionibacterium freudenreichii ET-3 isolated from Swiss-type cheese, as an AhR activator. DHNA activated the AhR pathway in human intestinal epithelial cell line Caco2 cells and in the mouse intestine. Oral treatment of mice with DHNA induced anti-microbial proteins RegIIIβ and γ in the intestine, altered intestinal microbial flora and inhibited dextran sodium sulfate (DSS)-induced colitis, which recapitulated the phenotypes of AhR activation in the gut. As DHNA is commercially available in Japan as a prebiotic supplement without severe adverse effects, DHNA or its derivatives might become a promising drug candidate for IBD via AhR activation. The results also implicate that intestinal AhR might act not only as a sensor for xenobiotics in diet and water but also for commensal bacterial activity because DHNA is a precursor of vitamin K2 produced by vitamin K2-synthesizing commensal bacteria as well as propionic bacteria. Hence, DHNA might be a key bacterial metabolite in the host-microbe interaction to maintain intestinal microbial ecosystem.Immunology and Cell Biology advance online publication, 11 February 2014; doi:10.1038/icb.2014.2.
    No preview · Article · Feb 2014 · Immunology and Cell Biology
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    ABSTRACT: Resveratrol is a bioactive polyphenol enriched in red wine that exhibits many beneficial health effects via multiple mechanisms. However, it is unclear whether resveratrol is beneficial for the prevention of food allergy. This study investigated whether resveratrol inhibited the development of food allergy by using a mouse model of the disease. Mice fed standard diet or standard diet plus resveratrol were sensitized by intragastric administration of ovalbumin (OVA) and mucosal adjuvant cholera toxin (CT). Several manifestations of food allergy were then compared between the mice. The effects of resveratrol on T cells or dendritic cells were also examined by using splenocytes from OVA-specific T cell-receptor (TCR) transgenic DO11.10 mice or mouse bone marrow-derived dendritic cells (BMDCs) in vitro. We found that mice fed resveratrol showed reduced OVA-specific serum IgE production, anaphylactic reaction, and OVA-induced IL-13 and IFN-ã production from the mesenteric lymph nodes (MLNs) and spleens in comparison to the control mice, following oral sensitization with OVA plus CT. In addition, resveratrol inhibited OVA plus CT-induced IL-4, IL-13, and IFN-ã production in splenocytes from DO11.10 mice associated with inhibition of GATA-3 and T-bet expression. Furthermore, resveratrol suppressed the OVA plus CT-induced CD25 expression and IL-2 production in DO11.10 mice-splenocytes in association with decreases in CD80 and CD86 expression levels. Finally, resveratrol suppressed CT-induced cAMP elevation in association with decreases in CD80 and CD86 expression levels in BMDCs. Ingestion of resveratrol prevented the development of a food allergy model in mice. Given the in vitro findings, resveratrol might do so by inhibiting DC maturation and subsequent early T cell activation and differentiation via downregulation of CT-induced cAMP activation in mice. These results suggest that resveratrol may have potential for prophylaxis against food allergy.
    Full-text · Article · Sep 2012 · PLoS ONE
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    ABSTRACT: Cytokines in breast milk may play crucial roles in the beneficial effects of breastfeeding in protecting against allergic and infectious diseases in infants. In particular, breast milk-borne transforming growth factor-beta (TGF-β) has an important potential role in developing the mucosal immune system in infants. However, little is known about what factors influence TGF-β expression in human milk. We investigated whether the behavioral and psychosocial characteristics of mothers affect breast milk TGF-β levels. We conducted a survey of all 139 mothers who were lactating between February and October 2010 in Koshu City, Japan. Participants completed a questionnaire and provided breast milk at the health checkups for their 3-month-old child (N = 129, 93%). Breast milk was assayed for total TGF-β2 levels by ELISA. We took an exploratory approach based on linear and ordered logistic regressions to model TGF-β2 concentrations with their multiple potential determinants. Mothers with depression or poor self-rated health had higher TGF-β2 concentrations than mothers without depression (odds ratio for a higher TGF-β2 quartile: 3.11, 95% confidence intervals: 1.03-9.37) or those reporting better health (odds ratio: 2.34, 1.21-4.55). Smoking, drinking alcohol, probiotics supplementation, social support, and maternal history of allergic diseases were not associated with milk TGF-β2 levels. Milk gathered between August and October or later in the afternoon (3-4 pm vs. 12-2 pm) contained less TGF-β2. Depression, as the consequence of psychosocial stress, may be a strong determinant of TGF-β levels in breast milk. Seasonal and daily fluctuations in milk TGF-β2 concentrations warrant further study.
    Full-text · Article · Sep 2011 · Pediatric Allergy and Immunology