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BackgroundThe HER-2/neu, potent oncogenic protein, has several characteristics that make it a good antigen to serve as the model for developing pDNA-based tumor vaccine strategies.1–3 The observation that immunity co-exists with antigen-positive cancer cells indicates that HER-2 is immunogenic. AST-301 (pNGVL3-hICD) is a plasmid DNA-based therapeutic cancer vaccine encoding HER2 ICD sequence. The clinical efficacy and safety of AST-301 were already proven in HER2-positive breast cancer population, and long-term immunogenicity and survival were demonstrated well via phase 1 study (PN 109, NCT00436254) In this in-vivo study, AST-301 was investigated to evaluate the efficacy in HER2/neu-expressed gastric cancer xenograft model.MethodsA HER2-expressed gastric cancer xenograft model was established with NCI-N87 cell line inoculation in athymic-nude mice. Treatment groups were assigned as AST-301 alone (AST-301, 0.1 mg/head, i.d.), Trastuzumab (TZM, 20 mg/kg, i.p.) or AST-301 combining with Trastuzumab (AST-301+TZM) respectively. To evaluate tumor protective effect of drugs, mice were immunized 3 times in every week. Immunization of AST-301 or AST-301+TZM was completed, followed by tumor cell line inoculation. In another study to verify the anti-tumor effect of them, the administration of drugs was started when the tumor volumes reached approximately 150 mm3. AST-301 was immunized 3 times in every week to post-implantation 32nd day and TZM was injected 5 times per week. The tumor volumes were estimated and the percentage of tumor growth inhibition was calculated.ResultsIn our two in vivo efficacy studies, there was no significant specific safety issue in all groups. Tumor protective effect was observed in AST-301 group (1506.7±1603.0 mm3) compared with control group (GM-CSF, 1266.3±862.5 mm3) as an immune adjuvant (figure 1). However, AST-301+TZM group (1533.0±1186.3 mm3) did not show the tumor protective effect. The groups of AST-301 and AST-301+TZM were significantly higher to the anti-tumor activity than control group, and AST-301 was more effective than AST-301+TZM or TZM alone. On day 33 (32 days after starting treatment), tumor growth inhibition rate were 38.3 % (2503.4±1034.6 mm3), 10.9 % (1545.0±599.9 mm3) and 23.6 % (1912.9±97.1 mm3) in groups of AST-301, TZM and AST-301+TZM compared with control group, respectively.ConclusionsTumor protective and tumor therapeutic effect of AST-301 were demonstrated well in various doses and regimens on HER2/neu positive gastric cancer xenograft model. These data would be supporting a proof of concept (PoC) clinical study of HER-2/neu ICD therapeutic cancer vaccine in certain type of HER2/neu-expressed gastric cancer patient.ReferencesDisis ML. Enhancing cancer vaccine efficacy via modulation of the tumor microenvironment. Clin Cancer Res 2009;15:6476–6478.Disis ML, Wallace DR, Gooley TA, et al. Concurrent trastuzumab and HER2/neu-specific vaccination vaccination in patients with metastatic breast cancer. J Clin Oncol 2009;27:4685–4692.Disis ML, Schiffman K, Guthrie K, et al. Effect of dose on immune response in patients vaccinated with an her-2/neu intracellular domain protein–based vaccine. J Clin Oncol 2004;22:1916–1925.Ethics ApprovalThis experiment was conducted ethically with the approval of the Institutional Animal Care and Use Committee (KBIO-IACUC-2021-038) in the Osong Medical Innovation Foundation Experimental Animal Center.ConsentN/AAbstract 776 Figure 1Tumor protective and tumor therapeutic effect of AST-301 on HER2/neu positive gastric cancer xenograft model

Imperatorin has been known to exert many biological functions including anti-inflammatory activity. In this study, we investigated the inhibitory effects of imperatorin on the production of inflammatory mediators in mouse bone marrow-derived mast cells (BMMC). Imperatorin inhibited degranulation and the generation of eicosanoids (leukotriene C4 (LTC4) and prostaglandin D2 (PGD2)) in IgE/antigen (Ag)-stimulated BMMC. To elucidate the molecular mechanism involved in this process, we investigated the effect of imperatorin on intracellular signaling in BMMC. Biochemical analyses of the IgE/Ag-mediated signaling pathway demonstrated that imperatorin dramatically attenuated degranulation and the production of 5-lipoxygenase-dependent LTC4 and cyclooxygenase-2-dependent PGD2 through the inhibition of intracellular calcium influx/phospholipase Cγ1, cytosolic phospholipase A2/mitogen-activated protein kinases and/or nuclear factor-κB pathways in BMMC. These results suggest that the effects of imperatorin on inhibition of degranulation and eicosanoid generation through the suppression of multiple steps of IgE/Ag-mediated signaling pathways would be beneficial for the prevention of allergic inflammation.

With the recent increase in the power of major retailers through consolidations, the world of brands has divided in two categories: national brands belonging to manufacturers and private brands belonging to retailers. While national brands are well studied in the literature, there is a dearth of studies on private brand phenomenon particularly from a manufacturer's point of view as opposed to that of retailers and consumers. To address this gap, we explore the antecedents and consequences of a manufacturer's private brand retailer dependence with a focus on the manufacturer's relationship with retailers. Drawing on the Resource Dependence Theory and Transaction Cost Economics, we examine various products and market characteristics as potential antecedents of a manufacturer's private brand retailer dependence while adopting private brand sales growth and returns from private brand production as outcomes using a sample of 153 South Korean manufacturers currently involved in private brand production. The results show that the private brand retailer dependence of a manufacturer leads to private brand sales growth directly and returns from private brand production indirectly through private brand sales growth, and has a negative effect on return from private brand production directly. Furthermore, product characteristics, such as product innovativeness through collaboration with retailers and search goods, and market characteristics, such as high retailer power and knowledge specificity of a retailer, increase a manufacturer's private brand retailer dependence and, therefore, private brand sales growth. The theoretical and managerial implications of the findings are discussed at the end.

We previously demonstrated the alleviation of ovalbumin (OVA)-induced airway inflammation by Inulae flos. In the present study, the effects of britanin, a sesquiterpene compound isolated from Inulae flos, were evaluated in an in vivo animal model for anti-asthma activity through observation of airway hyperresponsiveness (AHR), eosinophil recruitment, Th2 cytokine and IgE levels, and lung histopathology. Britanin administration effectively reduced AHR induced by aerosolized methacholine, airway eosinophilia, Th2 cytokines in bronchoalveolar lavage fluids and the supernatant of cultured splenocytes compared with OVA-induced mice. Histological studies showed that increased inflammatory cell infiltration and mucus secretion were reduced by britanin administration. Thus, britanin may have therapeutic potential for treating allergic asthma.

Background: A Korean herbal medicine, KOTMIN13, composed of Inula japonica Thunberg, Trichosanthes kirilowii Maximowicz var. japonica kitamura, Peucedanum praeruptorum Dunn, and Allium macrostemon Bge, has been used for anti-allergic and anti-asthmatic treatment in oriental clinics, but its activity has not been investigated. Materials and Methods: To evaluate the anti-inflammatory activity of KOTMIN13 for in vitro study, LPS-stimulated RAW 264.7 cells were used to induce the production and expression of inflammatory mediators and its mechanisms. 12-O-Tetradecanoylphorobol-13 aceate (TPA)-induced ear edema and carrageenan-induced paw edema models were also used to evaluate the effect of KOTMIN13 on acute inflammation in vivo. Results: KOTMIN13 reduced the release of inflammatory mediators [nitric oxide, prostaglandin E2, interleukin (IL)-1β, and IL-6] and the protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-stimulated RAW 264.7 cells. Mechanism studies showed the attenuation of LPS-induced NF-κB activation by KOTMIN13 via IκBα degradation abrogation and a subsequent decrease in nuclear p65 levels. Activation of mitogen-activated protein kinases (ERK, JNK, and p38) was also suppressed. Furthermore, KOTMIN13 ameliorated the development of TPA-induced ear edema and carrageenan-induced paw edema in acute inflammatory edema mouse models. Conclusion: Our study demonstrates that KOTMIN13 inhibits inflammatory mediators through the inhibitions of NF-κB and MAPK activities in LPS-induced RAW 264.7 cells, as well as acute inflammation in edema models, indicating that KOTMIN13 is an effective suppressor for anti-inflammatory activities. SUMMARY KOTMIN13 decrease the production of No, PGE2, and proinflammatory cytokine (TNF-∝, IL-1β,IL-6).KOTMIN13 Suppressed the degradation of NF-kβ and IKβα and the phosorylation of MAP Kinases.Topical application of KOTMIN13 reduced mouse ear edema.Oral administration of KOTMIN13 decreased carrageenan-induced paw edema. Abbreviations used: NO: nitric oxide; PGE2: prostaglandin E2; iNOS: inducible NO synthase; COX-2: cyclooxygenase-2; TNF-α: tumor necrosis factor-α; IL: interleukin; NF-κB: nuclear factor kappaB; MAPK: mitogen-activated protein kinases; ERK: extracellular signal regulated kinase; JNK: c-jun N terminal kinase; TPA: 12-O-tetradecanoylphorbol-13-acetate

Background and Objective: High-intensity exercise has been linked to immunity; however, the relationship between low-intensity exercise and the immune system is unclear. In this study, the effects of exercise on cytokine production in T helper 1 (interleukin-2 [IL-2] and interferon-gamma [INF-g]) and T helper 2 cells (interleukin-4 [IL-4]) in spleens were investigated. Material and Methods: Sprague–Dawley male rats were divided into a control group (CON, n = 10) and a low-intensity exercise group (EX, n = 10). EX rats were trained on a treadmill (8 m/min, 50 min/day, 5 times over 12 weeks). Spleen tissues were analyzed by hematoxylin-eosin staining and real-time PCR to quantify IL-4, INF-g, and IL-2 expression. Results: IL-4 expression was significantly higher in the EX group than in the CON group (p < 0.05). However, IL-2 and INF-g expression did not differ between groups (p > 0.05). Conclusion: These results suggest that exercise in rats enhances immune function by regulating cytokine production in T helper type 2 (IL-4) cells, but not in T helper type 1 (IL-2 and IFN-g) cells of the activated spleen.

Juncus effusus L. var. decipiens BUCHEN. f. leschenaultii GAY has been used in traditional medicine for the treatment of anxiety and insomnia.The objective of this study was to evaluate the effects of ethanol extract from the pith of Juncus effusus (JEE) on anti-inflammatory activities in RAW 264.7 cells.The production of inflammatory mediators and the underlying mechanisms using 3.1, 6.3, and 12.5 μg/mL concentrations of JEE were investigated. In addition, the topical anti-inflammatory effects of JEE (0.5, 1, and 2 mg/mL) on 12-O-tetradecanoylphorobol-13 acetate (TPA)-induced ear edema and oral administration of JEE (50, 100, and 200 mg/kg) on carrageenan-induced paw-edema were studied in mice.JEE reduced the release of nitric oxide (NO, IC50 value = 1.98 μg/mL), prostaglandin E2 (IC50 value = 5.5 μg/mL), and pro-inflammatory cytokines, IL-1β (IC50 value = 4.74 μg/mL) and IL-6 (IC50 value = 20.48 μg/mL). JEE also suppressed the protein expression of inducible NO synthase and cyclooxygenase-2 in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Mechanism studies showed attenuation of LPS-induced activation of NF-κB by JEE via abrogation of IκBα degradation and a subsequent decrease in nuclear p65 level. Phosphorylation of all three MAP kinases (ERK, JNK, and p38) in LPS-stimulated RAW 264.7 cells was also suppressed in a dose-dependent manner. In acute inflammation models of mice, topical application (1 and 2 mg) and oral administration (50, 100, and 200 mg/kg) of JEE ameliorated TPA-induced ear edema and carrageenan-induced paw edema, respectively, in dose-dependent manners.These results indicate that JEE exhibited anti-inflammatory activities by suppressing the production of inflammatory mediators in LPS-stimulated RAW 264.7 cells and by attenuating edema in mice.

The immediate-type allergic reaction is involved in many allergic diseases such as asthma, allergic rhinitis, and sinusitis. The discovery of drugs for the treatment of immediate-type allergic disease is a very important subject in human health. The formulated ethanol extract of Artemisia asiatica Nakai (DA-9601) has been reported to have anti-oxidative and anti-inflammatory activities. In this report, we investigated the effect of DA-9601 on the immediate-type allergic reaction and studied its possible mechanisms of action, focusing on the mast cell-mediated allergic reaction. DA-9601 inhibited compound 48/80-induced systemic anaphylactic reactions and serum histamine release in mice. DA-9601 decreased the IgE-mediated passive cutaneous anaphylaxis, the model of local allergic reaction in vivo. DA-9601 dose-dependently reduced histamine release from mast cells activated by compound 48/80 or IgE. Furthermore, DA-9601 decreased the gene expression and production of tumor necrosis factor (TNF)-α in phorbol 12-myristate 13-acetate plus A23187-stimulated mast cells. These findings provide evidence that DA-9601 could be a candidate as an anti-allergic agent.

Background Biyeom-Tang, a medicine prescribed by oriental clinics, has been used for the treatment of the allergic rhinitis (AR). In the present study, an ethanol extract of Biyeom-Tang (EBT) was investigated for anti-allergic properties on bone-marrow derived mast cells (BMMC) and in vivo models. Methods The anti-allergic properties of EBT were evaluated by measuring β-Hex release and the production of prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) on BMMC in vitro and PCA and OVA-induced AR models in vivo. Results EBT strongly inhibited a degranulation reaction in a dose dependent manner with an IC50 value of 35.6 μg/ml. In addition, the generation of PGD2 and LTC4 was inhibited in BMMC in a concentration-dependent manner with IC50 values of 7.0 μg/ml and 10.9 μg/ml, respectively. When administrated orally, EBT ameliorated the mast cell-mediated PCA reaction. In the OVA-induced AR model, the increased levels of IgE were reduced by EBT. The levels of cytokines, such as IL-4, IL-5, IL-10, and IL-13 decreased in the splenocytes of EBT-treated mice. The histological analysis shows that the infiltration of inflammatory cells increased by OVA-sensitization was also reduced. Conclusions Taken together, these results suggested that EBT has anti-allergic and anti-inflammatory effects in vitro and in vivo models.

Objectives: To investigate the expression of messenger RNA (mRNA) of the gene for pigment epithelium– derived factor (PEDF) (OMIM*172860) and PEDF protein and to localize the PEDF protein in the nasal mucosa of patients with allergic rhinitis and of control subjects. Design: Investigation of PEDF mRNA and PEDF protein expression in the nasal mucosa using reverse transcription–polymerase chain reaction, Western blotting, and immunohistochemical staining. Participants: We used inferior turbinate mucosal samples from 10 patients with allergic rhinitis and 10 matched healthy control subjects. Interventions: We extractedPEDF mRNA from the inferior turbinate mucosa samples and performed reverse transcription–polymerase chain reaction analysis. We used Western blotting to analyze differences in expression levels of PEDF protein between patients with allergic rhinitis and healthy controls, and the PEDF protein was localized immunohistochemically. Results: The expression levels ofPEDF mRNA and PEDF protein in the nasal mucosa were significantly increased in patients with allergic rhinitis compared with those in nonallergic controls. The PEDF protein was expressed in the epithelium and submucosal glands. Conclusions: We found that PEDF protein is expressed in the human nasal mucosa, and its expression is increased in allergic rhinitis. These results suggest a possible contribution of PEDF to the chronic inflammation of the nasal mucosa in allergic rhinitis. ArchOtolaryngolHeadNeckSurg.2008;134(10):1094-1098

Background: The ethanol extract of KOTMIN13, composed of Inula japonica Flowers, Trichosanthes kirilowii Semen, Peucedanum praeruptorum Radix, and Allium macrostemon Bulbs, was investigated for its anti-asthmatic and anti-allergic activities. Methods: The anti-asthmatic effects of KOTMIN13 were evaluated on ovalbumin (OVA)-induced murine asthma model. Anti-allergic properties of KOTMIN13 in bone-marrow derived mast cells (BMMC) and passive cutaneous anaphylaxis (PCA) in vivo were also examined. Results: In asthma model, KOTMIN13 effectively suppressed airway hyperresponsiveness induced by aerosolized methacholine when compared to the levels of OVA-induced mice. KOTMIN13 treatment reduced the total leukocytes, eosinophil percentage, and Th2 cytokines in the bronchoalveolar lavage fluids in OVA-induced mice. The increased levels of eotaxin and Th2 cytokines in the lung as well as serum IgE were decreased by KOTMIN13. The histological analysis shows that the increased inflammatory cell infiltration and mucus secretion were also reduced. In addition, the degranulation and leukotriene C-4 production were inhibited in BMMC with IC50 values of 3.9 mu g/ml and 1.7 mu g/ml, respectively. Furthermore, KOTMIN13 treatment attenuated mast-mediated PCA reaction. Conclusions: These results demonstrate that KOTMIN13 has anti-asthmatic and anti-allergic effects in vivo and in vitro models.