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ABSTRACT: Naturally occurring phenolic compounds, such as chavicol analogues, have been shown to have potent antioxidant and anti-inflammatory activities. We have previously isolated two chavicol acetate analogues, acetoxychavicol acetate (ACA) and hydroxychavicol acetate (HCA) from the rhizomes of Alpinia galanga. Although the function of ACA has been studied in many systems, the function of HCA has yet to be systemically examined. In this study, we have comparably examined the functions of ACA and HCA on the cytokine production in Th cells. ACA exhibited potent antioxidant activity and increased cell apoptosis; therefore, cytokine production by Th cells was diminished. Although HCA had neither antioxidant activity nor pro-apoptotic function, it was shown to increase IL-2 production and attenuate IFNgamma expression in Th cells. In addition, we demonstrated that HCA suppressed T-bet expression, which is responsible for IL-2 suppression and IFNgamma induction in Th cells and inhibited T-bet-mediated Th1 cell differentiation. Therefore, we suggest that HCA may be beneficial as therapeutics for treating inflammatory immune disorders caused by extravagant activation of Th1-mediated immune responses.
International immunopharmacology 03/2009; 9(4):448-54. · 2.21 Impact Factor
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ABSTRACT: Extracellular translationally controlled tumor protein (TCTP) is known to play a role in human allergic responses. TCTP has been identified outside of macrophages, in activated mononuclear cells, and in biological fluids from allergic patients. Even TCTP devoid of signal sequences, is secreted to extracellular environment by an yet undefined mechanism. This study is aimed at understanding the mechanism of TCTP release and its regulation. A secondary goal is to see if inhibitors of TCTP release can serve as potential anti-allergic asthmatic drugs.
Using Western blotting assay in HEK293 and U937 cells, we found that TCTP secretion is reduced by omeprazole and pantoprazole, both of which are proton pump inhibitors. We then transfected HEK293 cells with proton pump expression vectors to search for the effects of exogeneously overexpressed H(+)/K(+)-ATPase on the TCTP secretion. Based on these in vitro data we checked the in vivo effects of pantoprazole in a murine model of ovalbumin-induced allergy. Omeprazole and pantoprazole reduced TCTP secretion from HEK293 and U937 cells in a concentration-dependent fashion and the secretion of TCTP from HEK293 cells increased when they over-expressed H(+)/K(+)-ATPase. In a murine model of ovalbumin-induced allergy, pretreatment with pantoprazole reduced infiltration of inflammatory cells, increased goblet cells, and increased TCTP secretion induced by OVA challenge.
Since Omeprazole and pantoprazole decrease the secretion of TCTP which is associated with the development of allergic reaction, they may have the potential to serve as anti-allergic (asthmatic) drugs.
PLoS ONE 02/2009; 4(6):e5732. · 4.09 Impact Factor
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ABSTRACT: Translationally Controlled Tumor Protein (TCTP) found in nasal lavage fluids of allergic patients was named IgE-dependent histamine-releasing factor (HRF). Human recombinant HRF (HrHRF) has been recently reported to be much less effective than HRF produced from activated mononuclear cells (HRFmn).
We found that only NH(2)-terminal truncated, but not C-terminal truncated, TCTP shows cytokine releasing activity compared to full-length TCTP. Interestingly, only NH(2)-terminal truncated TCTP, unlike full-length TCTP, forms dimers through intermolecular disulfide bonds. We tested the activity of dimerized full-length TCTP generated by fusing it to rabbit Fc region. The untruncated-full length protein (Fc-HrTCTP) was more active than HrTCTP in BEAS-2B cells, suggesting that dimerization of TCTP, rather than truncation, is essential for the activation of TCTP in allergic responses. We used confocal microscopy to evaluate the affinity of TCTPs to its putative receptor. We detected stronger fluorescence in the plasma membrane of BEAS-2B cells incubated with Del-N11TCTP than those incubated with rat recombinant TCTP (RrTCTP). Allergenic activity of Del-N11TCTP prompted us to see whether the NH(2)-terminal truncated TCTP can induce allergic airway inflammation in vivo. While RrTCTP had no influence on airway inflammation, Del-N11TCTP increased goblet cell hyperplasia in both lung and rhinal cavity. The dimerized protein was found in sera from allergic patients, and bronchoalveolar lavage fluids from airway inflamed mice.
Dimerization of TCTP seems to be essential for its cytokine-like activity. Our study has potential to enhance the understanding of pathogenesis of allergic disease and provide a target for allergic drug development.
PLoS ONE 02/2009; 4(7):e6464. · 4.09 Impact Factor
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ABSTRACT: A T(H)1-specific transcription factor, T-box-containing protein expressed in T cells (T-bet), controls the production of both T(H)1 and T(H)2 cytokines in T(H) cell differentiation by means of distinct mechanisms. T-bet-deficient mice overproduce T(H)2 cytokines and have spontaneous airway inflammation.
We tested whether T-bet overexpression could protect against the development or progression of asthma.
We generated a T cell-specific and inducible line of T-bet-transgenic mice on a T-bet-deficient genetic background and used it to study the function of T-bet in an ovalbumin (OVA)-induced asthma model.
Induction of T-bet in a T cell-specific manner in an OVA model of asthma concomitant with OVA injection prevented airway hyperresponsiveness, eosinophilic and lymphocytic inflammation, and IL-5 and IL-13 production in bronchoalveolar lavage fluid and also reduced serum IgE and T(H)2 cytokine production by peripheral T cells. Even when T-bet expression was induced during later stages of asthma progression, T-bet overexpression still attenuated airway hyperresponsiveness and goblet cell hyperplasia, as well as T(H)2 cytokine production.
Our results suggest that T-bet expression in T cells can prevent the initiation of airway inflammation and progression of chronic inflammation and might be extrapolated to human asthma.
The Journal of allergy and clinical immunology 01/2009; 123(2):479-85. · 9.17 Impact Factor
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ABSTRACT: Quercetin is a popular flavonoid compound that is biosynthesized by plants; it is suggested to modulate a variety of inflammatory responses of macrophages and T lymphocytes. Oral administration of quercetin in arthritic rats dramatically diminishes clinical signs of arthritis. Moreover, quercetin ameliorates experimental autoimmune encephalomyelitis, which is associated with Th1-mediated immune responses. Like quercetin inhibits macrophage-induced cytokine production, it also blocks IL-12-dependent JAK-STAT signaling in Th cells. Despite the anti-inflammatory effects of quercetin acting through Th cells, the regulatory mechanisms remain unclear. Here, we studied the function of quercetin in Th cells and found that quercetin suppressed both IFNgamma and IL-2 production upon T cell receptor stimulation. Furthermore, we uncovered the regulatory mechanisms of quercetin involved in the inhibition of cytokine production during Th cell activation. The fact that quercetin-derived IFNgamma suppression was blocked in T-bet-deficient Th cells demonstrated quercetin act through the modulation of T-bet expression. Whereas IL-2 inhibition by quercetin was independent of T-bet expression, quercetin diminished IL-2R alpha expression, which is critical for positive regulatory loop of IL-2 autoactivation. Taken together, quercetin is suggested to repress both IFNgamma and IL-2 cytokine production by independent mechanisms; T-bet-dependent IFNgamma suppression and IL-2R alpha-dependent IL-2 inhibition.
Biochemical pharmacology 08/2008; 76(1):70-8. · 4.25 Impact Factor
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ABSTRACT: To evaluate the necessity of preserving the posterior branch of the great auricular nerve during parotidectomy.
Forty-six patients undergoing parotidectomy were prospectively analyzed. Twenty-four patients had preservation of the posterior branch of the great auricular nerve; in the remaining 22 patients the nerve was sacrificed. A sensory index score was defined as the area involved multiplied by the intensity grade of sensory loss. Quality-of-life was evaluated with a questionnaire.
The sensory index score was significantly higher in the sacrificed group as compared with the preserved group at both 1 week (41.87 vs 62.11) and 1 month (24.91 vs 46.11) after parotidectomy. The sensory deficit improved over time in both groups, and after 12 months only minimal sensory loss remained. Quality-of-life was not significantly different between the groups.
Irrespective of preservation of the posterior branch of the great auricular nerve, sensory deficit improved over time. Therefore, preservation of the posterior branch of the great auricular nerve might not be necessary during parotidectomy.
Otolaryngology Head and Neck Surgery 11/2007; 137(4):636-41. · 1.72 Impact Factor
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ABSTRACT: The RUNX3 gene is regarded as a tumor suppressor gene in many human solid tumors, and its inactivation is believed to be related with solid tumor carcinogenesis. As little information is available about the role of the RUNX3 gene in breast cancer, we investigated the relationship between the RUNX3 gene and breast cancer. We performed reverse transcriptase-polymerases chain reaction (RT-PCR), methylation specific PCR, and bicolor fluorescent in situ hybridization analysis in an effort to reveal related mechanisms. Forty breast tissue samples and 13 cell lines were used in this study. Eighty-five percent of breast cancer tissues showed downregulated RUNX3 gene expression, whereas it was downregulated in only 25% of normal breast tissues by RT-PCR assay. Sixty-seven percent of breast cancer cell lines showed downregulated RUNX3 expression, but the RUNX3 gene was not expressed in two normal breast cell lines. Hypermethylation was observed in 53% of breast cancer tissues and 57% of breast cancer cell lines. Hemizygous deletion was observed in 43% of breast cancer cell lines. Hypermethylation and/or hemizygous deletion was observed in 5 of 7 breast cancer cell lines, and the four of these five examined showed no RUNX3 gene expression. We suggest that various mechanisms, including methylation and hemizygous deletion, could contribute to RUNX3 gene inactivation.
Journal of Korean Medical Science 10/2007; 22 Suppl:S24-31. · 0.99 Impact Factor
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ABSTRACT: Immunoglobulin heavy chain (IgH) gene rearrangement, which is frequently observed in multiple myeloma, can now be detected easily by using a fluorescence in situ hybridization (FISH) method. The aim of this study was to determine the detection rate and compare the utility of the three most commonly used probes: IGH/CCND1 dual color, dual fusion probe; IGH/BCL2 dual color, dual fusion probe; and IGH dual color break apart rearrangement probe; all from Vysis Products (Downers Grove, IL, USA).
From October 1994 to July 2003, 99 patients were diagnosed as multiple myeloma at Seoul National University Hospital, Asan Medical Center and Gachon University Gil hospital. We applied the three different probes of IgH FISH on bone marrow specimens from the 99 Korean patients with multiple myeloma to detect IgH gene rearrangement.
Forty-one (41.4%) of the 99 patients had IgH gene rearrangement. Of those 41 patients, 23 (56.1%) showed positive to all three probes, but the remaining 18 (43.9%) showed a discrepancy between the three probes: 13 (72.2%) of the 18 patients were only positive to the IGH dual color break apart rearrangement probe and the detection rate was 39.6% on the average.
These results demonstrate that IGH dual color break apart rearrangement probe is superior to the other two probes in qualitative and quantitative ways. Thus, we recommend IGH dual color break apart rearrangement probe for the diagnosis and monitoring of multiple myeloma.
The Korean Journal of Laboratory Medicine 11/2006; 26(5):317-22. · 0.63 Impact Factor
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ABSTRACT: To evaluate the findings of computed tomography (CT) and histopathology of the bulla ethmoidalis as objective markers of bone remodeling in chronic rhinosinusitis (CRS).
Preoperative ostiomeatal unit (OMU) scans and histopathologic findings of the bulla ethmoidalis were performed on 23 patients (39 sides) undergoing endoscopic sinus surgery for CRS. Lund-Mackay scores and Hounsfield units (HU) of the bulla were checked in coronal CT scans. The pathologist graded the severities of the mucosal and bony changes in histopathology. Statistical analysis was performed using Mann-Whitney U test and Spearman correlation coefficient (r).
The HU values of the bulla were significantly increased with higher Lund-Mackay scores in OMU CT (r = 0.405, P = 0.01). The bony grades in histopathology were significantly increased with higher mucosal grades (r = 0.821, P = 0.0001). These findings in CT scans and histopathology were well correlated with each other (r > 0.3, P < 0.05).
HU may be a useful objective marker of bone remodeling in chronic rhinosinusitis.
Otolaryngology Head and Neck Surgery 09/2006; 135(3):404-8. · 1.72 Impact Factor
