• IMMUNE NETWORK
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• v.12 no.1
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• pp.27-32
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• 2012

Background: Toll-like receptors (TLRs) have been extensively studied in recent years. However, functions of these molecules in murine B cell biology are largely unknown. A TLR4 stimulant, LPS is well known as a powerful polyclonal activator for murine B cells. Methods: In this study, we explored the effect of a murine TLR9 stimulant, M6-395 (a synthetic CpG ODNs) on B cell proliferation and Ig production. Results: First, M6-395 was much more potent than LPS in augmenting B cell proliferation. As for Ig expression, M6-395 facilitated the expression of both TGF-${\beta}1$-induced germ line transcript ${\alpha}$ ($GLT{\alpha}$) and IL-4-induced $GLT{\gamma}1$ as levels as those by LPS and Pam3CSK4 (TLR1/2 agonist) : a certain Ig GLT expression is regarded as an indicative of the corresponding isotype switching recombination. However, IgA and IgG1 secretion patterns were quite different--these Ig isotype secretions by M6-395 were much less than those by LPS and Pam3CSK4. Moreover, the increase of IgA and IgG1 production by LPS and Pam3CSK4 was virtually abrogated by M6-395. The same was true for the secretion of IgG3. We found that this unexpected phenomena provoked by M6-395 is attributed, at least in part, to its excessive mitogenic nature. Conclusion: Taken together, these results suggest that M6-395 can act as a murine polyclonal activator but its strong mitogenic activity is unfavorable to Ig isotype switching.

• Journal of Physiology & Pathology in Korean Medicine
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• v.31 no.6
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• pp.313-327
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• 2017

The purpose of this study is to predict the effects of macroscopic and integrative therapies by finding active ingredients, potential targets of Astragalus membranaceus (Am) and Cornus officinalis (Co) for diabetic nephropathy. We have constructed network pharmacology-based systematic and network methodology by system biology, chemical structure, chemogenomics. We found several active ingredients of Astragalus membranaceus (Am) and Cornus officinalis (Co) that were speculated to bind to specific receptors which had been known to have a role in the progression of diabetic nephropathy. Four components of Am and eleven components of Co could bind to iNOS; two ingredients of Am and six ingredients of Co could docking to cGB-PDE; one component of Am and nine components of Co could bind to ACE; three ingredients of Co with neprilysin; three components of Co with ET-1 receptor; four ingredients of Am and fourteen ingredients of Co with mineralocorticoid receptor; one component of Am and seven components of Co with interstitial collagenase; one ingredient of Am and ten ingredients of Co with membrane primary amine oxidase; one component of Am and four components of Co with JAK2; two ingredients of Am and one ingredient of Co with MAPK 12; one component of Am and five components of Co could docking to TGF-beta receptor type-1. From this work we could speculate that the possible mechanisms of Am and Co for diabetic nephropathy are anti-inflammatory, antioxidant and antihypertensive effects.

• Parasites, Hosts and Diseases
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• v.53 no.4
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• pp.431-438
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• 2015

In Trichinella spiralis infection, type 2 helper T (Th2) cell-related and regulatory T ($T_{reg}$) cell-related immune responses are the most important immune events. In order to clarify which Toll-like receptors (TLRs) are closely associated with these responses, we analyzed the expression of mouse TLR genes in the small intestine and muscle tissue during T. spiralis infection. In addition, the expression of several chemokine- and cytokine-encoding genes, which are related to Th2 and $T_{reg}$ cell mediated immune responses, were analyzed in mouse embryonic fibroblasts (MEFs) isolated from myeloid differentiation factor 88 (MyD88)/TIR-associated proteins (TIRAP) and Toll receptor-associated activator of interferons (TRIF) adapter protein deficient and wild type (WT) mice. The results showed significantly increased TLR4 and TLR9 gene expression in the small intestine after 2 weeks of T. spiralis infection. In the muscle, TLR1, TLR2, TLR5, and TLR9 gene expression significantly increased after 4 weeks of infection. Only the expression of the TLR4 and TLR9 genes was significantly elevated in WT MEF cells after treatment with excretory-secretory (ES) proteins. Gene expression for Th2 chemokine genes were highly enhanced by ES proteins in WT MEF cells, while this elevation was slightly reduced in MyD88/$TIRAP^{-/-}$ MEF cells, and quite substantially decreased in $TRIF^{-/-}$ MEF cells. In contrast, IL-10 and $TGF-{\beta}$ expression levels were not elevated in MyD88/$TIRAP^{-/-}$ MEF cells. In conclusion, we suggest that TLR4 and TLR9 might be closely linked to Th2 cell and $T_{reg}$ cell mediated immune responses, although additional data are needed to convincingly prove this observation.

• Journal of Ginseng Research
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• v.36 no.4
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• pp.375-382
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• 2012

Ginsenoside Rp1 (G-Rp1) is a saponin derivate that provides anti-metastatic activities through inhibition of the NF-${\kappa}B$ pathway. In this study, we examined the effects of G-Rp1 on regulatory T cell (Treg) activation. After treatment of splenocytes with G-Rp1, Tregs exhibited upregulation of IL-10 expression, and along with dendritic cells (DCs), these Tregs showed increased cell number compared to other cell populations. The effect of G-Rp1 on Treg number was augmented in the presence of lipopolysaccharide (LPS), which mimics pathological changes that occur during inflammation. However, depletion of DCs prevented the increase in Treg number in the presence of G-Rp1 and/or LPS. In addition, G-Rp1 promoted the differentiation of the memory types of $CD4^+Foxp3^+CD62L^{low}$ Tregs rather than the generation of new Tregs. In vivo experiments also demonstrated that Tregs and DCs from mice that were fed G-Rp1 for 7 d and then injected with LPS exhibited increased activation compared with those from mice that were injected with LPS alone. Expression of TGF-${\beta}$ and CTLA4 in Tregs was increased, and upregulation of IL-2 and CD80/CD86 expression by DCs affected the suppressive function of Tregs through IL-2 receptors and CTLA4. These data demonstrate that G-Rp1 exerts anti-inflammatory effects by activating Tregs in vitro and in vivo.

• Biomolecules & Therapeutics
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• v.27 no.3
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• pp.318-326
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• 2019

Sphingosine 1-phosphate (S1P) levels are often found to be elevated in serum, bronchoalveolar lavage, and lung tissue of idiopathic pulmonary fibrosis patients and experimental mouse models. Although the roles of sphingosine kinase 1 and S1P receptors have been implicated in fibrosis, the underlying mechanism of fibrosis via Sphingosine 1-phosphate receptor 2 ($S1P_2$) has not been fully investigated. Therefore, in this study, the roles of $S1P_2$ in lung inflammation and fibrosis was investigated by means of a bleomycin-induced lung fibrosis model and lung epithelial cells. Bleomycin was found to induce lung inflammation on day 7 and fibrosis on day 28 of treatment. On the $7^{th}$ day after bleomycin administration, $S1P_2$ deficient mice exhibited significantly less pulmonary inflammation, including cell infiltration and pro-inflammatory cytokine induction, than the wild type mice. On the $28^{th}$ day after bleomycin treatment, severe inflammation and fibrosis were observed in lung tissues from wild type mice, while lung tissues from $S1P_2$ deficient mice showed less inflammation and fibrosis. Increase in TGF-${\beta}1$-induced extracellular matrix accumulation and epithelial-mesenchymal transition were inhibited by JTE-013, a $S1P_2$ antagonist, in A549 lung epithelial cells. Taken together, pro-inflammatory and pro-fibrotic functions of $S1P_2$ were elucidated using a bleomycin-induced fibrosis model. Notably, $S1P_2$ was found to mediate epithelial-mesenchymal transition in fibrotic responses. Therefore, the results of this study indicate that $S1P_2$ could be a promising therapeutic target for the treatment of pulmonary fibrosis.