• Journal of Applied Biological Chemistry
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• 제66권
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• pp.455-461
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• 2023

Glycyrrhiza glabra is a well-known medicinal herb that grows in various parts of the world and glabridin is a major chemical compound that is found in the root extract of Glycyrrhiza glabra. Glabridin is a natural compound known to have antioxidant, anti-inflammatory, anti-atherogenic, anti-osteoporotic and skin-whitening. In this study, we investigated if glabridin inhibited platelet aggregation and thrombus formation. We observed that glabridin inhibited collagen-induced platelet aggregation and suppressed signal transduction molecules such as phosphatidylinositol-3 kinase (PI₃K), Akt, glycogen synthase kinase-3α/β (GSK-3α/β), SYK, cytosolic phospholipase A₂, and p38 expression. In addition, glabridin suppressed thromboxane A₂ generation and thrombin-induced clot retraction. Taken together, glabridin showed strong antiplatelet effects and may be used to block thrombosis- and platelet-mediated cardiovascular diseases.

• Biomolecules & Therapeutics
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• 제31권6호
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• pp.611-618
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• 2023

Rhizome of Alisma orientale has been used as a traditional medicine for treating kidney diseases in East Asian countries. Its inhibitory effects on hypersensitivity responses have been reported for methanol extracts, with alisol B 23-acetate (AB23Ac) being the most active constituent among six terpenes in inhibiting the direct passive Arthus reaction. However, whether AB23Ac has efficacy against allergic asthma has not been tested to date. The in vivo efficacy of AB23Ac in an ovalbumin (OVA)-induced allergic asthma mouse model was evaluated by administrating AB23Ac before OVA sensitization or OVA challenge in BALB/c mice. AB23Ac suppressed antigen-induced degranulation of RBL-2H3 mast cells in a concentration-dependent manner. The administration of AB23Ac both before OVA sensitization and OVA challenge greatly lowered pulmonary resistance and the increase in immune cell counts and inflammatory responses around the peribronchial and perivascular regions. In addition, the inflammatory cytokine levels of Th1/Th2/Th17 cells in the bronchoalveolar lavage fluid decreased in the AB23Ac-treated groups. AB23Ac reduced the number of PAS-stained cells in the lungs. Furthermore, a computer modeling study indicated that AB23Ac can bind tightly to spleen tyrosine kinase (Syk). These results suggest that AB23Ac may ameliorate allergic asthma by suppressing immune responses in dendritic cells during sensitization and in mast cells during challenge periods.

• Biomolecules & Therapeutics
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• 제24권6호
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• pp.595-603
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• 2016

(E)-3-Phenyl-1-(2-pyrrolyl)-2-propenone (PPP) is a pyrrole derivative of chalcone, in which the B-ring of chalcone linked to ${\beta}$-carbon is replaced by pyrrole group. While pyrrole has been studied for possible Src inhibition activity, chalcone, especially the substituents on the B-ring, has shown pharmaceutical, anti-inflammatory, and anti-oxidant properties via inhibition of NF-${\kappa}B$ activity. Our study is aimed to investigate whether this novel synthetic compound retains or enhances the pharmaceutically beneficial activities from the both structures. For this purpose, inflammatory responses of lipopolysaccharide (LPS)-treated RAW264.7 cells were analyzed. Nitric oxide (NO) production, inducible NO synthase (iNOS) and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) mRNA expression, and the intracellular inflammatory signaling cascade were measured. Interestingly, PPP strongly inhibited NO release in a dose-dependent manner. To further investigate this anti-inflammatory activity, we identified molecular pathways by immunoblot analyses of nuclear fractions and whole cell lysates prepared from LPS-stimulated RAW264.7 cells with or without PPP pretreatment. The nuclear levels of p50, c-Jun, and c-Fos were significantly inhibited when cells were exposed to PPP. Moreover, according to the luciferase reporter gene assay after cotransfection with either TRIF or MyD88 in HEK293 cells, NF-${\kappa}B$-mediated luciferase activity dose-dependently diminished. Additionally, it was confirmed that PPP dampens the upstream signaling cascade of NF-${\kappa}B$ and AP-1 activation. Thus, PPP inhibited Syk, Src, and TAK1 activities induced by LPS or induced by overexpression of these genes. Therefore, our results suggest that PPP displays anti-inflammatory activity via inhibition of Syk, Src, and TAK1 activity, which may be developed as a novel anti-inflammatory drug.

• Biomolecules & Therapeutics
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• 제28권5호
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• pp.456-464
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• 2020

Mast cells (MCs) are systemically distributed and secrete several allergic mediators such as histamine and leukotrienes to cause type I hypersensitivity. Dasatinib is a type of anti-cancer agent and it has also been reported to inhibit human basophils. However, dasatinib has not been reported for its inhibitory effects on MCs or type I hypersensitivity in mice. In this study, we examined the inhibitory effect of dasatinib on MCs and MC-mediated allergic response in vitro and in vivo. In vitro, dasatinib inhibited the degranulation of MCs by antigen stimulation in a dose-dependent manner (IC₅₀, ~34 nM for RBL-2H3 cells; ~52 nM for BMMCs) without any cytotoxicity. It also suppressed the secretion of inflammatory cytokines IL-4 and TNF-α by antigen stimulation. Furthermore, dasatinib inhibited MC-mediated passive cutaneous anaphylaxis (PCA) in mice (ED₅₀, ~29 mg/kg). Notably, dasatinib significantly suppressed the degranulation of MCs in the ear tissue. As the mechanism of its effect, dasatinib inhibited the activation of Syk and Syk-mediated downstream signaling proteins, LAT, PLCγ1, and three typical MAP kinases (Erk1/2, JNK, and p38), which are essential for the activation of MCs. Interestingly, in vitro tyrosine kinase assay, dasatinib directly inhibited the activities of Lyn and Fyn, the upstream tyrosine kinases of Syk in MCs. Taken together, dasatinib suppresses MCs and PCA in vitro and in vivo through the inhibition of Lyn and Fyn Src-family kinases. Therefore, we suggest the possibility of repositioning the anti-cancer drug dasatinib as a treatment for various MC-mediated type I hypersensitive diseases.

• The Korean Journal of Physiology and Pharmacology
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• 제21권3호
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• pp.345-352
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• 2017

Since previous studies have reported that hydroquinone (HQ) exerted immunosuppressive and anti-inflammatory activity, various HQ derivatives have been synthesized and their biological activities investigated. In this study, we explored the anti-inflammatory activity of JS-III-49, a novel HQ derivative, in macrophage-mediated inflammatory responses. JS-III-49 suppressed the production of the inflammatory mediators nitric oxide (NO) and prostaglandin $E_2$ ($PGE_2$) and down-regulated the mRNA expression of the inflammatory enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as the expression of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-$1{\beta}$ without cytotoxicity in LPS-stimulated RAW264.7 cells. JS-III-49 inhibited nuclear translocation of the $NF-{\kappa}B$ transcription factors p65 and p50 by directly targeting Akt, an upstream kinase of the $NF-{\kappa}B$ pathway, in LPS-stimulated RAW264.7 cells. However, JS-III-49 did not directly inhibit the kinase activities of Src and Syk, which are upstream kinases of Akt, in LPS-stimulated RAW264.7 cells. Moreover, JS-III-49 suppressed the nuclear translocation of c-Fos, one of the components of AP-1, by specifically targeting p38, an upstream mitogen-activated protein kinase (MAPK) in the AP-1 pathway in LPS-stimulated RAW264.7 cells. These results suggest that JS-III-49 plays an anti-inflammatory role in LPS-stimulated macrophages by targeting Akt and p38 in the $NF-{\kappa}B$ and AP-1 pathways, respectively.

• Biomolecules & Therapeutics
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• 제22권1호
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• pp.27-34
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• 2014

Curcumin is naturally occurring polyphenolic compound found in turmeric and has many pharmacological activities. The present study was undertaken to evaluate anti-allergic inflammatory activity of curcumin, and to investigate its inhibitory mechanisms in immunoglobulin E (IgE)/Ag-induced mouse bone marrow-derived mast cells (BMMCs) and in a mouse model of IgE/Ag-mediated passive systemic anaphylaxis (PSA). Curcumin inhibited cyclooxygenase-2 (COX-2) dependent prostaglandin $D_2$ ($PGD_2$) and 5-lipoxygenase (5-LO) dependent leukotriene $C_4$ ($LTC_4$) generation dose-dependently in BMMCs. To probe the mechanism involved, we assessed the effects of curcumin on the phosphorylation of Syk and its downstream signal molecules. Curcumin inhibited intracellular $Ca^{2+}$ influx via phospholipase $C{\gamma}1$ ($PLC{\gamma}1$) activation and the phosphorylation of mitogen-activated protein kinases (MAPKs) and the nuclear factor-${\kappa}B$ (NF-${\kappa}B$) pathway. Furthermore, the oral administration of curcumin significantly attenuated IgE/Ag-induced PSA, as determined by serum $LTC_4$, $PGD_2$, and histamine levels. Taken together, this study shows that curcumin offers a basis for drug development for the treatment of allergic inflammatory diseases.

• 대한한의학방제학회지
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• 제29권4호
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• pp.191-203
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• 2021

Objectives : In this study, we investigate the anti-allergic effects of Ullmus macrocarpa Hance (Ulmus) on RBL-2H3 mast cell (basophilic leukemia cell line), which are mediated by FcεRIs. Methods : We evaluated the effect of the ethanol extract of Ulmus on the allergic inflammatory response in IgE-antigen-mediated RBL-2H3 cells. Cell toxicity was determined by MTT assay and the markers of degranulation such as beta-hexosaminidase, histamine, PGD2, TNF-α, IL-4, IL-6 production of inflammatory mediators and FcεRI-mediated protein expression by western blot. Results : Ulmus inhibited degranulation and production of allergic mediators (e.g., TNF-α, IL-4, and IL-6) in them. Ulmus reduced histamine levels, expression of FcεRI signaling-related genes such as Lyn, Syk, and Fyn, and extracellular signal-regulated kinase phosphorylation in mast cells. Also, Ulmus reduced PGD2 release and cyclooxygenase-2 expression, and cytosolic phospholipase A2 phosphorylation in FcεRI-mediated RBL-2H3 mast cells. Conclusions : These results indicate that Ulmus exhibits anti-allergic activity through inhibition of degranulation and inflammatory mediators and cytokine release. These findings suggest that Ulmus may have potential as a prophylactic and therapeutic agent for the treatment of various allergic diseases.