• Korean Journal of Plant Resources
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• v.25 no.6
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• pp.682-692
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• 2012

Sea Buckthorn (Hippophae rhamnoides L.) has been used in traditional medicine for the treatment of cough, indigestion, circulatory problems and pain. The associated anti-inflammatory effect of this agent is achieved via the inhibition of Nf-${\kappa}B$ signaling, a property that has been demonstrated to effectively control the symptoms of various skin disorders, including atopic dermatitis. Accordingly, the purpose of this study was to assess the efficacy of Sea Buckthorn in reducing the production of lipopolysaccharide (LPS) activated nitric oxide (NO) by inhibiting the Nf-${\kappa}B$ pathway, as measured by the symptoms of atopic dermatitis (AD) occurring secondarily to inflammation and immune dysregulation. Our data demonstrate that Sea Buckthorn significantly decreased the LPS-induced production of NO (p<0.001). Atopic dermatitis was induced by repeated application of 2,4-dinitrochlorobenzene to the dorsal skin of mice. Topical application of 5% Sea Buckthorn extract improved the symptoms of AD, specifically reducing disease severity scores, scratching behaviors and epidermal thickness. When compared to the control group, animals treated with Sea Buckthorn exhibited increased serum IL-12 levels and decreased serum TNF-${\alpha}$, IL-4 and IL-5 levels. Such a modulation of biphasic T-helper (Th)1/Th2 cytokines may result in a reduction in serum IgE levels. Our findings suggest that mechanism of action of Sea Buckthorn in the treatment of AD is associated with a marked anti-inflammatory effect as well as an inhibition of Th2-mediated IgE overproduction via the modulation of biphasic Th1/Th2 cytokines. Such results suggest that topical Sea Buckthorn extract may prove to be a novel therapy for AD symptoms with few side effects.

• Journal of Nutrition and Health
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• v.51 no.3
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• pp.208-214
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• 2018

Purpose: Platycodon grandiflorum (a domestic diploid variety, DV-PG) has been used as a food and component of various traditional oriental medicines. Although DV-PG is known to have an anti-allergic effect, little is known about the beneficial health effects of the tetraploid 'Etteum' variety in the Platycodon grandiflorum (TV-PG), which is a recently developed variety. In this study, we investigated the effect of TV-PG on the rat basophilic leukemia mast cell (RBL-2H3)-mediated allergic response. Methods: To examine the effects of TV-PG on the allergic response, RBL-2H3 cells were sensitized with dinitropheny (DNP)-immunoglobin E, treated with various concentrations of TV-PG, and challenged with DNP-human serum albumin. We estimated cell granulation by measuring the release of ${\beta}$-hexosaminidase and production of inflammatory mediators by ELISA. Results: TV-PG had no effect on the proliferation or cytotoxicity of RBL-2H3 cells within the concentration range of 0 to $200{\mu}g/mL$. TV-PG inhibited degranulation of RBL-2H3 cells by antigen stimulation in a dose-dependent manner. TV-PG also suppressed the production of inflammatory cytokines and mediators such as interleukin-4, tumor necrosis $factor-{\alpha}$, prostagladin E2, and leukotriene B4 in RBL-2H3 cells by antigen stimulation. Conclusion: These results indicate that TV-PG exhibits anti-allergic activity via inhibition of degranulation as well as suppression of inflammatory mediators and cytokine release. These findings suggest that TV-PG may have potential as a preventive and therapeutic agent for the treatment of various allergic diseases.

• Biomolecules & Therapeutics
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• v.19 no.4
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• pp.431-437
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• 2011

Aberrant activation of microglia has been reported to cause neuronal damages by releasing a variety of pro-inflammatory cytokines. Besides where microglia become active, damages have been also observed in remote places, which is considered due to the migration of activated microglia. Therefore, an agent that could suppress abnormal activation of microglia and their subsequent migration might be valuable in activated microglia-related brain pathologies. The objective of the present study was to evaluate anti-inflammatory effects of betulinic acid on lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Pretreatment of betulinic acid significantly attenuated LPS-induced NO production and protein expression of iNOS. Betulinic acid also significantly suppressed LPS-induced release and expression of cytokines such as TNF-${\alpha}$ and IL-$1{\beta}$. Furthermore, betulinic acid significantly uppressed LPS-induced MMP-9 expression, which has been suggested to play an important role in the migration of activated microglia. In order to understand the possible mechanism by which betulinic acid suppresses LPS-induced cytokine production and migration of microglia, the role of NF-kB, a major pro-inflammatory transcription factor, was examined. Betulinic acid significantly suppressed LPS-induced degradation of IKB, which retains NF-kB in the cytoplasm. Therefore, nuclear translocation of NF-kB upon LPS stimulation was significantly suppressed with betulinic acid. Taken together, the present study for the first time demonstrates that betulinic acid possesses anti-inflammatory activity through the suppression of nuclear translocation of NF-kB in BV2 microglial cells.

• Biomolecules & Therapeutics
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• v.28 no.5
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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.

• Journal of Physiology & Pathology in Korean Medicine
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• v.19 no.2
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• pp.481-489
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• 2005

Lonicerae Flos has antibacterial effects against Staphylococcus aureus, streptococci, pneumococci, Bacillus dysenterii, Salmonella typhi, and paratyphoid. It is an antiviral agent. The herb has a cytoprotective effect against $CCl_{4}-induced$ hepatic injury. It has antilipemic action, interfering with lipid absorption from the gut. Nowadays this herb is used mainly in the treatment of upper respiratory infections, such as tonsillitis and acute laryngitis. It is also used in the treatment of skin suppurations, such as carbuncles, and to treat viral conjunctivitis, influenza, pneumonia, and mastitis. Lonicerae Flos is dried flower buds of Lonicera japonica, L. hypoglauca, L. confusa, or L. dasystyla. But, for the most part, we use whole plant of Lonicera japonica, as a flower bud of it. And, little is known of the original copy of effects of whole plant, except for the 'Bon-Cho-Gang-Mok', which is written the effects of flower of Lonicera japonica are equal to effects of leaves and branch of it. The present study was conducted to evaluate the effect of flower and whole plant of Lonicera japonica on the regulatory mechanism of cytokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) for the immunological activities in Raw 264.7 cells. In Raw 264.7 cells stimulated with lipopolysaccharide (LPS) to mimic inflammation, flower and whole plant of Lonicera japonica water extracts inhibited nitric oxide production in a dose-dependent manner and abrogated iNOS and COX-2. Flower and whole plant of Lonicera japonica water extract did not affect on cell viability. To investigate the mechanism by which flower and whole plant of Lonicera japonica water extract inhibits iNOS and COX-2 gene expression, we examined the on phosphorylation of inhibitor ${\kappa}B{\alpha}$ and assessed production of $TNF-{\alpha}$, $interleukin-1{\beta}$ $(IL-1{\beta})$ and interleukin-6 (IL-6). Results provided evidence that flower and whole plant of Lonicera japonica inhibited the production of $IL-1{\beta}$, IL-6 and activated the phosphorylation of inhibitor ${\kappa}B{\alpha}$ in Raw 264.7 cells activated with LPS. These findings suggest that flower and whole plant of Lonicera japonica can produce anti-inflammatory effect, which may play a role in adjunctive therapy in Gram-negative bacterial infections, respectively.

• Microbiology and Biotechnology Letters
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• v.45 no.2
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• pp.110-117
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• 2017

The anti-inflammatory effect of Sargassum patens C. Agardh ethanol extract (SPEE) was examined based on the lipopolysaccharide (LPS)-induced inflammatory response in this study. SPEE treatment was not cytotoxic to macrophages compared to the control. The production of NO was suppressed by SPEE by approximately 28% at $100{\mu}g/ml$, and levels of interleukin-6, tumor necrosis $factor-{\alpha}$, and $interleukin-1{\beta}$ decreased in a dose-dependent manner. In addition, the expression of inducible nitric oxide synthase, cyclooxygenase-2, and nuclear $factor-{\kappa}B$ was suppressed by SPEE treatment. In vivo, croton oil-induced mouse ear edema was attenuated by SPEE and the infiltration of mast cells into the tissue decreased. Based on these results, SPEE inhibits the release of LPS-induced pro-inflammatory cytokines and mediators, suggesting that SPEE is a potential agent for anti-inflammatory therapies.

• Proceedings of the Plant Resources Society of Korea Conference
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• 2018.04a
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• pp.13-13
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• 2018

The anti-inflammatory (INF) compounds (1-15) were isolated from Agrimonia pilosa Ledeb. (APL) by activity-guided isolation technique. The isolated compounds (1-15) were identified as quercetin-7-O-rhanmoside (1), apigenin-7-O-glycoside (2), kaempferol-7-O-glycoside (3), apigenin-7-O-[6"-(butyl)-glycoside] (4), querceitn (5), kaempferol (6), apigenin (7), apigenin-7-O-[6"-(pentyl)-glycoside] (8), agrimonolide (9), agrimonolide-6-O-glucoside (10), desmethylagrimonolide (11), desmethylagrimonolide-6-O-glucoside (12), luteolin (13), vitexin (14) and isovitexin (15). Flavonoids, compound 2, 3, 11, and 14-15 have been found in APL for the first time. Furthermore, two novel flavone derivatives, compound 4 and 8, have been isolated inceptively in plant. In the no cytotoxicity concentration ranges of $0-20{\mu}M$, nitric oxide (NO) production level of 1-15 was estimated in LPS-treated Raw 264.7 macrophage cells. The flavone aglycones, 7 (apigenin, $IC_{50}=3.69{\pm}0.34{\mu}M$), 13 (luteolin, $IC_{50}=4.62{\pm}0.43{\mu}M$), 6 (kaempferol, $IC_{50}=14.43{\pm}0.23{\mu}M$) and 5 (quercetin, $IC_{50}=19.50{\pm}1.71{\mu}M$), exhibited excellent NO inhibitory (NOI) activity in dose-dependent manner. In the structure activity relationship (SAR) study of apigenin-derivatives (APD), apigenin; Api, apigenin-7-O-glucoside; Api-G, apignenin-7-O-[6"-(butyl)-glycoside]; Api-BG and apignenin-7-O-[6"-(pentyl)-glycoside]; Api-P, from APL on INF activity was investigated. The INF mediators level such as NO, INF-cytokines, NF-KB proteins, iNOS and COX-2 were sharply increased in Raw 264.7 cells by LPS. When pretreatment with APD in INF induced macrophages, NOI activity of Api was most effective than other APD with $IC_{50}$ values of $3.69{\pm}0.77{\mu}M$. And the NOI activity was declined in the following order: Api-BG ($IC_{50}=8.91{\pm}1.18{\mu}M$), Api-PG ($IC_{50}=13.52{\pm}0.85{\mu}M$) and API-G ($IC_{50}=17.30{\pm}0.66{\mu}M$). The NOI activity of two novel compounds, Api-PG and Api-BG were lower than their aglycone; Api, but more effective than Api-G (NOI: Api-PG and Api-BG). And their suppression ability on INF cytokines such as $TNF-{\alpha}$, $IL-1{\beta}$ and IL-6 mRNA showed the similar tendency. Therefore, the anti-INF mechanism study of Api-PG and Api-BG on nuclear factor-kappa B ($NF-{\kappa}B$) pathway, representative INF mechanism, was investigated and Api was used as positive control. Api-BF was more effectively prevent the than phosphorylation of $pI{\kappa}B$ kinase (p-IKK) and p65 than Api-PG in Raw 264.7 cells. In contrast, Api-PG and Api-BG were not reduced the phosphorylation of inhibitor of kappa B alpha ($I{\kappa}B{\alpha}$). Moreover, pretreatment with Api-PG and Api-BG, dose-dependently inhibited LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNAs and proteins in macrophage cells, and their expression were correlated with their NOI activity. Therefore, APL can be utilized to health promote agent associated with their AIN metabolites.

• Journal of Nutrition and Health
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• v.51 no.6
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• pp.498-506
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• 2018

Purpose: Lycopene, a carotenoid with anti-oxidant properties, occurs naturally in tomatoes and pink grapefruit. Although the beneficial effects of lycopene on various disorders have been established, little attention has been paid to the possible anti-diabetic effects of lycopene focusing on ${\beta}$-cells. Therefore, this study investigated the potential of lycopene to protect ${\beta}$-cells against apoptosis induced by a cytokine mixture. Methods: For toxicity experiments, the cells were treated with 0.1 ~ 10 nM of lycopene, and the cell viability in INS-1 cells (a rat ${\beta}$-cell line) was measured using a MTT assay. To induce cytokine toxicity, the cells were treated with a cytokine mixture (20 ng/mL of $TNF{\alpha}$ + 20 ng/mL of IL-$1{\beta}$) for 24 h, and the effects of lycopene (0.1 nM) on the cytokine toxicity were measured using the MTT assay. The expression levels of the apoptotic proteins were analyzed by Western blotting, and the level of intracellular reactive oxidative stress (ROS) was monitored using a DCFDA fluorescent probe. The intracellular ATP levels were determined using a luminescence kit, and mRNA expression of the genes coding for anti-oxidative stress response and mitochondrial function were analyzed by quantitative reverse-transcriptase PCR. Results: Exposure of INS-1 cells to 0.1 nM of lycopene increased the cell viability significantly, and protected the cells from cytokine-induced death. Lycopene upregulated the mRNA and protein expression of B-cell lymphoma-2 (Bcl-2) and reduced the expression of the Bcl-2 associated X (Bax) protein. Lycopene inhibited apoptotic signaling via a reduction of the ROS, and this effect correlated with the upregulation of anti-oxidative stress response genes, such as GCLC, NQO1, and HO-1. Lycopene increased the mRNA expression of mitochondrial function-related genes and increased the cellular ATP level. Conclusion: These results suggest that lycopene reduces the level of oxidative stress and improves the mitochondrial function, contributing to the prevention of cytokine-induced ${\beta}$-cell apoptosis. Therefore, lycopene could potentially serve as a preventive and therapeutic agent for the treatment of type 2 diabetes.

• Journal of Physiology & Pathology in Korean Medicine
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• v.21 no.1
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• pp.39-49
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• 2007

Rheumatoid arthritis is an autoimmune disease involving multiple joint. In order to access the suppressive effects of JTT on rheumatoid arthritis and it's effects on immune system we investigated whether JTT could suppress the disease progression of collagen-induced arthritis. DBA/1 mice were immunized with bovine type II collagen. After a second collagen immunization, mice were treated with DW, JTT (200 or 400 mg/kg) or methotrexate (MTX, 30 mg/kg) as a positive control. Oral administration of JTT significantly suppressed the progression of CIA, which extend is comparable to that of MTX. Histological examination reveled that JTT inhibited infiltration of inflammatory cells into affected paw joint and bone erosion and cartilage destruction were greatly reduced compared with control. Total cell number of spleen, lymph node and peripheral blood were significantly reduced. The absolute number of CD19$^+$, CD3$^+$/CD69$^+$, CD4$^+$/CD25$^+$ cell in spleen from JTT treated mice were significantly decreased. The absolute number of CD19$^+$, CD3$^+$, CD3$^+$/CD69$^+$, CD4$^+$, CD4$^+$/CD25$^+$ CD8$^+$, CD49b, CD3/CD49b cells in draining lymph node were significantly increased compared with control. In peripheral blood mononuclear cells of JTT treated mice, the absolute number of CD4$^+$, CD4$^+$/CD25$^+$, CD3$^+$/CD69$^+$ cells were significantly decreased compared with control, while that of CD49b$^+$ was slightly increased. Infiltration of CD3$^+$ cells and CD11b$^+$/Gr-1$^+$ cells into paw joint was significantly reduced in JTT treated mice. The levels of pathologic cytokines including TNF-a and IL-6 in serum were significantly decreased by oral treatment with JTT The levels of IFN-g in the culture supernatant of splenocyte stimulated with CD3$^+$/CD28$^+$ or collagen were dramatically decreased, while the levels of IL-4 was increased under CD3$^+$/CD28$^+$ or collagen stimulation. Rheumatoid factors including IgG, IgM and collagen specific antibody were present much lower in the serum of JTT treated mice than control. Taken together, JTT has suppressive effects on rheumatoid arthritis by modulating immune system, and has potential to use anti-rheumatic arthritic agent in human.

• BMB Reports
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• v.49 no.5
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• pp.297-302
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• 2016

Loss of pancreatic β-cells by oxidative stress or cytokines is associated with diabetes mellitus (DM). DJ-1 is known to as a multifunctional protein, which plays an important role in cell survival. We prepared cell permeable wild type (WT) and mutant type (M26I) Tat-DJ-1 proteins to investigate the effects of DJ-1 against combined cytokines (IL-1β, IFN-γ and TNF-α)-induced RINm5F cell death. Both Tat-DJ-1 proteins were transduced into RINm5F cells. WT Tat-DJ-1 proteins significantly protected against cell death from cytokines by reducing intracellular toxicities. Also, WT Tat-DJ-1 proteins markedly regulated cytokines-induced pro- and anti-apoptosis proteins. However, M26I Tat-DJ-1 protein showed relatively low protective effects, as compared to WT Tat-DJ-1 protein. Our experiments demonstrated that WT Tat-DJ-1 protein protects against cytokine-induced RINm5F cell death by suppressing intracellular toxicities and regulating apoptosisrelated protein expression. Thus, WT Tat-DJ-1 protein could potentially serve as a therapeutic agent for DM and cytokine related diseases.