Jin Kyeong Choi

Oleanolic acid acetate inhibits atopic dermatitis and allergic contact dermatitis in a murine model

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common allergic and inflammatory skin diseases caused by a combination of eczema, scratching, pruritus, and cutaneous sensitization with allergens. This paper examines whether oleanolic acid acetate (OAA) modulates AD and ACD symptoms by using an existing AD model based on the repeated local exposure of mite extract (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene to the ears of BALB/c mice. In addition, the paper uses a 2,4-dinitrofluorobenzene-sensitized local lymph node assay (LLNA) for the ACD model. The oral administration of OAA over a four-week period attenuated AD symptoms in terms of decreased skin lesions, epidermal thickness, the infiltration of immune cells (CD4⁺ cells, eosinophils, and mast cells), and serum IgE, IgG2a, and histamine levels. The gene expression of Th1, Th2, Th17, and Th22 cytokines was reduced by OAA in the lymph node and ear tissue, and the LLNA verified that OAA suppressed ACD. The oral administration of OAA over a three-day period attenuated ACD symptoms in terms of ear thickness, lymphocyte proliferation, and serum IgG2a levels. The gene expression of Th1, Th2, and Th17 cytokines was reduced by OAA in the thymus and ear tissue. Finally, to define the underlying mechanism, this paper uses a TNF-α/IFN-γ-activated human keratinocyte (HaCaT) model. OAA inhibited the expression of cytokines and chemokines through the downregulation of NF-κB and MAPKs in HaCaT cells. Taken together, the results indicate that OAA inhibited AD and ACD symptoms, suggesting that OAA may be effective in treating allergic skin disorders.

Inhibitory effect of galangin on atopic dermatitis-like skin lesions.

Galangin is a member of the flavonol class of flavonoids having anti-inflammatory and anti-oxidative potential. Previously we reported the inhibitory effect of galangin on the mast cell-mediated allergic inflammation. For incremental research, we investigated the effects of galangin on atopic dermatitis (AD)-like skin lesions and underlying mechanisms of action. We established an atopic dermatitis model in BALB/c mice by repeated local exposure of house dust mite (Dermatophagoides farinae) extract (DFE) and 2,4-dinitrochlorobenzene (DNCB) to the ears. Repeated alternative treatment of DFE/DNCB caused AD-like skin lesions. Topical application of galangin reduced AD symptoms based on ear thickness and histopathological analysis, in addition to serum IgE and IgG2a levels. Galangin inhibited mast cell infiltration into the ear and serum histamine level. Galangin suppressed DFE/DNCB-induced expression of interleukin (IL)-4, IL-5, IL-13, IL-31, IL-32, and interferon (IFN)-γ in the ear tissue. To define the underlying mechanisms of action, tumor necrosis factor-α/IFN-γ-activated human keratinocytes (HaCaT) model was used. Galangin significantly inhibited the expression of cytokines and chemokine by the down-regulation of nuclear factor-κB and mitogen-activated protein kinases in HaCaT cells. Taken together, the results demonstrate that galangin inhibited AD-like symptoms, suggesting that galangin might be a candidate for the treatment of AD.

Perfluorooctanoic acid induces mast cell-mediated allergic inflammation by the release of histamine and inflammatory mediators

Perfluorooctanoic acid (PFOA) has unique physical and chemical characteristics, water and oil repellency, thermal stability, and surfactant properties. PFOA has been regularly found in the blood of animals and humans worldwide, and has become an increasing concern because of its adverse effects in immune system. However, the role of PFOA in the allergic inflammation is not well-known. To further extend the immunotoxicity of PFOA, we examined the role of PFOA on the mast cell-mediated allergic inflammation and studied the possible mechanism of action. PFOA dose- and time-dependently increased histamine release from mast cells and serum histamine by the induction of intracellular calcium. PFOA exacerbated the IgE-dependent local allergic reaction in the mouse allergy model. PFOA induced gene expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 in mast cells. The inducing effect of PFOA on the pro-inflammatory cytokines was nuclear factor-κB, p38 mitogen-activated protein kinase, and caspase-1 dependent. Furthermore, the activation of cyclooxygenase-2 by PFOA suggests the induction of allergic inflammatory mediators by the PFOA. Our findings provide evidence that PFOA, the known immunotoxic agent, induces mast cell-derived allergic inflammatory reactions by histamine release and expression of pro-inflammatory cytokines.

Suppression of dust mite extract and 2,4-dinitrochlorobenzene-induced atopic dermatitis by the water extract of Lindera obtusiloba.

ETHNOPHARMACOLOGICAL RELEVANCE The Lindera obtusiloba has been used in traditional medicine for the treatment of inflammation and dermatitis. In this study, we investigated the effect of topical application of Lindera obtusiloba water extract (LOWE) on the house dust mite extract (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD). MATERIALS AND METHODS We established AD model in BALB/c mice by repeated local exposure of DFE/DNCB to the ears. After a topical application of LOWE on the skin lesions, the epidermal thickness, mast cell infiltration, and serum immunoglobulin E (IgE) and histamine were measured. In addition, the gene expression of interleukin (IL)-4, IL-13, IL-31, and tumor necrosis factor (TNF)-α in the ears was assayed. RESULTS LOWE reduced AD symptoms based on ear thickness, histopathological analysis, and serum IgE levels. LOWE inhibited mast cell infiltration into the ear and elevation of serum histamine in AD model. Moreover, LOWE suppressed DFE/DNCB-induced expression of IL-4, IL-13, IL-31, and TNF-α in the ears. CONCLUSIONS Our results showed that topical application of LOWE exerts beneficial effects in AD symptoms, suggesting that LOWE might be a candidate for the treatment of AD.

Rutin suppresses atopic dermatitis and allergic contact dermatitis

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) is a common allergic inflammatory skin disease caused by a combination of eczematous, scratching, pruritus and cutaneous sensitization with allergens. The aim of our study was to examine whether rutin, a predominant flavonoid having anti-inflammatory and antioxidative potential, modulates AD and ACD symptoms. We established an atopic dermatitis model in BALB/c mice by repeated local exposure of house dust mite (Dermatophagoides farinae) extract (DFE) and 2,4-dinitrochlorobenzene (DNCB) to the ears. In addition, 2,4-dinitroflourobenzene-sensitized a local lymph node assay was used for the ACD model. Repeated alternative treatment of DFE/DNCB caused AD symptoms. Topical application of rutin reduced AD based on ear thickness and histopathological analysis, in addition to serum IgE levels. Rutin inhibited mast cell infiltration into the ear and serum histamine level. Rutin suppressed DFE/DNCB-induced expression of interleukin (IL)-4, IL-5, IL-13, IL-31, IL-32 and interferon (INF)-γ in the tissue. In addition, rutin suppressed ACD based on ear thickness and lymphocyte proliferation, serum IgG2a levels, and expression of INF-γ, IL-4, IL-5, IL-10, IL-17 and tumour necrosis factor-α in ACD ears. This study demonstrates that rutin inhibits AD and ACD, suggesting that rutin might be a candidate for the treatment of allergic skin diseases.

Salvia plebeia extract inhibits the inflammatory response in human rheumatoid synovial fibroblasts and a murine model of arthritis

Salvia plebeia R. Br. has been used to treat a variety of inflammatory diseases and as an antioxidant in many countries, including Korea and China. In this study, we investigated the effects of S. plebeia extract (SPE) on inflammatory arthritis and the underlying mechanisms of action. We used a collagen-induced arthritis (CIA) mouse model. TNF-α-stimulated rheumatoid arthritis (RA) synovial fibroblasts were used to elucidate the underlying mechanisms of action. Oral administration of SPE improved the clinical arthritis score, footpad thickness, and histologic changes, as well as serum IgG1 and IgG2a levels. SPE administration inhibited Th1/Th2/Th17 phenotype CD4(+) T lymphocyte expansion in inguinal lymph node and expression of inflammatory mediators such as cytokines, MMP-1, and MMP-3 in the ankle joint tissue. SPE significantly suppressed the expression of cytokines and MMP-1 by down-regulating NF-κB, Akt, and mitogen-activated protein kinases in RA synovial fibroblasts. Taken together, these results indicate that SPE is therapeutically efficacious against chronic inflammatory arthritis, suggesting that SPE is a candidate for treating RA.

Effects of topical application of a recombinant staphylococcal enterotoxin A on DNCB and dust mite extract-induced atopic dermatitis-like lesions in a murine model

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease with biphasic T cell-mediated abnormalities. Staphylococcal superantigens contribute to the exacerbation of inflammation in AD. The underlying immunopathological mechanisms are not fully understood.ObjectiveTo determine whether epicutaneous application of recombinant staphylococcal enterotoxin A (rSEA) would exacerbate AD-like allergic inflammation induced by 2, 4-dinitrochlorobenzene (DNCB) and house dust mite extract (Dermatophagoides farinae extract, DFE) in a murine model.Materials and MethodsWe first established an AD-like model using BALB/c mice exposed to DNCB/DFE on the ear. Next, Staphylococcus (S.) aureus or rSEA were topically applied to the mice. We evaluated the clinical and histopathological features of the animals. Serum immunoglobulin levels were also measured. In addition, real-time PCR analysis of cytokines produced by T cell subsets in the earswas conducted.ResultsMice treated with S. aureus and rSEA had more severe clinical symptoms, including increased mean dermatitis scores and ear thickness, compared to animals with only AD-like lesions. Total IgE, IgG2a and serum histamine levels were increased in all groups except the normal control group. The S. Aureus- and rSEA-treated groups showed increased levels of cytokines such as IL-4, IL-13, INF-γ, IL-17, and IL-18. In particular, increased cytokine expressionwas more conspicuous in the rSEA-treated group than in mice exposed to S. aureus.ConclusionThe results of this study showed that topical exposure to rSEA as well as SEA-producing S. aureus aggravate atopic skin inflammation. This may be associated with the induction of a mixed Th1/Th2 type dermatitis.

Inhibitory effect of 1,2,4,5-tetramethoxybenzene on mast cell-mediated allergic inflammation through suppression of IκB kinase complex

As the importance of allergic disorders such as atopic dermatitis and allergic asthma, research on potential drug candidates becomes more necessary. Mast cells play an important role as initiators of allergic responses through the release of histamine; therefore, they should be the target of pharmaceutical development for the management of allergic inflammation. In our previous study, anti-allergic effect of extracts of Amomum xanthioides was demonstrated. To further investigate improved candidates, 1,2,4,5-tetramethoxybenzene (TMB) was isolated from methanol extracts of A. xanthioides. TMB dose-dependently attenuated the degranulation of mast cells without cytotoxicity by inhibiting calcium influx. TMB decreased the expression of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-4 at both the transcriptional and translational levels. Increased expression of these cytokines was caused by translocation of nuclear factor-κB into the nucleus, and it was hindered by suppressing activation of IκB kinase complex. To confirm the effect of TMB in vivo, the ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA model, hypothermia was decreased by oral administration of TMB, which attenuated serum histamine, OVA-specific IgE, and IL-4 levels. Increased pigmentation of Evans blue was reduced by TMB in a dose-dependent manner in the PCA model. Our results suggest that TMB is a possible therapeutic candidate for allergic inflammatory diseases that acts through the inhibition of mast cell degranulation and expression of pro-inflammatory cytokines.

Triamcinolone–carbon nanotube conjugation inhibits inflammation of human arthritis synovial fibroblasts

Repetitive intra-articular corticosteroid injections are inevitable for treating synovial inflammation in advanced arthritis. However, short- and long-term use of corticosteroids usually triggers serious side effects (i.e., adrenal insufficiency, hyperglycemia, Cushing syndrome, osteoporosis, Charcot arthropathy, etc.). This study demonstrated that conjugation of a corticosteroid (triamcinolone) on polyethylene-glycol (PEG)-fabricated multi-walled carbon nanotubes enhances intracellular drug delivery via increased lysosome transport and ultimately suppresses the expression of major pro-inflammatory cytokines (i.e., TNF-α, IL-1β, and IL-6) and matrix metalloproteinase-1 and -3 from fibroblast-like synoviocytes at a very low drug dose. Specifically, conjugation of triamcinolone and multi-walled carbon nanotubes inactivated nuclear factor-κB via inhibition of the phosphorylation of mitogen-activated protein kinases and the serine/threonine kinase Akt. In summary, low-dose triamcinolone conjugation with carbon nanotubes significantly inhibited the inflammatory response of fibroblast-like synoviocytes by achieving highly efficient intracellular trafficking and suggested a potential drug candidate for resolving side effects associated with conventional arthritis treatment.

4-(Hydroxymethyl)catechol Extracted from Fungi in Marine Sponges Attenuates Rheumatoid Arthritis by Inhibiting PI3K/Akt/NF-κB Signaling

Rheumatoid arthritis (RA) is a progressive autoimmune disease specific to synovial joints; it causes joint damage and other systemic abnormalities, thereby leading to physical disability and early mortality. Marine sponge-derived fungi, Pestalotiopsis sp., secrete immunosuppressive compounds in the culture broth. In the present study, we isolated 4-(hydroxymethyl)catechol (4-HMC) from these fungal species, and evaluated its anti-RA effects using a murine collagen-induced arthritis model and tumor necrosis factor-α-stimulated human RA synovial fibroblasts. Oral 4-HMC administration decreased the clinical arthritis score, paw thickness, histologic and radiologic changes, and serum IgG1 and IgG2a levels. It prevented the proliferation of helper T (Th) 1/Th17 CD4+ lymphocytes isolated from inguinal lymph nodes, thereby reducing inflammatory cytokine production in CIA mice. It decreased the expression of inflammatory mediators, including cytokines and matrix metalloproteinases (MMPs), both in vitro and in vivo. We observed that 4-HMC suppresses Th immune responses and MMP expression to inhibit inflammatory cytokine production in human RA synovial fibroblasts by modulating the PI3K/Akt/NF-κB pathway. These results verify the anti-RA potential of 4-HMC.