Gun-Dong Kim

Omega-3 fatty acid-derived mediator, Resolvin E1, ameliorates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice

Atopic dermatitis (AD) is a common inflammatory skin disease for which few effective treatments are available. Resolvin E1 (RvE1; 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an endogenous lipid mediator derived from omega-3 fatty eicosapentaenoic acid, which is a potent inhibitor of inflammation. AD-like skin lesion was induced by repetitive skin contact with DNFB in NC/Nga mice and the effects of RvE1 were evaluated on the basis of histopathological findings of skin, ear swelling and cytokine production of CD4(+) T cells. Intraperitoneal injection of RvE1 for one week after DNFB challenge significantly lowered ear swelling and improved back skin lesions. In addition, RvE1 significantly suppressed production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) by activated CD4(+) T cells and serum IgE level. Furthermore, RvE1 reduced DNFB-induced infiltration of eosinophils, mast cells, CD4(+) T cells, and CD8(+) T cells in skin lesions. Therefore, RvE1 may suppress the development of AD-like skin lesions in DNFB-treated NC/Nga mice by reducing IL-4 and IFN-γ of activated CD4(+) T cells and serum IgE levels and infiltration of immune cells to skin lesion.

Production and applications of rosmarinic acid and structurally related compounds

Rosmarinic acid (α-o-caffeoyl-3,4-dihydroxyphenyllactic acid; RA) is a naturally occurring hydroxylated compound commonly found in species of the subfamily Nepetoideae of the Lamiaceae and Boraginaceae, such as Rosmarinus officinalis, Salvia officinalis, and Perilla frutescens. RA is biosynthesized from the amino acids l-phenylalanine and l-tyrosine by eight enzymes that include phenylalanine ammonia lyase and cinnamic acid 4-hydroxylase. RA can also be chemically produced by the esterification of caffeic acid and 3,4-dihydroxyphenyllactic acid. RA and its numerous derivatives containing one or two RA with other aromatic moieties are well known and include lithospermic acid, yunnaneic acid, salvianolic acid, and melitric acid. Recently, RA and its derivatives have attracted interest for their biological activities, which include anti-inflammatory, anti-oxidant, anti-angiogenic, anti-tumor, and anti-microbial functions. Clinically, RA attenuates T cell receptor-mediated signaling, attenuates allergic diseases like allergic rhinitis and asthma, and 2,4-dinitrofluorobenzene-induced atopic dermatitis-like symptoms, protects from neurotoxicity, and slows the development of Alzheimer’s disease. These attributes have increased the demand for the biotechnological production and application of RA and its derivatives. The present review discusses the function and application of RA and its derivatives including the molecular mechanisms underlying clinical efficacy.

Melatonin inhibits the development of 2,4‐dinitrofluorobenzene‐induced atopic dermatitis‐like skin lesions in NC/Nga mice

Abstract:  Atopic dermatitis (AD) is a common disease in children, and epicutaneous treatment with a chemical hapten such as 2,4‐dinitrofluorobenzene (DNFB) evokes an AD‐like reaction in NC/Nga mice under specific pathogen‐free conditions. Melatonin (N‐acetyl‐5‐methoxytryptamine) is synthesized by the pineal gland, has several different physiologic functions, which include seasonal reproduction control, immune system modulation, free radical scavenging, and inflammatory suppression. In the present study, we investigated whether melatonin suppresses DNFB‐induced AD‐like skin lesions in NC/Nga mice. The topical administration of melatonin to DNFB‐treated NC/Nga mice was found to inhibit ear thickness increases and the skin lesions induced by DNFB. Furthermore, interleukin (IL)‐4 and interferon (IFN)‐γ secretion by activated CD4+ T cells from the draining lymph nodes of DNFB‐treated NC/Nga mice were significantly inhibited by melatonin, and total IgE levels in serum were reduced. Our findings suggest that melatonin suppresses the development of AD‐like dermatitis in DNFB‐treated NC/Nga mice by reducing total IgE in serum, and IL‐4 and IFN‐γ production by activated CD4+ T cells.

Melatonin suppresses acrolein‐induced IL‐8 production in human pulmonary fibroblasts

Abstract:  Cigarette smoke (CS) causes harmful alterations in the lungs and airway structures and functions that characterize chronic obstructive pulmonary disease (COPD). In addition to COPD, active cigarette smoking causes other respiratory diseases and diminishes health status. Furthermore, recent studies show that, α, β‐unsaturated aldehyde acrolein in CS induces the production of interleukin (IL)‐8, which is known to be related to bronchitis, rhinitis, pulmonary fibrosis, and asthma. In addition, lung and pulmonary fibroblasts secrete IL‐8, which has a chemotactic effect on leukocytes, and which in turn, play a critical role in lung inflammation. On the other hand, melatonin regulates circadian rhythm homeostasis in humans and has many other effects, which include antioxidant and anti‐inflammatory effects, as demonstrated by the reduced expressions of iNOS, IL‐1β, and IL‐6 and increased glutathione (GSH) and superoxide dismutase activities. In this study, we investigated whether melatonin suppresses acrolein‐induced IL‐8 secretion in human pulmonary fibroblasts (HPFs). It was found that acrolein‐induced IL‐8 production was accompanied by increased levels of phosphorylation of Akt and extracellular signal‐regulated kinases (ERK1/2) in HPFs, and that melatonin suppressed IL‐8 production in HPFs. These results suggest that melatonin suppresses acrolein‐induced IL‐8 production via ERK1/2 and phosphatidylinositol 3‐kinase (PI3K)/Akt signal inhibition in HPFs.

Rosmarinic acid attenuates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice.

Atopic dermatitis (AD) is one of the most common skin diseases, and its incidence is increasing in industrialized countries. Furthermore, the epicutaneous application of a hapten, such as 2,4-dinitrofluorobenzene (DNFB), evokes an AD-like lesion in NC/Nga mice under specific pathogen-free (SPF) conditions. Rosmarinic acid (RA) is a secondary metabolite that is frequently found in herbs, and has anti-inflammatory, anti-oxidant, and anti-microbial effects. In this study, we studied whether RA is an effective treatment against DNFB-induced AD-like skin lesions in NC/Nga mice. RA at 1 or 5 μM was found to suppress the productions of interferon (IFN)-γ and interleukin (IL)-4 significantly by activated CD4(+) T cells. Furthermore, an intraperitoneal injection of RA at 10 or 50 mg/kg significantly inhibited skin lesion development and ear thickness and total serum IgE level increases in DNFB-treated NC/Nga mice. In addition, intraperitoneal administered RA at 10 or 50 mg/kg significantly inhibited the infiltrations of CD4(+) T, CD8(+) T, and mast cells into DNFB-induced skin lesions in NC/Nga mice. This study suggests that RA suppresses the development of AD-like dermatitis in DNFB-treated NC/Nga mice by reducing IFN-γ and IL-4 production by activated T cells and total serum IgE levels.

The inhibitory effect of naringenin on atopic dermatitis induced by DNFB in NC/Nga mice

AIMS Atopic dermatitis (AD) is a chronic and relapsing inflammatory dermatitis characterized by pruritic and eczematous skin lesions. Here, we investigated the therapeutic effect of the fruit flavonoid naringenin on DNFB induced atopic dermatitis mice model. MAIN METHODS AD-like skin lesion was induced by repetitive skin contact with DNFB in NC/Nga mice and the effects of the fruit flavonoid naringenin were evaluated on the basis of histopathological findings of skin, ear swelling and cytokine production of CD4(+)T cells. KEY FINDINGS Intraperitoneal injection of naringenin for one week after DNFB challenge significantly lowered ear swelling and improved back skin lesions. In addition, naringenin significantly suppressed production of interferon-gamma (IFN-γ) by activated CD4(+) T cells and serum IgE level. Furthermore, naringenin reduced DNFB-induced infiltration of eosinophils, mast cells, CD4(+) T cells, and CD8(+) T cells in skin lesions. SIGNIFICANCE Naringenin may suppress the development of AD-like skin lesions in DNFB-treated NC/Nga mice by reducing IFN-γ production of activated CD4(+) T cells, serum IgE levels and infiltration of immune cells to skin lesion.

α‐Lipoic acid suppresses the development of DNFB‐induced atopic dermatitis‐like symptoms in NC/Nga mice

Abstract:  Atopic dermatitis (AD) is a common skin disease that has complex pathogenic mechanisms. Under specific pathogen‐free conditions, repeated epicutaneous treatment of 2‐4‐dinitrofluorobenzene (DNFB) evokes AD‐like clinical symptoms in NC/Nga mice. α‐Lipoic acid (α‐LA; 1, 2‐dithiolane‐3‐pentanoic acid) is a dietary component that is synthesized in bacteria, yeast, plants, and mammals. α‐LA and its reduced form, dihydrolipoic acid, are powerful antioxidants that have many physiological functions, including free radical scavenging of reactive oxygen species, generation of cellular antioxidants, chelation of metal ions, and inflammatory suppression. In this study, we investigated whether α‐LA suppresses AD‐like skin lesions induced by repeated DNFB application in NC/Nga mice. α‐LA significantly suppressed production of interferon (IFN)‐γ and interleukin (IL)‐4 by activated CD4+ T cells. We found that the oral administration of α‐LA reduced AD‐like clinical symptoms and inhibited increases of epidermal thickness in DNFB‐induced AD‐like skin lesions of NC/Nga mice. Furthermore, total serum IgE levels were dramatically reduced by topical α‐LA treatment. Our findings suggest that oral administration of α‐LA suppresses the development of AD in DNFB‐treated NC/Nga mice and reduces IFN‐γ and IL‐4 production from activated CD4+ T cells as well as total serum IgE levels.

The histone deacetylase inhibitor, trichostatin A, inhibits the development of 2,4-dinitrofluorobenzene-induced dermatitis in NC/Nga mice.

Repetitive skin contact with a chemical hapten like 2,4-dinitrofluorobenzene (DNFB) evokes an atopic dermatitis (AD)-like dermatitis reaction in NC/Nga mice maintained under specific pathogen-free (SPF) conditions. The histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), modulates the expression of several genes by inhibiting the activity of HDACs. Furthermore, TSA has been reported to suppress inflammatory cytokine expression and to induce T cell-suppression by increasing regulatory T cell (T reg cell) numbers. In addition, histone deacetylase inhibitors (HDACi) are currently undergoing clinical trials for the treatment of inflammatory disorders. In the present study, we examined whether treatment with TSA suppresses AD-like skin lesions in NC/Nga mice treated with DNFB under SPF conditions. Intraperitoneal (i.p.) administration of TSA to DNFB-treated NC/Nga mice was found to inhibit ear thickness increases and the skin lesions induced by DNFB. Furthermore, IL-4 production by CD4+ T cells from the lymph nodes of DNFB-treated NC/Nga mice was significantly inhibited by TSA, although levels of IFN-γ were not. Flow cytometric analysis of lymphocytes showed an increase in CD4+ CD25+ T cell proportions in mice given TSA-i.p. These findings suggest that TSA suppresses the development of AD-like dermatitis in DNFB-treated NC/Nga mice by reducing IL-4 production and increasing the T reg cell population.

Immune Response Against 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis-Like Clinical Manifestation is Suppressed by Spermidine in NC⁄Nga Mice

Of the biogenic polyamines, spermidine is a natural constituent of living cells and organisms. Spermidine is associated with regulation of cell growth, proliferation and differentiation, and with the suppression of oxidation and inflammation. Atopic dermatitis (AD) is a chronic inflammatory skin disease that has a complex and multiple pathogenesis, which includes genetic abnormality, modified or abnormal immune response and the production of nitric oxide and reactive oxygen species. We investigated whether spermidine can relieve AD‐like clinical manifestation induced by the continual application of 2,4‐dinitrofluorobenzene (DNFB) in NC⁄Nga mice. Spermidine at concentrations of 1 or 10 mg/kg reduced increasing ear swelling and attenuated oedema, haemorrhage and hyperkeratosis in AD‐like skin lesions. Repetitive application of DNFB induced inflammatory cell infiltration to skin lesions, whereas intraperitoneal injection of spermidine inhibited DNFB‐evoked infiltration of eosinophils, mast cells and T lymphocytes. Furthermore, spermidine suppressed mast cell degranulation and production of interferon‐gamma by activated CD4+ T cells in AD‐like skin lesions. Spermidine may be a potential therapeutic agent for treatment of AD.

Aspartame Attenuates 2, 4-Dinitrofluorobenzene-Induced Atopic Dermatitis–Like Clinical Symptoms in NC/Nga Mice

Atopic dermatitis (AD) is a common multifactorial chronic skin disease that has a multiple and complex pathogenesis. AD is gradually increasing in prevalence globally. In NC/Nga mice, repetitive applications of 2, 4-dinitrofluorobenzene (DNFB) evoke AD-like clinical symptoms similar to human AD. Aspartame (N-L-α-aspartyl-L-phenylalanine 1-methyl ester) is a methyl ester of a dipeptide, which is used as an artificial non-nutritive sweetener. Aspartame has analgesic and anti-inflammatory functions that are similar to the function of nonsteroidal anti-inflammatory drugs such as aspirin. We investigated whether aspartame can relieve AD-like clinical symptoms induced by DNFB treatment in NC/Nga mice. Sucrose did not relieve AD-like symptoms, whereas aspartame at doses of 0.5 μg kg(-1) and 0.5 mg kg(-1) inhibited ear swelling and relieved AD-like clinical symptoms. Aspartame inhibited infiltration of inflammatory cells including eosinophils, mast cells, and CD4(+) T cells, and suppressed the expression of cytokines including IL-4 and IFN-γ, and total serum IgE levels. Aspartame may have therapeutic value in the treatment of AD.