A newly synthesized macakurzin C-derivative attenuates acute and chronic skin inflammation: The Nrf2/heme oxygenase signaling as a potential target

Akram, Muhammad; Shin, Iljin; Kim, Kyeong-A; Noh, Dabi; Baek, Seung‐Hoon; Chang, Shau‐Jin; Kim, Hyoungsu; Bae, Ok‐Nam

doi:10.1016/j.taap.2016.07.013

Cited by 17 publications

(19 citation statements)

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“…According to previous studies, AD patients are known to have increased levels of chemokines (such as IL-8, CCL17, and CXCL10) and cytokines (such as IL-4, IL-6, and IL-13), compared to healthy individuals (Yamanaka and Mizutani, 2011). It is also known that the activation of several oxidative stress-related inflammatory signaling pathways, such as NF-E2 p45 related factors 2 (Nrf2) and heme oxygenase-1 (HO-1), is related to inflammation in AD (Choi et al, 2014;Akram et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Chijabyukpi-Tang Inhibits Pro-Inflammatory Cytokines and Chemokines via the Nrf2/HO-1 Signaling Pathway in TNF-α/IFN-γ-Stimulated HaCaT Cells and Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions in Mice

Lee

Lim

et al. 2020

Front. Pharmacol.

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Chijabyukpi-tang (CBT) is an oriental herbal formula consisting of three herbs (Gardeniae Fructus (Gardenia jasminoides J.Ellis.), Phellodendri Cortex (Phellodendron amurense Rupr.), Glycyrrhizae Radix (Glycyrrhiza uralensis Fisch. ex DC.) at the ratio of 2: 2: 1. CBT has traditionally been used to treat eczema with inflammation in Northeast Asia. The components of CBT have been shown to have anti-inflammatory and anti-oxidant properties, but the exact role and mechanism of CBT on atopic dermatitis (AD) remain unclear. In this study, we investigated the anti-inflammatory effect and mechanism of CBT in the HaCaT human keratinocyte cell line and investigated the anti-atopic effect in mice models of atopic dermatitis-like skin lesions. In the tumor necrosis factor alpha (TNF)-a/ interferon (IFN)-g-stimulated HaCaT cells, CBT inhibited the production of proinflammatory cytokines and chemokines and elevated the nuclear translocation of NF-E2 p45 related factors 2 (Nrf2) and subsequent production of heme oxygenase-1 (HO-1). CBT improved the symptoms of atopic dermatitis-like lesions in 2,4-dinitrochlorobenzene (DNCB)-treated mice by suppressing the levels of serum immunoglobulin E (IgE), and various pro-inflammatory cytokines and chemokines. The improvement effect of CBT on atopic dermatitis-like lesions can be predicted to be due to increased Nrf2 and HO-1 gene expression. These results suggest that CBT is an herbal medicine with the potential for use as a therapeutic agent for inflammatory skin diseases such as atopic dermatitis.

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Section: Introductionmentioning

confidence: 99%

Chijabyukpi-Tang Inhibits Pro-Inflammatory Cytokines and Chemokines via the Nrf2/HO-1 Signaling Pathway in TNF-α/IFN-γ-Stimulated HaCaT Cells and Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions in Mice

Lee

Lim

et al. 2020

Front. Pharmacol.

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“…LPS stimulates the release of NO and prostaglandin E 2 (PGE 2 ) through upregulated expression of iNOS and cyclooxygenase-II (COX-II), respectively [24]. Release of these mediators is important in the amplification of the inflammatory reaction [19,20]. CPD 6 significantly inhibited the release of NO and PGE 2 in activated macrophages in a dose-dependent manner (Figure 2A,B).…”

Section: Resultsmentioning

confidence: 99%

“…Keratinocytes are the first line of defense in skin, but are continuously challenged by various stimuli including bacteria, UV, and chemicals. Keratinocytes play a critical role in initiating the inflammatory response in the skin by releasing pro-inflammatory mediators contributing to skin diseases [12,20]. To examine the therapeutic potential of CPD 6 against skin disorders, we investigated the protective role of CPD 6 in inflammatory responses in human keratinocytes, HaCaT cells.…”

Section: Resultsmentioning

confidence: 99%

“…The use of natural compounds to treat inflammatory diseases has received special attention, as natural compounds have strong anti-oxidant and anti-inflammatory effects. Several flavonoids have been applied as anti-inflammatory agents in acute or chronic inflammatory models [20,21]. These naturally occurring compounds are not necessarily the final drug entity, but rather can serve as sources of novel structures.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory Effects of a Novel Chrysin-Derivative, CPD 6, on Acute and Chronic Skin Inflammation

Suh

Shin

et al. 2019

IJMS

Self Cite

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The skin is an important physiological barrier against external stimuli, such as ultraviolet radiation (UV), xenobiotics, and bacteria. Dermal inflammatory reactions are associated with various skin disorders, including chemical-induced irritation and atopic dermatitis. Modulation of skin inflammatory response is a therapeutic strategy for skin diseases. Here, we synthesized chrysin-derivatives and identified the most potent derivative of Compound 6 (CPD 6). We evaluated its anti-inflammatory effects in vitro cells of macrophages and keratinocytes, and in vivo dermatitis mouse models. In murine macrophages stimulated by lipopolysaccharide (LPS), CPD 6 significantly attenuated the release of inflammatory mediators such as nitric oxide (NO) (IC50 for NO inhibition: 3.613 μM) and other cytokines. In cultured human keratinocytes, CPD 6 significantly attenuated the release of inflammatory cytokines induced by the combination of IFN-γ and TNF-α, UV irradiation, or chemical irritant stimulation. CPD 6 inhibited NFκB and JAK2/STAT1 signaling pathways, and activated Nrf2/HO-1 signaling. In vivo relevancy of anti-inflammatory effects of CPD 6 was observed in acute and chronic skin inflammation models in mice. CPD 6 showed significant anti-inflammatory properties both in vitro cells and in vivo dermatitis animal models, mediated by the inhibition of the NFκB and JAK2-STAT1 pathways and activation of Nrf2/HO-1 signaling. We propose that the novel chrysin-derivative CPD 6 may be a potential therapeutic agent for skin inflammation.

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“…Atopic dermatitis. Redox dysregulation is an emerging causative factor contributing to compromised skin barrier function in atopic dermatitis, and pharmacological intervention targeting NRF2 has shown promise targeting atopic dermatitis-like skin lesions in 2,4-dinitrochlorobenzene (DNCB)-sensitized and challenged mice [ 68 , 69 ].…”

Section: Nrf2 In Skin Pathologymentioning

confidence: 99%

Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin

et al. 2017

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The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response. Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV (ultraviolet) radiation. The apocarotenoid bixin, a Food and Drug Administration (FDA)-approved natural food colorant (referred to as ‘annatto’) originates from the seeds of the achiote tree native to tropical America, consumed by humans since ancient times. Use of achiote preparations for skin protection against environmental insult and for enhanced wound healing has long been documented. We have recently reported that (i) bixin is a potent canonical activator of the NRF2-dependent cytoprotective response in human skin keratinocytes; that (ii) systemic administration of bixin activates NRF2 with protective effects against solar UV-induced skin damage; and that (iii) bixin-induced suppression of photodamage is observable in Nrf2+/+ but not in Nrf2−/− SKH-1 mice confirming the NRF2-dependence of bixin-induced antioxidant and anti-inflammatory effects. In addition, bixin displays molecular activities as sacrificial antioxidant, excited state quencher, PPAR (peroxisome proliferator-activated receptor) α/γ agonist, and TLR (Toll-like receptor) 4/NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) antagonist, all of which might be relevant to the enhancement of skin barrier function and environmental stress protection. Potential skin photoprotection and photochemoprevention benefits provided by topical application or dietary consumption of this ethno-pharmacologically validated phytochemical originating from the Americas deserves further preclinical and clinical examination.

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A newly synthesized macakurzin C-derivative attenuates acute and chronic skin inflammation: The Nrf2/heme oxygenase signaling as a potential target

Cited by 17 publications

References 50 publications

Chijabyukpi-Tang Inhibits Pro-Inflammatory Cytokines and Chemokines via the Nrf2/HO-1 Signaling Pathway in TNF-α/IFN-γ-Stimulated HaCaT Cells and Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions in Mice

Chijabyukpi-Tang Inhibits Pro-Inflammatory Cytokines and Chemokines via the Nrf2/HO-1 Signaling Pathway in TNF-α/IFN-γ-Stimulated HaCaT Cells and Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions in Mice

Inhibitory Effects of a Novel Chrysin-Derivative, CPD 6, on Acute and Chronic Skin Inflammation

Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin

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