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      p-coumaric acid, an active ingredient of Panax ginseng, ameliolates atopic dermatitis-like skin lesions through inhibition of thymic stromal lymphopoietin in mice

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          Abstract

          Background

          Atopic dermatitis (AD) is associated with chronic skin inflammatory reactions. p-coumaric acid ( pCA) is an active ingredient of Panax ginseng Meyer (Araliaceae).

          Methods

          Here, we estimated an anti-AD effect of pCA on activated mast cells, activated splenocytes, and a mouse model of AD. Cytokines levels were measured by ELISA and protein activation was analyzed by Western blotting. 2,4-dinitrofluorobenzene (DNFB) was used to induce AD-like skin lesions.

          Results

          The treatment with pCA suppressed the productions and mRNA expressions of thymic stromal lymphopoietin (TSLP), TNF-ɑ, IL-6, and IL-1β in HMC-1 cells. pCA downregulated the expressions of RIP2 and caspase-1, phosphorylated-(p)p38/pJNK/pERK, and pIKKβ/pIkBɑ/NF-κB in HMC-1 cells. pCA also decreased the productions of TSLP, TNF-ɑ, IL-6, IL-4, and IFN-γ in the supernatant of stimulated splenic cells. Comparing to DNFB-sensitized control group, pCA-treated group alleviated pathological changes of AD-like lesions. pCA decreased the proteins and mRNA expressions levels of TSLP, IL-6, and IL-4 in the skin lesions. Caspase-1 activation was also downregulated by pCA treatment in the AD-like lesions. The serum levels of histamine, IgE, TSLP, TNF-ɑ, IL-6, and IL-4 were suppressed following treatment with pCA.

          Conclusion

          This study suggests that pCA has the potential to improve AD by suppressing TSLP as well as inflammatory cytokines via blocking of caspase-1/NF-κB signal cascade.

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          Most cited references52

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          The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity

          Summary Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1C284A, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1C284A, we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis.
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            Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate‐to‐severe atopic dermatitis †

            Summary Background Moderate‐to‐severe atopic dermatitis (AD) is a chronic disease characterized by intense, persistent and debilitating itch, resulting in sleep deprivation, signs of anxiety and depression, impaired quality of life and reduced productivity. The Peak Pruritus Numerical Rating Scale (NRS) was developed and validated as a single‐item, patient‐reported outcome (PRO) of itch severity. Objectives To describe the content validity and psychometric assessment (test–retest reliability, construct validity, known‐groups validity, sensitivity to change) of the Peak Pruritus NRS, and to derive empirically a responder definition to identify adults with a meaningful change in itch. Methods Content validity was assessed through in‐depth patient interviews. Psychometric assessments used data from phase IIb and phase III dupilumab clinical trials and included test–retest reliability, construct validity, known‐groups validity and sensitivity to change in patients with moderate‐to‐severe AD. Results Interview participants indicated that the Peak Pruritus NRS was a relevant, clear and comprehensive assessment of itch severity. Peak Pruritus NRS scores showed large, positive correlations with existing PRO measures of itch, and weak or moderate correlations with clinician‐reported measures assessing objective signs of AD. Peak Pruritus NRS score improvements were highly correlated with improvements in other itch PROs, and moderately correlated with improvements in clinician‐reported measures assessing objective signs of AD. The most appropriate threshold for defining a clinically relevant, within‐person response was ≥ 2–4‐point change in the Peak Pruritus NRS. Conclusions The Peak Pruritus NRS is a well‐defined, reliable, sensitive and valid scale for evaluating worst itch intensity in adults with moderate‐to‐severe AD.
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              Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFkappaB.

              The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is important for the initiation of allergic airway inflammation through a dendritic cell-mediated T helper 2 response. To identify the factors that control TSLP expression, we examined the ability of inflammatory mediators to regulate TSLP production in human airway epithelial cells. We found that both IL-1beta and TNF-alpha were capable of inducing rapid TSLP production in primary human bronchial airway epithelial cells. We further characterized the human TSLP gene promoter, using two human epithelial cell lines, 16HBEo(-) and A549, and showed that IL-1beta- and TNF-alpha-mediated human TSLP promoter activation in these cells was mediated by an upstream NFkappaB site. Mutation of this NFkappaB site abolished activation, as did overexpression of a dominant-negative version of IkappaB kinase (IKK)beta (a kinase acting on IkappaB, the inhibitor of NFkappaB). Interestingly, human TSLP mRNA levels were also increased after exposure to Toll-like receptor (TLR) 2, TLR8, and TLR9 ligands, further supporting an important role for NFkappaB in TSLP gene regulation. Similarly, analysis of the mouse TSLP gene promoter revealed the presence of a similarly situated NFkappaB site that was also critical for IL-1beta-inducible expression of mouse TSLP. Taken together, these results demonstrate that the inflammatory mediators IL-1beta and TNF-alpha regulate human TSLP gene expression in an NFkappaB-dependent manner.
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                Author and article information

                Contributors
                Journal
                J Ginseng Res
                J Ginseng Res
                Journal of Ginseng Research
                Elsevier
                1226-8453
                2093-4947
                05 July 2020
                January 2021
                05 July 2020
                : 45
                : 1
                : 176-182
                Affiliations
                [1 ]Center for Converging Humanities, Kyung Hee University, Seoul, Republic of Korea
                [2 ]Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
                [3 ]Division of Food and Pharmaceutical Engineering, BioChip Research Center, Hoseo University, Asan, Chungnam, Republic of Korea
                Author notes
                []Corresponding author. Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea hmkim@ 123456khu.ac.kr
                [∗∗ ]Corresponding author. Division of Food and Pharmaceutical Engineering, BioChip Research Center, Hoseo University, Asan, Chungnam, 31499, Republic of Korea hjjeong@ 123456hoseo.edu
                [☆]

                P.-D. Moon and N.-R. Han contributed equally to this work.

                Article
                S1226-8453(20)30111-1
                10.1016/j.jgr.2020.06.004
                7790890
                33437169
                f99fb275-aebd-409f-806a-1be929663dce
                © 2020 The Korean Society of Ginseng. Publishing services by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 25 March 2020
                : 28 June 2020
                Categories
                Research Article

                atopic dermatitis,p-coumaric acid,mast cells,thymic stromal lymphopoietin,caspase-1

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