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Anti-atopic dermatitis effects of Parasenecio auriculatus via simultaneous inhibition of multiple inflammatory pathways
Won Kyu Kim1,2,* (Senior Research Scientist), Yujin Kwon1,2,# (Graduate student), Su-Yeon Cho1,2,# (Graduate student), Jaeyoung Kwon2,3,# (Senior Research Scientist), Min Hwang4 (Graduate student), Hoseong Hwang3 (Graduate student), Yoon Jin Kang1,5 (Graduate student), Hyeon-Seong Lee3 (Post-Doc), Jiyoon Kim4 (Assistant Professor)
1Natural Product Research Center, Korea Institute of Science and Technology (KIST),
2Division of Bio-Medical Science & Technology, University of Science and Technology (UST),
3Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST),
4Department of Pharmacology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea,
5Department of Marine Life Sciences, College of Life Science, Gangneung-Wonju National University
Abstract
Background: The treatment of atopic dermatitis (AD) is challenging due to its complex etiology. From epidermal disruption to chronic inflammation, various cells and inflammatory pathways contribute to the progression of AD. As with immunosuppressants, general inhibition of inflammatory pathways can be effective, but this approach is not suitable for long-term treatment due to its side effects.
Purpose: This study aimed to identify a plant extract (PE) with anti-inflammatory effects on multiple cell types involved in AD development and provide relevant mechanistic evidence.
Method: Degranulation was measured in RBL-2H3 cells to screen 30 PEs native to South Korea. To investigate the anti-inflammatory effects of Parasenecio auriculatus var. matsumurana Nakai extract (PAE) in AD, production of cytokines and nitric oxide, activation status of FcュRI and TLR4 signaling, cell-cell junction, and cell viability were evaluated using qRT-PCR, western blotting, confocal microscopy, Griess system, and an MTT assay in RBL-2H3, HEK293, RAW264.7, and HaCaT cells. For in vivo experiments, a DNCB-induced AD mouse model was constructed, and hematoxylin and eosin, periodic acid-Schiff, toluidine blue, and F4/80-staining were performed. The chemical constituents of PAE were analyzed by HPLC-MS.
Results: By measuring the anti-degranulation effects of 30 PEs in RBL-2H3 cells, we found that Paeonia lactiflora Pall., PA, and Rehmannia glutinosa (Gaertn.) Libosch. ex Steud. show an inhibitory activity of more than 50%. Of these, PAE most dramatically and consistently suppressed cytokine expression, including IL-4, IL-9, IL-13, and TNF-メ. PAE potently inhibited FcュRI signaling, which mechanistically supports its basophil-stabilizing effects, and PAE downregulated cytokines and NO production in macrophages via perturbation of toll-like receptor signaling. Moreover, PAE suppressed cytokine production in keratinocytes and upregulated the expression of tight junction molecules ZO-1 and occludin. In a DNCB-induced AD mouse model, the topical application of PAE significantly improved atopic index scores, immune cell infiltration, cytokine expression, abnormal activation of signaling molecules in FcュRI and TLR signaling, and damaged skin structure compared with dexamethasone. The anti-inflammatory effect of PAE was mainly due to integerrimine.
Conclusion: Our findings suggest that PAE could potently inhibit multi-inflammatory cells involved in AD development, synergistically block the propagation of inflammatory responses, and thus alleviate AD symptoms.
Abstract, Accepted Manuscript(in press) [Submitted on October 6, 2021, Accepted on January 10, 2022]
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