Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
Department of Microbiology, Soochow University, Taipei, Taiwan.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113486. doi: 10.1016/j.intimp.2024.113486. Epub 2024 Oct 29.
Dictamnine and fraxinellone constitute the primary alkaloid and limonoid components in Cortex Dictamni, respectively. Both compounds exhibit anti-inflammatory properties. This study aims to assess the ability of dictamnine and fraxinellone in treating atopic dermatitis (AD) through in silico-, cell-, and animal-based experiments. The effects of these compounds on the coordinated activation of keratinocytes, macrophages, and basophils in AD development were investigated. A dinitrochlorobenzene (DNCB)-sensitized AD model in mice was employed to examine the in vivo anti-AD effects. Dictamnine and fraxinellone effectively reduced the release of proinflammatory effectors, including interleukin (IL)-4, IL-13, chemokine (C-C motif) ligand (CCL)5, and CCL17, by suppressing extracellular signal-regulated kinase (ERK) signaling in activated keratinocytes. The conditioned medium from dictamnine-treated macrophages reduced signal transducer and activator of transcription (STAT)3 in keratinocytes by 39 %, indicating the inhibition of keratinocytes-immune cell interaction. Both compounds comparably suppressed RBL-2H3 cell degranulation by decreasing histamine production. In vitro permeation test (IVPT) demonstrated three-fold greater skin absorption of topically applied dictamnine than fraxinellone. The in silico molecular docking manifested a preferable ceramide interaction with dictamnine over fraxinellone. Topical application of dictamnine decreased the mouse skin lesion development and the overexpressed cytokines/chemokines. This attenuation is comparable to the activity of tacrolimus ointment, a standard clinical treatment. Histological analysis revealed that dictamnine inhibited epidermal proliferation, reducing thickness from 220 to 97 μm. However, dictamnine did not restore the barrier function, as evidenced by the results of filaggrin and loricrin expression and in vivo transepidermal water loss (TEWL). The findings suggest that topical dictamnine can be a promising agent for alleviating AD inflammation.
白鲜碱和吴茱萸新碱分别构成白鲜皮的主要生物碱和柠檬苦素成分。这两种化合物均具有抗炎特性。本研究旨在通过计算机模拟、细胞和动物实验评估白鲜碱和吴茱萸新碱治疗特应性皮炎（AD）的能力。研究了这些化合物对 AD 发展中角质形成细胞、巨噬细胞和嗜碱性粒细胞协同激活的影响。采用二硝基氯苯（DNCB）致敏 AD 小鼠模型，考察了体内抗 AD 作用。白鲜碱和吴茱萸新碱通过抑制激活的角质形成细胞中细胞外信号调节激酶（ERK）信号，有效减少包括白细胞介素（IL）-4、IL-13、趋化因子（C-C 基序）配体（CCL）5 和 CCL17 在内的促炎效应物的释放。白鲜碱处理的巨噬细胞的条件培养基使角质形成细胞中的信号转导和转录激活因子（STAT）3 减少了 39%，表明抑制了角质形成细胞-免疫细胞相互作用。两种化合物通过降低组胺产生，可比地抑制 RBL-2H3 细胞脱颗粒。体外渗透试验（IVPT）表明，局部应用白鲜碱的皮肤吸收率比吴茱萸新碱高 3 倍。计算机分子对接表明，白鲜碱与神经酰胺的相互作用优于吴茱萸新碱。局部应用白鲜碱可减少小鼠皮肤损伤和过度表达的细胞因子/趋化因子。这种衰减与他克莫司软膏（一种标准的临床治疗方法）的活性相当。组织学分析显示，白鲜碱抑制表皮增殖，使厚度从 220μm 减少至 97μm。然而，白鲜碱并没有恢复屏障功能，正如丝聚蛋白和兜甲蛋白表达以及体内经皮水分丢失（TEWL）的结果所示。这些发现表明，局部应用白鲜碱可能是缓解 AD 炎症的一种有前途的药物。
