Topical delivery of bioactive compounds from Cortex Dictamni alleviates atopic dermatitis-like lesion by inhibiting the activation of keratinocytes, macrophages, and basophils: Dictamnine versus fraxinellone

Article

作者: Wei, Shih-Hsuan ; Chou, Wei-Ling ; Alshetaili, Abdullah ; Fang, Jia-You ; Yang, Shih-Chun ; Yang, Sien-Hung

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.

2024-11-01·Biomedicine & Pharmacotherapy

Fraxinellone protects against cardiac injury and decreases ventricular fibrillation susceptibility during myocardial ischemia-reperfusion

Article

作者: Huang, Qingning ; Zhong, Xing ; Yang, Yaqin ; Chen, Xin ; Tang, Pusong ; Lei, Yuhua ; Ye, Lu ; Luo, Dan ; Huang, Rui

BACKGROUNDAcute myocardial ischemia/reperfusion injury (MIRI) with complicated mechanisms contributes to a high risk of ventricular arrhythmia, high lethality, and even sudden death. In vitro, Fraxinellone (FRA) exhibits an array of biologic activities and may possess cardioprotective effects. However, no relevant studies have examined FRA's protective potential against MIRI and related ventricular arrhythmias. The present study was undertaken to determine the effectiveness of FRA on MIRI and ventricular fibrillation (VF) susceptibility in rats and to elucidate the underlying mechanisms.METHODS48 healthy male Sprague-Dawley (SD) rats were randomly divided into the following four groups: Sham+vehicle(n=12), Sham+FRA(n=12), I/R+vehicle(n=12) and I/R+FRA(n=12). Histopathology, electrophysiological examination, HRV analysis in combination with molecular biology were used to investigate the therapeutic benefits of FRA on cardiac injury and VF susceptibility during myocardial IR. Finally, the potential mechanism by which FRA protects myocardium from MIRI was explored.RESULTSPretreatment with FRA ameliorated myocardial fibrosis after MIRI in vivo, alleviated myocardial injury, inflammation, oxidative stress and apoptosis in vivo and in vitro, thereby protecting myocardium from MIRI injury. In addition, FRA administration could improve HRV, prolong ventricular effective refractory period (ERP) and action potential duration (APD), attenuate VF induction rate, and contribute to improving ventricular sympathetic nerve remodeling and ion channel remodeling. Mechanistically, FRA may reduce MIRI via the PI3K/AKT pathway.CONCLUSIONFRA may exert cardioprotective effects during MIRI by inhibiting myocardial inflammation, oxidative stress and apoptosis, and decrease VF susceptibility by improving sympathetic remodeling and ion channel remodeling, which might represent a potential therapeutic strategy for attenuation of MIRI.

2024-08-15·Heliyon

Anti-atopic dermatitis effect of fraxinellone via inhibiting IL-31 in vivo and in vitro.

Article

作者: Deng, Jialin ; Yang, Niuniu ; Dai, Huijuan ; Jin, Han ; Shao, Haifeng ; Liu, Yanqing ; Xu, Huiwen

Chronic recurrent itch and skin inflammation are prominent features of atopic dermatitis (AD), which is closely related to the immune response driven by T-helper type 2 (Th2) cells. The expression of interleukin 31 (IL-31) is positively correlated with the severity of dermatitis. Anti-IL-31 receptor α (IL-31RA) targeted drugs have been used to treat AD, however, they are expensive and have side effects. Fraxinellone (FRA) is one of the main limonoid components in the dried root bark of Dictamnus dasycarpus Turcz.; however, its anti-inflammatory and antipruritic effects on atopic dermatitis (AD) have not been previously reported. In this study, we investigated the anti-dermatitis effect of FRA and its potential mechanism of action using a 2,4-dinitrofluorobenzene (DNFB)-induced AD-like mouse model and lipopolysaccharide (LPS)-stimulated HaCaT cells. FRA significantly inhibited chronic pruritus, epidermal thickening, and inflammatory infiltration in AD mice. FRA not only inhibited the levels of IL-31 in the serum and lesioned skin of AD mice but also significantly downregulated the mRNA expression and protein levels of IL-31, IL-31RA, transient receptor potential (TRP) V1, and TRPA1 in the lesioned skin and dorsal root ganglion (DRG) of AD mice. In LPS-stimulated HaCaT cells, FRA inhibited the production of iNOS and COX2, as well as the protein levels of IL-31, IL-31RA, TRPV1 and TRPA1, showing significant anti-inflammatory effects. In summary, our findings suggest that FRA exerts antipruritic and anti-inflammatory effects in AD by regulating the IL-31 pathway, and may hold promise for the clinical treatment of AD.

100 项与 Fraxinellone 相关的药物交易

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