Nucleophosmin modulates the alleviation of atopic dermatitis caused by the marine-derived compound dihydroaustrasulfone alcohol

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease, and its prevalence is increasing. AD usually elicits skin barrier dysfunction, dry skin and itching. As the mechanisms of AD remain unknown, there is an urgent need to find effective therapies. Because of the diversity and complexity of marine environments, the discovery of drugs from marine organisms as novel therapeutic agents for human diseases has seen renewed interest. Dihydroaustrasulfone alcohol (WA-25), the synthetic precursor of austrasulfone, which is a natural product isolated from a Formosan soft coral, has been shown to possess many therapeutic effects in our previous studies. However, the detailed mechanisms and therapeutic effects of WA-25 on AD are incompletely understood. We performed in vitro and in vivo studies to examine the effects of WA-25 on AD. We showed that WA-25 blocks inflammation and oxidative stress. Simultaneously, we also found that WA-25 reduces the AD scores and AD-induced transepidermal water loss (TEWL), scratching behavior, and alloknesis. WA-25 is more effective in cases of AD than are the drugs that are currently used clinically. Importantly, we also found that when nucleophosmin (NPM) was inhibited or when its expression was reduced, the anti-inflammatory and anti-AD effects of WA-25 were blocked. These data suggest that NPM plays dual roles in inflammation and AD. Overall, these results suggest that WA-25 is a potential anti-inflammatory and AD therapeutic agent that is modulated by NPM.

Cell‑penetrating heme oxygenase‑1 in the therapy of atopic dermatitis in mice

“…It was previously indicated that induction of HO-1 plays a protective role in several inflammation-related diseases (7), including AD, and HO-1 has been reported to exhibit therapeutic efficiency in AD (8)(9)(10)(11). Chen and Zhong (16) revealed that HO-1 combined with microRNAs may affect certain skin diseases, such as ischemia, hypoxia, rheumatoid arthritis and AD, by regulating the functions of T cells, dendritic cells and mast cells, and the release of chemokines and cytokines.…”

“…In 2016, Kim et al ( 18 ) reported that 2,3-dimethoxy-2'-hydroxychalcone, a derivative of 2'-hydroxychalcone in the flavonoid family, can alleviate skin inflammation by inhibiting TNF-α-induced intercellular adhesion molecule-1 expression and adhesion of monocytes to keratinocytes, by suppressing NF-κB activation and inducing HO-1 expression in keratinocytes. Hung et al ( 10 ) demonstrated that WA-25 can protect against AD by increasing the expression levels of HO-1 and Nrf2. Gene therapy of AD via targeting the HO-1 gene has been reported in several studies; however, AD therapy using the HO-1 protein is limited by its inability to enter cells.…”

“…The method for inducing AD was modified from a previous study ( 10 ). The dorsal skin hair was clipped and an area ~1x2 cm 2 was depilated with a hair removal cream.…”

“…Heme oxygenase-1 (HO-1) catalyzes the first and rate-limiting step in the oxidative degradation of free heme, and may affect several biological processes of aneurysmal diseases, articular diseases and hepatic gluconeogenesis, among others, via its enzymatic by-products (7). Previous studies on AD mouse models have demonstrated that certain agents, including Soshiho-tang, sulforaphane, dihydroaustrasulfone alcohol (WA-25) and Platycodon grandiflorus root-derived saponins, can alleviate AD-like skin lesions and skin inflammation by increasing the expression of HO-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) (8)(9)(10)(11). Another study also concluded that enhancement of HO-1 expression attenuated the development of skin lesions in mice (12).…”

New 1,4-Dienonesteroids from the Octocoral Dendronephthya sp.

“…The anti-inflammatory activity method used was modified from our previous studies [16,17,18]. We examined the effects of steroids 1 – 5 on pro-inflammatory iNOS and COX-2 protein expressions in LPS-stimulated RAW264.7 cells by Western blotting analysis.…”