Pollution has strong impact on the ecosystem and human health due to chronic exposure (1). In China, the amount of anthropogenic arsenic (As) is a big challenge as As emission is high in current industrialized scale (2). Other studies report that As exposure acts in a dose-effect manner in different tissues, such as the skin system (3). Toxicologic mechanisms have revealed that As-induced cytotoxicity may be involved in cellular oxidative stress, apoptosis, thiamine deficiency, and acetyl cholinesterase loss (4). In China, As-related skin lesions in patients have been linked to chronic exposure to As, resulting in poor skin health and quality of life (5). Other mechanical evidence shows that As-induced skin impairment may be involved in the activation of miR-155-5p, keratin 1, keratin 10, and keratin 6c in dermal samples (6). Additionally, occupational contact dermatitis is often observed in workers with prolonged exposure to As (7). Hence, there is an urgent need for effective procedures to reduce As-induced dermal toxicity. Vitamin A (VA), a well-known nutrient substance, is used extensively in medical treatment and health care due to its multi-functional features (8). Low-serum VA levels have been linked to inflammation in participants with retinol deficiency (9). VA deficiency has been reported to mediate some actions in the pathophysiology of atopic dermatitis via potentiating T-cell-related inflammation development (10). Meanwhile, primary clinical findings indicate that VA supplementation may relieve atopic dermatitis in children (11). There are reports that the physiological actions of VA are associated with the enhancement of skin immunity and maintenance of dermal microbiome (12). However, there are no reports regarding the anti-As-linked dermatitis activity and drug targets of VA treatment. As a drug development tool, network pharmacology is adequate for potential drug discovery in pharmacological target and mechanism in the treatment of clinical diseases (13, 14). Moreover, our group research findings based on network pharmacology approach and molecular docking analysis have been published, including the use of vitamin C against leukemia (15), sepsis (16), and calycosin for the treatment of meningitis (17) and cerebral ischemia/reperfusion injury (18). Therefore, in this study, we aimed to determine the therapeutic effects of VA against As-linked dermatitis and core drug targets in silico and to reveal the pharmacological pathways on the basis of network pharmacological assay and molecular docking technology.

Repurposing an existing drug can be achieved through bioinformatics analysis, such as network pharmacology approach (14). Identifying the existing VA drug with multiple targets may be potentially useful against some clinical diseases, such as COVID-19 (28). In this study, a bioinformatics methodology for complete identification of repurposing VA is used to predict the pharmacological mechanisms for potential treatment of dermatitis associated with As, a cytotoxic metallic element. Integration analysis of VA-target-pathway-dermatitis related to As findings and complete identification of PPI networks are essential for further biological structural docking. With network pharmacology determination, we recognized 62 candidate targets and 29 core drug targets in VA for treating As-related dermatitis. As shown in all core targets, JUN, TP53, MAPK3, MAPK1, MAPK14, IL6, AKT1, STAT1, FOS, ESR1, TNF, CREB1, IL10, IL2, SP1, CASP3, CDKN1A, IL4, EGFR, IL1B, MCL1, BCL2, CXCL8, TGFB1, IFNG, BCL2L1, NOS2, CCL2, and VEGFA were identified to be virtually associated with As-related dermatitis. Cytokines have been proven to possess pro-inflammation and immunodepression actions. Cytokines have developed promptly, leading to the induction of dermatitis (29). Previous evidence has suggested that As impacts the production of inflammatory cytokines in the skin, causing allergic dermatitis (30). VA is well evidenced as an anti-inflammatory micronutrient as it has a key role in heightening immune function (31). Thus, the anti-inflammatory action of VA is employed in pharmacologically treating As-related dermatitis. Low concentration of arsenic trioxide may induce human keratinocyte growth but concomitantly affects the DNA transcription function (32). Cyclins are the potential biomarkers of mild atopic dermatitis, characterized by molecular signatures in dermatitis cases (33). Additionally, it is important to note the modulation of the cyclin pathway in the treatment of As-related dermatitis with VA. As shown in further molecular docking imitation, in silico findings suggested that VA structurally docked well with some core target proteins, including JUN, TP53, MAPK3, MAPK1, and MAPK14. JUN can directly interact with specific target DNA sequences to regulate gene expression (34). JUN is one of the most important components of the activated protein-1 (AP-1) transcription factor complex, in which the increase in AP-1 activity can promote inflammation (35). In addition, c-Jun/AP-1 may serve as a potential pharmacological target in psoriatic skin inflammation by regulating immune responses (36). TP53 is a well-known anti-apoptotic gene. In the event of functional loss, TP53-induced systemic inflammation occurs and evolves over time (37). Clinical observations have revealed abnormal p53 immunoreactive patterns in human skin lesions (38). MAPKs, such as MAPK3, MAPK1, and MAPK14, are signal regulators that are responsible for cell proliferation, apoptosis, and survival through the regulation of inflammatory cytokines and growth factors (39). In particular, MAPK3 is activated through inflammatory cytokines and extracellular stimulation (40). Thereby, immediate modulation of MAPK activation may be another molecular mechanism for VA action in the treatment of As-related dermatitis. In this study, we proposed a computational methodology for the prediction of the VA compound for treatment against As-related dermatitis, detailed with core targets and pharmacological mechanisms. One of the limitations of our study is that our findings were mostly collected from publicly available databases, and some of the correlative data may be incomplete. As potential limitations in this study, preclinical study needs to be determined for in vitro therapeutic effectiveness and adverse actions in vivo prior to future clinical validation.

This study provides a potent, integrative pharmacological approach for the effective identification of repurposing VA as a potential therapy for As-related dermatitis. Using this bioinformatics methodology, we can reduce the translational period in clinical trials, resulting in rapid therapy strategy for the use of VA in As-related dermatitis.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

CG and BY contributed to the conception, design of the manuscript, drafted the manuscript, and revised the manuscript. QQ, LQ, RX, and SP contributed to the acquisition, analysis, and interpretation of data in the manuscript. All authors agreed to be accountable for all aspects of work ensuring integrity and accuracy.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.