| Styrene is a kind of compound with styrene skeleton,which has a wide range of applications in biological medicine,materials,physical optics,food and cosmetics and other fields.Styrene compounds with hydroxyl groups have been confirmed to have anti-aging and anti-oxidation effects,and have obvious inhibitory effects on the expansion of tumor cells.In addition,they also have anti-inflammatory and anti-cardiovascular effects,and can enhance immunity in the field of health products.Resveratrol,a phytoalexin found in grapes and other food products,is a styrene compound.As an antioxidant and pro-oxidant agent,it is a common component of the human diet.Tapinarof is an aromatic styrene compound extracted from the secretion of soil nematodes,which can be used as a drug for the treatment of psoriasis and eczema.Psoriasis is an immune-mediated genetic disease that manifestly occurs in the skin or joints or both.It is a serious global problem with at least 100 million individuals,which affects worldwide and brings a great psychological and physical burden to patients.In recent years,more and more drugs have been developed for the treatment of psoriasis,including small molecule drugs targeting retinoic acid receptors and vitamin D receptors,JAK kinases,and biological drugs targeting various inflammatory cytokines including TNF-α,IL-17 A,IL-23,and modulators of CD receptors.Pathogenesis of psoriasis is very complex.Although research has made great progress,psoriasis is still incurable.AhR signaling pathway can regulate gene expression and play a key role in immune system and in regulating skin homeostasis.As an aromatic styrene compound,the efficacy of benvitimod against psoriasis is attributed to its specific binding and activation of AhR(aromatic hydrogen receptor),resulting in down-regulation of proinflammatory cytokines,including IL-17,and regulation of skin barrier protein expression to promote skin barrier normalization.In this paper,we have synthesized a series of new styrene compounds.We have first investigated the effect of these compounds on nitric oxide(NO)production by mouse macrophage-like Raw 264.7 cells and screened out compounds with better anti-inflammatory effects.Then,we have established mouse psoriasis models to test their inhibitory activity on psoriasis skin lesions and studied their mechanism of action on mouse psoriasis.The main research contents and results are as following:(1)A series of new styrene compounds were designed and synthesized,and the structure and purity of the compounds were verified by NMR.(2)MTT toxicity test was carried out in mouse macrophages to investigate the toxicity of the synthesized novel styrene compounds.In addition,the inhibitory activity of these compounds on NO production of mouse macrophages in lipopolysaccharide(LPS)-activated mouse macrophage RAW 264.7 cells were evaluated was explored,and then the novel styrene compounds with better anti-inflammatory effect were screened out.(3)IMQ-induced mice psoriasis damage model was established to select compounds which can significantly improve skin thickness and inflammatory infiltrates.(4)Further study was performed for the most active compound 9J as compared with Tapinarof to explore its repairing effect on psoriasis injury in mice,and understand the underlying mechanism for the treatment of psoriasis.The experimental results showed that the compound 9J can remarkely reduce the expression of inflammatory factors including TNF-α and IL-17 compared with Tapinarof,leading to reducing inflammation in the skin of mice and repairing psoriasis damage.Its mechanism of action may be through inhibition of COX-2,p38 MAPK and NF-κB signaling pathways.In addition,9J can inhibit the proliferation and differentiation of CD8+ T cells,thereby inhibiting the excessive proliferation and abnormal differentiation of keratinocytes to treat psoriasis.Therefore,9J will provides a new potential for the development of new drugs in treating Psoriasis. |
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