Study On The Effect And Mechanism Of Quinoline Derivatives As Topo ? Inhibitors With Potent Anti-psoriasis Activity

Psoriasis has the symptoms such as silver crumbs and thickening of the skin in clinic.The symptoms are troubled patients.Psoriasis disease relapses easily and difficult to cure.Psoriasis is a chronic inflammatory and immune-mediated skin disease characterized by skin cutin cell hyperproliferation,poor differentiation of keratinocytes and new angiogenesis new angiogenesis.Although anti-psoriasis drugs have shown clinical successfully in treating psoriasis,but anti-psoriasis drugs associated with side effects.Hence,it is urgent to develop the new drugs for the treatment of psoriasis.DNA Topoisomerase ?(Topo ?)is a basic enzyme exists in the nucleus.Topo ? play an important role in all aspects of the DNA biological response(including DNA transcription,replication,and chromosome segregation).Topo ? is overexpressed in rapidly proliferating cells,and the Topo ? inhibitor camptothecin(CPT)can inhibit the proliferation of human keratinocyte(HaCaT)and promote the differentiation of HaCaT from inhibit the abnormal proliferation of HaCaT cells.CPT can significantly inhibit the formation of mouse tail squama epidermal granular layer.The study has shown that there are two kinds of Topo ? inhibitors(Novobiocin and Naphthalene organism keto acid)have a significant effect in treatment of psoriasis.Novobiocin and Naphthalene organism keto acid's mechanism of resistant psoriasis is inhibitted cutin cell proliferation and induced its apoptosis,inflammation factors and the expression of related genes.Research suggests that DNA Topo ? inhibitors may have potent psoriasis-ameliorating effects.In our work,the study of interacting between Topo ? inhibitors and targets of psoriasis,and the effect and mechanism of Topo ? inhibitors on anti-psoriasis were included.The main works and results in this thesis are shown as follow:(1)The research progress of psoriasis has carried on the summary,the research progress of Topo ? inhibitors and biological activity analysis.The literature,the research progress of psoriasis has carried on the summary,the research progress of Topo ? inhibitors and biological activity analysis.(2)To study the compounds of Topo ? inhibitory activity and mechanism.It was found that 5i and 5l had good inhibitory activity on Topo ? at the concentration of 20 ?M.The anti-inflammatory activity of 5i and 5l at the concentration of 50 mg/kg/day showed a good activity(inhibition of 83.7% and 69.3%,respectively)(3)To establish mouse psoriasis model induced by imiquimod(IMQ)and study the anti psoriatic effect of 5i and 5l.Experiments showed that compounds 5i and 5l could reduce the formation of psoriasis scales,alleviate inflammation and smooth skin on the back of mice(4)To explore the anti-psoriasis mechanism of 5i and 5l,In vitro studies we use lipopolysaccharide(LPS)to stimulate HaCaT,to build the LPS inflammatory cells model.Through experiment of CCK-8 to test the compounds inhibit HaCaT proliferation activity.By Real-time PCR method,we detected inflammatory factors of TNF-?,IL-6,IL-1 and IL-17 mRNA content.Experiments prove that HaCaT cells can reduce the generation of inflammation factors by the intervention of 5i and 5l.By immunohistochemistry and RT-PCR and Western blot experiments were used to detect the skin tissue samples from the back of mice.The expression levels of proinflammatory and immune factors,such as proinflammatory factors(TNF-?,IL-17,IL-22,IL-23 NF-?B and IFN-?)were dramatically inhibited in the dorsal skin of 5i and 5l treated mice.To analysis the anti-psoriasis action mechanism of quinoline compounds 5i and 5l.