| Psoriasis is a chronic,inflammatory skin disease characterized by erythema,scaling,and induration.The dysfunction of skin barrier function is both a initiating factor and a sustained facto in the occurrence and progression of psoriasis.Skin barrier damage in psoriasis is caused by abnormal proliferation and differentiation of Keratinocytes(KCs),dysregulation of skin structural proteins,disruption of epidermal cell connections,lipid abnormalities,dysregulation of skin microbiota,and excessive activation and release of cytokines,according to research.These factors interact,causing inflammatory cells to infiltrate the epidermis and dermis,resulting in typical dry,scaly erythema.Topical preparation is not only an essential component of treating mild to moderate psoriasis,but it also serves as a support technique for treating severe psoriasis.Modern pharmacological studies have shown that Indigo Naturalis multichannels participate in the regulation of psoriasis,but the safety and efficacy of Indigo Naturalis and its polypill in the treatment of psoriasis are still controversial.This study was the first to systematically assess the safety and efficacy of Indigo Naturalis and its polypill for external use in the treatment of psoriasis.The action mechanism of Qingshi Zhiyang Ointment,a typical Indigo Naturalis’s polypill,on the skin barrier was confirmed in a macroscopic-microscopic way through in vivo noninvasive optical imaging technique,histopathology,and cellular molecular science,providing a biological basis for its clinical application.Chapter 1 Meta analysis of efficacy and safety of Indigo Naturalis and its polypill for external use in the treatment of psoriasisObjective:To systematically evaluate the efficacy and safety of Indigo Naturalis and its polypill in the treatment of psoriasis,and to provide evidence-based medical evidence for further clinical application.Methods:A combination of subject words and free words was used to search Chinese databases(CNKI,VIP,WanFang,Sinomed)and English databases(PubMed,Embase,Cochrane Library)for randomized controlled trials of Qingdai preparation for external use in the treatment of psoriasis.The retrieval time is from the establishment of the database to November 28,2022.According to the inclusion and exclusion criteria,Cochrane risk assessment tool(Risk of bias)was used to evaluate the quality of the study,and ReviewManager5.4 software was used to analyze the data.Results:A total of 826 articles were searched,with 3 additional articles obtained from other sources.Finally,the systematic review included 13 studies.The total effective rate,PASI score,recurrence rate,pruritus score,serum IL-17,and safety index outcomes of indigo external use were studied.The results showed that:(1)after excluding a literature with obvious heterogeneity,the effective rate of external use of Indigo Naturalis and its polypill was better than that of placebo and positive drugs(RR=1.48,95%CI[1.18,1.86],P<0.00001);(2)the improvement of PASI score of Indigo Naturalis and its polypill for external use was similar to that of positive drugs(MD=-1.07,95%CI[-3.10,0.95],P=0.30),but significantly better than that of placebo(MD=-3.65,95%CI[-4.58,-2.71],P<0.00001).(3)in terms of safety analysis,the incidence of adverse reactions of Indigo Naturalis and its polypill for topical use was higher than that of placebo(RR=6.33,95%CI[1.15,34.80],P=0.03),but less than that of positive drugs(RR=0.11,95%CI[0.01,0.85],P=0.03).Conclusion:Indigo Naturalis and its polypill for external use have a good clinical effect in the treatment of psoriasis,which could improve the effective rate of clinical treatment,improve PASI score,and has high safety.However,due to the limitation of the quality of the literature,this conclusion needs to be further verified.Chapter 2 Optical imaging to evaluate the regulatory effect of Qingshi Zhiyang Ointment on skin barrier in psoriatic lesions induced by imiquimod in miceObjective:In order to observe the characteristics of skin barrier damage in psoriatic lesions and to investigate the effects of Qingshi Zhiyang Ointment,a imiquimod(IMQ)-induced psoriasis mouse model developed,on skin lesions,epidermis thickness,and epidermis,optical coherence tomography(OCT)and two-photon excited fluorescence microscope(TPM)were introduced into the in vivo and non-invasive optical imaging techniques,which is in order to provide basis for Qingshi Zhiyang Ointment to repair skin barrier function and improve psoriasis lesions and multi-target treatment of psoriasis.Methods:Forty BALB/c male mice were randomly assigned to one of five groups:blank control group(control group),model group(imiquimod cream group),Qingshi Zhiyang Ointment group(Qingshi Zhiyang group),positive control group(calcipotriol group)and negative control group(matrix group).The skin lesions of psoriatic mice were evaluated by corrected Psoriasis Area and Severity Index(PASI)score and trans-epidermal water loss testers and skin water content testers,respectively.Optical coherence tomography(OCT)was used to observe the thickness of epidermis in vivo and non-invasive.The morphology of epidermal cells,the thickness of each layer of epidermis and the thickness of epidermis were observed in vivo and non-invasively by two-photon excited fluorescence microscope(TPM).Results:Qingshi Zhiyang Ointment could lessen the erythema,scales,and infiltration of skin lesions caused by IMQ in psoriatic mice,and the PASI score’s declining trend is superior to that of the matrix and on par with that of calcipotriol.On Day 5,Qingshi Zhiyang Ointment ’s curative effect outperformed that of the matrix(P<0.001),and its therapeutic effect on reducing transepidermal water loss(TEWL)was comparable to that of calcipotriol(P>0.05).On Day 9,Qingshi Zhiyang Ointment’s curative effect on reducing TEWL was comparable to that of the model,matrix,or calcipotriol.The Qingshi Zhiyang Ointment had the ability to raise the skin’s water content,which was superior to the matrix(P<0.0001),and had a therapeutic effect comparable to that of calcipotriol(P>0.05).The OCT test results showed that Qingshi Zhiyang Ointment could prevent the epidermis from becoming overly thick,encourage the normalization of the distribution and expression of each epidermal layer,maintaining the stability of the skin barrier structure.TPM demonstrated that Qingshi Zhiyang Ointment could restore the tight junctions among epithelial cells,promote the maturation of granular layer cells,reduce the enlarged cell bodies of spinous layer cells and basal layer cells,inhibit the proliferation of KCs in epidermis,particularly inhibit the abnormal thickening of spinous layer,reduce the thickness of epidermis(excluding stratum corneum),and promote the morphology,delamination and keratosis of epidermal cells to return to normal.The inhibitory effect of Qingshi Zhiyang Ointment on epidermal hyperplasia was better than that of matrix(P<0.01),and the effect was similar to that of calcipotriol(P>0.05).Conclusion:Qingshi Zhiyang Ointment could effectively improve the skin damage of psoriasis-like mouse model,reduce PASI score and TEWL,increase skin water content,inhibit abnormal proliferation of KCs,normalize the process of epidermal keratosis,restore the normal morphology,arrangement and distribution of cells in each layer of epidermis,ensure the stability of "brick wall structure" of skin,and play an anti-psoriatic effect.Chapter 3 Effect of Qingshi Zhiyang Ointment on Epidermal structural proteins in psoriatic lesions induced by IMQObjective:Through the establishment of a mouse model of psoriasis induced by IMQ,the effects of Qingshi Zhiyang Ointment on histopathology,epidermal structural protein,microvascular proliferation and inflammatory factors in psoriatic lesions were observed,and the multiple effect targets of Qingshi Zhiyang Ointment on the regulation of skin barrier were further clarified,which provided ideas for the external treatment of psoriasis by dredging Xuanfu.clearing heat and detoxification,cooling blood and eliminating erythema.Methods:Forty BALB/c male mice,after hair removal,were randomly divided into five groups,each with eight mice:the control group,the model group,the positive control group(calcipotriol group),the negative control group(matrix group),and the Qingshi Zhiyang Ointment group(Qingshi Zhiyang group).Hematoxylin-eosin(HE)staining was used to assess the histological alterations of skin lesions.Immunohistochemical(IHC)analysis was used to assess the expression of proliferating cell nuclear antigen Ki 67,keratin 10(KRT10),Vascular endothelial growth factor(VEGF)and epidermis structural proteins(Claudin-1,Claudin-7,Occludin,Loricrin,and Filaggrin)in skin lesions.Real-time fluorescence quantitative polymerase chain reaction(qRT-PCR)was used to assess the mRNA expression of tumor necrosis factor(TNF-α),interleukin(IL)-6,and IL-22.Results:Qingshi Zhiyang Ointment could inhibit the epidermis thickening of skin lesions,which was better than that of matrix(P<0.001)and similar to that of calcipotriol(P>0.05).The curative effect of Qingshi Zhiyang Ointment was better than that of matrix in improving the overall skin thickness(P<0.001),but not as effective as calcipotriol(P<0.001).Qingshi Zhiyang Ointment could upregulate KRT10 expression while downregulating Ki 67 expression in psoriatic mice,whose curative effect was comparable to calcipotriol(P>0.05)and superior to matrix(P<0.05).Qingshi Zhiyang Ointment t could downregulate VEGF expression in psoriatic mice,whose curative effect was comparable to calcipotriol(P>0.05)and superior to matrix(P<0.05).Qingshi Zhiyang Ointment could up-regulate the expression of epidermal structural proteins(Filaggrin,Loricrin,Claudin-1,Claudin-7,Occludin)in skin lesions,whose curative effect was superior to that of matrix(P<0.05)and comparable to that of calcipotriol(P>0.05).Qingshi Zhiyang Ointment had the same curative effect as calcipotriol(P>0.05),which could inhibit the mRNA expression of TNF-α,IL-22 and IL-6,and was better than matrix in inhibiting the mRNA expression of TNF-α and IL-22.Conclusion:Qingshi Zhiyang Ointment could inhibit the abnormal proliferation of KCs in an IMQ-induced psoriatic mouse model,promote normal keratin expression,improve microangiogenesis,inhibit the high expression of TNF-α,IL-6,and IL-22 mRNA,and upregulate the low expression of Claudin-1,Claudin-7,Occludin,Loricrin,and Filaggrin.Furthermore,this study found that Qingshi Zhiyang Ointment matrix could reduce PASI score and TEWL to some extent,inhibit high expression of Ki67 and VEGF,up-regulate low expression of KRT10 and Occludin,and inhibit TNF-α mRNA overexpression,which somewhat aided in the lessening of psoriasis lesions.Summary:In this study,the non-invasive optical imaging technique was used for the first time to confirm that the psoriasis-like mouse model induced by IMQ had numerous manifestations of skin barrier damage.The abnormal proliferation and inflammation of KCs were inhibited,the expression of epidermal structural proteins increased,the keratinization process tended to be normal,and the skin damage was significantly reduced by using Qingshi Zhiyang Ointment.This suggests that inhibiting the abnormal activation of KCs and combating the cascade reaction of inflammation may be the main mechanisms by which bluestone antipruritic ointment repairs the skin barrier.This study further enhances the external treatment of psoriasis by offering a fresh experimental foundation for clinical application of Indigo Naturalis and its polypill. |
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