Clinical Basis And Mechanism Study Of Modified Simiao Yong'an Prescription In The Treatment Of Acute Radiation Dermatiti

BackgroundAcute Radiation-induced Dermatitis(ARD)is a common adverse reaction after radiotherapy.At present,there is no standard treatment plan for western medicine,and most clinical trials have poor or contradictory results.In traditional Chinese medicine(TCM),ARD belongs to the categories of "Huo Ban Chuang","Dan","Zi Dian" and " skin and external diseases",showing the characteristics of Yang.The heart is the most abundant organ of Yang Qi,which can promote the flow of qi and blood around the whole body.When the heart of Yang Qi is hyperactive,the skin symptoms also show the characteristics of "Yang",which is the same with the main characteristics of ARD.It is the concrete embodiment of "Yang" and "on the surface" of " all the problems with itching and pain can be blamed on the heart " in the theory of " heart governing exterior ".In addition,Jia-Wei-Si-Miao-Yong-An Fang(JWSMYA)has achieved clinical effect in the treatment of ARD.There are a total of 9 herbs in the prescription,5 of which enter the heart channel of Hand-shaoyin.Therefore,from the perspective of " heart governing exterior" and JWSMYA,the guiding significance of this theory in the treatment of ARD,the law of medication and the mechanism of promoting skin damage repair were discussed,which has a great clinical application prospect.Objectives1.Theory to explore the significance of "heart governing exterior" guiding treatment of ARD.2.Meta-analysis of clinical advantages of TCM topical preparations in guiding the treatment of ARD based on the theory of "heart governing exterior".3.Data mining was conducted on the medication characteristics of TCM external preparations guided on the theory of " heart governing exterior",and the key components and possible targets of herbs based on JWSMYA which entering the heart channel of Hand-shaoyin in promoting ARD repair were analyzed.4.Guided by the theory of "heart governing exterior ",the possible mechanism of JWSMYA in promoting ARD repair was discussed.Methods1.Discussion on the theory of "heart governing exterior ".Previous literature was retrieved,and the significance of "heart governing exterior "theory in guiding the treatment of ARD was discussed through the disease position,characteristics and clinical application,and in connection with the characteristics of ARD and the effect of JWSMYA which entering the heart channel of Hand-shaoyin were discussed.2.Meta-analysis was conducted to explore the clinical efficacy of "heart governing exterior"theory in the treatment of ARD.Randomized controlled clinical trials of traditional Chinese medicine(TCM)external preparations for the treatment of acute radiation-induced dermatitis were retrieved from Web of Science,Embase,PubMed,Cochrane Library Wanfang,VIP and CNKI self-established libraries until December 1,2022,in which more than half of TCM external preparations except excipients were required to enter the heart channel of Hand-shaoyin.Literature screening and data extraction were conducted by two researchers,and meta-analysis was performed using Rev Man 5.4 software provided by Cochrane to analyse skin response grade,radiation dose and dermatitis,clinical response rate,pain,time to first appearance of dermatitis,and time to healing.3.Based on data mining of the characteristics of TCM external preparations guided by the theory of "heart governing exterior" to analyses the key components and possible targets of drugs into the heart channel.Literature on the treatment of ARD with TCM external preparations published in Wanfang,VIP and CNKI from January 2002 to January 2022 were searched.The database was established by Execl software and the main description of the herbs entering the heart channel of Handshaoyin was carried out.After ranking the drugs entering the heart channel of Hand-shaoyin,those with top ranking were selected for network pharmacological study.Then screening the targets of herbs and diseases,the intersection target PPI network was established through the String database.At last,the possible mechanism of "heart governing exterior" theory in the treatment of ARD was clarified through GO and KEGG enrichment analysis.4.The experiment explored the mechanism of JWSMYA to promote ARD repair guided by the theory of "heart governing exterior".The left hind limb of SD rats was irradiated by Swedish Medical linear accelerator to establish ARD model.ARD skin response score,skin healing rate and histological staining were used to observe skin healing.In addition,immunohistochemical staining,Western blotting analysis,qRT-PCR and Elisa were used to investigate the mechanism of skin repair and antifibrosis.Results1.Discussion on the theory of "heart governing exterior".In view of skin injury,the "heart governing exterior" of the "exterior ",should be exchanged with the "surface" of the "heart governing face",that is,refers to the skin,muscle,blood.The characteristics of the heart is fire and summer is main qi,its characteristics belong to Yang,skin and epidermis are also managed by it.When the Yang qi of the heart running obstacles and blood transport difficulties,because the characteristics of fire is upward,so the damage in the skin have the characteristics of Yang.ARD is a special dryness disease,causing obstructing Qi and blood,damaging Qi and Yin and invading blood.The basic treatment is to clear heat,cool blood,promote blood circulation,and tonify qi and nourish Yin.The location of ARD and the characteristics of Yang are consistent with " heart governing exterior".In clinical application,the method of regulating the mind can treat the dermatitis with the Yang characteristics.In addition,JWSMYA created based on the theory of "heart governing exterior",which has 5 herbs into the heart channel of Hand-shaoyin,and has significant curative effect in the treatment of ARD.Therefore,from the analysis of disease characteristics and clinical application,the theory of " heart governing exterior" is consistent with ARD.2.Meta-analysis was conducted to explore the clinical efficacy of " heart governing exterior " theory in the treatment of ARD.A total of 16 RCTs with 1480 patients were included.Compared with western medicine or conventional nursing.TCM external preparation guided by the theory of " heart governing exterior " can prevent the development of severe radiation-induced dermatitis from skin injury[OR=2.13,95%CI(1.06,4.28),P=0.03],[OR=0.27,95%CI(0.19,0.39),P<0.00001].There are significant statistical differences in improving clinical response rate[OR=6.51,95%CI(3.61,11.74),P<0.00001]and relieving pain[OR=0.04,95%CI(0.02,0.09),P<0.00001].Compared with western medicine,there was no statistical difference in the incidence of ARD prevention under certain irradiation dose[OR=1.11,95%CI(0.08,15.09),P=0.94],[OR=6.51,95%CI(3.61,11.74),P<0.00001].However,there were statistically significant differences in delaying the occurrence time of radiation-induced dermatitis[MD=-4.93,95%CI(-7.07,-2.80),P<0.00001]and accelerating wound healing[MD=-4.93,95%CI(-7.07,-2.80),P<0.00001].3.Based on data mining of the characteristics of TCM external preparations guided by the theory of "heart governing exterior" to analyses the key components and possible targets of drugs into the heart channel.From the perspective of herbal classification,it was found in the theory of " heart governing exterior " and ARD data mining that the herbs entering the heart channel of Handshaoyin were mainly heat-clearing herbs and blood-activating herbs for removing blood stasis.In terms of herbal properties,cold and peace herbs were were used frequently,the main herbs were heat-clearing and blood-activating herbs.Among the herbal tastes,salty herbs was the main characteristic of the heart channel of Hand-shaoyin,followed by sweet,hot and bitter.Among the four herbal tastes,heat-clearing herbs were also the main classification.In terms of therapeutic principles,the main therapeutic principles were activating blood circulation and generating muscle when the proportion of herbs which entering the heart channel of Handshaoyin in each prescription was less than 50%.Among the prescriptions that accounted for more than 50%,promoting blood circulation,cooling blood and generating muscle were the main treatment principles,and more than half of the prescriptions used more than 50%of herbs which entering the heart channel of Hand-shaoyin.After sorting all the herbs entering the heart channel of Hand-shaoyin,it was found that the first 7 flavors of herbs included all the 5 flavors of JWSMYA which entering the heart channel of Hand-shaoyin:Borneolum Syntheticum,Arnebiae Radix,Angelicae Sinensis Radix,Lonicerae Japonicae Flos and Glycyrrhizae Radix et Rhizoma.Therefore,through the network pharmacological study of these 5 herbs,it was found that Quercetin,kaempferol,apigenin and other key chemical components mainly play their roles through inflammatory pathways(IL6,TNF signaling pathway,IL-17 signaling pathway,toll-like receptor signaling pathway)and cell cycle regulation pathways(PI3K/AKT signaling pathway,MAPK signaling pathway,CASP3,TP53,VEGFA).4.The experiment explored the mechanism of JWSMYA to promote ARD repair guided by the theory of "heart governing exterior".In vivo experiments showed that the JWSMYA based on the theory of " heart governing exterior" can effectively reduce the dermatitis score,improve the healing rate of skin lesions,reduce the wound area,promote the regeneration of skin appendages,reduce inflammatory cell infiltration,activate MAPK/ERK phosphorylation,inhibit the activation of PI3K/AKT,reduce the levels of α-sma,Col1a2 and TGF-β1 in skin tissue.There was no statistical difference between VEGF groups,but there was an increasing trend.Conclusion1.Skin diseases characterized by Yang syndrome,such as ARD,are in line with "all kinds of pain and itching sores belong to the heart" theory.In addition,the JWSMYA,which the mainly herbs were entering the heart channel of Hand-shaoyin,has significant curative effect on ARD from the perspective of "heart".Therefore,the theory of "heart governing exterior "can be used as one of the theories for the treatment of ARD to a certain extent.2.Compared with western medicines or conventional nursing,the topical preparation created guided by the theory of " heart governing exterior " has significant advantages in the classification of ARD,clinical effective rate,pain relief,time of first occurrence of dermatitis and healing time.The therapeutic effect is comparable to that of Western medicine in the irradiation dose and incidence of dermatitis.Therefore,the theory of " heart governing exterior"can be used as one of the theories to treat ARD.3.Under the guidance of the theory of "heart governing exterior",the herbs for external use of TCM preparation which entering the heart channel of Hand-shaoyin are often heatclearing herbs with cold and bitter characteristics and blood-activating herbs to remove blood stasis.The herbs which could promote blood circulation,cool blood and generate muscle played role in promoting the repair of ARD.In addition,network pharmacological studies found that quercetin,kaempferol,apigenin and other key chemical components of herbs which entering the heart channel of Hand-shaoyin mainly play their roles through inflammatory pathways and cell cycle regulation pathways.Therefore,the "heart governing exterior " theory may promote the repair of ARD by regulating inflammation and cell cycle pathways.4.JWSMYA,which is based on the theory of "heart governing exterior ",can promote the expression of VEGF to accelerate the repair of skin lesions by activating MAPK/ERK pathway,and reduce the secretion of a-sma,Colla2 and TGF-β1 to inhibit the formation of fibrosis by inhibiting PI3K/AKT pathway.These studies indicate that the "heart governing exterior "theory can promote rapid and high-quality ARD repair through the MAPK/ERK and PI3K/AKT pathways.