| The dose is the criterion to estimate the curative effect,and the curative effect is the criterion to test the success or failure of the treatment.Throughout the ages,there has been a Chinese medicine dose is not transmitted.As Zhu Liangchun,a famous Chinese doctor,said,"....For the same drug,due to the different dosage,it is possible to have different efficacy or even new therapeutic function,which may play a greater role.As early as Zhang Zhongjing's Treatise on Miscellaneous Diseases of Typhoid Fever,there are records on the difference of drug dose and effect.For example,when comparing guizhi decoction with guizhi decoction and shaoyao decoction,there is only a difference in the "dosage" of "peony" in the composition,but there is a huge difference in clinical indications.The former is used to treat Taiyang Diseases.The latter is used for the treatment of Taiyin Diseases caused Taiyang Diseases which was defecate wrongly.Traditional Chinese medicine(TCM)is a complex of many monomer molecules,and its metabolism can produce multiple pharmacological effects through multiple pathways and multiple targets.This pharmacological effect cannot be simply explained by the "Dose-effect" relationship.The variation of the pharmacodynamic site should also be explained along with the variation of the pharmacodynamic intensity.In view of this,we put forward a new perspective and a new concept to understand TCM – "Dose-position" relationship." "Dose-position" relationship of TCM: it refers to the phenomenon that the effect site(target organ)of TCM changes with the dosage in the clinical application process.The organic combination of "Dose-effect" relationship and "Dose-position" relationship can make a more "comprehensive and objective" evaluation of TCM and guide the clinical application of TCM more reasonably.Taking Angelica sinensis as an example,this research investigated and analyzed the effects of different dosage of angelica on constipation and alopecia areata model mice,to explore the changes of "dose and effect" and "dose and position" of different doses of Angelica sinensis in the models of constipation and alopecia areata by means of constipation and alopecia areata models,interpreted the changes of "dose and effect" of different doses of Angelica sinensis in colon and skin,and provided experimental support for the new concept of "Dose-position" relationship of TCM.Part ?: Effects of different doses of angelica sinensis on laxative effect of constipation model miceMethods: 40 male KM mice were randomly divided into blank control group,model group,low dose,medium dose and high dose groups.The mice were yellow,less exercise and less food,indicating that the model was successfully constructed.Fecal moisture content,intestinal propulsion rate,Western Blot and Immunohistochemical analysis of colon AQP4 expression were detected.The contents of AC,cAMP,PKA and serum IL-10,ICAM-1 and ELAM-1 in the colon of mice were detected by ELISA and HE staining respectively,and the number of hair follicles per unit visual field was calculated.At the same time,the hair growth in the hair removal area on the back of the mice was evaluated.Results:(1)Different doses of angelica can improve the fecal moisture content and intestinal propulsion rate of constipation model mice,reduce the contents of AC,cAMP and PKA in the colon,and down-regulate the expression of colon AQP4.The high dose group(40g)has the best defecation effect(P<0.05).(2)The skin gloss and hair density of constipated mice in the three dose groups were better than those in the model group,but there were no statistically significant differences in hair score,number of hair follicles per unit visual field,and serum IL-10,ICAM-1,and ELAM-1 between the groups(P>0.05).Conclusion: Angelica sinensis has a purgative effect on constipated mice,and the high dose effect is the best.The mechanism may be to reduce the content of various factors in the AC-cAMP-PKA signaling pathway,down-regulate the expression of AQP4 in the proximal colon,reduce the absorption of intestinal water,increase the intestinal water content,and give play to the "moistening and defecating" effect.Part ?: Effects of different doses of angelica sinensis on hair generation in alopecia areata model miceMethods: 8% sodium sulphide solution was applied topically to make aloparea areata model.Forty male KM mice were randomly divided into blank control group,model group,low dose,medium dose and high dose groups.Levels of IL-10,ICAM-1 and ELAM-1 in serum of mice were detected by ELISA and hematoxylin(HE)staining,respectively,and the number of hair follicles per unit of visual field was calculated.At the same time,the hair growth in the hair removal area on the back of the mice was evaluated.Fecal moisture content,intestinal propulsion rate,WB and IHC methods were used to detect the expression of AQP4 in the colon,and the contents of AC,cAMP and PKA in the colon of mice were detected by ELISA method.Results:(1)Compared with the model group,the three dose groups of angelica can improve the fecal moisture content,intestinal propulsion rate,reduce the content of AC,cAMP and PKA in the colon,and down-regulate the expression of AQP4 in the colon,among which the high dose group has a significant laxative effect(P<0.05).(2)Different doses of Angelica sinensis can improve hair score in depilating area,number of hair follicles per unit visual field and serum IL-10 level in bald mice,and reduce serum ICAM-1 and ELAM-1 levels.Medium dose group(20g)has the best hair growth effect(P<0.05).Conclusion: Angelica sinensis has hair growth effect on alopecia areata mouse model,and medium dose is the best.Its hair growth effect effect may inhibit the migration and chemotaxis of inflammatory cells by reducing serum ICAM-1 and ELAM-1 levels,and reduce the activation of pro-inflammatory white blood cells attacking hair follicles.Inhibits T lymphocyte infiltration into the hair follicle,alleviates inflammatory and immune damage caused by hair follicle cells,and treats hair loss.It is also possible to increase serum IL-10 level,inhibit mTOR signaling pathway,regulate BMP,promote HFSC activation,regulate hair follicle cycle,and promote hair growth.The research conclusion:1.Angelica can promote gastrointestinal peristalsis by regulating relevant factors of intestinal peristalsis,reducing the contents of AC,cAMP and PKA in the colon,down-regulating the expression of AQP4 in the proximal colon,reducing the absorption of intestinal water,increasing the intestinal water content,and giving play to the effect of "moistening and defecating the intestine".Angelica can reduce the level of ICAM-1 and ELAM-1,inhibit the migration and chemotaxis of inflammatory cells,reduce the inflammatory and immune damage to hair follicle cells,and treat hair loss.At the same time,it can increase IL-10 level,inhibit mTOR signaling pathway,regulate BMP signal,promote HFSC activation,regulate hair follicle cycle and promote hair growth.It is also possible to restore the dynamic balance of Th1/Th2 by upregulation of Th2 cell function to play an immunomodulatory role and promote hair regeneration.2.The dose-effect relationship of angelica sinensis in mice with constipation model and alopecia areata model was different.In the constipation model mice,defecation effect was observed in all three dose groups,among which high dose(40 g)had the best defecation effect,with a "dose-effect" relationship.In alopecia areata model mice,germination effect was observed in all three dose groups,among which the medium dose(20 g)showed the best germination effect,with a "dose effect" relationship.3.When the dose of angelica sinensis varied from 20 g to 40 g,the optimal "site" of efficacy of angelica sinensis changed from "skin hair" to "colon",indicating the "quantum position" relationship of angelica sinensis in colon and skin.This is providing experimental support for the new concept of "quantity-position" relationship of traditional Chinese medicine,which is also the innovation of this experiment.The reason for the relationship between "quantum position" and "quantum position" in traditional Chinese medicine(such as differences in drug composition and solubility,etc.)will be our next research direction. |
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