CN111679045A - Method for screening active ingredient groups in different processed products of curcuma aromatica by using bivariate correlation analysis method - Google Patents
Method for screening active ingredient groups in different processed products of curcuma aromatica by using bivariate correlation analysis method Download PDFInfo
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Abstract
The discovery of active ingredients related to the drug effect of the traditional Chinese medicine is a recognized difficulty in the field due to the diversity of the traditional Chinese medicine ingredients and the self characteristics of synergistic action. The invention provides a method for screening active ingredient groups in different processed products of common turmeric by a bivariate correlation analysis method, which comprises the following steps: measuring the change rule of the blood-entering components and the pharmacodynamic indexes of different processed products of the curcuma wenyujin along with time, and carrying out bivariate correlation analysis on the component change and the pharmacodynamic index change. With the method, three active ingredients of rhizoma Wenyujin Concisa, rhizoma Curcumae, and rhizoma Curcumae Longae with effects of promoting blood circulation and removing blood stasis can be obtained; in addition, although the blood-entering components of the rhizoma wenyujin concinnatae are more, the correlation of the efficacy of the rhizoma wenyujin concinnatae is poorer than that of the raw rhizoma wenyujin concinnatae and the vinegar rhizoma wenyu, the quantity of the blood-entering components of the vinegar rhizoma wenyujin concinnatae is reduced, but the correlation with the efficacy index is very obvious. The method provided by the invention defines the relevance and the similarities and differences between the blood-entering components and the effects of promoting blood circulation to remove blood stasis of the three decoction pieces, and provides a detailed material basis for the research of the traditional Chinese medicine effect and the processing mechanism, the guidance of clinical practice and the development of traditional Chinese medicine products.
Description
Technical Field
The invention belongs to the technical field of traditional Chinese medicine active ingredient group screening, and particularly relates to a method for screening active ingredient groups in different processed products of curcuma wenyujin by a bivariate correlation analysis method.
Background
The traditional Chinese medicine has various components and wide effect, and exerts the self characteristics of the drug effect through synergistic action, the whole component proportion of different processed varieties of the same medicinal material is obviously changed, except for quantitative change of some varieties, new components can be generated before and after processing, and the change of the material basis can be an important reason for the difference of the drug effect. However, it is more difficult to find active ingredients related to drug effect from a plurality of chemical ingredients and explain the action relationship between the active ingredients and the improvement of drug effect, which becomes a bottleneck restricting the forward progress of basic research of traditional Chinese medicine decoction pieces and large and medium-sized medicine products. With the rapid development of computer statistical analysis technology in recent years, the spectrum effect of traditional Chinese medicine is gradually rising, and becomes an important method for traditional Chinese medicine researchers to search the action relationship between the chemical components and the drug effect of traditional Chinese medicine, and after the development of over ten years, the spectrum effect research is widely applied and has remarkable effect in the research on the aspects of drug effect substance basis, process design and optimization, component combined compatibility, processing mechanism, drug effect prediction and evaluation and the like of single medicine and compound preparations thereof, the chemical fingerprint spectrum of traditional Chinese medicine is associated with drug effect indexes, data processing is carried out by adopting computer mathematical statistical methods such as grey correlation degree, bivariate correlation analysis, artificial neural network and the like, the internal relationship between the components and the drug effect is explored, a spectrum-effect relationship model is established, so as to find out the active ingredient group closely related to the drug effect and more objectively and reasonably clarify the action mechanism of the traditional Chinese medicine and the compound preparation thereof.
Different processed products of the common turmeric are clinically common medicines for promoting blood circulation and removing blood stasis, and modern pharmacological and clinical researches show that the principal components of the turmeric rhizome are volatile oil and curcumin components, and the β -elemene, germacrone, curdione, curcumenol and other components contained in the volatile oil have stronger physiological activity and have better effects on the aspects of tumor resistance, bacteria resistance, virus resistance and the like[11-13]. The chemical components of the processed curcuma zedoary are obviously changed, and documents show that the content of (4S,5S) -germacrone-4,5-epoxide in the raw curcuma zedoary obtained by steaming is obviously increased by nearly 13 times, the content of curzerene is increased by 3 times and the content of curcumenone is increased by 4 times, compared with that of curcuma zedoary, and the reason is probably caused by thermal rearrangement reaction of heat-sensitive components under heating condition; the three decoction pieces have different effects due to the obvious change of material basis, the rhizoma wenyujin concubine is good at breaking blood and moving qi, the rhizoma zedoariae is good at moving qi and relieving pain, and the rhizoma wenyujin concubine is mainly in liver meridian blood after being processed with vinegar and is good at breaking blood and dissolving stasis. However, the three decoction pieces have good effects of promoting blood circulation and removing blood stasis, so that clinical medication is disordered, and the three decoction pieces have the best clinical curative effect to a certain extent.
The invention analyzes the dynamic change process of the main blood-entering components of different processed products of the curcuma wenyujin along with the change of time and the dynamic process of the pharmacodynamic indexes of the blood rheology, the blood coagulation and the like along with the change of time by adopting statistical methods such as grey correlation degree and the like, finds out the main active components playing the roles of promoting blood circulation and removing blood stasis in the different processed products of the curcuma wenyujin, provides a research basis for the elucidation of the functions and mechanisms of promoting blood circulation and removing blood stasis of the three processed products, and simultaneously provides a demonstration for the elucidation of the.
Disclosure of Invention
The invention provides a method for screening active ingredient groups in different processed products of radix curcumae by a bivariate correlation analysis method aiming at the technical problem that active ingredients related to the drug effect of different processed products of radix curcumae are unknown, which is characterized in that: measuring the change rules of the blood-entering components and the pharmacodynamic indexes of different processed products of the curcuma wenyujin along with time, carrying out bivariate correlation analysis on the component change and the pharmacodynamic index change by adopting SPSS 20.0 statistical software, selecting bivariate test, calculating a Pearson coefficient, judging that the two variables are moderately correlated when the R absolute value is more than 0.5 and less than 0.8, judging that the two variables are highly correlated when the R absolute value is more than 0.8, and judging that the hypothesis that the two variables are uncorrelated is negated when the double-tail test Sig.less than 0.05; the two-tailed test Sig. <0.01 shows that the correlation of the two variables is obvious; the bivariate correlation coefficient calculation formula is as follows:
wherein X, Y represent two variables, respectively;
each representing the average of two variables.
As a further improvement, the pharmacodynamic index is related to blood rheology, and comprises the following indexes of low cut 1s, medium cut 5s, medium cut 30s, high cut 200s, plasma viscosity, PT, APTT, TT, FIB, t-PA, TNF-alpha, PAI-1 and IL-6.
As a further improvement, the Curcuma wenyujin different processed products comprise Curcuma wenyujin, curcuma zedoary and curcuma zedoaria with vinegar, and the blood-entering components comprise Zedoalcanone B, Aeridiol, Zedoarofruran, Zederone, furanodiene, curcurenol, curberolactone, neocurdione, Curcumenolides A and germacrone.
Advantageous effects
The bivariate correlation analysis method provided by the invention is used for screening active ingredient groups in different processed products of the curcuma wenyujin, and the active ingredient groups of the curcuma wenyujin, the curcuma zedoary and the curcuma zedoary are respectively screened as follows:
the turmeric root tuber has 10 ingredients entering blood, and Zedoalcanone B, Aerogeniol, Zedoarofruran, Zederone, furanodiene, neocurdione, Curcumenolides A and germacrone 8 ingredients show correlation to different efficacy indexes. Wherein, Zedoalcanone B has obvious correlation on the whole blood viscosity and the plasma viscosity (r is more than 0.5, and P is less than 0.05); two components of Zedoarofruan and germacrone are obviously related to IL-6, TNF-alpha inflammatory factor and PAI-1, and the germacrone is more strongly related (P is less than 0.01); the blood-entering component is more related to the viscosity of whole blood, APTT and FIB at low shear rate, and the PT, TT and FIB are not obviously related to the blood-entering component.
The 10 zedoary turmeric components enter the blood, and 8 Zedoalactone B, Aerocarinol, Zedoarofruran, Zederone, curenol, zedoary bicyclic ketene, zedoary furanoketene and germacrone show the relativity to different drug effect indexes (r is more than 0.5, P is less than 0.05). Wherein, the two components of Zedoarofruran and curzefuranone are obviously related to various drug effect indexes such as hemorheology and the like (r is more than 0.5, and P is less than 0.05); the amount of components highly correlated with the viscosity of whole blood and the viscosity of plasma is large, and the amount of active components correlated with FIB, IL-6 and t-PA is small.
8 pieces of vinegar curcuma zedoary enter blood components, the content of Zedoalactone B is the highest, but the Zedoalactone B has no obvious correlation with each efficacy index; the relevance between the furanodiene, the curcumenone and the curdione and the efficacy index is highest; the related components of APTT and PAI-1 are few, only one component is needed, and other efficacy indexes are related to the change of a plurality of components.
The active ingredient group difference of the three decoction pieces is further statistically analyzed: the active ingredients of the three decoction pieces related to the efficacy of promoting blood circulation to remove blood stasis and the efficacy change process in vivo are greatly different. The rhizoma wenyujin concubie group is identified to obtain 10 blood-entering components, wherein Curcumenolides A is detected only in rhizoma wenyujin concubie decoction pieces; 10 blood-entering components are identified in the curcuma zedoaria group, but the species of the components are different, and compared with the curcuma zedoaria group, Curdione and Curcumenone are the specific components; the vinegar zedoary group identifies 8 blood-entering components, and although the number of the blood-entering components is reduced, the analysis result of bivariate correlation of the components and the drug effect shows higher correlation. From the change of a pharmacokinetic curve, blood-entering components in rhizoma curcumae longae decoction pieces basically reach blood concentration within 4 hours, rhizoma curcumae zedoariae decoction pieces reach the highest concentration within 2 hours, and vinegar rhizoma curcumae zedoariae decoction pieces reach the highest concentration within 0.5 hours, which may cause the change of the blood-entering process with the change of the whole decoction pieces decoction liquid to the internal environment of intestinal tracts and the whole environment of blood, thereby generating different pharmacodynamic reactions. From the analysis result of the bivariate correlation of the blood-entering components and the pharmacodynamic indexes of the three decoction pieces, although the blood-entering components of the curcuma longa are more, the correlation of the component change trend and the pharmacodynamic effect is poorer than that of raw and vinegar curcuma zedoary, the number of the blood-entering components of the vinegar curcuma zedoary is reduced, but the significant correlation is shown with more pharmacodynamic indexes. By combining the analysis, the relevance and the similarities and differences between the blood-entering components and the effects of promoting blood circulation to remove blood stasis of the three decoction pieces are clearly determined, and a detailed material basis is provided for the research of the traditional Chinese medicine effect and the processing mechanism, the clinical practice guidance and the development of traditional Chinese medicine products.
Drawings
FIG. 1 UPLC-Q/TOF-MS Total ion flow graph in positive ion mode for plasma samples from Wenyujin Concisa group
FIG. 2 shows the time-dependent change of the ion strength of the blood-entering component of Wenyujin Concisa (C.Y.)
n＝6)
FIG. 3 UPLC-Q/TOF-MS total ion flow diagram of plasma sample of raw zedoary turmeric group in positive ion mode
FIG. 4 shows the time-dependent change of the ion intensity of the blood-entering component of raw zedoary (0-12 h)
n＝6)
FIG. 5 UPLC-Q/TOF-MS total ion flow graph of plasma samples of Curcumae rhizoma group with vinegar in positive ion mode
FIG. 6 shows the time-dependent change of ionic strength of the blood-entering component of Curcumae rhizoma processed with vinegar (0-12 hr)
n＝6)
FIG. 7 shows the body weight change trend of rats in each group
FIG. 8 shows the change of ear margins after molding of rats (A: blank group; B: model group; C: positive group; D: Wenyujin Concisa group; E: raw Zedoariae group; F: vinegar Zedoariae group)
FIG. 9 shows the effect of different processed products of Curcuma wenyujin on the blood rheology of a rat model with qi stagnation and blood stasis. # # # #, # #, and # respectively represent the ratio of P <0.001, P <0.01and P <0.05 to the blank group; represents the ratio P <0.001 to model group, P <0.01and P <0.05, respectively.
FIG. 10 shows the effects of different processed products of Curcuma wenyujin on blood coagulation in rat model with qi stagnation and blood stasis. # # # #, # #, and # respectively represent the ratio of P <0.001, P <0.01and P <0.05 to the blank group; represents the ratio P <0.001, P <0.01and P <0.05 to the model group, respectively.
FIG. 11 shows the effect of different processed products of Curcuma wenyujin on fibrinolytic system and inflammatory factors of rat model with qi stagnation and blood stasis. # # # #, # #, and # respectively represent the ratio of P <0.001, P <0.01and P <0.05 to the blank group; represents the ratio P <0.001, P <0.01and P <0.05 to the model group, respectively.
Detailed Description
The technical solution of the present invention is further described below with reference to specific examples, which are not intended to limit the technical solution.
Example 1 double-variable correlation analysis method for screening groups of active ingredients of traditional Chinese medicines of Curcuma wenyujin Y.H.Chen et C.Ling, Curcuma zedoaria C.Ling and Curcuma zedoaria C.Ling processed with vinegar
Analyzing and identifying blood components of plasma samples of different processed products of curcuma longa, curcuma zedoary and curcuma zedoary, determining related drug effect indexes of promoting blood circulation to remove blood stasis, and screening active ingredient groups of traditional Chinese medicines by using a bivariate correlation analysis method.
1. Experimental methods
Measuring the relative content change trend of blood-entering components of three decoction pieces of rhizoma Wenyujin Concisa, rhizoma Curcumae and rhizoma Curcumae Longae processed with vinegar in 0-12h (the measuring method is shown in example 2), and the change process of pharmacodynamic indexes such as hemorheology in the same time (the measuring method is shown in examples 2 and 3), performing bivariate correlation analysis on the component change and the pharmacodynamic index change by using SPSS 20.0 statistical software, selecting bivariate test, calculating Pearson coefficient, wherein when the absolute value of R is more than 0.5 and less than 0.8, the medium correlation of the two variables is shown, when the absolute value of R is more than 0.8, the high correlation of the two variables is considered, and when the absolute value of R is more than 0.8, the irrelevant correlation of the; two-tailed test sig. <0.01 indicated significant correlation between the two variables. The bivariate correlation coefficient calculation formula is as follows:
whereinX, Y represent two variables, respectively;
each representing the average of two variables.
2. Results of the experiment
2.1 analysis of correlation between blood circulation-promoting and blood stasis-removing spectrum effects of Wenyujin Concisa
The plasma sample blood-entering components of the rhizoma Wenyujin Concisa of each group are analyzed and identified by UPLC-Q/TOF-MS, the change of the ion intensity of the blood-entering components of the rhizoma Wenyujin Concisa plasma sample within 0-12h is shown in Table 1, the change trend is shown in figure 2, 10 blood-entering components are obtained by identification, wherein the ion intensity of the blood-entering components of Zedoalcanone B, curenol and Aerogeniol is higher, and the blood concentration of each component is highest within 2-4 h. Meanwhile, the pharmacodynamic indexes of the curcuma longa such as hemorheology and the like 0-12h after the last administration are measured, and the results are shown in table 2. The SPSS 20.0 statistical software is adopted to carry out bivariate correlation analysis on the blood-entering components of the curcuma longa and a hyperbola of which the pharmacodynamic indexes change along with time, the Pearson correlation coefficient and the bilateral test significance result are shown in the table 3, and the statistical result shows that in 10 blood-entering components of the curcuma longa, Zedoalcanone B, Aeridiol, Zedoarofrunone, furanone, neozedoary dione, Curcumenolides A and germacrone 8 components have correlation on different pharmacodynamic indexes. Wherein, Zedoalcanone B has obvious correlation on the whole blood viscosity and the plasma viscosity (r is more than 0.5, and P is less than 0.05); two components of Zedoarofruan and germacrone are obviously related to IL-6, TNF-alpha inflammatory factor and PAI-1, and the germacrone is more strongly related (P is less than 0.01); the blood-entering component is more related to the viscosity of whole blood, APTT and FIB at low shear rate, and the PT, TT and FIB are not obviously related to the blood-entering component.
TABLE 1 Ionic Strength of turmeric in plasma samples 0-12h of bleeding component: (
n＝6)
TABLE 2 Wenyujin administration0-12h influence on pharmacodynamic indexes of promoting blood circulation to remove blood stasis (
n＝6)
TABLE 3 correlation analysis results of Pearson correlation coefficient between blood-entering component and drug effect index of Wenyujin Concisa
Note: significance <0.05 for two-tailed assay; representative two-tailed assay significance < 0.01.
2.2 correlation analysis of blood circulation promoting and blood stasis removing spectrum effect of raw zedoary
Through analysis and identification of blood components of each group of plasma samples of the curcuma zedoaria by UPLC-Q/TOF-MS, the change of the ion intensity of the blood components of the plasma samples of the curcuma zedoaria within 0-12h is shown in Table 4, the change trend is shown in figure 3, wherein the relative content of five blood components of Zedoalcanone B, Aeroglidol, curenol, curenone and curdione is high, and each component reaches the highest blood concentration within about 2 h. And the pharmacodynamic indexes of the raw curcuma zedoary, such as hemorheology and the like, 0-12h after the last administration are measured, and the results are shown in a table 5. The SPSS 20.0 statistical software is adopted to carry out bivariate correlation analysis on hyperbolas of the zedoary turmeric blood-entering components and the pharmacodynamic indexes changing along with time, the Pearson correlation coefficient and the bilateral test significance result are shown in Table 6, and the statistical result shows that in 10 zedoary turmeric blood-entering components, 8 Zedoalcanone B, Aeridiol, Zedoarofruran, Zederone, curcumenol, zedoary bicyclenone, zedoary furanone and germacrone show the correlation (r is more than 0.5, and P is less than 0.05) to different pharmacodynamic indexes. Wherein, the two components of Zedoarofruran and curzefuranone are obviously related to various drug effect indexes such as hemorheology and the like (r is more than 0.5, and P is less than 0.05); the amount of components highly correlated with the viscosity of whole blood and the viscosity of plasma is large, and the amount of active components correlated with FIB, IL-6 and t-PA is small.
TABLE 4 rhizoma CurcumaeIonic strength of blood component 0-12h in plasma samples: (
n＝6)
TABLE 5 Effect of raw zedoary administration for 0-12h on the pharmacodynamic indices of activating blood circulation to dissipate blood stasis: (
n＝6)
TABLE 6 correlation analysis results of Pearson correlation coefficient between blood components of raw zedoary turmeric and drug effect index bivariate
Note: significance <0.05 for two-tailed assay; representative two-tailed assay significance < 0.01.
2.3 analysis of correlation between blood circulation-promoting and stasis-removing spectrum effects of Curcumae rhizoma processed with vinegar
The ion intensity change of the blood-entering components of each group of plasma samples of the curcuma zedoaria obtained by analyzing and identifying the blood-entering components of the plasma samples of the curcuma zedoaria in 0-12h through UPLC-Q/TOF-MS is shown in Table 7, the change trend is shown in figure 6, wherein the relative contents of the four blood-entering components of Zedoalcanone B, Aeroglidiol, Zederone and curenol are higher, and the blood concentration of each component reaches the highest in about 0.5 h. Meanwhile, the pharmacodynamic indexes of 0-12h after the last administration of the curcuma zedoary are measured, and the results are shown in table 8. Carrying out bivariate correlation analysis on the blood-entering components of the curcuma zedoaria and a hyperbola of which the pharmacodynamic indexes change along with time by adopting SPSS 20.0 statistical software, wherein Pearson correlation coefficients and bilateral test significance results are shown in a table 9, and the statistical results show that the content of Zedoalcanone B is highest in 8 blood-entering components of the curcuma zedoaria, but the Zedoalcanone B has no significant correlation with each pharmacodynamic index; the relevance between the furanodiene, the curcumenone and the curdione and the efficacy index is highest; the related components of APTT and PAI-1 are few, only one component is needed, and other efficacy indexes are related to the change of a plurality of components.
TABLE 7 ion strength of Vinegar-Curcumae rhizoma in blood sample for 0-12 h: (
n＝6)
TABLE 8 influence of 0-12h administration of Curcumae rhizoma (Curcumae rhizoma with vinegar) on the pharmacodynamic indices of promoting blood circulation and removing blood stasis: (
n＝6)
TABLE 9 correlation analysis results of Pearson correlation coefficient between blood components of zedoary vinegar and drug effect index bivariate
Note: significance <0.05 for two-tailed assay; representative two-tailed assay significance < 0.01.
3. Small knot
The research content in this chapter adopts the research idea of 'Chinese medicine spectrum effectiveness' and combines a bivariate correlation analysis statistical method, and the similarities and differences of the three decoction pieces in the aspect of playing the roles of promoting blood circulation and removing blood stasis are comprehensively analyzed from the types and relative contents of blood-entering components of the three decoction pieces, the metabolic change trend in vivo and the correlation with the efficacy indexes of promoting blood circulation and removing blood stasis. The results show that the active ingredients of the three decoction pieces related to the efficacy of promoting blood circulation to remove blood stasis and the efficacy change process in vivo are greatly different. The rhizoma wenyujin concubie group is identified to obtain 10 blood-entering components, wherein Curcumenolides A is detected only in rhizoma wenyujin concubie decoction pieces; the raw zedoary turmeric group identifies 10 blood components, but the species is different, and compared with the zedoary turmeric group, Curdione and Curcumenone are the specific components; the vinegar zedoary group identifies 8 blood-entering components, and although the number of the blood-entering components is reduced, the analysis result of bivariate correlation of the components and the drug effect shows higher correlation. From the change of a pharmacokinetic curve, blood-entering components in rhizoma curcumae longae decoction pieces basically reach blood concentration within 4 hours, raw rhizoma curcumae zedoariae decoction pieces reach the highest concentration within 2 hours, and vinegar rhizoma curcumae zedoariae decoction pieces reach the highest concentration within 0.5 hours, so that the blood-entering process is possibly changed along with the change of the whole decoction piece water decoction liquid to the internal environment of intestinal tracts and the whole environment of blood, and different pharmacodynamic reactions are generated. From the analysis result of the bivariate correlation of the blood-entering components and the pharmacodynamic indexes of the three decoction pieces, although the blood-entering components of the curcuma longa are more, the correlation of the component change trend and the pharmacodynamic effect is poorer than that of raw and vinegar curcuma zedoary, the number of the blood-entering components of the vinegar curcuma zedoary is reduced, but the significant correlation is shown with more pharmacodynamic indexes. By combining the analysis, the relevance and the similarities and differences between the blood-entering components and the drug effects of promoting blood circulation to remove blood stasis of the three decoction pieces are clearly determined, and a sufficient substance basic research basis is provided for the follow-up processing mechanism research.
4. Discussion of the related Art
According to the change trend of the blood-entering components and the pharmacodynamic indexes of different processed products of the common turmeric along with time and the bivariate analysis result of the two, the active components related to the pharmacodynamic action of promoting blood circulation to remove blood stasis and the pharmacodynamic change process in vivo of the three decoction pieces are greatly different.
From the blood-entering components, 10 blood-entering components are obtained by the joint identification of the plasma of rats subjected to the blood stasis model of rhizoma wenyujin conciliae, wherein Curcumenolactones A are only detected in rhizoma wenyujin conciliate slices, and the analysis result of bivariate correlation shows that the components are obviously related to APTT and FIB. Literature studies have shown that Curcumenolactones A show a protective effect on d-galactosamine-induced cytotoxicity in primary-cultured rat hepatocytes[24]Presumably, the component can play a role of breaking blood and promoting qi circulation of the rhizoma wenyujin concinnatae decoction pieces by protecting liver and combining with other blood-entering components; 10 blood-entering components are identified in the blood plasma sample of a rat model of blood stasis of administration of raw zedoary turmeric decoction pieces, but the types are differentCompared with the common turmeric group, the curdione and the curdlone are special components, wherein the curdione has no obvious correlation with efficacy indexes, but the curdlone has obvious correlation with blood viscosity and APTT, and the components are found to show effective protective effect on D-galactosamine/lipopolysaccharide-induced mouse acute liver injury[25]. Compared with Curcumae rhizoma group, germacrone, neocurdione, and curfuranone are the special blood-entering components, and have protective effect on D-galactosamine/lipopolysaccharide induced acute liver injury of mice[25]The curcumenone can obviously inhibit cell proliferation in human cancer cell lines MCF-7, Ca Ski and HCT-116, and induce apoptosis by activating caspase-3[26](ii) a The vinegar curcuma zedoary decoction pieces are applied to a blood stasis model rat plasma sample to identify and obtain 8 blood-entering components, although the number of the blood-entering components is reduced, the analysis result of bivariate correlation analysis of the components and the drug effect shows higher correlation, the relative content of Zedoalactone B is obviously increased, but no direct correlation is reflected with the drug effect, the relative content of Zederone is also increased in a small amplitude, and the component has obvious correlation with whole blood viscosity, PT and FIB, and has the inhibition effect on cell proliferation in human cancer cell lines MCF-7, Ca Ski and HCT-116[26]。
From the trend that blood-entering components change along with time, the component metabolism change processes of the three decoction pieces also change remarkably, the blood-entering components in the rhizoma curcumae longae decoction pieces basically reach blood concentration within 4 hours, raw rhizoma curcumae decoction pieces reach the highest concentration within 2 hours, and vinegar rhizoma curcumae decoction pieces reach the highest concentration within 0.5 hour, which may cause the change of the blood-entering process with the change of the whole decoction pieces water decoction liquid to the internal environment of intestinal tracts and the whole environment of blood, thereby generating different pharmacodynamic reactions.
From the analysis result of the bivariate correlation of the blood-entering components and the pharmacodynamic indexes of the three decoction pieces, although the blood-entering components of the curcuma longa are more, the correlation of the component change trend and the pharmacodynamic effect is poorer than that of raw and vinegar curcuma zedoary, the number of the blood-entering components of the vinegar curcuma zedoary is reduced, but the curcuma longa shows extremely obvious correlation with more pharmacodynamic indexes (P is less than 0.01).
By combining the analysis, the relevance and the similarities and differences between the blood-entering components and the drug effects of promoting blood circulation to remove blood stasis of the three decoction pieces are clearly determined, and a sufficient substance basic research basis is provided for the follow-up processing mechanism research.
Example 2 the relative content change trend of the blood-entering components of three decoction pieces of curcuma longa, curcuma zedoary and curcuma zedoaria with vinegar in 0-12h and the change process of the pharmacodynamic indexes of the three decoction pieces such as hemorheology and the like in 0-12h after administration
In example 1, the relative content change trend of the three decoction pieces of turmeric, zedoary and vinegar-processed zedoary in blood in 0-12h and the change process of the pharmacodynamic indexes of hemorheology and the like in 0-12h after the three decoction pieces are administrated are determined as follows:
1. sample preparation
1.1 reagent
Fresh Curcuma wenyujin rhizome is purchased from Chunming Curcuma wenyujin professional cooperative of Ruan city, Zhejiang and identified as fresh rhizome of Curcuma wenyujin Y.H.Chen et C.Ling, Zingiberaceae plant Curcuma wenyuma wenyujin Y.H.Chen et C.Ling by professor Languilin, Nanjing Chinese medicine university. A curdione reference substance (batch No. K19D5C1, purity: HPLC ≥ 98%), a curcumenol reference substance (batch No. RM0331FB14, purity: HPLC ≥ 98%), a germacrone reference substance (batch No. P10S6F3197, purity: HPLC ≥ 98%), a furanodiene reference substance (batch No. 11824-. Milli-Q ultrapure water, methanol and acetonitrile were chromatographically pure (Merck, Germany) and ethanol (analytical grade).
TABLE 1010 batches of Curcuma wenyujin rhizome origin information
The preparation method of different processed products of the curcuma wenyujin comprises the following steps:
1) preparation of rhizoma Wenyujin Concisa decoction pieces
Cleaning fresh Curcuma wenyujin rhizome, removing fibrous root, longitudinally cutting into thick slices, and drying at low temperature of 60 deg.C to obtain Curcuma wenyujin decoction pieces;
2) preparation of raw zedoary turmeric decoction pieces
Cleaning fresh Curcuma wenyujin rhizome, removing fibrous root and impurities, steaming to remove fibrous root and impurities, and drying at 60 deg.C to obtain Curcumae rhizoma; steaming Curcumae rhizoma to soft, slicing, and drying at 60 deg.C to obtain rhizoma Curcumae decoction pieces;
3) preparation of vinegar curcuma zedoary decoction pieces
Decocting Curcumae rhizoma in vinegar, cooling, slicing, and drying at 60 deg.C to obtain vinegar-processed Curcumae rhizoma decoction pieces. (20 kg of rice vinegar per 100 kg)
The processing method of the decoction pieces is required under the processing item of one part of turmeric and zedoary in 2015 edition of Chinese pharmacopoeia.
1.2 sample preparation
1kg of rhizoma curcumae longae, raw rhizoma zedoariae and vinegar rhizoma zedoariae decoction pieces are taken respectively, added with 10 times of distilled water, soaked for 0.5h and decocted for 0.5h twice, filtered while being hot by gauze, the two water decoctions are combined, concentrated to 2g/ml at 55 ℃ by a rotary evaporator and stored at 4 ℃ for standby.
2. Grouping and administration of drugs
The temperature of the animal room is 25 +/-1 ℃ and the relative humidity is 55 percent. SPF SD male rats are adaptively bred for 1 week, and then are randomly divided into 22 groups according to body weight, wherein each group comprises 6 mice, namely blank groups, rhizoma curcumae longae groups of 0.5, 1, 2, 4, 6, 8 and 12 hours, rhizoma zedoariae groups of 0.5, 1, 2, 4, 6, 8 and 12 hours, and rhizoma zedoariae groups of 0.5, 1, 2, 4, 6, 8 and 12 hours (the administration dose is 3 times of the clinical equivalent administration dose, and the administration dose of all three decoction pieces is 4.5 g/kg). The administration groups are administered with corresponding drugs by gavage respectively, 1 time every morning, and 7 days continuously.
3. Duplicating model of qi stagnation and blood stasis of rat
And (3) fasting is carried out after administration on the 7 th day, except for a blank control group, the neck parts of other groups are injected with 0.8ml/kg of adrenaline hydrochloride subcutaneously for two times at an interval of 4h, and the rats are placed into an ice water bath at the temperature of 0-4 ℃ for swimming for 5min after the first subcutaneous injection for 2h to replicate a model of the rats with qi stagnation and blood stasis.
1. Detection of pharmacodynamic indexes such as hemorheology
The weight of the rat is weighed daily, and the hair color, defecation and movement of the rat are observed. In the morning of 8 days, after each group of rats normally takes the medicine for 0.5h, 10% chloral hydrate is used for anesthesia, the common carotid artery is used for taking blood, the blood is subpackaged into a sodium citrate vacuum blood collection tube for anticoagulation, and 1ml of whole blood is taken for measuring the high, medium and low cut viscosity of the whole blood; the remaining whole blood was centrifuged at 3000r/min for 10min, plasma viscosity, intrinsic and extrinsic coagulation function indicators (TT, PT, APTT, FIB) were measured, and t-PA, PAI, IL-6, TNF- α levels were measured by ELISA.
5. Detection of blood-entering components of different processed products of common turmeric
5.1 preparation of plasma sample test solutions
After 0.5h of last administration, 10% chloral hydrate is used for anesthesia, the common carotid artery is bled until sodium citrate is subjected to vacuum blood sampling and is centrifuged for 10min at 3000r/min, 200 mu l of supernatant blood plasma is taken and is placed in a 1.5ml centrifuge tube, 1.2ml of methanol is added, the mixture is uniformly mixed and is fully oscillated for 30s by a vortex oscillation mixer, protein is fully precipitated, the mixture is centrifuged for 10min at 12000r/min at 4 ℃, the supernatant is taken and is placed in a 1.5ml centrifuge tube, the mixture is dried for 4h in a refrigerated centrifugal drier until the solvent is volatilized, finally, 200 mu l of methanol is added for redissolution, the centrifugation is carried out for 10min, 100 mu l of supernatant is taken and is placed in an inner lining tube to be tested. At the same time, 10. mu.l of each sample was pipetted and mixed, Quality Control (QC) samples were prepared, proteins were precipitated and centrifuged as before.
5.2 chromatographic conditions
A chromatographic column: agilent Zorbax SB-C18(2.1 mm. times.100 mm, 1.8 μm); the mobile phase system was acetonitrile (a) -0.1% formic acid (B), and the gradient elution procedure was: 0-1 min, 5% -25% A; 1-3 min, 25% -30% A; 3-13 min, 30% -55% A; 13-15 min, 55% -70% A; 15-25 min, 70% -100% A; 25-28 min, 100% -5% A. Sample introduction amount: 1 mu L of the solution; flow rate: 0.3mL/min, column temperature: 35 ℃ is carried out.
5.3 TOF/MS Mass Spectrometry conditions
With ESI ion source, positive ion mode full wavelength scan. The mass spectrometer detector parameters were set as follows: ion spray voltage (ion voltage)5.5kV, ion source temperature (source temperature)550 ℃, declustering voltage (declustering potential)60V, Collision Energy (CE): 35 eV; the auxiliary gas being N2Air curtain Gas (currain Gas)35psi, Gas1(nebulizer Gas)55psi, Gas2(heater Gas)65 psi; scanning in an MS/MS two-stage mass spectrum mode, wherein the mass number scanning range is 50-1000 m/z; dynamic background subtraction. Data ofIs collected by
TF 1.6software (AB SCIEX Co.).
5.4 identification of blood-entering component structure of different processed products of Curcuma wenyujin
Establishing a curcuma zedoary chemical composition database according to domestic and foreign documents and related component retrieval websites (Pubmed, Chemscope, SciFinder MassBank, and Chinese National Knowledge Infrastructure (CNKI)) and the like, adopting analysis TF 1.6software (AB Sciex, USA) to collect an original map, extracting primary and secondary mass spectrograms of chemical components by Peakview 1.2 software, setting error values between different samples to be less than or equal to 10ppm, setting a retention time error range to be +/-0.2 min, comparing secondary fragments with the database, matching compounds according to various information such as molecular weight, chemical structural formula, characteristic fragment ions and the like, and analyzing the chemical components in the curcuma zedoary, raw curcuma zedoary decoction piece extracts.
EXAMPLE 3 pharmacodynamic experiment
Hemorheology is an emerging branch of biomechanics and biorheology, and gradually develops into an independent subject in recent 20 years, and is a science for mainly researching blood flow, cell deformation, interaction rules between blood and blood vessels and heart and biochemical components. The research content mainly comprises more than 10 indexes of whole blood viscosity, plasma viscosity, erythrocyte electrophoresis time, platelet electrophoresis time, fibrinogen determination, blood sedimentation, erythrocyte deformability and the like. Literature research shows that four indexes of blood coagulation in the current research on blood stasis diseases, including Prothrombin Time (PT), Thrombin Time (TT), Activated Partial Thromboplastin Time (APTT), Fibrinogen (FIB) and the like, are closely related to the occurrence and development of the blood stasis. Wherein PT is mainly used for reflecting the condition of an exogenous coagulation system, APTT is mainly used for reflecting the condition of an endogenous coagulation system, TT represents the time for converting fibrinogen into fibrin, and FIB represents the content of fibrinogen. Hemorheology has important significance for the research of the essence of blood stasis syndrome in traditional Chinese medicine and the discussion of the mechanism of activating blood and dissolving stasis.
Ecchymosis of different degrees is often seen in the body of a patient with blood stasis, and is caused by unsmooth blood flow and blood stasis. Fibrin is formed in the process of blood coagulation, the formation and decomposition process (namely a fibrinolytic system) of the fibrin is closely related to the blood coagulation, in the fibrinolytic process, a tissue plasminogen activator (t-PA) and a plasma Plasminogen Activator Inhibitor (PAI) are important regulatory factors, the PAI has an inhibition effect on the t-PA, the t-PA has a remarkable effect on preventing thrombosis, and the balance of the t-PA and the t-PA has an important significance on intravascular thrombolysis, so that the research on the fibrinolytic factor has an important significance on understanding the disease state of blood stasis and serving as a diagnostic index for evaluating the blood stasis; in addition, the correlation between blood stasis and inflammation has recently attracted more attention from researchers, and the inflammation reaction inevitably occurs in the blood stasis process, so that the condition of the blood stasis syndrome is further aggravated, and the blood stasis syndrome can be effectively improved by improving the inflammation reaction.
In addition, there are plasminogen activator inhibitor (PAI-1), Interleukin-6 (Interleukin-6, IL-6), tumor necrosis factor (tumor necrosis factor-alpha, TNF-alpha) levels.
Based on the reasons, in the aspect of selecting the pharmacodynamic evaluation index, in addition to the conventional hemorheology index, t-PA and PAI-1 are also considered, and the t-PA and the PAI-1 serve as a pair of antagonistic factors and have important effects on maintaining the balance of an in-vivo fibrinolytic system and the blood flow state, and in addition, related inflammatory factors are also detected to comprehensively evaluate the pharmacodynamic differences of the three decoction pieces in various aspects such as hemorheology, fibrinolytic system, inflammation and the like.
1. Experimental methods
1.1 sample preparation
1kg of rhizoma curcumae longae, raw rhizoma zedoariae and vinegar rhizoma zedoariae decoction pieces are taken respectively, added with 10 times of distilled water, soaked for 0.5h and decocted for 0.5h twice, filtered while being hot by gauze, the two water decoctions are combined, concentrated to 2g/ml at 55 ℃ by a rotary evaporator and stored at 4 ℃ for standby.
1.2 animal grouping and administration
The temperature of the animal room is 25 +/-1 ℃ and the relative humidity is 55 percent. After the SPF SD male rats are adaptively raised for 5 days, the SPF SD male rats are randomly divided into 9 groups according to the body weight, and each group comprises 10 rats, namely a blank group, a model group, a compound salvia miltiorrhiza group (1.5g/kg), a curcuma longa high-low dose group, a curcuma zedoary high-low dose group and a curcuma zedoary high-low dose group (the high dose is 3 times of the clinical equivalent dose, the doses of the three decoction pieces are 4.5g/kg, and the low dose is 1.5g/kg according to the clinical equivalent dose). The administration groups are respectively administered with corresponding drugs by intragastric administration, and the control group and the model group are administered with physiological saline with the same volume by intragastric administration for 1 time every day and 7 days continuously.
1.3 duplication of rat model of qi stagnation and blood stasis
And (3) fasting is carried out after administration on the 7 th day, except for a blank control group, the neck parts of other groups are injected with 0.8ml/kg of adrenaline hydrochloride subcutaneously for two times at an interval of 4h, and the rats are placed into an ice water bath at the temperature of 0-4 ℃ for swimming for 5min after the first subcutaneous injection for 2h to replicate a model of the rats with qi stagnation and blood stasis.
1.4 determination of pharmacodynamic indices such as hemorheology
The weight of the rat is weighed daily, and the hair color, defecation and movement of the rat are observed. In the morning of 8 days, after each group of rats normally takes the medicine for 0.5h, 10% chloral hydrate is used for anesthesia, the common carotid artery is used for taking blood, the blood is subpackaged into a sodium citrate vacuum blood collection tube for anticoagulation, and 1ml of whole blood is taken for measuring the high, medium and low cut viscosity of the whole blood; the remaining whole blood was centrifuged at 3000r/min for 10min, plasma viscosity, intrinsic and extrinsic coagulation function indicators (TT, PT, APTT, FIB) were measured, and t-PA, PAI, IL-6, TNF- α levels were measured by ELISA.
1.5 statistical treatment
SPSS 20.0 statistical software is adopted to carry out double-sample t test and variance analysis on the data, and the experimental data is obtained
Is represented by P<0.05 is statistically significant.
2. Results of the experiment
2.1 Effect of different processed products of Curcuma wenyujin on the weight and hair color of rats with blood stasis model
The weight of each group of rats steadily increased during the gastric lavage administration period, the weight of each group of rats significantly decreased except for the blank group after 7 days of molding, and the weight of each group of rats increased again on 8 days (see figure 7); in the molding process, the ice-water bath time of the rats in the curcuma longa group is obviously shorter than that of other groups, the physical strength is fast, the extravasated blood symptoms appear at the ear margin after the ice-water bath of the rats in each group except the blank group, the bleeding point can be seen in eyes, and the extravasated blood symptoms of the model group are the most serious (see figure 8).
2.2 influence of different processed products of Curcuma wenyujin on blood viscosity index due to qi stagnation and blood stasis
Compared with a control group, the viscosity and the plasma viscosity of the model group rat whole blood are obviously increased at each shear rate (P is less than 0.01); compared with the model group, the positive drug (compound salvia tablets) group can obviously reduce the whole blood viscosity and the plasma viscosity (P is less than 0.01) of the model rat at each shear rate; wherein, except that the low-dose group of the rhizoma wenyujin concubine has no statistical significance to the improvement of the hemorheology indexes, other groups have obvious improvement effect on qi stagnation and blood stasis models, and the effect of the high-dose group is more obvious; the vinegar curcuma zedoary high-dosage group has very obvious improvement effect on the viscosity and the plasma viscosity of the blood stasis model rat at each shear rate (P is less than 0.001); the results are shown in Table 11.
TABLE 11 influence of different processed products of Curcuma wenyujin on the viscosity of whole blood and the viscosity of plasma of rats with qi stagnation and blood stasis model: (
n＝10)
Note: l represents a low dose; h represents high dose. # # # #, # #, and # respectively represent the ratio of P <0.001, P <0.01and P <0.05 to the blank group; represents the ratio P <0.001, P <0.01and P <0.05 to the model group, respectively.
2.3 influence of different processed products of Curcuma wenyujin on four aspects of qi stagnation and blood stasis blood coagulation
Compared with a control group, the TT, PT and APTT time of the model group is obviously prolonged, and the FIB level is obviously increased; compared with the model group, the positive group and the high-dose group of each administration group have extremely obvious effect of shortening the TT time of the model rat (P is less than 0.001); PT time (P is less than 0.05) can be shortened in various groups of rhizoma Wenyujin Concisa and various groups of rhizoma Zedoariae, and PT time can be shortened more obviously in high-low dosage group of rhizoma Zedoariae vinegar (P is less than 0.01); the positive group and the rhizoma Wenyujin Concisa high-dose group can shorten the APTT time (P is less than 0.05), and the high-dose group of the rhizoma Zedoariae group and the rhizoma Zedoariae vinegar group has more obvious effect (P is less than 0.01); the influence of the curcuma zedoaria group on the FIB has no statistical significance, the FIB level (P is less than 0.05) of each raw curcuma zedoary group can be obviously reduced, and the high-dose group of the vinegar curcuma zedoary has extremely obvious reduction effect on the FIB.
TABLE 12 influence of different processed Curcuma wenyujin rhizome products on blood coagulation of rats with qi stagnation and blood stasis model: (
n＝10)
Note: l represents a low dose; h represents high dose. # # # #, # #, and # respectively represent the ratio of P <0.001, P <0.01and P <0.05 to the blank group; represents the ratio P <0.001, P <0.01and P <0.05 to the model group, respectively.
2.4 influence of different processed products of Curcuma wenyujin on fibrinolytic system and inflammatory factor due to qi stagnation and blood stasis
Compared with a control group, the t-PA content of the model group is reduced (P is less than 0.05), PAI-1 is remarkably increased, and inflammatory factors IL-6 and TNF-alpha are remarkably increased; compared with the model group, the positive group and each administration group have extremely obvious increasing effect on t-PA; the influence of rhizoma Wenyujin Concisa and low dose of rhizoma Curcumae has no statistical significance on PAI-1, rhizoma Curcumae can reduce PAI-1 level (P <0.05), and rhizoma Curcumae processed with vinegar has more obvious effect (P < 0.01); except that the low dose groups of raw and vinegar curcuma zedoary have no obvious influence on IL-6 and the low dose group of raw curcuma zedoary has no obvious influence on TNF-alpha, the other administration groups can obviously reduce the IL-6 and TNF-alpha levels (P is less than 0.01).
TABLE 13 influence of different processed products of Curcuma wenyujin rhizome on model of qi stagnation and blood stasis rat t-PA, PAI-1, IL-6, TNF- α ((
n＝10)
Note: l represents a low dose; h represents high dose. # # # #, # #, and # respectively represent the ratio of P <0.001, P <0.01and P <0.05 to the blank group; represents the ratio P <0.001, P <0.01and P <0.05 to the model group, respectively.
3. Small knot
The influence of different processed products of the rhizome of the common turmeric on the whole blood viscosity and the plasma viscosity of the qi-stagnation and blood-stasis model rat is examined, and the strength of the blood stasis removing effect of each processed product is compared. The results show that three processed products of the curcuma wenyujin rhizome can improve the high blood viscosity state of rats with qi stagnation and blood stasis, wherein the effect of the curcuma wenyujin is the best.
The efficacy difference of the three processed products is further compared from the perspective of the blood coagulation system by comparing the regulation effect of the four blood coagulation items of the blood stasis model rats on each administration group. The results show that the three processed products have extremely obvious regulating effect on TT and obvious influence on PT and APTT, wherein the rhizoma curcumae longae has weaker effect than that of raw rhizoma curcumae longae and vinegar rhizoma curcumae zedoariae, the influence of the rhizoma curcumae longae on FIB has no statistical difference, and the raw rhizoma curcumae longae and the vinegar rhizoma curcumae longae after being processed have obvious regulating effect on FIB; the three kinds of decoction pieces can improve blood stasis syndrome through internal and external coagulation systems, and the vinegar product has the best curative effect.
In addition, the research simultaneously inspects the influence of different processed products of the curcuma wenyujin rhizome on the fibrinolytic system and the inflammatory factor of the blood stasis model. The fibrinolysis system is a reaction system for converting plasminogen into plasmin through the action of a specific activator, so that fibrin in a body is continuously dissolved. Research shows that the essence of blood stasis is fibrous connective tissue hyperplasia and degeneration and microcirculation disturbance, and is closely related to the dynamic balance of the fibrinolytic system of the body and the function of the fibrinolytic system[21]. After activation by plasmin, the insoluble fibrin block produced during coagulation can be broken down into various soluble fragments, thereby degrading the thrombus. t-PA is fibrinolysis activator and can promote fibrinolysis, PAI-1 is t-PA inhibitor and can reduce fibrinolysis function, promote peripheral microcirculation stasis, and increase thrombosis tendency[22]. The amount of t-PA in the model group rats is reducedThe amount of PAI-1 was increased, and it was found to match the characteristics of the model of blood stasis. Each administration group has obvious effect of reducing t-PA, the adjustment effect of the curcuma longa group on PAI-1 is in an ascending trend, but no statistical difference exists, the PAI-1 can be reduced by the raw curcuma zedoary group, and the effect of the vinegar curcuma zedoary group is better.
With the development of modern medicine and the deep understanding of immune inflammation mechanism, inflammatory factors gradually occupy a place in blood stasis syndrome. The inflammatory factors can cause endothelial injury, after the injury, platelets are activated, and the activated platelets promote thrombosis, namely blood stasis. In recent years, many experimental studies prove that inflammatory factors playing pathogenic roles are related to blood stasis syndrome[23]In the research, the levels of TNF- α and IL-6 of rats in a model group are obviously increased, the model accords with the blood stasis model characteristic, and three processed products have obvious regulation effects on TNF- α and IL-6 inflammatory factors, but the administration groups have no obvious difference.
The research evaluates the treatment effects of the turmeric root-tuber decoction pieces on promoting blood circulation and removing blood stasis from multiple angles of hemorheology, fibrinolysis system and inflammatory response, and the results show that the turmeric root-tuber decoction pieces have the effects of improving the hemorheology, the fibrinolysis system and the inflammatory abnormality of a qi stagnation and blood stasis model rat, are in dose correlation within a certain range, and the treatment effect of each decoction piece high-dose group is better than that of a lower-dose group. The vinegar-processed curcuma zedoary has very obvious improvement effect among three decoction piece high-dose groups, and verifies the processing theory of the Chinese medicine that vinegar is processed into liver and the effect of promoting blood circulation and removing blood stasis is enhanced.
Claims (3)
1. A method for screening active ingredient groups in different processed products of common turmeric by a bivariate correlation analysis method is characterized by comprising the following steps: measuring the change rules of the blood-entering components and the pharmacodynamic indexes of different processed products of the curcuma wenyujin along with time, carrying out bivariate correlation analysis on the component change and the pharmacodynamic index change by adopting SPSS 20.0 statistical software, selecting bivariate test, calculating a Pearson coefficient, judging that the two variables are moderately correlated when the R absolute value is more than 0.5 and less than 0.8, judging that the two variables are highly correlated when the R absolute value is more than 0.8, and judging that the hypothesis that the two variables are uncorrelated is negated when the double-tail test Sig.less than 0.05; the two-tailed test Sig. <0.01 shows that the correlation of the two variables is obvious; the bivariate correlation coefficient calculation formula is as follows:
wherein X, Y represent two variables, respectively;
each representing the average of two variables.
2. The method of claim 1, wherein: the drug effect indexes are related indexes of blood rheology, including whole blood viscosity low cut 1s, medium cut 5s, medium cut 30s, high cut 200s, plasma viscosity, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, plasminogen activator, tumor necrosis factor, plasminogen activator inhibitor and interleukin-6.
3. The method according to claim 1 or 2, wherein: the processed products of the curcuma wenyujin comprise curcuma longa, curcuma zedoary and curcuma zedoaria with vinegar, and the blood-entering components comprise Zedoalcanone B, Aerogeniol, Zedoarofruran, Zederone, furanodiene, curcurzenolone, curzeranenone A and germacrone.
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