CN116687990A - New use of herba Cichorii extract for preventing and treating cardiotoxicity caused by doxorubicin - Google Patents

New use of herba Cichorii extract for preventing and treating cardiotoxicity caused by doxorubicin Download PDF

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CN116687990A
CN116687990A CN202310827795.2A CN202310827795A CN116687990A CN 116687990 A CN116687990 A CN 116687990A CN 202310827795 A CN202310827795 A CN 202310827795A CN 116687990 A CN116687990 A CN 116687990A
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chicory
doxorubicin
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rats
extract
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张冰
林志健
张晓朦
王雨
殷玉玲
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Beijing University of Chinese Medicine
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Abstract

The invention discloses application of chicory extract in preparing a medicament for preventing, relieving and/or treating cardiotoxicity caused by doxorubicin. The invention not only widens the application range of chicory extract, but also provides a brand-new, safe and effective method for preventing and treating cardiotoxicity caused by doxorubicin.

Description

New use of herba Cichorii extract for preventing and treating cardiotoxicity caused by doxorubicin
Technical Field
The invention relates to the technical field of traditional Chinese medicines, in particular to a new application of chicory extract in preventing and treating doxorubicin cardiotoxicity.
Background
Doxorubicin (adriamycin, ADR), also known as Doxorubicin (DOX), is a highly potent broad-spectrum anthracycline anticancer drug, but it can cause severe cardiotoxicity. It is counted that with increasing cumulative doses of doxorubicin, the incidence of heart failure can be as high as 48%, severely affecting the prognosis and survival of cancer patients. Dexrazoxane is the only drug clinically recommended for preventing doxorubicin cardiotoxicity, but it is at risk of inducing secondary malignancy, and has extremely stringent requirements for indication, limited clinical use. Therefore, there is a need to find a safe and effective drug against doxorubicin cardiotoxicity.
Although the traditional Chinese medicine has no record of cardiotoxicity caused by doxorubicin, according to clinical manifestations of patients and research results of modern medicine, the traditional Chinese medicine can be classified into categories such as palpitation, chest stuffiness and pain, and the like, pathogenesis involves various aspects such as deficiency, dampness, blood stasis, and the like, and clinical sympathology researches show that the total content of dampness and blood stasis in disease elements of the cardiotoxicity of anthracyclines is up to 73%, which suggests that dampness stagnation and blockage can be a key pathogenesis of the cardiotoxicity of doxorubicin. Modern research suggests that doxorubicin cardiotoxicity is associated with a variety of molecular events, with oxidative stress being one of the currently accepted mechanisms. Meanwhile, the inflammatory reaction is an important characteristic of the toxicity of the doxorubicin heart, can be cooperated with oxidative stress to jointly induce and promote the generation and development of the toxicity of the doxorubicin heart, and suggests that the medicine with the effects of eliminating dampness and removing arthralgia and capable of resisting inflammation and oxidative stress may have the potential effect of resisting the toxicity of the doxorubicin heart.
The chicory is dried aerial parts or roots of chicory Cichorium glandulosum Boiss et Huet or chicory Cichorium intybus L, which are Chinese pharmacopoeia recorded medicinal materials, and are also Chinese pharmacopoeia recorded varieties, which are bitter and salty, cool, and have the effects of removing dampness and removing arthralgia. At present, no related study or report on the fact that chicory can be used for preventing and treating cardiotoxicity caused by doxorubicin exists.
Disclosure of Invention
The invention aims to provide a new application of chicory extract in preventing and treating cardiotoxicity caused by doxorubicin aiming at the defects in the prior art, so as to further expand the clinical application range of the chicory extract.
The invention provides application of chicory extract in preparing medicines for preventing, relieving and/or treating cardiotoxicity caused by doxorubicin.
Preferably, the cardiotoxicity caused by doxorubicin is cardiac insufficiency, heart failure, arrhythmia or pericardial disease.
Preferably, the chicory extract is an aqueous chicory extract, the preparation method of which comprises:
extracting chicory with water at 50-90 deg.c for 1-3 times, with 7-13 times of water for 30-90 min;
filtering while hot after extraction, mixing the extractive solutions, and drying under reduced pressure.
More preferably, the preparation method of the chicory aqueous extract comprises the following steps:
extracting herba Cichorii with water at 90deg.C for 3 times, each time with 10 times of water, each time for 90 minutes;
filtering while hot after extraction, mixing the extractive solutions, and drying under reduced pressure.
Wherein, the chicory is carried in Chinese pharmacopoeia (2020 edition) and accords with various regulations under the pharmacopoeia item.
Preferably, the active ingredient in the chicory extract is chicory polysaccharide. More preferably, the chicory polysaccharide content of the chicory extract is not less than 70% by weight. Further preferably, the chicory polysaccharide content in the chicory extract is 70% to 75%.
Preferably, the medicament comprises an effective amount of chicory extract and pharmaceutically acceptable excipients.
Where "effective amount" or "therapeutically effective amount" refers to a non-toxic, but sufficient amount of a drug or agent to provide the desired effect. In the present invention, an "effective amount" of an ingredient or unit of formulation refers to that amount of the ingredient which, when used in combination with other ingredients, provides the desired effect. The "effective amount" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent, and the like. Thus, it is not always possible to refer to an exact "effective amount", however, a suitable "effective amount" in any individual case may be determined by one of ordinary skill in the art using routine experimentation. For example, for a normal adult, administration may be in an effective amount of 9 to 18g/kg, although this is merely exemplary.
Wherein, pharmaceutically acceptable auxiliary materials include: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, matrices, and the like. The filler comprises: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, and the like; the disintegrating agent comprises: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, and the like; the lubricant comprises: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; the suspending agent comprises: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; the adhesive comprises: starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and the like; the sweetener comprises: saccharin sodium, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, etc.; the flavoring agent comprises: sweetener and various flavors; the preservative comprises: nipagin, benzoic acid, sodium benzoate, sorbic acid and salts thereof, benzalkonium bromide, chlorhexidine acetate, eucalyptus oil and the like; the matrix comprises: PEG6000, PEG4000, insect wax, and the like.
More preferably, the medicament is an oral dosage form. Oral dosage forms include any conventional oral dosage form, such as tablets, capsules, granules, pills, powders, oral liquids, and the like. Those skilled in the art can refer to related schemes in the prior art to prepare the desired dosage forms, and are not described in detail herein.
Compared with the prior art, the technical scheme of the invention has at least the following beneficial effects:
the invention discovers that the aqueous extract of the aerial parts of chicory can obviously reduce the level of myocardial injury markers of serum and heart tissue homogenate of animals accumulated by doxorubicin, enhance the function of heart contraction, improve myocardial structural disorder, inflammatory infiltration and fibrosis, and examine the mechanism of improving the toxicity of doxorubicin by chicory based on the level of oxidative stress and inflammation.
The invention provides a new prevention and treatment medicine for cardiotoxicity caused by doxorubicin, the medicine is single Chinese medicine chicory, belongs to medicine and food dual-purpose medicine, and has high safety when being used for preventing and treating the symptoms.
Drawings
FIG. 1 is a graph of the results of cardiac ultrasound for each group of rats in example 3.
FIG. 2 is a chart showing the pathology of HE staining of heart tissue of rats in each group in example 3.
FIG. 3 is a map of the Masson staining pathology of the heart tissue of each group of rats in example 3.
Detailed Description
Example 1 study of the extraction Process of chicory medicinal materials
1. Instrument and reagent
1.1 instruments
Three-purpose electric heating constant temperature water tank (420 type produced by Yongguangming medical instrument factory in Beijing); analytical balance (model AE160, manufactured by mertrehler, germany); ultraviolet-visible spectrophotometers (model DU800, manufactured by BECKMAN Inc.), and the like.
1.2 reagents
Phenol (Tianjin Fuchen chemical reagent factory, lot number 20081120), sulfuric acid (Beijing chemical factory, 200810002), and the like.
1.3 pharmaceutical products
Fructose control (lot number 100231-200303, from Beijing city drug inspection company)
Medicinal materials: chicory in the prescription meets the related requirements under the first edition of Chinese pharmacopoeia 2020. The chicory materials used in the experiment are respectively prepared from Jiangsu Dongtai, shandong Shou and Shandong Zibo, and are identified as dried root of chicory Cichorium intybus L. The preparation process of the chicory particles is that chicory medicinal materials are purchased from Jiangsu Dongtai.
The experiment adopts chicory root decoction pieces, and the identification picture of the medicinal materials is shown in an annex figure 1.
2. Determination of orthogonal test design-factor level table
Different levels are selected by taking water addition amount, extraction time, extraction times and temperature as factors, and chicory polysaccharide content and dry extract yield as indexes (the chicory polysaccharide determination method is a phenol-sulfuric acid method). 18 parts of chicory medicinal material are weighed, 50g of chicory medicinal material is taken as each part, and two orthogonal tests are carried out in parallel. The samples were prepared by extraction according to the design of L9 (34) orthogonal test chart, filtered while hot, the extracts were combined, dried under reduced pressure, and weighed, and the results are shown in Table 1.1.
TABLE 1.1 chicory extraction Process factor level Table
3 results of experiments
3.1 results of determination of the content of chicory polysaccharide
The experimental results are shown in Table 1.2.
TABLE 1.2 determination of the content of chicory polysaccharide
3.2 results of orthogonal experiments and analysis of variance
The experimental results are shown in tables 1.3 and 1.4.
TABLE 1.3 chicory extraction Process orthogonal test Table
TABLE 1.4 chicory extraction Process orthogonal test analysis of variance table
As shown in the table, when the polysaccharide extraction amount (g) is taken as an examination index, the factors A (temperature), B (extraction times), C (water addition amount) and D (extraction time) are all significantly different, A3 is more than A2 and more than A1, B3 is more than B2 and more than B1, C2 is more than C1 and more than C3, D3 is more than D1 and more than D2, the influence of the factor A on the extraction amount of chicory polysaccharide is the largest, the factor B and the factor D are the factor D and the factor C the most, and the result of statistics by SAS8.0 software shows that the optimal process is A3B3C2D3.
4. Analysis of results
The chicory polysaccharide is used as an active ingredient, the extraction process is preferably carried out by an experiment design L9 (34) orthogonal test, and the factors influencing the water extraction process are A (temperature), B (extraction times), C (water adding amount) and D (extraction time) in sequence through analysis of variance, wherein the four factors have obvious differences. Finally, the optimal process for extracting chicory polysaccharide in chicory medicinal materials by using aqueous solution is determined as follows: taking a certain amount of chicory, adding 10 times (weight) of water, extracting with water at 90deg.C for 3 times, each time for 1.5 hr.
Example 2 verification test of chicory extraction Process
1. Instrument and reagent
As in example 1.
2. Test method
Preparing 3 batches of chicory samples according to the optimal extraction process, and measuring the total sugar content of each batch of chicory; the specific measurement method was the same as in example 1.
3. Test results
3.1 content investigation of chicory polysaccharide
The results are shown in Table 2.1.
TABLE 2.1 investigation of the extraction yield of chicory polysaccharide
From the above table, three samples prepared by the best process extraction of the orthogonal test were substantially stable in content and the polysaccharide extraction was greater than that of each chicory polysaccharide in the orthogonal process described above.
3.2 investigation of extract rate of medicinal materials
The extract was extracted according to a defined process and the extract yield was examined and the results are shown in Table 2.2.
TABLE 2.2 investigation of paste yield
Conclusion: the ointment yield of the medicinal materials is above 60%.
4. Analysis of results
Adding 10 times of water, extracting with 90 deg.C water for 3 times, and under each extraction process for 1.5 hr, the chicory polysaccharide has the highest extraction amount, and drying to obtain brownish red dry extract with dry extract yield above 60%. Therefore, the process is taken as the optimal process for water extraction of chicory.
EXAMPLE 3 study of the anti-doxorubicin cardiotoxicity of aqueous chicory extracts
1. Instrument and reagent
1.1 instruments
Name of the name Model number Manufacturer' s
Electromagnetic oven HY-221 Guangdong Hemisphere Industry Group Co.
Rotary evaporator RE-501 Beijing shentai equipment company
Electronic balance TLE303E Mettler Toledo instruments (Shanghai) Co.,Ltd.
Desk type centrifugal machine DT5-3 type Beijing era North centrifuge Co., ltd
Freezing embedding machine KH-BL HUBEI XIAOGAN KUOHAI MEDICAL TECHNOLOGY Co.,Ltd.
Paraffin tissue slicer KH-Q320 HUBEI XIAOGAN KUOHAI MEDICAL TECHNOLOGY Co.,Ltd.
Microscope Olmpus BX53 Orinbas Corp Japan
Camera with camera body DP72CCD Orinbas of Japan
Enzyme label instrument sunrise TeCAN company Switzerland
Water bath kettle HH-1 high-end type Jintan city and west sense, laboratory instrumentation factory
Biological signal acquisition and analysis system BL-420N CHENGDU TAIMENG SOFTWARE Co.,Ltd.
Ultra-high resolution small animal ultrasonic imaging system VEVOTM2100 VisuaaLSonics Co Canada
Tissue refiner JXFSTPRP-CL-48 SHANGHAI JINGXIN INDUSTRIAL DEVELOPMENT Co.,Ltd.
1.2 reagents
Name of the name Product lot number Manufacturer' s
Doxorubicin hydrochloride for injection 2206E2 SHENZHEN MAIN LUCK PHARMACEUTICALS Inc.
Chicory (Cichorium intybus) 200701 Xinjiang Minhai Chinese medicine decoction piece Co., ltd
Dexrazoxane for injection (Oruo first) E210012 JIANGSU AOSAIKANG PHARMACEUTICAL Co.,Ltd.
0.9% sodium chloride injection solution SHIJIAZHUANG NO.4 PHARMACEUTICAL Co.,Ltd.
10% buffered formalin 20201010 BEIJING YILI FINE CHEMICALS Co.,Ltd.
Xylene (P) 20201101 TIANJIN DAMAO CHEMICAL REAGENT FACTORY
Absolute ethyl alcohol 2021010117 TIANJIN ZHIYUAN CHEMICAL REAGENT Co.,Ltd.
Improved Hematoxylin Eosin (HE) staining kit G1121 BEIJING SOLARBIO TECHNOLOGY Co.,Ltd.
Improved Masson trichromatic staining kit BEIJING SOLARBIO TECHNOLOGY Co.,Ltd.
Neutral gums 20150208 Exemplary foreign instruments Co., shanghai, china
ELISA kit for rat interleukin 6 (IL-6) KT3066-A Jiangsu enzyme free Utility Co Ltd
ELISA kit for rat tumor necrosis factor alpha (TNF-alpha) KT3056-A Jiangsu enzyme free Utility Co Ltd
ELISA kit for rat interleukin 1 beta (IL-1 beta) KT2923-A Jiangsu enzyme free Utility Co Ltd
Malondialdehyde (MDA) kit A003-1-2 Nanjing established technology Co.Ltd
Superoxide dismutase (SOD) kit A001-1-2 Nanjing established technology Co.Ltd
Catalase (CAT) kit A007-1-1 Nanjing established technology Co.Ltd
Reduced Glutathione (GSH) kit A006-2-1 Nanjing established technology Co.Ltd
ELISA kit for rat N-terminal forebrain natriuretic peptide (NT-proBNP) KT3205-A Jiangsu enzyme free Utility Co Ltd
Rat Brain Natriuretic Peptide (BNP) ELISA kit KT2943-A Jiangsu enzyme free Utility Co Ltd
ELISA kit for rat myocardial troponin I (cTn-I) KT3302-A Jiangsu enzyme free Utility Co Ltd
2. Experimental method
2.1 grouping of animals
After 2 days of adaptive feeding, 60 rats were randomly divided into 6 groups of 10 animals each according to body weight, i.e. normal, model, positive (dexrazoxane), low, medium and high chicory dose groups.
2.2 establishment of a Doxorubicin cardiotoxicity rat model
The preparation method comprises the steps of adding 10mL of physiological saline into each powder injection before use, and completely dissolving the powder injection by using a vortex device for 10min and avoiding light in the whole process. The model group, the yang medicine group and the chicory low, medium and high dose group rats are intraperitoneally injected with 3.5mg/kg of doxorubicin hydrochloride solution (DOX) for injection every 72 hours, the normal group is intraperitoneally injected with 3.5ml/kg of physiological saline every 72 hours, the model is molded in the morning, the total injection is 6 times, the accumulated dose is 21mg/kg, and the total experimental period is 18d. Weigh once every 3d and readjust the molding amount based on body weight.
2.3 experimental dosing
Extraction method of herba Cichorii water extract extraction is performed by referring to the best extraction process obtained in example 1 and example 2. The high, medium and low dose groups of chicory are respectively administered according to the crude drug dosage of 30g/kg, 15g/kg and 7.5g/kg, and the chicory is administered by intragastric administration in the afternoon every day, in order to ensure that the intragastric volume is similar, the concentration of chicory extract in the high, medium and low dose groups is respectively 3g/mL, 2g/mL and 1g/mL, and the other groups are respectively administered by intragastric administration of 20mL/kg of animal drinking water for 18d continuously, and the dosage is re-adjusted according to the body weight after weighing every 3 d.
2.4 general State viewing
The general state of the rats, such as mental state, hair color, gait, urination and defecation state, reaction force to grasping, and voluntary activity, etc., were observed every day.
2.4 cardiac ultrasound
Experiment 18d cardiac ultrasound was performed on each group of rats. Abdominal injections of 1.5% pentobarbital solution (3 ml/kg) were used for anaesthesia. After anesthesia, the heat preservation is carried out, and the chest part is prepared. The back lying position is fixed after skin preparation, and the heart function index of the rat is measured by using a cardiac ultrasonic monitor: left Ventricular Ejection Fraction (LVEF), left ventricular short axis shortening (LVFS), diastolic and systolic volumes (LV vol; d, lvvol; s), left ventricular volume (LV Mass); heart structural index: the left ventricular post wall thickness at end diastole and end systole (Lvpw; d, LVpWs), the anterior wall thickness of the left ventricle at end diastole and end systole (LVAwd, LVAW; s), the left ventricular inner diameter at end diastole and end systole (IVID: d, LVID: s), the ventricular septum thickness at end diastole and end systole (IVS; d, IVS; s).
2.5 serum Biochemical index detection
Experiment 18d blood was taken before the rats were sacrificed and centrifuged at 3000r/min for 10min to separate serum. Serum BNP, NT-ProBNP, cTnI, IL-6, IL-1β, TNF- α, T-SOD, GSH-Px, and CAT levels were assayed.
2.6 preparation of cardiac tissue homogenate and index detection
Heart tissue transection, washing blood stain in the lower half with pre-cooled sterile physiological saline, weighing, preparing tissue homogenate with PBS, and detecting homogenate protein concentration and BNP, NT-ProBNP, cTnI, IL-6, IL-1β, TNF- α, T-SOD, GSH-Px, CAT level.
2.7 histopathological observations of the heart
The heart tissue is transected, the upper half is fixed in 10% formalin solution, the heart tissue is treated with 70%, 80% and 90% gradient ethanol, then dehydrated in absolute ethanol, embedded in xylene, sectioned, and after sectioning, stained with HE staining and Masson, and the myocardial structure and degree of myocardial fibrosis are observed under a microscope.
3. Data analysis
Statistical analysis was performed using GraphPad prism7.0 software, and data were averaged ± standard deviation ± ) Indicating that the data comparison among multiple groups is selected according to the normal state and the variance of each groupOne-way anova or Kruskal-Wallis anecdotal test, group-by-group comparison with Dunnett-t test or Dunnett's T3 test based on whether the anova was selected for P<0.05 is statistically significant, P<0.01 indicates a very significant difference.
4. Results
4.1 serum cardiac injury marker levels in rats
The results are shown in Table 4.1.
Table 4.1 rat serum cardiac injury marker levels (pg/ml,n＝10)
note that: in contrast to the normal group, * P<0.05 or ** P<0.01; in contrast to the set of models, # P<0.05 or ## P<0.01. Experiment 12d Normal group middle ultrasonic detection anesthesia lethal 1, 12d-18d chicory low, medium dose group and right propyleneimine group each death 2.
The results showed that on day 18 of the experiment, the cumulative dose of doxorubicin was 21mg/kg, and that the serum cTnI and NT-proBNP were significantly increased (P <0.05 or P < 0.01) in the rats of the model group compared to the normal group. Compared with the model group, the serum cTnI of the low, medium and high dose rats of the dexrazoxane group is obviously reduced (P is less than 0.05 or P is less than 0.01); compared with the model group, the dexrazoxane group and the serum NT-proBNP of the chicory rats at high doses are significantly reduced (P <0.05 or P < 0.01).
4.2 rat cardiac tissue homogenate cardiac injury marker levels
The results are shown in Table 4.2.
Table 4.2 rat heart tissue homogenate heart injury marker levels (pg/mg,)
note that: in contrast to the normal group, * P<0.05 or ** P<0.01; in contrast to the set of models, # P<0.05 or ## P<0.01. Normal group n=9, dexrazoxane group, low and high chicory group n=8, model group and chicory group n=10.
The results showed that on day 18 of the experiment, the cumulative dose of doxorubicin was 21mg/kg, and that the heart tissue homogenate BNP, NT-proBNP, cTnI was significantly elevated (P < 0.01) in the model group compared to the normal group. Compared with the model group, the right propyleneimine group and chicory are remarkably reduced in each dose of rat heart tissue homogenate BNP, NT-proBNP and cTnI (P <0.05 or P < 0.01).
4.3 results of rat cardiac ultrasound examination
The echocardiogram M-Mode image of the left ventricle structure of the rat is shown in figure 1, and the heart function and heart structure related index are shown in table 4.3. TABLE 4.3 two groups of rats 18d heart ultrasonic detection cardiac function index changesn＝10)
Note that: in contrast to the normal group, * P＜0.05， ** p is less than 0.01; in contrast to the set of models, # P＜0.05， ## P＜0.01。
the 18d cardiac ultrasound M-Mode image shows that model group rat heart chambers are enlarged, and that the model group rat end diastole and end systole left ventricular anterior wall thicknesses, end systole left ventricular posterior wall thicknesses (LVAW; d, LVAW; s, LVPW; s) are all significantly reduced (P < 0.01), end diastole left ventricular posterior wall thicknesses (LVPW; d) have a decreasing trend, and end systole left ventricular inner diameters (LVID; s) have an increasing trend, compared with the normal group. Right propylimine group LVAW compared to model group; d, LVPW; s significantly increased (P <0.01 or P < 0.05), LVPW; d has a rising trend, LVID; s has a decreasing trend, LVAW; s, LVID; d no significant change; a chicory low dose group LVAW compared to the model group; d, LVAW; s, LVPW; d, LVID; d has no significant change, LVID; s has a decreasing trend, LVPW; s has a rising trend; dose group LVAW in chicory; s, LVID; d, LVPW; d has no significant change, LVAW; d, LVID; s has a decreasing trend, LVPW; s has a rising trend; chicory high dose group LVAW; d, LVAW; s, significantly elevated (P < 0.01), LVID; s, LVID; d has a decreasing trend, LVPW; s has an increasing trend, LVPW; d has no significant change. The left ventricular contraction function parameter shows that compared with a normal group, the Left Ventricular Ejection Fraction (LVEF) and the short axis shortening rate (LVFS) of the model group have obviously reduced quality (P < 0.01) before and after left ventricular correction (LV Mass AW, LV Mass AW (Corrected)), the left ventricular contraction period and the volume (LVVol; s) have an increasing trend, and the left ventricular diastole volume (LVVol; d) has a decreasing trend; LVVol; s is significantly reduced (P < 0.01), LVEF and LVFS are both significantly increased (P < 0.01).
4.4 results of HE staining of rat heart tissue
HE staining results are shown in fig. 2, and the results show that the heart tissue and the myocardial structure of the normal group of rats are normal, the myocardial cell nuclei are normal, and no broken myocardial fibers or inflammatory cell infiltration is found. The doxorubicin group rats had myocardial fiber disorder accompanied by fracture and massive inflammatory cell infiltration, and the positive drug group and chicory dose groups had different degrees of improvement on this condition, and the myocardial fibers were orderly arranged and did not appear inflammatory cell infiltration.
4.5 results of Masson staining of rat heart tissue
The Masson staining results are shown in FIG. 3, and the collagen fibers are blue, and the cytoplasm, red blood cells and myocardial fibers are red. Compared with the control group, the doxorubicin group obviously shows excessive accumulation of interstitial collagen fibers; the interstitial collagen fibers of the dexrazoxane group and chicory group at each dose are significantly less than those of the doxorubicin group.
4.6 changes in serum inflammatory factor levels in rats
The results are shown in Table 4.4.
Table 4.4 serum inflammatory factor level change in rats (U/ml,)
note that: in contrast to the normal group, * P＜0.05， ** p is less than 0.01; in contrast to the set of models, # P＜0.05， ## P＜0.01。
the results show that on experiment day 18, the cumulative dosage of doxorubicin was 21mg/kg, and that the serum inflammatory factors IL-6, IL-1β, TNF- α were significantly increased (P < 0.01) in the rats of the model group compared with the normal group. Compared with the model group, the serum inflammatory factors IL-6, IL-1 beta and TNF-alpha of rats with various doses of chicory are obviously reduced (P <0.05 or P < 0.01).
4.7 changes in the levels of inflammatory factor in rat heart tissue homogenates
The results are shown in Table 4.5.
Table 4.5 rat heart tissue homogenate inflammatory factor level change (U/mg,)
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note that: in contrast to the normal group, * P＜0.05， ** p is less than 0.01; in contrast to the set of models, # P＜0.05， ## P＜0.01。
the results showed that on day 18 of the experiment, the cumulative dose of doxorubicin was 21mg/kg, and that the cardiac tissue homogenate inflammatory factors IL-6, IL-1β, TNF- α were significantly elevated (P <0.05 or P < 0.01) in the model group compared to the normal group. Compared with the model group, the right propylimine group and chicory are remarkably reduced in cardiac tissue homogenate inflammatory factors IL-6, IL-1 beta and TNF-alpha (P <0.05 or P < 0.01) of rats at each dose.
4.8 changes in serum oxidative stress levels in rats
Table 4.6 serum oxidative stress index levels for each group of rats (U/ml,)
note that: in contrast to the normal group, * P＜0.05， ** p is less than 0.01; in contrast to the set of models, # P＜0.05， ## P＜0.01。
the results showed that on day 18 of the experiment, the cumulative dose of doxorubicin was 21mg/kg, and that the serum CAT, GSH, T-SOD was significantly reduced (P <0.05 or P < 0.01) in the rats of the model group compared to the normal group. Compared with the model group, the serum CAT, GSH, T-SOD of rats with various doses of the dexrazoxane group and chicory is obviously increased (P is less than 0.05 or P is less than 0.01).
4.9 changes in the level of oxidative stress in rat heart tissue homogenates
Table 4.7 serum oxidative stress index levels for each group of rats (U/ml,)
note that: in contrast to the normal group, * P＜0.05， ** p is less than 0.01; in contrast to the set of models, # P＜0.05， ## P＜0.01。
the results show that on the 18 th day of the experiment, the cumulative dosage of the doxorubicin is 21mg/kg, compared with the normal group, the heart tissue homogenate CAT, GSH, T-SOD of rats in the model group is obviously reduced ** P < 0.01). Compared with the model group, the heart tissue homogenate CAT, GSH, T-SOD of rats with different doses of dexrazoxane group and chicory is obviously increased # P <0.05 or ## P＜0.01)。
5. Analysis of results
The study preliminarily discusses the effect and mechanism of chicory for preventing and treating the toxicity of doxorubicin, and results show that after the corresponding medicines are given to the group of yang medicines and the group of chicory, the general state of rats in each group is improved, the heart muscle injury markers, the echocardiogram and the pathological staining of serum and heart tissue homogenate all indicate that the toxicity of the heart of the rats is relieved, and the oxidative stress related indexes CAT, GSH, T-SOD and inflammatory factors IL-6, TNF-alpha and IL-1 beta in the serum and heart tissue homogenate of the rats are obviously reduced compared with the model group, so that the chicory possibly plays a role in resisting the toxicity of doxorubicin by inhibiting oxidative stress and inflammatory reaction.
The present study therefore concluded that aqueous extracts of the aerial parts of chicory significantly improve the cardiotoxicity of doxorubicin, have a good control effect and suggest that they may act by inhibiting oxidative stress and inflammatory reactions. The invention explores the heart toxicity and action mechanism of the chicory for resisting the doxorubicin, and provides a new drug choice for preventing and treating the doxorubicin heart toxicity.

Claims (7)

1. Use of chicory extract for the preparation of a medicament for the prevention, alleviation and/or treatment of cardiotoxicity caused by doxorubicin.
2. The use according to claim 1, wherein the doxorubicin-induced cardiotoxicity is cardiac insufficiency, heart failure, arrhythmia or pericardial disease.
3. Use according to claim 1, characterized in that the preparation method of chicory extract comprises:
extracting chicory with water at 50-90 deg.c for 1-3 times, with 7-13 times of water for 30-90 min;
filtering while hot after extraction, mixing the extractive solutions, and drying under reduced pressure.
4. A use according to claim 3, characterized in that the preparation method of chicory extract comprises:
extracting herba Cichorii with water at 90deg.C for 3 times, each time with 10 times of water, each time for 90 minutes;
filtering while hot after extraction, mixing the extractive solutions, and drying under reduced pressure.
5. Use according to claim 1, characterized in that the chicory polysaccharide content in the chicory extract is not lower than 70%.
6. Use according to claim 5, characterized in that the chicory polysaccharide content of the chicory extract is 70-75%.
7. The use according to claim 1, wherein the medicament is an oral dosage form.
CN202310827795.2A 2023-07-06 2023-07-06 New use of herba Cichorii extract for preventing and treating cardiotoxicity caused by doxorubicin Pending CN116687990A (en)

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