CN102973554B - Medical or pabular application of alantolactone used for preventing and treating ulcerative colities - Google Patents
Medical or pabular application of alantolactone used for preventing and treating ulcerative colities Download PDFInfo
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- CN102973554B CN102973554B CN201210553437.9A CN201210553437A CN102973554B CN 102973554 B CN102973554 B CN 102973554B CN 201210553437 A CN201210553437 A CN 201210553437A CN 102973554 B CN102973554 B CN 102973554B
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Abstract
The invention relates to the field of medicine, and in particular relates to medical application of alantolactone. The alantolactone can be used for preventing and treating enteritis.
Description
Technical field
The present invention relates to Medicines and Health Product field, particularly relate to a kind of medical usage of alantolactone.
Background technology
Ulcerative colitis (Ulcerative colitis, UC) is the inflammatory bowel chronic, that repeatedly show effect that betides colon.Clinical main manifestations is diarrhoea, mucus bloody purulent stool, stomachache.Major complications has: hemorrhage, intestinal perforation, anal fistula, intestinal obstruction, colon cancer and septic shock etc.
Alantolactone (Alantolactone) is a kind of sesquiterpene lactones, is one of main active of Radix Inulae, is also one of main effective ingredient of four-Tibet inula root soft capsule.Alantolactone has anthelmintic, the multiple pharmacologically active such as antibacterial.
Summary of the invention
Object of the present invention aims to provide a kind of new medical usage of alantolactone.
Specifically, the invention provides a kind of alantolactone and prevent and treat the application in medicine or the food of enteritis in preparation.
In a preference, described enteritis is ulcerative colitis.
The details of various aspects of the present invention will be able to detailed description in chapters and sections subsequently.By below and the description of claim, feature of the present invention, object and advantage will be more obvious.
Brief description of the drawings
Fig. 1 has embodied the impact of alantolactone on ulcerative colitis Mouse Weight;
Fig. 2 has embodied the impact of alantolactone on ulcerative colitis mice hemafecia incidence rate;
Fig. 3 has embodied the impact of alantolactone on ulcerative colitis mice colon length;
The impact of alantolactone on ulcerative colitis mice colon pathology embodied in Fig. 4-5;
The TNF-α of alantolactone on ulcerative colitis mice colon and the impact of IL-6 mrna expression have been embodied in Fig. 6-7;
(in above-mentioned figure: a represents Normal group, b represents model control group, and c represents SASP group, and d represents alantolactone group)
Detailed description of the invention
The part of coming out of the present invention is based on so unexpected discovery: alantolactone can obviously improve that the losing weight of ulcerative colitis mice, hemafecia, colon are shortened and the symptom such as histopathology damage, and can reduce the content of the inflammatory cytokine TNF-α of colon and IL-6.Therefore, alantolactone can be used for preparing medicine or the health food of preventing and treating enteritis, particularly ulcerative colitis.
And then, the invention provides alantolactone and prevent and treat the application in medicine or the health food of enteritis in preparation.
The molecular formula of alantolactone of the present invention is: C
15h
20o
2, molecular weight is: 232.31, and its structural formula is as follows:
Alantolactone of the present invention can obtain from purchases such as Sigma chemical company, Man Site bio tech ltd, Chengdu by commercial sources.Its purity all meets medicinal standard.The purity of alantolactone of the present invention is with >98% the best.
Alantolactone of the present invention can use separately or use with the form of pharmaceutical composition.Pharmaceutical composition comprises alantolactone of the present invention and the pharmaceutically suitable carrier as active component.Preferably, the alantolactone of the present invention as active component that pharmaceutical composition of the present invention contains 0.1-99.9% percentage by weight." pharmaceutically suitable carrier " can not destroy the pharmaceutical active of alantolactone of the present invention, simultaneously its effective dose, and can bringing into play pharmaceutical carrier, to make the consumption of used time nontoxic to human body.
Described pharmaceutically suitable carrier includes but not limited to: soft phospholipid, aluminium stearate, aluminium oxide, ion exchange material, self-emulsifying drug delivery system, tween or other surfactants, serum albumin, buffer substance are if phosphate, glycine, sorbic acid, water, salt, electrolyte are as sulfate protamine, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, magnesium silicate, satisfied fatty acid partial glycerol ester admixture etc.
Other conventional excipient substances are as binding agent (as microcrystalline Cellulose), filler (as starch, glucose, Lactis Anhydrous and lactose beadlet), disintegrating agent (as cross-linked pvp, crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose), lubricant (as magnesium stearate) and absorption enhancer, absorption carrier, flavouring agent, sweeting agent, excipient, diluent, wetting agent etc.
Alantolactone of the present invention with and pharmaceutical composition can and can pass through intestinal or non-intestinal or topical routes by this area conventional method preparation.Oral formulations comprises capsule, tablet, oral liquid, granule, pill, powder, sublimed preparation, unguentum etc.; Non-intestinal drug delivery agent comprises injection etc.; Local administration preparation comprises cream, patch, ointment, spray etc.Be preferably oral formulations.
Alantolactone of the present invention taking and the route of administration of pharmaceutical composition can be as oral, Sublingual, percutaneous, through muscle or subcutaneous, mucocutaneous, vein, urethra, vagina etc.
Except making medicament, also can in alantolactone of the present invention, add the various food additive such as antioxidant, pigment, enzyme preparation, make health food by the conventional method of this area.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, the condition of conventionally advising according to normal condition or according to manufacturer.Unless otherwise indicated, otherwise all percent, ratio, ratio or umber by weight.
Unless otherwise defined, the same meaning that all specialties that use in literary composition and scientific words and one skilled in the art are familiar.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can combination in any.All features that patent specification discloses can with any composition forms use, each feature disclosing in description, can anyly provide the alternative characteristics of identical, impartial or similar object to replace.Therefore apart from special instruction, the feature disclosing is only the general example of equalization or similar features.
Embodiment 1:
1, experiment material
1.1 medical material
Alantolactone (CAS:546-43-0, MW 232.31, HPLC purity >=98%, Man Site bio tech ltd, Chengdu); Dextran sulfate sodium (MW 36000-50000, is produced by MP Biomedicals company of the U.S. for DSS, CAS:9011-18-1); Sulfasalazine (SASP, CAS:599-79-1, molecular weight 398.39, HPLC purity >=98%, is produced by Sigma-Aldrich company of the U.S.).
1.2 laboratory animal
The C57BL/6 female mice (8 weeks) of body weight 20 ± 2g, is provided the animal quality certification number: SYXK(Shanghai by Shanghai Univ. of Traditional Chinese Medicine's Experimental Animal Center) 2009-0069.Be placed in conventional feeding environment, ad lib and drinking-water.
2, experimental technique
The foundation of 2.1 Ulcerative Colitis Models
The C57BL/6 female mice (20 ± 2g) of selective body weight average one, adopts international ulcerative colitis modeling method (Gastroenterology, 1990,98:694-702; DigestiveDisease and Science, 1993,38:1722-34; And U.S. Patent No. 5,869,048), in the research incipient stage, make mice ad lib and drinking-water, after adaptive phase, change water into 5%(w/v in the early stage) DSS, freely drink 5 days, to cause ulcerative colitis.
2.2 grouping and medications
Normal group: 15, give normal diet.
Model control group: 15, give 5%DSS solution and freely drink 5 days, changed normal drinking water into since the 5th day, gavage gives continuous normal saline 7 days simultaneously.
SASP group: 15, give 5%DSS solution and freely drink 5 days, changed normal drinking water into since the 5th day, gavage gives SASP(350mg/kg simultaneously) continuous 7 days.
Alantolactone group: 15, give 5%DSS solution and freely drink 5 days, changed normal drinking water into since the 5th day, gavage gives alantolactone (50mg/kg) continuous 7 days simultaneously.
Experimental session, every day, the fresh dosage particles of preparing, dissolved with 0.5% sodium carboxymethyl cellulose, and used in 1 hour in preparation.
The assessment of 2.3 enteritis
Diarrhoea, hemafecia, histopathological analysis etc. are all with reference to early-stage Study (PLoS One.2012,7:e36075) the described method that publishes thesis.Experimental session records body weight change, diarrhoea and hemafecia symptom every day.Experiment finishes rear anesthesia and mice is put to death in cervical vertebra dislocation, opens abdominal cavity, takes out colon, measures the colon length from caecum to rectum.And get DC and make tissue slice, carry out H & E dyeing, H & E dyeing colon specimen is carried out to pathological score: (1) inflammatory cell ooze out standards of grading: in 0 point-mucosa lamina propria, have minute quantity inflammatory cell, in 1 point-mucosa lamina propria, there is the inflammatory cell in more inflammatory cell or mucosa lamina propria to increase, 2 points-inflammatory cell diffuses to Submucosa, and 3 points-holostrome all has inflammatory cell to ooze out; (2) tissue damage standards of grading: 0 point-without mucosa injury, 1 point-discrete mucosal epithelium is damaged, 2 points-top layer mucosal erosion, and 3 points-mucosa breakage widely is also expanded to intestinal wall deep layer.Oozing out of inflammatory cell scored and tissue damage score addition, calculate histopathology scoring (1-6 divides).
2.4 fluorescence quantitative RT-RCRs detect the TNF-α of colon and the mrna expression of IL-6
In body, effect experiment finishes Hou Qu colon, extracts the total RNA of colon fragment also quantitative with Trizol reagent, gets 3 μ g RNA M-MLV reverse transcription and prepares cDNA.Taking cDNA as template, on ABI7300 quantitative real time PCR Instrument, increase.PCR reaction system: 2 × SYBR Premix Ex Taq(TakaRa, cat:DRR420A) 5 μ L, Forward Primer 0.4 μ L, Reverse Primer0.4 μ L, 50 × ROX Reference Dye, 0.4 μ L, cDNA 1 μ L, dH
2o 2.8 μ L, cumulative volume is 10 μ L.PCR response parameter: 95 DEG C, 30s denaturation, 95 DEG C, 5s degeneration, 60 DEG C, 30s annealing, totally 40 circulations.Each amplification arranges β-actin internal reference.Primer sequence is as follows:
MTNF-α: positive-sense strand 5 '-CGTGGAACTGGCAGAAGAGG-3 ',
Antisense strand 5 '-AGACAGAAGAGCGTGGTGGC-3 ';
MIL-6: positive-sense strand 5 '-ACCACGGCCTTCCCTACTTC-3 ',
Antisense strand 5 '-CATTTCCACGATTTCCCAGA-3 ';
β-Actin: positive-sense strand 5 '-CAGCCTTCCTTCTTGGGTAT-3 ',
Antisense strand 5 '-GGTCTTTACGGATGTCAACG-3 '.
Carry software with pcr amplification instrument and carry out quantitative fluorescence analysis, and draw Ct value.Draw the expression of each group of gene with respect to β-Actin by calculating 2-△ Δ CT.
2.5ELISA method detects the content of the TNF-α of colon and IL-6
Experiment finishes rear anesthesia and mice is put to death in cervical vertebra dislocation, opens abdominal cavity, takes out colon, homogenate after weighing.Homogenate is in 4 DEG C, centrifugal 10 minutes of turn 2000/min.Get 10 μ L supernatant, measure the content of TNF-α and IL-6 with ELISA test kit (R & D systems, Minneapolis, MN, USA), the equal reference reagent box of concrete operations description.With BCA method mensuration protein content.Result is expressed as pg/mg protein.
2.6 statistical analysis
All experimental datas all repeat 3 times, result represents with mean+SD, adopt SPSS16.0 statistical software to adopt one way analysis of variance (One-way ANOVA) and LSD inspection to experimental data, P<0.05 has significance for difference statistically.
3, result
The therapeutical effect of 3.1 alantolactones to ulcerative colitis
3.1.1 the impact on ulcerative colitis Mouse Weight
Fig. 1 has embodied the impact of alantolactone on ulcerative colitis Mouse Weight.In whole experimentation, (amount to 12 days, comprise 5 days of processing with DSS and 7 days of treated with medicaments subsequently), the body weight change of Normal group mice is steady, and the body weight (19.8 ± 0.2g) of the 12nd day has increased by 1.4%; The body weight continuous decrease of model group mice, body weight (17.3 ± 0.2g) rate of alleviating of the 12nd day is 11.3%; The body weight continuous decrease to the of SASP group (18.4 ± 0.3g) and alantolactone group (18.6 ± 0.2g) mice 7 days, fall is less than model group, tend to be steady subsequently and slightly raise, the rate of losing weight of the 12nd day is respectively 5.5% and 4.4%, all has significant difference (P<0.01 and P<0.001) compared with model group.Illustrate that SASP and alantolactone all can obviously improve the symptom that loses weight of the ulcerative colitis mice that DSS causes.
3.1.2 the impact on ulcerative colitis mice hemafecia incidence rate
Fig. 2 has embodied the impact of alantolactone on ulcerative colitis mice hemafecia incidence rate.In whole experimentation, (amount to 12 days, comprise 5 days of processing with DSS and 7 days of treated with medicaments subsequently), mice occurs without hemafecia Normal group.Since the 4th day, 3 groups of mices of all the other except Normal group started to occur hemafecia symptom, the most serious with model group mice.Model group hemafecia continues to occur to the 10th day, tends to be steady subsequently, and the hemafecia incidence rate of the 12nd day is 96.7%; SASP group and alantolactone group mice hemafecia continue to occur to the 6th day, tend to be steady subsequently and slightly decline, and the hemafecia incidence rate of the 12nd day is respectively 46.7% and 33.3%, all has significant difference (P<0.001) compared with model group.Illustrate that SASP and alantolactone all can obviously improve the hemafecia symptom of the ulcerative colitis mice that DSS causes.
3.1.3 the impact on ulcerative colitis mice colon length
Fig. 3 has embodied the impact of alantolactone on ulcerative colitis mice colon length.Compared with Normal group (8.8 ± 0.3cm), the colon of model group (5.5 ± 0.5cm) mice obviously shortens, and LVFS is 37.7%; The colon LVFS of SASP group (6.8 ± 0.5cm) and alantolactone group (7.3 ± 0.4cm) mice is respectively 22.6% and 17.7%, all has significant difference (P<0.05 and P<0.01) compared with model group.Illustrate that the colon that SASP and alantolactone all can obviously improve the ulcerative colitis mice that DSS causes shortens symptom.
3.1.4 the impact on ulcerative colitis mice colon pathology
Fig. 4 has embodied the injury repairing effect of alantolactone to ulcerative colitis mice colon.The colon of model group mice is typical inflammation mucosa performance, visible mucosa, even flesh layer massive inflammatory cells infiltrated of Submucosa, and organizational structure disorder, fracture, Submucosa is hemorrhage, edema, telangiectasis; The visible pathological changes of colon of SASP group mice and alantolactone group mice alleviates, ulcer healing, and Submucosa is hemorrhage to be alleviated.
Fig. 5 has embodied colon specimen pathological score result.According to 1-6 point of standards of grading that represent inflammatory tissue damage, the score of Normal group mice is 0; Model group mice score (5.5 ± 0.5 points) significantly increases; SASP group (2.5 ± 0.5 points) and the score of alantolactone group (2.0 ± 0.4 points) mice all reduce, and all have significant difference (P<0.001) compared with model group.
To sum up colon's pathological analysis result shows, SASP and alantolactone all can significantly improve the damage of colonic mucosa histopathology and the inflammatory cell infiltration symptom of the ulcerative colitis mice that DSS causes.
3.1.5 the impact that the TNF-α on ulcerative colitis mice colon and IL-6 express
Fig. 6 has embodied the impact of the TNF-alpha expression of alantolactone on ulcerative colitis mice colon.Model group (255.7 ± 10.2) TNF-of mice colon alpha expression is apparently higher than Normal group (1.0 ± 0.1); Gavage gives after SASP (89.7 ± 5.5) or alantolactone (41.2 ± 5.8), and the TNF-alpha expression of mice colon declines, and the two all has significant difference (P<0.001) compared with model group.Show that SASP and alantolactone all can significantly reduce the expression of TNF-α in the inflammatory reaction that DSS causes.
Fig. 7 has embodied the impact that alantolactone is expressed the IL-6 of ulcerative colitis mice colon.Model group (196.4 ± 14.7) IL-6 of mice colon expresses apparently higher than Normal group (1.0 ± 0.56); Gavage gives after SASP (64 ± 8.9) or alantolactone (44.9 ± 5.8), and the IL-6 of mice colon expresses and declines, and the two all has significant difference (P<0.001) compared with model group.Show that SASP and alantolactone all can significantly reduce the expression of IL-6 gene in the inflammatory reaction that DSS causes.
3.1.6 the impact on the TNF-α of ulcerative colitis mice colon and IL-6 content
Get colon specimen weigh after homogenate, with the content of TNF-α and IL-6 in ELISA kit measurement homogenate supernatant, the results are shown in Table 1.
The impact of table 1. alantolactone on the TNF-α of ulcerative colitis mice colon and IL-6 content
###p<0.001, model group is compared with matched group;
* *p<0.001, treatment group is compared with matched group.
Table 1 has embodied the impact of alantolactone on the TNF-α of ulcerative colitis mice colon and IL-6 content.Compared with Normal group (14.6 ± 1.7), model group (255.4 ± 13.5) TNF-of mice colon alpha content is apparently higher than Normal group (P<0.001); Gavage gives SASP(84.6 ± 8.5) or alantolactone (53.4 ± 2.9) after, the TNF-alpha content of mice colon declines, and compared with model group, all has significant difference (P<0.001).Show that SASP and alantolactone all can significantly reduce the tissue content of TNF-α in the inflammatory reaction that DSS causes.
In addition, compared with Normal group (28.9 ± 2.3), model group (214.3 ± 17.9) IL-6 of mice colon content apparently higher than Normal group (
* *p<0.001); Gavage gives after SASP (93.3 ± 7.9) or alantolactone (47.6 ± 3.5), and the IL-6 content of mice colon declines, and compared with model group, all has significant difference (P<0.001).Show that SASP and alantolactone all can significantly reduce the tissue content of IL-6 in the inflammatory reaction that DSS causes.
To sum up result of study shows, alantolactone can obviously improve that the losing weight of ulcerative colitis mice, hemafecia, colon are shortened and the symptom such as inflammatory tissue damage, and significantly reduces expression and the tissue content of inflammatory cytokine TNF-α and IL-6.
Many aspects involved in the present invention have been done as above and have been set forth.But, it should be understood that before not departing from spirit of the present invention and put, those skilled in the art can be equal to and change and modify it, and described change and modification fall into the coverage of the application's claims equally.
Claims (1)
1. alantolactone is prevented and treated the application in medicine or the food of ulcerative colitis in preparation.
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| CN104663662B (en) * | 2015-01-22 | 2016-10-05 | 浙江大学宁波理工学院 | A kind of purposes of eudesmane type natural product derivant 13-benzylamine-alantolactone and preparation method thereof |
| CN104666295B (en) * | 2015-02-04 | 2017-01-11 | 广东省农业科学院动物卫生研究所 | Application of alantolactone in preparation of medicines for resisting cryptosporidium parvum |
| CN104771430B (en) * | 2015-04-10 | 2018-05-08 | 上海交通大学 | For treating the medicine of intestinal irritable syndrome |
| CN106491593B (en) * | 2016-10-09 | 2019-12-17 | 天承南运(天津)科技有限公司 | Application of alantolactone derivatives and salts thereof in preparation of medicines for treating inflammatory bowel diseases |
| CN106474109A (en) * | 2016-10-09 | 2017-03-08 | 天承南运(天津)科技有限公司 | The application in preparation treatment inflammatory bowel medicine of isoalantolactone derivant and its salt |
| CN107157983B (en) * | 2017-05-19 | 2021-04-09 | 苏州大学附属第一医院 | Application of alantolactone in preparation of medicine for preventing and treating liver injury |
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| WO2004066912A2 (en) * | 2003-01-31 | 2004-08-12 | Technion Research & Development Foundation Ltd. | Anti-inflammatory compositions and uses thereof |
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