CN105796764B - Preparation method and application of negundo chastetree fruit total lignans - Google Patents
Preparation method and application of negundo chastetree fruit total lignans Download PDFInfo
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- CN105796764B CN105796764B CN201610274653.8A CN201610274653A CN105796764B CN 105796764 B CN105796764 B CN 105796764B CN 201610274653 A CN201610274653 A CN 201610274653A CN 105796764 B CN105796764 B CN 105796764B
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- A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
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Abstract
The invention relates to the technical field of medicines, in particular to negundo chastetree fruit total lignans and application thereof in preparing medicines for resisting rheumatoid arthritis and prostatic cancer. The invention proves that the vitex negundo total lignans can obviously improve the symptoms of rats with rheumatoid arthritis through a rat rheumatoid arthritis model induced by type II collagen, and has good effect of resisting the rheumatoid arthritis; the tumor-bearing mouse model is adopted to prove that the vitex negundo total lignans can obviously inhibit the tumor growth of prostate cancer and have good effect of resisting the prostate cancer. The invention relates to a negundo chastetree fruit total lignanoid which can be used for preparing anti-rheumatoid arthritis and anti-prostate cancer drugs, and provides a new source for seeking safe and effective anti-rheumatoid arthritis and anti-prostate cancer drugs.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to negundo chastetree fruit total lignans, a preparation method thereof and application thereof in preparing medicines for preventing or treating rheumatoid arthritis and prostate cancer.
Background
Rheumatoid Arthritis (RA) is one of the most important diseases currently endangering human health, called "immotile cancer". RA is a chronic systemic autoimmune inflammatory disease characterized mainly by multiple joint involvement, synovial inflammation, bone and cartilage destruction, and the pathogenesis of RA has not been fully elucidated so far, and is widely considered to be closely related to genetic, infectious and immunoregulatory disorders (imbden jb. the immunopathogenesis of rhematoid arthritis. annu rev pathway Mech Dis 2009,4: 417. 434.). The prevalence rate of RA in China is about 0.3% -0.4%, about 400 thousands of patients exist, the disability rate in the course of 5-10 years is 60%, and the loss of social labor and self-care ability in the late 90% of patients is one of the main reasons for the loss of adult labor (Dai SM, Han XH, Zhao DB, Shi YQ, Liu Y, Meng JM.Presence of pharmaceutical systems, pharmaceutical arms, and on vitality, and goinShanghai, China: a COPCORD study. J Rheumatology 2003,30: 2245-. The current methods for treating rheumatoid arthritis mainly include surgical treatment, chemical drug therapy and treatment with cytokine-type biological agents. Generally, the surgical operation is only suitable for the advanced malformation case, the cost is high, and the body trauma is large; long-term application of chemical drugs such as non-steroidal anti-inflammatory drugs, antirheumatic drugs, glucocorticoids and the like can cause severe adverse reactions such as gastrointestinal discomfort, bone marrow suppression, liver injury, hypertension and the like; biological agents also have a certain effect on normal cells while interfering with diseased cells, thus generating greater toxicity and risk of destroying the body's defense (1. Zhang Yi, Liu Zhi Ming, Xiong Ling Shuang. rheumatoid Arthritis pathogenesis and treatment method research progress. journal of cellular and molecular immunology 2005-94.2. Doan T, Massarotti E. Rheumatoid Arthritis: An Overview of New and Emerging therapeutics JClin Pharmacol 2005,45: 751). Therefore, the search for high-efficiency and low-toxicity medicines for preventing and treating RA is still a difficult task and problem faced by the world medical community.
Prostate Cancer is one of the most common malignancies of the male urogenital system, with high morbidity and mortality, severely compromising human health (Ahmedin Jemal, Rebecca Siegel, Jiaquan Xu and elizabethward. Cancer statistics,2010.CA Cancer J Clin 2010,60: 277) and a significant risk to the human health. The incidence of prostate cancer in men in China shows a continuous and rapid growth trend in recent years, the annual incidence rate of prostate cancer in men in China is increased by about 12%, the incidence rate of prostate cancer in men in China is over 11.00/10 ten thousand, and prostate cancer becomes a malignant urinary tumor which seriously affects the health of men in China (Han Su Jun, Zhang Xin, Chenwanqing, Li Chang Ling, analysis of the current situation and the epidemic trend of prostate cancer in China, journal of clinical oncology, 2013,8(4): 330-. Anti-androgen therapy is one of the effective treatments for advanced prostate cancer, but almost all patients will continue to progress after a period of time, turning into castration-resistant prostate cancer (CRPC), with a poor prognosis, with CRPC patients having poor quality of life, with a median survival of 12-20 months (Thompson I, thresher JB, Aus G, et al. Guideline for the management of clinical localized cancer:2007 upper. urology2007,177(6): 2106-2131.). At present, the mechanism of CRPC generation is not completely clear, and effective therapeutic drugs are still lacking clinically. Therefore, the search for highly effective and low toxic drug therapy for CRPC is one of the main subjects in the study of prostate cancer.
the fructus Viticis negundo is dry mature fruit of Vitex negundo L. of Vitex of Verbenaceae, and is produced in 20 provinces and cities in China, and has abundant resources. Warm in nature, pungent and bitter in flavor; entering lung, stomach and liver meridians; has the effects of dispelling pathogenic wind, removing dampness, promoting qi circulation and relieving pain, and can be used for treating anemogenous arthralgia, asthma, etc. (Jiangsu New medical college, Chinese medicine dictionary, Shanghai science and technology Press, 1986: 2057.). At present, the research on the pharmacological activity of negundo chastetree fruit mainly focuses on the anti-inflammatory, analgesic, anti-tumor and anti-oxidation aspects, and the main types of chemical components reported from negundo chastetree fruit are lignans, terpenes (iridoids, sesquiterpenes, diterpenes and triterpenes), flavonoids, phytosterols and the like (prune, pervirens, junipers, vitex phytochemicals and biological activity research progress],2005, 36(6): 930-938). Wherein the arylnaphthalene lignans is one of the main characteristic components of fructus Viticis negundo, including 6-hydroxy-4 beta- (4-hydroxy-3-methoxyphenyl) -3 alpha-hydroxymethyl-7-methoxy-3, 4-dihydro-2-naphthaldehyde, Vitedoin A, Vitedoamine A, Viterofolals E-F. Tetrahydrojuniperus chinensis lignan (Detetrahydroconconindendrin), Videoamin B, and Vitexodins A-I, etc. (Ono M, Nishida Y, Masuoka C, Li JC, Okawa M, Ikeda T, Noharan T.Lignan derivatives and a nordoterpene from the seeds of Vitex regulation O.J.Nat.Prod.,2004,67(12): 2073-2075; ZHENG CJ, Huang BK, Han T, ZhangQY, Zhang H, Rhman K, Qin LP. Nitroc oxidation coding of lignans from vitamin regulation O.J.Nat.Prod., 2009,72 (1627-1639): CJ 1630; ZHENG W, Zhuang T, JP J.T; JP-D, J.J.J.Nat.D. (P.),72 (D.),1630; CJ-1630; Zhang W, JP-X, J.M, JP-D, J.D, JP-D-,D, Qin LP, anti-inflomatology and anti-osteoporotic lignans from vitamin negundino seeds, Fitotterapia 2014,10.1016/j.fitote 2013.12.006.). Modern pharmacological tests have shown that the arylnaphthalene lignans in negundo chastetree fruit have various biological activities, among which 6-hydroxy-4 β - (4-hydroxy-3-methoxyphenyl) -3 α -hydroxymethyl-7-methoxy-3, 4-dihydro-2-naphthaldehyde has analgesic activity (Zheng CJ, TangWZ, Huang BK, Han T, Zhang QY, Zhang H, Qin lp, biological-guided activity for analgesic properties and constraints of ex negunol, seeds, phytomedine, 2009,16: 560-; 6-hydroxy-4 β - (4-hydroxy-3-methoxyphenyl) -3 α -hydroxymethyl-7-methoxy-3, 4-dihydro-2-naphthaldehyde and Vitexdoins A-E have anti-inflammatory activity (Zheng CJ, Huang BK, Han T, Zhang QY, Zhang H, Rhman K, Qin LP. Nitric oxide scanning lignans from bovine bone seed. J. Nat. Prod. 2009,72(9): 1627-4:, Chawla AS, Sharma AK, Handa SS. A lignan from bovine bone seed. phytochemical, 1992,31(12): 4378-4379); 6-hydroxy-4 beta- (4-hydroxy-3-methoxyphenyl) -3 alpha-hydroxymethyl-7-methoxy-3, 4-dihydro-2-naphthaldehyde, Vitredolin A, Vitreoamine A, Vitrofolas E-F, Detetrahydrojuniper lignan (Detetrahydrocondensindin) have antioxidant activity (Ono M, Nishida Y, Masuoka C, Li JC, OkawaM, Ikeda T, Nohara T.Lignan derivatives and a nordoterpene from the seeds of Vitrex negundino.J.Nat.Prod., 2004,67(12): 2073-2072075), and the like.
The present inventors have been working on the study of negundo chastetree fruit extract, including monomeric compounds.
The inventor has applied for Chinese invention patent on the extract of negundo chastetree fruit and the application thereof in the drugs or foods for preventing or treating rheumatoid arthritis, and has acquired patent right with the patent number of CN201110186425.2 and the name of invention of 'negundo chastetree fruit extract and the application thereof', and the granted publication number of CN 102258633B.
the inventor has applied for Chinese patent invention for the application of the benzonaphthalene lignan compound (comprising VNL, Vitedoin A, Vitedoamine A or Vitrofola F) in the preparation of the anti-radiation medicine, and has acquired patent right, the patent number is CN201110186436.0, the invention name is the application of the benzonaphthalene lignan compound in the preparation of the anti-radiation medicine, and the patent publication number is CN 102349886B.
the inventor has applied for Chinese invention patent for the application of benzene-substituted naphthalene type lignans compound vitexin VNL in the preparation of anti-prostate cancer drugs, with the application number of CN201410025746.8, the name of the invention is 'the application of aryl naphthalene type lignans in the preparation of anti-prostate cancer drugs', and the application publication number of CN 103860528A.
The inventor has applied for Chinese patent application with application number of CN201510278639.0, namely application of benzene-substituted naphthalene type lignan compound of vitexin VNL in preparation of anti-rheumatoid arthritis drugs, and application publication number of CN 105030740A.
in the modernization research of traditional Chinese medicine, one of the characteristic advantages of the traditional Chinese medicine is that the traditional Chinese medicine is composed of active substance groups, and the active substance groups play an integrated role through multiple targets, multiple links and multiple ways (Junling, Li Zu Lun, Paqiang, Xiao river. research on the integrated roles of traditional Chinese medicine and compound. Chinese herbal medicine, 2007,38(1): I0002-I0004). Each Chinese medicine is equivalent to a small compound prescription, contains a plurality of chemical components, each effective component has various biological activities, and the effective components can be mutually cooperated and integrated to take effect.
The use of the vitex negundo total lignans in the treatment of rheumatoid arthritis and prostate cancer has not been reported so far.
Disclosure of Invention
The invention aims to provide a negundo chastetree fruit total lignanoid and a new medical application thereof.
Although, we have found that the extract of negundo chastetree fruit has activity against rheumatoid arthritis; it has also been found that the monomer compound, vitexin VNL, extracted from fructus Viticis negundo has activity against prostate cancer and rheumatoid arthritis. However, separation and purification of the vitexin VNL are very difficult, and about 2g of the vitexin VNL can be extracted from 10 kg of vitexin medicinal materials, so that raw medicinal materials are greatly wasted; however, the activity of the total extract of the negundo chastetree fruit against prostate cancer is not reported at present, and in addition, other benzonaphthalene type lignan monomer compounds extracted from the negundo chastetree fruit, such as Vitrefoil A, Vitreoamine A, Vitexdin A, Vitrofolal F, Vitrofolal E and the like, are not reported whether the activity against prostate cancer and rheumatoid arthritis is good or not. The inventor imagines whether the vitex negundo total lignans can be obtained, and can also have good activity for resisting prostatic cancer and rheumatoid arthritis.
In view of the above, the lignanoid components in the fructus viticis negundo are enriched to obtain the fructus viticis negundo total lignanoid.
The fructus Viticis negundo total lignanoid mainly contains the following four benzonaphthalene type lignanoid compounds, including VNL, Vitedoin A, Vitedeoamine A and Vitexdoin A, and the respective structural formulas are as follows:
the invention provides an application of negundo chastetree fruit total lignans in a medicament for preventing or treating rheumatoid arthritis and/or prostate cancer.
the invention also provides a preparation method of the negundo chastetree fruit total lignans.
The fructus Viticis negundo total lignanoid is extracted and separated from fructus Viticis negundo of Vitex of Verbenaceae, and its preparation method comprises:
1) Preparing an extracting solution: crushing the negundo chastetree fruits, carrying out hot extraction for 2-3 times by using 50-80% ethanol, wherein the extraction temperature is 50-80 ℃, the solvent dosage is 8-10 times of the crude drug dosage each time, and the extraction time is 1-2 hours each time, and combining the extracting solutions;
2) refining, concentrating and drying: concentrating the above extractive solution under reduced pressure, recovering solvent, defatting concentrated solution (0.15g/mL) with petroleum ether (1:1, v/v), and diluting with 70% ethanol to obtain solution containing 0.1g/mL of extract; 3) separation and purification: mixing the solution containing 0.1g/mL of the impregnated paste with polyamide adsorbent resin at a ratio of 1.5:1w/w, loading the mixture onto a polyamide adsorbent resin column at a ratio of 2:1w/w, washing with water, and collecting 35% ethanol eluate; concentrating 35% ethanol eluate under reduced pressure, recovering solvent, dissolving with water, loading the solution onto D-101 macroporous adsorbent resin, eluting with water, collecting 35% ethanol eluate, recovering solvent, suspending with water, extracting with ethyl acetate, and concentrating the ethyl acetate extractive solution under reduced pressure to obtain fructus Viticis negundo total lignanoid.
Preferably, in the total lignans of negundo chastetree fruit of the present invention, the total of VNL, Vitedoin a, vitedeoamine a and Vitexdoin a accounts for 40% or more of the total lignans of negundo chastetree fruit.
More preferably, the content of VNL is more than 20%, the content of Viedein A is more than 20%, the content of Videoamine A is more than 0.1%, and the content of Vitexoin A is more than 4%.
most preferably, the VNL content is 23% or more, Viedesin A content is 25% or more, Viedeamine A content is 0.2% or more, and Vitexdin A content is 4% or more. (the above proportions are W/W)
The medicine is as follows: fructus Viticis negundo total lignanoid, or pharmaceutical composition containing fructus Viticis negundo total lignanoid.
In the medicine, the content of the vitex negundo total lignans is 1-99 wt%, preferably 40-90 wt%.
The pharmaceutical composition can be prepared into pharmaceutical preparations with conventional pharmaceutical excipients in pharmaceutics.
The medicinal preparation can be tablets, granules, dispersible tablets, capsules, soft capsules, dripping pills, injections, powder injections, aerosols and the like.
The invention adopts a rheumatoid arthritis animal model (Trentham DE, Townes AS, Kang AH. autoimmunity to type II collegen-type experiment model of arthritis. J ExpMed1977,146: 857-868; Viji V, Kavitha SK, Helen A. Bacopa monniera (L.) Wettstinhibits type II collegen-induced arthritis in rates. Phytother Res 2010,24: 1377-1383) to observe the therapeutic effect of the fructus vitis negundo total lignans intragastric administration provided by the invention.
Experimental results show that after the negundo chastetree fruit total lignans (40mg/kg) are administrated by gastric lavage, the RA rat arthritis index can be obviously reduced, and ankle joint swelling degree can be inhibited. The above studies indicate that the vitex negundo total lignans have good anti-RA activity.
The invention adopts a prostate cancer tumor-bearing mouse model (Zhan Y, Cao B, Qi YF, Liu S, Zhang Q, Zhou WD, Xu D, Lu H, Sartor O, Kong W, Zhang HT, Dong Y.Methylelenol pro drug handling MDV3100efficacy for treatment of cancer-resistant cancer. int Jcancer.2013 november; 133(9):2225 2233.) to observe the inhibition effect of the cercis negundo total lignan gastric administration provided by the invention on the growth of prostate cancer tumor.
experimental results show that the fructus Viticis negundo total lignans (40mg/kg) can remarkably inhibit the growth of non-hormone-dependent prostate cancer tumor after gastric administration. The above studies indicate that the vitex negundo total lignans have good anti-prostate cancer activity.
Further, the safety of the compound is preliminarily evaluated by adopting an acute toxicity test, and the result shows that the maximum tolerated dose of the negundo chastetree fruit total lignans is 16.0g/kg (8000g crude drug/kg, which is 6400 times of the clinical dosage of human), no animal death occurs during the test, the spontaneous activity and the weight average of the animal are not obviously affected, and no obvious toxicity is caused to the main organs of a mouse, thus the negundo chastetree fruit total lignans has higher safety.
Compared with the vitexin VNL, the vitexin total lignans have the advantages that:
1) The extraction and purification process of the vitexin total lignans is superior to the vitexin VNL, and the used solvent and chromatographic column packing meet the new drug application requirements and are more suitable for industrial production;
2) The yield of the vitex negundo total lignans is about 0.2 percent, and the yield of the vitex negundo VNL is less than 0.02 percent, so that the vitex negundo medicinal material resources can be more fully utilized;
3) The maximum tolerated dose of the vitex negundo fruit total lignans is 16.0g/kg (8000g crude drug/kg, which is equivalent to 6400 times of the clinical dosage of human), which indicates that the safety is higher;
4) In an in vivo anti-rheumatoid arthritis experiment, the same dose of 30mg/kg of total lignans has the same effect as that of VNL, but the animals are more tolerant to the total lignans, the weight of the animals is not obviously reduced compared with that of a model group, and the weight of the animals is obviously reduced compared with that of the model group during the administration of the VNL.
5) Total lignans (IC) in anti-inflammatory assays in vitro (RAW264.7 cells)500.20. mu.g/mL) has an effect of inhibiting NO production better than that of VNL (IC)50 0.80μg/mL)。
6) Total lignans (IC) in vitro anti-prostate cancer experiments (DU145 cells)500.30. mu.g/mL) has better cell proliferation inhibiting effect than VNL (IC)50 3.0μg/mL)。
The invention finds out safe and effective medicines for preventing and treating RA and CRPC.
Drawings
FIG. 1: the effect of negundo chastetree fruit total lignans and VNL on type II collagen-induced RA model rat left posterior podarthritis index (model group of. about. vs, p < 0.05;. about. v, model group of. about. p < 0.01);
FIG. 2: the inhibition effect of negundo chastetree fruit total lignans and VNL on type II collagen-induced RA model rat left hind paw swelling (mean + -SD, n ═ 10) (model group of vs, p < 0.05;. model group of vs, p < 0.01); FIG. 3: the effect of negundo chastetree fruit total lignans and VNL on type II collagen-induced RA model rat body weight (mean + -SD, n 10) (. about.. about.vs. model group, p < 0.05;. about.vs. model group, p < 0.01);
FIG. 4: the effect of negundo chastetree fruit total lignans and VNL on prostate cancer tumor weight in nude mice (mean + -SD, n 10) (. about.. about.vs. model group, p < 0.05;. about.. about.vs. model group, p < 0.01);
Detailed Description
The present invention will now be described in detail with reference to examples, but the practice of the present invention is not limited thereto.
example 1: preparation of negundo chastetree fruit total lignanoid
1) Preparing an extracting solution: crushing the negundo chastetree fruits, carrying out hot extraction for 2-3 times by using 50-80% ethanol, wherein the extraction temperature is 50-80 ℃, the solvent dosage is 8-10 times of the crude drug dosage each time, and the extraction time is 1-2 hours each time, and combining the extracting solutions;
2) Refining, concentrating and drying: concentrating the above extractive solution under reduced pressure, recovering solvent, defatting concentrated solution (0.15g/mL) with petroleum ether (1:1, v/v), and diluting with 70% ethanol to obtain solution containing 0.1g/mL of extract;
3) separation and purification: mixing the solution containing 0.1g/mL of the above impregnated paste with polyamide adsorbent resin, loading onto polyamide adsorbent resin column (2:1, w/w), washing with water, and collecting 35% ethanol eluate; concentrating 35% ethanol eluate under reduced pressure, recovering solvent, suspending with water, extracting with ethyl acetate, concentrating ethyl acetate extractive solution under reduced pressure, recovering solvent, dissolving with water (1.5mg/mL), loading the solution onto D-101 macroporous adsorbent resin, eluting with water, collecting 35% ethanol eluate fraction to obtain fructus Viticis negundo total lignanoid TOV, and measuring by HPLC content to obtain fructus Viticis negundo total lignanoid TOV with VNL content of 23.14%, Videoin A content of 25.17%, Videoamine A content of 0.23%, Vitexoin A content of 4.63%, and measurable component content of 53.17%.
Example 2: pharmacodynamic experiment of anti-rheumatoid arthritis of vitex negundo total lignans
2.1 materials of the experiment
Adult male 180-220 g SD rats (provided by the Experimental animals center of second department of military medical university) 40. The main apparatus is as follows: toe volume measuring instrument (YLS-7A, Equipment station of Shandong province institute of medical science), microplate reader (BIO-RAD 550), centrifuge (Labofuge 400R, Heraeus), electronic balance (FA110A, Shanghai precision scientific instruments, Ltd.).
2.2 Experimental modeling and drug administration
Before the experiment, 40 rats were weighed, and randomly divided into 4 groups of 10 rats each, which were fed with free diet and water. Comprises blank group, model group, positive drug group and fructus Viticis negundo total lignanoid group.
Blank group: no treatment is carried out;
Model group: mixing the bovine type II collagen acetic acid solution with Freund incomplete adjuvant with equal volume, and fully emulsifying. On day 0, SD rats were injected intradermally (1mg/ml) into the tail root, 0.1ml each; after 7 days, the immunity is strengthened, the tail root of the rat is injected with 0.1 ml/solution as the stimulating injection, and the RA animal model is created about 15 days;
A positive drug group: dexamethasone, 0.05mg/kg, administered by intragastric administration, 1 time daily;
Fructus Viticis negundo total lignanoid group: from the day of successful model building, the rat fructus Viticis negundo total lignans is administered for intragastric administration 1 time a day, the dose is 30mg/kg, and the administration is continued for 30 days.
2.3 Observation index
(1) The degree of joint swelling in rats was scored for the arthritic index once every 3 days.
(2) The swelling degree of the toes of the rats was measured by a toe volume measuring instrument, once every 3 days.
(3) Rats were weighed on the day of experiment completion.
2.4 results of the experiment
Statistical analysis of the experimental data was performed using SPSS14.0 using a t-test, and differences were considered statistically significant when P < 0.05.
(1) Rat arthritis index score
As shown in figure 1, on day 30 of administration, the left posterior podophyllitis index of the fructus viticis negundo total lignans group is 0.2 +/-0.4, and the left posterior podophyllitis index of the model group is 2.6 +/-0.5, which indicates that the fructus viticis negundo total lignans can significantly reduce the type II collagen-induced RA rat left posterior podophyllitis index, and has significant difference compared with the model group, which indicates that the fructus viticis negundo total lignans has better anti-inflammatory effect on the rat rheumatoid arthritis model and the effect is equivalent to VNL.
(2) Swelling degree of big toe
As shown in fig. 2, the left hind toe of the rats in the blank group has no obvious change, the model group has obvious swelling, and the model group has significant difference with the blank group, which indicates that the modeling is successful; on the 30 th day of administration, the volume of the left hind paw of the negundo chastetree fruit total lignan group is 1357.0 +/-319.4, and the volume of the left hind paw of the model group is 2297.1 +/-177.2, which indicates that the swelling degree of the left hind paw of the rat in the negundo chastetree fruit total lignan administration group is lighter, and the significant difference exists compared with the model group, and indicates that the negundo chastetree fruit extract has better anti-inflammatory effect on the rat rheumatoid arthritis model and the effect is equivalent to VNL.
(3) Rat body weight
As shown in figure 3, on day 30 of administration, the weight of rats in the positive drug group and VNL group was significantly reduced compared with that in the model control group, while the weight of rats in the fructus Viticis negundo total lignanoid group was not significantly changed, suggesting that the animals had better tolerance to the fructus Viticis negundo total lignanoid.
Example 3: pharmacodynamic experiment of vitex negundo linn total lignans for resisting prostate cancer
3.1 Experimental materials
SPF-grade male BALB/c nude mice 60, provided by Changzhou Kavens laboratory animals Co., Ltd. (laboratory animal production permit: SCXK (Su) 2011-; license for use of experimental animal: SCXK (Su) 2011-. C4-2 human prostate cancer cells (hormone independent), cells were cultured in RPMI1640 medium containing 10% fetal bovine serum. ChemBase CBS-CJ-1FD clean bench, MCO-15AC carbon dioxide incubator, sanyo saryoxd-202 fluorescence inverted biomicroscope (nanjing yonghin optics ltd), 0-150 type vernier caliper (taiwan south jiahua precision measuring tool ltd).
3.2 Experimental modeling and drug administration
the human prostate cancer C4-2 nude mouse transplantation tumor is established by inoculating human prostate cancer C4-2 nude cell strain under the axilla of the nude mouse. After the inoculation to form transplantation tumor, the transplanted tumor is used after 3 generations in nude mice.
Inoculating 60 nude mice right axillary subcutaneous cells with vigorous growth stage tumor cells under aseptic condition, wherein the cell inoculation amount is 1 × 106. Measuring the diameter of the transplanted tumor of the nude mouse by using a vernier caliper until the tumor grows to 70-100mm3On the left and right, 40 tumor-bearing nude mice with good growth state and good tumor size uniformity were selected and randomly divided into 4 groups of 10 mice, namely, a model group, a TOV group of 40mg/kg, a VNL group of 40mg/kg, a positive drug MDV3100 group of 20mg/kg, and a TOV 20mg/kg combined MDV310010 mg/kg. Each group was administered by gavage once a day in a volume of 0.2ml/2Lg body weight. Administration is carried out 21 timesThe nude mice were sacrificed by cervical dislocation and the tumor mass was surgically removed and weighed.
3.3 Observation index
(1) Effect of drug administration treatment on tumor weight in nude mice
3.4 results of the experiment
as shown in FIG. 3, the TOV group, VNL group, positive drug MDV3100 group and combination group all significantly inhibited tumor growth and reduced tumor weight. The TOV and VNL groups have equivalent drug effect, and the TOV and MDV3100 groups have equivalent drug effect with the positive drug MDV3100 group, and the combined drug effect of the TOV and MDV3100 groups is optimal, so that the drug dosage can be reduced, and the effect is obviously improved compared with the single drug administration of the TOV and MDV.
example 4: acute toxicity test of fructus Viticis negundo total lignans
4.1 Experimental animals
50 ICR mice (provided by the experimental animal center of second army medical university) of 18-22 g are respectively male and female.
4.2 Maximum Tolerated Dose (MTD) assay
Mice were randomly divided into control and administration groups by body weight. Two groups of mice are fasted and are not forbidden to be watered for 12 hours before the gavage administration, the administration group is administered with a test solution containing 0.4g/ml of total lignans and the maximum soluble concentration according to the gavage volume of 0.4ml/10g of the body mass for 2 times in 24 hours, and the control group is administered with the same method for 2 times of gavage with 0.5 percent of CMC-Na with the same quantity. The condition of the mice was observed immediately after administration and continuously for 2 weeks, and general changes and death conditions of the two groups of mice in terms of body mass, fur color, respiration, secretion of eye mucosa and oral cavity, stool and urine, activity, external reaction and the like were recorded in detail at 1h, 1d to 14d after administration. And (3) if the mouse dies, dissecting and carrying out autopsy, observing main organs, killing all the mice after the experiment is finished, and carrying out pathological changes of the main organs such as brain, heart, spleen, liver, kidney, lung and the like, wherein if the pathological changes are obvious through visual observation, the pathological changes are immediately sent to pathological examination of a tissue section.
4.3 Observation index
(1) Effect of Total lignan TOV on general conditions of mice
(2) Effect of Total lignan TOV on mouse body weight
(3) Effect of Total lignan TOV on major organs of mice
4.4 results of the experiment
In the experiment of the maximum tolerance, after the total lignan TOV is intragastrically administered for 2 times within 1d by the maximum suspension mass concentration of 0.4g/ml and the maximum volume of 0.4ml/10g which can be borne by mice, most of the mice and a control group have no two effects, the activity and the reaction are normal, only a small part of the mice have slight reduction of the activity and the reaction, and the serious conditions of mouse trembling, toppling and the like do not occur in the experimental process. Mice did not die after the maximum gavage and during the observation period.
As shown in Table 1, the total lignan TOV was not significantly different between the mice in the experimental group and the control group in weight gain (P >0.05) after the gavage of the male and female mice.
After 2 weeks of observation, mice were sacrificed and dissected to visualize changes in the organs: the liver surface is smooth without pathological changes such as focus, lump and the like, the size and the shape of the liver are normal, and after the liver is transversely cut, the color and the texture of a cut surface are glossy and dense without abnormities such as looseness and the like; the condition of the spleen of the mouse is checked by the same method, the pathological phenomena of nodules, swelling and the like do not appear on the surface of the spleen, and the size, the shape, the surface, the section and the texture of the spleen are normal; the condition of the kidney of the mouse is checked by the same method, and all the parts of the kidney are normal; the size and color of the heart are not abnormal by visual observation; the stomach has normal size and shape, the gastric mucosa has no bleeding, necrosis and other conditions, and no bleeding point on the stomach wall. The coefficient of the weight ratio of the mouse organ to the body weight is recorded in table 2, and the main organ coefficient shows that the total lignan TOV has no obvious toxicity to the mouse organ.
the result shows that the maximum tolerance amount of the total lignans of the negundo chastetree fruit is 16.00g/kg (8000g crude drug amount/kg, which is equivalent to 6400 times of the clinical dosage of human). The animals do not die in all the doses, and the negundo chastetree fruit total lignans have no obvious influence on the spontaneous activity and the weight average of the animals and the main organs of mice, thus prompting that the negundo chastetree fruit total lignans have higher safety.
TABLE 1 Effect of Total lignan TOV on weight Change in mice: (n＝10)
TABLE 2 Effect of Total lignan TOV on organ coefficients of mice: (n＝10)
Example 5: in vitro anti-inflammatory activity of negundo chastetree fruit total lignans: inhibition of Nitric Oxide (NO) production in LPS-stimulated RAW264.7 cells
5.1 cell culture
RAW264.7 cell culture System is DMDE Medium (HyClone) containing 10% fetal bovine serum (FBS, HyClone), 100U/ml penicillin, 100U/ml streptomycin at 37 deg.C, 5% CO2Culturing under saturated humidity condition.
5.2 measurement of NO Release amount
RAW264.7 cells at 1X 105One/well was seeded in 96-well plates. Putting into an incubator to adhere to the wall for 4 h. Different concentrations of compounds were added, LPS (final concentration 10. mu.g/ml) was added, and corresponding cell control and stimulation control (LPS was added to RAW264.7 cells at the above concentrations) were added. 37 ℃ and 5% CO2The culture was carried out in an incubator for 24 hours. And (4) after the culture is finished, carefully sucking the supernatant into a 1.5ml centrifuge tube at 5000rpm for 10min, sucking the supernatant into the 1.5ml centrifuge tube again, and freezing and storing for detection. The NO release amount is detected by a Griess method.
5.3 results of the experiment
the results show that the total lignans TOV and VNL of the negundo chastetree fruit can obviously inhibit the generation of Nitric Oxide (NO) and IC in RAW264.7 cells stimulated by LPS500.20 mu g/mL and 0.80 mu g/mL respectively, shows good in vitro anti-inflammatory effect, and the TOV effect is superior to VNL.
Example 6: in vitro anti-prostate cancer activity of vitex negundo total lignans: effect on proliferation of human prostate cancer cells (DU145)
6.1 cell culture
DU145 cell culture system was RPMI1640 medium (Gibco) containing 10% fetal bovine serum (hyclone), 100U/ml penicillin, 100U/ml streptomycin at 37 ℃ with 5% CO2Culturing under saturated humidity condition.
6.2 cell proliferation assay
A Cell Counting Kit-8 Kit (CCK-8) is adopted, a certain number of DU145 cells in an exponential growth phase are inoculated in a 96-well plate, and 6 multiple wells are arranged in each group of a blank control group and a dosing group (0.1,1 and 10 mu M). Continuously incubating for 48h after cell administration, culturing for a specified time, adding CCK-810 μ l, continuously incubating for 2h, detecting Optical Density (OD) value at 450nm (630nm as reference wavelength) with microplate reader, repeating the experiment for 3 times, and calculating drug IC50The value is obtained.
6.3 results of the experiment
The results show that the vitex negundo total lignans TOV and VNL can obviously inhibit the proliferation and IC of DU145 cells500.30 mu g/mL and 3.00 mu g/mL respectively show good in-vitro anti-prostate cancer effect, and the TOV effect is superior to VNL.
In view of the pharmacodynamic experiment and safety evaluation results, the fructus viticis negundo total lignanoid disclosed by the invention has remarkable activities of resisting rheumatoid arthritis and resisting prostate cancer and good safety, and therefore, the fructus viticis negundo total lignanoid can be used for preparing medicines or foods for resisting rheumatoid arthritis and prostate cancer.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full scope of the invention.
Claims (6)
1. The application of the vitex negundo total lignans in preparing medicaments or foods for preventing or treating rheumatoid arthritis and prostatic cancer;
The preparation method of the vitex negundo total lignans comprises the following steps:
A. Preparing an extracting solution: crushing the negundo chastetree fruits, carrying out hot extraction for 2-3 times by using 50-80% ethanol, wherein the extraction temperature is 50-80 ℃, the solvent dosage is 8-10 times of the crude drug dosage each time, and the extraction time is 1-2 hours each time, and combining the extracting solutions;
B. Refining, concentrating and drying: concentrating the above extractive solution under reduced pressure, recovering solvent, defatting the concentrated solution with petroleum ether 1:1v/v, and diluting with 70% ethanol to obtain solution containing 0.1g/mL of extract;
C. Separation and purification: mixing the solution containing 0.1g/mL of the impregnated paste with polyamide adsorbent resin at a ratio of 1.5:1w/w, loading the mixture onto a polyamide adsorbent resin column at a ratio of 2:1w/w, washing with water, and collecting 35% ethanol eluate; concentrating 35% ethanol eluate under reduced pressure, recovering solvent, dissolving with water, loading the solution onto D-101 macroporous adsorbent resin, eluting with water, collecting 35% ethanol eluate, recovering solvent, suspending with water, extracting with ethyl acetate, and concentrating the ethyl acetate extractive solution under reduced pressure to obtain fructus Viticis negundo total lignanoid;
the total lignans of the negundo chastetree fruits at least contain four benzonaphthalene type lignans compounds VNL, Viedesin A, Viedeamine A and Vitexdin A shown as the structural formula:
And the total weight of the four benzonaphthalene lignan compounds VNL, Vitedoin A, Vitedeoamine A and Vitexdin A accounts for more than 40% of the total weight of the total lignans of fructus Viticis negundo;
In the total lignans of the negundo chastetree fruit, the content of VNL is more than 20 percent, the content of Viedein A is more than 20 percent, the content of Viedeamine A is more than 0.1 percent, and the content of Viexedin A is more than 4 percent.
2. The use of the total lignans of negundo chastetree fruit according to claim 1 in the preparation of a medicament or food for the prevention or treatment of rheumatoid arthritis and prostate cancer, wherein the medicament comprises the total lignans of negundo chastetree fruit as the sole active ingredient or a pharmaceutical composition comprising the total lignans of negundo chastetree fruit.
3. The use of the total lignans of negundo chastetree fruit according to claim 1 in the preparation of a medicament or food for the prevention or treatment of rheumatoid arthritis and prostate cancer, wherein the total lignans of negundo chastetree fruit in said medicament is present in an amount of 1-99 wt%.
4. The use of the total lignans of negundo chastetree fruit according to claim 1 in the preparation of a medicament or food for the prevention or treatment of rheumatoid arthritis and prostate cancer, wherein the total lignans of negundo chastetree fruit in said medicament is present in an amount of 1-90 wt%.
5. The use of the negundo chastetree fruit total lignans in the preparation of the medicament or food for preventing or treating rheumatoid arthritis and prostate cancer according to claim 2, wherein the pharmaceutical composition and pharmaceutically acceptable conventional pharmaceutical excipients are prepared into pharmaceutical preparations.
6. the use of the fructus viticis negundo total lignans in the preparation of a medicament or food for preventing or treating rheumatoid arthritis and prostate cancer according to claim 5, wherein the pharmaceutical preparation is tablet, granule, capsule, dripping pill, injection or aerosol.
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| CN102258633A (en) * | 2011-07-05 | 2011-11-30 | 中国人民解放军第二军医大学 | Negundo chastetree fruit extract and application thereof |
| CN102349886A (en) * | 2011-07-05 | 2012-02-15 | 中国人民解放军第二军医大学 | Application of benzene-substituted naphthalene type lignans in preparing radio-resistant medicines |
| CN103860528A (en) * | 2014-01-21 | 2014-06-18 | 中国人民解放军第二军医大学 | Application of aryl naphthalene type lignan in preparation of medicine for resisting prostate cancer |
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| CN102349886A (en) * | 2011-07-05 | 2012-02-15 | 中国人民解放军第二军医大学 | Application of benzene-substituted naphthalene type lignans in preparing radio-resistant medicines |
| CN103860528A (en) * | 2014-01-21 | 2014-06-18 | 中国人民解放军第二军医大学 | Application of aryl naphthalene type lignan in preparation of medicine for resisting prostate cancer |
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