CN105106224A - Application of Isowithalongolide B in preparation of endothelial cell protection drug - Google Patents
Application of Isowithalongolide B in preparation of endothelial cell protection drug Download PDFInfo
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- CN105106224A CN105106224A CN201510590533.4A CN201510590533A CN105106224A CN 105106224 A CN105106224 A CN 105106224A CN 201510590533 A CN201510590533 A CN 201510590533A CN 105106224 A CN105106224 A CN 105106224A
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- isowithalongolide
- isowithalongolideb
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Abstract
The invention discloses an application of Isowithalongolide B in preparation of an endothelial cell protection drug and belongs to the pharmaceutical field. The research adopts an MTT method test and finds that the Isowithalongolide B can improve the cell viability of an HUVEC (human umbilical vein endothelial cell) damaged by ox-LDL and has an effect of inhibiting damage induced by ox-LDL, and the Isowithalongolide B can be further researched and developed into the endothelial cell protection drug.
Description
Technical field
The present invention relates to the novelty teabag of Compound I sowithalongolideB, be specifically related to IsowithalongolideB and preparing the application in endotheliocyte protection medicine.
Background technology
The people such as Cong-MeiCao separation and purification first goes out Compound I sowithalongolideB, and achievement is published in famous natural product magazine (WithanolideArtifactsFormedinMethanol, J.Nat.Prod., 2013,76,2040-2046).
The active reporter not yet having this compound to protect about endotheliocyte at present.
Summary of the invention
The object of the present invention is to provide the medical usage of a kind of IsowithalongolideB.
Above-mentioned purpose is achieved by the following technical solution:
IsowithalongolideB is preparing the application in endotheliocyte protection medicine, and described IsowithalongolideB chemical structural formula is as follows,
Detailed description of the invention
Essentiality content of the present invention is further illustrated below in conjunction with embodiment.
The separation preparation of embodiment 1:IsowithalongolideB and structural identification
The preparation method of IsowithalongolideB is with the preparation method (WithanolideArtifactsFormedinMethanol, J.Nat.Prod., 2013,76,2040-2046) of bibliographical information.
Structural identification: white amorphous powder; HR-ESIMS shows [M+Na]
+for m/z493.2546, can obtain molecular formula in conjunction with nuclear-magnetism feature is C
28h
38o
6, degree of unsaturation is 10.Hydrogen nuclear magnetic resonance modal data δ
h(ppm, DMSO-d
6, 500MHz): H-2 (2.95, dd, J=18.8, 3.3), H-2 (2.41, dd, J=18.8, 2.2), H-3 (4.21, dd, J=3.3, 2.2), H-4 (3.62, d, J=9.4), H-6 (3.28, d, J=3.2), H-7 (2.06, dt, J=14.6, 3.5), H-7 (1.21, dd, J=14.6, 11.3), H-8 (1.53, m), H-9 (1.81, m), H-11 (1.11, m), H-11 (0.89, dd, J=13.2, 4.0), H-12 (1.80, m), H-12 (1.12, m), H-14 (0.99, m), H-15 (1.57, m), H-15 (1.09, m), H-16 (1.62, m), H-16 (1.29, m), H-17 (1.04, m), H-18 (0.64, s), H-19 (4.11, d, J=9.0), H-19 (3.82, d, J=9.0), H-20 (1.93, m), H-21 (0.96, d, J=6.7), H-22 (4.25, dt, J=13.3, 3.5), H-23 (2.33, br, dd, J=17.0, 13.3), H-23 (1.90, m), H-27 (1.79, s), H-28 (1.90, s), 4-OH (3.11, d, J=9.4), carbon-13 nmr spectra data δ
c(ppm, DMSO-d
6, 125Hz): 207.4 (C, 1-C), 42.3 (CH
2, 2-C), 74.0 (CH, 3-C), 69.5 (CH, 4-C), 60.0 (C, 5-C), 56.6 (CH, 6-C), 29.4 (CH
2, 7-C), 28.2 (CH, 8-C), 36.5 (CH, 9-C), 49.6 (C, 10-C), 21.7 (CH
2, 11-C), 38.8 (CH
2, 12-C), 42.9 (C, 13-C), 54.1 (CH, 14-C), 23.7 (CH
2, 15-C), 27.0 (CH
2, 16-C), 51.8 (CH, 17-C), 11.1 (CH
3, 18-C), 63.2 (CH
2, 19-C), 38.6 (CH, 20-C), 13.2 (CH
3, 21-C), 78.1 (CH, 22-C), 29.3 (CH
2, 23-C), 148.6 (C, 24-C), 121.6 (C, 25-C), 167.0 (C, 26-C), 12.2 (CH
3, 27-C), 20.1 (CH
3, 28-C).Structural identification data are consistent with bibliographical information, therefore can determine that compound prepared by the present invention is the IsowithalongolideB of bibliographical information.
The pharmacological action test of embodiment 2:IsowithalongolideB
One, material and instrument
Human umbilical vein endothelial cells pearl (HUVEC) is provided by Shanghai Wu Li Bioisystech Co., Ltd cell bank.IsowithalongolideB makes by oneself, and HPLC normalization purity is greater than 98%.RPMI-1640 culture medium, MTT, dimethyl sulfoxide are all purchased from Sigma company.Hyclone is purchased from HyCLone company.FITC labelling goat anti-rabbit igg, the anti-human factor Ⅷ related antigen of rabbit are purchased from Beijing Bo Aosen Bioisystech Co., Ltd.MDA reagent box for detecting content is purchased from Nanjing and builds up biological study institute.AnnexinV-FITC apoptosis detection kit is purchased from Centrebio company.Ethylenediaminetetraacetic acid (EDTA) is purchased from Guangzhou Wei Jia Science and Technology Ltd..
DK-8AD type electric heating constant temperature tank (Shanghai Yiheng Scientific Instruments Co., Ltd), ER-120A type electronic analytical balance (Shimadzu Corporation), 6219 type electronics pH meters (Shanghai Ren Shi Electronics Co., Ltd.), high speed low temperature centrifugal machine (Sigma company), L420 table-type low-speed autobalance centrifuge (Xiang Yi centrifuge Instrument Ltd.), SYC-2101 horizontal shaker (its woods Bel instrument manufacturing company limited), 1000 μ L micro sample-adding rifle × 1, 20-100 μ L micro sample-adding rifle × 1, 1-20 μ L micro sample-adding rifle × 1 (French Ji Ersen company), CO
2(incubator Heraeus company), super-clean bench (safe and sound company of Su Jing group), inverted phase contrast microscope (German Lycra company), microplate reader (Sigma company), FACSCaLibur (flow cytometer).
Two, test method
1, the cultivation of huve cell
1.1 condition of culture
The HUVEC cell strain newly bought is inoculated in the RPMI-1640 culture medium containing 10% hyclone.Be placed in 37 DEG C, 5%CO
2in incubator, within every 2 days, change 1 subculture.
1.2 passage
Getting one bottle of HUVEC observation of cell under inverted phase contrast microscope, as grown up to fine and close monolayer, can go down to posterity; Shaken gently by culture bottle for several times, suspended and floated over the fragment of cell surface, then poured out together with culture fluid, draw 2 ~ 3mLPBS liquid and add in culture bottle, hypsokinesis of vibrating gently is gone, and repeats 3 times; Add 1mL0.25% pancreatin, be limited can cover at the bottom of bottle, rotate culture bottle, make moistening whole cellular layer, put 37 DEG C of digested 2 ~ 3min of incubator, till oneself contraction of cell to be confirmed becomes bowlder; Add 1mL culture fluid in culture bottle, stop digestion, draw culture fluid with suction pipe and repeatedly blow and beat bottle parietal cell gently, make it to depart from from bottle wall to form cell suspension, inject centrifuge tube centrifugal (800r/min, 5min) abandoning supernatant afterwards; Add 3mL culture fluid in centrifuge tube, draw culture fluid with suction pipe and blow and beat gently for several times, make cell suspending weight, then press 1:3 or 1:4 and distribute Secondary Culture; Be placed in 37 DEG C, 5%CO in incubator
2cultivate in calorstat, after 24h, change liquid, within usual 3-4 days, can monolayer be formed, now just interchangeable maintenance medium for experiment.
The counting of 1.3HUVEC
First get cell suspension 50 μ L to be measured to instill in cell counting count board, by numeration of leukocyte method, under low power lens, count the total cellular score in 4 block plaid of 4 jiaos, then with following formulae discovery cell concentration: viable count/4 × 10 in 4 block plaid
4=cell number/mL
2, the qualification of huve cell
Sterile cover slips 1cm × 1cm is placed, by endotheliocyte suspension inoculation on coverslip, when endotheliocyte grows to converging state in 6 well culture plates, take out coverslip, with PBS flush cover slide, put into 100% acetone and fix 15min, rinse 3 times with PBS, each 2min, drip the H of 3%
2o
2incubated at room 8min, PBS rinse 3 times, each 2min, drip rabbit anti-human boron factor monoclonal antibodies (1:100), another coverslip do not add primary antibodie and make negative control 4 DEG C and spend the night.Next day, rinse 3 times with PBS, each 2min, drip the goat anti-rabbit igg of FITC mark one note, hatch 60min for 37 DEG C, rinse 3 times with PBS, each 2min, fluorescence microscopy Microscopic observation is also taken pictures.
3, the cytoactive of MTT colorimetric method for determining HUVEC is utilized
3.1 utilize MTT colorimetry to observe different dense IsowithalongolideB to the impact of huve cell activity
3.1.1 Secondary Culture
By HUVEC by 2 × 10
4the density of/mL is with the RPMI-1640 culture medium inoculated containing 10%FBS in 96 orifice plates, and 200 μ L are planted in every hole.
3.1.2 to divide into groups dosing
After passage cell cultivates 24h, with the RPMI-1640 culture medium compounding pharmaceutical containing 10%FBS, cell is divided into 6 groups at random: matched group (control), IsowithalongolideB5 μ g/mL group, IsowithalongolideB10 μ g/mL group, IsowithalongolideB20 μ g/mL group, IsowithalongolideB40 μ g/mL group, IsowithalongolideB80 μ g/mL group, hole, every hole 6.Continue cultivation after 48 hours, mtt assay detects cytoactive.
3.1.3MTT method detects
Add oneself MTT solution of preparing of 20 μ L directly to every hole, hatch 4h for 37 DEG C, exhaustion supernatant, then adds 150 μ LDMSO.After abundant dissolving to be crystallized, microplate reader is utilized to measure OD value at wavelength 490nm place.
3.2 utilize MTT colorimetry to observe variable concentrations ox-LDL to the impact of huve cell activity
3.2.1 Secondary Culture: the same.
3.2.2 to divide into groups dosing
After cell culture 24h, with the RPMI-1640 culture medium compounding pharmaceutical containing 10%FBS, cell is divided into 6 groups at random: matched group (control), ox-LDL (for self-control) 10 μ g/mL groups, ox-LDL20 μ g/mL group, ox-LDL40 μ g/mL group, ox-LDL80 μ g/mL group, ox-LDL160 μ g/mL group, hole, every hole 6.Continue cultivation 24 hours, mtt assay detects cytoactive.
The intervention effect that 3.3 utilize MTT colorimetry to observe IsowithalongolideB induces huve cell to damage to ox-LDL
3.3.1 Secondary Culture: the same.
3.3.2 to divide into groups dosing
After cell culture 24h, with the RPMI-1640 culture medium compounding pharmaceutical of 10%FBS, cell is divided into 6 groups at random: matched group (control), ox-LDL50 μ g/mL group, ox-LDL50 μ g/mL+IsowithalongolideB5 μ g/mL group, ox-LDL50 μ g/mL+IsowithalongolideB10 μ g/mL group, hole, ox-LDL50 μ g/mL+IsowithalongolideB20 μ g/mL every hole 6.Continue cultivation after 24 hours, mtt assay detects cytoactive.
4, utilizing Flow Cytometry to observe IsowithalongolideB induces the intervention of huve cell apoptosis to do to ox-LDL
4.1 use Secondary Culture
By HUVEC by 2 × 10
5the density of/mL is with the RPMI-1640 culture medium inoculated containing 10%FBS in 6 orifice plates, and 1500 μ L are planted in every hole.
4.2 grouping dosings
After cell culture 24h, with RPMI-1640 serum-free medium serum deprivation 24h, cell is made to enter resting state.With containing RPML-1640 blood serum medium compounding pharmaceutical, cell is divided into 5 groups at random: matched group (control), ox-LDL50 μ g/mL group, ox-LDL50 μ g/mL+IsowithalongolideB5 μ g/mL group, ox-LDL50 μ g/mL+IsowithalongolideB10 μ g/mL group, the every hole of ox-LDL50 μ g/mL+IsowithalongolideB20 μ g/mL adds 1mL pastille culture medium.
4.3 operating procedure
After dosing, 12h draws materials, and cell culture fluid sucking-off in centrifuge tube, PBS washs attached cell once, with pancreatin cell dissociation buffer peptic cell.After cell dissociation gets off, transfer in centrifuge tube, PBS washes three times (centrifugal 10 minutes of 1000g).Add 200 μ L binding buffer liquid, re-suspended cell.Add 10 μ LAnnexinv-FITC, 10 μ LPI dyeing liquors mix gently.Room temperature lucifuge hatches 15 minutes, upper machine testing apoptosis in 30 minutes.
5, statistical analysis
Adopt SPSS13.0 to add up a software to analyze, result is expressed as: mean scholar standard deviation
when variance is neat, two groups are compared and adopt LSD, to compare more uses Dunnett to check as organized with matched group, when heterogeneity of variance, and employing WeLch robust iterative, then adopt T3 method to compare between two.P<0.05 indicates statistical significance.
Three, result and conclusion
1, variable concentrations IsowithalongolideB is on the impact of HUVEC cell viability
IsowithalongolideB medicine is in certain its pharmacological action of concentration range competence exertion, and different cell systems also can be different to the sensitivity of medicine.For this reason, the drug level scope of experiment is first determined with mtt assay.Result is as table 1 (VS matched group
#p<0.01) show, the action effect of the IsowithalongolideB Human Umbilical Vein Endothelial Cells of variable concentrations is different, and drug level (5 ~ 20 μ g/mL) cytoactive of low dosage compares with matched group, does not have significant difference.40 μ g/mL act on 48 hours later cell vigor and have dropped about 50%, and 80 μ g/mL act on 48 hours later cell vigor and have dropped 70%, compare and have significant difference (P<0.01), create certain toxic and side effects with matched group.Therefore this tests IsowithalongolideB concentration used is 5,10,20 μ g/mL, to get rid of the toxic action of medicine self to cell.
2, variable concentrations ox-LDL is on the impact of huve cell vigor
Due to the difference of OxLDL ELISA degree of oxidation, the cytotoxicity scope of OxLDL ELISA can be different.Therefore we first adopt MTT to determine the cytotoxic scope of ox-LDL.Result is as table 2 (VS matched group
*p<0.05
#p<0.01), shown in, variable concentrations ox-LDL is different on the impact of HUVEC cytoactive.Compared with matched group, 10 μ g/mL groups have the trend promoting that HUVEC cytoactive increases, but compare with matched group and do not have significant difference (P>0.05); 20-100 μ g/mL respectively organizes endothelial cell activity to be increased with concentration and reduces, and compares have significant difference (P<0.05 or P<0.01) with matched group.
3, IsowithalongolideB induces the intervention effect of huve cell damage to ox-LDL
Result is as table 3 (VS.ox-LDLgroup
#p<0.01) shown in, the cytoactive that ox-LDL (50 μ g/mL) organizes declines, compare with matched group and have significant difference (P<0.01), illustrate that ox-LDL group cytoactive significantly reduces, ox-LDL (50 μ g/mL) has damaging action to normal HUVEC.The cytoactive of IsowithalongolideB various dose group is all higher than ox-LDL group, statistical significance (P<0.01) is had with ox-LDL group comparing difference, illustrate that the cytoactive of these three dosage groups is significantly higher than ox-LDL group, the HUVEC damage that prompting IsowithalongolideB can suppress ox-LDL to induce.The cytoactive of IsowithalongolideB10 μ g/mL and IsowithalongolideB20 μ g/mL group, higher than IsowithalongolideB5 μ g/mL group, compares with IsowithalongolideB5 μ g/mL and has significant difference (P=0.01 or P<0.01).IsowithalongolideB20 μ g/mL cytoactive comparatively IsowithalongolideB10 μ g/mL group has rising trend, but does not have significant difference (P=0.185).The Endothelium Protective effect of prompting IsowithalongolideB has dose-effect relationship within the specific limits.
4, IsowithalongolideB is on the impact of the huve cell apoptosis of ox-LDL induced damage
Each group of fluidic cell result display: the apoptosis rate difference of each group cell has statistical significance (P<0.01), the proliferation index of ox-LDL group obviously raises, compare with matched group have significant difference (P<0.01) to illustrate ox-LDL (50 μ g/mL) has damaging action to normal HUVEC.The apoptosis rate of IsowithalongolideB various dose group is all lower than ox-LDL group, statistical significance (P<0.01) is had with ox-LDL group comparing difference, illustrate that the apoptosis rate of these three dosage groups is significantly lower than ox-LDL group, the HUVEC apoptosis that prompting IsowithalongolideB can suppress ox-LDL to induce.The apoptosis rate of IsowithalongolideB various dose group reduces gradually along with dosage raises, and between each group, difference has statistical significance (P<0.01).The results are shown in Table 4 (VSox-LDLgroup
#p<0.01).The protection of ecs effect of prompting IsowithalongolideB has dose-effect relationship within the specific limits.
Conclusion, this research adopts mtt assay to detect and finds that IsowithalongolideB can significantly improve the cell viability of the Human umbilical vein endothelial cells of ox-LDL damage, illustrates that it has the effect of the HUVEC damage suppressing ox-LDL induction.The two staining for flow cell art of further employing AnnexinV-FITC, PI detects apoptosis, and research finds that each concentration group IsowithalongolideB all significantly can reduce the HUVEC apoptosis of ox-LDL induction, and effect is dose dependent.Prompting IsowithalongolideB realizes Endothelium Protective effect by suppressing the HUVEC apoptosis of ox-LDL induction.
Table 1 variable concentrations IsowithalongolideB on the impact of HUVEC cell viability (
n=6)
| Group | Cell viability (%) |
| Control (matched group) | 100.14±3.82 |
| Isowithalongolide B 5μg/mL | 100.45±9.67 |
| Isowithalongolide B 10μg/mL | 101.22±10.57 |
| Isowithalongolide B 20μg/mL | 92.77±8.54 |
| Isowithalongolide B 40μg/mL | 48.92±5.62 # |
| Isowithalongolide B60μg/mL | 32.79±2.54 # |
| Isowithalongolide B80μg/mL | 30.21±2.28 # |
| F value | 298.51 |
| P value | <0.01 |
Table 2ox-LDL on the impact of HUVEC cell viability (
n=6)
| Group | Cell viability (%) |
| Control (matched group) | 100.02±5.01 |
| ox-LDL 10μg/mL | 104.52±4.01 |
| ox-LDL 20μg/mL | 93.484.77 * |
| ox-LDL 40μg/mL | 86.96±5.78 # |
| ox-LDL 60μg/mL | 64.22±3.58 # |
| ox-LDL 80μg/mL | 57.21±2.54 # |
| F value | 116.248 |
| P value | <0.001 |
The different agent IsowithalongolideB of table 3 to ox-LDL induce HUVEC damage intervention effect (
n=6)
| Group | Cell viability (%) |
| Control (matched group) | 100.01±3.74 # |
| ox-LDL 50μg/mL | 73.92±7.04 |
| ox-LDL 50μg/mL+Isowithalongolide B 5μg/mL | 82.59±4.80 # |
| ox-LDL50μg/mL+Isowithalongolide B 10μg/mL | 90.01±3.70 # |
| ox-LDL 50μg/mL+Isowithalongolide B 20μg/mL | 93.61±2.11 # |
| F value | 29.15 |
| P value | <0.001 |
Table 4 various dose IsowithalongolideB to ox-LDL induce HUVEC apoptosis effect (
n=3)
| Group | Apoptosis rate (%) |
| Control (matched group) | 1.84±0.05 # |
| ox-LDL 50μg/mL | 9.87±0.40 |
| ox-LDL 50μg/mL+Isowithalongolide B 5μg/mL | 4.65±0.56 # |
| ox-LDL 50μg/mL+Isowithalongolide B 10μg/mL | 3.67±0.23 # |
| ox-LDL 50μg/mL+Isowithalongolide B 20μg/mL | 2.51±0.17 # |
| F value | 274.678 |
| P value | <0.001 |
Claims (1)
1.IsowithalongolideB is preparing the application in endotheliocyte protection medicine, and described IsowithalongolideB chemical structural formula is as follows,
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348361A (en) * | 2015-10-19 | 2016-02-24 | 淄博夸克医药技术有限公司 | Triterpene compound used for protecting endothelial cells |
| CN105461531A (en) * | 2016-01-12 | 2016-04-06 | 郑平珍 | Novel sesquiterpene compound and preparation method and medical application thereof |
-
2015
- 2015-09-16 CN CN201510590533.4A patent/CN105106224A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348361A (en) * | 2015-10-19 | 2016-02-24 | 淄博夸克医药技术有限公司 | Triterpene compound used for protecting endothelial cells |
| CN105461531A (en) * | 2016-01-12 | 2016-04-06 | 郑平珍 | Novel sesquiterpene compound and preparation method and medical application thereof |
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Application publication date: 20151202 |