CN110305190B - Application of novel polypeptide for improving preeclampsia placenta dysfunction - Google Patents
Application of novel polypeptide for improving preeclampsia placenta dysfunction Download PDFInfo
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- CN110305190B CN110305190B CN201910611509.2A CN201910611509A CN110305190B CN 110305190 B CN110305190 B CN 110305190B CN 201910611509 A CN201910611509 A CN 201910611509A CN 110305190 B CN110305190 B CN 110305190B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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Abstract
The invention discloses application of a novel polypeptide for improving preeclampsia placenta dysfunction, relates to the field of medicine correlation, and aims to solve the problem that most of medicines for improving preeclampsia placenta dysfunction in the prior art have certain toxic and side effects on a maternal fetus. The application of the polypeptide is the application in preparing a medicament or medicament for improving the preeclampsia placental dysfunction; the polypeptide sequence is Ac-RFAACAA-COOH.
Description
Technical Field
The invention relates to the field related to medicines, in particular to application of a novel polypeptide for improving preeclampsia placenta dysfunction.
Background
Preeclampsia (Pre-eclampsia, PE) is a specific disease during pregnancy, can cause the damage of the functions of multiple organs of a pregnant woman, cerebral edema, limited growth of a fetus and the like, and is one of the diseases causing the highest fatality rate of the pregnant woman and the fetus. According to statistics, about 49000 pregnant and lying-in women and 50000 perinatal infants die of preeclampsia and complications thereof every year, accounting for 14% of various death causes of the pregnant and lying-in women; the incidence of PE in China is more 3.91-5.57%, and the PE seriously harms the health of puerperae and fetuses. At present, except that very few drugs such as labetalol, nifedipine and the like are relatively safe in clinic, the rest drugs have toxic and side effects on a maternal fetus; today with extreme lack of therapeutic measures, termination of pregnancy remains the ultimate means, and newborns are extremely burdened for their small gestational age, personal, family, and society.
The polypeptides (peptidoms) are referred to as naturally occurring Low Molecular Weight (LMW) peptides and proteolytic fragments having a molecular weight of less than 10 kDa. LMW peptides associated with the disease microenvironment are easily shed into the extracellular interstitium and easily cross the endothelial barrier of the vasculature, eventually entering the circulation. In recent years, the important role of polypeptides in the prevention and treatment of diseases has attracted attention of scholars: human beta-defensin 2 (beta-defensin 2) can selectively act on calcium activated potassium (BK) channels to reduce the diastolic pressure, systolic pressure and blood flow velocity of blood vessels, and is expected to become a novel hypertension treatment drug; glucagon peptide (GLP-1) can improve vascular endothelial cell injury by regulating NF-kB signal channel, and can be used for treating diabetic atherosclerosis.
Most of the medicines for improving the preeclampsia placental dysfunction have certain toxic and side effects on a mother fetus, and the termination of pregnancy is still the final means when the preeclampsia placental dysfunction appears; therefore, the market urgently needs to develop a novel polypeptide for improving the preeclampsia placenta dysfunction to help people solve the existing problems.
Disclosure of Invention
The invention aims to provide application of a novel polypeptide for improving preeclampsia placenta dysfunction, and aims to solve the problem that most of medicines for improving preeclampsia placenta dysfunction in the background technology have certain toxic and side effects on a maternal fetus.
In order to achieve the purpose, the invention provides the following technical scheme: the application of a novel polypeptide for improving preeclampsia placental dysfunction is characterized in that the polypeptide sequence is Ac-RFAACAA-COOH.
Preferably, the polypeptide is applied to improving preeclampsia placental dysfunction.
Preferably, the polypeptide is used for reducing the level of pre-eclampsia progestational murine urine protein/creatinine.
Preferably, the polypeptide is applied to improving the utilization rate of the placenta of the pregnant mice before eclampsia.
Preferably, the use of said polypeptide for reversing the inhibitory effect of TNF α on trophoblast migration and invasion.
Preferably, the polypeptide is obtained by screening through a polypeptinomics method.
Compared with the prior art, the invention has the beneficial effects that:
1. in the invention, the Cys-peptide polypeptide sequence is Ac-RFAACAA-COOH, the purity is more than 95 percent, the proteinuria symptom of a pregnant mouse at the preeclampsia can be obviously improved, the placenta utilization rate (fetal weight/placental weight) of a pregnant mouse suffering from the eclampsia is improved, the contents of sFlt-1 and TNF alpha in the blood of the pregnant mouse are reduced, and the medicinal function of the pregnant mouse can meet the target requirement through the observation experiment on the pregnant mouse;
2. in the invention, the Cys-peptide polypeptide can effectively improve the reduction of trophoblast migration and invasion induced by TNF alpha, and the Cys-peptide polypeptide has no adverse effect on the reproductive capacity, embryo/fetus lethality rate and teratogenesis rate of rats, namely, the Cys-peptide polypeptide has no obvious toxic or side effect and has certain safety;
3. in the invention, the Cys-peptide polypeptide has good molecular basis as a polypeptide medicament, such as low molecular weight, good stability, good lipophilicity, easy cell entry and nuclear entry and the like.
Drawings
FIG. 1 is a graph showing the effect of Cys-peptide of the present invention on proteinuria in rats;
FIG. 2 is a graph showing the effect of Cys-peptide of the present invention on placenta availability;
FIG. 3 is a graph showing the effect of Cys-peptide of the present invention on the invasive potential of trophoblasts;
FIG. 4 is a graph showing the effect of Cys-peptide of the present invention on the migration ability of trophoblasts.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments.
An application of a novel polypeptide for improving preeclampsia placental dysfunction is disclosed, wherein the sequence of the polypeptide (Cys-peptide) is Ac-RFAACAA-COOH.
Cys-peptide was synthesized by the following sequence Ac-RFAACAA-COOH (purity: more than 95%) by solid phase method from Shanghai peptide Biotech Co., Ltd., 10 mg/tube.
Taking 1mg of polypeptide, diluting the polypeptide with sterile double distilled water to 10mmol/L-20 ℃ for storage and standby.
Example 1
Further, the application of the polypeptide in the medicines or medicaments for improving the preeclampsia placental dysfunction, wherein the polypeptide and the polypeptide composition can be prepared into any pharmaceutically acceptable dosage forms.
Rats were housed in a light and humidity controlled environment, ad libitum fed and freely drunk tap water, acclimatized for one week under these conditions, fertile females and males were housed overnight at a ratio of 1:1, and emboli were picked up in the morning, if present, to confirm pregnancy, which was day GD 0. Pregnant mice were randomly assigned to three groups at day 14 of gestation. First group (salt) (n ═ 10): on day 14 of pregnancy, each rat received normal saline (1mg/kg) via the tail vein; second group (LPS): on 14 days of pregnancy, LPS (1. mu.g/kg) was injected via the tail vein; third group (LPS + Cys-peptide): on day 14 of pregnancy, rats were treated with LPS (1 μ g/kg) via the tail vein and then administered Cys-peptide daily from day 14 to day 20 of pregnancy. On days 12 and 19 of pregnancy, 24 hour urine samples were collected from rats, centrifuged at 2000rpm for 15 minutes at room temperature, assayed for urine protein and urine creatinine levels using a urine protein quantification kit (C035-2, China) and a creatinine assay kit (C011-2, China), respectively, and the urine protein to creatinine ratio was calculated. At 20 days of gestation, rats are euthanized, fetal rats and placentas are weighed and recorded, and indicators such as placentalization rate are calculated.
As shown in figures 1 and 2, to assess whether LPS administration induced a preeclamptic phenotype, rats were assessed for both urinary protein levels and placental availability. At GD19, the urine protein/creatinine levels were increased more than 2-fold higher in the LPS-treated group than in the Saline group (fig. 1), fetal body weight was reduced by about 23% and placental efficiency was reduced by about 25% in the LPS-treated group compared to the Saline group (fig. 2), and significant FGR was observed in the LPS-treated rats. Thus, a rat model of LPS-induced preeclampsia was established.
By receiving Cys-peptide daily from GD14 to GD20, the urine protein/creatinine ratio was significantly reduced for the LPS + Cys-peptide group compared to the LPS group, and thus Cys-peptide could improve LPS-induced proteinuria.
Furthermore, fetal weight and placental efficiency can be restored to higher levels in the (LPS + Cys-peptide) group, 16% and 18% respectively, compared to the LPS group.
Therefore, Cys-peptide can obviously improve the proteinuria symptom of a pregnant mouse before eclampsia, improve the placenta utilization rate (fetal weight/placental weight) of a pregnant mouse suffering from eclampsia and reduce the content of sFlt-1 and TNF alpha in the blood of the pregnant mouse. Meanwhile, the peptide has no adverse effect on the reproductive capacity, embryo/fetus lethality rate and teratogenesis rate of rats.
Cys-peptide is expected to provide a new pharmaceutical means for clinical treatment of preeclampsia due to the fact that Cys-peptide has good molecular basis as a polypeptide drug, such as low molecular weight, good stability, good lipophilicity, and easy cell entry and nucleus entry.
Example 2
Further, the use of a polypeptide for reducing the level of protein/creatinine in pre-eclampsia pregnant mouse.
Sprague-Dawley (SD) rats (10-12 weeks, 280-350g) were purchased from Nanjing university of medical laboratory animals center. Rats were housed in a light and humidity controlled environment, fed ad libitum and drunk tap water ad libitum.
One week after acclimation, fertile females and males were raised overnight at a 1:1 ratio, picked up in the morning and confirmed to be pregnant if present, which was day GD 0. (Standard laboratory conditions (temperature 23-26 ℃, relative humidity 50-60%, irradiation between 06:00am and 06:00 pm) free access to particulate food and water)
Pregnant mice were randomly assigned to three groups at day 14 of gestation: group 1 (salt) (n ═ 10): on day 14 of pregnancy, each rat received physiological saline (1mg/kg) through the tail vein; group 2 (PE) rats were injected with LPS (1. mu.g/kg) via tail vein on day 14 of pregnancy (SigmaAldrich, USA); for 14 days of pregnancy in group 3 (LPS + Cys-peptide), rats were treated with LPS (1. mu.g/kg) via the tail vein and then administered with Cys-peptide (5mg/kg, intraperitoneal (ip)) daily for 14 to 20 days of pregnancy.
At GD12 and 19, a 24 hour urine sample was collected from the rats. Urine samples were centrifuged at 2000rpm for 15 minutes at room temperature and the supernatant stored at-80 ℃ for subsequent analysis. Urine protein and urine creatinine levels were performed using a urine protein quantitative test kit (C035-2, China) and a creatinine assay kit (C011-2, China), respectively.
And evaluating the treatment effect of the medicament on the preeclampsia animal model by calculating the ratio of urine protein to creatinine.
As shown in FIG. 1, in the LPS group GD19, the urine protein/creatinine level was increased to be more than 2 times higher than that of Saline, and the urine protein/creatinine level of LPS + Cys-peptide group was decreased, so Cys-peptide could improve the proteinuria induced by LPS.
Example 3
Further, the application of the polypeptide in improving the utilization rate of the placenta of the pregnant rat in the preeclampsia period.
prague-Dawley (SD) rats (10-12 weeks, 280-350g) were purchased from Nanjing university of medicine laboratory animal center. Rats were housed in a light and humidity controlled environment, fed ad libitum and had tap water ad libitum.
One week after acclimation, fertile females and males were housed overnight at a 1:1 ratio and picked up in the morning, which was confirmed to be pregnant if present, day GD 0. (Standard laboratory conditions (temperature 23-26 ℃, relative humidity 50-60%, irradiation between 06:00am and 06:00 pm) free access to particulate food and water)
Pregnant mice were randomly assigned to three groups at day 14 of gestation: group 1 (salt) (n ═ 10): on day 14 of pregnancy, each rat received physiological saline (1mg/kg) through the tail vein; group 2 (PE) rats were injected with LPS (1. mu.g/kg) via tail vein on day 14 of pregnancy (SigmaAldrich, USA); in group 3 (LPS + Cys-peptide), the rats were treated with LPS (1. mu.g/kg) via the tail vein and then administered with Cys-peptide (5mg/kg, intraperitoneal (ip)) daily for 14 days to 20 days of pregnancy.
On day 20 of pregnancy, rats were euthanized and blood samples were taken from the inferior vena cava. Sera were stored at-80 ℃ for further evaluation, and fetal mice and placentas were weighed and recorded.
And evaluating the treatment effect of the medicament on the preeclampsia animal model by calculating the placenta utilization ratio.
The results are shown in figure 2, the weight of the fetus in LPS group is reduced by 23%, the effective rate of the placenta in LPS group is reduced by 25%, the weight of the fetus in LPS + Cys-peptide group is improved by 16%, the effective rate of the placenta in LPS + Cys-peptide group is improved by 18% (as shown in figure 2), and the placenta utilization rate of the pregnant mouse with the disease is improved.
Example 4
Further, the use of the polypeptide for reversing the inhibitory effect of TNF α on trophoblast migration and invasion.
Invasion test: matrigelbegmentmembrane array (Corning, 356234) was diluted 1:7 with serum-free RPMI1640 medium, 60. mu.L/well in the upper chamber of polycarbonate membrane cell culture insert (Costar, Corning corporation, 3422, NY)) was placed overnight at 37 ℃, the pre-treated cells were collected, resuspended in serum-free RPMI1640 medium, 5 ^ 10^4 cells per well in the upper chamber of a transwell chamber, 4 replicates per well were made, and 800. mu.L of 10% FBS-containing medium was added to the lower chamber.
After 48 hours incubation at 37 ℃ the medium in the upper chamber was discarded, washed twice with PBS, and the chamber was placed in a new 24-well plate, and the cells were fixed by adding 800ul of 4% paraformaldehyde in the lower chamber at 4 ℃ for 30 min.
Then 1% crystal violet working solution is added into the lower chamber, after being dyed in dark place for 15min, the chamber is placed in ddh2o for washing, the residual cells which cannot be invaded in the upper chamber are lightly wiped off by a cotton swab, and the invaded cells and images are counted and photographed under a ZEISS microscope respectively.
Migration experiment: feeder cells were cultured in six-well plates until confluent. Using a 200. mu.l pipette tip, 3 wounds were made while randomly marking 5 spots along the wound, and after 1 hour pretreatment of HTR-8 cells with Cys-peptide (0, 10, 20. mu. mol/L), TNF20ng/ml was added for co-incubation in serum-free medium for 48 hours.
Pictures were taken at 0 and 48 hour time points, respectively, and wound area was calculated using ImageJ software, with the wound healing rate being the difference between the scratch area at the 0 hour time point and the 48 hour time point divided by the scratch area at the 0 hour time point.
The results are shown in FIGS. 3 and 4, where the trophoblast migration and invasion capacity subjected to TNF α treatment is significantly reduced compared to the control (in order to illustrate the effect of Cys-peptide on trophoblast migration and invasion, scratch and transwell invasion experiments were performed on HTR-8 cells).
After incubation with same dose of TNF alpha for 48H after 1 hour of Cys-peptide pretreatment of HTR-8 cells, compared with the group with only TNF alpha, the scratched area after migration of trophoblasts from Cys-peptide (10, 20. mu. mol/L) + TNF alpha group was significantly reduced and the number of cells successfully passing through matrix gel-coated transwells was significantly increased with a concentration gradient trend.
Cys-peptide can reverse the inhibitory effect of TNF α on trophoblast migration and invasion.
Example 5
Further, the polypeptide is obtained by screening through a peptide omics method.
Serum endogenous polypeptides (<10KD) are extracted by an ultrafiltration interception method, specific components of the serum endogenous polypeptides are further identified and analyzed by means of a tandem mass spectrometry technology, 1277 endogenous polypeptides are identified together in the result, 142 endogenous polypeptides with obvious differences exist, and IPA software is adopted to perform functional analysis on protein precursors of the different polypeptides, so that the polypeptides are possibly related to TGF-beta, Calcium, MAPK and other signal pathways and are closely related to placenta function damage.
Combining the mass spectrum quantitative detection result, and analyzing the position of Cys-peptide by bioinformatics analysis [ the biological characteristics of Cys-peptide is analyzed by using a Uniprot online tool; the polypeptide is analyzed by a ProtParamol on-line tool, wherein the isoelectric point (Isoelectrocpoint, pI), the molecular weight (Mw), the instability coefficient (Instabilityindex), the lipid solubility index (Aliphaticindix) and the hydrophilicity (GRAVY) of the polypeptide are analyzed, and a polypeptide with the function of protecting vascular endothelial cells (vascular endothelial cell damage is a central link of preeclampsia pathogenesis, shallow trophoblasts of eclampsia patients are selected from the identified polypeptide fragments, so that the placental perfusion is insufficient, the ischemia and oxygen deficiency are caused, the placenta-derived toxic factors are generated, the vascular toxic substances and inflammatory mediators are increased, and further the systemic vascular endothelial damage is caused).
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Claims (2)
1. The application of a novel polypeptide for improving preeclampsia placental dysfunction is characterized in that: the application of the polypeptide is the application in preparing a medicament or medicament for improving the preeclampsia placental dysfunction;
the polypeptide sequence is Ac-RFAACAA-COOH.
2. The use of the novel polypeptide for improving pre-eclampsia placental dysfunction of claim 1, wherein: the polypeptide is obtained by screening through a polypeptide omics method.
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| FR2945042A1 (en) * | 2009-04-30 | 2010-11-05 | Immunosearch | NOVEL POLYPEPTIDES FOR THE IN VITRO ASSESSMENT OF THE SENSITIZING POTENTIAL OF A TEST COMPOUND |
| CN103173404A (en) * | 2013-04-16 | 2013-06-26 | 中国人民解放军第三军医大学第三附属医院 | Establishing method of hypertensive disorder complicating pregnancy mouse model |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2945042A1 (en) * | 2009-04-30 | 2010-11-05 | Immunosearch | NOVEL POLYPEPTIDES FOR THE IN VITRO ASSESSMENT OF THE SENSITIZING POTENTIAL OF A TEST COMPOUND |
| CN103173404A (en) * | 2013-04-16 | 2013-06-26 | 中国人民解放军第三军医大学第三附属医院 | Establishing method of hypertensive disorder complicating pregnancy mouse model |
Non-Patent Citations (1)
| Title |
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| Method for detecting the reactivity of chemicals towards peptides as an alternative test method for assessing skin sensitization potential;Sun-A Cho，et al;《Toxicology Letters》;20131219;第225卷(第1期);第185页摘要 * |
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