CN114042150A - Oral stem cell factor compound and application thereof - Google Patents
Oral stem cell factor compound and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of biological medicines, and particularly discloses an oral stem cell factor compound. The oral stem cell factor compound comprises a stem cell factor concentrated solution and albumin peptide, wherein the mixing ratio of the stem cell factor concentrated solution to the albumin peptide is 80-140 ml: 1-5g, and the protein content in the stem cell factor concentrated solution is 0.65-1.2 mg/ml. The oral stem cell factor compound provided by the invention can be sublingually taken, and has the effect of promoting the regeneration of islet beta cells.
Description
Technical Field
The invention relates to the technical field of biological medicines, and particularly discloses an oral stem cell factor compound and application thereof.
Background
According to the reports of nutrition and chronic disease states of Chinese residents (2020), Chinese diabetics reach 1.21 hundred million. At present, the treatment of diabetes patients mainly comprises oral hypoglycemic drugs and insulin injection, and chronic and acute complications caused by diabetes are relieved by regulating the blood sugar of the patients. However, oral hypoglycemic drugs are prone to produce hepatorenal toxicity, insulin treatment risks hypoglycemia, both of which belong to the indexes of improving blood sugar and do not fundamentally improve the function of pancreatic islet beta cells.
The current research on the recovery of beta cell function in diabetic patients mainly focuses on the infusion of stem cells and exosomes. The stem cells and exosomes promote the improvement of beta cell functions through the aspects of inhibiting inflammation, regulating immunity, recovering islet microcirculation, promoting beta cell regeneration and the like, and are proved by a plurality of experiments at present. However, the infusion has certain traumatic property, has certain requirements on the physical condition of patients, has narrow application range and has certain risk.
Therefore, it is necessary to develop an oral stem cell product capable of restoring the function of islet beta cells of diabetic patients.
Disclosure of Invention
Aiming at the technical problems, the invention provides an oral stem cell factor compound which is prepared in a freeze-drying mode and can play a role in promoting the regeneration of islet beta cells through sublingual mucosal absorption.
The oral stem cell factor compound provided by the invention comprises a stem cell factor concentrated solution and albumin peptide, wherein the mixing ratio of the stem cell factor concentrated solution to the albumin peptide is 80-140 ml: 1-5g, and the protein content in the stem cell factor concentrated solution is 0.65-1.2 mg/ml.
Preferably, the mixing ratio of the stem cell factor concentrated solution to the albumin peptide is 60 ml: 1g, and the protein content in the stem cell factor concentrated solution is 1.2 mg/ml.
Preferably, the stem cell factor concentrated solution is prepared by concentrating supernatant obtained by culturing stem cells separated from umbilical cords, umbilical cord blood or placenta.
Preferably, the oral stem cell factor complex further comprises one or more of soybean peptide, yam peptide, ginseng peptide or pancreatic peptide.
The invention also provides application of the compound in preparing medicaments for promoting beta cell proliferation, recovering beta cell function and regulating blood sugar.
The invention also provides an oral freeze-drying agent with the function of repairing islet beta cells, which comprises the oral stem cell factor compound and a pharmaceutically acceptable freeze-drying protective agent.
Preferably, the freeze-drying protective agent is one or a mixture of several of D-mannitol, beta-glucan or trehalose.
Preferably, the oral lyophilizate is administered sublingually.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention provides an orally taken stem cell factor compound, which changes the use form of stem cells from infusion to daily oral administration, avoids the traumatism and inconvenience of stem cell and exosome infusion, and is safer and more convenient.
2. The oral stem cell factor compound can be further prepared into lyophilized powder for sublingual buccal administration, and solves the problems of gastric acid intolerance and gastrointestinal tract digestive damage in the oral administration of stem cells.
3. The oral stem cell factor compound directly utilizes the cell factors secreted by stem cells to achieve the purpose of promoting the regeneration of beta cells, and the albumin peptide (egg white peptide) has the function of enhancing the stem cell factors: the freeze-drying process of the stem cell concentrated factor plays a role in protection, and the activity loss of the stem cell factor in the freeze-drying process is reduced; after the albumin peptide and the stem cell factor are used in a compounding way, the content of 1L-1 beta, 1L-6 and TNF-alpha in the pancreatic islets is reduced, the inflammation of the pancreatic islets is relieved, and an excellent environment is created for the activity of the stem cell factor; and thirdly, the albumin peptide provides raw materials for protein required by cell repair and regeneration and is beneficial to islet beta repair and regeneration.
4. The experimental results prove that: the oral stem cell factor compound provided by the invention can promote insulin secretion and C peptide secretion, inhibit the expression of Caspase3 in pancreatic islets and simultaneously has a continuous regulating effect on the blood sugar of an organism.
Drawings
FIG. 1 shows the serum insulin levels of rats in each group;*P<0.05，**P<0.01；
FIG. 2 is the serum C-peptide content of rats in each group;*P<0.05，**P<0.01；
FIG. 3 shows the serum IL-1 β, IL-6, TNF- α levels of each group of rats;*P<0.05，**P<0.01；
FIG. 4 is a graph showing HE staining results of pancreatic islet cells of rats in each group;
FIG. 5 shows the WB assay of Caspase3 and Bcl2 expression levels in islets of rats in each group;
fig. 6 is a glucose tolerance curve for each group of rats.
Detailed Description
The following detailed description is to be read in connection with specific embodiments, but it should be understood that the scope of the invention is not limited to the specific embodiments. In the description of the present invention, reagents used are commercially available and methods used are conventional in the art, unless otherwise specified.
Example 1
An oral stem cell factor compound is prepared from 1g albumin peptide and 80ml stem cell factor concentrated solution (1.2mg/ml, pH6.0);
wherein the stem cell concentration factor is derived from culture supernatant of umbilical cord mesenchymal stem cells, and is concentrated to a protein concentration of 1.2mg/ml by ultrafiltration. The specific preparation method of the umbilical cord mesenchymal stem cell culture supernatant concentrated solution comprises the following steps:
1. receiving by an organization: collecting umbilical cord of infant in vitro of clinical healthy delivery, placing in sterile physiological saline (containing 5% (v/v) streptomycin), sealing, storing, and delivering to laboratory as soon as possible within 1 h;
2. tissue cleaning: taking out the received umbilical cord tissue in a clean bench, putting the umbilical cord tissue into a culture dish, washing the umbilical cord tissue twice with physiological saline (containing 5% (v/v) streptomycin), cutting off ligation parts at two ends of the umbilical cord, and washing the umbilical cord tissue for 2-3 times with the physiological saline again; cutting off the umbilical cord with sterile scissors along the growth direction of the umbilical cord, and washing blood clots in the umbilical cord with physiological saline (containing 5% streptomycin) until the tissue turns white;
3. tissue adherent culture: umbilical vessels (2 arteries and 1 vein) are removed by using sterile scissors and forceps, and the umbilical vessels are washed once by using normal saline (containing 5% streptomycin) to obtain the Wharton jelly. Cutting the Buton gum into pieces of 1mm3Uniformly spreading the tissue block in a sterile culture dish, dripping a little fetal calf serum (covering the tissue) on the surface of the tissue block, and placing at 37 deg.C and 5% CO2And (5) incubation in an incubator. Supplementing complete culture medium (90% alpha-MEM + 10% FBS) after 6-8h, continuing culturing in the incubator, and changing the culture medium at intervals of 3-4 d;
4. obtaining cells: culturing the tissue block for 10-14 days, observing a large amount of cells around the tissue block to climb out under a microscope, transferring the tissue block at the moment, washing the cell surface by PBS buffer solution, adding 0.25% of trypsin without EDTA to digest for 2-3min, blowing and beating to obtain cell suspension after the complete culture medium is stopped, centrifuging at 800rpm for 5min, and removing supernatant to obtain precipitate, namely P0 generation cells;
5. obtaining a stem cell factor concentrated solution: the mesenchymal stem cells of the P0 generation are added at a ratio of 1.0 × 105/cm2Inoculating the cells into a cell culture bottle at a density, adding a mesenchymal stem cell culture medium for culture, collecting cell culture supernatant in a sterile operating platform environment when the cells grow to reach the density of 80%, centrifuging to remove cell debris, and performing interception treatment by using an ultrafiltration concentration membrane to obtain a concentrated solution.
The mesenchymal stem cells are prepared from isolated materials, and the isolated materials are collected and used instead of surgical methods. One skilled in the art may also select other legally ethical means of obtaining cord, or select cultured cord tissue.
The compound can be further added with a freeze-drying protective agent to prepare oral freeze-drying powder, and the preparation process comprises the following steps:
mixing 10g D-mannitol and 1g albumin peptide, dissolving with small amount of water at room temperature, adding dry cell concentration factor 80ml (1.2mg/ml, pH6.0), adding water to desired volume of 100ml, mixing, and making into oral liquid
The filter membrane is filtered and sterilized, then the mixture is filled into 5ml national standard low-boron penicillin bottles, each bottle is filled with 2ml, and the mixture is sent into a freeze dryer for freeze drying, so that the medicine is obtained.
Example 2
An oral dry cell factor compound is prepared from 8g D-mannitol, 2g beta-dextran, 5g albumin peptide, 140ml dry cell factor concentrated solution (0.65mg/ml, pH6.0), and 200mg soybean peptide.
Example 3
An oral stem cell factor complex is prepared from 2g D-mannitol, 2g trehalose, 2g albumin peptide, 120ml stem cell factor concentrated solution (1.2mg/ml, pH6.0), and 100mg Ginseng radix peptide.
Example 4
An oral stem cell factor complex is prepared from 8g D-mannitol, 5g albumin peptide, 80ml stem cell factor concentrate (0.65mg/ml, pH6.0), and 150mg pancreatic peptide.
Examples of the experiments
40 SD rats weighing 200 + -20 g were purchased from the laboratory animal center of military university, 8 rats were used as normal group and fed with basal diet, and the rest were not treated. Feeding the rest 32 high-fat feeds (60% of basal feed, 16% of lard, 20% of cane sugar and 3% of egg yolk) for 8 weeks, fasting for 12 hours, carrying out one-time intraperitoneal injection of 30mg/Kg streptozotocin, and continuing to feed the high-fat feeds for 1 week to establish a hyperglycemia animal model. The 32 rats were divided into four groups, model (8), complex (8), stem cell factor (8) and albumin peptide (8), and the groups were treated with the following treatments: the model group is not processed; the compound group is administered with the stem cell factor compound provided in example 1 of the present invention; the stem cell factor group was given an equal amount (same amount of stem cell factor as in the complex of example 1) of stem cell factor; the albumin peptide group was given an equal amount (same amount as the albumin peptide in the complex of example 1) of albumin peptide, and each was injected sublingually into rats for 2 weeks.
After the administration, the tail veins of the rats in each group are collected, and the secretion of insulin and C peptide and the inflammatory factors IL-1 beta, IL-6 and TNF-alpha in serum are respectively measured.
After blood collection is finished, 4 animals are selected for each group, the animals are killed after neck removal, a small pancreas is taken out after dissection, the pancreas is fixed and embedded to prepare a wax block, and the pancreas islet repairing condition is observed through HE staining. Meanwhile, the pancreas is taken to carry out tissue homogenate, after cracking, the supernatant is obtained by centrifugation to prepare protein supernatant, and Western Blot is used for detecting the expression of Caspase3 and Bcl2 related to islet beta cell apoptosis in the pancreas.
Each group of surviving rats was continued to be fed with basal diet for 1 week after the end of treatment, and then oral glucose was subjected to glucose tolerance test (OGTT), verifying the persistence of the hypoglycemic effect of oral stem cell factor complex. The specific method comprises the following steps: after fasting for 12h, tail vein blood is taken, serum is separated to detect blood sugar, which is recorded as 0min blood sugar, then 40% glucose solution is performed for gastric lavage, timing is started at the time of gastric lavage, and tail vein blood is taken respectively for 30min, 60min and 120min to determine the content of glucose in serum.
Results
(1) Effect of Stem cell factor Complex on insulin
Insulin is a protein hormone secreted by islet beta cells stimulated by exogenous or endogenous substances such as glucose, glucagon and the like, is the only hormone for reducing blood sugar in vivo, and is a key index for responding to the function of human islets. The results of measuring the insulin content in the serum of each group of rats are shown in FIG. 1.
The results in FIG. 1 show that the serum insulin content of the rats in the model group is significantly reduced compared with that in the normal group, and the statistical difference is present, which indicates that the diabetes model is successfully modeled; compared with the model group, the insulin secretion amount of the albumin peptide group has no significant difference with the model group, the insulin secretion amounts of the stem cell factor compound group and the stem cell factor group are increased compared with the model group, and the insulin content of the compound group is higher, which shows that the stem cell factor compound has the function of improving the insulin secretion and the effect is better than that of the single use of the stem cell factor and the albumin peptide.
(2) Effect of Stem cell factor Complex on C peptide
The C peptide is secreted by the pancreatic islet beta cells and has a common precursor proinsulin with insulin. Proinsulin is cleaved into 1 molecule of insulin and one molecule of C peptide, and thus the C peptide is in molar agreement with the insulin itself. The C-peptide level is generally used to assess islet beta cell function. The results of measuring the serum C-peptide content of each group of rats are shown in FIG. 2.
FIG. 2 shows that the serum C peptide content of the rats in the model group is significantly reduced compared with that in the normal group, and the statistical difference is generated, which indicates that the diabetes model is successfully modeled; compared with the model group, only the content of the C peptide in the stem cell factor compound group is increased, which shows that the stem cell factor compound has the function of improving the secretion of the C peptide, and the effect of promoting the secretion of the C peptide is not obvious when the stem cell factor and the albumin peptide are used independently.
(3) Effect of Stem cell factor Complex on IL-1 beta, IL-6, TNF-alpha
Research shows that diabetes is a natural immune and low-grade inflammatory disease, and inflammatory reaction is involved in the whole process of diabetes and is closely related to the development of diabetes. Under the induction of high-sugar and high-fat environment, human monocytes can generate a large amount of IL-1 beta, IL-6 and TNF-alpha, promote the over-activation of killer T lymphocytes, and cause the damage and the apoptosis of islet beta cells. Meanwhile, the increase of the inflammatory factors can also lead the phosphorylation site of the insulin receptor substrate to occur on serine/threonine, thereby preventing the phosphorylation of normal tyrosine, leading the capability of the insulin receptor substrate for combining with the insulin receptor to be reduced, further weakening the action of insulin and weakening the insulin sensitivity. The results of measuring the IL-1. beta. IL-6 and TNF-. alpha.content in the serum of each group of rats are shown in FIG. 3.
The results in FIG. 3 show that the serum contents of IL-1 beta, IL-6 and TNF-alpha in the rat in the model group are obviously increased and have statistical difference compared with the normal group; compared with the model group, the contents of IL-1 beta, IL-6 and TNF-alpha in the serum of the rat of the stem cell factor compound group, the stem cell factor group and the albumin peptide group are all reduced, which shows that the three groups of substances have anti-inflammatory effect; but the compound groups IL-1 beta, IL-6 and TNF-alpha are reduced most obviously, which shows that the anti-inflammatory effect of the stem cell factor compound is better than that of the stem cell factor and the albumin peptide which are used independently.
(4) Effect of Stem cell factor Complex on pancreas and islet cells
The results are shown in FIG. 4.
FIG. 4 shows the result of HE staining, the combination between the islets and acini of the rats in the normal group is tight, the boundary is clear, the morphology is full, the number of the islet cells is large, the morphology is uniform, and the distribution is uniform; the islet tissues of the rats in the model group are atrophied, the islet tissues are separated from acinus, islet cells are obviously reduced, and partial cells are degenerated; the tissue morphology of the rat islet is improved, the number of islet cells is increased, particularly the compound group has more islet cells and regular cell arrangement, and the islet tissue morphology is basically recovered to be normal, so that the stem cell factor compound can obviously reduce the damage of high-fat feed and STZ to the islet morphological structure of the rat.
(5) Effect of Stem cell factor Complex on Caspase3, Bcl2 expression
Previous researches show that mitochondrial dysfunction in islet beta cells is a main pathway for triggering islet beta cell apoptosis, Caspase3 is a performer in the pathway, and high expression of Caspase3 inhibits expression of anti-apoptotic protein Bcl2, so that detection of expression of Caspase3 and Bcl2 in islets is a key index for evaluating islet repair degree. The results of the detection are shown in FIG. 5.
FIG. 5WesternBlot test results show that compared with the normal group, the expression level of Caspase3 in the rat islets of the model group is increased, the expression level of Bcl2 is reduced, and the increase of islet cell apoptosis and the reduction of anti-apoptosis are indicated; the expression of the Bcl2 in the compound group, the stem cell factor group and the albumin peptide group is in an increasing trend, the expression level of Caspase3 in the compound group and the stem cell factor group is obviously reduced, and particularly the expression level of Caspase3 in the compound group is more obviously reduced; the expression level of Caspase3 in the albumin peptide group is not obviously changed. The results show that the stem cell factor compound group has the effects of increasing the secretion of anti-apoptosis protein, inhibiting the apoptosis of islet cells and protecting the islets.
(6) Effect of Stem cell factor Complex on the ability of the repaired body to regulate blood glucose
Whether or not the repaired islets are able to sustain an exogenous hyperglycemic response after the end of administration requires an Oral Glucose Tolerance Test (OGTT). The oral glucose tolerance test is a glucose load test, which is used for understanding the function of islet beta cells and the regulation capacity of a body to blood sugar by giving high-dose glucose at a time, and is clinically used for a diabetes diagnosis test at present. The glucose tolerance curves of the rats in each group are shown in fig. 6.
The results in fig. 6 show that the rats in the model group reached the highest level 60min after intragastric glucose administration, the rats in the normal group reached the peak 30min, and the area under the curve of the model group was higher than that in the normal group, indicating that the model group had obvious impaired glucose tolerance. The stem cell factor group and the albumin peptide group both reach a peak at 60min and then show a descending trend, and the area under the curve is obviously lower than that of the model group, which shows that the phenomenon of impaired glucose tolerance is improved. The compound group reaches a peak 30min after gastric lavage, then continuously decreases, is consistent with the trend of the normal group, and the area under the curve is obviously lower than that of the model group, the stem cell factor group and the albumin group peptide group, which shows that the stem cell factor compound group has the capability of continuously regulating the blood sugar of the organism and has better effect than that of the single albumin peptide and the stem cell factor.
The above disclosure is only for a few specific embodiments of the present invention, however, the present invention is not limited to the above embodiments, and any variations that can be made by those skilled in the art are intended to fall within the scope of the present invention.
Claims (8)
1. An oral stem cell factor compound is characterized by comprising a stem cell factor concentrated solution and albumin peptide, wherein the mixing ratio of the stem cell factor concentrated solution to the albumin peptide is 80-140 ml: 1-5g, and the protein content in the stem cell factor concentrated solution is 0.65-1.2 mg/ml.
2. The oral stem cell factor complex of claim 1, wherein the mixing ratio of the stem cell factor concentrate to the albumin peptide is 60 ml: 1g, and the protein content in the stem cell factor concentrate is 1.2 mg/ml.
3. The oral stem cell factor complex according to claim 1 or 2, wherein the stem cell factor concentrate is prepared by concentrating a supernatant obtained by culturing stem cells isolated from umbilical cord, cord blood or placenta.
4. The oral stem cell factor complex of claim 1, further comprising one or a combination of soy, yam, ginseng, or pancreatic peptides.
5. Use of the oral stem cell factor complex of claim 1 or 2 in the preparation of a medicament for promoting beta cell proliferation, restoring beta cell function, and regulating blood glucose.
6. An oral lyophilizate having a function of repairing islet beta cells, comprising the oral stem cell factor complex of claim 1 or 2, and a pharmaceutically acceptable lyoprotectant.
7. The oral lyophilizate with the function of repairing islet beta cells of claim 6, wherein the lyoprotectant is one or a mixture of D-mannitol, beta-glucan or trehalose.
8. The oral lyophilizate having a pancreatic islet beta cell repairing function according to claim 6, wherein said oral lyophilizate is administered sublingually.
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