CN115844916A - Pharmaceutical use of jujuboside A - Google Patents
Pharmaceutical use of jujuboside A Download PDFInfo
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- CN115844916A CN115844916A CN202310172885.2A CN202310172885A CN115844916A CN 115844916 A CN115844916 A CN 115844916A CN 202310172885 A CN202310172885 A CN 202310172885A CN 115844916 A CN115844916 A CN 115844916A
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- spina date
- date seed
- pharmaceutical composition
- diabetes
- seed saponin
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- SQHQDXGIJPHZRZ-AAWDLAKASA-N Jujuboside A Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)CO2)O)[C@@H](O)CO[C@H]1O[C@@H]1C(C)(C)[C@H](CC[C@@]2(C)[C@@]34C[C@]5([C@H]([C@@](C[C@@H](O5)C=C)(C)O)[C@H]4CC[C@H]42)OC3)[C@]4(C)CC1 SQHQDXGIJPHZRZ-AAWDLAKASA-N 0.000 title description 10
- KVKRFLVYJLIZFD-OPGZLHQPSA-N jujuboside A Natural products C[C@@H]1O[C@@H](O[C@H]2[C@H](O[C@H]3CC[C@@]4(C)[C@@H](CC[C@]5(C)[C@@H]4CC[C@@H]6[C@H]7[C@](C)(O)C[C@@H](O[C@@]78C[C@@]56CO8)C=C(C)C)C3(C)C)OC[C@H](O)[C@@H]2O[C@@H]9O[C@H](CO[C@@H]%10O[C@H](CO)[C@@H](O)[C@H](O)[C@H]%10O)[C@@H](O)[C@H](O)[C@H]9O[C@@H]%11OC[C@@H](O)[C@H](O)[C@H]%11O)[C@H](O)[C@H](O)[C@H]1O KVKRFLVYJLIZFD-OPGZLHQPSA-N 0.000 title description 10
- QCLBRNPQMDEDIM-UHFFFAOYSA-N jujuboside C Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(O)C(O)C(COC3C(C(O)C(O)C(CO)O3)O)O2)O)C(O)COC1OC1C(C)(C)C(CCC2(C)C34CC5(C(C(CC(O5)C=C(C)C)(C)O)C4CCC42)OC3)C4(C)CC1 QCLBRNPQMDEDIM-UHFFFAOYSA-N 0.000 title description 10
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- SMRPGWBDLOQHOS-UHFFFAOYSA-N 5-[4,5-dihydroxy-6-(hydroxymethyl)-3-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxy-3,4-dihydroxy-6-[[9-hydroxy-4-(hydroxymethyl)-4,6a,6b,8a,11,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1H-picen-3-yl]oxy]oxane-2-carboxylic acid Chemical compound OC1C(O)C(O)C(C)OC1OC1C(OC2C(OC(C(O)C2O)C(O)=O)OC2C(C3C(C4C(C5(CCC6(C)C(O)CC(C)(C)CC6C5=CC4=O)C)(C)CC3)(C)CC2)(C)CO)OC(CO)C(O)C1O SMRPGWBDLOQHOS-UHFFFAOYSA-N 0.000 claims abstract description 31
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Abstract
The invention provides an application of spina date seed saponin A or derivatives thereof in preparing a medicament for preventing or treating diabetes. The invention also provides a pharmaceutical composition, which comprises the spina date seed saponin A or the derivatives thereof and a pharmaceutically acceptable carrier. The invention discovers that the spina date seed saponin A shows a remarkable effect of reducing blood sugar, can improve insulin resistance and treat diabetes, and has important clinical significance and application prospect as an antidiabetic.
Description
Technical Field
The invention belongs to the technical field of biological medicine, and relates to application of spina date seed saponin A in preparation of a medicine for preventing or treating diabetes.
Background
Diabetes Mellitus (DM) is a chronic endocrine and metabolic disease, wherein type 2 Diabetes Mellitus accounts for most of the Diabetes Mellitus, and the number of Diabetes Mellitus patients in China is more than 2000 thousands, wherein nearly 90% of Diabetes Mellitus patients in China are type 2 Diabetes Mellitus, and the Diabetes Mellitus has the characteristics of multiple occurrence and youthfulness, so that the health of the people is seriously threatened.
According to the research reports at home and abroad, many scholars consider that the type 2 diabetes is possibly a cytokine-mediated inflammatory response and is an innate immune disease, and the view is called the 'inflammation theory' of the type 2 diabetes. The inflammatory mechanism of type 2 diabetes has therefore become a focus of global scholars.
Disclosure of Invention
The invention provides a medicament for preventing or treating diabetes.
The invention aims to provide application of spina date seed saponin A in preparation of a diabetes medicament.
The invention also aims to provide a pharmaceutical composition for treating or preventing various diabetes mellitus, which takes the spina date seed saponin A or the pharmaceutically acceptable salt thereof as an active ingredient.
In a first aspect, the present invention provides the use of jujuboside a or a derivative thereof for the manufacture of a medicament for the prevention or treatment of diabetes.
In the present invention, the jujuboside may be present in different forms, for example, the present invention includes all the variant forms of the compound. In some embodiments, the derivatives of spina date seed saponin include a free acid, a free base, an ester, a prodrug, a pharmaceutically acceptable salt, or a tautomer of spina date seed saponin a.
In some embodiments, the diabetes is type 2 diabetes.
In some embodiments, the jujuboside a or its derivatives are used in combination with other diabetes drugs.
In some embodiments, the other diabetes drugs include at least one of biguanide drugs, sulfonylurea drugs, grine drugs, thiazolidinedione drugs, glucosidase inhibitors, DPP-4 inhibitors or glucose transporter 2 inhibitors.
In some embodiments, the biguanide drug is selected from the group consisting of metformin; the sulfonylurea drug is selected from glipizide or gliclazide; the thiazolidinedione drug is selected from pioglitazone or rosiglitazone; the glucosidase inhibitor is selected from acarbose; the DPP-4 inhibitor is selected from alogliptin; the glucose transporter 2 inhibitor is selected from dapagliflozin.
The inventor of the invention carries out animal drug effect experiments on the spina date seed saponin A, and finds that the spina date seed saponin A shows a remarkable blood sugar reduction effect, which shows that the spina date seed saponin A has stronger blood sugar reduction activity. Therefore, the jujuboside A and the derivatives thereof can be developed into the anti-type 2 diabetes drugs.
In a second aspect, the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising spina date seed saponin A or a derivative thereof, and a pharmaceutically acceptable carrier.
In some embodiments, the derivatives of spina date seed saponin include a free acid, a free base, an ester, a prodrug, a pharmaceutically acceptable salt, or a tautomer of spina date seed saponin a.
In some embodiments, the pharmaceutical composition comprises spina date seed saponin A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In some embodiments, the pharmaceutically acceptable carrier comprises one or more of diluents, excipients, fillers, wetting agents, binders, disintegrants, lubricants, conditioning agents, surfactants, and adsorptive carriers.
In some embodiments, the effective amount of the jujuboside a or its derivative in the pharmaceutical composition is 1-95%, such as 1%, 5%, 10%, 20%, 40%, 60%, 80%, 95% or any value therebetween.
The composition of the medicine composition contains the spina date seed saponin A with a therapeutically effective dose or pharmaceutically acceptable salts thereof, and the spina date seed saponin A compound can be used independently in the medicine composition or can be matched with other medicines for use. Wherein the single dose of the pharmaceutical composition contains active ingredient of spina date seed saponin A and the effective content of derivatives thereof in the pharmaceutical composition is 1-95%. The actual dosage level of the active ingredient in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, one skilled in the art can start with a lower dose than is required to achieve the desired therapeutic effect and then gradually increase the dose until the desired therapeutic effect is achieved.
The pharmaceutical composition comprises not only spina date seed saponin A or pharmaceutically acceptable salt thereof with a therapeutically effective amount, but also pharmaceutically acceptable carriers, wherein the pharmaceutically acceptable carriers refer to conventional pharmaceutical carriers in the pharmaceutical field, such as: diluents, excipients, and water, etc.; fillers such as starch, sucrose, lactose, microcrystalline cellulose, and the like; binders such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone, and the like; humectants such as glycerol; disintegrating agents such as agar, calcium carbonate, sodium bicarbonate, etc.; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol and the like; adsorption carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, polyethylene glycol, etc., and other adjuvants such as flavoring agents, sweetening agents, etc., may also be added to the composition.
The pharmaceutical composition is any one of the dosage forms in pharmaceutics, including tablets, capsules, soft capsules, gels, oral agents, suspensions, medicinal granules, patches, ointments, pills, powder, injections, infusion solutions, freeze-dried injections, intravenous emulsions, liposome injections, suppositories, sustained-release preparations or controlled-release preparations. Preferred forms are tablets, coated tablets, capsules, granules, oral liquids and injections.
The pharmaceutical compositions of the present invention may be administered to a patient in need of such treatment by oral, rectal or parenteral administration.
Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional production methods in the pharmaceutical field, and then prepared into desired dosage forms. The pharmaceutical compositions may be prepared using any of a variety of methods, including but not limited to, conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, entrapping, and lyophilizing.
The present invention also provides a method for preventing or treating diabetes, the method comprising administering to an individual in need thereof a therapeutically effective amount of spina date seed saponin A or a derivative thereof.
In some embodiments, the diabetes is type 2 diabetes.
In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of spina date seed saponin A, or a pharmaceutically acceptable salt thereof.
The methods of the invention include treatment of mammals. Mammals include humans.
The invention provides a spina date seed saponin A or a derivative thereof with effective treatment amount. A "therapeutically effective amount" is synonymous with a "therapeutically effective dose" and, when used to treat diabetes, refers to the dose of a compound, composition or combination necessary to achieve the desired therapeutic effect, including doses sufficient to alleviate symptoms or to bring a patient into clinical remission. The amount of active ingredient in the compounds, compositions or combinations of the invention for the treatment of diabetes can be varied in order to obtain a suitable dosage.
In addition, where repeated administrations of the compounds or pharmaceutical compositions of the invention are used, the actual effective amount of the compound or pharmaceutical composition of the invention will further depend on factors including, but not limited to, the frequency of administration, the half-life of the compound or pharmaceutical composition of the invention. The large differences in the necessary effective amounts are to be expected in view of the different efficiencies of the various routes of administration. For example, oral administration typically requires higher dosage levels than administration by intravenous injection.
Administration can be single dose or cumulative (continuous administration) and can be readily determined by one skilled in the art. For example, treatment of diabetes may comprise a single administration of an effective dose of a compound or pharmaceutical composition of the invention. Alternatively, treating diabetes may comprise administering an effective dose of a compound or pharmaceutical composition of the invention multiple times over a period of time, e.g., daily, every few days, weekly, monthly, or yearly.
The inventor finds that the spina date seed saponin A shows a remarkable effect of reducing blood sugar and can improve insulin resistance to treat diabetes, particularly type 2 diabetes through experiments, so that the spina date seed saponin A has important clinical significance and application prospect as a medicine for treating diabetes, particularly type 2 diabetes.
Drawings
FIG. 1 shows the inhibitory effect of jujuboside A on NF- κ B signaling pathway targeting based on reporter gene.
FIG. 2 shows the effect of jujuboside A on blood glucose in rats.
FIG. 3 shows the effect of jujuboside A on blood lipid level in rats.
In fig. 1-3, P <0.05, P <0.01, P <0.001.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. The specific embodiments described herein are merely illustrative of the invention and do not constitute any limitation on the invention. Moreover, in the following description, descriptions of well-known structures and techniques are omitted so as to not unnecessarily obscure the concepts of the present disclosure. Such structures and techniques are also described in numerous publications.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly used in the art to which this invention belongs. For the purpose of explaining the present specification, the following definitions will apply and, where appropriate, terms used in the singular will also include the plural and vice versa.
As used herein, the expressions "a" and "an" include plural references unless the context clearly dictates otherwise. For example, reference to "a cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art, and so forth.
In the present application, jujujuboside A, formula C 58 H 94 O 26 And the molecular weight of 1207.36 is a triterpenoid saponin compound contained in Chinese date. The structural formula of the spina date seed saponin A is as follows:
the term "treatment" includes treatment to ameliorate one or more symptoms of diabetes, or to delay the progression of such disease, for example, to lower blood glucose; it also includes treatments to cure such diseases, to bring the patient into a normal functional state and/or to maintain the patient in a normal functional state or to prolong the time to relapse. Therapeutic uses may include prophylactic uses, preventing, controlling or lessening the severity of the onset of diabetes in a patient, and treatments that control or lessen the severity of an existing disease. The drug or pharmaceutical composition may be administered prior to the onset of symptoms; administration can also be after the onset of symptoms. It can be administered to a patient who may be at risk of the onset of diabetes.
The following examples and figures are provided to aid in the understanding of the present invention. It is to be understood that these examples and drawings are illustrative of the invention and are not to be construed as limiting in any way. The actual scope of the invention is set forth in the following claims. It is to be understood that any modifications and variations may be made without departing from the spirit of the invention.
The various reagents used in the experiments are commercially available in conventional amounts unless otherwise indicated.
Example 1: research on inhibition effect of spina date seed saponin A compound on reporter gene-based targeted NF-kB signal channel
NF- κ B-RE-Luci 293 cell strain (Beijing Olympic Biotech) grown in logarithmic phase was blown down, and a vial of cell conditioned cell suspension was seeded into a 96-well cell culture plate at a ratio of 1. Placing at 37 ℃ with 5% CO 2 After 24h of cultivation in the incubator, 100. Mu.L of the culture medium was discarded per well. TNF-alpha (Kingsry) is not added to the blank group, and PBS with the proportion of 100 mu L and the DMSO of the experimental group is added; adding 50 muL of PBS with the same DMSO proportion as that of the experimental group and 50 muL of TNF-alpha stimulation of 1000ng/mL into each hole of the inflammation model group; adding 50 mu LPDTC solution (Biyunnan company) and 50 mu L TNF-alpha stimulation of 200ng/mL into each well of the positive control group; different concentrations of drug solutions and 50 μ L of 200ng/mL TNF-. Alpha.solutions were added to each well of the experimental group (note: TNF-. Alpha.solutions were added 1h after drug addition). After further incubation for 24h, the culture medium was aspirated from each well, gently added with 25. Mu.L PBS, and lysed at-80 ℃ for at least 30min. The plates were removed and thawed at room temperature, substrates Steady-Glo Reagent (Promega Corp.) 25. Mu.L were added per well and lysed in the dark for at least 20 min. Taking a white enzyme label plate with 40 mu L to 384 holes of reaction liquid, and detecting a chemiluminescence value (RLU) by using an enzyme label instrument, wherein the value represents the expression level of luciferase in each detection sample, thereby indirectly reflecting the activation level of NF-kB.
The results after drug treatment (see figure 1) show that the spina date seed saponin A (Bao chicken morning glory organism) has obvious NF-kB inhibition activity at the concentration of 0.1, 1 and 10 mu m/L and is in a dose effect relationship.
Example 2: research on in vivo hypoglycemic activity of spina date seed saponin A
The molding method comprises the following steps:
healthy Wistar rats (southern medical university laboratory animal center) with the weight of 220g-280g are divided into a normal control group and a model group, distilled water is given to the normal group rats at 10ml/kg, after model group rats are fed with 10ml/kg ig fat emulsion on the basis of normal diet for 10 days, 12 tail veins of the normal group rats and the model group rats are randomly taken to test the content of TC, TG and FFA in serum. Then, the animals in each group were fasted for 12 hours without water deprivation, and the normal group was sublingual iv 0.1mol/L, pH4.4 citrate-sodium citrate buffer, the model group was sublingual iv STZ (Sigma) 55mg/kg, and the administration volumes were all 5ml/kg. After 72 hours, rats with fasting blood glucose value of more than 11.1mmol/L are selected from the model rats as type 2 diabetes mellitus model rats.
The test method comprises the following steps:
the model rats are divided into 3 groups according to the blood sugar interval, and then divided into 5 groups according to the weight interval, namely: spina date seed saponin A30mg/kg, 60mg/kg, 120mg/kg dose group, metformin group and model control group, each group comprises 6 pieces. The rats of the normal control group and the model control group are given 10ml/kg of distilled water per day ig; 30mg/kg, 60mg/kg and 120mg/kg of spina date seed saponin A are respectively given to the group of dosage groups of 30mg/kg, 60mg/kg and 120mg/kg of spina date seed saponin A per day in an ig way; the metformin group was administered ig 20mg/kg metformin daily and fasting blood glucose was measured 1 time per week with a glucometer (Roche). In each group of living animals, fasting is carried out for 12 hours before the last 1 administration in the 4 th week, 1h ip 3% sodium pentobarbital is anesthetized for 30mg/kg after the next daily administration, abdominal aorta is subjected to blood sampling, TC, TG, HDL-c and LDL-c contents in serum are measured by a full-automatic biochemical analyzer (Olympus Japan), and TC/HDL-c and LDL-c/HDL-c values are calculated; FFA was detected according to the FFA kit (Shanghai Crystal resistance-Biocide) instructions.
The experimental results are as follows: the results of the effect of jujuboside A on the blood sugar of rats are shown in figure 2, compared with the normal group, the model group rats have blood lipid metabolism disorder after 10 days of continuous ig fat emulsion: the TC, TG and FFA contents are all obviously increased (P is less than 0.01), and the model has characteristics similar to those of clinical type 2 diabetes patients, which indicates that the rat T2DM model is successfully established. The results of the effect of jujuboside A on the blood lipid level of rats are shown in figure 3, and experiments show that the jujuboside A can reduce the blood sugar and the levels of TG, TC and FFA at the same time after the model rats are treated by the medicament for 4 weeks, which indicates that the medicament can improve the sensitivity of liver and peripheral tissues to insulin and reduce the insulin resistance.
As can be seen from the above, the experimental results of examples 1-2 show that spina date seed saponin A has strong NF-kB inhibition effect, has the effects of reducing blood sugar and improving insulin resistance, and has good anti-type 2 diabetes activity. Therefore, the jujuboside A can be used for preparing the medicine for resisting the type 2 diabetes.
The technical solution of the present invention is not limited to the limitations of the above specific embodiments, and all technical modifications made according to the technical solution of the present invention fall within the protection scope of the present invention.
Claims (10)
1. Use of spina date seed saponin A or its derivative in preparing medicine for preventing or treating diabetes is provided.
2. The use of claim 1, wherein the derivative of spina date seed saponin comprises a free acid, a free base, an ester, a prodrug, a pharmaceutically acceptable salt, or a tautomer of spina date seed saponin A.
3. The use according to claim 1, wherein the diabetes is type 2 diabetes.
4. The use according to claim 1, wherein the jujuboside a or a derivative thereof is used in combination with other diabetes drugs, preferably the other diabetes drugs comprise at least one of biguanide drugs, sulfonylurea drugs, grine drugs, thiazolidinedione drugs, glucosidase inhibitors, DPP-4 inhibitors or glucose transporter 2 inhibitors; more preferably, the biguanide drug is selected from metformin; the sulfonylurea drug is selected from glipizide or gliclazide; the thiazolidinedione drug is selected from pioglitazone or rosiglitazone; the glucosidase inhibitor is selected from acarbose; the DPP-4 inhibitor is selected from alogliptin; the glucose transporter 2 inhibitor is selected from dapagliflozin.
5. A pharmaceutical composition for preventing or treating diabetes comprises spina date seed saponin A or derivatives thereof and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5, wherein the derivative of spina date seed saponin comprises a free acid, a free base, an ester, a prodrug, a pharmaceutically acceptable salt, or a tautomer of spina date seed saponin A.
7. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises spina date seed saponin A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable carrier comprises one or more of a diluent, an excipient, a filler, a wetting agent, a binder, a disintegrant, a lubricant, a conditioning agent, a surfactant, and an adsorptive carrier.
9. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a soft capsule, a gel, an oral preparation, a suspension, a granule, a patch, an ointment, a pill, a powder, an injection, an infusion solution, a lyophilized injection, an intravenous emulsion, a liposome injection, a suppository, a sustained release preparation or a controlled release preparation, preferably a tablet, a coated tablet, a capsule, a granule, an oral liquid or an injection.
10. The pharmaceutical composition of claim 5, wherein the effective amount of the spina date seed saponin A or the derivative thereof in the pharmaceutical composition is 1-95%.
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| WO2021194110A1 (en) * | 2020-03-27 | 2021-09-30 | 경희대학교 산학협력단 | Composition for preventing or treating metabolic diseases, containing jujuboside a as active ingredient |
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| Title |
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| YUJIE ZHONG 等: "Jujuboside A ameliorates high fat diet and streptozotocin induced diabetic nephropathy via suppressing oxidative stress, apoptosis, and enhancing autophagy" * |
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