CN111388461B - Blood sugar reducing composition and application thereof - Google Patents
Blood sugar reducing composition and application thereof Download PDFInfo
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- CN111388461B CN111388461B CN202010317075.8A CN202010317075A CN111388461B CN 111388461 B CN111388461 B CN 111388461B CN 202010317075 A CN202010317075 A CN 202010317075A CN 111388461 B CN111388461 B CN 111388461B
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- naringenin
- glucosidase
- alpha
- methyl quercetin
- composition
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention discloses a blood sugar reducing composition and application thereof, and belongs to the technical field of medicines. The hypoglycemic composition is prepared from 3-O-methyl quercetin and naringenin according to the mass concentration ratio of 1: 25-6: 25. Preferably, the mass concentration ratio of the 3-O-methyl quercetin to the naringenin is 2: 25-6: 25. The composition of the 3-O-methyl quercetin and the naringenin has obvious synergistic effect of inhibiting alpha-glucosidase, has better effect than that of singly using the flavone compound, can reduce the dosage of the medicine and reduce the occurrence of drug resistance; has wide application prospect in preparing medicaments, health-care products or foods for treating diabetes.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a blood sugar reducing composition and application thereof.
Background
In recent years, type II diabetes has developed into one of chronic diseases seriously harming human health worldwide, and it is expected that the worldwide population of diabetes will reach 6 billion by 2035 years. Research shows that controlling postprandial blood sugar is an effective means for preventing diabetes and complications thereof, and inhibiting the activity of alpha-glucosidase on the brush border of small intestine villus mucous membrane cells is a very effective means for reducing postprandial blood sugar. At present, acarbose, voglibose and miglitol are drugs which are already used for lowering blood sugar in clinical practice on the market, but the continuous use causes some side effects. Therefore, it is urgent to discover a novel α -glucosidase inhibitor having less toxic and side effects from natural products.
Flavonoids are widely found in natural plants. A large number of researches show that the flavonoid compounds have wide pharmacological activities, such as anti-inflammatory, antioxidant, anticancer, antibacterial and analgesic activities, and the flavonoid compounds also have the reported blood sugar reducing effect. In recent years, there are a lot of reports on food-derived flavonoids as research objects, and some compounds with hypoglycemic activity are obtained by in vitro or in vivo activity screening. Zheng et al found that ferulic acid has significant inhibitory activity on alpha-glucosidase and alpha-amylase in vitro, and the inhibitory activity IC thereof500.866mg/mL and 0.622mg/mL, respectively, the Inhibition types are non-competitive Inhibition (ZHEN, Y., TIAN, J., Yang, W., Chen, S., Liu, D., Fang, H., Zhang, H., Ye, X.,2020.Inhibition mechanism of inductive acid acquisition alpha-amylase and alpha-glucosidase. food Chem 317, 126. 346.). Researches of Jia et al find that dietary flavonoid compounds have certain inhibition effect on alpha-glucosidase, and in vitro models prove that myricetin, apigenin-7-O-glucoside and fisetin have obvious inhibition activity and IC5011.63. + -. 0.36. mu.M, 22.80. + -. 0.36. mu.M and 46.39. + -. 0.36. mu.M (Jia, Y., Ma, Y.L., Cheng, G.G., Zhang, Y.Y., Cai, S.B.,2019. comprehensive study of secondary fluorine with secondary structure as. alpha. -glycosylation enzyme inhibitors and insulin sensors. J. Agr Food Chem 67, 10521. sup. 10533.) respectively.
At present, most researches on alpha-glucosidase inhibitors focus on a single compound, certain side effects and tolerance can be generated by continuous use, and the reports of synergistic effect among active molecules are few. The Chou-Talalay method is a widely accepted drug combination quantitative analysis method at present, and the addition, synergy and antagonism between drugs are expressed by a Combination Index (CI). The drug Dose Reduction Index (DRI) is the fold of dose reduction evaluated for drugs used in combination versus alone to achieve the same effect. CI <1 represents the synergy between the medicaments; CI-1 represents that the drugs have an additive effect; CI >1 represents antagonism between drugs.
Disclosure of Invention
Aiming at the problems of limited hypoglycemic effect and high dosage of a single natural active ingredient in the prior art, the invention aims to provide the hypoglycemic composition, and the effective ingredients of the composition are 3-O-methyl quercetin and naringenin; the composition has the synergistic effect of inhibiting the activity of alpha-glucosidase, and has wide application prospect in preparing medicines, health products or foods for treating diabetes.
In order to achieve the purpose, the invention adopts the following technical scheme:
a hypoglycemic composition comprises 3-O-methyl quercetin and naringenin according to a mass concentration ratio of 1: 25-6: 25.
On the basis of the scheme, the mass concentration ratio of the 3-O-methyl quercetin to the naringenin is 2: 25-4: 25.
The composition can be used for preparing medicines, health products or foods with blood sugar lowering effect.
On the basis of the scheme, the hypoglycemic effect is to achieve the purpose of controlling postprandial hyperglycemia by inhibiting the activity of alpha-glucosidase and blocking the digestion and absorption of carbohydrates.
A medicine with blood sugar lowering effect contains 3-O-methyl quercetin and naringenin as effective components; the mass concentration ratio of the 3-O-methyl quercetin to the naringenin is 2: 25-4: 25.
A health product with blood sugar lowering effect contains 3-O-methyl quercetin and naringenin as effective components; the mass concentration ratio of the 3-O-methyl quercetin to the naringenin is 2: 25-4: 25.
A food with blood sugar lowering effect contains 3-O-methyl quercetin and naringenin as effective components; the mass concentration ratio of the 3-O-methyl quercetin to the naringenin is 2: 25-4: 25.
Within the limited mass concentration ratio range, the 3-O-methyl quercetin and naringenin composition achieves the technical effect of synergy.
The medicine or health care product or food can be mixed with carriers, solvents, diluents, excipients and other media which are acceptable in pharmacy or food, and can be prepared into powder, granules, capsules, injections, oral liquid or tablets according to different requirements.
The technical scheme of the invention has the advantages
The composition of the 3-O-methyl quercetin and the naringenin has obvious synergistic effect of inhibiting alpha-glucosidase, has better effect than that of singly using the flavone compound, can reduce the dosage of the medicine and reduce the occurrence of drug resistance. Through an in vitro alpha-glucosidase inhibition test and by applying a Chou-Talalay method, the composition of the 3-O-methyl quercetin and the naringenin has obvious synergistic effect on the alpha-glucosidase and reaches 50 percent (GI)50)、75％(GI75) And 90% (GI)90) The CI values at the inhibition rates were all less than 0.8, and the intensity of synergy between drugs was generally higher at high inhibition rates than at low inhibition rates.
Drawings
FIG. 1 is a graph of the inhibition of alpha-glucosidase by a 3-O-methyl quercetin and naringenin (2: 25) composition;
FIG. 2 is a graph of the inhibition of alpha-glucosidase by the 3-O-methyl quercetin and naringenin (1: 25) composition;
FIG. 3 is a graph of the inhibition of alpha-glucosidase by the 3-O-methyl quercetin and naringenin (4: 25) composition;
FIG. 4 is a graph of the inhibition of alpha-glucosidase by the 3-O-methyl quercetin and naringenin (6: 25) composition;
FIG. 5 is a graph of the Fa-CI trend for the 3-O-methyl quercetin and naringenin (2: 25) composition to inhibit alpha-glucosidase;
FIG. 6 is a graph of the Fa-CI trend for the 3-O-methyl quercetin and naringenin (4: 25) composition to inhibit alpha-glucosidase.
Detailed Description
Terms used in the present invention have generally meanings as commonly understood by one of ordinary skill in the art, unless otherwise specified.
The present invention will be described in further detail with reference to the following data in conjunction with specific examples. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
3-O-Methyl Quercetin (3-O-Methyl Quercetin), molecular formula is C16H12O7(ii) a Molecular weight: 316.26, respectively; CAS accession number: 1486-70-0, structural formula:
naringenin (Naringin) with molecular formula C15H12O5(ii) a Molecular weight: 272.25, respectively; CAS accession number: 480-41-1, and the structural formula is as follows:
example 1
A composition with blood sugar lowering effect contains 3-O-methyl quercetin and naringenin as effective components; the mass concentration ratio of the 3-O-methyl quercetin to the naringenin in the composition is 2: 25.
Test for inhibiting activity of alpha-glucosidase in vitro when mass concentration ratio of 3-O-methyl quercetin to naringenin is 2: 25
1.1 materials & instruments: alpha-glucosidase (alpha-glucosidase, Sigma,10U/mg), 4-nitrobenzene-alpha-D-glucopyranoside (pNPG, TOKYO Chemica Industry Co., LTD), acarbose, corosolic acid (TOKYO Chemica Industry Co., LTD), 3-O-methyl quercetin, naringenin (Solebao, Beijing), disodium hydrogen phosphate, sodium dihydrogen phosphate (Tianjin Majo.), TECAN infinite M200 PRO enzyme-linked immunosorbent assay (Teacan Group Ltd., Swizerland).
1.2 Experimental procedures:
1.2.1 preparation of drug solution: preparing 3-O-methyl quercetin, naringenin, corosolic acid and acarbose into 10mg/mL mother liquor by using dimethyl sulfoxide (DMSO); ultrapure water, disodium hydrogen phosphate, and sodium dihydrogen phosphate were prepared in 67mmol/mL phosphate buffered saline PBS (pH 6.8); pNPG and alpha-glucosidase (0.25U/mL) were formulated with PBS.
1.2.2 operating method:
preparation of sample solutions of different concentration gradients: respectively carrying out gradient dilution on 3-O-methyl quercetin, naringenin, a composition with the mass concentration ratio of 2: 25, corosolic acid and acarbose by PBS, wherein:
the dilution concentration gradient of 3-O-methyl quercetin is 2 mug/mL, 1 mug/mL, 0.5 mug/mL, 0.25 mug/mL and 0.125 mug/mL;
the dilution concentration gradient of naringenin is 25 mug/mL, 12.5 mug/mL, 6.25 mug/mL, 3.125 mug/mL, 1.5625 mug/mL;
the dilution concentration gradient of the composition is 27. mu.g/mL, 13.5. mu.g/mL, 6.75. mu.g/mL, 3.375. mu.g/mL, 1.6875. mu.g/mL;
the dilution concentration gradient of the acarbose is 1000 mug/mL, 500 mug/mL, 250 mug/mL, 125 mug/mL and 62.5 mug/mL;
the dilution concentration gradient of corosolic acid was 50. mu.g/mL, 25. mu.g/mL, 12.5. mu.g/mL, 6.25. mu.g/mL, 3.125. mu.g/mL.
Detecting the gradient concentration solution of the 3-O-methyl quercetin, the naringenin and the composition with the mass concentration ratio of 2: 25 as a sample solution. The gradient concentration solution of corosolic acid and acarbose was used as a positive control group for detection. Adding 40 mu L of 0.25U/mL alpha-glucosidase, and reacting at 37 ℃ for 15 min; then 60. mu.L of 5mmol/mL substrate pNPG is added; after a reaction time of 15min at 37 ℃ it was determined at a wavelength of 405 nm.
The groups operate as follows:
sample group: 100 μ L of sample solution +40 μ L of enzyme +60 μ L of pNPG;
sample blank group: 100 μ L of sample solution +40 μ L LPBS +60 μ L pNPG;
positive control group: 100 μ L corosolic acid or acarbose +40 μ L enzyme +60 μ L npg;
negative control group: 2 μ L of LDMSO +98 μ L of PBS +40 μ L of enzyme +60 μ L of npg;
blank group: 2 μ L DMSO +98 μ LPBS +40 μ LPBS +60 μ LpNPG.
1.3 calculation formula: inhibition rate [1- (OD)Sample (I)–ODSample blank)/(ODNegative control-ODBlank space)]×100％
Where the half inhibitory concentration IC of the compound tested50The SPSS 20.0 statistic is adopted, and CI and DRI values are calculated according to software CompuSyn to evaluate the synergistic effect between the medicines.
1.4 Experimental results:
the inhibition curves of 3-O-methyl quercetin and naringenin and the composition with the mass concentration ratio of 2: 25 on alpha-glucosidase are shown in figure 1, and the Fa-CI trend of the 3-O-methyl quercetin and naringenin and the composition with the mass concentration ratio of 2: 25 on alpha-glucosidase is shown in figure 5.
TABLE 13 IC for alpha-glucosidase inhibitory activity of O-methyl quercetin, naringenin and compositions thereof50Value of
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
As is clear from the results in Table 1, IC against alpha-glucosidase when 3-O-methyl quercetin was used alone50Is 2.12 +/-0.11 mu g/mL, IC of naringenin5024.51 + -2.01 μ g/mL, positive control IC of acarbose and corosolic acid for alpha-glucosidase50324.85 + -8.56 and 12.6 + -0.12 μ g/mL, respectively, IC of the composition509.24 +/-0.32 mu g/mL; the results show that the combination greatly reduces the dosage of the single medicine and improves the inhibitory activity.
TABLE 23 Combined dosing Coefficient (CI) for combination of O-methyl Quercetin and naringenin
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
As is clear from the results in Table 2, the combined administration coefficients CI of 3-O-methyl quercetin and naringenin (2: 25) were all less than 0.7, showing a synergistic effect, wherein in GI75And GI90Are all less than 0.4, show strong synergistic effect, and have combined medication index mean value (CI)avg) Is 0.43.
TABLE 33 dosage reduction factor (DRI) for the combination of O-methyl Quercetin and naringenin
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
As is clear from the results in Table 3, 3-O-methyl quercetin was found in GI90The DRI value of (1) is 3.06 + -0.05, while naringenin is in GI90When, the DRI value of naringenin was 6.37 ± 0.03, this means: when the inhibition rate of the alpha-glucosidase is 90%, the dosages of the combined drug group of the 3-O-methyl quercetin and the naringenin are about 1/3 and 1/6 of the dosages of the single drug groups respectively, the combined drug group greatly reduces the dosage and shows a synergistic effect.
Example 2
A composition with blood sugar lowering effect contains 3-O-methyl quercetin and naringenin as effective components; the mass concentration ratio of the 3-O-methyl quercetin to the naringenin in the composition is 1: 25.
Test for inhibiting activity of alpha-glucosidase in vitro when mass concentration ratio of 3-O-methyl quercetin to naringenin is 1: 25
2.1 materials & instruments: alpha-glucosidase (alpha-glucosidase, Sigma,10U/mg), 4-nitrobenzene-alpha-D-glucopyranoside (pNPG, TOKYO Chemica Industry Co., LTD), acarbose, corosolic acid (TOKYO Chemica Industry Co., LTD), 3-O-methyl quercetin, naringenin (Solebao, Beijing), disodium hydrogen phosphate, sodium dihydrogen phosphate (Tianjin Majo.), TECAN infinite M200 PRO enzyme-linked immunosorbent assay (Teacan Group Ltd., Swizerland).
2.2 Experimental procedures:
2.2.1 preparation of drug solution: preparing 3-O-methyl quercetin, naringenin, corosolic acid and acarbose into 10mg/mL mother liquor by using dimethyl sulfoxide (DMSO); ultrapure water, disodium hydrogen phosphate, and sodium dihydrogen phosphate were prepared in 67mmol/mL phosphate buffered saline PBS (pH 6.8); pNPG and alpha-glucosidase (0.25U/mL) were formulated with PBS.
2.2.2 operating method:
preparation of sample solutions of different concentration gradients: respectively carrying out gradient dilution on 3-O-methyl quercetin, naringenin, a composition with the mass concentration ratio of 1: 25, corosolic acid and acarbose by PBS, wherein:
the dilution concentration gradient of 3-O-methyl quercetin is 1 mug/mL, 0.5 mug/mL, 0.25 mug/mL, 0.125 mug/mL, 0.0625 mug/mL;
the dilution concentration gradient of naringenin is 25 mug/mL, 12.5 mug/mL, 6.25 mug/mL, 3.125 mug/mL, 1.5625 mug/mL;
the dilution concentration gradient of the composition is 26. mu.g/mL, 13. mu.g/mL, 6.5. mu.g/mL, 3.25. mu.g/mL, 1.625. mu.g/mL;
the dilution concentration gradient of the acarbose is 1000 mug/mL, 500 mug/mL, 250 mug/mL, 125 mug/mL and 62.5 mug/mL;
the dilution concentration gradient of corosolic acid was 50. mu.g/mL, 25. mu.g/mL, 12.5. mu.g/mL, 6.25. mu.g/mL, 3.125. mu.g/mL.
Detecting the gradient concentration solution of the 3-O-methyl quercetin, the naringenin and the composition with the mass concentration ratio of 1: 25 as a sample solution. The gradient concentration solution of corosolic acid and acarbose was used as a positive control group for detection. Adding 40 mu L of 0.25U/mL alpha-glucosidase, and reacting at 37 ℃ for 15 min; then 60. mu.L of 5mmol/mL substrate pNPG is added; after a reaction time of 15min at 37 ℃ it was determined at a wavelength of 405 nm.
The groups operate as follows:
sample group: 100 μ L of sample solution +40 μ L of enzyme +60 μ L of pNPG;
sample blank group: 100 μ L of sample solution +40 μ L LPBS +60 μ L pNPG;
positive control group: 100 μ L corosolic acid or acarbose +40 μ L enzyme +60 μ L npg;
negative control group: 2 μ L of LDMSO +98 μ L of PBS +40 μ L of enzyme +60 μ L of npg;
blank group: 2 μ L DMSO +98 μ LPBS +40 μ LPBS +60 μ LpNPG.
2.3 calculation formula: inhibition rate [1- (OD)Sample (I)–ODSample blank)/(ODNegative control-ODBlank space)]×100％
Where the half inhibitory concentration IC of the compound tested50The SPSS 20.0 statistic is adopted, and CI and DRI values are calculated according to software CompuSyn to evaluate the synergistic effect between the medicines.
2.4 Experimental results:
the inhibition curves of 3-O-methyl quercetin and naringenin and the composition with the mass concentration ratio of 1: 25 on alpha-glucosidase are shown in figure 2.
TABLE 43 IC of alpha-glucosidase inhibitory activity of O-methyl quercetin and naringenin and compositions thereof50Value of
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
From the results in Table 4, it is clear that IC for α -glucosidase is observed when 3-O-methyl quercetin is used alone50Is 2.12 +/-0.11 mu g/mL, IC of naringenin5024.51 + -2.01 μ g/mL, positive control IC of acarbose and corosolic acid for alpha-glucosidase50324.85 + -8.56 and 12.6 + -0.12 μ g/mL, respectively, IC of the composition5019.88. + -. 1.22. mu.g/mL.
TABLE 53 Combined dosing Coefficient (CI) for combination of O-methyl Quercetin and naringenin
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
As is clear from the results in Table 5, the combination of 3-O-methyl quercetin and naringenin (1: 25) exhibited antagonistic action with a combination coefficient CI of greater than 1.
Example 3
A composition with blood sugar lowering effect contains 3-O-methyl quercetin and naringenin as effective components; the mass concentration ratio of the 3-O-methyl quercetin to the naringenin in the composition is 4: 25.
Test for inhibiting activity of alpha-glucosidase in vitro when mass concentration ratio of 3-O-methyl quercetin to naringenin is 4: 25
3.1 materials & instruments: alpha-glucosidase (alpha-glucosidase, Sigma,10U/mg), 4-nitrobenzene-alpha-D-glucopyranoside (pNPG, TOKYO Chemica Industry Co., LTD), acarbose, corosolic acid (TOKYO Chemica Industry Co., LTD), 3-O-methyl quercetin, naringenin (Solebao, Beijing), disodium hydrogen phosphate, sodium dihydrogen phosphate (Tianjin Majo.), TECAN infinite M200 PRO enzyme-linked immunosorbent assay (Teacan Group Ltd., Swizerland).
3.2 Experimental procedures:
3.2.1 preparation of drug solution: preparing 3-O-methyl quercetin, naringenin, corosolic acid and acarbose into 10mg/mL mother liquor by using dimethyl sulfoxide (DMSO); ultrapure water, disodium hydrogen phosphate, and sodium dihydrogen phosphate were prepared in 67mmol/mL phosphate buffered saline PBS (pH 6.8); pNPG and alpha-glucosidase (0.25U/mL) were formulated with PBS.
3.2.2 operating method:
preparation of sample solutions of different concentration gradients: respectively carrying out gradient dilution on 3-O-methyl quercetin, naringenin, a composition with the mass concentration ratio of the two being 4: 25, corosolic acid and acarbose by PBS, wherein:
the dilution concentration gradient of 3-O-methyl quercetin is 4 mug/mL, 2 mug/mL, 1 mug/mL, 0.5 mug/mL, 0.25 mug/mL;
the dilution concentration gradient of naringenin is 25 mug/mL, 12.5 mug/mL, 6.25 mug/mL, 3.125 mug/mL, 1.5625 mug/mL;
the dilution concentration gradient of the composition is 29. mu.g/mL, 14.5. mu.g/mL, 7.25. mu.g/mL, 3.625. mu.g/mL, 1.8125. mu.g/mL;
the dilution concentration gradient of the acarbose is 1000 mug/mL, 500 mug/mL, 250 mug/mL, 125 mug/mL and 62.5 mug/mL;
the dilution concentration gradient of corosolic acid was 50. mu.g/mL, 25. mu.g/mL, 12.5. mu.g/mL, 6.25. mu.g/mL, 3.125. mu.g/mL.
Detecting the gradient concentration solution of the 3-O-methyl quercetin, the naringenin and the composition with the mass concentration ratio of 4: 25 as a sample solution. The gradient concentration solution of corosolic acid and acarbose was used as a positive control group for detection. Adding 40 mu L of 0.25U/mL alpha-glucosidase, and reacting at 37 ℃ for 15 min; then 60. mu.L of 5mmol/mL substrate pNPG is added; after a reaction time of 15min at 37 ℃ it was determined at a wavelength of 405 nm.
The groups operate as follows:
sample group: 100 μ L of sample solution +40 μ L of enzyme +60 μ L of pNPG;
sample blank group: 100 μ L of sample solution +40 μ L LPBS +60 μ L pNPG;
positive control group: 100 μ L corosolic acid or acarbose +40 μ L enzyme +60 μ L npg;
negative control group: 2 μ L of LDMSO +98 μ L of PBS +40 μ L of enzyme +60 μ L of npg;
blank group: 2 μ L DMSO +98 μ LPBS +40 μ LPBS +60 μ LpNPG.
3.3 calculation formula: inhibition rate [1- (OD)Sample (I)–ODSample blank)/(ODNegative control-ODBlank space)]×100％
Where the half inhibitory concentration IC of the compound tested50The SPSS 20.0 statistic is adopted, and CI and DRI values are calculated according to software CompuSyn to evaluate the synergistic effect between the medicines.
3.4 Experimental results:
the inhibition curves of 3-O-methyl quercetin and naringenin and the composition with the mass concentration ratio of 4: 25 on alpha-glucosidase are shown in figure 3, and the Fa-CI trend of the 3-O-methyl quercetin and naringenin and the composition with the mass concentration ratio of 4: 25 on alpha-glucosidase is shown in figure 6.
TABLE 63 IC for alpha-glucosidase inhibitory activity of O-methyl quercetin, naringenin and compositions thereof50Value of
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
From the results in Table 6, it is clear that IC for α -glucosidase when 3-O-methyl quercetin is used alone50Is 2.12 +/-0.11 mu g/mL, IC of naringenin5024.51 + -2.01 μ g/mL, positive control IC of acarbose and corosolic acid for alpha-glucosidase50324.85 + -8.56 and 12.6 + -0.12 μ g/mL, respectively, IC of the composition509.12 +/-0.31 mu g/mL; the results show that the combination greatly reduces the dosage of the single medicine and improves the inhibitory activity.
TABLE 73-O-Combined dosing Coefficient (CI) for combined use of methyl Quercetin and naringenin
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
From the results in Table 7, it is found that the combined administration coefficients CI of 3-O-methyl quercetin and naringenin (4: 25) are all less than 1.0, and that the synergistic effect is shown, and the mean value of the combined administration indexes (CI)avg) Is 0.79.
TABLE 83 dosage reduction coefficient (DRI) for the combination of O-methyl Quercetin and naringenin
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
From the results in Table 8, it is found that 3-O-methyl quercetin is present in GI90The DRI value of (1.60. + -. 0.02) and naringenin in GI90At this time, the DRI value of naringenin was 7.66 ± 0.03, which means that: when the inhibition rate of the alpha-glucosidase is 90 percent, the dosages of the combined drug group of the 3-O-methyl quercetin and the naringenin are respectively about 1/1.6 and 1/7 of the dosages of the single drug groups, the combined drug group greatly reduces the dosage, and shows the synergistic effect
Example 4
A composition with blood sugar lowering effect contains 3-O-methyl quercetin and naringenin as effective components; the mass concentration ratio of the 3-O-methyl quercetin to the naringenin in the composition is 6: 25.
Test for inhibiting activity of alpha-glucosidase in vitro when mass concentration ratio of 3-O-methyl quercetin to naringenin is 6: 25
4.1 materials & instruments: alpha-glucosidase (alpha-glucosidase, Sigma,10U/mg), 4-nitrobenzene-alpha-D-glucopyranoside (pNPG, TOKYO Chemica Industry Co., LTD), acarbose, corosolic acid (TOKYO Chemica Industry Co., LTD), 3-O-methyl quercetin, naringenin (Solebao, Beijing), disodium hydrogen phosphate, sodium dihydrogen phosphate (Tianjin Majo.), TECAN infinite M200 PRO enzyme-linked immunosorbent assay (Teacan Group Ltd., Swizerland).
4.2 Experimental procedures:
4.2.1 preparation of drug solution: preparing 3-O-methyl quercetin, naringenin, corosolic acid and acarbose into 10mg/mL mother liquor by using dimethyl sulfoxide (DMSO); ultrapure water, disodium hydrogen phosphate, and sodium dihydrogen phosphate were prepared in 67mmol/mL phosphate buffered saline PBS (pH 6.8); pNPG and alpha-glucosidase (0.25U/mL) were formulated with PBS.
4.2.2 operating method:
preparation of sample solutions of different concentration gradients: respectively carrying out gradient dilution on 3-O-methyl quercetin, naringenin, a composition with the mass concentration ratio of the two being 6: 25, corosolic acid and acarbose by PBS, wherein:
the dilution concentration gradient of 3-O-methyl quercetin is 6 mug/mL, 3 mug/mL, 1.5 mug/mL, 0.75 mug/mL, 0.375 mug/mL;
the dilution concentration gradient of naringenin is 25 mug/mL, 12.5 mug/mL, 6.25 mug/mL, 3.125 mug/mL, 1.5625 mug/mL;
the dilution concentration gradient of the composition is 31. mu.g/mL, 15.5. mu.g/mL, 7.75. mu.g/mL, 3.875. mu.g/mL, 1.9375. mu.g/mL;
the dilution concentration gradient of the acarbose is 1000 mug/mL, 500 mug/mL, 250 mug/mL, 125 mug/mL and 62.5 mug/mL;
the dilution concentration gradient of corosolic acid was 50. mu.g/mL, 25. mu.g/mL, 12.5. mu.g/mL, 6.25. mu.g/mL, 3.125. mu.g/mL.
Detecting the gradient concentration solution of the 3-O-methyl quercetin, the naringenin and the composition with the mass concentration ratio of 6: 25 as a sample solution. The gradient concentration solution of corosolic acid and acarbose was used as a positive control group for detection. Adding 40 mu L of 0.25U/mL alpha-glucosidase, and reacting at 37 ℃ for 15 min; then 60. mu.L of 5mmol/mL substrate pNPG is added; after a reaction time of 15min at 37 ℃ it was determined at a wavelength of 405 nm.
The groups operate as follows:
sample group: 100 μ L of sample solution +40 μ L of enzyme +60 μ L of pNPG;
sample blank group: 100 μ L of sample solution +40 μ L LPBS +60 μ L pNPG;
positive control group: 100 μ L corosolic acid or acarbose +40 μ L enzyme +60 μ L npg;
negative control group: 2 μ L of LDMSO +98 μ L of PBS +40 μ L of enzyme +60 μ L of npg;
blank group: 2 μ L DMSO +98 μ LPBS +40 μ LPBS +60 μ LpNPG.
4.3 calculation formula: inhibition rate [1- (OD)Sample (I)–ODSample blank)/(ODNegative control-ODBlank space)]×100％
Where the half inhibitory concentration IC of the compound tested50The SPSS 20.0 statistic is adopted, and CI and DRI values are calculated according to software CompuSyn to evaluate the synergistic effect between the medicines.
4.4 results of the experiment:
the inhibition curves of 3-O-methyl quercetin and naringenin and the composition with the mass concentration ratio of 6: 25 on alpha-glucosidase are shown in figure 4.
TABLE 93 IC for alpha-glucosidase inhibitory activity of O-methyl quercetin, naringenin and compositions thereof50Value of
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
From the results in Table 9, it is clear that IC for α -glucosidase when 3-O-methyl quercetin is used alone50Is 2.12 +/-0.11 mu g/mL, IC of naringenin5024.51 + -2.01 μ g/mL, positive control IC of acarbose and corosolic acid for alpha-glucosidase50324.85 + -8.56 and 12.6 + -0.12 μ g/mL, respectively, IC of the composition50Is 2.07 + -0.31 μ g/mL, and has IC with 3-O-methyl quercetin50There was no significant difference in the values, indicating that naringenin in the composition may have no relevant effect.
TABLE 103 Combined dosing Coefficient (CI) for combination of O-methyl Quercetin and naringenin
Note: data are derived from the results of three independent experiments, expressed as mean ± standard deviation
From the results in Table 10, it is found that GI was observed when 3-O-methyl quercetin and naringenin (6: 25) were used in combination50And GI75Are all less than 1.0, and the mean value of combined medication index (CI)avg) Is 1.06>1, no synergistic effect, 3-O-methyl quercetin plays a main role in the composition, and naringenin is added when the concentration is too high, so that no synergistic effect exists.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (4)
1. A hypoglycemic composition is characterized by comprising 3-O-methyl quercetin and naringenin according to the mass concentration ratio of 2: 25-4: 25.
2. Use of a composition according to claim 1 for the preparation of a medicament having a hypoglycemic effect.
3. The use according to claim 2, wherein the hypoglycemic effect is to control postprandial hyperglycemia by inhibiting the activity of alpha-glucosidase and blocking the digestion and absorption of carbohydrates.
4. A medicine with blood sugar lowering effect is characterized in that the effective components comprise 3-O-methyl quercetin and naringenin; the mass concentration ratio of the 3-O-methyl quercetin to the naringenin is 2: 25-4: 25.
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| Beneficial Effects of Poplar Buds on Hyperglycemia, Dyslipidemia, Oxidative Stress, and Inflammation in Streptozotocin-Induced Type-2 Diabetes;Peng SQ等;《Journal of Immunology Research》;20180918;第2018卷;第1-10页 * |
| Caffeic acid, naringenin and quercetin enhance glucose-stimulated insulin secretion and glucose sensitivity in INS-1E cells;S Bhattacharya等;《Diabetes, Obesity and Metabolism》;20140731;第16卷(第7期);第602–612页 * |
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