CN102293762B - Application of curcumin derivative in preparation of medicines for resisting diabetes and complication thereof - Google Patents
Application of curcumin derivative in preparation of medicines for resisting diabetes and complication thereof Download PDFInfo
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Abstract
The invention discloses application of a curcumin derivative to preparation of medicines for resisting diabetes and complication thereof and in particular relates to application of (1E,6E)-1,7-di(3,5-ditertbutyl-4-hydroxyl phenyl)heptyl-1,6-diene-3,5-diketone to preparation of medicines, health-care products and food for preventing and treating diabetes and complication thereof. The (1E,6E)-1,7-di(3,5-ditertbutyl-4-hydroxyl phenyl)heptyl-1,6-diene-3,5-diketone can obviously reduce serum, liver triglyceride, total cholesterol and low-density lipoprotein of high fat feed and streptozotocin induced diabetes model mice, can reduce fasting blood glucose and glycated hemoglobin of the model mice, can improve glucose tolerance of the model mice, can obviously improve glycometabolism and lipid metabolism of the diabetes model mice, and can obviously reduce fatty degeneration of liver and aortic arch and lesion of atherosclerosis.
Description
Technical field
The present invention relates to a kind of curcumin derivate (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the 5-diketone is preparing prevention and treatment diabetes and the medicine of complication thereof, the application in the health product.
Background technology
Diabetes are to cause human dead the third-largest disease, and present global patient surpasses 200,000,000 people, and China patient nearly 2,000 ten thousand.In recent years, the sickness rate cumulative year after year of diabetes has a strong impact on people's life even threat to life, has brought heavy financial burden for society and individual, has become a more and more serious public health problem of countries in the world.
Diabetes cause time consuming hyperglycemia, cause sugar, fat, protein and insecondary vitamin, water, metabolic disturbance of electrolyte, Chang Bingfa atherosclerosis, microangiopathies, nervous system lesion etc., thus the infringement of a plurality of systems, a plurality of internal organs caused.Diabetes are in carcinogenesis of human, and the chronic complicating diseases sickness rate is up to 96.5%, and performance is complicated, is the main cause that causes diabetics to be disabled.Diabetic vascular complications comprises microvascular complication (diabetic nephropathy, Diabetic retinopathy) and macrovascular complications (atherosclerotic cardiovascular disease, coronary artery disease, cerebrovascular disease, peripheral blood vessel), wherein cardiovascular complication is the primary cause of the death of diabetics.As seen the metabolism disorder of diabetes with secondary, especially disorders of lipid metabolism, and vascular lesion is the main cause of diabetic complication, therefore effectively control blood glucose, improve lipid metabolism, suppress the generation that the generation of vascular lesion just might have the diabetes of preventing and treating and complication thereof.Studies have shown that in a large number high sugared state induces the free radical of generation to cause and unbalance between body oxidative stress and the anti-oxidative defense cause making progress of diabetes and related complication; Also exist between oxidative stress and the type ii diabetes insulin resistant to contact, hyperinsulinism also increases ROS, further causes insulin function impaired.Therefore use antioxidant to improve oxidative stress and may become the available strategy that reduces diabetic complication.
The synthetic antidiabetic drug untoward reaction of having gone on the market at present is serious, and price is more expensive.Acting on the chemicals that chronic complicating diseases of diabetes may target spot only has several (such as protein glycosylation inhibitor aminoguanidine, aldose reductase inhibitor fidarestats etc.), still is in during each clinical trial phase carries out, and also can not meet clinical needs far away.Motherland's medical science is having long history and significant curative effect aspect treatment diabetes and the complication thereof, seek effective ingredient or carry out on this basis structure of modification to obtain better medicine from Chinese herbal medicine, and DEVELOPMENT PROSPECT is very wide.
Curcumin is one of a few antioxidant that has simultaneously in a molecule phenolic hydroxyl group and two kinds of antioxidant groups of beta-diketon, and unique conjugated system of the enol-type structure of two phenolic hydroxyl groups and a beta-diketon makes its ability with significant Trapped free radical and ends the antioxidant activity of chain reaction.Studies have shown that in the external body that curcumin can remove ultra-oxygen anion free radical and hydroxyl radical free radical, suppress lipid peroxidation, increase the activity of polyphenoils such as SOD, GSH, GST, GPx etc.
(1E, 6E)-1,7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3,5-diketone (L3) is the derivant of curcumin, VENKATESAN etc. (J.Pharm.Pharmacol., 2000,52:1123-1128.) synthesized (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the 5-diketone, and find that this chemical compound has the activity that suppresses lipid peroxidation and remove free radical.Majeed etc. disclose the patent (U.S.Patent that this chemical compound is used for the treatment of cystic fibrosis, US 7,521,580), (1E still, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, whether the 5-diketone has the effect of the diabetes of preventing and treating and complication thereof, so far there are no bibliographical information.
Summary of the invention
The object of the present invention is to provide with curcumin derivate (1E, 6E)-1,7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the 5-diketone is raw material, for the preparation of alleviate, improve, prevent and treat type i diabetes, type ii diabetes or because of diabetes cause comprise hyperglycemia, impaired glucose tolerance, lipid metabolism is unusual and the medicine of the complication that above-mentioned illness causes.Described medicine comprises (1E, 6E)-1 of dose therapeutically effective, 7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3,5-diketone, and pharmaceutically acceptable carrier.
Another goal of the invention of the present invention is to provide a kind of (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the application of 5-diketone in preparation prevention and treatment diabetes and complication medicine thereof; With (1E, 6E)-1,7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the 5-diketone is raw material, prepares to can be used for preventing or improve hyperglycemia, abnormal carbohydrate metabolism, diabetes or the purposes of health product, food or the food additive of the various clinical complications that cause because of diabetes.
Curcumin derivate of the present invention (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the structural formula of 5-diketone is as follows, hereinafter to be referred as L3.
The invention provides a kind of curcumin derivate (1E, 6E)-1 that contains dose therapeutically effective, 7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the medicine of the prevention of 5-diketone or treatment diabetes and complication thereof.
The invention provides a kind of curcumin derivate (1E, 6E)-1 that contains effective dose, 7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, health product or the food additive of the prevention of 5-diketone or treatment diabetes and complication thereof.
The invention provides a kind of curcumin derivate (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the application of 5-diketone in preparation prevention or treatment diabetes and complication medicine thereof.
The invention provides a kind of curcumin derivate (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the application of 5-diketone in health product, food or the food additive of preparation prevention or treatment diabetes and complication thereof.
Described curcumin derivate (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the application of 5-diketone in the medicine of preparation prevention or treatment diabetes and complication thereof is characterized in that: it is 1% to 100% (1E, 6E)-1 that described pharmaceutical pack contains mass percentage content, 7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the medicine of 5-diketone.Certainly contain mass percentage content and be 1% to 100% (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-I, 6-diene-3, the medicine of 5-diketone are the effective doses for the treatment of.
Described (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the application of 5-diketone in health product, food or the food additive of preparation prevention or treatment diabetes and complication thereof is characterized in that: it is 1% to 99% (1E, 6E)-1 that described pharmaceutical pack contains mass percentage content, 7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the health product of 5-diketone or food or food additive.
Described medicine comprises pharmaceutically acceptable any dosage form that comprises in tablet, pill, capsule, granule, oral liquid, the injection that is selected from.
Described pharmaceutical pack contains pharmaceutically acceptable following any carrier or adjuvant, and described carrier or adjuvant comprise the various natural or synthetic pharmaceutical polymerses such as polyvinylpyrrolidone PVP, PLURONICS F87 (pluronic F68) and carbamide, organic acid, saccharide, alcohols, starch based and derivant thereof, cellulose family and derivant thereof, acrylic compounds, vinyl-based, ethylene oxide.
The medicine that described pharmaceutical dosage form can adopt the preparation method pharmaceutically of one of the following to make, described preparation method pharmaceutically comprises fusion method, solvent method, solvent-fusion method, polishing, spray drying method, hypobaric drying method, freeze-drying etc.
Principle of the present invention is based on (1E, 6E)-1,7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3,5-diketone (be called for short L3) can significantly reduce for a long time to feed with high lipid food and adds streptozotocin and induce the plasma triglyceride of diabetic mice, T-CHOL and low density lipoprotein, LDL, reduce fasting glucose and the glycolated hemoglobin of model mice, improve glucose tolerance in mice, obviously improve sugar, the lipid metabolism of diabetic mice, the steatosis of liver and aortic arch and atherosclerosis degeneration are obviously alleviated.
Beneficial effect of the present invention: the present invention has proved curcumin derivate (1E by zoopery, 6E)-1,7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the 5-diketone can alleviate, improve prevention and treatment type i diabetes, type ii diabetes or comprise hyperglycemia because of what diabetes caused, impaired glucose tolerance, the complication that the unusual and above-mentioned illness of lipid metabolism causes can be used for preparation prevention or improvement or treatment hyperglycemia, abnormal carbohydrate metabolism, the medicine of diabetes or the various clinical complications that cause because of diabetes, health product, food or food additive; Can significantly reduce blood plasma and liver tg, T-CHOL and low density lipoprotein, LDL that high lipid food adds the diabetic mice that streptozotocin induces, reduce model mice fasting glucose and glycolated hemoglobin, raising carbohydrate tolerance, obviously improve sugar, the lipid metabolism of diabetic mice, the steatosis of liver and aortic arch and Atherosclerosis pathological changes are obviously alleviated.And has preferably Expected Results.
Description of drawings
Fig. 1 is Normal group mouse liver pathology sheet figure of the present invention.
Fig. 2 is model group mouse liver pathology sheet figure of the present invention.
Fig. 3 is the 266mg/kg group mouse liver HE dyeing pathology sheet figure of L3 of the present invention.
Fig. 4 is the 532mg/kg group mouse liver HE dyeing pathology sheet figure of L3 of the present invention.
Fig. 5 is the 1064mg/kg group mouse liver HE dyeing pathology sheet figure of L3 of the present invention.
Fig. 6 is Normal group mouse aorta HE dyeing pathology sheet figure of the present invention.
Fig. 7 is model group mouse aorta HE dyeing pathology sheet figure of the present invention.
Fig. 8 is the 266mg/kg group mouse aorta HE dyeing pathology sheet figure of L3 of the present invention.
Fig. 9 is the 532mg/kg group mouse aorta HE dyeing pathology sheet figure of L3 of the present invention.
Figure 10 is the 1064mg/kg group mouse aorta HE dyeing pathology sheet figure of L3 of the present invention.
The specific embodiment
The present invention can further understand the present invention by specific embodiment given below and described accompanying drawing, but following embodiment is not limitation of the present invention.
Embodiment one:
Curcumin derivate (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3,5-diketone (hereinafter to be referred as L3) is on the impact of hyperlipemia diabetic mice glycolipid metabolism
1.1 the foundation of hyperlipemia diabetic mice model
After all mice adaptabilities fed for 1 week, reserve at random 18 as Normal group, all the other modelings.Modeling all mice overnight fastings the previous day, streptozotocin is dissolved in to be made into weight percent concentration in the 0.1mol/L citric acid-sodium citrate buffer (pH 4.2) be 0.5% solution, model group and each treatment group are with 50mg/kg body weight lumbar injection, once totally 5 times every other day, the Normal group mouse peritoneal is injected isopyknic citric acid-sodium citrate buffer.In one week of interval after injecting 5 times, overnight fasting is cut tail blood sampling, and the rapid blood sugar instrument is surveyed fasting glucose, and with the dosage gavage glucose solution of 2g/kg body weight, cuts the tail blood sampling in 30,60,120 minutes after the gavage to survey carbohydrate tolerance, calculates area under the glucose tolerance curve.
1.2 the detection of pharmaceutical intervention and index
Carry out the stratified random grouping by area under the glucose tolerance curve, be divided into is 16 groups: Normal group (control, reserve), diabetic model group (model), L3 adopt respectively each 2 groups of 0.5mmol/kg (266mg/kg) dosage groups, 1mmol/kg (532mg/kg) dosage group, 2mmol/kg (1064mg/kg) dosage group, 9 every group of normal group, all the other every group 12.Begin gastric infusion after the grouping, once a day.Normal group and model group are given the excipient aqueous solution of equivalent every day.Normal group is raised with normal feedstuff, and all the other are respectively organized in grouping and begin to raise after the administration take high lipid food (by weight percentage prescription as: 10% Adeps Sus domestica, 2% cholesterol, 0.5% sodium cholate, 10% milk powder, 7.5% sucrose and 70% normal feedstuff powder).The experimental session animal freely drinks water, and quantitatively raises food by body weight.Monitoring body weight next day of mice.After 4 weeks of administration, put to death wherein 8 groups.After 16 weeks of administration, put to death all the other 8 groups.Survey blood glucose with glucose oxidase method, enzymic colorimetric is surveyed serum total cholesterol and serum triglycerides, use iodine [
125I] insulin radioimmunoassay, RIA medicine box plasma insulin level.
1.3 experimental result
1.3.1 on the glycometabolic impact of diabetic mice
As seen, after 4 weeks of L3 administration, area and glycolated hemoglobin all are significantly higher than Normal group under model group mice fasting glucose, the glucose tolerance curve from table 1, table 2, show that carbohydrate tolerance descends; Compare with model group, each dosage group mice fasting glucose of L3 all descends to some extent, and wherein high dose group significantly reduces; Administration group mice glycolated hemoglobin descends to some extent, and wherein middle dosage group and high dose group mice glycolated hemoglobin significantly reduce than model group; Compare with model group, administration group glucose tolerance in mice area under curve descends to some extent.16 weeks of L3 administration are similar to the situation in 4 weeks for the treatment of, and the fasting glucose of each dosage group of L3 and glycolated hemoglobin all obviously descend than model group, and plasma insulin level is also than the remarkable decline of model group.
Table 1L3 treated for 4 weeks to the impact of diabetic mice fasting glucose, carbohydrate tolerance and glycolated hemoglobin
*: P＜0.05vs Normal group; *: P＜0.01vs Normal group; #:P＜0.05vs model group; ##:P＜0.01vs model group, lower same.
Table 2L3 treated for 16 weeks to the impact of diabetic mice fasting glucose, glycolated hemoglobin and plasma insulin level
1.3.2 on the lipometabolic impact of diabetic mice
As seen from Table 3, administration 4 all model group mice plasma triglyceride (TG), T-CHOL (TC) and low density lipoprotein, LDL (LDL-C), high density lipoprotein (HDL-C) all are significantly higher than Normal group; Each administration group mice plasma TG all has remarkable reduction than model group; Dosage group and high dose group mice plasma TC all have remarkable reduction than model group among the L3; Dosage group and high dose group mice plasma LDL-C significantly reduce than model group among the L3.Each administration group HDL-C changes not obvious.After L3 treated for 16 weeks as seen from Table 4, the decline of each dosage group plasma TG of L3, TC, LDL-C was more obvious.
Table 3L3 treated for 4 weeks to the impact of diabetic mice blood fat
Table 4L3 treated for 16 weeks to the impact of diabetic mice blood fat
As seen, after 4 weeks of administration, 16 weeks, model group mouse liver TG, TC and LDL-C all are significantly higher than Normal group from table 5; Each administration group mouse liver TG all has remarkable reduction than model group; Dosage group and high dose group mouse liver TC all have remarkable reduction than model group among the L3; Dosage group and high dose group mouse liver LDL-C significantly reduce than model group among the L3.After L3 treated for 16 weeks as seen from Table 6, the decline of TG, TC, LDL-C was more obvious in each dosage group liver homogenate of L3.
Table 5L3 treated for 4 weeks to the impact of diabetic mice liver fat
Table 6L3 treated for 16 weeks to the impact of diabetic mice liver fat
Embodiment two
Curcumin derivate (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3,5-diketone (L3) is on the impact of hyperlipemia diabetic mice vitals complication
2.1 the foundation of hyperlipemia diabetic mice model
With 1.1 methods.
2.2 the detection of pharmaceutical intervention and index
Animal grouping and administration together 1.1 methods.4 weeks of administration, 16 weeks are put to death respectively mice, separating mouse pancreas, liver, bilateral renal, heart and thoracic aorta, ventral aorta, and the cold saline rinsing, filter paper blots, and liver, two kidney are weighed, respectively the calculating body weight index.Thoracic aorta, ventral aorta are fixed take weight percent concentration as 4% paraformaldehyde solution, and liver and kidney weight percent concentration are that 10% neutral formalin solution is fixed.Liver, aorta are with paraffin embedding, section, and conventional H E dyes.
2.3 experimental result
2.3.1 the impact on Mouse Weight and liver/renal index
As seen from Table 4, after 4 weeks of administration, the Normal group weight of mice, the model group Mouse Weight significantly is lower than Normal group.Model group mice compared with normal matched group liver index significantly increases, and renal index is without significant change.Each administration group Mouse Weight, liver index and renal index than model group without significant change.
After treating for 4 weeks, table 7L3 respectively organizes Mouse Weight and liver/renal index
2.3.2 pathology of livers is observed
Perusal Normal group mouse liver profile is normal, kermesinus, and tunicle is smooth.The model group liver volume obviously increases, and peplos is nervous, and the edge is blunt thick, and the quality deliquescing has greasy feeling, and mattness is faint yellow.Each administration group liver outward appearance is between Normal group and model group.
Observed result is shown in Figure of description 1-5 under the light microscopic, Normal group murine liver tissue structural integrity, clear, and the lobules of liver structure is normal, and sinus hepaticus is high-visible, liver rope marshalling.The hepatocyte normal in size, karyon is placed in the middle, the abnormal changes such as fat-free degeneration (Figure of description 1).Model group lobules of liver boundary is unclear, the hepatic cords arrangement disorder, and most of sinus hepaticus disappears, and the hepatocyte volume obviously increases, even swelling is rounded, and cytoplasm contains a large amount of fat vacuoles not of uniform size, and karyon is pushed to periphery, exactly likes adipose cell.Endochylema is loose, is hydropic degeneration, and inflammatory cell infiltration (Figure of description 2) is arranged.
Hepatic cell fattydegeneration is respectively organized in administration all in various degree improve (Figure of description 3,4,5), and dose dependent is arranged, and drips minimizing the most obviously (Figure of description 5) with L3 high dose group fat.
2.3.3 changing, observes aorta pathology
The result is shown in Figure of description 6-10, and the aorta of Normal group mice comprises inner membrance, middle film and adventitia.Theca interna is thin, visible endotheliocyte and nucleus, and the endotheliocyte marshalling, inner membrance is smooth; Middle rete has plurality of resilient membranes, therebetween visible smooth muscle cell; Adventitia forms (Figure of description 6) by connective tissue.The apparition of model group aortic arch disease, the ductus arteriosus wall became uneven, inner membrance obviously thickens, and intimal surface is rough, endotheliocyte disappearance or discontinuous, SES broadening, it is common that fat stricture of vagina fat pinta becomes; The obvious irregular thickening of middle film, smooth muscle fiber significantly disorderly (Figure of description 7).Each administration group pathological change makes moderate progress (Figure of description 8,9,10), visible inner membrance limitation protuberance, and intimal thickening, middle film smooth muscle fiber is arranged slightly disorderly.High dose group and L3 high dose group are improved the most obviously (Figure of description 10).
Claims (7)
1. a curcumin derivate (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the application of 5-diketone in the medicine of preparation prevention or treatment diabetes and complication thereof.
2. a curcumin derivate (1E, 6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the application of 5-diketone in health product, food or the food additive of preparation prevention or treatment diabetes and complication thereof.
3. curcumin derivate (1E as claimed in claim 1,6E)-1,7-two (3,5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the application of 5-diketone in the medicine of preparation prevention or treatment diabetes and complication thereof is characterized in that: it is 1% to 100% (1E, 6E)-1 that described pharmaceutical pack contains mass percentage content, 7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3,5-diketone.
4. curcumin derivate (1E as claimed in claim 2,6E)-1,7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3, the application of 5-diketone in health product, food or the food additive of preparation prevention or treatment diabetes and complication thereof, it is characterized in that: it is 1% to 99% (1E that described health product, food or food additive include mass percentage content, 6E)-1,7-two (3, the 5-di-tert-butyl-hydroxy phenyl) heptan-1,6-diene-3,5-diketone.
5. such as claim 1 or 3 described application, it is characterized in that: the dosage form of described medicine is any dosage form that is selected from tablet, pill, capsule, granule, oral liquid, the injection.
6. such as claim 1 or 3 described application, it is characterized in that: the carrier of described medicine or adjuvant have at least a kind of for being selected from the natural or synthetic pharmaceutical polymers of polyvinylpyrrolidone PVP, PLURONICS F87 and starch based, cellulose family, acrylic compounds, vinyl-based, oxirane apoplexy due to endogenous wind.
7. application as claimed in claim 5 is characterized in that: described medicine adopts the preparation method of one of the following to make: fusion method, solvent method, solvent-fusion method, polishing, spray drying method, hypobaric drying method, freeze-drying.
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| US7521580B1 (en) * | 2008-02-18 | 2009-04-21 | Sami Labs Ltd. | Non-cytotoxic synthetic analogues of (1E, 6E)-1, 7-Bis (4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3, 5-Dione and therapeutic applications thereof in cystic fibrosis |
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| US7521580B1 (en) * | 2008-02-18 | 2009-04-21 | Sami Labs Ltd. | Non-cytotoxic synthetic analogues of (1E, 6E)-1, 7-Bis (4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3, 5-Dione and therapeutic applications thereof in cystic fibrosis |
Non-Patent Citations (4)
| Title |
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| P. VENKATESAN et al..Structure-Activity Relationships for the Inhibition of Lipid Peroxidation and the Scavenging of Free Radicals by Synthetic Symmetrical Curcumin Analogues.《J.Pharm.Pharmacol.》.2000,第52卷第1123-1128页. |
| Structure-Activity Relationships for the Inhibition of Lipid Peroxidation and the Scavenging of Free Radicals by Synthetic Symmetrical Curcumin Analogues;P. VENKATESAN et al.;《J.Pharm.Pharmacol.》;20001231;第52卷;第1123-1128页 * |
| 姜黄素对2型糖尿病大鼠血糖的影响;石磊;《河北医学》;20081031;第14卷(第10期);第1195-1197页 * |
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