CN101574144A - Application of 3'-deoxyadenosine in reducing weight, enhancing insulin sensitivity and improving lipid metabolism - Google Patents
Application of 3'-deoxyadenosine in reducing weight, enhancing insulin sensitivity and improving lipid metabolism Download PDFInfo
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- CN101574144A CN101574144A CNA200810106024XA CN200810106024A CN101574144A CN 101574144 A CN101574144 A CN 101574144A CN A200810106024X A CNA200810106024X A CN A200810106024XA CN 200810106024 A CN200810106024 A CN 200810106024A CN 101574144 A CN101574144 A CN 101574144A
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Abstract
The invention discloses application of 3'-deoxyadenosine in reducing weight, enhancing insulin sensitivity and improving lipid metabolism, and particularly relates to the application of the 3'-deoxyadenosine shown in a formula (1), which is used as a weight reduction pill, an insulin sensitizer and a blood fat regulator, in medicaments and/or health care products, in particular to the application of the 3'-deoxyadenosine in preventing and treating hypercholesterolemia, mixed type hyperlipidemia, and dyslipoproteinemia.
Description
Technical field
The present invention relates to 3 '-desoxyadenossine and prevent and/or treat application in obesity, insulin resistance, disorders of lipid metabolism medicine and/or the health products in preparation, particularly 3 '-desoxyadenossine prevents and/or treats application in hypercholesterolemia, combined hyperlipidemia familial and high and low density lipoprotein metabolic disorder medicine and/or the health products in preparation.
Background technology
Obesity is meant that fat accumulation is too much or distribute unusually a kind of pathological state that causes body weight to increase because of body fat cell hypertrophy number increases or the volume increase.The World Health Organization (WHO) assert that clearly obesity is the chronic disease of global adult's maximum, is listed in one of the world's four big medical science social concerns.Obesity is one of main hazard factor of many serious diseases such as diabetes B, coronary heart disease, hypertension, carcinoma of endometrium/breast cancer/colon cancer/carcinoma of the rectum/prostate cancer, gall-bladder and bile duct disease, osteoarthritis, sleep-apnea syndrome, phlebothrombosis.At present, the drug main of treatment of obesity will comprise that the anorectic, nutrient absorption depressant, the medicine that influences lipid-metabolism and the energetic supersession that influence maincenter catecholamines and/or serotonin class promote medicine clinically.
(insulin resistance IR) refers to that body reduces the reactivity of insulin to insulin resistance, is the common main pathophysiological basis of metabolism syndrome such as high fat of blood, diabetes.Insulin resistance and sugar tolerance reduction, diabetes B, obesity, blood fat disorder, NASH, coronary heart disease etc. are clinical closely related unusually.At present mainly contain traditional antidiabetic medicines such as thiazolidinediones insulin sensitizer and melbine at the oral drugs of insulin resistance clinically.
Blood fat is the general name of contained lipid material in the blood, mainly comprises triglycerides, cholesterol, phosphatide and free fatty.Normal adult plasma lipid content is relatively stable in certain fluctuation range.If one or more lipids of blood plasma continue to be higher than normal value, then be called hyperlipidemia (Hyperlipidemia, HP), comprise hypercholesterolemia (Hypercholesterolemia), hypertriglyceridemia (Hypertriglyceridemia) and combined hyperlipidemia familial.Lipid is insoluble or be slightly soluble in water, must exist with the lipoprotein form with combined with protein, could turn round in blood circulation, and therefore, hyperlipidemia often is the reflection of hyperlipoprotememia.It also is a kind of metabolism disorder of blood lipid that blood plasma middle-high density lipoprotein reduces, so the lipoprotein abnormalities mass formed by blood stasis comprises that HDL reduces and low-density lipoprotein raises.Dyslipidemia and lipoprotein abnormalities mass formed by blood stasis are the important risk factor of cerebral apoplexy, coronary heart disease, cardiac sudden death, also are important risk factor that promotes hypertension, carbohydrate metabolism disturbance.Dyslipidemia and lipoprotein abnormalities mass formed by blood stasis also can cause fatty liver, cirrhosis, cholelithiasis, pancreatitis, fundus hemorrhage, blind, peripheral vascular disease, limping, hyperuricemia.At present, the hypolipidemic species is more, mainly be divided into the fat-splitting medicines of influence such as Statins 3-such as (statin) hydroxyl 3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, special class MF activated receptor alpha such as (Fibrates) peroxidase (PPAR α) activator of shellfish, Cholestyramine cholic acid intercalating agents such as (cholestyramine) and nicotinic acid class (NicotinicAcid has another name called Niacin).
In sum, though at present existing many medicines be applied to separately respectively clinical prevention and/treatment or obesity, insulin resistance, particularly hypercholesterolemia, mixed type hyperlipemia and high and low density lipoprotein metabolic disorder of disorders of lipid metabolism, but there is not a kind of medicine the various aspects of metabolic syndrome all to be had the effect of prevention and treatment, the medicine that improves metabolic syndrome also needs constantly to be optimized, reduce types of medicines, reduce toxic and side effect and reduce the health care cost.
3 '-desoxyadenossine (3-deoxyadenosine has another name called cordycepin: Cordycepin), and molecular formula C
10H
13N
5O
3, MW 251, are to separate to obtain nucleosides material from Cordyceps militaris (Cordyceps militaris), and aspergillus nidulans (Aspergillus nidulans) also can produce this material.Its structural formula is as follows:
Do not see in the prior art that 3 '-desoxyadenossine has the report of hypercholesterolemia, combined hyperlipidemia familial and high and low density lipoprotein metabolic disorder function in the obesity of preventing and/or treating, insulin resistance, the disorders of lipid metabolism.
Summary of the invention
Regulate the deficiency of medicine in order to overcome slimming drugs in the prior art, insulin sensitizer and lipid, the invention provides suc as formula 3 '-desoxyadenossine shown in (I) and prevent and/or treat application in obesity, insulin resistance, hypercholesterolemia, combined hyperlipidemia familial and lipoprotein abnormalities mass formed by blood stasis medicine and/or the health products in preparation.
Specifically, 3 '-desoxyadenossine of the present invention can be used to prepare prevent and/or treat fat medicine and/health products.
Obesity is one of main hazard factor of many serious diseases such as diabetes B, coronary heart disease, hypertension, carcinoma of endometrium/breast cancer/colon cancer/carcinoma of the rectum/prostate cancer, gall-bladder and bile duct disease, osteoarthritis, sleep-apnea syndrome, phlebothrombosis.
Therefore, 3 '-desoxyadenossine of the present invention can prepare medicine and/or the health products that prevent and/or treat the obesity-related disease.Described obesity-related disease is diabetes B, coronary heart disease, hypertension, carcinoma of endometrium/breast cancer/colon cancer/carcinoma of the rectum/prostate cancer, gall-bladder and bile duct disease, osteoarthritis, sleep-apnea syndrome, phlebothrombosis preferably.
3 '-desoxyadenossine of the present invention can be used for the preparation prevent and/or treat the insulin resistance medicine and/health products.
Insulin resistance and sugar tolerance reduction, diabetes B, obesity, blood fat disorder, NASH, coronary heart disease etc. are clinical closely related unusually.
Therefore, 3 '-desoxyadenossine of the present invention can prepare the reduction of the diseases related preferably sugar tolerance of the insulin resistance that prevents and/or treats, diabetes B, obesity, dyslipidemia, NASH, coronary heart disease.
3 '-desoxyadenossine of the present invention prevent and/or treat hypercholesterolemia and/or mixed type hyperlipemia and lipoprotein abnormalities mass formed by blood stasis.Described lipoprotein abnormalities mass formed by blood stasis preferably HDL reduces mass formed by blood stasis and/or low-density lipoprotein rising mass formed by blood stasis.
Hypercholesterolemia and/or mixed type hyperlipemia and lipoprotein abnormalities mass formed by blood stasis are the important risk factor of cerebral apoplexy, coronary heart disease, cardiac sudden death, also are important risk factor that promotes hypertension, carbohydrate metabolism disturbance.
Hypercholesterolemia and/or mixed type hyperlipemia and lipoprotein abnormalities mass formed by blood stasis also can cause fatty liver, cirrhosis, cholelithiasis, pancreatitis, fundus hemorrhage, blind, peripheral vascular disease, limping, hyperuricemia.
In addition, take in higher fatty acid and high cholesterol diet and can bring out atherosclerotic, have among the people of heredity lipid metabolism disorder performance apparent in view in a part.
Therefore, 3-desoxyadenossine of the present invention can prepare the medicine that prevents and/or treats the relevant cardiac and cerebral vascular diseases of hypercholesterolemia and/or mixed type hyperlipemia and lipoprotein abnormalities mass formed by blood stasis/or health products.Described cardiac and cerebral vascular diseases is cerebral apoplexy, coronary heart disease, myocardial infarction, cardiac sudden death, hypertension, atherosclerotic, peripheral vascular disease preferably.
3-desoxyadenossine of the present invention also can prepare medicine and/or the health products that prevent and/or treat the relevant IGT of hypercholesterolemia and/or mixed type hyperlipemia and lipoprotein abnormalities mass formed by blood stasis, diabetes, fatty liver, cirrhosis, cholelithiasis, pancreatitis, fundus hemorrhage, blind, limping, hyperuricemia.
3-desoxyadenossine of the present invention also can be used to prepare treatment heredity lipid metabolism disorder patient's the dyslipidemia and the medicine of lipoprotein abnormalities mass formed by blood stasis.
Taking the body weight increase level of fat model (PF) mouse of 3 '-desoxyadenossine compares with the PF model group, 3 '-desoxyadenossine (100mg/kg) is similar to fenofibrate (150mg/kg) effect, all can significantly reduce mouse body weight increase level, and statistics shows that both have significant difference; 3 '-desoxyadenossine (100mg/kg) is opposite with the effect of taking Rosiglitazone (15mg/kg).Illustrate that 3 '-desoxyadenossine (100mg/kg) is similar to fenofibrate (150mg/kg) effect, can reduce the increase of PF mouse body weight, do not have the further side effect of PF mouse body weight increase of Rosiglitazone (15mg/kg) simultaneously.
Taking fat model (IRF) mouse with insulin resistance of 3 '-desoxyadenossine compares with the IRF model group the sensitiveness of exogenous insulin, 3 '-desoxyadenossine (100mg/kg) is similar with Rosiglitazone (15mg/kg) effect, all make insulin load back blood sugar reduce amplitude and obviously increase, area under blood sugar-time graph (AUC) obviously reduces.Illustrate that 3 '-desoxyadenossine has the effect of increase IRF mouse to exogenous insulin sensitivity.
Taking the IRF mouse of 3 '-desoxyadenossine compares with the IRF model group the influence of oral glucose tolerance experiment (OGTT), 3 '-desoxyadenossine (100mg/kg) group and Rosiglitazone (15mg/kg) group all make the glycemic peaks behind the oral glucose obviously reduce, area under blood sugar-time graph (AUC) obviously reduces, and reduces 21.5% and 34.3% respectively.Illustrate 3 '-desoxyadenossine have reduce the IRF mouse to oral glucose load after the effect of blood sugar.
(163 ± 21mg/dl) compare with IRF model group mouse TC level, 3 '-desoxyadenossine (100mg/kg) and fenofibrate (150mg/kg) can reduce serum TC level (135 ± 21mg/dl) and (139 ± 11mg/dl), and statistics shows all significant difference, illustrates that 3 '-desoxyadenossine has the effect of the serum TC that reduces the IRF model mice.
Compare with the TG content in the IRF model group mice skeletal, 3 '-desoxyadenossine (100mg/kg) and fenofibrate (150mg/kg) can make its content reduce by 41.2% and 77.7% respectively, and statistics shows all significant difference, illustrates that 3 '-desoxyadenossine has the effect that reduces TG content in the IRF model mice skeletal muscle.
Compare with the model group with hyperlipemia rat, orally give 3 '-desoxyadenossine effect is similar to fenofibrate, TC, the TG, the LDL-C content that raise in the model group with hyperlipemia rat blood serum are obviously reduced, and the high, medium and low dosage group of 3 '-desoxyadenossine action intensity have certain dose-effect relationship; High dose 3 '-desoxyadenossine (50mg/kg) also can reduce the activity of plasma hepatic lipase, lipoprotein lipase simultaneously, in, low dose group then acts on not obvious.Generally speaking, show that 3 '-desoxyadenossine has the effect of tangible reduction hyperlipemia model rat fat.
Compare with the model group with hyperlipemia Golden Hamster, orally give 3 '-desoxyadenossine effect is similar to fenofibrate, TC, the TG, the LDL-C content that raise in the model group with hyperlipemia Golden Hamster serum are obviously reduced, and the high, medium and low dosage group of 3 '-desoxyadenossine action intensity have certain dose-effect relationship; High dose 3 '-desoxyadenossine (50mg/kg) also can reduce the activity of hyperlipidemia Golden Hamster plasma hepatic lipase, lipoprotein lipase simultaneously, in, low dose group then acts on not obvious.Generally speaking, show that 3 '-desoxyadenossine has the effect of tangible reduction hyperlipemia model Golden Hamster blood fat.
Description of drawings
Fig. 1 .3 '-desoxyadenossine is to the influence of area under the blood sugar-time graph of the plain load of IRF mouse islets back
Remarks:
###P＜0.001 is compared with the normal control group;
*P＜0.05,
* *P＜0.001 is compared with the IRF group.
Fig. 2 .3 '-desoxyadenossine to IRF mouse glucose load after the influence of area under blood sugar-time graph
Remarks:
###P＜0.001 is compared with the normal control group;
*P＜0.01,
* *P＜0.001 is compared with the IRF group.
Fig. 3 .3 '-desoxyadenossine is to the influence of IRF mice skeletal TG content
Remarks:
###P＜0.001 is compared with the normal control group;
*P＜0.05,
* *P＜0.001 is compared with the IRF group.
The specific embodiment
The following examples are used for further specifying the present invention, but this and do not mean that the present invention is had any restriction.
One, the test of pesticide effectiveness
Embodiment 1:3 '-desoxyadenossine is to the influence of PF weight of mice
Materials and methods
[animal used as test] 4 age in week, C57BL mouse was male, and Beijing dimension tonneau China animal breeds center (animal quality certification No.SCXK (capital).Feed free diet drinking-water with high lipid food.Establish simultaneously to the same batch of mouse of feeding with basal feed as the normal control group.After continuously feeding for 20 weeks, select body weight apparently higher than the animal of normal control group as obesity mice model (PF).
[being subjected to test product] 3-desoxyadenossine (separate obtaining from fruiting bodies of cordyceps militaris, purity is more than 99.9% by analysis).
[feed] basal feed contains 12% fat, 62% carbohydrate and 26% protein, total amount of heat 12.6kJ/g..The self-control high lipid food contains 60% fat, 26% carbohydrate and 14% protein, total amount of heat 21.0kJ/g..
[positive drug] fenofibrate is a French Li Bofuni drugmaker product (lot number: 83844).Rosiglitazone is that Beijing high manganese worker Co., Ltd produces (purity is 99%).Semilente Insulin is a Denmark Novo Nordisk Co.,Ltd product (lot number: PW51688).
[instrument] SPN150IF balance is made by plum Teller-Tuo benefit (Changzhou) weighing-appliance Co., Ltd.
[grouping and administration] mouse is divided into five groups at random: normal control group, obesity mice model (PF) group, 3 '-desoxyadenossine group (100mg/kg), fenofibrate group (150mg/kg), Rosiglitazone group (15mg/kg), 10 every group.The normal control group gives normal diet, and other each groups all give high lipid food.Each administration group is irritated stomach once every day, and each organizes the administration volume is 0.1ml/kg.5 weeks of successive administration.PF group and normal control group give equal-volume water every day.
Before [evaluating drug effect] administration and after 5 weeks of administration, each is organized mouse and weighs respectively.And the increase situation (g) of calculating and self comparing animals body weight.
[data analysis] data represent that with mean+SD the t check is taked in data analysis.
Use high lipid food, feed male 20 weeks of C57BL mouse childhood, form the obesity mice model (PF) that body weight and body fat content obviously increase.Divide 4 groups at random with the PF mouse: PF, 3 '-desoxyadenossine, fenofibrate and Rosiglitazone group, the oral water of difference, 3 '-deoxyadenosine compounds (100mg/kg), fenofibrate (150mg/kg) and Rosiglitazone (15mg/kg), 5 weeks of gastric infusion.With animal before the administration self weight ratio, observe the variation of the weight of animals.Simultaneously, establishing the same batch of mouse that gives normal forage feed organizes as normal control Con.
The result
1. before the administration, (32.0 ± 3.1g) compare, and (51.1 ± 2.4g) have utmost point significant difference to PF group body weight, show this experiment PF mouse model modeling success with normal control group body weight.
2. after the administration, compare with the increase of PF group body weight, 3 '-desoxyadenossine group can significantly reduce mouse body weight increase level (P＜0.01), shows that 3 '-desoxyadenossine group has the effect that reduces the body weight increase; Fenofibrate then has the effect of tangible minimizing body weight.(seeing Table 1).
Conclusion
The effect that the PF model mice that 3 '-desoxyadenossine oral administration is induced high lipid food has certain reduction mouse body weight to increase.
Table 1.3 '-desoxyadenossine is to the influence of PF mouse changes of weight
Remarks:
###P＜0.001 is compared with the normal control group;
*P＜0.01,
* *P＜0.001 is compared with the RF group.
Embodiment 2:3 '-desoxyadenossine is to the influence of the insulin sensitivity of IRF mouse
Materials and methods
[animal used as test] 4 age in week, C57BL mouse was male, and Beijing dimension tonneau China animal breeds center (animal quality certification No.SCXK (capital).Feed free diet drinking-water with high lipid food.Establish simultaneously to the same batch of mouse of feeding with basal feed as the normal control group.After continuously feeding for 20 weeks, select in the insulin tolerance experiment and have the obesity mice of obvious insulin resistance as animal pattern (IRF).
[being subjected to test product] 3-desoxyadenossine (separate obtaining from fruiting bodies of cordyceps militaris, purity is more than 99.9% by analysis).
[feed] basal feed contains 12% fat, 62% carbohydrate and 26% protein, total amount of heat 12.6kJ/g..The self-control high lipid food contains 60% fat, 26% carbohydrate and 14% protein, total amount of heat 21.0kJ/g..
[positive drug] fenofibrate is a French Li Bofuni drugmaker product (lot number: 83844).Rosiglitazone is that Beijing high manganese worker Co., Ltd produces (purity is 99%).Semilente Insulin is a Denmark Novo Nordisk Co.,Ltd product (lot number: PW51688).
The μ Quant ELIASA that [instrument] U.S. Bio-Tek company produces.
[grouping and administration] mouse is divided into four groups: the normal control group, have fat model (IRF) group, Rosiglitazone group (15mg/kg), 3 '-desoxyadenossine group (100mg/kg) of insulin resistance, 10 every group.The normal control group gives normal diet, and other each groups all give high lipid food.Each administration group is irritated stomach once every day, and the administration volume is 0.1ml/kg., 4 weeks of successive administration.Normal control group and IRF organize and give equal-volume water every day.
[evaluating drug effect] estimates the sensitiveness of body to insulin with the ITT experiment.Promptly respectively at 20min, 40min before the hypodermic injection 0.4U/kg insulin, after the injection, 90min gets blood, with the determination of glucose oxidase blood sugar level.
[data analysis] data represent that with mean+SD the t check is taked in data analysis.
The result
1. compare with normal control group ITT experimental result, IRF model group mouse shows obvious insulin resistance, blood sugar level behind its hypodermic injection 0.4U/kg insulin does not change basically, and area under blood sugar-time graph (AUC) obviously increases, and shows this experiment modeling success.(see Table 2, Fig. 1)
2. compare with the IRF model group, 3 '-desoxyadenossine (100mg/kg) group and Rosiglitazone (15mg/kg) group all make insulin load back blood sugar reduction amplitude obviously increase, and area under blood sugar-time graph (AUC) obviously reduces (see figure 1).The effect that 3 '-desoxyadenossine and Rosiglitazone are described is similar, and all having increases the effect of insulin resistance mouse to exogenous insulin sensitivity.
Conclusion
The IRF model mice that 3 '-desoxyadenossine oral administration is induced high lipid food has the effect of increase to exogenous insulin sensitivity.
Table 2.3 '-desoxyadenossine is to the influence of the plain load of IRF mouse islets back blood sugar level
Remarks:
##P＜0.01,
###P＜0.001 is compared with the normal control group;
*P＜0.05,
*P＜0.01 is compared with the IRF group.
Embodiment 3:3 '-desoxyadenossine is to the influence of IRF mouse oral glucose tolerance (OGTT)
Materials and methods
[animal used as test] 4 age in week, C57BL mouse was male, and Beijing dimension tonneau China animal breeds center (animal quality certification No.SCXK (capital).Feed free diet drinking-water with high lipid food.Establish simultaneously to the same batch of mouse of feeding with basal feed as the normal control group.After continuously feeding for 20 weeks, select in the insulin tolerance experiment and have the obesity mice of obvious insulin resistance as animal pattern (IRF).
[being subjected to test product] 3-desoxyadenossine (separate obtaining from fruiting bodies of cordyceps militaris, purity is more than 99.9% by analysis).
[feed] basal feed contains 12% fat, 62% carbohydrate and 26% protein, total amount of heat 12.6kJ/g..The self-control high lipid food contains 60% fat, 26% carbohydrate and 14% protein, total amount of heat 21.0kJ/g..
[positive drug] fenofibrate is a French Li Bofuni drugmaker product (lot number: 83844).Rosiglitazone is that Beijing high manganese worker Co., Ltd produces (purity is 99%).Semilente Insulin is a Denmark Novo Nordisk Co.,Ltd product (lot number: PW51688).
The μ Quant ELIASA that [instrument] U.S. Bio-Tek company produces.
[grouping and administration] mouse is divided into four groups: the normal control group, have fat model (IRF) group, Rosiglitazone group (15mg/kg), 3 '-desoxyadenossine group (100mg/kg) of insulin resistance, 10 every group.The normal control group gives normal diet, and other each groups all give high-sugar-fat-diet.Each administration group is irritated stomach once every day, and the administration volume is 0.1ml/kg., 6 weeks of successive administration.Normal control group and IRF organize and give equal-volume water every day.
After [evaluating drug effect] 6 weeks, row oral glucose tolerance experiment (OGTT), promptly irritate stomach 2g/kg glucose load before, and load back 30min, 60min, 120min gets blood respectively, with the determination of glucose oxidase blood sugar level.And area (AUC) under calculating blood sugar-time graph.
[data analysis] data represent that with mean+SD the t check is taked in data analysis.Each time point blood sugar level adopts paired t-test before and after the oral glucose.
The result
1. compare with the normal control group, IRF model group mouse shows that tangible glucose tolerance lowers, and the glycemic peaks behind its oral glucose obviously raises, and area under blood sugar-time graph (AUC) obviously increases, and shows this experiment modeling success.(see Table 3, Fig. 2)
2. compare with the IRF model group, 3 '-desoxyadenossine (100mg/kg) group and Rosiglitazone (15mg/kg) group all make the glycemic peaks behind the oral glucose obviously reduce, and area under blood sugar-time graph (AUC) obviously reduces, and reduces 21.5% and 34.3% respectively.(see Table 3, Fig. 2).The effect that 3 '-desoxyadenossine and Rosiglitazone are described is similar, all has the effect that improves insulin resistance mouse oral glucose tolerance.
Conclusion
The IRF model mice that 3 '-desoxyadenossine oral administration is induced high lipid food has the effect that improves the pancreas oral glucose tolerance.
Table 3.3 '-desoxyadenossine is to the influence of IRF mouse oral glucose tolerance
Remarks:
#P＜0.05,
###P＜0.001 is compared with the normal control group;
*P＜0.05,
*P＜0.01,
* *P＜0.001 is compared with the IRF group.
Embodiment 4:3 '-desoxyadenossine is to the influence of IRF mouse hypercholesterolemia
Materials and methods
[animal used as test] 4 age in week, C57BL mouse was male, and Beijing dimension tonneau China animal breeds center (animal quality certification No.SCXK (capital).Feed free diet drinking-water with high lipid food.Establish simultaneously to the same batch of mouse of feeding with basal feed as the normal control group.After continuously feeding for 20 weeks, select in the insulin tolerance experiment and have the obesity mice of obvious insulin resistance as animal pattern (IRF).
[being subjected to test product] 3-desoxyadenossine (separate obtaining from fruiting bodies of cordyceps militaris, purity is more than 99.9% by analysis).
[feed] basal feed contains 12% fat, 62% carbohydrate and 26% protein, total amount of heat 12.6kJ/g..The self-control high lipid food contains 60% fat, 26% carbohydrate and 14% protein, total amount of heat 21.0kJ/g..
[positive drug] fenofibrate is a French Li Bofuni drugmaker product (lot number: 83844).Rosiglitazone is that Beijing high manganese worker Co., Ltd produces (purity is 99%).Semilente Insulin is a Denmark Novo Nordisk Co.,Ltd product (lot number: PW51688).
The mensuration kit of [kit] T-CHOL TC is available from Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd.'s (lot number: 070421).
The μ Quant ELIASA that [instrument] U.S. Bio-Tek company produces.
[grouping and administration] mouse is divided into four groups: normal control group, IRF group, fenofibrate group (150mg/kg), 3 '-desoxyadenossine group (100mg/kg), 10 every group.The normal control group gives normal diet, and other each groups all give high lipid food.Each administration group is irritated stomach once every day, and the administration volume is 0.1ml/kg, 5 weeks of successive administration.IRF group and normal control group give equal-volume water every day.
After [evaluating drug effect] 5 weeks, mouse tail vein is got hematometry blood T-CHOL TC content, and assay method carries out according to CHO kit specification, measures absorbance with ELIASA under the 500nm wavelength.Calculate TC content: TC (mg/dl)=mensuration pipe absorbance/standard pipe absorbance * 193 (mg/dl) by following formula.
[data analysis] data represent that with mean+SD the t check is taked in data analysis.
The result
1. (68 ± 15mg/dl) compare, and (163 ± 21mg/dl) obviously raise IRF model group mouse CHO level, and statistical calculations has utmost point significant difference, show this experiment modeling success with normal control group TC level.(seeing Table 4).
2. (163 ± 21mg/dl) compare with IRF model group mouse TC level, 3 '-desoxyadenossine (100mg/kg) and fenofibrate (150mg/kg) can reduce blood TC level (135 ± 21mg/dl) and (139 ± 11mg/dl), and statistical calculations shows all significant difference, 3 '-desoxyadenossine is described with similar, all has the effect that reduces IRF model mice blood TC with the fenofibrate effect.(seeing Table 4).
Conclusion
The IRF model mice that 3-desoxyadenossine oral administration is induced high lipid food has the effect that reduces the blood T-CHOL.
Table 4.3 '-desoxyadenossine is to the influence of IRF mouse TC level
Remarks:
###P＜0.001 is compared with the normal control group;
*P＜0.05,
*P＜0.01 is compared with the IRF group.
Embodiment 5:3 '-desoxyadenossine is to the influence of IRF mice skeletal fat content
Materials and methods
[animal used as test] 4 age in week, C57BL mouse was male, and Beijing dimension tonneau China animal breeds center (animal quality certification No.SCXK (capital).Feed free diet drinking-water with high lipid food.Establish simultaneously to the same batch of mouse of feeding with basal feed as the normal control group.After continuously feeding for 20 weeks, select in the insulin tolerance experiment and have the obesity mice of obvious insulin resistance as animal pattern (IRF).
[being subjected to test product] 3-desoxyadenossine (separate obtaining from fruiting bodies of cordyceps militaris, purity is more than 99.9% by analysis).
[feed] basal feed contains 12% fat, 62% carbohydrate and 26% protein, total amount of heat 12.6kJ/g..The self-control high lipid food contains 60% fat, 26% carbohydrate and 14% protein, total amount of heat 21.0kJ/g..
[positive drug] fenofibrate is a French Li Bofuni drugmaker product (lot number: 83844).Rosiglitazone is that Beijing high manganese worker Co., Ltd produces (purity is 99%).Semilente Insulin is a Denmark Novo Nordisk Co.,Ltd product (lot number: PW51688).
The mensuration kit of [kit] T-CHOL TC is available from Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd.'s (lot number: 070421).
The μ Quant ELIASA that [instrument] U.S. Bio-Tek company produces.
[grouping and administration] mouse is divided into four groups: the normal control group, have fat model (IRF) group, Rosiglitazone group (15mg/kg), the 3-desoxyadenossine group (100mg/kg) of insulin resistance, 10 every group.The normal control group gives normal diet, and other each groups all give high-sugar-fat-diet.Each administration group is irritated stomach once every day, and the administration volume is 0.1ml/kg., 6 weeks of successive administration.Normal control group and IRF organize and give equal-volume water every day.
After 6 weeks of [evaluating drug effect] administration, the sacrificed by decapitation mouse is got gastrocnemius fast, liquid nitrogen flash freezer ,-80 ℃ of preservations.Make homogenate with PBS, chloroform methanol solution (chloroform: the triglyceride TG in extracting homogenate methyl alcohol=2: 1); Behind the volatilization organic solvent, redissolve TG, measure the content of TG with the enzyme reaction method with PBS.
[data analysis] data represent that with mean+SD the t check is taked in data analysis.
The result
1. compare with the TG content in the normal control group mice skeletal, the TG content in the IRF model group mice skeletal has increased by 164.9%, and statistical calculations shows utmost point significant difference, shows this experiment modeling success.(see figure 3).
2. compare with the TG content in the IRF model group mice skeletal, 3 '-desoxyadenossine (100mg/kg) and fenofibrate (150mg/kg) can make its content reduce by 41.2% and 77.7% respectively, and statistical calculations shows all significant difference, 3 '-desoxyadenossine is described with similar, all has the effect (see figure 3) that reduces TG content in the IRF model mice skeletal muscle with the fenofibrate effect.
Conclusion
The IRF model mice that 3-desoxyadenossine oral administration is induced high lipid food has the effect that reduces TG content in the skeletal muscle.
Embodiment 6:3 '-desoxyadenossine is to the influence of hyperlipemia model rat fat
Material and method
[animal used as test] male and healthy cleaning level Wistar rat, 150～180g; Available from preclinical medicine institute of Jilin University Experimental Animal Center, the lucky 2003-0007 of the quality certification number: SCXK-.
[being subjected to test product] 3-desoxyadenossine (separate obtaining from fruiting bodies of cordyceps militaris, purity is more than 99.9% by analysis).
[feed] basal feed and high lipid food, feed: basal feed and high lipid food provide credit number by Institute of Experimental Animals, Chinese Academy of Medical Sciences: the capital is moving is betrothed to 003, the quality certification number: 0015790.Basal feed prescription: 20% flour, 10% ground rice, 20% corn, 20% bean powder, 25% wheat bran, 2% bone meal, 2% fish meal.High lipid food prescription: 85.5% basal feed, 10% lard, 4% cholesterol, 0.2% methylthiouracil (lucky star chemical plant, Beijing, lot number 951010).
[positive drug] fenofibrate, fenofibrate, French Li Bofuni drugmaker, authentication code H20050004, lot number: 87517
[kit] triglycerides (TG) kit, T-CHOL (CHO) kit, LDL-C (LDL-C) kit, highdensity lipoprotein-cholesterol (HDL-C) kit, cholesterol, Shanghai favour generation biochemical reagents Co., Ltd; The propylthiouracil (PTU) sheet, Shanghai Fosun Zhaohui Pharmaceutical Co., Ltd.; NaTDC, the extensive and profound in meaning star biotechnology in Beijing Co., Ltd; TC, TG, HDL-C, LDL-C, ALT detection kit, Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd.; The SOD detection kit, Changchun remittance power Bioisystech Co., Ltd; MDA, total lipase, free fatty, Coomassie brilliant blue Protein Detection examination box, bio-engineering research institute is built up in Nanjing.
[instrument] Seperate
TMMax 190 ELIASAs, Molecular Devices CorporationSunnyvale, CA.
[grouping and administration] rat is fed with normal diet and adapts to experimental situation 1 all posterior orbit venous blood collections, measures serum TC and TG content.Take into account body weight serum TC and TG and content, carry out the stratified random grouping.Rat is divided into six groups: normal control group, hyperlipidemia model group, fenofibrate group (40mg/kg), 3 '-desoxyadenossine 50mg/kg group, 3 '-desoxyadenossine 25mg/kg group, 3 '-desoxyadenossine 12.5mg/kg group, 8 every group.Rats in normal control group gives normal diet, and other each groups are given high lipid food, continuous 4 weeks, all endless supply.Each administration group is irritated stomach once every day simultaneously, and each is organized the administration volume and is the 1.0ml/100g body weight, 4 weeks of successive administration.Normal control group and hyperlipidemia model control group give equal-volume physiological saline every day.
Behind [evaluating drug effect] each treated animal administration 4 week back fasting 12h, the eye socket vein is got blood, and conventional preparation serum is surveyed serum total cholesterol (TC), triglycerides (TG), HDL (HDL), low-density lipoprotein (LDL) content with kit.And the ratio (HDL/LDL) of calculating HDL and low-density lipoprotein.Assay method carries out according to the kit specification, measures absorbance with ELIASA (wavelength 500nm).VLDL (VLDL-C) is calculated by CHO-LDL-C.In addition, each treated animal administration 4 week back fasting 14h, animal is pressed 100U/kg body weight tail vein injection heparin again with 45mg/kg yellow Jackets intraperitoneal injection of anesthesia.In the 15min, abdominal aortic blood, separated plasma are used to detect lipoproteinesterase (LPL), hepatic lipase (HL) activity.The result per hour produces 1 micromolar free fatty with every milliliter of blood plasma in reaction system be that 1 unit of enzyme activity represents.
[data analysis] data represent that with mean+SD all data are by variance analysis row statistical procedures.
The result
1. compare with the normal control group, model group with hyperlipemia Serum TC, TG, LDL-C content obviously increase, and HDL/LDL ratio obviously reduces, and plasma hepatic lipase, lipoprotein lipase activity all obviously reduce, and statistics shows significant difference, shows that the hyperlipemia model rat duplicates successfully.(seeing Table 5).
2. compare with the model group with hyperlipemia rat, orally give 3 '-desoxyadenossine effect is similar to fenofibrate, TC, the TG, the LDL-C content that raise in the model group with hyperlipemia rat blood serum are obviously reduced, and the high, medium and low dosage group of 3 '-desoxyadenossine action intensity have certain dose-effect relationship; High dose 3 '-desoxyadenossine (50mg/kg) also can reduce the activity of plasma hepatic lipase, lipoprotein lipase simultaneously, in, low dose group then acts on not obvious.Generally speaking, show that 3 '-desoxyadenossine has tangible effect for reducing blood fat.(seeing Table 5).
Conclusion
The 3-desoxyadenossine has the effect that reduces serum TC, TG, LDL-C content and plasma hepatic lipase, lipoprotein lipase activity preferably to the hyperlipemia model rat that feeds high lipid food formation.
Table 5.3-deoxyadenosine is to the influence of hyperlipidemia rats blood fat, blood plasma lipase
Remarks:
#P＜0.05,
###P＜0.001 is compared with the normal control group;
*P＜0.05,
*P＜0.01,
* *P＜0.001 is compared with the model group with hyperlipemia group.
Embodiment 7:3 '-desoxyadenossine is to the influence of hyperlipemia model Golden Hamster blood lipid level
Material and method
[animal used as test] Golden Hamster, 56 of Golden Hamster, male, 90～110g, available from Changchun High-technology Medical Animal Experiment Research Center, the lucky 2003-0004 of the quality certification number: SCXK-.
[being subjected to test product] 3-desoxyadenossine (separate obtaining from fruiting bodies of cordyceps militaris, purity is more than 99.9% by analysis).
[feed] basal feed and high lipid food, high lipid food prescription: 79.8% common basal feed, 20% lard, 0.2% cholesterol.Feed: basal feed and high lipid food provide credit number by Institute of Experimental Animals, Chinese Academy of Medical Sciences: capital moving meter word 003, the quality certification number: 0015790.Basal feed prescription: 20% flour, 10% ground rice, 20% corn, 20% bean powder, 25% wheat bran, 2% bone meal, 2% fish meal.High lipid food prescription: 85.5% basal feed, 10% lard, 4% cholesterol, 0.2% methylthiouracil (lucky star chemical plant, Beijing, lot number 951010).
[positive drug] fenofibrate, fenofibrate, French Li Bofuni drugmaker, authentication code H20050004, lot number: 87517
[kit] triglycerides (TG) kit, T-CHOL (TC) kit, LDL-C (LDL-C) kit, highdensity lipoprotein-cholesterol (HDL-C) kit, all available from Beijing Zhong Shengbei control reagent company, TC:070172,070381; TG:071472,071571; HDL-C:061204,070308; LDL-C:070108,070407; The ALT:070631 cholesterol, Shanghai favour generation biochemical reagents Co., Ltd; The propylthiouracil (PTU) sheet, Shanghai Fosun Zhaohui Pharmaceutical Co., Ltd.; NaTDC, the extensive and profound in meaning star biotechnology in Beijing Co., Ltd; TC, TG, HDL-C, LDL-C, ALT detection kit, Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd.; The SOD detection kit, Changchun remittance power Bioisystech Co., Ltd, lot number: 2007001; 20070402), total lipase (lot number: 070118,070814), free fatty (lot number: 20070721), (lot number: 070514) bio-engineering research institute is built up in Nanjing to Coomassie brilliant blue Protein Detection examination box MDA (lot number:.
[instrument] Seperate
TMMax 190 ELIASAs, Molecular Devices CorporationSunnyvale, CA.
[grouping and administration] Golden Hamster is fed with normal diet and is adapted to experimental situation 1 all posterior orbit venous blood collections, measures serum TC and TG content.Take into account body weight serum TC and TG and content, carry out the stratified random grouping.Rat is divided into six groups: normal control group, hyperlipidemia model group, fenofibrate group (40mg/kg), 3 '-desoxyadenossine 50mg/kg group, 3 '-desoxyadenossine 25mg/kg group, 3 '-desoxyadenossine 12.5mg/kg group, 8 every group.Rats in normal control group gives normal diet, and other each groups are given high lipid food, continuous 4 weeks, all endless supply.Each administration group is irritated stomach once every day simultaneously, and each is organized the administration volume and is the 1.0ml/100g body weight, 4 weeks of successive administration.Normal control group and model group with hyperlipemia give equal-volume physiological saline every day.
Behind [evaluating drug effect] each treated animal administration 4 week back fasting 12h, the eye socket vein is got blood, and conventional preparation serum is surveyed serum total cholesterol (TC), triglycerides (TG), HDL (HDL), low-density lipoprotein (LDL) content with kit.And the ratio (HDL/LDL) of calculating HDL and low-density lipoprotein.Assay method carries out according to the kit specification, measures absorbance with ELIASA (wavelength 500nm).In addition, each treated animal administration 4 week back fasting 14h, animal is pressed 100U/kg body weight tail vein injection heparin again with 45mg/kg yellow Jackets intraperitoneal injection of anesthesia.In the 15min, abdominal aortic blood, separated plasma are used to detect lipoproteinesterase (LPL), hepatic lipase (HL) activity.The result per hour produces 1 micromolar free fatty with every milliliter of blood plasma in reaction system be that 1 unit of enzyme activity represents.
[data analysis] data represent that with mean+SD all data are by variance analysis row statistical procedures.
The result
1. compare with the normal control group, model group with hyperlipemia Golden Hamster serum TC, TG, LDL-C content obviously increase, HDL/LDL ratio obviously reduces, plasma hepatic lipase, lipoprotein lipase activity all obviously reduce, and statistics shows significant difference, shows the success of hyperlipidemia Golden Hamster model copy.(seeing Table 5).
2. compare with the model group with hyperlipemia Golden Hamster, orally give 3 '-desoxyadenossine effect is similar to fenofibrate, TC, the TG, the LDL-C content that raise in the model group with hyperlipemia Golden Hamster serum are obviously reduced, and the high, medium and low dosage group of 3 '-desoxyadenossine action intensity have certain dose-effect relationship; High dose 3 '-desoxyadenossine (50mg/kg) also can reduce the activity of hyperlipidemia Golden Hamster plasma hepatic lipase, lipoprotein lipase simultaneously, in, low dose group then acts on not obvious.Generally speaking, show that 3 '-desoxyadenossine has tangible effect for reducing blood fat.(seeing Table 6).
Conclusion
The 3-desoxyadenossine has the effect that reduces serum TC, TG, LDL-C content and plasma hepatic lipase, lipoprotein lipase activity preferably to the hyperlipidemia hyperlipidemia Golden Hamster model of feeding high lipid food formation.
Table 7.3 '-desoxyadenossine is to the influence of hyperlipidemia Golden Hamster blood fat, blood plasma lipase
Remarks:
##P＜0.01,
###P＜0.001 is compared with the normal control group;
*P＜0.05,
*P＜0.01,
* *P＜0.001 is compared with the model group with hyperlipemia group.
Claims (10)
1. prevent and/or treat the medicine of obesity and obesity-related disease and/or the application in the health products suc as formula 3 '-desoxyadenossine shown in (I) in preparation
2. application according to claim 1, it is characterized in that described obesity-related disease is: diabetes B, coronary heart disease, hypertension, carcinoma of endometrium/breast cancer/colon cancer/carcinoma of the rectum/prostate cancer, gall-bladder and bile duct disease, osteoarthritis, sleep-apnea syndrome, phlebothrombosis.
3. prevent and/or treat insulin resistance and diseases related medicine and/or the application in the health products suc as formula 3 '-desoxyadenossine shown in (I) in preparation
4. application according to claim 3 is characterized in that, described insulin resistance and diseases relatedly be: sugar tolerance reduction, diabetes B, obesity, dyslipidemia, NASH, coronary heart disease.
5. prevent and/or treat application in hypercholesterolemia and/or combined hyperlipidemia familial and lipoprotein abnormalities mass formed by blood stasis medicine and/or the health products suc as formula 3 '-desoxyadenossine shown in (I) in preparation
6. application according to claim 5 is characterized in that, described lipoprotein abnormalities mass formed by blood stasis is meant that HDL reduces and/or low-density lipoprotein raises.
7. prevent and/or treat application in the relevant cardiovascular and cerebrovascular diseases medicament of hypercholesterolemia and/or combined hyperlipidemia familial and lipoprotein abnormalities mass formed by blood stasis suc as formula 3 '-desoxyadenossine shown in (I) in preparation
8. application according to claim 7 is characterized in that, described cardiac and cerebral vascular diseases is: cerebral apoplexy, coronary heart disease, cardiac sudden death, hypertension, atherosclerotic, peripheral vascular disease.
9. prevent and/or treat the application of the medicine of the relevant IGT of hypercholesterolemia and/or combined hyperlipidemia familial and lipoprotein abnormalities mass formed by blood stasis, diabetes B, fatty liver, cirrhosis, cholelithiasis, pancreatitis, fundus hemorrhage, blind, limping, hyperuricemia in preparation suc as formula 3 '-desoxyadenossine shown in (I)
10. prevent and/or treat application in heredity lipid metabolism disorder patient's dyslipidemia and the lipoprotein abnormalities mass formed by blood stasis medicine suc as formula 3 '-desoxyadenossine shown in (I) in preparation
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193865A (en) * | 2015-09-15 | 2015-12-30 | 上海市农业科学院 | Preparation method of blood fat reduction cordyceps culture medium extractive |
| CN106565806A (en) * | 2016-10-20 | 2017-04-19 | 广东肇庆星湖生物科技股份有限公司 | Synthetic method for 3-deoxyadenosine and product thereof, and application of product |
| CN109381476A (en) * | 2018-11-26 | 2019-02-26 | 于录 | A kind of pharmaceutical composition of weight-reducing |
| WO2023206378A1 (en) * | 2022-04-29 | 2023-11-02 | 中国科学院深圳先进技术研究院 | Use of cordycepin in preparation of product for relieving pressure |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1256094C (en) * | 2003-10-27 | 2006-05-17 | 中国医学科学院药物研究所 | Deoxyadenosine in aplication of preparing bypolipidemic |
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2008
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193865A (en) * | 2015-09-15 | 2015-12-30 | 上海市农业科学院 | Preparation method of blood fat reduction cordyceps culture medium extractive |
| CN106565806A (en) * | 2016-10-20 | 2017-04-19 | 广东肇庆星湖生物科技股份有限公司 | Synthetic method for 3-deoxyadenosine and product thereof, and application of product |
| CN109381476A (en) * | 2018-11-26 | 2019-02-26 | 于录 | A kind of pharmaceutical composition of weight-reducing |
| CN109381476B (en) * | 2018-11-26 | 2020-08-04 | 于录 | Weight-losing pharmaceutical composition |
| WO2023206378A1 (en) * | 2022-04-29 | 2023-11-02 | 中国科学院深圳先进技术研究院 | Use of cordycepin in preparation of product for relieving pressure |
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