CN102579420A - Application of leonurine to preparation of medicament for treating 2-type diabetes - Google Patents
Application of leonurine to preparation of medicament for treating 2-type diabetes Download PDFInfo
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- CN102579420A CN102579420A CN2011100093267A CN201110009326A CN102579420A CN 102579420 A CN102579420 A CN 102579420A CN 2011100093267 A CN2011100093267 A CN 2011100093267A CN 201110009326 A CN201110009326 A CN 201110009326A CN 102579420 A CN102579420 A CN 102579420A
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Abstract
The invention belongs to the field of traditional Chinese medicine manufacturing, and relates to application of leonurine to preparation of a medicament for treating 2-type diabetes. Animal experiments prove that the fasting blood glucose of a 2-type diabetes mouse, i.e., a db/db mouse, can be lowered by the leonurine, and the tolerance of oral glucose is improved; and meanwhile, fasting plasma insulin is increased, the plasma triglyceride is reduced and the content of the plasma high-density lipoprotein is increased. Experiment results also show that the expression of liver glucose metabolic enzymes such as glucokinase, glucose-6-phosphatase and phosphoenolpyruvate carboxyl enzyme is adjusted by the leonurine in an Akt dependent mode; and the biological response of an inflammatory mediator, such as generation of TNF (Tumor Necrosis Factor)-alpha, degradation of IkB-alpha and subsequent phosphorylation of NF-kBp65, is suppressed. Through the leonurine, the inflammatory state of the 2-type diabetes can be corrected, and the symptoms of the 2-type diabetes can be improved; and the leonurine can be used as a treatment medicament to be applied to the treatment of the 2-type diabetes.
Description
Technical field
The invention belongs to pharmaceutical field, relate to the new purposes of leonurine (SCM-198) in pharmacy, be specifically related to the purposes of leonurine (SCM-198) in preparation treatment type 2 diabetes mellitus medicine.
Background technology
Prior art discloses diabetes has become the disease that a kind of serious danger is coerced human health.In recent years, be accompanied by human life style's transformation, its sickness rate rises rapidly just with surprising rapidity.Estimate that according to IDF (IDF) global maturity-onset diabetes patient's in 2010 number reaches 2.85 hundred million approximately, wherein is the type 2 diabetes mellitus patient more than 90%.The drug main that is used at present to treat type 2 diabetes mellitus clinically will comprise sulphanylureas, meglitinide, biguanides, Thiazolidine ketone and alpha-glucosidase inhibitor etc.And these above-mentioned hypoglycemic medicines have all been reported side effect.So it is imperative to seek hypoglycemic medicine efficient, low toxicity at present.
The cause of disease of type 2 diabetes mellitus is mainly insulin resistant and secretion of insulin is not enough.A large amount of reports points out to be accompanied by in the pathogenic process of type 2 diabetes mellitus minuent, chronic systemic inflammatory reaction.Relevant research worker is thought, will help the therapeutic effect of type 2 diabetes mellitus to the improvement of type 2 diabetes mellitus inflammatory conditions.Leonurine is gone up and is not seen the report of relevant leonurine to the type 2 diabetes mellitus therapeutical effect as a kind of main alkaloid in the Chinese medicine Herba Leonuri so far.Leonurine of the present invention is intended the inflammatory conditions through the correction type 2 diabetes mellitus, thereby improves the symptom of type 2 diabetes mellitus.
Summary of the invention
The purpose of this invention is to provide and relate to the new purposes of leonurine (SCM-198) in pharmacy, be specifically related to the purposes of leonurine (SCM-198) in preparation treatment type 2 diabetes mellitus medicine.
Its molecular formula of leonurine according to the invention (abbreviation: SCM-198, commercially available) is: C14H21N3O5 has formula
(I)Structure:
（Ⅰ）
The present invention is through spontaneous type 2 diabetes mellitus animal model (db/db mice); Carried out blood sugar monitoring; The oral glucose tolerance experiment; The detection of blood plasma index, to glucokinase (GK) gene, G-6-Pase (G6pase) and the influence of PEP carboxylase (PEPCK) expression of gene, with
AndTo the experiments such as influence of inflammatory mediator TNF-α, COX-2 and iNOS expression of gene, experimental result shows that described leonurine (SCM-198) can reduce the fasting glucose of type 2 diabetes mellitus mice db/db mice, improves oral glucose tolerance; Simultaneously, rising fasting plasma insulin reduces plasma triglyceride and rising plasma high density lipoprotein level content.Further research shows that leonurine passes through the mode that Akt relies on and regulates the liver glucose metabolic enzyme: glucokinase (GK), the expression of G-6-Pase (G6pase) and PEP carboxylase (PEPCK); The inflammation-inhibiting medium is like the generation of TNF-α, the degraded of I κ B-α and the phosphorylation of NF-κ Bp65 subsequently.Experimental result shows that leonurine of the present invention can be corrected the inflammatory conditions of type 2 diabetes mellitus, improves the symptom of type 2 diabetes mellitus, can be used as medicine and is applied to treat type 2 diabetes mellitus.
For the ease of understanding, through accompanying drawing and specific embodiment the purposes of leonurine of the present invention (SCM-198) in preparation treatment type 2 diabetes mellitus medicine carried out detailed description below.What need particularly point out is, specific embodiment and accompanying drawing only are in order to explain that obviously those skilled in the art can explain according to this paper, and the present invention is carried out various corrections or change, and these corrections and changing also will be included within the scope of the invention.
Description of drawings
Fig. 1 A is the effect of leonurine to fasting blood glucose level; Fig. 1 B is oral glucose tolerance experiment (OGTT); Fig. 1 C is the blood sugar concentration TG-AUC (AUC) of oral glucose tolerance experiment.Experimental session detects blood sugar concentration weekly once, the back row oral glucose tolerance experiment of two weeks.* other each group is compared with db/db vehicle group,
P<0.05.
Fig. 2 is the influence that leonurine (SCM-198) is expressed liver glucose metabolic enzyme gene GK, G6pase, PEPCK,
Wherein, Vehi, Vehicle, S-50, SCM-198 50mg/kg, S-100, SCM-198 mg/kg, S-200, other each group of SCM-198 2000mg/kg. * is compared with db/db vehicle group,
P<0.05.
Fig. 3 is the influence that leonurine (SCM-198) is expressed liver inflammatory mediator gene TNF-α, COX-2, iNOS,
Wherein, Vehi, Vehicle, S-50, SCM-198 50mg/kg, S-100, SCM-198 mg/kg, S-200, SCM-198 200mg/kg; * other each group is compared with db/db vehicle group, and P < 0.05.
Fig. 4 is the influence of leonurine (SCM-198) to liver Akt Expression of phosphorylated,
Wherein, Vehi, Vehicle, S-50, SCM-198 50mg/kg, S-100, SCM-198 mg/kg, S-200, SCM-198 2000mg/kg; * other each group is compared with db/db vehicle group,
P<0.05.
Fig. 5 is the influence of leonurine (SCM-198) to liver inflammatory mediator protein expression, wherein, and Vehi, Vehicle, S-50, SCM-198 50mg/kg, S-100, SCM-198 mg/kg, S-200, SCM-198 2000mg/kg; * other each group is compared with db/db vehicle group,
P<0.05.
The specific embodiment
(1) laboratory animal
42 male C57BLKS/J db/db mices, 5 C57BLKS/J db/m mices (the db/m mice is as normal control) are raised in its SPF level Animal House.Per 12 hours light and shades of illumination replace, free diet drinking-water.Raise with experimentation in accordance with the relevant criterion of management of laboratory animal with protection.Laboratory animal that this experiment is adopted is available from Shanghai Ruizhi Chemical Study Co., Ltd..Described db/db mice is typical spontaneous type 2 diabetes mellitus animal model.Its morbidity is due to leptin receptor suddenlys change, to be autosomal recessive inheritance, AR, possesses and the similar metabolism disorder characteristic of people's type 2 diabetes mellitus: hyperglycemia, hyperinsulinemia, polyuria, glycosuria and obesity.
(2) experiment is divided into groups and is handled
9 weeks, the db/db mice was divided into five groups at random when big, and every group of 8-9 only.Be respectively: Vehicle group: untreated diabetic mice group; Pioglitazone group: positive drug pioglitazone group; SCM-198 50mg/kg group; SCM-198 100mg/kg group; SCM-198 200mg/kg group.The db/m mice is as the normal control group.Wherein, it is the suspension of solvent that SCM-198 and pioglitazone are prepared into freshly prepared 1% sodium carboxymethyl cellulose (CMC-Na), and db/db vehicle group and db/m group are all irritated with isopyknic 1% sodium carboxymethyl cellulose (CMC-Na) solution.
Be three weeks experimental period.Monitor body weight twice during this time weekly, monitor 12 hours fasting glucose concentration once.Experimental period, body weight and fasting glucose were measured in fasting 12 hours when finishing; Every group of gastric infusion or 1% CMC-Na, after 3 hours, the conventional treatment animal; Collect blood sample and detect the blood plasma index; Separate liver, heart, kidney, spleen, epididymal adipose tissues pad, pancreas rapidly, put into liquid nitrogen immediately, place-80 ℃ of preservations after a while.
(3) blood sugar monitoring, the oral glucose tolerance experiment
Experimental session detects blood glucose weekly once.After the fasting 12 hours, cut tail and get blood, measure blood sugar concentration with Johnson & Johnson's blood glucose meter.After the treatment of three weeks, the result shows, compares with db/db vehicle group; Leonurine (SCM-198) treatment group (50mg/kg; 100mg/kg, 200mg/kg) fasting glucose of db/db mice has reduced by 39.6%, 24.5% a and 64.0% (shown in Fig. 1 A) respectively.
After two weeks of treatment, carry out the oral glucose tolerance experiment.Behind all mice fasting 12h, press 2g/kg perfusion glucose solution, respectively before the perfusion glucose (0min) and after cut tail when 15min, 30min, 60min, 120min and get blood, with Johnson & Johnson's blood glucose meter mensuration blood sugar concentration.The result shows; Pouring into glucose solution after 120 minutes; The mouse blood sugar of db/db vehicle group fails to return to the preceding level of perfusion glucose solution, but leonurine (SCM-198) 200mg/kg treatment group mouse blood sugar returns to perfusion glucose solution level (shown in Figure 1B) before basically; Simultaneously, the blood sugar concentration TG-AUC (AUC) of leonurine (SCM-198) 200mg/kg treatment group significantly is lower than db/db vehicle group, P 0.05, shown in Fig. 1 C).The result shows that leonurine (SCM-198) can reduce the blood sugar concentration of type 2 diabetes mellitus mice db/db mice, improves oral glucose tolerance.
Embodiment 2Detect the blood plasma index
Laboratory animal and experiment are divided into groups and are handled with embodiment 1.
Collect blood sample with the test tube that contains heparin, in 4 ℃, centrifugal 15 minutes of 3000g; Adopt the mode of ELISA to detect plasma insulin content; Detect plasma triglyceride, T-CHOL, high density lipoprotein and low density lipoprotein, LDL and liver function index glutamic oxaloacetic transaminase, GOT and glutamate pyruvate transaminase with Hitachi's 7080 type automatic biochemistry analyzers.
Blood plasma index testing result shows, leonurine (SCM-198) 100mg/kg, and 200mg/kg treatment group plasma insulin content is compared with db/db vehicle group, increases significantly; Leonurine (SCM-198) 200mg/kg treatment group triglyceride is compared with db/db vehicle group, significantly reduces, and high density lipoprotein then significantly raises, and P < 0.05; Simultaneously, the liver function index glutamic oxaloacetic transaminase, GOT is not compared with db/>db vehicle with glutamate pyruvate transaminase and is obviously changed, and shows that leonurine does not have overt toxicity to liver.
Table 1It is blood plasma index testing result.
Table 1
Table 1 is put to death after having shown all animal via three weeks treatments, collects plasma sample and is used to detect the blood plasma index, wherein; Vehicle: represent untreated diabetic mice group, Pio: expression is with positive drug pioglitazone treatment group, and SCM-198: expression is with leonurine treatment group; ALT: glutamate pyruvate transaminase, AST: glutamic oxaloacetic transaminase, GOT, TC: T-CHOL; TG: triglyceride, HDL-C: high density lipoprotein, LDL-C: low density lipoprotein, LDL; *: other each group is compared with db/db vehicle group,
P<0.05.
Embodiment 3Leonurine (
SCM-198)To glucokinase (GK) gene, G-6-Pase (G6pase) and the influence of PEP carboxylase (PEPCK) expression of gene
Laboratory animal and experiment are divided into groups and are handled with embodiment 1.
Glucokinase (GK) is first rate-limiting enzyme in the glycolytic cycle, and the increase of its expression can promote the utilization of glucose sugar, plays the effect of blood sugar lowering.And G-6-Pase (G6pase) and PEP carboxylase (PEPCK) are the rate-limiting enzymes of two keys in the glyconeogenesis process, and they are expressed increases the decomposition that can increase glyconeogenesis process and glycogen, and blood glucose consequently raises.Present embodiment detects the influence of leonurine (SCM-198) to glucokinase (GK) gene and G-6-Pase (G6pase) and PEP carboxylase (PEPCK) expression of gene by conventional method; The result shows; Described SCM-198 can improve glucokinase GK gene and reduce G-6-Pase (G6pase) and PEP carboxylase PEPCK expression of gene; Compare P < 0.05 (as shown in Figure 3) with db/>db vehicle group.
Embodiment 4Leonurine (
SCM-198)Influence to inflammatory mediator TNF-α, COX-2 and iNOS expression of gene
Laboratory animal and experiment are divided into groups and are handled with embodiment 1.
Be accompanied by minuent, chronic systemic inflammatory reaction in the pathogenic process of type 2 diabetes mellitus; The expression of transcribing in the type 2 diabetes mellitus individuality of inflammatory mediator such as TNF-α, COX-2 and iNOS increases, by conventional method, to said laboratory animal after the SCM-198 treatment; The gene expression of these media is compared with db/db vehicle; All show the decline of significance, P 0.05, (as shown in Figure 4).Show that leonurine of the present invention (SCM-198) can reduce inflammatory mediator TNF-α, COX-2 and iNOS expression of gene.
Embodiment 5Leonurine (SCM-198) improves the expression experiment of Akt phosphorylation
Laboratory animal and experiment are divided into groups and are handled with embodiment 1.
Akt can positivity the expression of regulation and control GK, the expression of negativity regulation and control G6pase, PEPCK.Experimental result shows that db/db vehicle group Akt Expression of phosphorylated reduces, (
P<0.05 compare with the dbm group), leonurine (SCM-198) processed group can obviously increase Akt phosphorylation (as shown in Figure 5) than db/db vehicle group.
Embodiment 6Leonurine (SCM-198) is to the influence experiment of inflammatory mediator
Laboratory animal and experiment are divided into groups and are handled with embodiment 1.
Show by the conventional method experimental result, leonurine (SCM-198) but the proteic expression of inflammation-inhibiting medium T NF-α and suppresses the degraded of I κ B-α; And then the phosphorylation of inhibition NF-κ Bp65; Compare with db/db vehicle group, P 0.05, (as shown in Figure 6).But the degraded of inflammation-inhibiting medium T NF-α albumen, I κ B-α and the phosphorylation of NF-κ Bp65.
Claims (7)
1. leonurine SCM-198 treats the purposes in the type 2 diabetes mellitus medicine in preparation.
2. by the described purposes of claim 1, it is characterized in that described its molecular formula of leonurine SCM-198 is: C14H21N3O5 has formula
(I)Structure:
（Ⅰ） 。
3. by the described purposes of claim 1, it is characterized in that described leonurine reduces the fasting glucose of type 2 diabetes mellitus mice db/db mice, improves oral glucose tolerance; Rising fasting plasma insulin reduces plasma triglyceride and rising plasma high density lipoprotein level content.
4. by the described purposes of claim 1, it is characterized in that described leonurine improves the glycolipid metabolism disorder of type 2 diabetes mellitus mice db/db mice.
5. by the described purposes of claim 1, it is characterized in that said leonurine is regulated the liver glucose metabolic enzyme through the mode that Akt relies on, the inflammation-inhibiting medium is corrected the inflammatory conditions of type 2 diabetes mellitus, improves the symptom of type 2 diabetes mellitus.
6. by the described purposes of claim 4, it is characterized in that said leonurine is regulated glucokinase, the expression of G-6-Pase and PEP carboxylase through the mode that Akt relies on.
7. by the described purposes of claim 4, it is characterized in that said leonurine suppresses generation, the degraded of I κ B-α and the phosphorylation of NF-κ Bp65 of TNF-α.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619602A (en) * | 2017-01-23 | 2017-05-10 | 南京医科大学 | Novel application of leonurine |
| CN108261412A (en) * | 2016-12-30 | 2018-07-10 | 珠海横琴新区中珠正泰医疗管理有限公司 | Purposes of the leonurine in insulin sensitizer is prepared |
| CN109692172A (en) * | 2017-10-23 | 2019-04-30 | 珠海横琴新区中珠正泰医疗管理有限公司 | Leonurine crystal and its preparing the purposes in insulin sensitizer, hypoglycemic and fat-reducing medicament |
| CN114452277A (en) * | 2021-12-09 | 2022-05-10 | 澳门科技大学 | Application of leonurine in improving non-alcoholic fatty liver and in liver lipid metabolism |
| CN115068462A (en) * | 2021-03-12 | 2022-09-20 | 中国海洋大学 | Application of novel leonurine marine derivative in preparation of medicines for preventing and treating inflammatory diseases or allergy |
| WO2022237798A1 (en) * | 2021-05-10 | 2022-11-17 | 青岛海洋生物医药研究院 | Benzoylguanidine derivative, and preparation method therefor and use thereof |
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| CN1915292A (en) * | 2006-09-10 | 2007-02-21 | 郝书平 | Application of acetylcholine esterase inhibitor medication of Yidancao extractive as cholinomimetic |
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2011
- 2011-01-17 CN CN2011100093267A patent/CN102579420A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1915292A (en) * | 2006-09-10 | 2007-02-21 | 郝书平 | Application of acetylcholine esterase inhibitor medication of Yidancao extractive as cholinomimetic |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108261412A (en) * | 2016-12-30 | 2018-07-10 | 珠海横琴新区中珠正泰医疗管理有限公司 | Purposes of the leonurine in insulin sensitizer is prepared |
| CN106619602A (en) * | 2017-01-23 | 2017-05-10 | 南京医科大学 | Novel application of leonurine |
| CN106619602B (en) * | 2017-01-23 | 2019-05-10 | 南京医科大学 | The purposes of leonurine |
| CN109692172A (en) * | 2017-10-23 | 2019-04-30 | 珠海横琴新区中珠正泰医疗管理有限公司 | Leonurine crystal and its preparing the purposes in insulin sensitizer, hypoglycemic and fat-reducing medicament |
| EP3685834A4 (en) * | 2017-10-23 | 2020-12-09 | Zhuhai Hengqin New District Zhongzhu Zhengtai Medical Management Co. Ltd. | Leonurine crystal and use thereof in preparation of insulin sensitizer, hypoglycemic drug and lipid-lowering drug |
| US11446270B2 (en) | 2017-10-23 | 2022-09-20 | Zhuhai Hengqin New District Zhongzhu Zhengtai Medical Management Co., Ltd. | Leonurine crystal and use thereof in preparation of insulin sensitizer, hypoglycemic drug and lipid-lowering drug |
| CN115068462A (en) * | 2021-03-12 | 2022-09-20 | 中国海洋大学 | Application of novel leonurine marine derivative in preparation of medicines for preventing and treating inflammatory diseases or allergy |
| WO2022237798A1 (en) * | 2021-05-10 | 2022-11-17 | 青岛海洋生物医药研究院 | Benzoylguanidine derivative, and preparation method therefor and use thereof |
| CN114452277A (en) * | 2021-12-09 | 2022-05-10 | 澳门科技大学 | Application of leonurine in improving non-alcoholic fatty liver and in liver lipid metabolism |
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Application publication date: 20120718 |