CN105078946A - Application of salmeterol in medicine for treating type 2 diabetes and insulin resistance - Google Patents
Application of salmeterol in medicine for treating type 2 diabetes and insulin resistance Download PDFInfo
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- CN105078946A CN105078946A CN201510482210.3A CN201510482210A CN105078946A CN 105078946 A CN105078946 A CN 105078946A CN 201510482210 A CN201510482210 A CN 201510482210A CN 105078946 A CN105078946 A CN 105078946A
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Abstract
The invention provides application of salmeterol in medicine for treating type 2 diabetes and insulin resistance. The salmeterol has effects of lowering blood sugar, resisting diabetes and increasing the cell glucose consumption of a 3T3-L1 insulin resistance model. Measuring of PPAR gamma protein expression quantity through an ELISA method shows that the salmeterol can increase the PPAR gamma protein expression quantity. The salmeterol has evident curative effect on the type 2 diabetes.
Description
Technical field
The present invention relates to medical art, be specifically related to salmaterol at treatment insulin resistant, the medicine of the application on anti-type-II diabetes medicine and treatment type-II diabetes.
Technical background
Type-II diabetes becomes topmost diabetes type, ill population rapid development and rejuvenation increasingly, and insulin resistant is the principal pathogenetic reason of type-II diabetes.If euglycemic agent drug main thiazolidinediones (TZD) antidiabetic drug of primary treatment insulin resistant on market, Thiazolidinediones is as the antidiabetic medicine can treating insulin resistant, because this compounds is the agonist of PPAR γ receptor, PPAR γ can regulate the expression of CAP albumen after activating, Cbl/CAP connects albumen can activate again its downstream albumen Crk, TC10 equimolecular, they promote glucose transporter the most at last by glucose by being shipped in born of the same parents outside born of the same parents, reduce blood glucose object to reach.But can cause the untoward reaction such as heart failure, edema and hepatic insufficiency due to this type of medicine, it is very necessary for therefore studying novel insulin sensitizer antidiabetic medicine.
In prior art, salmaterol (Salmeterol), has powerful suppression pulmonary mastocyte release anaphylaxis medium effect, can suppress to suck the early stage of antigen induced and late phase reaction, reduce airway hyperreactivity.Be mainly used in asthma (comprising Nocturnal and exercise-induced asthma), asthmatic bronchitis and Reversible airway obstruction.The present invention, by a large amount of experimentatioies, has invented the application that salmaterol is treated in preparation or prevented diabetes in medicine.
Summary of the invention
For the deficiency that medicament of insulin sensitizer on existing market is less, the present invention is treatment type-II diabetes, insulin resistant is more selected, the application of invention salmaterol in the medicine for the treatment of or prevent diabetes.
The present invention's research shows, salmaterol (Salmeterol), No. CAS: 89365-50-4, chemical name: 4-(1-hydroxyl-2-(6-(4-phenylbutoxy) hexylamino) ethyl)-2-(methylol) phenol, molecular formula: C
25h
37nO
4, molecular weight: 415.57, molecular structure:
3T3-L1 cell sets up insulin resistant model, after oil red O stain identification of cell model, salmaterol acts on the 3T3-L1 cell of the successful insulin resistant of modeling, the consumption of grape cell sugar is measured after 24h, when drug level is 1.5nmol/L and normal group, the positive glucose utilization the having drug level group most not property of there are differences, and glucose utilization is the highest.Therefore, can determine that salmaterol has the drug effectiveness (see Fig. 1) improving 3T3-L1 insulin resistant model grape cell sugar consumption amount.
SD male rat adopts high glucose and high fat feedstuff to feed, and the method for low dose of STZ (streptozotocin) injection induction builds type-II diabetes rat model.After salmaterol acts on rat model surrounding, the blood glucose value of medicine group has all dropped in range of normal value (see accompanying drawing 2), glucose content in liver and blood has all dropped in range of normal value (accompanying drawing 3), triglyceride and total cholesterol level have been tending towards normal value (accompanying drawing 4,5), free fatty and insulin content value be the not property of there are differences (see table 1) between normal group, and the property of there are differences between model group, shows that salmaterol has and reduces blood glucose, diabetes effect.ELISA method measures PPAR γ expressing quantity and finds that salmaterol has the function (see table 2) improving PPAR γ expressing quantity.
Table 1 salmaterol is on type-II diabetes rat model free fatty and insulin content impact
Table 2SD rat respectively organize in the ratio of PPAR γ albumen and total protein content
Accompanying drawing illustrates:
Fig. 1 is that salmaterol affects block diagram to insulin resistant 3T3-L1 cell model glucose utilization;
Fig. 2 is that salmaterol is to type-II diabetes rat model blood sugar influence change broken line graph;
Fig. 3 is that salmaterol affects block diagram to the glucose content in type-II diabetes rat model liver and blood;
Fig. 4 is that salmaterol affects block diagram to type-II diabetes rat model content of triglyceride;
Fig. 5 is that salmaterol affects block diagram to type-II diabetes rat model total cholesterol level.
Detailed description of the invention:
Below by concrete experiment, prove that salmaterol has treatment insulin resistant, diabetes effect.
Embodiment 1:
1,3T3-L1 cell tryptase insulin resistance model construction:
(1) by after 3T3-L1 cell dissociation good for growth conditions, with 3*10
4individual/mL cell density is inoculated in 6 orifice plates, 2mL/ hole, base culture base.36h changes liquid once, changes liquid twice rear cell and can reach 90%-100% cell density, continuation base culture base, make cell be in contact inhibition state.
(2) converge (contact inhibition) (DAY0) two days later, change cell induction culture medium one and cultivate two days, the color according to cell culture medium determines whether change liquid, and general 24-36h changes a culture fluid.
(3) inducing culture one is cultivated two days later (DAY2), change inducing culture two, cultivate and determine whether change liquid according to cell culture medium color in two days, general 24-36h changes a culture fluid, must slowly, softly avoid occurring cells float phenomenon when changing liquid.
(4) inducing culture two is cultivated two days later (DAY4), gain base culture base, 36-48h changes a culture fluid, must slowly, softly avoid occurring cells float phenomenon when changing liquid, general cultivation about 4-5 days (DAY8), namely completes cell induction differentiation.
2, insulin resistant 3T3-L1 cell model dyeing qualification:
(1) fixing: by cell culture fluid slowly sucking-off in 3T3-L1 cell 6 orifice plate of induce, to add 1% paraformaldehyde cell fixative after 0.01MPBS slowly cleans twice, fix 15min.
(2) dye: sucking-off 1% paraformaldehyde cell fixative, 0.01MPBS slowly cleans twice, adds oil red O stain agent 2mL dyeing 20min.
(3) rinse: sucking-off stain, ultrapure water three times, microscopy observation of cell state Taking Pictures recording.
3, salmaterol acts on 3T3-L1 insulin resistant cell model:
(1) successful for differentiation-inducing modeling 3T3-L1 cell is divided into model group, solvent control group, rosiglitazone 0.5nmol/L concentration group, rosiglitazone 1.0nmol/L concentration group, rosiglitazone 1.5nmol/L concentration group, medicine 0.5nmol/L concentration group, medicine 1.0nmol/L concentration group, medicine 1.5nmol/L concentration group, medicine 2.0nmol/L concentration group, medicine 2.5nmol/L concentration group, with do not carry out differentiation-inducing normal group one and be divided into 11 groups, often group establishes three multiple holes.
(2) after positive drug and 794ap storage liquid being dissolved, with liquid cell culture medium according to the concentration dilution of above-mentioned grouping to certain concentration, solvent control group adds corresponding volume 0.5%DMSO, and normal group, model group then add corresponding volume liquid cell culture medium.All experimental group cell basal mediums are placed in carbon dioxide cell incubator and cultivate.
(3) inhale normal group cell culture medium Glucose estimation kit during cell culture 12h, 24h, 36h respectively and carry out glucose content mensuration and record.
(4) draw different group cell culture medium respectively in the cultivation moment of glucose utilization summit and carry out glucose content mensuration and record.
(5) test repetition twice more than, the experimental data SPSS software of record is carried out data analysis.
According to Fig. 1 salmaterol, block diagram is affected on insulin resistant 3T3-L1 cell model glucose utilization, can find out: known salmaterol optimal drug concentration can promote the normal decomposition glucose of the cell of insulin resistant mould well, and and the not property of there are differences between positive drug rosiglitazone.
Embodiment 2:
1, the structure of SD rat type-II diabetes model:
The male SD rat of (1) 80 SPF rank, body weight is 120 ± 20 grams, and basic rat grain examination nursing is after 3 days, random choose goes out 7 as model control group, still feed basic Mus grain, other rat starts high glucose and high fat Mus grain of feeding, all free drinking public water supply of all rats.Every day changes drinking-water, and every two days cleaning feces, weighs a body weight and record in every three days.
(2) after feeding two weeks, jejunitasly not cut off the water supply, after 10h, blood got by tail vein blood pin on an empty stomach, measures rat blood sugar, and record result.After this measure a fasting glucose weekly, still within every three days, measure and record body weight.
(3) after feeding 6 weeks, according to dosage lumbar injection streptozotocin (STZ) injection of 25mg/kg after the jejunitas empty stomach 14h that do not cut off the water supply of model group rats.
(4) inject STZ after tri-days, after the jejunitas empty stomach 10h that do not cut off the water supply, measure rat blood sugar, if blood glucose, all higher than 11.1mmol/L, assert that SD Rat Type II diabetes model successfully constructs after so measuring twice.
2, salmaterol acts on type-II diabetes SD rat model
(1) divide into groups: the type ii diabetes rat model successfully constructed is divided into 7 groups according to the packet mode that blood glucose is streamlined from high to low, be followed successively by model group, positive group, 1mg/kg drug level group, 3mg/kg drug level group, 5mg/kg drug level group, 7mg/kg drug level group, solvent control group, be divided into altogether 8 groups together with original normal group.
(2) medicine dissolution: rosiglitazone and 794ap dissolubility poor, be configured to homogenous suspension with 0.5%CMC-Na solvent, so that gavage.
(3) gavage: from the 8th week, positive group is with 3mg/kg dosage gavage rosiglitazone, four groups of drug level groups distinguish the 794ap of gavage 1mg/kg, 3mg/kg, 5mg/kg, 7mg/kg dosage, the volume gavage drug solvent 0.5%CMC-Na that solvent control group calculates according to 3mg/kg radiacmeter.Every day, same time point carried out gavage, basic Mus grain of normally feeding, drinking public water supply.
(4) within after gavage every three days, measure a body weight, within every five days, measure a blood glucose and record data.
(5) gavage gavage carried out Oral glucose tolerance test after three weeks, the jejunitas 12h on an empty stomach that do not cut off the water supply measures tail vein liquid blood glucose value, then according to 2g/kg dosage gavage 0.5g/mL glucose solution, blood glucose value is measured after gavage glucose solution 0.5h, 1h, 2h, 3h, record data, comparison model group and normal group sugar tolerate to be distinguished.
(6) after gavage surrounding, etherization SD rat after the jejunitas empty stomach 8h that do not cut off the water supply, cut off left femoral artery and get blood in 10mL blood taking tube, cervical dislocation puts to death rat, win pancreas, the clean blood of liver normal saline flushing, the paraformaldehyde being placed in 4% is fixed for subsequent use.Get liver, pancreas, skeletal muscle, attached kidney or epididymal adipose, clean blood with normal saline, moisture cleaned by filter paper, is placed in 1.5mLEP pipe, the good group of labelling and organization name, good seal is lost rapidly in liquid nitrogen, then in transposition ultra cold storage freezer-75 DEG C save backup.
(7) serum preparation: after the blood taking tube getting blood is statically placed in room temperature 2h, be statically placed in 30min in 37 DEG C of calorstats, be placed in centrifuge medium speed 3500rpm/min again, 20min is centrifugal, take out blood taking tube, Aspirate supernatant, be dispensed in 1.5mLEP pipe with every pipe 300 μ L, after the good group of labelling and organization name, be placed in ultra cold storage freezer-75 DEG C and save backup.
(8) 10% livers, pancreatic tissues homogenate preparation: take 0.5g liver, pancreatic tissues in mortar, shred rear abundant grinding to make to organize pulp, pour 5mL0.9% cold saline into be uniformly mixed and to pour in 50mL centrifuge tube, then rinse mortar with 5mL0.9% cold saline and pour in centrifuge tube and (operate on ice pan and carry out).Centrifuge tube is placed in high speed low temperature centrifugal machine, 4 DEG C, gets supernatant after 3000rpm/min, 15min are centrifugal and be sub-packed in the EP pipe of 4mL and be placed in ultra cold storage freezer-75 DEG C and save backup.
(9) internal organs pathological section and HE dyeing, the liver fixed and pancreas are repaired, rinse 24 hours in tap water, put into 75% ethanol, through dehydration, transparent, then carry out waxdip, embedding after, with microtome to embedding wax stone cut into slices, carry out HE dyeing after exhibition sheet, then carry out mounting.Basis of microscopic observation is cut into slices and is taken pictures.
(10) get and prepare serum, liver and pancreatic tissues homogenate and measure test kit, triglyceride determination test kit description according to Glucose estimation kit, T-CHOL glucose, TCH, TG biochemical indicator are measured.
(11) each zoopery group random selecting three each samples of sample arrange two multiple holes, get and prepare serum and operate according to rat free fatty enzyme-linked immunoassay kit description, rat insulin enzyme-linked immunoassay kit description, record rat blood serum free fatty acid and insulin content.
2 salmaterol can be found out when gavage salmaterol 20-25 days to type-II diabetes rat model blood sugar influence change broken line graph by reference to the accompanying drawings, the blood glucose of type-II diabetes rat model is tending towards in blood glucose range of normal value substantially, and and the not property of there are differences between positive drug rosiglitazone group.Composition graphs 3 salmaterol affects block diagram to the glucose content in type-II diabetes rat model liver and blood, can find out that in optimum salmaterol drug level group, glucose content and positive drug are roughly equal, and and the not property of there are differences between the glucose content of normal group.Composition graphs 4 salmaterol affects block diagram to type-II diabetes rat model content of triglyceride can find out that salmaterol medicine group makes TG value in liver, serum decline all to some extent, and and the not property of there are differences between positive rosiglitazone group.Composition graphs 5 salmaterol affects block diagram to type-II diabetes rat model total cholesterol level, can find out that salmaterol medicine group makes mainly to be present in TCH value in serum and declines all to some extent, and and the not property of there are differences between positive rosiglitazone group.Associative list 1 salmaterol, on type-II diabetes rat model free fatty and insulin content impact, can find out that salmaterol medicine group FFA is all higher than model group, and the property of there are differences, and the not property of there are differences between normal structure.INS content is all lower than model group, and the property of there are differences, and the not property of there are differences between normal structure.
Embodiment 3:
1, total protein extraction in serum, liver, skeletal muscle, fatty tissue:
(1) every zoopery group chooses a sample at random, and each sample arranges multiple hole, by for subsequent use from-80 DEG C of taking-ups for serum, liver, skeletal muscle, the fatty tissue sample kept.
(2) take out animal tissue and directly put into the mortar be placed on ice pan fast, add liquid nitrogen, fast piece of tissue is broken into pieces, grind, will again add liquid nitrogen and again grind during deliquescing until tissue, three times so repeatedly.
(3) be ground into powder, claim to add cell pyrolysis liquid 400 μ L in 40mg to 1.5mLEP pipe, agitator mix homogeneously is placed on ice.
(4) once, each 40s, so continues 6-8 time, will ensure low temperature, protein invariance in this process in every 10min vibration.
(5), after cracking on ice, low-temperature and high-speed refrigerated centrifuger 4 DEG C is put into, 12000rnp/min, centrifugal 15min.Take out centrifuge tube, get supernatant often pipe 100 μ L subpackage, to use immediately or to be placed in-80 DEG C of freezen protective for subsequent use.
2, BCA method measures total protein content in serum, liver, skeletal muscle, fatty tissue
(1) standard substance dilution: get 10 μ LBSA standard substance and add that standard concentration to be diluted to after 0.5mg/mL again according to following form configuration standard product, sample application of sample by 90 μ LPBS.
Table 3 standard substance dilution table
Table3Attenuationofstandards
(2) Sample Dilution: the supernatant getting 20 μ L extraction albumen joins mix homogeneously in 80 μ LPBS sample diluting liquids and namely obtains the sample of dilution 5 times, afterwards by sample according to the form below application of sample.
Table 4 standard substance dilution table
Table4Applicationofsamples
(3) carry out application of sample according to shown in (1), (2) to standard substance, sample, three multiple holes established by each sample.
(4) with BCA reagent with Cu reagent volume than 50:1 configuration effort liquid, every hole adds 200 μ L working solutions, and sealed membrane is sealed the calorstat that 96 orifice plates put into 37 DEG C and left standstill 20min, 562nm wavelength, surveys OD value.
(5) Data Processing in Experiment, SPSS software data processing calculates total protein concentration in histone extracting solution.
3, ELISA method measures PPAR γ expressing quantity in serum, liver, skeletal muscle, fatty tissue
(1) carrying out dilution application of sample according to measuring the suitableeest extension rate in step 2 to sample, arranging multiple hole, PPAR γ Elisa test kit description operates.
Associative list 2SD rat respectively organize in the ratio of PPAR γ albumen and total protein content can show that the relative amount tissue from high to low of PPAR γ albumen is respectively fat, skeletal muscle, liver, salmaterol optimal drug concentration group in three kinds of tissues PPAR γ albumen relative expression quantity all far away higher than model group, and and between positive drug rosiglitazone group with the not property of there are differences.
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from aim and the scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.
Claims (3)
1. the application of salmaterol on treatment type-II diabetes medicine.
2. the application of salmaterol on treatment insulin resistant medicine.
3. an antidiabetic medicine, is characterized in that, comprises salmaterol, and wherein salmaterol is as diabetes main active.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018011588A1 (en) * | 2016-07-13 | 2018-01-18 | Atrogi Ab | Combinations of adrenergic receptor agonists for the treatment of type 2 diabetes |
| US10288602B2 (en) | 2013-01-08 | 2019-05-14 | Atrogi Ab | Screening method, a kit, a method of treatment and a compound for use in a method of treatement |
| US11357757B2 (en) | 2017-09-13 | 2022-06-14 | Atrogi Ab | Heteroaryl substituted beta-hydroxyethylamines for use in treating hyperglycaemia |
| US11427539B2 (en) | 2017-09-13 | 2022-08-30 | Atrogi Ab | Beta-hydroxy heterocyclic amines and their use in the treatment of hyperglycaemia |
| US11648216B2 (en) | 2017-09-13 | 2023-05-16 | Atrogi Ab | Fluorophenyl beta-hydroxyethylamines and their use in the treatment of hyperglycaemia |
| US11793774B2 (en) | 2017-09-13 | 2023-10-24 | Atrogi Ab | Chiral beta-hydroxyethylamines and their use in the treatment of hyperglycemia |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080254053A1 (en) * | 2003-04-09 | 2008-10-16 | Mullally John P | Protocol for treatment of diabetes |
| CN101712622A (en) * | 2009-11-10 | 2010-05-26 | 浙江万里学院 | Method for preparing anti-asthmatic medicament of salmeterol |
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2015
- 2015-08-07 CN CN201510482210.3A patent/CN105078946A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080254053A1 (en) * | 2003-04-09 | 2008-10-16 | Mullally John P | Protocol for treatment of diabetes |
| CN101712622A (en) * | 2009-11-10 | 2010-05-26 | 浙江万里学院 | Method for preparing anti-asthmatic medicament of salmeterol |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10288602B2 (en) | 2013-01-08 | 2019-05-14 | Atrogi Ab | Screening method, a kit, a method of treatment and a compound for use in a method of treatement |
| WO2018011588A1 (en) * | 2016-07-13 | 2018-01-18 | Atrogi Ab | Combinations of adrenergic receptor agonists for the treatment of type 2 diabetes |
| US11357757B2 (en) | 2017-09-13 | 2022-06-14 | Atrogi Ab | Heteroaryl substituted beta-hydroxyethylamines for use in treating hyperglycaemia |
| US11427539B2 (en) | 2017-09-13 | 2022-08-30 | Atrogi Ab | Beta-hydroxy heterocyclic amines and their use in the treatment of hyperglycaemia |
| US11648216B2 (en) | 2017-09-13 | 2023-05-16 | Atrogi Ab | Fluorophenyl beta-hydroxyethylamines and their use in the treatment of hyperglycaemia |
| US11793774B2 (en) | 2017-09-13 | 2023-10-24 | Atrogi Ab | Chiral beta-hydroxyethylamines and their use in the treatment of hyperglycemia |
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