CN109893655A - The application of miR-327 inhibitor and/or FGF10 promotor in the drug for preventing and/or treating diabetes - Google Patents
The application of miR-327 inhibitor and/or FGF10 promotor in the drug for preventing and/or treating diabetes Download PDFInfo
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- CN109893655A CN109893655A CN201711310791.8A CN201711310791A CN109893655A CN 109893655 A CN109893655 A CN 109893655A CN 201711310791 A CN201711310791 A CN 201711310791A CN 109893655 A CN109893655 A CN 109893655A
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Abstract
The present invention provides miR-327 inhibitor and/or the new applications of FGF10 promotor, specifically the purposes in the drug of preparation prevention and/or treatment diabetes.MiR-327 inhibitor, FGF10 promotor can promote the increase of FGF10 in the stroma cell ingredient of adipose tissue, promote stroma cell constituents fats cell precursors to brown fat cell differentiation, promote blood glucose consumption, improve insulin sensitivity, achievees the purpose that prevention and/or treatment diabetes.The present invention also provides a kind of prevention and/or the drugs for the treatment of diabetes, including one of miR-327 inhibitor and FGF10 promotor or a variety of and pharmaceutically acceptable carrier.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, are preventing more particularly to miR-327 inhibitor and/or FGF10 promotor
And/or the application in the drug for the treatment of diabetes.
Background technique
Diabetes are one group of metabolic diseases characterized by hyperglycemia.Hyperglycemia be then due to defect of insulin secretion or
Its biological effect is impaired, or both have concurrently and cause.Diabetes are generally caused by inherent cause or environmental factor, wherein feeding
More, physical exertion reduces and obesity is caused to be the main environmental factor of type II diabetes.Over time, diabetes can
Heart, blood vessel, eyes, kidney and nerve can be damaged.Heart attack and the danger of apoplexy, which occurs, in diabetes adult can rise two
To three times；Diabetic retinopathy is the Etiological of blindness, it be small retinal blood vessels long-term accumulated it is impaired as a result,
2.6% blind disease is attributable to diabetes；Diabetes occupy the column of kidney failure Etiological.Therefore, diabetes are prevented and treated
It is particularly important to the health of itself.
Currently, there are many methods, including diet control, modest movement, drug therapy etc. that prevent and treat diabetes.Its
In, medication effect becomes apparent than the effect of other methods.But in the commercially available drug for preventing and treating diabetes
In, most drugs are all based on the secretion of stimulation insulin, reduce gastrointestinal tract to the principles such as the absorption of glucose control sugar
Urine disease, but these drugs are used for a long time can cause damage to be not conducive to good health to organs such as livers.Therefore, it is necessary to a kind of pre-
Anti- and treatment diabetes, while not damaging the drug of health again.
Summary of the invention
To solve the above problems, the present invention provides a kind of miR-327 inhibitor and/or FGF10 promotor to prepare in advance
Application in anti-and/or treatment diabetes drugs.MiR-327 inhibitor, FGF10 promotor can promote the increase of FGF10,
Promote adipocyte precursor to brown fat cell differentiation, promote blood glucose consumption, improves body to insulin sensitivity, reach pre-
Anti- and/or treatment diabetes purposes.
In a first aspect, the present invention provides miR-327 inhibitor and/or FGF10 promotor to prevent and/or control in preparation
Treat the application in the drug of diabetes.
Wherein, the miR-327 inhibitor is dropped for targeting miR-327 in adipose tissue mesostroma vascular components (SVF)
The expression of low miR-327 promotes and is used as miR-327 target in non-fat cell (various types of cells i.e. in stromal vascular fraction)
Fibroblast growth factor-10 (FGF10) increase, promote in stromal vascular fraction adipocyte precursor to brown fat
Cell differentiation increases organism metabolism rate, promotes blood glucose consumption, improves insulin sensitivity.And then can achieve prevention and/or
The effect for treating diabetes.
Wherein, the FGF10 promotor can promote the increase of FGF10 in lipid substrate vascular components (SVF), promote SVF
Middle adipocyte precursor increases organism metabolism rate to brown fat cell differentiation, promotes blood glucose consumption, improves insulin sensitivity
Property.Also it can achieve prevention and/or treat the effect of diabetes.
Optionally, promote simultaneously containing miR-327 inhibitor and FGF10 in the drug of the prevention and/or treatment diabetes
Into agent.The two exists simultaneously down, can play the role of collaboration and promote insulin sensitivity.
In the present invention, miR-327 is a kind of Microrna (MicroRNA), and short non-coding RNA adjusts egg after transcription
White matter expression.
Optionally, the miR-327 inhibitor includes chemicals, polypeptide drug, the protide medicine for inhibiting miR-327
One of object and gene class drug are a variety of.
Further, the chemicals for inhibiting miR-327 refer generally to small molecular organic compounds.The inhibition miR-
327 protein medicaments include native protein, recombinant protein, including but not limited to antibody." the gene for inhibiting miR-327
Class drug " includes but is not limited to nucleic acid fragment, such as DNA fragmentation, RNA segment.
In an embodiment of the present invention, the miR-327 inhibitor is the antagonism miR-327 customized in Exiqon company
LNA inhibitor probe, the miR-327 inhibitor can target and inhibit miR-327, the miR-327 inhibitor and miR-
327 sequence is complementary.Wherein, the nucleotide sequence of miR-327 includes ACUUGAGGGGCAUGAGGAU.
Optionally, the FGF10 promotor includes promoting the increased chemicals of FGF10, polypeptide drug, protein drug
With one of genomic medicine or a variety of.
Further, the increased chemicals of the promotion FGF10 refer generally to small molecular organic compounds.The promotion
The increased protein medicaments of FGF10 include native protein, recombinant protein, including but not limited to antibody.The promotion FGF10 increases
" gene class drug " include but is not limited to nucleic acid fragment, such as DNA fragmentation, RNA segment.Specifically, the FGF10 promotor
Including FGF10 albumen etc..
It optionally, further include pharmaceutically acceptable carrier in the drug of the prevention and/or treatment diabetes.
Optionally, the pharmaceutically acceptable carrier includes solvent, polymer, liposome, recombinant viral vector and true
At least one of core recombinant expression carrier, but not limited to this.
Wherein, the solvent includes but is not limited to water, physiological saline and other non-aqueous solvents.
The polymer includes polylysine, polyethyleneimine (branch shape and/or chain) and its modifier, polyamide-amide
Type dendrimer (PAMAM) and its derivative, polypropyleneimine dendrimer (PPI) and its derivative, chitosan,
One of poly lactic-co-glycolic acid (PLGA), polylactic acid, gelatin, cyclodextrin, sodium alginate, albumin and hemoglobin or
It is a variety of, but not limited to this.Wherein, polyethyleneimine and its modifier, PAMAM and its derivative, PPI and its derivative, shell gather
Sugar etc. can be described as cationic polymer.
The liposome can be by cation lipoid, neutral auxiliary lipoid, cholesterol, phosphatide (such as beans lecithin, yolk ovum
Phosphatide, cephalin etc.) self assembly forms, can also be worn by distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG)
It inserts in the phospholipid layer of phospholipid molecule formation and is formed.
The recombinant viral vector may include one of slow virus carrier, adenovirus vector and retroviral vector
Or it is a variety of, but not limited to this.
In the present invention, the effect of " pharmaceutically acceptable carrier " is the heretofore described drug of transport, makes its performance
Due effect.In general, transport be from an organ or certain a part reach another organ or another
Part, carrier must be mutually compatible with drug ingedient, not influence the biological activity of drug, and opposite is nontoxic, such as should
Carrier enters in vivo without causing toxic side effect or the drug carried with it that serious reaction occurs, and does not generate to patient negative
Face is rung.
Active pharmaceutical ingredient-miR-327 inhibitor and/or FGF10 promotor can disperse or be adsorbed in above-mentioned carrier
And dispersion is formed, it can also be coated/be encapsulated by above-mentioned liposome, polymer etc., formation chondritic (such as nanometer
Capsule or micron capsule).For example, when the miR-327 inhibitor is to inhibit the nucleic acid fragment of miR-327, it is described to prevent and/or control
When treating the drug of diabetes, which includes but is not limited to wrap up, combination or the cationic polymer, more for having nucleic acid fragment be blended
Peptide, protein drug etc..
For another example the miR-327 inhibitor being encapsulated in chondritic can carry out slow-release controlled-release or Targeting delivery,
The drug is allowed to play optimal efficiency, additionally it is possible to improve the stability of the drug.For example, albumin, gelatin, shell are poly-
Sugar, polylactic acid, which can generally form, can disperse or the microballoon of packaging medicine.
Optionally, in the drug of the prevention and/or treatment diabetes, the content of the miR-327 inhibitor is 5-
20mg/kg.Further it is chosen as 5-10mg/kg.
Optionally, in the drug of the prevention and/or treatment diabetes, the content of the FGF10 promotor is 1-
100mg/kg。
Further, the content ratio of the miR-327 inhibitor and FGF10 promotor is (0.2-20): 1.
In the present invention, in the drug of the prevention and/or treatment diabetes, miR-327 inhibitor can choose as single
One active constituent also can choose FGF10 promotor as single active ingredient, can also use and contain miR-327 inhibitor
With FGF10 promotor as its active constituent.This is also " miR-327 inhibitor and/or FGF10 promotor " institute's generation in the present invention
The meaning of table.
On this basis, further, also pharmaceutically may be used containing other in the drug of the prevention and/or treatment diabetes
The active constituent of receiving.The miR-327 inhibitor and/or FGF10 promotor can with described other are pharmaceutically acceptable
Active constituent collective effect achievees the purpose that prevention and/or treatment diabetes.
Wherein, other described pharmaceutically acceptable active constituents include Glimepiride, Glipizide, orinase,
Troglitazone, voglibose and insulin it is one or more.
Preferably, contain miR-327 inhibitor and FGF10 promotor in the drug of the prevention and/or treatment diabetes
One or both of and insulin；The miR-327 inhibitor and FGF10 promotor are also used to improve insulin sensitivity
Property.
" insulin sensitivity " that the present invention refers to refers to body cell (or being " application object ") to insulin action
Sensitivity.Cell is then passed signal by PI3K/Akt/mTOR transduction pathway by insulin receptor identification signal
Enter, accelerates cell to the utilization of glucose to reduce blood glucose.If insulin sensitivity is low, also referred to as insulin resistance (refers mainly to flesh
Cell), body generally requires more endogenous or external source insulin to maintain blood glucose balance at this time, and then generates hyperinsulinemia
Disease is also susceptible to suffer from type-2 diabetes mellitus.
In the present invention, other described pharmaceutically acceptable active constituents have the effect prevented and/or treat diabetes
Fruit.The Glimepiride (Glimepiride) is second generation sulfonylurea oral hypoglycemic, the main machine of hypoglycemic effect
System is stimulation islet β cell insulin, and surrounding tissue is improved to the sensibility of insulin in part.The Glipizide
(Glipizide) it is second generation sulfonylurea oral hypoglycemic agents, islet β cell insulin, enhancing insulin pair can be promoted
The effect of target tissue, also can stimulate alpha Cell of islet to keep glucagon secretion suppressed, still have and inhibit hepatic glycogenolytic, promote
Muscle utilizes and the effect of consumption of glucose.The orinase (Tolbutamide) is the oral drop of first generation sulfonylurea
Blood glucose medicine, selectively acting stimulate the secretion of insulin in beta Cell of islet, reduce blood glucose.The troglitazone (Noscal) is
Thiazolidinediones can improve insulin resistance, increase tissue to the sensibility of insulin, enhance the work of insulin
With.The voglibose (Voglibose) is α glucosidase inhibitor, inhibits such as maltose, isomaltase, Portugal
The activity of grape saccharogenic amylase and invertase delays the digestion and absorption of sugar, make starch resolve into oligosaccharides such as maltose (disaccharide),
The speed that maltotriose and dextrin (oligosaccharide) resolve into glucose in turn slows down, and makes sucrose decomposition at the speed of glucose and fructose
Degree slows down, therefore the absorption of enteron aisle glucose is caused to slow down, to alleviate postprandial hyperglycemia.Insulin (Insulin) ginseng
With adjusting glycometabolism, blood glucose balance, prevention and/or treatment diabetes are controlled.Specifically, lattice can be selected to arrange according to actual needs
U.S. urea, Glipizide, orinase, troglitazone, voglibose, insulin or other have prevention and/or treatment sugar
Urinate the drug of disease.
Optionally, it is described prevention and/or treatment diabetes drug in further include one of diluent and excipient or
It is a variety of.
The main function of the diluent is to fill the weight or volume of tablet consequently facilitating tabletting.Optionally, described dilute
Releasing agent includes one of starch, carbohydrate, cellulose family and inorganic salts or a variety of.The excipient refers to removing in drug
Key agents activity is at additives in addition, including binder, filler, disintegrating agent, lubricant in such as tablet, in pill
Wine, vinegar, decoction etc., the base portion in semi-solid preparation ointment, creme, preservative in liquid preparation antioxidant, rectifys
Taste agent, aromatic, cosolvent, emulsifier, solubilizer, osmotic pressure regulator, colorant etc..
Optionally, it is described prevention and/or treatment diabetes drug form include tablet, capsule, pulvis, granule,
Pill, syrup, solution or suspension.The form of the drug of the prevention and/or treatment diabetes depends in practice
Application.
Optionally, the drug of the prevention and/or treatment diabetes is applied by way of oral or injection.
Preferably, the drug of the prevention and/or treatment diabetes is applied by way of injection.At this point, the prevention
And/or treatment diabetes drug be preferably solution, such as be dissolved in water or physiological saline in.Further, the note
It penetrates by way of intraperitoneal injection, subcutaneous injection, intramuscular injection or intravenous injection and applies.
Optionally, the drug of the prevention and/or treatment fat metabolism disease can pass through local administration or Formulations for systemic administration.
Optionally, the amount of application of the drug of the prevention and/or treatment diabetes is daily 5-20 mg kg of body weights.
Specifically, the dosage of the drug of the prevention and/or treatment diabetes depends on many factors, including but not limited to required life
Object activity and subject are to drug tolerance.
A kind of miR-327 inhibitor and/or FGF10 promotor that first aspect present invention provides in preparation prevention and/or
Treat the application in the drug of diabetes.MiR-327 inhibitor, FGF10 promotor can promote in lipid substrate vascular components
The increase of FGF10 promotes adipocyte precursor in stromal vascular fraction to promote blood glucose consumption to brown fat cell differentiation, reach
To the purpose for preventing and/or treating diabetes.Body also can be improved to insulin sensitivity in they in the presence of insulin.This hair
The new application of the miR-327 inhibitor of bright offer, FGF10 promotor.Open new approach for the treatment of diabetes, have compared with
Significant prevention or therapeutic effect, can effectively reduce the risk that people suffer from diabetes.
Second aspect, the present invention provides a kind of prevention and/or the drug for the treatment of diabetes, the prevention and/or treatments
The drug of diabetes includes one of miR-327 inhibitor and FGF10 promotor or a variety of and pharmaceutically acceptable load
Body.
Wherein, the miR-327 inhibitor is dropped for targeting miR-327 in adipose tissue mesostroma vascular components (SVF)
The expression of low miR-327 promotes and is used as miR-327 target in non-fat cell (various types of cells i.e. in stromal vascular fraction)
Fibroblast growth factor-10 (FGF10) increase, promote in stromal vascular fraction adipocyte precursor to brown fat
Cell differentiation increases organism metabolism rate, promotes blood glucose consumption.And then it can achieve prevention and/or treat the effect of diabetes.
Wherein, the FGF10 promotor can promote the increase of FGF10 in lipid substrate vascular components (SVF), promote SVF
Middle adipocyte precursor increases organism metabolism rate to brown fat cell differentiation, promotes blood glucose consumption.Also it can achieve prevention
And/or the effect for the treatment of diabetes.
Wherein, the pharmaceutically acceptable carrier is as described in the first aspect of the invention.
It wherein, further include insulin in the drug of the prevention and/or treatment diabetes.At this point, in the presence of insulin,
Body can be improved to insulin sensitivity in miR-327 inhibitor and FGF10 promotor.
A kind of prevention that second aspect of the present invention provides and/or the drug for treating diabetes, including miR-327 inhibitor and
One of FGF10 promotor or a variety of and pharmaceutically acceptable carrier.The drug can promote lipid substrate blood vessel at
The increase of FGF10 in point promotes adipocyte precursor in stromal vascular fraction to increase organism metabolism to brown fat cell differentiation
Rate promotes blood glucose consumption, and then improves diabetes.
The advantages of embodiment of the present invention, will partially illustrate in the following description, a part according to specification be it is aobvious and
Be clear to, or can implementation through the embodiment of the present invention and know.
Detailed description of the invention
Fig. 1 is the histology structure of the control group 2 and control group 3 whether giving medicine irritation.；
Fig. 2 is the quantization figure of the fat cell average diameter of the control group 2 and control group 3 whether giving cold stimulation；
Fig. 3 is glucose tolerance (a), HOMA-IR (b) and the core of the control group 2 and control group 3 whether giving cold stimulation
The test result of heart body temperature (c)；
Fig. 4 is the histology result of the experimental group and control group 1 whether giving cold stimulation；
Fig. 5 is the test result of the maximum oxygen uptake capacity of the experimental group and control group 1 whether giving cold stimulation；
Fig. 6 is the insulin resistance Homeostasis model assessment (HOMA- of the experimental group and control group 1 whether giving cold stimulation
IR) the test result of index；
Fig. 7 is the test result of the core temperature of the experimental group and control group 1 whether giving cold stimulation.
Specific embodiment
As described below is the preferred embodiment of the embodiment of the present invention, it is noted that for the common skill of the art
For art personnel, without departing from the principles of the embodiments of the present invention, several improvements and modifications can also be made, these improvement
Also it is considered as the protection scope of the embodiment of the present invention with retouching.
Experimental group: select the LNA inhibitor probe of the antagonism miR-327 of customization as miR-327 inhibitor (miR-
327 inhibitor can target, inhibit miR-327, and sequence is complementary with the nucleotide sequence of miR-327.The wherein nucleosides of miR-327
Acid sequence includes ACUUGAGGGGCAUGAGGAU).12 female C57BL/6 mouse of 8 week old are placed in neutral condition (30
DEG C) under, mouse is subcutaneously injected weekly 1 time with 8mg/kg dosage for above-mentioned miR-327 inhibitor, then gives cold (4 DEG C)
Or medicine irritation (such as beta-2 adrenoceptor agonist, such as CL316243), injection carry out 2 weeks altogether.Carried out respectively after 2 weeks with
Lower experiment:
Excess CO is used to 6 mouse therein after (1) 2 week2It puts to death, careful its subcutaneous fat of dissection, in precision balance
Upper measurement weight, and it is for statistical analysis, obtain mouse adipose tissue weighing results.Tissue is carried out to mouse adipose tissue simultaneously
Detection is learned, specifically includes: adipose tissue being fixed using 4% PFA, is thinly sliced, disappeared using cathepsin K (20mM)
Change, and with 100% methanol permeabilization.Sample is stayed overnight using the 0.1%Triton X-100PBS solution containing 3% milk
Closing, in 4 DEG C and primary antibody such as AntiCD3 McAb 1 (1:100, catalog number (Cat.No.) AF3628, R&D) and anti-Perilipin (1:200, catalog number (Cat.No.)
20R-PP004, Fitzgerald Industries), the antibody incubations such as anti-UCP1 (1:200, Abcam).After being washed with PBS,
Sample is closed with 3% milk, and at room temperature with the secondary antibody of fluorescent marker (1:300, Thermo Fisher Scientific
Inc. it) is incubated for 2 hours.After flushing, sample load is observed and is surveyed on Laser Scanning Confocal Microscope (LSM510Confocal, Zeiss)
Amount.
Mouse core body temperature is first measured to 6 mouse therein after (2) 2 weeks, it is specific as follows: to use MicroTherma 2T
Thermometer inserts a probe into the body temperature of mouse rectum (article No. TW2 and RET-3, Agntho's AB) detection each group mouse.
Oral glucose tolerance test is carried out to these female mices later, is specifically included: fasting 6 hours, during which can be with
Free water.Then glucose catalog number (Cat.No.) G8270, Sigma-Aldrich) is dissolved in physiological saline, with 15mg/g Mice Body
The dosage of weight feeds mouse.(0,15,30,60,120 minute) tail vein blood at every point of time, uses Accu-Chek
Aviva blood glucose meter and test paper (Roche Diagnostics) measure blood glucose level.
2nd day, the experiment of insulin resistance Homeostasis model assessment (HOMA-IR) index is carried out to 6 female mices.Wherein,
HOMA-IR is the maturation method for detecting insulin resistance.Use the sky in insulin ELISA kit detection mice serum sample
Abdomen insulin level.Fasting blood glucose level is measured using Aviva blood glucose meter.HOMA-IR index is calculated using following formula: on an empty stomach
Blood glucose (mg dL-1) × fasting insulin (mU L-1)/405.
3rd day, metaboilic level measurement is carried out to this 6 female mices, includes the following steps: to quantify generation using oxygen demand
Thank to the heat production of rate and norepinephrine (NE) induction.Use Oxymax CLAMS-HC system (Columbus
Instruments).Lambda sensor heats at least 6 hours, uses two kinds of reference gas calibrations after stablizing.Two kinds of gases are 100%
Nitrogen and 20.5% O2Or 0.5% CO2Mixed gas.For Fundamentals of Measurement metabolism, mouse is transferred to the cell Oxymax,
Fundamentals of Measurement is metabolized at different conditions.It adapts to 24 hours, measures 48-72 hours in cell before measurement.First kidney is removed in measurement
When the heat production of upper parathyrine induction, Oxymax system is maintained at neutral 30 DEG C.With first 24 hours of norepinephrine injection
Metabolic rate be baseline, norepinephrine is injected with the dose subcutaneous of 1mg/kg weight.It calculates injection first 30 minutes and arrives injection
The area under the curve of the oxygen demand in 140 minutes sections afterwards compare between group.
Control group 1: by do not inhibit miR-327 without effect miR mortifier drug (random sequence) with the dosage of 8mg/kg
Weekly in subcutaneous injection to 12 C57BL/6 mouse white adiposes of 8 week old, cold (4 DEG C) stimulations are then given, are infused weekly
It penetrates 1 time, carries out 2 weeks altogether；Excess CO is used to wherein 6 mouse after 2 weeks2It puts to death, weighs, go forward side by side to its adipose tissue
Row histology；Mouse core measurement of bldy temperature, oral glucose tolerance test, HOMA-IR are successively carried out to other 6 mouse
Index test, metaboilic level measurement.
Control group 2: the slow virus carrier (Vector Biosystems) of non-functional miR will be carried with 1 × 109PFU/
In each dosage subcutaneous injection to 12 C57BL/6 mouse white adiposes of 8 week old, cold (4 DEG C) thorns are given after a week
Swash, injects weekly 1 time, carry out 2 weeks altogether；Excess CO is used to wherein 6 mouse after 2 weeks2It puts to death, its adipose tissue is carried out
Weighing, and carry out histology；Mouse core measurement of bldy temperature, oral glucose tolerance examination are successively carried out to other 6 mouse
It tests, the test of HOMA-IR index, metaboilic level measurement.
Control group 3: the adenovirus (Ad-EF1a-mmu-miR-327-eGFP of mmu-miR-327 will be overexpressed；1×
109PFU；Vector Biosystems) with 1 × 109PFU/ each dosage 12 to 8 week old of subcutaneous injection weekly
In C57BL/6 mouse white adipose, cold (4 DEG C) stimulations are given after a week, injects weekly 1 time, carries out 2 weeks altogether；；After 2 weeks
Excess CO is used to wherein 6 mouse2It puts to death, weighs to its adipose tissue, and carry out histology；To other 6
Mouse successively carries out Mouse core measurement of bldy temperature, oral glucose tolerance test, the test of HOMA-IR index, metaboilic level measurement.
Control group 2 and the histology result of control group 3 are as depicted in figs. 1 and 2, and Fig. 1 is control group 2 and control group 3
Histology result when whether giving medicine irritation.When Fig. 2 is whether control group 2 and control group 3 give cold stimulation
The quantization of fat cell average diameter.Wherein, Ad-miRNC represents control group 2, and Ad-miR-327 represents control group 3.In Fig. 1,
H&E, which is represented, carries out the dyeing of adipose tissue morphology using haematoxylin and Yihong.UCP1 dyeing display milkproduct position, PERI are shown
Fat cell form, DAPI redye nucleus.
From in Fig. 1 and Fig. 2 as can be seen that for control group 3, the adenovirus of injection expression miR-327, simultaneously in mouse
(Ad-miR-327 can be abbreviated as) after expression miR-327 in its adipose tissue, if promoting milkproduct without cold, drug etc.
Stimulation, fat cell size are constant compared with control group 2 (wherein double-head arrow indicates fat cell size).If there is cold, medicine
When object etc. promotes the stimulation of milkproduct, expresses the adipose tissue of miR-327 its cell dia and do not reduce and (be increased slightly), UCP1
Dyeing shows that its milkproduct degree reduces, and arrow indicates the position of obvious milkproduct.
Fig. 3 is glucose tolerance (a), HOMA-IR (b) and the core of the control group 2 and control group 3 whether giving cold stimulation
The test result of heart body temperature (c).(a) and (b) display in Fig. 3 has cold thorn after expressing miR-327 in adipose tissue
Swash or without cold stimulation, does not influence insulin sensitivity.Wherein, ns represents no significant difference.(c) display in Fig. 3, in rouge
After expressing miR-327 in fat tissue, if promoting the stimulation of milkproduct, the body core temperature of control group 3 without cold, drug etc.
It is constant compared with control group 2.If have cold, drug etc. promote milkproduct stimulation, fat in express miR-327 mouse its
Body core temperature reduces.
The result of Fig. 1-Fig. 3 illustrates, imports miR-327 in mouse adipose tissue using viral vectors, can significantly inhibit
White adipocyte milkproduct hinders combustion rouge effect.Reduce mouse energetic supersession.
Experimental group and histology, the metabolism test result of control group 1 are as shown in Figure 4-Figure 7, wherein Inh-miRNC
Control group 1 is represented, Inh-miR-327 represents experimental group.
Figure 4, it is seen that after injecting miR-327 inhibitor to mouse, if promoting milkproduct without cold, drug etc.
Stimulation, fat cell size (double-head arrow indicate fat cell size) has been substantially reduced with control group 1 compared with, and UCP1 contaminates
Color shows that its milkproduct degree significantly increases.If when the stimulation for having cold, drug etc. to promote milkproduct, injection miR-327 inhibits
The fat cell size of the mouse of agent further decreases, and UCP1 dyeing shows that its milkproduct degree further increases, arrow instruction
The position of obvious milkproduct.
As seen from Figure 5, after injecting miR-327 inhibitor to mouse, if promoting milkproduct without cold, drug etc.
Stimulation, metabolic index-maximum oxygen uptake capacity (VO2) significantly improved compared with control group 1.If thering is cold, drug etc. to promote palm fibre
When the stimulation of color, its metabolic index of the mouse of injection miR-327 inhibitor is further increased.
As seen from Figure 6, after injecting miR-327 inhibitor to mouse, under non-cold conditions, HOMA-IR is just
Through significantly reducing, this illustrates that miR-327 inhibitor can increase insulin sensitivity at room temperature.
As seen from Figure 7, after injecting miR-327 inhibitor, under non-cold conditions, mouse just can be increased
Body core temperature improves metabolic rate.
The result of Fig. 4-Fig. 7 illustrates, can significantly promote the white adipose milkproduct of mouse using miR-327 inhibitor, increases
Add organism metabolism rate, promotes blood glucose consumption, improve insulin sensitivity.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention
Protect range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (10)
- The application of 1.miR-327 inhibitor and/or FGF10 promotor in the drug of preparation prevention and/or treatment diabetes.
- 2. application as described in claim 1, which is characterized in that the miR-327 inhibitor and FGF10 promotor can promote The increase of FGF10 in the stromal vascular fraction of adipose tissue promotes in stromal vascular fraction adipocyte precursor to brown fat Cell differentiation increases organism metabolism rate, promotes blood glucose consumption, improves insulin sensitivity；Wherein, the miR-327 inhibits Agent promotes the increase of the FGF10 as miR-327 target by inhibiting the expression of miR-327 in lipid substrate vascular components.
- 3. application as described in claim 1, which is characterized in that the miR-327 inhibitor includes the chemistry for inhibiting miR-327 One of drug, polypeptide drug, protein drug and genomic medicine are a variety of；The FGF10 promotor includes promoting the increased chemicals of FGF10, polypeptide drug, protein drug and genomic medicine One of or it is a variety of.
- 4. application as described in claim 1, which is characterized in that contain simultaneously in the drug of the prevention and/or treatment diabetes There are miR-327 inhibitor and FGF10 promotor.
- 5. application as described in claim 1, which is characterized in that further include in the drug of the prevention and/or treatment diabetes Pharmaceutically acceptable carrier；The pharmaceutically acceptable carrier includes solvent, polymer, liposome, recombinant viral vector At least one of with recombinant eukaryotic expression plasmid.
- 6. application as described in claim 1, which is characterized in that also contain in the drug of the prevention and/or treatment diabetes Other pharmaceutically acceptable active constituents；Other described pharmaceutically acceptable active constituents include Glimepiride, lattice column pyrrole Piperazine, orinase, troglitazone, voglibose and insulin it is one or more.
- 7. application as described in claim 1, which is characterized in that contain in the drug of the prevention and/or treatment diabetes One or both of miR-327 inhibitor and FGF10 promotor and insulin.
- 8. the drug of a kind of prevention and/or treatment diabetes, which is characterized in that including miR-327 inhibitor and FGF10 promotor One of or a variety of and pharmaceutically acceptable carrier.
- 9. the drug of prevention as claimed in claim 8 and/or treatment diabetes, which is characterized in that the prevention and/or treatment In the drug of diabetes, the content of the miR-327 inhibitor is 5-20mg/kg.
- 10. the drug of prevention as claimed in claim 8 and/or treatment diabetes, which is characterized in that described to prevent and/or control Treating in the drug of diabetes further includes insulin；The miR-327 inhibitor and/or FGF10 promotor are also used to improve pancreas islet Plain sensibility.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711310791.8A CN109893655B (en) | 2017-12-11 | 2017-12-11 | Application of miR-327 inhibitor and/or FGF10 promoter in medicine for preventing and/or treating diabetes |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711310791.8A CN109893655B (en) | 2017-12-11 | 2017-12-11 | Application of miR-327 inhibitor and/or FGF10 promoter in medicine for preventing and/or treating diabetes |
Publications (2)
| Publication Number | Publication Date |
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| CN109893655A true CN109893655A (en) | 2019-06-18 |
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| CN111450254A (en) * | 2020-05-18 | 2020-07-28 | 徐州医科大学 | Application of mPGES-2 as drug target for treating and/or preventing diabetes |
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| CN103210089A (en) * | 2010-08-13 | 2013-07-17 | 格拉斯哥大学大学行政评议会 | Therapeutic uses of microvesicles and related microRNAs |
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| CN106255748A (en) * | 2014-02-24 | 2016-12-21 | 释放能量医药股份有限公司 | The method and composition of induction people's brown adipocyte progenitors differentiation |
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| CN111450254A (en) * | 2020-05-18 | 2020-07-28 | 徐州医科大学 | Application of mPGES-2 as drug target for treating and/or preventing diabetes |
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