CN109453191A - GSK-3 beta inhibitor and diabetic nephropathy intervene novel targets application - Google Patents
GSK-3 beta inhibitor and diabetic nephropathy intervene novel targets application Download PDFInfo
- Publication number
- CN109453191A CN109453191A CN201811485443.9A CN201811485443A CN109453191A CN 109453191 A CN109453191 A CN 109453191A CN 201811485443 A CN201811485443 A CN 201811485443A CN 109453191 A CN109453191 A CN 109453191A
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- China
- Prior art keywords
- gsk
- diabetic nephropathy
- beta inhibitor
- novel targets
- podocytes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention belongs to the medicinal preparation technical fields containing effective component, disclose the application that a kind of GSK-3 beta inhibitor intervenes novel targets in diabetic nephropathy, GSK-3 beta inhibitor provided by the invention intervenes the method for novel targets as diabetic nephropathy, utilize siRNA technology and its inhibitor, it was found that after the expression or activity of inhibition GSK-3 β, Podocytes in Renal Tissue caused by high sugar is mitigated, it is meant that GSK-3 β takes part in Podocytes in Renal Tissue process caused by high sugar, and played an important role；The research of zoopery further demonstrates the conclusion that cellular level obtains, and reconfirms that GSK-3 beta inhibitor can slow down Podocytes in Renal Tissue and albuminuria caused by high sugar, provides new approaches to find the remedy measures of new diabetic nephropathy.
Description
Technical field
The invention belongs to containing effective component medicinal preparation technical field more particularly to a kind of GSK-3 beta inhibitor and
The application of diabetic nephropathy intervention novel targets.
Background technique
Currently, the prior art commonly used in the trade is such thatDiabetic nephropathy (diabetic nephropathy, DN) is
The important disease of diabetes (Diabetes Mellitus, DM) the most common microvascular complication of patient and End-stage renal disease
One of because, with albuminuria for main clinical manifestation.Current research suggests that Podocytes in Renal Tissue is the important machine that albuminuria occurs
System, but high sugar causes the mechanism of Podocytes in Renal Tissue to still need to further study.DN is that most serious caused by DM and harmfulness are maximum
A kind of the characteristics of chronic complicating diseases, glomerulosclerosis caused by the microangiopathies as caused by diabetes is this disease.It also is DM
Patient's underlying cause of death.The infection such as pyelonephritis, necrosis of renal papillae that DM patient occurs, the macroangiopathy such as arteria renalis are hard
Change, does not belong to the scope of DN.With being constantly progressive for DM treatment means and technology, DM acute complications such as ketoacidosis is died of
Patient is fewer and fewer, and DM concurrent cardiovascular disease and kidney trouble become DM patient in recent years it is main it is lethal, disable
Reason.DN is one of the important complication of 1 type and 2 type DM, is in recent years in be gradually increasing trend.Current treatment technology has use
Intravenous infusion in physiological saline is added in reductive glutathione, plays the antioxidation of itself, and the above method makees the protection of kidney
With limited, and a large amount of medical resource is occupied, a kind of method for being badly in need of new safe and efficient economy treats the generation for slowing down DN
Development.
In conclusion problem of the existing technology is:Podocytes in Renal Tissue caused by height is sugared in some treatment technologies is more
Seriously；DN patient while reducing patient's albuminuria, cannot have both the effect of protection renal in treatment clinical course.It is existing
The most close person for the treatment of technology using reductive glutathione be added physiological saline in intravenous infusion, play the antioxidation of itself,
It is limited to the protective effect of kidney.
Solve the difficulty and meaning of above-mentioned technical problem:How to reduction patient's albuminuria in the clinical treatment of DN patient
Better Renoprotective Effect is played simultaneously, is the technical issues of this programme solves, is regulated and controled by using GSK-3 beta inhibitor
Nrf2 assembles in nucleus and in conjunction with Antioxidant responsive element, raises the expression of anti-oxidant albumen, enhances sertoli cell
Protective effect plays better Renoprotective Effect by Cascaded amplification effect, and tissue glutathione can be improved in lithium agent
Level and SOD activity, contain the cure mechanism of above-mentioned technology, while the use of tablet and injection also can be reduced medical resource
Occupancy.
Summary of the invention
In view of the problems of the existing technology, intervene novel targets the present invention provides a kind of GSK-3 beta inhibitor and in DN
Using.
The invention is realized in this way a kind of GSK-3 beta inhibitor, the GSK-3 beta inhibitor are as follows: LiCl.By non-
Keap1 dependence mode raises the protein expression level protection Renal Structure of Nrf2, mitigates podocytic process fusion and podocyte apoptosis,
It often plays a protective role in low dose, and it is dead that cytotoxicity can be caused even to increase when large dosage use because of undershooting-effect
Die rate.
Another object of the present invention is to provide a kind of GSK-3 beta inhibitors as described in claim 1 to intervene novel targets in DN
Application method, the GSK-3 beta inhibitor DN intervene novel targets application method include: oral lithium salts tablet, lithium salts is oral
Enter to absorb blood quickly after clothes, be discharged from urine with prototype, half-life period is 12 hours, and the lithium after rule is 5-7 days oral in blood is dense
Degree reaches stable state.Lithium salts therapeutic dose range is 0.5-2g/ days, and the effective blood drug concentration in blood is 0.5-1.0mmol/L.
Or application LiCl injection is administered.
In conclusion advantages of the present invention and good effect are as follows:GSK-3 beta inhibitor provided by the invention is intervened as DN
The method of novel targets, using siRNA technology and inhibitor, after discovery inhibits the expression or activity of GSK-3 β, caused by high sugar
Podocytes in Renal Tissue is mitigated, it is meant that GSK-3 β takes part in Podocytes in Renal Tissue process caused by high sugar, and has played important
Effect；The research of zoopery further demonstrates the conclusion that cellular level obtains, and reconfirms that GSK-3 beta inhibitor can
Slow down Podocytes in Renal Tissue and albuminuria caused by high sugar, provides new approaches to find the remedy measures of new DN.GSK-3 β inhibits
Agent is assembled in nucleus by regulation Nrf2 and in conjunction with Antioxidant responsive element, and the expression of anti-oxidant albumen is raised,
Enhance sertoli cell protective effect and better Renoprotective Effect is played by Cascaded amplification effect, and group can be improved in lithium agent
The level and SOD activity for knitting glutathione, play antioxidation.
Detailed description of the invention
Fig. 1 is GSK-3 beta inhibitor provided in an embodiment of the present invention and intervenes the application method of novel targets in diabetic nephropathy
Flow chart.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Application principle of the invention is explained in detail with reference to the accompanying drawing.
GSK-3 beta inhibitor is assembled in nucleus by regulation Nrf2 and in conjunction with Antioxidant responsive element, and antioxygen is raised
Change the expression of albumen, enhance sertoli cell protective effect by Cascaded amplification effect and play better Renoprotective Effect,
And the level and SOD activity of tissue glutathione can be improved in lithium agent, plays antioxidation.
GSK-3 beta inhibitor LiCl provided in an embodiment of the present invention.Lithium chloride, white crystal is soluble easily in water, standard shape
Solubility 67g/100ml water under condition.Fusing point is 605 DEG C, and boiling point is 1350 DEG C, lattice energy 853kJ/mol.
GSK-3 beta inhibitor provided in an embodiment of the present invention includes: mouth in the application method that diabetic nephropathy intervenes novel targets
It takes lithium salts tablet or vein and uses LiCl injection.The therapeutic dose range of oral lithium salts tablet is 0.5-2g/ days, having in blood
Effect blood concentration is 0.5-1.0mmol/L.
Application principle of the invention is further described combined with specific embodiments below.
(1) Podocytes in Renal Tissue caused by high sugar is effectively relieved using GSK-3 β specific inhibitor (LiCl), alleviates animal
Model protein urine；
(2) inhibit the expression and activity of GSK3 β by conditional gene knockout and drug SB216763 in animal model,
Assemble Nrf2 in nucleus and in conjunction with Antioxidant responsive element, raise the expression of anti-oxidant albumen, enhancing foot is thin
Born of the same parents' protective effect；
(3) establishing GSK-3 β is the new intervention target spot of diabetic nephropathy, and GSK-3 β specific inhibitor is low dose of
LiCl is applied to the clinical treatment of Diabetic Nephropathy patients.
It is provided by the invention to utilize siRNA technology and inhibitor, after the expression or activity of discovery inhibition GSK-3 β, high sugar
Caused Podocytes in Renal Tissue is mitigated, it is meant that GSK-3 β takes part in Podocytes in Renal Tissue process caused by high sugar；The present invention mentions
What is supplied is applied to GSK-3 β specific inhibitor low dose LiCl the clinical treatment of Diabetic Nephropathy patients, and discovery can reduce
Patient's albuminuria has Renoprotective Effect, and further demonstrating GSK-3 β is one intervention novel targets of diabetic nephropathy.
Prove part (specific embodiment/experiment/emulation/Pharmacological Analysis /)
(1) Podocytes in Renal Tissue caused by high sugar is effectively relieved using GSK-3 β specific inhibitor (LiCL), alleviates animal
Model protein urine；
(2) inhibit the expression and activity of GSK3 β by conditional gene knockout and drug SB216763 in animal model,
Assemble Nrf2 in nucleus and in conjunction with Antioxidant responsive element, raise the expression of anti-oxidant albumen, enhancing foot is thin
Born of the same parents' protective effect.
(3) in cell experiment, inhibit GSK-3 β that the Antioxidation reaction mediated to Nrf2 can be enhanced, this effect is logical
Cross and inhibit non-Keap1 dependence Nrf2 access, reduce Nrf2 go out core, degradation and realize.Nrf2 assembles in nucleus, and with
Anti-oxidant reflection element combines, and will start the transcription of antioxidant genes, plays sertoli cell protective effect.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (2)
1. a kind of GSK-3 beta inhibitor, which is characterized in that the GSK-3 beta inhibitor are as follows: LiCl.
2. a kind of GSK-3 beta inhibitor as described in claim 1 intervenes the application method of novel targets, feature in diabetic nephropathy
It is, the GSK-3 beta inhibitor includes: low-dose Oral lithium salts tablet in the application method that diabetic nephropathy intervenes novel targets
Or low dose of vein uses LiCl injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811485443.9A CN109453191A (en) | 2018-12-06 | 2018-12-06 | GSK-3 beta inhibitor and diabetic nephropathy intervene novel targets application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811485443.9A CN109453191A (en) | 2018-12-06 | 2018-12-06 | GSK-3 beta inhibitor and diabetic nephropathy intervene novel targets application |
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| Publication Number | Publication Date |
|---|---|
| CN109453191A true CN109453191A (en) | 2019-03-12 |
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|---|---|---|---|
| CN201811485443.9A Pending CN109453191A (en) | 2018-12-06 | 2018-12-06 | GSK-3 beta inhibitor and diabetic nephropathy intervene novel targets application |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997041854A1 (en) * | 1996-05-07 | 1997-11-13 | The Trustees Of The University Of Pennsylvania | Inhibitors of glycogen synthase kinase-3 and methods for identifying and using the same |
| CN101453999A (en) * | 2005-12-22 | 2009-06-10 | 神经化学（国际）有限公司 | Treatment of renal disorders, diabetic nephopathy and dyslipidemias |
| CN101884789A (en) * | 2004-02-11 | 2010-11-17 | 法布罗根股份有限公司 | CTGF is as the treatment target spot of diabetic nephropathy |
| CN103461992A (en) * | 2013-08-05 | 2013-12-25 | 买世禄 | Production method of health care food with characteristics of rich multiple nutrients and diabetes rehabilitation |
-
2018
- 2018-12-06 CN CN201811485443.9A patent/CN109453191A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997041854A1 (en) * | 1996-05-07 | 1997-11-13 | The Trustees Of The University Of Pennsylvania | Inhibitors of glycogen synthase kinase-3 and methods for identifying and using the same |
| CN101884789A (en) * | 2004-02-11 | 2010-11-17 | 法布罗根股份有限公司 | CTGF is as the treatment target spot of diabetic nephropathy |
| CN101453999A (en) * | 2005-12-22 | 2009-06-10 | 神经化学（国际）有限公司 | Treatment of renal disorders, diabetic nephopathy and dyslipidemias |
| CN103461992A (en) * | 2013-08-05 | 2013-12-25 | 买世禄 | Production method of health care food with characteristics of rich multiple nutrients and diabetes rehabilitation |
Non-Patent Citations (1)
| Title |
|---|
| 唐皓月等: ""GSK － 3β 抑制剂对糖尿病肾病大鼠的作用研究"", 《中国中西医结合肾病杂质》 * |
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Application publication date: 20190312 |