CN115581697A - Application of nicotine and derivatives as FXR-meglin/cublin regulator in preparation of choleretic products - Google Patents
Application of nicotine and derivatives as FXR-meglin/cublin regulator in preparation of choleretic products Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of nicotine and derivatives as FXR-meglin/cublin regulators in preparing choleretic products, wherein the choleretic products are anti-cholestasis or anti-cholecystolithiasis products. In the application, the nicotine and the nicotine derivative are used for effectively treating bile stasis and gallstone by inhibiting the expression and the function of FXR-megalin/cublin in a gallbladder, and have the advantages of novel action target, reliable curative effect, no toxic or side effect, rich resources, low price and the like.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to application of nicotine and derivatives as FXR-meglin/cublin regulators in preparation of choleretic products.
Background
Gallstone disease is one of the most common and expensive gastrointestinal disorders worldwide. Cholesterol gallstones are a major public health problem in all developed countries. Gallstone formation is affected by a variety of factors, including smoking. However, some studies have shown that smoking is not a risk factor for gallstones and may even produce the opposite effect. Older smokers who smoke in older children are at lower risk of developing cholelithiasis than non-smokers. In view of the above, the development of novel effective drugs from tobacco changes the level of gallstone-related proteins in the gallbladder or bile components, thereby affecting the formation of gallstones, and has positive significance for the prevention and treatment of gallstone.
Gallstones are formed in the biliary system by cholesterol secretions in the bile, which are caused by either cholesterol excess or/and bile salt deficiency. It has been found that many genes are related to the formation of gallstones, and they are involved in regulating factors such as cholesterol supersaturation, crystal nucleation, lipid metabolism abnormality, bile component abnormality, gallbladder dysfunction and gallbladder inner wall mucous membrane absorption function abnormality in bile, thereby affecting cholesterol/bile acid metabolism, inducing cholesterol supersaturation from bile and forming gallstones. Thus, modulation of the expression of genes involved in cholesterol/bile acid metabolism may be associated with calculus formation.
Currently, the clinically used oral gallstone drugs mainly include chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (VDCA). The two medicines desaturate bile by reducing secretion of bile cholesterol, unsaturated bile has effect of dissolving cholesterol, so that cholesterol molecules on surface of cholelithiasis are continuously dissolved, and cholelithiasis volume is gradually reduced to completely dissolve cholelithiasis. However, studies have shown that these stone therapeutic agents are only suitable for conditions where the diameter of gallstones is below 2 cm. In addition, the calculus treatment medicine has high value, certain side effects and toxic reactions (mainly including gastrointestinal tract, liver and gall dysfunction and anaphylactic reaction), and the medicine must be taken for a lifetime, if the medicine is stopped for 3 months, cholesterol in the bile is changed into a supersaturated state again, and calculus will relapse, and the recurrence rate can reach 25% in 3 years according to statistics. Therefore, there is an urgent need to find a new drug with high efficiency and low toxicity based on a new action target for treating gallstones clinically.
Nicotine, commonly known as nicotine, is a potent parasympathomimetic alkaloid found in solanaceae plants, is the main chemical component and the main addictive component of cigarettes, and belongs to one of stimulants. Nicotine is a nicotinic acetylcholine receptor agonist and acts as a receptor antagonist on nAChR α 9 and nAChR α 10. Several authoritative lines of evidence suggest that nicotine can be used to treat a variety of diseases such as depression, parkinson, and the like. At the same time, the nicotine has anti-inflammatory effect, so the nicotine is beneficial to the ulcerative colitis. However, the effect on gallstones has not been reported.
Disclosure of Invention
The invention aims to solve the technical problem of providing an application of nicotine and derivatives as FXR-meglin/cublin regulators in preparation of choleretic products, wherein the nicotine and the derivatives as FXR novel regulators can regulate bile cholesterol metabolism and effectively inhibit the formation of gallstones by inhibiting the expression and function of the FXR-meglin/cublin in gallbladders.
The technical problem to be solved by the invention is realized by the following technical scheme:
application of nicotine and derivatives as FXR-megalin/cublin regulator in preparing choleretic product is provided.
Preferably, the choleretic product is an anti-cholestasis or anti-gallstone product.
Preferably, the nicotine is extracted from tobacco and the derivative is (1 ' S.2' S) -nicotine 1' -oxide. Of course, the nicotine may be pure or obtained from other sources, and the application is not limited thereto.
Preferably, the nicotine affects gallstone formation by modulating cholesterol metabolism in gallbladder epithelial cells.
Preferably, the cholagogic product is a medicament or a health-care product.
A pharmaceutical composition comprises nicotine and derivatives.
Preferably, the composition is administered intravenously or orally.
Preferably, the pharmaceutical composition is a tablet, granule, capsule, suspension or lyophilizate.
Preferably, the pharmaceutical composition further comprises medically acceptable excipients.
The technical scheme of the invention has the following beneficial effects:
the invention provides application of nicotine and derivatives thereof in antagonizing gallstone formation through FXR-megalin/cublin, wherein the nicotine and the derivatives thereof are used as FXR-megalin/cublin regulators and used for effectively treating bile stasis and gallstone by inhibiting expression and function of FXR-megalin/cublin in gallstone.
In addition, nicotine and its derivatives have FXR-megalin/cublin expression inhibiting activity, and can be used for preparing choleretic drugs or health products, and drugs for treating cholestasis or cholelithiasis.
The application clarifies a regulation mechanism of nicotine between gall-bladder stone formation and cholesterol/bile acid balance, and provides a theoretical basis for developing preventive medicaments for corresponding diseases.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description, serve to explain the principles of the invention.
FIG. 1 is a graph of the therapeutic effect of nicotine on gall stone in mice according to the present application (wherein: A is the formation of gall stone in mice of different groups, and B is a bar graph of gall stone weight in mice of different groups).
FIG. 2 shows the control effect of nicotine on bile metabolism (wherein: A is the cholesterol level, B is the phospholipid level, C is the bile salt level, D is the triglyceride level, E is the total cholesterol level, F is the low density lipoprotein level, G is the high density lipoprotein level, and H is the total bile acid level) in different groups of mice according to the present invention.
FIG. 3 shows the regulation effect of nicotine on FXR-Megalin/cublin in mouse gallbladder (wherein: A is mRNA level of fluorescence quantitative determination of bile acid metabolism-related factor, B is protein level of FXR, megalin and Cubilin by Western blotting, and C is expression of FXR and Megalin by immunohistochemical staining).
Detailed Description
Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be noted that: the relative arrangement of the components and steps, the numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless it is specifically stated otherwise.
EXAMPLE 1 therapeutic Effect of Nicotine on gall bladder calculi in mice
Experimental materials:
wild C57 mice, 8 weeks old, male. Randomized into 5 groups: normal diet group (ND), normal diet + nicotine group (ND + nicotine (H)), stone-forming diet group (LD), stone-forming diet + low dose nicotine group (LD + nicotine (L)), stone-forming diet + high dose nicotine group (LD + nicotine (H)).
The experimental method comprises the following steps:
(1) Week 1 normal diet, high bile salt diet (1.25% cholesterol +0.5% cholic acid) was changed from week 2. The normal diet group was given physiological saline, the normal diet + nicotine group, the stone-forming diet + low-dose nicotine group, and the stone-forming diet + high-dose nicotine group was given nicotine (low dose of 1.1mg/kg and high dose of 6.6 mg/kg) from the 5 th week, administered by intraperitoneal injection once every 2 days, and ended at the 10 th week.
(2) At week 10, the mice were opened after they died, the cholecystolithiasis was observed, photographs were taken, the common bile duct was ligated, the gallbladder was removed, and the stones were weighed.
The experimental results are as follows:
the results show that after the stone-forming diet, the formation rate of the gall-bladder stones of the mice is higher. Under the nicotine administration, the weight of the gall bladder is obviously reduced compared with that of the stone-forming diet group, and the volume of the bile is increased, which shows that the nicotine has the function of treating gallstone and cholestasis and is shown in figure 1.
Example 2 Effect of nicotine on bile metabolism in vivo
Experimental materials:
wild C57 mice, 8 weeks old, male, randomly divided into 5 groups: normal diet group (ND), normal diet + nicotine group (ND + nicotine (H)), stone-forming diet group (LD), stone-forming diet + low-dose nicotine group (LD + nicotine (L)), stone-forming diet + high-dose nicotine group (LD + nicotine (H)).
The experimental method comprises the following steps:
(1) Week 1 normal diet, high bile salt diet (1.25% cholesterol +0.5% cholic acid) was changed from week 2. The normal diet group was given physiological saline, the normal diet + nicotine group, the stone-forming diet + low-dose nicotine group, and the stone-forming diet + high-dose nicotine group was given nicotine (low dose of 1.1mg/kg and high dose of 6.6 mg/kg) from the 5 th week, administered by intraperitoneal injection once every 2 days, and ended at the 10 th week.
(2) At week 10, the mice were anesthetized with 35mg/kg barbiturate-free sodium, gallbladder bile was collected, and blood was collected intravenously. The biochemical analyzer detects cholesterol, phospholipid, bile salt, triglyceride (TG), total Cholesterol (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C), and Total Bile Acid (TBA). Liver tissues are taken, and qPCR is carried out to determine the expression level of mRNA related to bile metabolism, wherein the expression level comprises FXR, cyp7A1, cyp7B1, cyp8B1, cyp27A1, BSEP, NTCP, OATP1, OST alpha, OST beta, MRP2, MRP3 and MRP4.
The experimental results are as follows:
the results showed that cholesterol levels in gall bladder bile were significantly reduced in the LD + nicotine (H) group compared to the LD group. The cholesterol level was not significantly reduced in the LD + nicotinine (L) group compared to the LD group. There was no significant difference between phospholipids and bile salts in the experimental group bile compared to the LD group. Compared with the ND group, the levels of TG, TC and LDL-C in the serum of the LD group are remarkably increased, and the levels of HDL-C and TBA are remarkably reduced. The levels of these indicators were unchanged after low nicotine concentration treatment. Compared with the LD group, the mouse serum TG, TC and LDL-C of the LD + nicotinine (H) group are obviously reduced, and the HDL-C and TBA levels are increased. Cyp7A1, NTCP, OST β mRNAs were significantly up-regulated in the nicotine-treated group compared to the LD group; FXR and Cyp7B1 mRNA were down-regulated. The nicotine has the function of regulating bile cholesterol, and is shown in figure 2.
Example 3 inhibitory Activity of Nicotine against FXR-megalin/cublin and its Effect on metabolic genes
Experimental materials:
wild C57 mice, 8 weeks old, males, randomly divided into 5 groups: normal diet group (ND), normal diet + nicotine group (ND + nicotine (H)), stone-forming diet group (LD), stone-forming diet + low-dose nicotine group (LD + nicotine (L)), stone-forming diet + high-dose nicotine group (LD + nicotine (H)). Week 1 normal diet, high bile salt diet (1.25% cholesterol +0.5% cholic acid) was changed from week 2.
The experimental method comprises the following steps:
(1) The normal diet group was given physiological saline, the normal diet + nicotine group, the stone-forming diet + low-dose nicotine group, and the stone-forming diet + high-dose nicotine group was given nicotine (low dose of 1.1mg/kg and high dose of 6.6 mg/kg) from the 5 th week, administered by intraperitoneal injection once every 2 days, and ended at the 10 th week.
(2) On week 10, mice were euthanized under 35mg/kg sodium pentobarbital. Taking gallbladder tissues, and measuring the expression level of FXR-megalin/cublin signal pathway related mRNA by qPCR; detecting the protein expression level of FXR-megalin/cublin by protein immunoblotting; immunohistochemistry was used to detect the expression of FXR-megalin (4).
The experimental results are as follows:
the results showed that the expression levels of NPC1L1 and megalin in the LD group were significantly decreased, while those of ABCG5/G8 and SR-BI were increased, as compared with the ND group. Low and high concentrations of nicotine can attenuate their expression levels. Immunoblotting and immunohistochemistry results showed that nicotine did not alter cubilin protein levels, but restored LD down-regulated FXR and megalin levels. Illustrating that nicotine may influence the formation of gallstones by regulating cholesterol metabolism in the gallbladder epithelial cells, see figure 3.
In the application, nicotine and derivatives thereof as FXR novel regulators can regulate bile cholesterol metabolism and effectively inhibit the formation of gallstones by inhibiting the expression of FXR-meglin/cublin signal pathways; has the advantages of reliable curative effect, low price and the like.
Although the present invention has been described with reference to the above embodiments, it should be understood that the present invention is not limited thereto, and various changes and modifications may be made by those skilled in the art without departing from the spirit and scope of the present invention.
Claims (9)
1. Application of nicotine and its derivatives as FXR-megalin/cublin regulator in preparing choleretic product is provided.
2. Use according to claim 1, wherein the choleretic product is an anti-cholestasis or anti-gallstone product.
3. Use according to claim 1, wherein the nicotine is extracted from tobacco and the derivative is (1 ' s.2's) -nicotine 1' -oxide.
4. The use of claim 1, wherein the nicotine affects gallstone formation by modulating cholesterol metabolism in gallbladder epithelial cells.
5. The use according to claim 1, wherein the choleretic product is a pharmaceutical or nutraceutical.
6. A pharmaceutical composition comprising nicotine and derivatives according to any of claims 1-5.
7. The pharmaceutical composition of claim 6, wherein the composition is administered intravenously or orally.
8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a tablet, granule, capsule, suspension, or lyophilizate.
9. The pharmaceutical composition of claim 6, further comprising a medically acceptable excipient.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1997034605A1 (en) * | 1996-03-21 | 1997-09-25 | Mayo Foundation For Medical Education And Research | Use of nicotine to treat liver disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1997034605A1 (en) * | 1996-03-21 | 1997-09-25 | Mayo Foundation For Medical Education And Research | Use of nicotine to treat liver disease |
Non-Patent Citations (3)
| Title |
|---|
| KERSHBAUM A, BELLET S, KHORSANDIAN R.: "Elevation of serum cholesterol after administration of nicotine", AMERICAN HEART JOURNAL, vol. 69 * |
| LATHA M S, VIJAYAMMAL P L, KURUP P A: "Effect of nicotine administration on lipid metabolism in rats", THE INDIAN JOURNAL OF MEDICAL RESEARCH, vol. 98 * |
| RHODES M, ZIJLASTRA F J, BRADBURN D M, 等: "Effect of nicotine on gallbladder bile", 《 CANADIAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 》, vol. 8, pages 2 - 3 * |
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