CN114288282A - Application of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of drugs for preventing and/or treating obesity - Google Patents
Application of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of drugs for preventing and/or treating obesity Download PDFInfo
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Abstract
The invention relates to an application of an anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of a medicine for preventing and/or treating obesity, belonging to the technical field of new application of medicines. The anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid can be applied to preparation of a medicine for effectively treating obesity, effectively relieves obesity caused by high-fat diet, reduces body weight, reduces accumulation of visceral fat, scapular fat and epididymal fat, and effectively relieves sugar metabolism abnormality caused by obesity. The use of the anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in the preparation of a medicament for the treatment of obesity is disclosed for the first time and has an unexpected effect on inhibiting the occurrence of obesity.
Description
Technical Field
The invention relates to the technical field of new application of medicaments, in particular to application of an anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid (DIDS) in preparation of a medicament for preventing and/or treating obesity.
Background
Obesity refers to a chronic metabolic disease caused by the interaction of various factors including genetic and environmental factors, such as excessive fat accumulation and/or abnormal distribution in the body, which leads to weight gain. Overweight and obesity, especially abdominal obesity, have a variety of metabolic abnormalities that are important risk factors for cardiovascular and cerebrovascular diseases, diabetes, certain cancers, and other chronic diseases.
In recent years, with the change of dietary structure and life style, the occurrence of obesity in China is increased obviously. Obesity is an important risk factor for cardiovascular and cerebrovascular diseases, diabetes, certain cancers and other chronic diseases. Therefore, the positive prevention and treatment of obesity has very important significance for preventing cardiovascular and cerebrovascular diseases, diabetes, certain cancers and the like.
At present, the clinical treatment of obesity emphasizes comprehensive treatment mainly based on behaviors, diet and exercise, and is supplemented with medicaments or operation treatment when necessary. The patient needs to maintain physical activity and physical exercise for a long time, and the weight of the obese patient can be reduced. However, most obese patients have difficulty adhering to long-term physical activity and physical exercise, and thus it is still necessary to develop effective drugs for treating obesity.
Disclosure of Invention
The invention aims to provide application of an anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of a medicament for preventing and/or treating obesity. The 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid can be applied to preparation of a medicine for effectively treating obesity, effectively relieving obesity caused by high-fat diet, reducing weight, reducing accumulation of visceral fat, scapular fat and epididymal fat, and effectively relieving sugar metabolism abnormality caused by obesity.
The invention provides application of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of a medicament for preventing and/or treating obesity.
The invention also provides application of the 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of a medicine for preventing and/or treating obesity caused by high-fat diet.
The invention also provides application of the 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of a medicine for improving obesity symptoms.
Preferably, the improvement of obesity symptoms comprises one or more of reduction of body weight, reduction of visceral fat in the abdominal cavity, reduction of scapular fat and reduction of epididymal fat.
The invention also provides application of the 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of a medicine for improving abnormal glycometabolism.
Preferably, the improvement of the abnormal glucose metabolism includes one or more of reduction of an increase in blood glucose, reduction of glucose tolerance, reduction of insulin resistance, and increase of sensitivity to insulin.
Preferably, the carbohydrate metabolism disorder includes an obesity-induced carbohydrate metabolism disorder.
The invention also provides a medicament for preventing and/or treating obesity, which comprises 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid and auxiliary materials.
Preferably, the auxiliary materials comprise one or more than two of diluent, adhesive, disintegrant, glidant, lubricant, flavoring agent, inclusion material and adsorbing material.
Preferably, the medicament is in the form of capsules, pills, tablets, granules or injections.
The invention provides application of an anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of a medicament for preventing and/or treating obesity. The invention discovers that 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid can effectively relieve obesity caused by high-fat diet, reduce the weight, reduce the accumulation of visceral fat, scapular fat and epididymal fat, and effectively relieve the abnormal carbohydrate metabolism caused by obesity. The anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid can be applied to the preparation of a medicament for effectively treating obesity, and the application of the 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid to the preparation of the medicament for treating obesity is disclosed for the first time and has an unexpected effect on inhibiting the occurrence of obesity.
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FIG. 1 is a graph showing the effect of prophylactic administration of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid, an anion transport inhibitor provided by the present invention, on weight gain in mice following administration of a high fat diet;
FIG. 2 is a graph showing the effect of prophylactic administration of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid, an anion transport inhibitor provided by the present invention, on visceral fat, scapular fat, epididymal fat accumulation in mice following high fat diet;
FIG. 3 is a graph showing the effect of therapeutic administration of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid, an anion transport inhibitor provided by the present invention, on weight gain in mice following administration of a high fat diet;
FIG. 4 is a graph showing the effect of therapeutic administration of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid, an anion transport inhibitor provided by the present invention, on visceral fat, scapular fat, epididymal fat accumulation in mice following high fat diet;
FIG. 5 is a graph of the effect of therapeutic administration of the anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid of the present invention on the increase of fasting plasma glucose in mice following obesity in mice administered a high fat diet;
FIG. 6 is a graph of the effect of therapeutic administration of the anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid of the present invention on the increase in glucose tolerance in mice following obesity induced by administration of a high fat diet;
FIG. 7 is a graph showing the effect of therapeutic administration of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid, an anion transport inhibitor of the present invention, on the increase in insulin resistance in mice following obesity in the mice following administration of a high fat diet.
Detailed Description
The invention provides application of an anion transport inhibitor 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid (DIDS) in preparation of a medicament for preventing and/or treating obesity. DIDS is an inhibitor of anion channels such as chloride ions and can inhibit the transport of chloride ions in tissue cells. The DIDS can effectively reduce the weight gain of the mice caused by high-fat diet, reduce the accumulation of fat in the bodies of the mice, effectively relieve the abnormal carbohydrate metabolism (caused by obesity) and realize the treatment of the obesity.
The invention also provides application of the anion transport inhibitor DIDS in preparing a medicament for preventing and/or treating obesity caused by high-fat diet. The results of animal model experiments show that DIDS inhibits the weight gain of mice caused by high-fat diet, reduces the accumulation of fat in the bodies of the mice, and relieves the abnormal carbohydrate metabolism caused by obesity.
The invention also provides application of the anion transport inhibitor DIDS in preparing a medicament for improving obesity symptoms. In the present invention, the improvement of obesity symptoms includes one or more of reduction of body weight, reduction of visceral fat in the abdominal cavity, reduction of scapular fat, and reduction of epididymal fat. The specific examples show that DIDS can effectively relieve the obesity of mice caused by high-fat diet, reduce the weight of the mice, reduce the content of visceral fat, scapular fat and epididymal fat in abdominal cavities of the mice, and effectively relieve the increase of blood sugar, the increase of sugar tolerance and the increase of insulin resistance of the mice caused by the obesity.
The invention also provides application of the 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of a medicine for improving abnormal glycometabolism. In the present invention, the improvement of the abnormal glucose metabolism preferably includes one or more of reduction of blood sugar elevation, reduction of glucose tolerance, reduction of insulin resistance and increase of sensitivity to insulin. In the present invention, the abnormal sugar metabolism preferably includes abnormal sugar metabolism caused by obesity. The specific examples show that the administration of DIDS, an anion transport inhibitor, can effectively relieve the increase of blood sugar in mice caused by obesity, reduce the sugar tolerance and insulin resistance of the mice and increase the sensitivity of the mice to insulin. Is effective in treating sugar metabolism disorder caused by obesity.
The invention also provides a medicament for preventing and/or treating obesity, which comprises 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid and auxiliary materials. The auxiliary material is preferably a pharmaceutically acceptable auxiliary material. In the present invention, the auxiliary material preferably includes one or more of a diluent, an adhesive, a disintegrant, a glidant, a lubricant, a corrigent, an inclusion material and an adsorbing material. The sources of the auxiliary materials in the present invention are not particularly limited, and conventional commercially available auxiliary materials well known to those skilled in the art may be used. In the present invention, the dosage form of the drug preferably includes capsules, pills, tablets, granules or injections. The medicament of the invention can comprise an oral preparation or an injection.
The following examples are provided to describe in further detail the application of the DIDS as an anion transport inhibitor in the preparation of drugs for preventing and/or treating obesity, and the technical solutions of the present invention include, but are not limited to, the following examples.
The control vehicle described in the examples of the present invention preferably includes all solvents capable of dissolving DIDS, and in particular, DMSO is used in the examples.
Example 1
Effect of DIDS, an anion transport inhibitor, on obesity in mice on high fat diet
The development of obesity in mice on a high fat diet is a common animal model of obesity in experimental studies. In order to research the effect of the administration for preventing the anion transport inhibitor DIDS on obesity, the invention selects C57BL6 male mice with the age of 5-6 weeks for carrying out experiments, and provides high-fat diet to establish an obesity model. Before obesity occurred, the effect of administering different doses of DIDS on the occurrence of obesity in mice was observed. At 2 weeks after administration of the high fat diet, the mice were randomly divided into a high fat diet group, a control vehicle and did 10mg/kg and 20mg/kg treatment groups, and a normal mouse group to which a normal diet was simultaneously given was a normal control (normal group). Each group contains 20-22 mice. DIDS was administered intraperitoneally once daily to mice in the form of 10mg/kg, 20mg/kg or control vehicle, and high-fat diet was administered to each group, and at 14 weeks after administration, the mice were sacrificed, and the body weight condition and accumulation condition of visceral fat, scapular fat, and epididymal fat of the mice were examined. The results showed that the control vehicle group (control group) had no effect on the body weight of the mice and the accumulation of visceral fat, scapular fat and epididymal fat of the mice caused by the high fat diet, compared to the normal group (no high fat diet), but the DIDS groups significantly reduced the body weight of the mice (fig. 1) and significantly reduced the accumulation of visceral fat, scapular fat and epididymal fat of the mice (fig. 2).
Figure 1 shows the effect of DIDS prophylactic administration on the body weight gain of mice after administration of a high fat diet. The body weight of the mice was significantly increased after the administration of a High Fat Diet (HFD) compared to the Normal group (Normal, no High fat diet). Control vehicle (Control) had no effect on weight gain in mice, and DIDS10mg/kg and 20mg/kg groups significantly reduced weight compared to the Control group. Compared with the Normal group (Normal),$P<0.01; compared with high fat diet group (HFD)#P>0.05; p compared to Control group (Control)<0.01。
Fig. 2 shows the effect of DIDS prophylactic administration on accumulation of visceral fat (VAT), scapular fat (SAT), epididymal fat (EAT) in mice after administration of a high fat diet. Accumulation of visceral fat, scapular fat, epididymal fat was significantly increased in mice after administration of High Fat Diet (HFD) compared to Normal group (Normal, no High fat diet). Control vehicle (Control) treatment had no effect on accumulation of visceral fat, scapular fat, and epididymal fat in mice, and accumulation of visceral fat, scapular fat, and epididymal fat was significantly reduced in mice of DIDS10mg/kg and 20mg/kg groups, as compared to the Control group. Compared with the Normal group (Normal),$P<0.01; compared with high fat diet group (HFD)#P>0.05; p compared to Control group (Control)<0.05，**P<0.01。
The results indicate that prophylactic administration of the anion transport inhibitor DIDS is effective in preventing the occurrence of obesity in mice caused by high fat diet. The DIDS as an anion transport inhibitor is feasible to prepare the drug which can effectively prevent the obesity.
Example 2
Effect of DIDS therapeutic administration as an anion transport inhibitor on obesity in mice on high fat diet
The development of obesity in mice on a high fat diet is a common animal model of obesity in experimental studies. In order to research the effect of the DIDS treatment administration as an anion transport inhibitor on relieving obesity, the invention selects a 5-6-week-old C57BL6 male mouse for experiment, and provides a high-fat diet to establish an obesity model. After obesity occurred, the relief of obesity in mice given different doses of DIDS was observed. At 16 weeks after administration of the high fat diet, after the mice were obese, the mice were randomly divided into a high fat diet group, a control vehicle, and did 10mg/kg and 20mg/kg treatment groups, each group was administered with the high fat diet all the time, and a normal mouse group on a normal diet was also set as a normal control (normal group). Each group of 22-24 mice. DIDS is administered in the abdominal cavity of mice once a day in 10mg/kg, 20mg/kg or control vehicle 16 weeks after administration, and the body weight condition and accumulation condition of visceral fat, scapular fat and epididymal fat of the mice are examined. The results showed that the control vehicle-treated group (control group) had no effect on the body weight of the mice and the accumulation of visceral fat, scapular fat and epididymal fat of the mice caused by the high fat diet, compared to the normal group (no high fat diet), but the DIDS groups significantly reduced the body weight of the mice (fig. 3), and significantly reduced the accumulation of visceral fat, scapular fat and epididymal fat of the mice (fig. 4).
Figure 3 shows the effect of DIDS treatment administration on body weight gain in mice following high fat diet. The body weight of the mice was significantly increased after the administration of a High Fat Diet (HFD) compared to the Normal group (Normal, no High fat diet). Control vehicle(Control) had no effect on the weight gain of the mice, and the DIDS10mg/kg and 20mg/kg groups significantly reduced the weight of the mice compared to the Control group. Compared with the Normal group (Normal),$P<0.01; compared with high fat diet group (HFD)#P>0.05; p compared to Control group (Control)<0.01。
Fig. 4 shows the effect of DIDS treatment administration on accumulation of visceral fat (VAT), scapular fat (SAT), epididymal fat (EAT) in mice after administration of a high fat diet. Accumulation of visceral fat, scapular fat, epididymal fat was significantly increased in mice after administration of High Fat Diet (HFD) compared to Normal group (Normal, no High fat diet). Control vehicle (Control) treatment had no effect on accumulation of visceral fat, scapular fat, and epididymal fat in mice, and accumulation of visceral fat, scapular fat, and epididymal fat was significantly reduced in mice of DIDS10mg/kg and 20mg/kg groups, as compared to the Control group. Compared with the Normal group (Normal),$P<0.01; compared with high fat diet group (HFD)#P>0.05; p compared to Control group (Control)<0.05，**P<0.01。
The results show that administration of the anion transport inhibitor DIDS treatment is effective in relieving obesity in mice caused by high fat diet. The DIDS, an anion transport inhibitor, is feasible to prepare the drug which can effectively treat the obesity.
Example 3
Effect of DIDS administration as an anion transport inhibitor on abnormal carbohydrate metabolism caused by obesity in mice
Obesity often causes abnormalities in glucose metabolism including increased blood glucose, increased glucose tolerance, and increased insulin resistance. In order to research the effect of the DIDS treatment administration as an anion transport inhibitor on relieving the abnormal glucose metabolism caused by obesity, the invention selects 5-6-week-old C57BL6 male mice for experiment, and provides high-fat diet to establish an obesity model. After obesity occurred, the effect of administering different doses of DIDS on the increase in blood glucose, glucose tolerance and insulin resistance in mice was observed. After obesity occurred 16 weeks after administration of the high fat diet, the mice were randomly divided into a high fat diet group, a control vehicle, and did 10mg/kg and 20mg/kg treatment groups, and a normal mouse group, which was also given a normal diet, was a normal control. Each group of 22-24 mice. Administering DIDS by 10mg/kg, 20mg/kg or control vehicle in the abdominal cavity of the mouse once a day 16 weeks after administration, and after fasting the mouse for 12 hours, performing a glucose tolerance test on the mouse by injecting glucose in the abdominal cavity of the mouse; and after the mice are fasted for 4 hours on the next day, insulin tolerance experiments are carried out by injecting insulin into the abdominal cavities of the mice, and the glucose tolerance and the insulin resistance of the mice are respectively detected. Mice were sacrificed after 12 hours of fasting after 2 days and fasting mice were examined for plasma glucose levels. The results showed that the administration of the high fat diet resulted in a significant increase in blood glucose and an increase in glucose tolerance and insulin resistance in mice, compared to the normal group (no administration of the high fat diet). The control vehicle treatment group had no effect on the increase in blood glucose and the increase in glucose tolerance and insulin resistance of the mice caused by the high fat diet, but each group of DIDS significantly reduced the increase in blood glucose in the mice (fig. 5), significantly reduced the glucose tolerance and insulin resistance of the mice, and increased the sensitivity of the mice to insulin (fig. 7).
Figure 5 shows the effect of DIDS treatment administration on the increase in fasting plasma glucose in mice following high fat diet. Fasting plasma glucose was significantly elevated in mice following administration of a High Fat Diet (HFD) compared to Normal group (Normal, no High fat diet). Control vehicle (Control) had no effect on the blood glucose elevation in mice. DIDS10mg/kg and 20mg/kg groups significantly reduced the blood glucose rise in mice compared to the control group. Compared with the Normal group (Normal),$P<0.01; compared with high fat diet group (HFD)#P>0.05; p compared to Control group (Control)<0.01。
Figure 6 demonstrates the effect of DIDS treatment administration on the increase in glucose tolerance in mice following administration of a high fat diet. After the mice were fasted for 12 hours, the mice were subjected to a glucose tolerance test by intraperitoneal injection of glucose. The glucose tolerance of the mice was significantly increased after administration of a High Fat Diet (HFD) compared to the Normal group (Normal, no High fat diet). Control vehicle (Control) treatment had no effect on glucose tolerance in mice. DIDS10 compared to control groupThe glucose tolerance of the mice in the mg/kg and 20mg/kg groups was significantly reduced. Compared with the Normal group (Normal),$P<0.01; compared with high fat diet group (HFD)#P>0.05; p compared to Control group (Control)<0.01。
Figure 7 shows the effect of DIDS treatment administration on the increase in insulin resistance in mice following administration of a high fat diet. After fasting for 4 hours, the mice were subjected to an intraperitoneal injection of insulin for a mouse insulin tolerance test. The insulin resistance of the mice was significantly increased after administration of a High Fat Diet (HFD) compared to the Normal group (Normal, no High fat diet). Control vehicle (Control) treatment had no effect on mouse insulin resistance. Compared with the control group, the insulin resistance of mice in DIDS10mg/kg and 20mg/kg groups is obviously reduced. Compared with the Normal group (Normal),$P<0.01; compared with high fat diet group (HFD)#P>0.05; p compared to Control group (Control)<0.01。
These results indicate that administration of the DIDS, an anion transport inhibitor, is effective in alleviating increased blood glucose in mice caused by obesity, reducing glucose tolerance and insulin resistance in mice, and increasing the sensitivity of mice to insulin. The DIDS as an anion transport inhibitor can be used for preparing a medicament capable of effectively treating sugar metabolism disorder caused by obesity.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
- Application of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of medicines for preventing and/or treating obesity.
- Application of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of medicines for preventing and/or treating obesity caused by high-fat diet.
- Application of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of a medicament for improving obesity symptoms.
- 4. The use of claim 3, wherein the improvement in obesity comprises one or more of weight loss, reduction in visceral fat in the abdominal cavity, reduction in scapular fat, and reduction in epididymal fat.
- Application of 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid in preparation of medicines for improving abnormal carbohydrate metabolism.
- 6. The use of claim 5, wherein the amelioration of abnormal glucose metabolism comprises one or more of a decrease in elevated blood glucose, a decrease in glucose tolerance, a decrease in insulin resistance, and an increase in sensitivity to insulin.
- 7. Use according to claim 5 or 6, wherein said carbohydrate metabolism disorder comprises an obesity-induced carbohydrate metabolism disorder.
- 8. A medicament for preventing and/or treating obesity, which comprises 4,4 '-diisothiocyanostilbene-2, 2' -disulfonic acid and auxiliary materials.
- 9. The medicament of claim 8, wherein the excipients comprise one or more of diluents, binders, disintegrants, glidants, lubricants, flavoring agents, inclusion materials and adsorbing materials.
- 10. The medicament of claim 8, wherein the medicament is in the form of capsules, pills, tablets, granules or injections.
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| CN102091061A (en) * | 2010-11-12 | 2011-06-15 | 河北医科大学 | Application of 1,2-diphenylethylene derivative in pharmacy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102091061A (en) * | 2010-11-12 | 2011-06-15 | 河北医科大学 | Application of 1,2-diphenylethylene derivative in pharmacy |
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| A H HENKIN，等: "Evidence for protein-mediated fatty acid efflux by adipocytes", vol. 204, no. 4, pages 562 - 570 * |
| BYUNG-HYUN PARK ；等: "Demonstration of reverse fatty acid transport from rat cardiomyocytes", 《J LIPID RES》, vol. 45, no. 11, pages 1992 - 1999 * |
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