TWI624477B - Peptide composition and use thereof - Google Patents

Abstract

The present invention is to provide a peptide comprising an amino acid sequence encoding line comprising SEQ ID No. 1. By administering a composition containing an effective amount of the peptide to one body, liver-related diseases such as fatty liver, liver fibrosis, liver damage and the like can be improved or/prevented.

Description

Peptide composition and use thereof

The present invention relates to a small molecule protein, in particular to a peptide composition and use thereof.

According to the process of aging, it is often associated with insulin resistance. The poor regulation of blood glucose caused by aging can cause poor control of liver glucose and triglyceride secretion. Therefore, aging can lead to dyslipidemia or hyperinsulinemia. The occurrence of diseases related to metabolic disorders. When excessive intake of fat or insulin resistance occurs, excess fat accumulates in the liver, resulting in fatty liver or related metabolic diseases.

Clinically, there are no effective drugs for fatty liver, which can only be improved by diet control or exercise habits. However, diet control and exercise habits are difficult for most people to maintain, and are caused by aging. The metabolic diseases are not effective. Because eating habits and exercise habits are difficult to change, scientists are now turning to the development of substances that can be used to prevent or control obesity, especially the biologically active small molecule peptides.

Therefore, when all countries are facing the problem of population aging, maintaining the health of the elderly has become an important issue. Accordingly, the development of a component capable of effectively preventing and/or treating metabolic syndrome-related diseases is currently an important research goal.

The main object of the present invention is to provide a peptide comprising an amino acid sequence encoding comprising SEQ ID No. 1. By administering a composition containing an effective amount of the peptide to one body, liver-related diseases such as fatty liver, liver fibrosis, liver damage and the like can be improved or/prevented.

In an embodiment of the invention, the amino acid sequence of the peptide is encoded as SEQ ID No. 1, SEQ ID No. 3 or SEQ ID No. 5.

In an embodiment of the invention, the composition is a food or a pharmaceutical composition.

In one embodiment of the invention, there is provided a pharmaceutical composition comprising a peptide encoded by the amino acid sequence as SEQ ID No. 1 and at least one pharmaceutically acceptable carrier.

Wherein, the amino acid sequence of the peptide is encoded as SEQ ID No. 1, SEQ ID No. 3 or SEQ ID No. 5.

Wherein, the pharmaceutical composition comprises a peptide group encoded by the amino acid sequence encoding SEQ ID Nos. 2 to 6.

Another object of the present invention is to provide a use of the above pharmaceutical composition which can be used for the treatment or/and prevention of liver diseases.

Preferably, the liver disease is fatty liver, liver fibrosis, liver damage or a disease associated with liver cell apoptosis.

A second object of the present invention is to provide a use of the above pharmaceutical composition which can be used for inhibiting proteins associated with apoptosis.

Preferably, the apoptosis-associated protein line is Fas, FADD, Bax or Apoptosis protease 3.

Hereinafter, the effects of the present invention will be further illustrated by a number of examples and in conjunction with the drawings.

The amino acid sequence encoding of the peptide of the present invention comprises SEQ ID No. 1. For example, the amino acid sequence of the peptide is encoded as SEQ ID No. 1, SEQ ID No. 3 or SEQ ID No. 5. Since the peptides disclosed in the present invention have the ability to improve liver function, increase liver fat metabolism, reduce fat accumulation in liver cells, and inhibit the expression of proteins related to liver apoptosis, the present invention is enhanced by administering an effective amount. The peptide to a body is effective for treating or/and improving liver related diseases such as nonalcoholic fatty liver, liver fibrosis, liver damage and the like.

Furthermore, the peptides of the present invention can be prepared as a composition such as a food or a pharmaceutical composition. The pharmaceutical composition disclosed in the present invention can further comprise other peptides, such as the amino acid encoded as the peptide of SEQ ID No. 2, SEQ ID No. 4, and SEQ ID No. 6. For example, the pharmaceutical composition disclosed in the present invention comprises the peptide of SEQ ID No. 2-6 and at least one pharmaceutically acceptable carrier, and the ratio of each peptide in the composition can be adjusted according to actual needs. In general, each of the peptides has the same proportion in the composition.

The peptides disclosed in the present invention are isolated by extraction or hydrolysis from a living body, and can also be prepared by chemical synthesis of peptides or by using recombinant microorganisms and gene-transforming animals as a production platform. It will be understood by those skilled in the art and without the ordinary physiology of the peptides of the present invention that the 5' or 3' end of the amino acid sequence is additionally added for modification. The other peptide fragments can achieve the effects of the present invention by improving the stability or characteristics of the peptides of the present invention.

The "pharmaceutical composition" of the present invention comprises an effective amount of the active ingredient, and a pharmaceutically acceptable carrier or/and excipient. The pharmaceutical composition can be prepared into a suitable dosage form according to the needs of use, and includes an injection, a tablet, a pill, a powder, a liquid, a colloid, a milk, a suspension, a suppository and the like.

The "pharmaceutically acceptable carrier" of the present invention is compatible with the active ingredients of the pharmaceutical composition, preferably to increase the stability of the pharmaceutical composition and is not dangerous to the individual. The pharmaceutically acceptable amount may vary depending on the dosage form used, including, but not limited to, corn starch, lactose, cellulose, magnesium stearate, glucoside cerium oxide, maltodextrin, water, and the like.

The probucol used in the present invention, the Chinese name is probucol, is a clinically used hypolipidemic agent, and has the effects of lowering blood triglyceride, cholesterol and the like.

The animal experiment system disclosed in the present invention was examined and approved by the Laboratory Animal Care and Use Committee of the Chinese Medical University of Taiwan and was carried out according to the procedure of IACUC-100-12.

Example 1: Preparation of peptides

According to the general knowledge of the present invention, amino acid sequences encoded by SEQ ID Nos. 1 to 6 are prepared by biosynthesis, chemical synthesis, extraction, hydrolysis, and the like.

Further, please refer to the first figure, which analyzes the composition comprising the peptide group having the sequence of SEQ ID No. 2-6 by MS/MS/TIC, and analyzes the mass spectrometry results (as shown in the first panel A). The peptide sequence identified by the TurboSequest algorithm (Thermo Fisher Scientific, MA, USA) and the protein database (UniProt, Solanum tuberosum) confirmed that the amino acid sequence of the peptide was encoded as SEQ ID Nos. 2-6.

Example 2: Animal Experiment (1)

Five-month-old SAMP8 strain mice were randomly divided into 6 groups and started the trial for three months (12 weeks). At the first 1-4 weeks of the experiment, the feeding conditions of the mice in each group were as follows: Groups 1-1 and 1-3 were fed normal feed; 1-2, 1-4, 1-5 and 1-6, respectively. The groups were fed high fat diets. In the 5th week to the 12th week of the experiment, the interventional test was carried out by exercise or/and the peptide of the present invention, respectively, and the treatment conditions were as follows: Group 1-1 was a blank group, and normal feed was fed; Group 1-2 was fed with high fat. Feed; Groups 1-3 were fed normal feed and exercise; Groups 1-4 were fed a high-fat diet and the peptide encoded as SEQ ID No. 1 at a dose of 50 mg/kg BW; Groups 1-5 were fed high Fat feed and exercise; Groups 1-6 were fed a high fat diet and the peptide encoded as SEQ ID No. 1, at a dose of 50 mg/kg BW, and exercised. The movement patterns of the mice in groups 1-3, 1-5 and 1-6 were as follows: the mice in each group were allowed to adapt to water for 7 days at the third week of the experiment; for 5 minutes at the fifth week of the test, each 5 days in the week; swimming for 10 minutes a day, 5 days a week for the 8th week of the test; swimming for 15 minutes, 5 days a week for the 9th to 12th week of the test.

The body weight of each group of mice was measured weekly during the test, and the results are shown in Figure 2A. After the end of the experiment, each group of mice was sacrificed, and the visceral fat weight of each group of mice was measured, and the results are shown in Fig. 2B.

From the results of the second figure, it can be seen that simply feeding high-fat diet does induce a pattern of obesity in mice, resulting in an increase in body weight and an increase in visceral fat. Compared with those who only fed high-fat diets, the exercise system can increase the weight of mice fed high-fat diets slowly and reduce the weight of visceral fat. Compared with mice fed only high-fat diet, simultaneous feeding of the peptide encoded by SEQ ID No. 1 and the high-fat diet disclosed in the present invention, although not reducing the body weight of the mouse, can be reduced. The visceral fat weight of the mouse. Further, comparing the results of groups 1-2 and 1-4, groups 1-5 and 1-6, the obese individuals induced by the high-fat diet, even if they did not change their eating habits and did not have exercise habits, The peptide system encoded by SEQ ID No. 1 of the present invention is still effective in reducing the increase in visceral fat caused by the high-fat diet, and if the obese individual can be simultaneously administered, the invention is encoded as SEQ ID No. 1. By winning the peptide and maintaining exercise, the body weight can be reduced without changing the habit of a high-fat diet, and the visceral fat is approximated to a blank group.

In other words, the peptide system encoded by SEQ ID No. 1 disclosed in the present invention can effectively reduce the content of visceral fat in an individual, and can prevent the lesion caused by the increase of visceral fat.

Example 3: Detecting blood biochemical values

The contents of GOT, GPT, cholesterol, triglyceride and low-density cholesterol in the blood of each group of mice in Example 2 were examined, and the results are shown in the third to seventh figures.

The results of the figures show that feeding high-fat diets does increase the GOT, GPT, cholesterol, triglyceride and low-density cholesterol in the blood of mice. Comparing the contents of GOT, GPT, cholesterol, triglyceride and low-density cholesterol in the blood of the mice of Groups 1-4 and 1-5 in the condition of feeding the high-fat diet, showing feeding the present invention The peptide system encoded as SEQ ID No. 1 can achieve at least the same effect as exercise, and can make the content of GOT, GPT, cholesterol, triglyceride and low density cholesterol in blood significantly lower than that of simply feeding high fat. Feed the mice and even achieve the same effect as feeding normal feed and exercise mice.

Thus, it can be seen that the peptide of the present invention encoded by SEQ ID No. 1 has the effect of preventing or treating liver dysfunction or liver disease caused by a high-fat diet.

Example 4: Liver tissue section (1)

The liver of each group of mice of Example 2 was taken for liver sectioning and H&E staining, and the results are shown in the eighth figure.

As can be seen from the results of the eighth figure, feeding high-fat diet causes fat to accumulate in liver cells, producing a large amount of vacuoles and forming fatty liver. Comparing groups 1-4 and 1-5 with group 1-2, it can be seen that although exercise reduces the accumulation of fat caused by high-fat diet, the effect is limited, and there are still visible fat vacuoles in liver cells. However, the peptide of SEQ ID No. 1 of the present invention can significantly reduce fat vacuoles and reduce the accumulation of fat in liver cells.

It can be seen that the peptide of SEQ ID No. 1 disclosed in the present invention does have the effect of improving and/or treating fatty liver, and the effect is superior to simple exercise.

Example 5: Detection of apoptosis in TUNEL cells (1)

The liver cells of each group of the mice in Example 2 were sectioned, and the apoptosis of TUNEL cells was detected, and stained with DAPI, and the results were observed under a microscope at a wavelength of 454 nm, and the liver cell apoptosis of each group of mice was calculated. The number, the results are shown in the ninth and tenth figures.

From the results of the ninth and tenth figures, it can be seen that administration of a high-fat diet causes a large amount of liver cell apoptosis and damage of liver cells. Compared with the group 1-2, the number of liver cell apoptosis in the groups 1-4 to 1-6 was significantly decreased, indicating that the peptide of the present invention disclosed in SEQ ID No. 1 can reduce the high fat. Feed damage to liver cells, and its effect is better than simple exercise. In other words, the peptide of SEQ ID No. 1 of the present invention can effectively prevent or/and treat liver damage and related diseases.

Example 5: Meisheng three-color dyeing (1)

The livers of each group of mice in Example 2 were taken and sectioned and then stained by Meisheng Sansheng staining. The results are shown in Fig. 11.

From the results of Fig. 11, it is shown that the liver fibrosis system of the group 1-2 is very severe, and the condition of liver fibrosis of the mice of the groups 1-4 to 1-6 is markedly improved. Furthermore, comparing the groups 1-4 and 1-5, it can be seen that the peptide of SEQ ID No. 1 administered by the present invention can improve the liver fibrosis caused by the high-fat diet compared with exercise. situation.

Therefore, the above results show that the peptide of SEQ ID No. 1 of the present invention can effectively prevent or/and treat liver damage and related diseases.

Example 6: Performance of proteins associated with apoptosis (1)

The protein was extracted from the liver cells of each group in the second example, and the expression of proteins related to apoptosis and survival in the liver of each group was observed by Western blotting. The results are shown in Fig. 12 to Fig. 19 Show.

As can be seen from the results of the present example, the peptide of SEQ ID No. 1 of the present invention can enhance the expression of proteins associated with cell survival under the condition of administering a high-fat diet: p-PI3K (phosphatidylinositol 3-kinase) and p -Akt (serine-threonine kinase), and can effectively inhibit the expression of apoptosis-associated proteins: Fas, FADD, Bax and activated apoptosis protease 3.

Example 7: Animal Experiment (2)

A total of 5 weeks old SD rats were housed in an environment with a temperature of 24 ± 2 ° C, a humidity of 55 ± 10%, and a 12-hour light cycle, and were kept in normal feed for 22 months, and then the large Rats were randomly divided into 6 groups and housed for 8 weeks under the following conditions: Group 2-1 was a blank group, fed normal diet (PMI Nutrition International, Brentwood, MO, USA); Group 2-2 was a high-fat group, fed High-fat diet (58Y1, LabDiet, Missouri, USA); Groups 2-3 were low-dose, fed high-fat diet and peptide composition at a dose of 15 mg/kg/day; Groups 2-4 were medium-dose Group, fed a high-fat diet and peptide composition at a dose of 45 mg/kg/day; Groups 2-5 were in a high-dose group, fed a high-fat diet and a peptide composition at a dose of 75 mg/kg/day; Groups 2-6 are the drug group, fed with high-fat diet and drug probucol at a dose of 500 mg/kg/day, wherein the peptide composition contains the amino acid sequence encoding the peptides of SEQ ID No. 2-6. group. At the end of the experiment, the body weight of each group of rats was tested and sacrificed. The results of the weight test are shown in the twentieth chart.

From the results of the twentieth panel, it was shown that the body weight of the rats in the 2nd-2nd group was significantly higher than that in the 2-1st group, and it was found that the high-fat diet could indeed induce the formation of obese animal models in rats. Compared with group 2-2, the body weight of rats in groups 2-3 to 2-6 did decrease, indicating that the peptide composition is helpful for reducing body weight, and the effect is similar to that of drug probucol.

Example 8: Liver section staining (2)

The livers of each group of the rats in Example 7 were taken for paraffin section and H&E staining. The results of section staining were observed by a microscope (Zeiss Axiophot microscopes, Carl Zeiss Microscopy, Thornwood, NY, USA). The results are shown in Fig. 21. .

From the results of the 21st chart, even if the normal feed is fed, the liver cells of the rat will accumulate fat as the age increases, and feeding the high-fat diet will accumulate a large amount of fat in the liver of the rat to form fatty liver. Model rat. Compared with Group 2-2, feeding different doses of peptide composition or drug probucol improved the liver fat accumulation in each group, and fat accumulation increased with the feeding dose of the peptide composition. The situation has slowed down. Furthermore, although the administration of the drug probucol can improve the accumulation of liver fat, it can be seen from the comparison of the liver sections of groups 2-5 and 2-6 that the administration of the high dose of the peptide composition is for reducing the liver. The effect of fat accumulation is superior to the drug probucol.

From the above results, it was revealed that the peptide composition of the present invention can indeed reduce liver fatty liver accumulation caused by aging or a high-fat diet. Therefore, the sequence encoded by the present invention as SEQ ID No. 1 or the peptide composition containing the same has the effect of preventing or/and treating fatty liver and related diseases.

Example 9: Detection of apoptosis in TUNEL cells (2)

The liver tissue sections of each group of the rats in Example 7 were tested for apoptosis of TUNEL cells, and stained with DAPI, and the results were observed under a microscope at a wavelength of 454 nm, as shown in Fig. 22. Further, cell counts were further performed on the results of TUNEL apoptosis detection, and the results of the analysis are shown in Fig. 23.

From the results of the 22nd and 23rd, the liver tissue sections of Groups 2-2 have a large number of cells stained with TUNEL (ie, the green part of the figure). ), that is, a high-fat diet can have liver toxicity and damage liver cells. In contrast to Group 2-2, administration of the peptide composition or the drug probucol can effectively ameliorate or treat liver cell damage or apoptosis, and with the dosage of the peptide composition. The increase in liver cell damage is reduced, and the effect of administering a high dose of the peptide composition is similar to that of the drug probucol.

From the above results, it is revealed that the sequence encoded by the present invention as SEQ ID No. 1 or the peptide composition containing the same can effectively prevent or/and treat liver damage and related diseases.

Example 10: Meisheng three-color dyeing (2)

The livers of each group of the rats in Example 7 were obtained, and after paraffin-embedded sections, they were stained by the Meisheng Sansheng staining method, and the results are shown in Fig. 24 .

Please refer to the 24th figure. The condition of liver fibrosis in the 2nd-2nd group was significantly more severe than that in the 2-1st group, indicating that the high-fat diet induced liver fibrosis. Compared with group 2-2, the liver fibrosis of rats in groups 2-3 to 2-6 was significantly improved, indicating that administration of the combination peptide composition or drug probucol can reduce or avoid liver fibrosis. occur. Furthermore, the higher the dose of the peptide composition, the better the efficacy of reducing liver fibrosis, and the effect of the high dose peptide composition is superior to the drug probucol.

From this result, it was revealed that the sequence encoded by the present invention as SEQ ID No. 1 or the peptide composition containing the same can effectively prevent or/and treat diseases associated with liver damage such as liver fibrosis.

Example 11: Performance of proteins associated with apoptosis (2)

According to the general knowledge in the technical field of the present invention, proteins were extracted from liver tissues of each group of rats, and the expression of proteins related to apoptosis and survival in liver tissues of each group was observed by Western blotting method, wherein primary resistance was observed. The system was from Santa Cruz Biotechnology (Santa Cruz, CA, USA) and the secondary anti-system was labeled with horseradish peroxidase. The protein expression and its expression in the liver tissue of each group of rats are shown in Fig. 25 to Fig. 30.

Referring to the twenty-fifth to the thirty-first graphs, it can be seen that the peptide composition is capable of effectively inhibiting the expression of apoptosis-related proteins: Fas, FADD, Bax and activated apoptosis protease 3, and Enhance the performance of proteins associated with cell survival: p-PI3K and p-Akt, in which the effect of the middle dose and high dose peptide composition is better, and similar to the drug probucol.

Thus, it can be seen that the sequence encoded by the present invention as SEQ ID No. 1 or the peptide composition containing the sequence can prevent by inhibiting the expression of an apoptotic protein and enhancing the expression of a protein associated with cell survival. Or / and the efficacy of treatment of liver disease.

As is apparent from the results of the above examples, the peptides of the present invention do have therapeutic and/or prophylactic liver-related diseases such as fatty liver, liver fibrosis, liver cell apoptosis and the like. Further, the sequence disclosed in the present invention is the peptide of SEQ ID No. 1 or the peptide containing the sequence of SEQ ID No. 1 can be used as an active ingredient in a food or a pharmaceutical composition, specifically, According to the above example, according to the conversion formula announced by the US Food and Drug Administration in 2005: human 1g/kg bw=rat 6.2 g/kg bw, the dose of the rat is estimated to be 60 kg human body. The dose of the composition encoded as the peptide group of SEQ ID No. 2-6.

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The first panel A is the result of mass spectrometry analysis of the peptide composition of the present invention. The first panel B shows the results of mass spectrometric analysis of the peptide encoded by the amino acid sequence of SEQ ID No. 2 in the peptide composition of the present invention. The first panel C shows the results of mass spectrometric analysis of the peptide encoded by the amino acid sequence of SEQ ID No. 3 in the peptide composition of the present invention. The first panel D shows the results of mass spectrometry analysis of the peptide encoded by the amino acid sequence of SEQ ID No. 4 in the peptide composition of the present invention. The first panel E shows the results of mass spectrometric analysis of the peptide encoded by the amino acid sequence of SEQ ID No. 5 in the peptide composition of the present invention. The first panel F shows the results of mass spectrometric analysis of the peptide encoded by the amino acid sequence of SEQ ID No. 6 in the peptide composition of the present invention. Figure 2A shows the results of changes in body weight during the feeding period after feeding the mice in different conditions. Figure B is the change in visceral fat weight of each group of mice after feeding under different conditions. The third figure is the content of GOT in the blood of each group of mice after being fed under different conditions. The fourth picture shows the content of GPT in the blood of each group of mice after being fed under different conditions. The fifth picture shows the content of cholesterol in the blood of each group of mice after being fed under different conditions. The sixth picture shows the content of triglyceride in the blood of each group of mice after being fed under different conditions. The seventh picture shows the content of low-density cholesterol in the blood of each group of mice after being fed under different conditions. The eighth figure is the result of H&E staining of liver sections of each group of mice after being fed under different conditions. The ninth figure shows the results of TUNEL cell apoptosis detection in liver slices of each group of mice after different conditions. The tenth figure is the result of counting the proportion of TUNEL positive cells in the liver of each group of mice. The eleventh figure shows the results of the three-color staining of the liver slices of the mice in each group after different conditions. The twelfth image shows the expression of proteins associated with cell survival in the liver cells of each mouse. The thirteenth image shows the amount of p-PI3K expression in the liver cells of each mouse. Figure 14 shows the amount of p-Akt in the liver cells of each mouse. The fifteenth image shows the expression of proteins involved in apoptosis in the liver cells of each mouse. Figure 16 shows the amount of Fas in the liver cells of each mouse. Figure 17 is the amount of FADD in the liver cells of each mouse. The eighteenth figure is the amount of Bax expression in the liver cells of each mouse. The nineteenth figure is the expression amount of the apoptosis protease 3 in the liver cells of each mouse. The twentyth figure is the body weight of each group of rats after being fed under different conditions. The twenty-first figure is the result of H&E staining of liver slices of each group of rats. The twenty-second graph is the result of detection of apoptosis of TUNEL cells in liver slices of each group of rats. The twenty-third figure shows the proportion of TUNEL-positive cells in the liver sections of each group of rats. The twenty-fourth figure is the result of tricolor staining of rat liver sections by Meisheng. The twenty-fifth graph shows the expression of proteins associated with cell survival in the liver of each group of rats. The twenty-sixth graph shows the amount of p-PI3K expression of each of the rats in the seventh panel. The twenty-seventh panel shows the p-Akt expression of each of the rats in the seventh panel. The twenty-eighth panel shows the expression of apoptosis-related proteins in the liver of each group of rats. The twenty-ninth panel shows the FAS performance of each group of rats in the tenth graph. The thirtieth chart shows the amount of FADD expression of each group of rats in the tenth graph. The thirty-first panel shows the BAX performance of each of the rats in the tenth graph. The thirty-second graph shows the amount of apoptotic enzyme 3 present in each group of rats in the tenth graph.

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Claims (8)

A peptide having an amino acid sequence selected from the group consisting of SEQ ID No. 3 and SEQ ID No. 5. A food product comprising the peptide as described in claim 1 of the patent application. A pharmaceutical composition comprising a peptide and at least one pharmaceutically acceptable carrier, wherein the amino acid sequence of the peptide is selected from the group consisting of SEQ ID No. 3 and SEQ ID No. . The pharmaceutical composition according to claim 3, further comprising at least one peptide, wherein the amino acid sequence of the peptide is selected from the group consisting of SEQ ID No. 2, SEQ ID No. 4 and SEQ ID No. 6. The group formed. A use of a pharmaceutical composition according to any one of claims 3 or 4 for the manufacture of a composition for the treatment or/and prevention of liver disease. The use according to claim 5, wherein the liver disease is selected from the group consisting of fatty liver, liver fibrosis and liver damage. A use of a pharmaceutical composition according to any one of claims 3 or 4 for the manufacture of a composition for inhibiting apoptosis related proteins of liver cells. The use according to the seventh aspect of the patent application, wherein the apoptosis-related protein is selected from the group consisting of Fas, FADD, Bax and apoptotic protease 3.