CN112168822B - Application of kynurenic acid in improving hyperlipidemia induced dyslipidemia, obesity and intestinal flora disorder - Google Patents
Application of kynurenic acid in improving hyperlipidemia induced dyslipidemia, obesity and intestinal flora disorder Download PDFInfo
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- A61K31/47—Quinolines; Isoquinolines
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Abstract
The invention relates to application of canine uric acid in improving high-fat diet induced dyslipidemia, obesity and intestinal flora confusion, wherein oral canine uric acid can obviously inhibit the degree of weight increase caused by high-fat diet, has an inhibition effect on the weight increase caused by high-fat diet, and is similar to positive control simvastatin (simvastatin) with the same dose; can obviously reduce the daily average food intake of a high-fat diet group and obviously inhibit the daily average energy intake increase induced by high-fat diet; can reduce serum triglyceride level and increase serum high density lipoprotein cholesterol level; inhibition of high fat diet induced increases in serum low density lipoprotein cholesterol, coronary risk index and atherosclerosis index. Helps to recover the structure of dominant flora in intestinal tract, and can inhibit the increase of ratio (F/B) of intestinal bacteria Firmicutes and bacteria induced by high fat diet.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of kynurenic acid in preparing a preparation for improving high-fat diet induced dyslipidemia, obesity and intestinal flora confusion.
Background
Long-term high fat diets are known to cause many human hazards, such as hyperlipidemia and obesity. It is considered to be one of the major risk factors for cardiovascular and cerebrovascular diseases, such as atherosclerosis (atherosclerosis), coronary heart disease (coronary heart disease), and stroke. Especially for patients with hypertension, diabetes and cardiovascular diseases, the death rate of hyperlipidemia is greatly increased, and the condition is also common for the elderly. Therefore, there is an urgent need for new, effective and safe functional foods or drugs to alleviate the effects of high fat diets, including the adjuvant management of dyslipidemia. The intestinal flora (gut microbiota) has a regulating effect on physiological metabolism, and is also indicated to be related to physiological abnormal conditions of human bodies, including obesity, cardiovascular abnormality and the like. In recent years, the food functional factor can regulate and control intestinal flora to relieve the effect of high fat diet.
4-hydroxyquinoline-2-carboxylic acid, also known as Kynurenic Acid (KA), is a metabolite of tryptophan (tryptophan) via the kynurenine pathway. Kynurenic acid is present in some human diets (broccoli, potato and bee products, etc.). The role of kynurenic acid in the brain under physiological and pathological conditions has been studied in large numbers, but the role of kynurenic acid in the peripheral system has still been relatively incompletely elucidated. Previous researches show that the kynurenic acid has the effects of resisting inflammation, easing pain, resisting ulcer, resisting atherosclerosis, resisting oxidation, protecting liver and the like. Kynurenic acid is a ligand (ligand) for the endogenous (endogenous) aryl hydrocarbon (aryl hydrocarbon) receptor. Previous studies indicated that dietary supplementation with kynurenic acid (250 mg/L in drinking water) elicited no toxic response in either normal adult rats (21 days of continuous supplementation) or normal adult mice (14 days of continuous supplementation). Dietary supplementation of canine uric acid (at drinking water concentration: 250 mg/L) for 40 days did not have an adverse effect on skeletal development in normal young rats. However, the role of kynurenic acid as a functional food is still unknown at present, and especially the metabolic regulation of oral kynurenic acid on high-fat diet is unclear.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide the application of kynurenic acid in improving high-fat diet dyslipidemias, obesity and intestinal flora confusion.
According to the use of the embodiment of the invention, the inventor finds that oral administration of canine uric acid can obviously inhibit the degree of weight gain caused by high-fat diet, and the inhibition effect on the weight gain caused by high-fat diet is similar to that of positive control simvastatin (simvastatin) with the same dosage; the oral administration of low dose (1.25 mg/kg/day) or high dose (5 mg/kg/day) of kynurenic acid can respectively remarkably reduce the daily average food intake of a high-fat diet group and remarkably inhibit the increase of the daily average energy intake induced by the high-fat diet. In a high-fat diet group, the low dose or the high dose of canine uric acid respectively remarkably reduces the serum TG level and remarkably improves the serum HDL-C level; inhibit increase of LDL-C, CRI and AI induced by high fat diet. Canine uric acid (5 mg/kg/day) can remarkably inhibit the increase of F/B ratio induced by high-fat diet, and partially reverse the change of the composition of intestinal flora (genera) caused by high-fat diet, and is helpful for the restoration of the dominant flora structure in intestinal tract.
In addition, the application of the kynurenic acid provided by the embodiment of the invention in preparing the preparation for improving the high fat diet dyslipidemias, obesity and intestinal flora disorder can also have the following additional technical characteristics:
optionally, kynurenic acid is administered orally to inhibit weight gain on a high fat diet.
Alternatively, the oral administration of kynurenic acid inhibits an increase in the F/B ratio of the intestinal flora on a high-fat diet.
Alternatively, the oral administration of kynurenic acid to inhibit an increase in food energy intake on a high fat diet.
Optionally, kynurenic acid is administered orally to reduce serum triglycerides, low density lipoprotein cholesterol, an atherosclerotic index and an increase in coronary risk index on a high lipid diet.
Optionally, kynurenic acid is orally administered to inhibit the increase in abundance of enteric bacteria Lachnospiraceae _ UCG-006, lactococcus, roseburia induced by a high-fat diet, and to attenuate the decrease in abundance of enteric bacteria Alisipes caused by a high-fat diet.
Optionally, the oral administration of kynurenic acid to promote a decrease in the abundance of enterobacteria Lactobacillus caused by a high-fat diet;
optionally, the canine uric acid is orally administered to decrease the abundance of enteric bacteria Desulfovibrio and increase the abundance of enteric bacteria uncultured _ bacteria _ filtricutes, blautia, ruminicildium, uncultured _ bacteria _ Proteobacteria.
Alternatively, oral administration of kynurenic acid to reduce a high fat diet results in an increase in serum low density lipoprotein cholesterol, coronary risk index, and atherosclerotic index.
In a second aspect of the present invention, embodiments of the present invention provide a medicament for ameliorating dyslipidemias, obesity, and gut flora disturbance from a high-fat diet, the medicament comprising kynurenic acid and a pharmaceutically acceptable carrier.
In a third aspect of the invention, the embodiment of the invention provides a food for improving dyslipidemias, obesity and disturbed intestinal flora of high-fat diet, which comprises kynurenic acid and an auxiliary material acceptable in food science.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is the chemical structure of kynurenic acid according to an embodiment of the present invention;
FIG. 2 is a graph showing the change in food intake in the week of mice according to an embodiment of the present invention;
FIG. 3 is a graph showing the change in energy intake in the week of mice according to an embodiment of the present invention;
FIG. 4 is a graph showing the change in average daily food intake of mice according to an embodiment of the present invention;
FIG. 5 is a graph showing the variation of the average daily energy intake of mice according to an embodiment of the present invention;
FIG. 6 shows the body weight variation of a mouse according to an embodiment of the present invention;
FIG. 7 is an increase in body weight of mice at week 8 according to an embodiment of the present invention;
FIG. 8 is a graph showing the change in total cholesterol in serum of a mouse according to an example of the present invention;
FIG. 9 is a graph of the change in triglycerides in mouse serum according to an embodiment of the present invention;
FIG. 10 is a graph showing the change in low density lipoprotein cholesterol in the serum of a mouse according to an embodiment of the present invention;
FIG. 11 is a graph showing the change in high density lipoprotein cholesterol in the serum of a mouse according to an embodiment of the present invention;
FIG. 12 is a graph showing the change in the coronary risk index of mice according to an embodiment of the present invention;
FIG. 13 is a graph of the change in the atherosclerotic index of mice according to an embodiment of the present invention;
FIG. 14 is a graph of the percentage of abundance of each population of mouse gut flora at the phylum level, according to an embodiment of the present invention;
FIG. 15 is a ratio (F/B) of mouse enteric bacteria Firmicutes and Bacteroides according to an embodiment of the present invention;
fig. 16 is a heat map analysis of intestinal flora in mice at the genus level according to an embodiment of the present invention.
Detailed Description
The technical solution of the present invention is illustrated by specific examples below. It is to be understood that one or more method steps mentioned in the present invention do not exclude the presence of other method steps before or after the combination step or that other method steps may be inserted between the explicitly mentioned steps; it should also be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Moreover, unless otherwise indicated, the numbering of the various method steps is merely a convenient tool for identifying the various method steps, and is not intended to limit the order in which the method steps are arranged or the scope of the invention in which the invention may be practiced, and changes or modifications in the relative relationship may be made without substantially changing the technical content.
In order to better understand the above technical solutions, exemplary embodiments of the present invention are described in more detail below. While exemplary embodiments of the invention have been shown, it should be understood that the invention may be embodied in various forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The test materials adopted by the invention are all common commercial products and can be purchased in the market.
The invention will now be described with reference to specific examples, which are intended to be illustrative only and not to be limiting in any way.
Example 1 Effect of Canine uric acid on body weight and food intake of high-fat diet mice
Kynurenic Acid (KA), having the chemical structure shown in fig. 1, is available from sigma aldrich trade ltd (cat # K3375).
The SPF grade KM mice are 36, 20g and 4 weeks old and are sourced from Beijing Hua Fukang biotech GmbH; normal feed and high-fat feed for mice were purchased from Beijing Huafukang Biotech GmbH.
Experimental mice (SPF, 4 weeks) were kept in a comfortable environment (temperature: 24. + -. 2 ℃ C., humidity: 55. + -. 5%,12 hours day and night cycle) with good ventilation and daily feed and drinking water supplementation.
All mice were randomized to drink water ad libitum. Normal feed (NC) is fed to control groups, other groups are fed with high-fat feed (DIO series feed, 60% H10060), wherein the high-fat diet group (HFD) is only fed with the high-fat feed, other experimental groups are respectively combined with a combination and orally taken with 1.25mg/kg KA (KAL) and 5mg/kg KA (KAH) every day, and a positive control group is combined with a combination and orally taken with 5mg/kg Simvastatin (SV) every day. The oral administration is continued for 8 weeks. Data are presented as mean values and analyzed on Graphpad Prism 6. Significance was determined by analysis of variance (ANOVA) and Duncan multiple comparison test. P <0.05 indicates that there was a statistically significant difference. P <0.05, P <0.01, P <0.001 compared to the control group (NC). Compared to the high fat diet group (HFD), P <0.05, # # P <0.01, # # P <0.001.
The mice were analyzed from different angles for food intake, energy intake and body weight over an 8-week feeding experiment. As can be seen from fig. 2 and 3 (NC, HFD, n =3 for SV group, kal, n =6 for KAH group), the weekly intake and weekly energy intake of NC group mice were increased with raising time by comparing them in the group; the HFD group had significantly increased food intake and energy intake in the second week compared to the first week. Weekly and energy intake in KAL group, KAH group mice did not increase significantly in week two compared to week one. The first week energy intake of the KAL group and KAH group was not statistically different from the first week of the NC group (fig. 3). The mice were then compared for changes in average daily and energy intake, as shown in fig. 4 and 5. The average daily food intake was significantly reduced in the positive control group (SV), KAL group and KAH group compared to the HFD group. The energy intake of the HFD group and SV group was significantly increased, and the energy intake of the KAL group and KAH group was significantly decreased, compared to the NC group. The energy intake was significantly reduced in the KAL group, KAH group and SV group compared to the HFD group. It is demonstrated that oral administration of low dose (1.25 mg/kg/day) canine uric acid has a better effect of inhibiting the increase in energy intake caused by high fat diet than positive control simvastatin at 5mg/kg/day dose. As can be seen from fig. 6 and 7 (NC, HFD, n =5 for SV group, n =6 for kal, KAH group), the weight of the NC group mice tended to increase with time. The body weight of mice in the HFD group and KAL group was significantly increased compared to the NC group. The body weight of the SV group and KAH group tended to decrease compared to the HFD group. The weight increase of mice caused by high-fat diet is inhibited to a certain degree by the canine uric acid, which shows that the inhibition effect of oral canine uric acid on the weight increase caused by high-fat diet is similar to that of positive control simvastatin of the same dose.
Example 2 Effect of Canine uric acid on the blood lipid reduction in high-fat diet mice
At the 8-week experimental end point, the mice of each group of example 1 were fasted for 12h before collecting blood from the mice. Blood of a mouse is centrifuged at 10000g for 20min at 4 ℃, supernatant is taken as serum, and Total Cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) in the serum are measured by using a serum determination kit. And analyzed by a BS-240VET full-automatic analyzer of Mirui International medicine Co. The Atherosclerosis Index (AI) and the Coronary Risk Index (CRI) are calculated by the following formulas.
AI＝LDL-C(mg/dL)/HDL-C(mg/dL)；
CRI＝TC(mg/dL)/HDL-C(mg/dL)。
High-fat diet feeding is closely related to hyperlipidemia in mice. Serum indices were detected experimentally and analyzed (each group n = 5). At serum Total Cholesterol (TC) levels (fig. 8), total cholesterol levels were significantly elevated in the HFD group, SV group, KAL group, and KAH group, as compared to the NC group. This indicates that kynurenic acid does not affect the serum TC levels in mice. In the Triglyceride (TG) level (fig. 9), the TG level of the HFD group had an upward trend compared to the NC group. TG levels were significantly reduced in SV group, KAL group and KAH group compared to HFD group. This indicates that KA has a significant down-regulation effect on serum TG content of high-fat diet mice, and the down-regulation effect is close to that of a positive control. The LDL-C level in the HFD group was significantly higher than that in the NC group in the serum low-density lipoprotein cholesterol (LDL-C) level (FIG. 10). The SV group, KAL group and KAH group all significantly reduced LDL-C levels compared to the HFD group. The result shows that the KA has the capacity of reducing the serum low-density lipoprotein cholesterol level of the high-fat diet mice, the down-regulation capacity is close to that of a positive control, and the potential possibility of preventing and assisting in regulating the cardiovascular and cerebrovascular diseases such as atherosclerosis is shown. At the level of serum high density lipoprotein cholesterol (HDL-C) (FIG. 11), HDL-C in HFD group was increased, and HDL-C in SV group, KAL group and KAH group were significantly increased, as compared with NC group. The result shows that the serum high-density lipoprotein cholesterol level of the mouse is obviously up-regulated under the action of the canine uric acid, and the up-regulation capability is close to that of a positive control. HDL-C is thought to transport tissue and vascular cholesterol to the liver via the "reverse cholesterol transport" pathway and clear cholesterol via the bile acid pathway. Further analysis was performed by calculating the coronary artery risk index (CRI) and the Atherosclerosis Index (AI). In terms of CRI (fig. 12), the CRI level of the HFD group rises significantly compared to the NC group. CRI levels were significantly reduced for the SV group, KAL group and KAH group compared to HFD. This indicates that kynurenic acid can significantly down-regulate the coronary risk index of high-fat diet mice, and has no significant difference from the positive control group. In the AI aspect (fig. 13), the AI level of the HFD group significantly increased compared to the NC group. AI levels were significantly reduced for the SV group, KAL group and KAH group compared to the HFD group. This indicates that KA can significantly down-regulate the atherosclerotic index of high-fat diet mice, and has no significant difference from the positive control. In the high fat diet group, kynurenic acid can reduce serum triglyceride level and increase serum high density lipoprotein cholesterol level. Inhibition of high fat diet by kynurenic acid induces an increase in serum low density lipoprotein cholesterol, coronary risk index and atherosclerosis index. The improvement effect of oral low dose (1.25 mg/kg/day) canine uric acid on serum indicators of high-fat diet group is similar to that of positive control simvastatin at 5mg/kg/day dose. Canine uric acid is considered to have the function of reducing blood fat and protecting the cardiovascular system.
Example 3 Effect of Canine uric acid on intestinal flora of high fat diet mice
At the end of the experiment at week 8, the mice of each group of example 1 were fasted for 12h before collecting their feces. Total bacterial DNA was extracted from mouse feces using the DNA extraction Kit (TIANAmp Bacteria DNA Kit) instructions. The V3 and V4 regions of bacterial 16S rRNA were amplified using primers 341F (5 '-CCTAYGGGRBGCASCAG-3') and 806R (5 '-GGACTACNNGGGTATCTAAT-3'). The purified amplicons were sequenced using paired-end method on the Illumina Hiseq 2500 platform according to PE-250bp sequencing protocol.
1,440,504 high quality sequences of the 1696 rRNA V3-V4 region were collected from 18 stool samples. The average number of sequences is 72,196, the minimum number of sequences is 70,514, and the maximum number of sequences is 74,037. While the average length is 420bp, after deleting the low-quality reads, 1,174,687 operation classification units (OTU) with 97% similarity are reserved.
As shown in fig. 14 (n =3 for control group (NC), n =5 for high fat diet group (HFD), simvastatin group (SV), and KAH group), analysis of intestinal microbial composition was performed from the portal level. Among them, firmicutes and bacteroidides (two phyla of microorganisms that can produce short chain fatty acids) dominate the composition of intestinal microorganisms. It has been reported that an increase in the ratio (F/B) of the enteric bacteria Firmicutes and Bacteroides in obese hosts is associated with an increase in the amount of energy available from food. KA significantly reduced the F/B ratio in high-fat diet mice (fig. 15). KA has the inhibiting effect on the increase of the F/B ratio caused by high-fat diet, and is similar to positive control simvastatin in the same dose. In addition, to gain a better understanding of the effect of KA on the intestinal flora of high-fat diet mice, analyzed at a lower taxonomic level (genus level), fig. 16 shows a heat map of the relative abundance of 40 key genera. The abundance of Lachnospiraceae _ UCG-006, lactococcus, roseburia in the HFD group was significantly increased compared to the NC group; the abundance of Alisipes, prevoteceae _ UCG-001, lactobacillus in the HFD group was significantly reduced. Compared with the HFD group, SV and KAH respectively have obvious regulation and control effects on several genera of intestinal flora. Both SV and KAH significantly inhibited the increase in abundance of Lachnospiraceae _ UCG-006, lactococcus, roseburia induced by high fat diet. Both SV and KAH significantly attenuated high fat diets leading to decreased abundance of Alistipes. Although neither SV nor KAH affected the decrease in abundance of Prevoteceae _ UCG-001 caused by high-fat diet, both significantly contributed to the decrease in abundance of Lactobacillus caused by high-fat diet. Both SV and KAH significantly reduced the abundance of Desulfovibrio and both significantly increased the abundance of uncultured _ bacterium _ cultures, blautia, ruminicotridium, compared to the NC group. In addition to the similar effects of these SV and KAH described above, there are also different effects of the following SV and KAH. Compared with the HFD group, the abundance of the SV group uncultred _ bacteria _ bacilli, anaerotruncus was significantly increased. Compared with the NC group, SV obviously improves the abundance of Alloprovella, odoribacter, ruminociclsidium _9, oscillbacter, GCA-900066575 and Bacteroides. KAH significantly increased the abundance of uncultured _ bacterium _ Proteobacteria compared to NC group.
The above indicates that kynurenic acid can reduce some gut bacteria positively associated with obesity, for example previous studies indicate the Lachnospiraceae family which may be associated with obesity and metabolic disorders. High fat diet increased the abundance of Lachnospiraceae _ UCG-006 compared to the control group, consistent with previous studies; this phenomenon is attenuated by kynurenic acid. The group KA has a tendency to increase the abundance of some of the intestinal flora that are indicated to be negatively associated with obesity, such as Bacteroides. The previous study indicates that oral administration of Enterobacter Bacteroides unidentiformis CECT 7771 can improve metabolism and immune dysfunction of high fat diet mice. Therefore, we speculate that the improvement effect of oral canine uric acid on weight gain and dyslipidemia induced by high-fat diet may be mainly related to the ability of canine uric acid to regulate intestinal flora. Overall, these results provide an explanation for the significant changes in the above-mentioned lower levels of the biotypes (genus levels), indicating that kynurenic acid works to alleviate high fat diets by modulating the gut flora. Compared with the SV group, the KAH group intestinal flora is closer to the NC group in the overall composition condition of relative abundance of 40 key genera.
In conclusion, the kynurenic acid provided by the embodiment of the invention can obviously inhibit the degree of weight increase caused by high-fat diet, and has an inhibition effect on the weight increase caused by high-fat diet, similar to that of the positive control simvastatin (simvastatin) with the same dosage; the oral administration of low dose (1.25 mg/kg/day) or high dose (5 mg/kg/day) of the canine uric acid can respectively remarkably reduce the daily average food intake of the high-fat diet group and remarkably inhibit the increase of the daily average energy intake induced by the high-fat diet. The inhibitory effect of low dose (1.25 mg/kg/day) canine uric acid on the increase in energy intake caused by high fat diet was better than that of simvastatin at 5mg/kg/day dose. In the high-fat diet group, the low dose or the high dose of the canine uric acid respectively significantly reduces the serum TG level and significantly improves the serum HDL-C level. Both doses of kynurenic acid significantly inhibited, respectively, the increase in serum LDL-C, CRI and AI induced by high fat diet. The improvement effect of low dose (1.25 mg/kg/day) of canine uric acid on the serum index of the high-fat diet group is similar to that of the 5mg/kg/day dose of simvastatin. Canine uric acid (5 mg/kg/day) can remarkably inhibit the increase of F/B ratio induced by high-fat diet, wherein the F/B ratio is the ratio of two dominant phyla in intestinal flora. The inhibition effect of the canine uric acid on the increase of the F/B ratio caused by high-fat diet is similar to that of the same dose of simvastatin. Canine uric acid partially reversed the alteration in gut flora composition caused by high-fat diet compared to control and high-fat diet groups.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above should not be understood to necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples described in this specification can be combined and combined by those skilled in the art.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (2)
1. Use of kynurenic acid for the preparation of a preparation for ameliorating a high-fat diet-induced intestinal flora disturbance, wherein the kynurenic acid is orally administered to inhibit an increase in the F/B ratio of the high-fat diet-induced intestinal flora; oral administration of canine uric acid for inhibiting high-fat diet-induced intestinal bacteriaLachnospiraceae_UCG-006、Lactococcus、RoseburiaIncrease in abundance, and decrease in intestinal bacteria caused by high-fat dietAlistipesA decrease in abundance of; oral administration of kynurenic acid for promoting intestinal bacteria caused by high-fat dietLactobacillusDecrease in abundance of; oral administration of canine uric acid for reducing intestinal bacteriaDesulfovibrioIs rich and increases intestinal bacteriauncultured_bacterium_Firmicutes、Blautia、Ruminiclostridium、uncultured_ bacterium_ProteobacteriaThe abundance of (a).
2. The use of claim 1 wherein the oral administration of canine uric acid to reduce a high fat diet results in an increase in serum low density lipoprotein cholesterol, coronary risk index, and atherosclerotic index.
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