CN117838712A - Application of punica granatum polyphenol in preventing and treating hypercholesterolemia - Google Patents
Application of punica granatum polyphenol in preventing and treating hypercholesterolemia Download PDFInfo
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Abstract
The invention provides a safe application in preparing a preparation for preventing and treating hypercholesterolemia. The invention uses punicalagin which is a main active substance of punica granatum skin polyphenol, and is applied to preparation of preparations for preventing and treating hypercholesterolemia, and experiments show that the punicalagin can obviously reduce the total cholesterol level in serum and liver of mice induced by high-fat high-cholesterol diet, and cholesterol reduction effect is realized by down-regulating cholesterol synthesis and increasing cholesterol catabolism, which can be realized by regulating intestinal flora, changing bile acid composition and regulating FXR signal paths. And the preparation method is safe and has no toxic or side effect, and has very important application prospect.
Description
Technical Field
The invention belongs to the technical field of biological medicine preparation, and particularly relates to application of punicalagin in preparation of a preparation for preventing and treating hypercholesterolemia.
Background
Hypercholesterolemia is the most common of the different forms of dyslipidemia. Dyslipidemia, particularly elevated plasma cholesterol levels, is associated with increased risk of cardiovascular disease and stroke. Currently, drugs for treating hypercholesterolemia are mainly lipid-regulating drugs such as statins, intestinal cholesterol absorption inhibitors, bile acid chelating agents, and the like. However, the drugs have limitations in use due to side effects thereof, such as increased risk of diabetes, muscle pain, cognitive dysfunction, headache, etc. due to long-term administration of statin drugs. Therefore, it is urgent to find a substitute having therapeutic effects, high safety, little side effects and low cost. Plasma cholesterol levels are determined by a number of physiological process interactions, including absorption and excretion of cholesterol from the intestinal lumen, absorption and secretion from the plasma circulation, biosynthesis of cholesterol from the head, cholesterol efflux and conversion. Bile acid synthesis is the primary pathway of hepatic cholesterol catabolism. Many epidemiological studies have shown that the vegetal diet has a protective effect on cardiovascular diseases and cancer. Punicalagin (PU) is an ellagitannin existing in pericarpium Granati, and has antioxidant and antiinflammatory effects. Punicalagin has been reported by Fouad et al to reduce cyclophosphamide-induced hepatotoxicity in rats (Fouad AA, qub H O, AI-Melhim W N.2016.Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide. Environmental Toxicology and Pharmacology, 45:158-162); miao Jianan et al report on the effects of punicalagin on lipid metabolism and oxidative stress in diabetic mice (Miao Jianan, jiang Anjian, answeet, pan Yanyun, mo Fangfang.2018. The effects of punicalagin on lipid metabolism and oxidative stress in diabetic mice. World traditional Chinese medicine, 11 (5): 681-684); also reported are the effects of punicalagin on lipid metabolism and oxidative stress in diabetic mice, e.g., 2018, gu Limi heat (Gu Limi heat, zhu Junyu, liang Huaping, yan Huan, gu Zheng. 2018. Progression of the anti-inflammatory, antioxidant and anti-infective activity of punicalagin. Infection, inflammation, repair, 019 (1): 44-47). However, it is not known whether the punica granatum polyphenol can relieve the hypercholesterolemia through intestinal flora and the bile metabolism effect of the individual with the hypercholesterolemia is not clear, so that research is urgently needed to obtain a new strategy for relieving the hypercholesterolemia through the punica granatum polyphenol.
Disclosure of Invention
In order to solve the problems, the punicalagin which is a main active substance of the pericarpium Granati polyphenol is applied to the preparation of the preparation for preventing and treating the hypercholesterolemia, and can obviously reduce the cholesterol level in the serum and liver of a mouse induced by high-fat high-cholesterol diet, promote the conversion of cholesterol to bile acid, inhibit the reabsorption of bile acid and promote the excretion of the bile acid, so that the serum cholesterol level is regulated. The punicalagin is safe and has no toxic or side effect, and has very important application prospect.
The first technical scheme provided by the invention is the application of punicalagin in preparing medicines for preventing, relieving and/or treating hypercholesterolemia, wherein the punicalagin is punicalagin.
In certain embodiments, the application includes at least one of the following:
(1) Inhibiting liver cholesterol synthesis in an individual;
(2) Promoting transport of serum cholesterol to the liver in an individual;
(3) Promoting the conversion of cholesterol to bile acids in an individual;
(4) Inhibiting reabsorption of bile acids in an individual;
(5) Reducing the abundance of individual bile hydrolase producing bacteria;
(6) Reducing the ratio of primary bile acid to secondary bile acid in an individual;
(7) Reducing the bile acid content of the individual for activating the farnesol X receptor gene FXR.
Further, the bile hydrolase producing bacteria include clostridium and bifidobacterioceae.
Further, the bile acid for activating FXR includes Taurine (TCA), taurodeoxycholic acid (TDCA), taurodeoxycholic acid (TCDCA).
In certain embodiments, the agent is an Fdps/Cyp51 pathway inhibitor, a bile acid synthase gene expression inhibitor, a liver X receptor gene LXR expression promoter, an LDL receptor gene LDL-R expression promoter, and an intestinal FXR/Fgf15 pathway inhibitor.
In certain embodiments, the punicalagin is added to the drug in an amount of not less than 50mg/kg body weight.
In certain embodiments, the medicament also contains a pharmaceutical carrier and/or pharmaceutical excipients.
Further, the carrier includes one or more of fillers, binders, wetting agents, disintegrants, lubricants, flavoring agents, which are commonly used in medicine.
Further, the dosage form of the medicine is granule, capsule, tablet, pill or oral liquid.
The second technical scheme provided by the invention is the application of punicalagin in health care products or feeds for controlling cholesterol in an individual body.
In certain embodiments, the application includes at least one of the following:
(1) Inhibiting liver cholesterol synthesis in an individual;
(2) Promoting transport of serum cholesterol to the liver in an individual;
(3) Promoting the conversion of cholesterol to bile acids in an individual;
(4) Inhibiting reabsorption of bile acids in an individual;
(5) Reducing the abundance of individual bile hydrolase producing bacteria;
(6) The ratio of primary bile acid to secondary bile acid in the individual is reduced.
(7) Reducing the bile acid content of an individual for activating the farnesol X receptor FXR.
The third technical scheme provided by the invention is that the Fdps/Cyp51 pathway inhibitor contains punicalagin, and the punicalagin is punicalagin.
The fourth technical scheme provided by the invention is a bile acid synthetase gene expression inhibitor containing punicalagin, wherein the punicalagin is punicalagin.
The fifth technical scheme provided by the invention is that the liver X receptor gene LXR and/or LDL receptor gene LDL-R expression promoter contains punicalagin, and the punicalagin is punicalagin.
The sixth technical scheme provided by the invention is an intestinal FXR/Fgf15 pathway inhibitor containing punicalagin, wherein the punicalagin is punicalagin.
The invention has the beneficial effects that:
the invention provides an application of plant polyphenol in preparing a preparation for preventing and treating hypercholesterolemia, in particular to a new application of punicalagin in preparing a medicine, a health care product or a feed for preventing and treating hypercholesterolemia induced by high-fat and high-cholesterol diet.
Punicalagin can significantly reduce cholesterol levels in serum and liver of mice induced by high-fat high-cholesterol diet, and the levels of TC, LDL-C, TC/HDL-C of the mice are reduced by 33.9%, 27.6% and 49.4%, respectively.
The punicalagin can reduce liver burden, remarkably reduce liver index, cholesterol content and glutamic-pyruvic transaminase content, reduce liver cell lipogenesis and fat accumulation, reduce possibility of tissue lesion, and reduce liver injury degree.
Punicalagin reduces serum cholesterol levels by increasing expression of LXR LDL receptor, a transcriptional regulator of liver cholesterol metabolism, and inhibiting expression of Fdps, cyp51, a gene involved in liver cholesterol biosynthesis.
Punicalagin promotes conversion of cholesterol to bile acid and inhibits reabsorption of bile acid in the ileum to promote excretion thereof, thereby regulating serum cholesterol levels. Can realize the effect of preventing and treating hypercholesterolemia from various angles
Punicalagin reduces the abundance of bile salt hydrolase producing bacteria (clostridium and bifidobacteria) in hypercholesterolemic mice and the ratio of primary bile acid to secondary bile acid.
Punicalagin inhibits the intestinal FXR-Fgf15 pathway in hypercholesterolemic mice.
Punicalagin reduces the content of FXR activators TCA, TDCA and TCDCA in feces.
In conclusion, the medicine, health care product and feed prepared from the punica granatum polyphenol punica granatum glycoside can prevent and treat hypercholesterolemia from various angles, is safe and has no toxic or side effect, and has very important application prospect.
Drawings
FIG. 1 is a graph showing comparison of serum cholesterol levels in mice of the normal diet blank (Chow), model group (HFHC), and punicalagin intervention group (HFHC+PU) of example 1 of the present invention, wherein (A) serum total cholesterol level (TC); (B) Serum low density lipoprotein cholesterol level (LDL-C); (C) Serum total cholesterol to high density lipoprotein cholesterol ratio level (TC/HDL-C);
FIG. 2 is a graph showing liver index of each group of mice in example 1 of the present invention;
FIG. 3 shows liver cholesterol (TC) levels in groups of mice in example 1 of the present invention;
FIG. 4 shows liver glutamic pyruvic transaminase (ALT) levels of each group of mice in example 1 of the invention;
FIG. 5 is an H & E staining image of liver histopathological sections of mice of each group in example 1 of the present invention;
FIG. 6 shows RT-PCR detection of cholesterol synthesis-related genes (Fdps and Cyp 51) in liver of each group of mice, important transcription regulator of cholesterol metabolism Liver X Receptor (LXR), and mRNA transcription level of LDL receptor (LDL-R) involved in transfer of cholesterol from serum to liver in example 2 of the present invention;
FIG. 7 shows the RT-PCR assay of mRNA transcription levels of bile acid synthetases (Cyp 7a1 and Cyp27a 1) in liver of mice of each group in example 3 of the present invention;
FIG. 8 shows the RT-PCR assay of mRNA transcript levels of bile acid transporter (ASBT) in the ileum of mice in each group according to example 3 of the present invention;
FIG. 9 shows the total bile acid content in the feces of each group of mice in example 3 of the present invention.
FIG. 10 shows the ratio of primary bile acid to secondary bile acid in the feces of mice in each group in example 3 of the present invention.
FIG. 11 shows a least squares discriminant analysis (PLS-DA) of (A) intestinal flora based on genus level in example 4 of the present invention; (B) the relative abundance of bacteria at the portal level in the fecal sample; (C-D) based on the 16S rRNA sequencing results, the relative abundance of Clostridiaceae and Bifidobacteriaceae.
FIG. 12 shows the RT-PCR detection of mRNA transcription levels of bile acid receptor FXR and target gene Fgf15 in ileum of mice of each group in example 5 of the present invention.
FIG. 13 shows the content of Taurine (TCA), deoxycholic acid (TDCA) and deoxycholic acid (TCDCA) in the feces of each group of mice in example 5 of the present invention.
In the above figures, experimental data are expressed as mean ± standard error (mean ± SEM); the designations "," represent statistical differences between the two groups, indicating p <0.05, p <0.01, p <0.001, respectively.
Detailed Description
The present invention will be further described in detail below with reference to specific embodiments and with reference to the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent. The test methods used in the following experiments are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
The experimental methods involved in the following examples are as follows:
1. liver index determination
At the end of the animal experiment, the liver weight of the model mice was measured and the liver index was recorded: liver weight (g)/fasting weight (g) 100%.
2. Determination of cholesterol content in mouse serum and liver
At the end of the animal experiment, the mice were bled and sacrificed without water withdrawal for 6h, and the serum was centrifuged (4 ℃,2500×g,20 min) to determine serum total cholesterol level, serum low density lipoprotein cholesterol level and ratio of serum total cholesterol level to high density lipoprotein cholesterol level. And (3) detecting the total cholesterol level by adopting a Beijing solebone corresponding kit after liver homogenization is prepared by grinding the liver.
3. Determination of glutamic pyruvic transaminase content in mouse liver
A proper amount of liver tissue is sheared, a proper amount of PBS (pH=7.4) solution is added, a freeze grinder is used for homogenizing the liver tissue, centrifugation is carried out for 10min at 4 ℃ and 3000 Xg, supernatant is sucked, and the content of glutamic pyruvic transaminase (ALT) is measured by adopting Nanjing institute of biological engineering and kit.
4. Hematoxylin and eosin (H & E) staining
Liver tissue was fixed with 10% formalin at room temperature for 24 hours, then embedded in paraffin, and cut into 5 μm thick sections. The sectioned tissue was then subjected to H & E staining for histological changes. Images were acquired using an optical microscope at 40 and 100 magnification of the objective lens, respectively.
5. Detection of mRNA levels in tissues
Total RNA of liver tissue or ileum was extracted with Trizol (TaKaRa, dalian, china) reagent, and was used for reverse transcription (Prime Script RT-PCR reverse transcription kit) as cDNA after concentration adjustment with RNase-free water, and mRNA level of the target gene in liver or ileum was detected by RT-PCR method, and the primer sequences are shown in Table 1.
TABLE 1 RT-PCR primer sequences
Use of TBPremix ex Taq TM II, real-time quantitative PCR instrument detects mRNA transcription level. Normalizing the expression level of the target gene to the transcription level of the reference gene Actb, and using formula 2 -ΔΔCt And (5) calculating.
6. Detection of total bile acid content in mouse feces
Weighing a proper amount of mouse feces, adding phosphate buffer solution, shaking and mixing, freezing and thawing with liquid nitrogen for three times, homogenizing with a bead mill type pulverizer, centrifuging, collecting supernatant, and detecting with Nanjing kit.
EXAMPLE 1 symptomatic relief of punicalagin in hypercholesterolemic mice
The method comprises the following specific steps:
(1) Male C57BL/6J mice (18-22 g) at 6 weeks of age were used as subjects. Feeding environment: the temperature, the temperature and the humidity are 22+/-2 ℃ and 50% -60%, and the animal house environment is in a circulation mode of 12h illumination and 12h darkness.
(2) After one week of acclimation, the cells were randomly divided into three groups: normal diet blank (Chow group, feed containing 12% fat), model group (HFHC group, feed containing 42% fat, 1.25% cholesterol), punicalagin intervention group (hfhc+pu group, high fat high cholesterol feed (containing 42% fat, 1.25% cholesterol)) were fed while oral gavage punicalagin at a dose of 50mg/kg mouse body weight per day. Wherein, punicalagin is dissolved in sterile physiological saline with the concentration of 5mg/mL. The mice were fed continuously for 7 weeks, and the feces of each group were collected the day before the end of the experiment.
After molding, the mice are sacrificed, and serum, liver and ileum tissues are collected, wherein the liver and the ileum tissues are frozen by liquid nitrogen and then preserved at-80 ℃ for later use. Further, serum and liver tissue index detection and liver tissue staining observation were carried out, and all animal experiments were approved by the ethical committee of university of Dalian Industrial university, and were carried out according to guidelines of national animal experiment institute.
Determination of serum and liver cholesterol levels in mice with punicalagin intervention groups showed 33.9%, 27.6% and 49.4% decrease in serum TC (FIG. 1A), LDL-C (FIG. 1B) and TC/HDL-C (FIG. 1C), respectively, compared with mice in model group, indicating that punicalagin (50 mg/kg/day) has preventive effect on hypercholesterolemia.
As shown in fig. 2-5, after the mice were fed with a high-fat high-cholesterol diet for 7 weeks, the serum and liver cholesterol levels were significantly increased, and the liver burden was increased to cause liver function damage, which was manifested in that the mice in the model group had significantly increased liver glutamic pyruvic transaminase content and H & E staining sections observed immune cell infiltration, increased liver cell volume, transparent liver cell cytoplasm, and nuclei floating in the centers of liver cells in the mice fed with the high-fat high-cholesterol diet.
Example 2 modulation of protein involved in cholesterol metabolism by punicalagin in liver tissue of hypercholesterolemic mice
The specific embodiment is the same as steps (1) to (2) in example 1;
mice obtained in the step (2) in the example 1 are sacrificed after the molding is finished, and the obtained liver tissues are subjected to RT-PCR detection, as shown in figure 6, the liver Fdps and the Cyp51 levels of an punicalagin intervention group are obviously reduced, the two are respectively key genes for synthesizing biological cholesterol and sterol, and punicalagin plays a role in inhibiting the biosynthesis of liver cholesterol by inhibiting the expression of mRNA level of punicalagin, so that the aim of reducing the cholesterol level is fulfilled.
The high-fat high-cholesterol feed obviously reduces the transcription level of a transcription regulator LXR of cholesterol metabolism in the liver of a mouse, the LDL receptor gene LDL-R, and the punicalagin intervention obviously increases the mRNA transcription level of LXR and LDL-R, so that the transfer of cholesterol and low-density lipoprotein cholesterol in the serum of the mouse is effectively promoted.
Example 3 punicalagin modulation of hypercholesterolemic mouse bile acid metabolism
The specific embodiment is the same as steps (1) to (2) in example 1;
mice were sacrificed after the modeling obtained in step (2) in example 1, and the obtained liver tissues and ileum tissues were subjected to RT-PCR detection, as shown in fig. 7, the mRNA expression levels of bile acid synthetases Cyp7a1 and Cyp27a1 in the livers of the punicalagin intervention group mice were significantly increased, and in addition, as shown in fig. 8, punicalagin was reduced by down-regulating the intestinal ASBT expression levels. It is shown that punicalagin is effective in promoting continuous conversion of liver cholesterol to bile acid, thereby reducing body cholesterol level. As shown in fig. 9-10, the total bile acid content results in the mouse faeces of each group showed that punicalagin promoted bile acid excretion, and further targeted metabonomics analysis showed that the ratio of primary bile acid to secondary bile acid in the mouse faeces of the punicalagin intervention group was significantly down-regulated.
Example 4 punicalagin modulation of intestinal flora in hypercholesterolemic mice
The specific embodiment is the same as steps (1) to (2) in example 1;
after the modeling obtained in step (2) of example 1 was completed, the mouse feces were collected for 16S rRNA gene sequencing analysis, as shown in fig. 10, and intestinal flora analysis showed that the microbiota of three groups of mice formed three clusters that were significantly separated (fig. 11A), indicating that punicalagin intervention could significantly alter the composition of intestinal flora induced by high-fat high-cholesterol diet. As shown in fig. 11B, at the portal level, the first three in abundance in the murine faeces of the model group were Firmicutes (85.75%), actinomycetes (actionobacteria, 6.10%), proteobacteria (5.62%), while in the punicalagin intervention group were Firmicutes (78.95%), warts microcolonia (verrucomicrobia, 13.79%) and actinomycetes (actionobacteria, 4.04%), respectively. Further analysis found that punicalagin reduced the abundance of Bile-salt hydrolase (BSH) producing bacteria clostridium (clostridium) and bifidobacterium (Bifidobacteriaceae) (fig. 11C-D).
Example 5 modulation of the FXR-associated pathway of the hypercholesterolemic mouse bile acid receptor by punicalagin
The specific embodiment is the same as steps (1) to (2) in example 1;
mice were sacrificed after the modeling obtained in step (2) of example 1, and the resulting ileal tissue was subjected to RT-PCR detection, and the farnesoid X receptor (Farnesoid X receptor, FXR), also known as bile acid receptor, was endogenously activated by bile acids, which regulated various aspects of bile acid metabolism, such as synthesis, bile duct export, intestinal resorption, etc. The results of studies have shown that activating the FXR pathway in the intestine results in short-term inhibition of gene transcription of bile acid synthase Cyp7a1 in the liver, as shown in fig. 12, punicalagin inhibits activation of the ileal FXR/Fgf15 pathway, which in turn results in upregulation of the transcription level of bile acid synthase genes, and down-regulation of the expression of bile acid reabsorption gene ASBT, thereby reducing the process of intestinal hepatic circulation of bile acids, resulting in a reduction of liver bile acid pool, promoting continuous conversion of cholesterol to bile acids. In addition, taurine (TCA), deoxycholic acid (TDCA) and deoxycholic acid (TCDCA) are known to have an effect of activating FXR receptor, and as shown in fig. 13, the research results indicate that punicalagin is effective in reducing the content of FXR activators TCA, TDCA and TCDCA in feces, thereby reducing the activation of FXR pathway.
In summary, the cholesterol-lowering effect of punicalagin is achieved in part by down-regulating cholesterol synthesis and increasing cholesterol catabolism, which may be achieved by modulating intestinal flora, altering bile acid composition, and modulating FXR signaling pathways. The punica granatum polyphenol punica granatum glycoside has obvious blood lipid reducing effect, can be used for preparing medicines, health products, foods or feeds for preventing and treating hypercholesterolemia, and provides a novel safe and effective prevention and treatment means for the hypercholesterolemia.
While the invention has been described with reference to the preferred embodiments, it is not limited thereto, and various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. Use of punicalagin for the manufacture of a medicament for the prevention, alleviation and/or treatment of hypercholesterolemia, characterized in that said punicalagin is punicalagin.
2. The use according to claim 1, characterized in that the use comprises at least one of the following actions:
(1) Inhibiting liver cholesterol synthesis in an individual;
(2) Promoting transport of serum cholesterol to the liver in an individual;
(3) Promoting the conversion of cholesterol to bile acids in an individual;
(4) Inhibiting reabsorption of bile acids in an individual;
(5) Reducing the abundance of individual bile hydrolase producing bacteria;
(6) Reducing the ratio of primary bile acid to secondary bile acid in an individual;
(7) Reducing the bile acid content of the individual for activating the farnesol X receptor gene FXR.
3. The use according to claim 2, wherein the bile hydrolase producing bacteria comprise clostridium and bifidobacteria; the bile acids used to activate FXR include taurine, taurodeoxycholic acid and taurodeoxycholic acid.
4. The use according to claim 1 or 2, wherein the medicament is an Fdps/Cyp51 pathway inhibitor, a bile acid synthase gene expression inhibitor, a liver X receptor gene LXR expression promoter, an LDL receptor gene LDL-R expression promoter, and an intestinal FXR/Fgf15 pathway inhibitor.
5. The application of the punica granatum polyphenol in health care products or feeds for controlling cholesterol in an individual is characterized in that the punica granatum polyphenol is punicalagin.
6. The use according to claim 5, characterized in that the use comprises at least one of the following actions:
(1) Inhibiting liver cholesterol synthesis in an individual;
(2) Promoting transport of serum cholesterol to the liver in an individual;
(3) Promoting the conversion of cholesterol to bile acids in an individual;
(4) Inhibiting reabsorption of bile acids in an individual;
(5) Reducing the abundance of individual bile hydrolase producing bacteria;
(6) Reducing the ratio of primary bile acid to secondary bile acid in an individual;
(7) Reducing the bile acid content of the individual for activating the farnesol X receptor gene FXR.
7. An Fdps/Cyp51 pathway inhibitor comprising punicalagin, wherein said punicalagin is punicalagin.
8. A bile acid synthetase gene expression inhibitor comprising punica granatum polyphenol, wherein said punica granatum polyphenol is punicalagin.
9. An expression promoter of liver X receptor gene LXR and/or LDL receptor gene LDL-R containing punicalagin, characterized in that said punicalagin is punicalagin.
10. An inhibitor of the intestinal FXR/Fgf15 pathway comprising punicalagin, characterized in that said punicalagin is punicalagin.
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