CN119424400A - Isobutyric acid and isovaleric acid, branched-chain amino acid metabolites of intestinal flora for alleviating aging, and their application - Google Patents
Isobutyric acid and isovaleric acid, branched-chain amino acid metabolites of intestinal flora for alleviating aging, and their application Download PDFInfo
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Abstract
本发明公开了缓解衰老的肠道菌群支链氨基酸代谢产物异丁酸和异戊酸及其应用，属于微生物技术领域以及医药技术领域。本发明通过动物实验证实肠道菌群支链氨基酸代谢产物异丁酸或异戊酸具有提高衰老小鼠倡导菌群支链氨基酸关键代谢基因porA丰度、改变小鼠肠道对营养物质的代谢、改善小鼠衰弱指数，升高小鼠肝脏过氧化物歧化酶，降低丙二醛，升高谷胱甘肽过氧化酶(GSH‑px)的水平，升高过氧化氢酶的水平，降低炎症因子IL‑6，降低炎症因子TNF‑alpha，升高小鼠大脑乙酰胆碱水平，提高小鼠抓力的作用。本发明的菌株在制备改善代谢缓解衰老的产品中，具有巨大的应用前景。
The present invention discloses intestinal flora branched-chain amino acid metabolites isobutyric acid and isovaleric acid and their applications for relieving aging, belonging to the fields of microbial technology and medical technology. The present invention confirms through animal experiments that intestinal flora branched-chain amino acid metabolites isobutyric acid or isovaleric acid have the effects of increasing the abundance of porA, a key metabolic gene for branched-chain amino acids in aging mice, changing the metabolism of nutrients in the intestine of mice, improving the frailty index of mice, increasing superoxide dismutase in mouse liver, reducing malondialdehyde, increasing the level of glutathione peroxidase (GSH‑px), increasing the level of catalase, reducing inflammatory factors IL‑6, reducing inflammatory factors TNF‑alpha, increasing the level of acetylcholine in mouse brain, and improving the grip of mice. The strain of the present invention has great application prospects in the preparation of products that improve metabolism and relieve aging.
Description
Technical Field
The invention relates to ageing-relieving intestinal flora branched-chain amino acid metabolites isobutyric acid and isovaleric acid and application thereof, belonging to the technical field of microorganisms and the technical field of medicines.
Background
Aging is a complex process involving changes in cells, tissues, organs, etc., which include not only deterioration of physiological functions, but also increased risks of various diseases including neurodegenerative diseases, cardiovascular diseases, metabolic diseases, musculoskeletal diseases, immune system diseases, etc. The molecular mechanisms of senescence are complex involving accumulation of DNA damage, shortening of telomeres, oxidative stress, cell senescence, depletion of stem cells, and the like.
Intervention in aging is also becoming increasingly important. Research shows that the aging process can be delayed by methods such as caloric restriction, microbiota transplantation, nutrition intervention and the like. In addition, drug therapy, stem cell therapy, antioxidant and anti-inflammatory therapy, hormone replacement therapy, and the like have also been explored for the treatment of aging-related diseases. Drugs such as rapamycin, metformin, spermidine, nad+ supplements, senolytics class of drugs, etc. have shown potential in delaying aging. Among the last markers of aging 12 released heretofore, disorders and imbalances of the intestinal microbiome are one of the important markers of aging, and the balance of the intestinal microbiota has an important role in maintaining metabolic health and delaying the aging process in humans, and methods of alleviating aging associated with intestinal microorganisms have shown great potential.
Branched Chain Amino Acids (BCAAs), including leucine, isoleucine and valine, are essential amino acids for the human body and play a critical role in regulating metabolic health and the progression of aging. Intestinal microorganisms participate in the metabolism of branched-chain amino acids in various ways, and the existing literature shows that, unlike the metabolism of organisms and the metabolism of industrial zymophytes, the branched-chain amino acid metabolism of some intestinal flora in organisms can produce three metabolites, i.e. isobutyric acid, isovaleric acid and 2-methylbutyric acid, through special atypical pathways. Both the preliminary study of the influence of short-chain fatty acid on the life span of caenorhabditis elegans and the antioxidant effect of substituted short-chain fatty acid on caenorhabditis elegans show that in the oxidative stress experiment, the traditional short-chain fatty acids formic acid, acetic acid, propionic acid, butyric acid and valeric acid caproic acid have no in-vivo antioxidant activity, cannot prolong the survival time of nematodes under the oxidative stress condition, and possibly have no effect of delaying aging. 2-methylbutyric acid can increase the antioxidant activity of nematodes and prolong the life of wild-type nematodes, but 2-methylbutyric acid has a weak degree of improvement on the aging organism and cannot bring the aging organism to an ideal state at a healthy level. Thus, there is a need to screen for natural metabolites that significantly improve the health level of the aging organism.
Disclosure of Invention
The invention provides an application of a branched-chain amino acid metabolite in preparing a medicament for relieving aging of mice, wherein the branched-chain amino acid metabolite comprises isobutyric acid (isobutyrate, ISB) or isovaleric acid (isovalerate, ISV).
In one embodiment of the invention, the isobutyric acid (isobutyrate, ISB) has the formula (CH 3)2CHCO2 H; the isovaleric acid (isovalerate, ISV) has the formula (CH 3)2CHCH2 COOH);
The structural formula is as follows:
In one embodiment of the present invention, the medicament is used in at least one of (a) - (j):
(a) Isobutyric acid and isovaleric acid increase the abundance of key metabolic genes of branched-chain amino acids in the intestinal flora of mice of aging individuals;
(b) Altering the metabolism of the intestinal flora of the aging mice on nutrients;
(c) Decreasing the debilitating score index of aging individuals;
(d) Reducing the level of MDA in liver tissue of an aging individual;
(e) Increasing the level of SOD enzymes in liver tissue of an aging individual;
(f) Increasing the level of CAT enzyme in liver tissue of an aging individual;
(g) Increasing the level of GSH-px enzyme in liver tissue of an aging individual;
(h) Increasing the level of acetylcholine in brain tissue of an aging individual;
(i) Reducing the expression level of a pro-inflammatory factor in colon tissue of an aging individual, said pro-inflammatory factor comprising IL-6 or TNF-alpha
(J) Improving the gripping power of the aged individuals.
In one embodiment of the invention, the branched chain amino acid metabolite is added in an amount of at least 5mmol/L or 0.005mmol/g.
In one embodiment of the invention, the medicament comprises a branched chain amino acid metabolite, a pharmaceutical carrier and/or a pharmaceutical adjuvant.
In one embodiment of the invention, the pharmaceutical carrier comprises microcapsules, microspheres, nanoparticles, and liposomes.
In one embodiment of the invention, the pharmaceutical excipients comprise excipients and additives.
In one embodiment of the invention, the pharmaceutical excipients comprise anti-adhesive, permeation enhancers, buffers, plasticizers, surfactants, defoamers, thickeners, inclusion agents, absorbents, humectants, solvents, propellants, solubilizers, co-solvents, emulsifiers, colorants, pH modifiers, adhesives, disintegrants, fillers, lubricants, wetting agents, integration agents, tonicity modifiers, stabilizers, glidants, flavoring agents, preservatives, foaming agents, suspending agents, coating materials, fragrances, diluents, flocculants and deflocculants, filter aids, and release retarders.
In one embodiment of the invention, the additive comprises microcrystalline cellulose, hydroxypropyl methylcellulose, or lecithin.
In one embodiment of the invention, the dosage form of the medicament comprises a granule, capsule, tablet, pill or liquid formulation.
The beneficial effects are that:
the invention provides a branched chain amino acid metabolite isobutyric acid or isovaleric acid for relieving aging of mice. The concrete steps are as follows:
(1) Isobutyric acid and isovaleric acid increase the abundance of the branched chain amino acid key metabolic gene porA in the intestinal flora of mice of aging individuals.
(2) Isobutyric acid and isovaleric acid change the metabolism of intestinal flora of aging mice on nutrient substances, and the branched chain amino acid metabolites of the three intestinal flora, isobutyric acid and isovaleric acid, change the intestinal protein digestion and absorption paths of aging mice.
(3) Isobutyric acid and isovaleric acid obviously reduce the weakening index of the aging mice, the weakening index is reduced by 49.15 percent after isobutyric acid is orally taken, the weakening index is reduced by 57.26 percent after isovaleric acid is orally taken, the weakening index is reduced by 33.33 percent after 2-methyl butyric acid is orally taken, the weakening index is reduced by 59.00 percent compared with spermidine medicine group, and the effect of reducing the weakening index of isobutyric acid and isovaleric acid is better than that of 2-methyl butyric acid.
(4) Isobutyric acid and isovaleric acid obviously raise the level of superoxide dismutase (SOD) of aged mice, the SOD is raised by 75.21% after isobutyric acid is orally taken, the SOD is raised by 49.28% after isovaleric acid is orally taken, and compared with spermidine pharmaceutical group, the SOD level is raised by 1%.
(5) Isobutyric acid and isovaleric acid significantly reduce the liver Malondialdehyde (MDA) level of aged mice, MDA is reduced by 42.03% after isobutyric acid is orally taken, MDA is reduced by 38.97% after isovaleric acid is orally taken, and MDA is reduced by 34.20% after 2-methylbutyric acid is orally taken. Isobutyric acid and isovaleric acid were superior to 2-methylbutyric acid in reducing liver MDA levels in mice.
(6) Isobutyric acid and isovaleric acid significantly raise the level of aged mouse liver glutathione peroxidase (GSH-px), GSH-px rises by 118.26% after isobutyric acid is orally taken, GSH-px rises by 112.50% after isovaleric acid is orally taken, GSH-px rises by 83.46% after 2-methylbutyric acid is orally taken, the level of isobutyric acid and isovaleric acid raise the level of mouse liver GSH-px higher than 2-methylbutyric acid, and the level of isobutyric acid raises by 4.2% compared with spermidine pharmaceutical group.
(7) Isobutyric acid and isovaleric acid significantly raise liver Catalase (CAT) levels in aged mice, CAT is raised by 33.32% after isobutyric acid is orally administered, CAT is raised by 21.53% after isovaleric acid is orally administered, CAT is raised by 23.51% after 2-methylbutyric acid is orally administered, and liver CAT levels in isobutyric acid-raised mice are superior to 2-methylbutyric acid.
(8) Isobutyric acid and isovaleric acid reduce IL-6 levels in colon homogenates of aging mice, IL-6 is reduced by 38.44% after oral administration of isobutyric acid, IL-6 is reduced by 28.33% after oral administration of isovaleric acid, IL-6 is reduced by 35.83% after oral administration of 2-methylbutyric acid, and isobutyric acid reduces IL-6 levels in mice better than 2-methylbutyric acid.
(9) Isobutyric acid and isovaleric acid reduced the levels of TNF-alpha in colon homogenates of aging mice, and after oral administration of isobutyric acid, TNF-alpha was reduced by 35.46%, and after oral administration of isovaleric acid, TNF-alpha was reduced by 32.03%, compared to spermidine drug groups, isobutyric acid TNF-alpha was reduced by 21.63% and isovaleric acid TNF-alpha was reduced by 9.96%.
(10) Isobutyric acid and isovaleric acid increase the level of acetylcholine in the brain of aged mice, and after isobutyric acid is orally taken, acetylcholine is increased by 133.94%, after isovaleric acid is orally taken, acetylcholine is increased by 215.14%, after 2-methylbutyric acid is orally taken, acetylcholine is increased by 108.50%, and the effect of isobutyric acid and isovaleric acid on increasing the level of acetylcholine in the brain is superior to that of 2-methylbutyric acid and to spermidine pharmaceutical groups.
(11) The holding power of aged mice is improved by isobutyric acid and isovaleric acid, the holding power is improved by 22.10% after isobutyric acid is orally taken, the holding power is improved by 22.37% after isovaleric acid is orally taken, the holding power is improved by 16.81% after 2-methylbutyric acid is orally taken, and the holding power improving effect of isobutyric acid and isovaleric acid is superior to that of 2-methylbutyric acid and is superior to that of spermidine pharmaceutical groups.
Therefore, the intestinal flora metabolite isobutyric acid and isovaleric acid of the branched chain amino acid have great application prospect in preparing medicines for relieving aging.
Drawings
FIG. 1 shows the abundance of the branched-chain amino acid metabolism key gene porA of intestinal flora of mice in different groups of experiments;
FIG. 2 enrichment analysis of intestinal flora metabolic pathways of different groups of experimental mice;
FIG. 3 shows the debilitation index of different groups of experimental mice;
FIG. 4 liver superoxide dismutase (SOD) levels from different groups of experimental mice;
FIG. 5 liver Malondialdehyde (MDA) levels in different groups of experimental mice;
FIG. 6 liver glutathione peroxidase (GSH-px) levels from different groups of experimental mice;
FIG. 7 liver Catalase (CAT) levels of different groups of experimental mice;
FIG. 8 IL-6 levels in colon homogenates of different groups of experimental mice;
FIG. 9 TNF-alpha levels in colon of various groups of experimental mice;
FIG. 10 brain acetylcholine levels of different groups of experimental mice;
FIG. 11 levels of grip in different groups of experimental mice;
FIG. 12 is a flow chart of animal experiments.
Detailed Description
D-galactose (D-gal) (CAS No. 59-23-4), isobutyric acid (isobutyrate, ISB, CAS: 79-31-2), isovaleric acid (isovalerate, ISV, CAS: 503-74-2) and 2-methylbutanoic acid (2-methylbutyrate, 2-MB, CAS: 116-53-0) referred to in the examples below were purchased from Allatin.
The following examples relate to the preparation method of D-galactose solution:
D-galactose solution, namely, weighing a certain amount of D-galactose, dissolving the D-galactose in sterile physiological saline to prepare the D-galactose, and subcutaneously injecting the D-galactose into 700mg/kg of body weight and 1000mg/kg of body weight.
Example 1 branched chain amino acid intestinal flora metabolite isobutyric acid, isovaleric acid increases the abundance of the branched chain amino acid metabolism key gene porA in the intestinal flora of mice
SPF class C57BL/6J male mice of 8 weeks old are raised in laboratory animal centers of Jiangnan university, fed with common feed, at constant temperature 20-26 ℃, humidity 40% -70%, noise less than or equal to 60dB, animal illuminance 15-20LX,12h illumination, and 12h darkness (all animal experimental procedures are examined and approved by the university animal welfare and ethics management committee of Jiangnan).
The experimental design was 20 weeks, and the detailed flow is shown in FIG. 10. After the mice entered the feeding facility, they were acclimatized for one week and were modeled with galactose (CAS No. 59-23-4, allatin) for 2-13 weeks. The control group mice are subcutaneously injected with sterile physiological saline, the other treatment groups are subcutaneously injected with 700mg/kg BW/D sterile physiological saline dissolved D-galactose, and the mice can generate certain drug resistance to the D-galactose, and the treatment is continued by using 1000mg/kg BW/D subcutaneous injection for 14-20 weeks, and meanwhile, each group of mice is subjected to corresponding experimental treatment, and the control group and the model group are filled with 200 mu L of sterile physiological saline daily. All groups were injected in the same volume.
The method comprises the following steps:
the blank group is that after the mice enter the feeding facility, the mice are firstly adapted for one week, 2 to 13 weeks, the blank group mice are subcutaneously injected with sterile physiological saline, and the blank group mice are subcutaneously injected with sterile physiological saline for 14 to 20 weeks, and 200 mu L of sterile physiological saline is infused once a day.
The model group is that after the mice enter the feeding facility, the mice are firstly adapted for one week for 2-13 weeks, the model group is subcutaneously injected with 700mg/kg BW/D sterile physiological saline-dissolved D-galactose, and is subcutaneously injected with 1000mg/kg BW/D sterile physiological saline-dissolved D-galactose for 14-20 weeks, and 200 mu L of sterile physiological saline is infused into the stomach every day, and the mice are freely ingested and drunk.
The isobutyric acid experimental group (ISB group) is that mice are firstly adapted for one week and 2-13 weeks after entering a feeding facility, the model group is subcutaneously injected with 700mg/kg BW/D of D-galactose dissolved in sterile physiological saline, and the model group is subcutaneously injected with 1000mg/kg BW/D of D-galactose dissolved in sterile physiological saline and is filled with 6.5mmol/L,100 mu L/10g body weight isobutyric acid every day for 14-20 weeks, and the model group is freely ingested and drunk.
The isovaleric acid experimental group (ISV group) is adapted for one week, 2-13 weeks after the mice enter the feeding facility, the model group is subcutaneously injected with 700mg/kg BW/D of D-galactose dissolved in sterile physiological saline, 14-20 weeks is subcutaneously injected with 1000mg/kg BW/D of D-galactose dissolved in sterile physiological saline, and 5.5mmol/L,100 mu L/10g of body weight isovaleric acid is infused daily, and the mice are freely fed and drunk.
2-Methylbutyric acid control group (2-MB group) mice were acclimatized for one week, 2-13 weeks after entering the feeding facility, and the model group was subcutaneously injected with 700mg/kg BW/D sterile saline-dissolved D-galactose, 14-20 weeks with 1000mg/kg BW/D sterile saline-dissolved D-galactose, and were gavaged 5.5mmol/L daily, 100. Mu.L/10 g body weight of 2-methylbutyric acid, and fed and drunk freely.
Before the mice were sacrificed, the mouse feces were collected, total DNA of the feces was extracted using QIAAMP DNA Stool Mini Kit (Qiagen, hilden, germany) extraction Kit, purity and integrity of the DNA was checked by 1% agarose gel electrophoresis, and metagenomic sequencing was performed on DNBSEQ-T7 platform of Beijing norelsen Co. Original sequencing reads used Trimmomatic (version 0.39) to remove sequencing adaptors and low mass sequences. The filtered sequences were aligned with the human reference genome using BWA (version 0.7.17), samtools (version 1.9) and BEDTools (version 2.30.0) to remove the host sequences. The sequence subjected to quality control and host removal operation is subjected to metabolic function annotation of intestinal flora based on a MetaCyc database by using HUMAnN (version 3.8), and then renamed corresponding to a Uniref database to obtain the family abundance information of metabolic genes of the intestinal flora.
The document reports that the porA gene is a key gene for metabolism of branched-chain amino acids by intestinal flora, and the strain loses the ability of metabolism of branched-chain amino acids and production of isobutyric acid, isovaleric acid and 2-methyl butyric acid after knocking out the porA gene. Comparing the base sequence of the porA gene reported in the literature with a Uniref database, selecting base sequences with the base sequence similarity of 85% and above, and matching uniref 90 numbers of the genes with the gene family file of the intestinal flora of the aging mice. Obtaining the gene abundance of the branched chain amino acid key gene porA of the intestinal flora metabolism of the aging mice, and the result is shown in figure 1:
The result shows that compared with a model group, the abundance of the branched chain amino acid metabolism key gene porA of the intestinal flora of the mice in the isobutyric acid group and the isovaleric acid group is obviously increased. The isobutyric acid and the isovaleric acid are proved to have the capability of improving the metabolism of branched-chain amino acids of intestinal flora. The enhancement degree of isobutyric acid and isovaleric acid on gene porA abundance is 1.9 times and 1.5 times of that of a model group respectively, and the effect is better than that of a 2-methyl butyric acid group.
Example 2 modification of the metabolism of the nutrient by the intestinal flora of the branched-chain amino acid metabolite isobutyric acid, isovaleric acid
Detailed description referring to example 1, the mouse feces were collected prior to the sacrifice of the mice. Non-target metabolome detection was performed by taking 100. Mu.L of the sample, mixing with 400. Mu.L of extraction solution (MeOH: ACN,1:1 (v/v)) containing deuterated internal standard, vortexing the mixed solution for 30 seconds, sonicating in a 4℃water bath for 10 minutes, incubating for 1 hour-40℃to precipitate the protein. The samples were then centrifuged at 12000rpm (rcf=13800 (x g), r=8.6 cm) at 4 ℃ for 15 minutes. The supernatant was transferred to a new glass vial for analysis. Quality Control (QC) samples were prepared by mixing equal amounts of sample supernatant.
For polar metabolites, MS analysis was performed using a UHPLC system (Vanquish, siemens technologies) using Waters ACQUITY UPLC BEH amide (2.1 mm. Times.50 mm,1.7 μm) coupled to a Orbitrap Exploris mass spectrometer (Orbitrap MS, thermo). The mobile phase consisted of 25mmol/L ammonium acetate and 25 ammonia in water (ph=9.75) (a) and acetonitrile (B). The automatic sample injection temperature was 4℃and the sample injection amount was 2. Mu.L. Orbitrap Exploris 120mass spectrometer is used to acquire MS/MS spectra in an Information Dependent Acquisition (IDA) mode under control of acquisition software (Xcalibur, thermo). In this mode, the acquisition software continues to evaluate the full-scan mass spectrum. The ESI source conditions were set such that the sheath gas flow was 50Arb, the auxiliary gas flow was 15Arb, the capillary temperature was 320 ℃, the full MS resolution was 60000, the MS/MS resolution was 15000, the collision energy was SNCE/30/40, and the spray voltage was 3.8kV (positive) or-3.4 kV (negative), respectively.
As shown in FIG. 2, the results of KEGG metabolic pathway enrichment analysis on metabolites show that both isobutyric acid and isovaleric acid can change the metabolic pathway of various amino acids in the intestinal tract of an aging mouse, and simultaneously change the metabolic pathway of protein digestion and absorption.
Example 3 alleviation of the debilitating index of aging mice by the branched-chain amino acid metabolite isobutyric acid, isovaleric acid of the intestinal flora
Detailed description referring to example 1, each of the mice with aging was scored for their vulnerability prior to sacrifice, including an assessment of 13 variables. The frailty index ((Frailty Index, FI) was calculated from the scores of the individual variables, the specific score criteria being that for each variable a score of 0 represents no defects, a score of 0.5 represents mild defects, and a score of 1 represents severe defects.
TABLE 1 mice debilitation index table
As can be seen from fig. 3, the average of the blank group weakening index was 2.06, the average of the model group weakening index was 4.68, the average of the isb group weakening index was 2.4, the average of the isv group weakening index was 2, the average of the 2-MB group weakening index was 3.12, and the average of the spermidine group weakening index was 2. Compared with a model group, isobutyric acid and isovaleric acid obviously reduce the weakening index of a wealth mouse, the weakening index is reduced by 49.15 percent after isobutyric acid is orally taken, the weakening index is reduced by 57.26 percent after isovaleric acid is orally taken, the weakening index is reduced by 33.33 percent after 2-methyl butyric acid is orally taken, the effect of isobutyric acid and isovaleric acid for reducing the weakening index is superior to that of 2-methyl butyric acid compared with spermidine medicine group, and the experimental results show that the metabolic products isobutyric acid and isovaleric acid of the intestinal flora of branched-chain amino acids can effectively reduce the weakening index of the mouse, improve the weakening state of the mouse, achieve the effect superior to that of medicines, and achieve the effect superior to that of 2-methyl butyric acid of the branched-chain amino acid of other intestinal flora.
Example 4 effect of intestinal flora on increasing liver superoxide dismutase (SOD) levels in senescent mice by the branched-chain amino acid metabolite isobutyric acid, isovaleric acid
Detailed description referring to example 1, after the end of the experiment, the mice were sacrificed in the methylbutyric acid control group, the livers of the mice were removed, placed in liquid nitrogen, stored in a-80 ℃ refrigerator, the tissues were rinsed with pre-chilled PBS (0.01 m, ph=7.4), residual blood was removed, and minced. 1.2g of tissue with fresh weight is weighed, PBS is added according to the weight-to-volume ratio of 1:9, 1mL of general protease inhibitor (Biyun) is added to each 100mL of PBS, equal amount of grinding beads are added to each tissue, and the tissue is fully ground on ice by using a precooled tissue grinder die until no solid matters are seen at all. Further repeatedly freezing and thawing to fully crack. Centrifuging the homogenate at 5000 Xg for 5-10 minutes, taking supernatant and sub-packaging for later use. Protein concentration was measured by BCA method, 1.2ml of protein standard preparation (0.5 g of bovine serum albumin, dissolved in distilled water and fixed to 100ml of volume to prepare a 5mg/ml solution, ten times diluted when used) was added to a tube of protein standard (30 mg BSA), and after complete dissolution, 25mg/ml of protein standard solution was prepared. A proper amount of 25mg/ml protein standard was taken and diluted to a final concentration of 0.5mg/ml. According to the number of samples, adding 1 volume BCA reagent B (2 g CuSO 4·5H2 O (4%) and distilled water to 50 ml) (50:1) into 50 volumes of BCA reagent A (10g BCA(1％),20g Na2CO3·H2O(2％),1.6g Na2C4H4O6·2H2O(0.16％),4g NaOH(0.4％),9.5g NaHCO3(0.95％), is respectively weighed and added with water to 1L, and pH value is adjusted to 11.25 by NaOH or solid NaHCO 3), and then preparing an appropriate amount of BCA working solution, and fully and uniformly mixing. And (3) selecting proper concentration within the standard substance concentration of 0-1.5mg/mL to prepare a standard curve, and pre-experiment on the sample to obtain proper dilution. In the formal experiment, 20 mu L of sample or standard substances with different concentrations are added into each hole, 200 mu LBCA of working solution is added into each hole, and the mixture is incubated for 30 minutes at 37 ℃ in a dark place. Absorbance was measured at 562nm using a microplate reader. The sample protein concentration was calculated.
The content of superoxide dismutase (SOD) in the mouse liver homogenate was measured according to the procedure of the liver superoxide dismutase (SOD) ELISA kit specification, and the result is shown in FIG. 4.
The results show that:
As can be seen from FIG. 4, the average value of the superoxide dismutase (SOD) in the liver of the blank group is 27.90ng/mg protein, the average value of the superoxide dismutase (SOD) in the liver of the model group is 16.254ng/mg protein, the average value of the superoxide dismutase (SOD) in the liver of the ISB group is 28.48ng/mg protein, the average value of the superoxide dismutase (SOD) in the liver of the ISV group is 24.26ng/mg protein, and the average value of the superoxide dismutase (SOD) in the liver of the spermidine drug group is 29.51ng/mg protein. Isobutyric acid and isovaleric acid obviously raise the level of superoxide dismutase (SOD) of aged mice, the SOD is raised by 75.21% after isobutyric acid is orally taken, the SOD is raised by 49.28% after isovaleric acid is orally taken, and compared with spermidine pharmaceutical group, the SOD level is raised by 1%. The experimental results show that the metabolites of the branched chain amino acid intestinal flora, i.e. isobutyric acid and isovaleric acid, can effectively raise the level of superoxide dismutase (SOD) in the liver of mice, improve the debilitating state of the mice, and achieve the effect superior to that of drugs.
Example 5 reduction of the level of Malondialdehyde (MDA) in the liver of aged mice by the branched-chain amino acid metabolite isobutyric acid, isovaleric acid of the intestinal flora
Detailed description referring to the examples, the Malondialdehyde (MDA) content in mouse liver homogenates was measured according to the procedure of the liver Malondialdehyde (MDA) level ELISA kit instructions and the results are shown in fig. 5.
The results show that:
As can be seen from FIG. 5, the average of the values of Malondialdehyde (MDA) in the blank group and spermidine drug group was 21.95nmol/mg protein, the average of the values of Malondialdehyde (MDA) in the model group was 34.71nmol/mg protein, the average of Malondialdehyde (MDA) in the ISB group was 20.12nmol/mg protein, the average of Malondialdehyde (MDA) in the ISV group was 21,18nmol/mg protein, the average of Malondialdehyde (MDA) in the 2-MB group was 22.84nmol/mg protein, and the average of Malondialdehyde (MDA) in the spermidine drug group was 44.38nmol/mg protein. Isobutyric acid and isovaleric acid significantly reduce the liver Malondialdehyde (MDA) level of aged mice, MDA is reduced by 42.03% after isobutyric acid is orally taken, MDA is reduced by 38.97% after isovaleric acid is orally taken, and MDA is reduced by 34.20% after 2-methylbutyric acid is orally taken. Isobutyric acid and isovaleric acid were superior to 2-methylbutyric acid in reducing liver MDA levels in mice.
The experimental results show that the branched chain amino acid intestinal flora metabolites isobutyric acid and isovaleric acid can effectively reduce the level of Malondialdehyde (MDA) in the liver of a mouse, improve the debilitating state of the mouse and achieve the effect superior to that of drugs and other products 2-methylbutyric acid.
Example 6 Effect of intestinal flora branched-chain amino acid metabolites on the elevation of liver glutathione peroxidase (GSH-px) levels in aged mice
Detailed description referring to example 4, the glutathione peroxidase (GSH-px) content in mouse liver homogenates was measured according to the procedure of the liver glutathione peroxidase (GSH-px) level ELISA kit specification, and the results are shown in fig. 6.
The results show that:
As can be seen from FIG. 6, the average value of glutathione peroxidase (GSH-px) in the blank group was 180.25U/mg protein, the average value of glutathione peroxidase (GSH-px) in the model group was 77.07U/mg protein, the average value of glutathione peroxidase (GSH-px) in the ISB group was 168.21U/mg protein, the average value of glutathione peroxidase (GSH-px) in the ISV group was 163.77U/mg protein, the average value of glutathione peroxidase (GSH-px) in the 2-MB group was 141.38U/mg protein, the average value of glutathione peroxidase (GSH-px) in the spermidine drug group was 161.38U/mg protein, and when isobutyric acid was orally administered, GSH-px increased by 118.26%, when isobutyric acid was orally administered, GSH-px increased by 112.50%, and when isobutyric acid was orally administered, GSH-px increased by 2-methyl butyrate, and when compared with the model group, the levels of isobutyric acid and isobutyric acid were increased by 2.83.46% and so that the levels of isobutyric acid were significantly increased. Compared with spermidine pharmaceutical group, the liver GSH-px level of mice is increased by 4.2%.
The experimental results show that the metabolites of the branched-chain amino acid of the intestinal flora, namely isobutyric acid and isovaleric acid, can effectively raise the glutathione peroxidase (GSH-px) level of the liver of the mice and improve the debilitating state of the mice, wherein the isobutyric acid effect is superior to that of a medicament, and the isobutyric acid and isovaleric acid effect is superior to that of the other product of the branched-chain amino acid of the intestinal flora, namely 2-methylbutyric acid.
Example 7 effect of branched chain amino acid metabolites of intestinal flora on the elevation of liver Catalase (CAT) levels in senescent mice
Detailed description referring to example 4, the Catalase (CAT) content of the mouse liver homogenate was measured according to the procedure of the Catalase (CAT) level ELISA kit specification, and the results are shown in fig. 7.
The results show that:
As can be seen from FIG. 7, the average value of the liver Catalase (CAT) in the blank group was 539.19pg/mg protein, the average value of the liver Catalase (CAT) in the model group was 258.53pg/mg protein, the average value of the liver Catalase (CAT) in the ISB group was 344.67pg/mg protein, the average value of the liver Catalase (CAT) in the ISV group was 314.20pg/mg protein, the average value of the liver Catalase (CAT) in the 2-MB group was 319.31pg/mg protein, and the average value of the liver Catalase (CAT) in the spermidine drug group was 575.71pg/mg protein. Compared with the model group, isobutyric acid and isovaleric acid obviously raise the level of liver Catalase (CAT) of aged mice, CAT is raised by 33.32% after isobutyric acid is orally taken, CAT is raised by 21.53% after isovaleric acid is orally taken, CAT is raised by 23.51% after 2-methylbutyric acid is orally taken, and the liver CAT level of isobutyric acid raising mice is superior to that of 2-methylbutyric acid. The experimental result shows that the branched chain amino acid metabolite of the intestinal flora can effectively raise the liver Catalase (CAT) level of mice and improve the debilitating state of the mice, wherein the isobutyric acid effect is superior to that of another product 2-methylbutyric acid of the branched chain amino acid of the intestinal flora.
Example 8 Effect of intestinal flora branched-chain amino acid metabolites on IL-6 level reduction in colon homogenates of aged mice
Detailed description referring to example 5, after mice were sacrificed, the colon of the mice was removed, placed in liquid nitrogen, stored in a-80 ℃ refrigerator, the tissue was rinsed with pre-chilled PBS (0.01 m, ph=7.4), residual blood was removed, and minced. 1.2g of tissue with fresh weight is weighed, PBS is added according to the weight-to-volume ratio of 1:9, 1mL of general protease inhibitor (Biyun) is added to each 100mL of PBS, equal amount of grinding beads are added to each tissue, and the tissue is fully ground on ice by using a precooled tissue grinder die until no solid matters are seen at all. Further repeatedly freezing and thawing to fully crack. Centrifuging the homogenate at 5000 Xg for 5-10 minutes, taking supernatant and sub-packaging for later use. Protein concentration was measured by BCA method, 1.2ml of protein standard preparation (0.5 g of bovine serum albumin, dissolved in distilled water and fixed to 100ml of volume to prepare a 5mg/ml solution, ten times diluted when used) was added to a tube of protein standard (30 mg BSA), and after complete dissolution, 25mg/ml of protein standard solution was prepared. A proper amount of 25mg/ml protein standard was taken and diluted to a final concentration of 0.5mg/ml. According to the number of samples, adding 1 volume BCA reagent B (2 g CuSO 4·5H2 O (4%) and distilled water to 50 ml) (50:1) into 50 volumes of BCA reagent A (10g BCA(1％),20g Na2CO3·H2O(2％),1.6g Na2C4H4O6·2H2O(0.16％),4g NaOH(0.4％),9.5gNaHCO3(0.95％), is respectively weighed and added with water to 1L, and pH value is adjusted to 11.25 by NaOH or solid NaHCO 3), and then preparing an appropriate amount of BCA working solution, and fully and uniformly mixing. And (3) selecting proper concentration within the standard substance concentration of 0-1.5mg/mL to prepare a standard curve, and pre-experiment on the sample to obtain proper dilution. In the formal experiment, 20 mu L of sample or standard substances with different concentrations are added into each hole, 200 mu LBCA of working solution is not added, and the mixture is incubated for 30 minutes at 37 ℃ in a dark place. Absorbance was measured at 562nm using a microplate reader. The sample protein concentration was calculated.
The IL-6 content of the colon homogenate of the mice was measured according to the procedure of the IL-6ELISA kit, and the results are shown in FIG. 8.
The results show that:
As can be seen from FIG. 8, the average of blank colon homogenate IL-6 was 306.95pg/mg protein, the average of model colon homogenate IL-6 was 366.24pg/mg protein, the average of ISB colon homogenate IL-6 was 225.47pg/mg protein, the average of ISV colon homogenate IL-6 was 262.49pg/mg protein, the average of 2-MB colon homogenate IL-6 was 235.02pg/mg protein, and the average of spermidine drug group colon homogenate IL-6 was 312.41pg/mg protein. Compared with the model group, the isobutyric acid and the isovaleric acid reduce the IL-6 level in colon homogenate of aged mice, the IL-6 is reduced by 38.44 percent after the isobutyric acid is orally taken, the IL-6 is reduced by 28.33 percent after the isovaleric acid is orally taken, the IL-6 is reduced by 35.83 percent after the 2-methyl butyric acid is orally taken, and the IL-6 level of the mice is reduced by the isobutyric acid and is superior to that of the 2-methyl butyric acid.
The experimental result shows that the branched chain amino acid metabolite of the intestinal flora can effectively reduce colon homogenate IL-6 of mice and improve the debilitating state of the mice, wherein the isobutyric acid effect is superior to that of the other metabolite 2-methylbutyric acid of the branched chain amino acid of the intestinal flora.
Example 9 Effect of intestinal flora branched chain amino acid metabolites on reduction of TNF-alpha levels in colon homogenates of aged mice
Description of the preferred embodimentsreferring to example 5, the TNF-alpha content of a mouse colon homogenate was measured according to the procedure described in the TNF-ALPHA ELISA kit, and the results are shown in FIG. 9.
The results show that:
As can be seen from FIG. 9, the average of the blank colon homogenate TNF-alpha is 281.00pg/mg protein, the average of the model colon homogenate TNF-alpha is 324.56pg/mg protein, the average of the ISB colon homogenate TNF-alpha is 209.48pg/mg protein, the average of the ISV colon homogenate TNF-alpha is 220.61pg/mg protein, and the average of the spermidine drug colon homogenate TNF-alpha is 267.28pg/mg protein. Compared with a model group, isobutyric acid and isovaleric acid reduce the level of TNF-alpha in colon homogenate of a aged mouse, after isobutyric acid is orally taken, TNF-alpha is reduced by 35.46%, after isovaleric acid is orally taken, TNF-alpha is reduced by 32.03%, compared with spermidine medicament group, isobutyric acid TNF-alpha level is reduced by 21.63%, isovaleric acid TNF-alpha level is reduced by more than 9.96%, and experimental results show that branched chain amino acid metabolites of intestinal flora can effectively reduce colon homogenate TNF-alpha of the mouse, and the weakness state of the mouse is improved, and isobutyric acid and isovaleric acid effects are superior to spermidine medicaments.
Example 10 action of branched-chain amino acid metabolites of intestinal flora on the elevation of acetylcholine levels in brain homogenates of senescent mice
Detailed description referring to example 5, the acetylcholine content of the rat brain homogenate was measured following the procedure of the acetylcholine kit, and the results are shown in figure 10.
The results show that:
As can be seen from FIG. 10, the average of the blank group brain homogenized acetylcholine was 842.99. Mu.g/mg protein, the average of the model group brain homogenized acetylcholine was 440.88. Mu.g/mg protein, the average of the ISB group brain homogenized acetylcholine was 1031.40. Mu.g/mg protein, the average of the ISV group brain homogenized acetylcholine was 1389.40. Mu.g/mg protein, the average of the 2-MB group brain homogenized acetylcholine was 919.26. Mu.g/mg protein, and the average of the spermidine drug group brain homogenized acetylcholine was 401.33. Mu.g/mg protein. Compared with the model group, isobutyric acid and isovaleric acid increase the level of acetylcholine in brain of aged mice, the acetylcholine is increased by 133.94% after isobutyric acid is orally taken, the acetylcholine is increased by 215.14% after isovaleric acid is orally taken, the acetylcholine is increased by 108.50% after 2-methylbutyric acid is orally taken, and the effect of isobutyric acid and isovaleric acid on increasing the level of acetylcholine in brain is better than that of 2-methylbutyric acid and is better than that of spermidine drug group. The experimental result shows that the branched chain amino acid metabolite of the intestinal flora can effectively raise the level of acetylcholine in the brain homogenate of mice, improve the debilitating state of the mice, and obtain the effect superior to that of the drug and the 2-methylbutyric acid serving as another metabolite of the branched chain amino acid of the intestinal flora.
Example 11 increasing Effect of branched chain amino acid metabolites of intestinal flora on the grip of aging mice
Detailed description referring to example 4, before the mice were sacrificed, the mice were placed on a T-frame of a holding power apparatus (jinan Yiyan technology limited) and the tail of the mice was slowly pulled backward to read data, and the results are shown in fig. 11.
The results show that:
as can be seen from FIG. 11, the average of the holding power of mice in the blank group was 101.26g, the average of the holding power of mice in the model group was 80.54g, the average of the holding power of mice in the ISB group was 98.34g, the average of the holding power of mice in the ISV group was 98.56g, the average of the holding power of mice in the ISB group was 94.08g, and the average of the holding power of mice in the spermidine drug group was 68.27g. Compared with a model group, isobutyric acid and isovaleric acid improve the holding power of aged mice, the holding power is improved by 22.10 percent after isobutyric acid is orally taken, the holding power is improved by 22.37 percent after isovaleric acid is orally taken, the holding power is improved by 16.81 percent after 2-methyl butyric acid is orally taken, and the holding power improving effect of isobutyric acid and isovaleric acid is superior to that of 2-methyl butyric acid and is superior to that of spermidine medicine groups. The experimental result shows that the branched chain amino acid metabolite of the intestinal flora can effectively raise the holding power level of mice, improve the debilitating state of the mice, and have better effects than the 2-methylbutyric acid which is another metabolite of the branched chain amino acid of the intestinal flora.
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 (9)
1. Use of a branched-chain amino acid metabolite in the manufacture of a medicament for the alleviation of aging, characterized in that the branched-chain amino acid metabolite comprises isobutyric acid or isovaleric acid.
2. The use of claim 1, wherein said reducing aging comprises at least one of (a) - (j):
(a) Improving the abundance of branched chain amino acid key metabolic genes porA in intestinal flora of mice of aging individuals;
(b) Altering the metabolism of the intestinal flora of the aging mice on nutrients;
(c) Decreasing the debilitating score index of aging individuals;
(d) Reducing the level of MDA in liver tissue of an aging individual;
(e) Increasing the level of SOD enzymes in liver tissue of an aging individual;
(f) Increasing the level of CAT enzyme in liver tissue of an aging individual;
(g) Increasing the level of GSH-px enzyme in liver tissue of an aging individual;
(h) Increasing the level of acetylcholine in brain tissue of an aging individual;
(i) Reducing the expression level of a pro-inflammatory factor in colon tissue of a aging individual, wherein the pro-inflammatory factor comprises IL-6 or TNF-alpha;
(j) Improving the gripping power of the aged individuals.
3. The use according to claim 2, wherein the branched chain amino acid metabolite is added to the medicament in an amount of at least 5mmol/L or 0.005mmol/g.
4. The use according to claim 3, wherein the medicament comprises a branched chain amino acid metabolite, a pharmaceutical carrier and/or a pharmaceutical adjuvant.
5. The use according to claim 4, wherein the pharmaceutical carrier comprises microcapsules, microspheres, nanoparticles and liposomes.
6. The use according to claim 5, wherein the pharmaceutical excipients comprise excipients and/or additives.
7. The use according to claim 5, wherein the pharmaceutical excipients comprise anti-adhesive agents, permeation enhancers, buffers, plasticizers, surfactants, defoamers, thickeners, inclusion agents, absorbents, humectants, solvents, propellants, solubilizers, co-solvents, emulsifiers, colorants, pH modifiers, adhesives, disintegrants, fillers, lubricants, wetting agents, integration agents, osmotic pressure modifiers, stabilizers, glidants, flavoring agents, preservatives, foaming agents, suspending agents, coating materials, fragrances, diluents, flocculants and deflocculants, filter aids, and release retarders.
8. The use according to claim 6, wherein the additive comprises microcrystalline cellulose, hydroxypropyl methylcellulose or lecithin.
9. The use according to any one of claims 1 to 8, wherein the pharmaceutical dosage form comprises a granule, capsule, tablet, pill or liquid formulation.
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Citations (3)
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|---|---|---|---|---|
| CN115350171A (en) * | 2015-01-23 | 2022-11-18 | 坦普尔大学 | Application of short-chain fatty acids in cancer prevention |
| US20230027362A1 (en) * | 2019-10-30 | 2023-01-26 | Digmbio. Inc. | Isoquinolinone derivatives, method for preparing the same, and pharmaceutical composition for preventing or treating poly(adp-ribose) polymerase-1-related diseases, comprising the same as active ingredient |
| CN118370776A (en) * | 2024-03-15 | 2024-07-23 | 安琪酵母股份有限公司 | A postbiotic with the function of regulating intestinal flora and its application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115350171A (en) * | 2015-01-23 | 2022-11-18 | 坦普尔大学 | Application of short-chain fatty acids in cancer prevention |
| US20230027362A1 (en) * | 2019-10-30 | 2023-01-26 | Digmbio. Inc. | Isoquinolinone derivatives, method for preparing the same, and pharmaceutical composition for preventing or treating poly(adp-ribose) polymerase-1-related diseases, comprising the same as active ingredient |
| CN118370776A (en) * | 2024-03-15 | 2024-07-23 | 安琪酵母股份有限公司 | A postbiotic with the function of regulating intestinal flora and its application |
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