CN118806747A - Use of flavonol structure-containing compounds for maintaining physiological balance of lactic acid - Google Patents
Use of flavonol structure-containing compounds for maintaining physiological balance of lactic acid Download PDFInfo
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 235000014655 lactic acid Nutrition 0.000 title claims abstract description 33
- 239000004310 lactic acid Substances 0.000 title claims abstract description 33
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
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- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims abstract description 68
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of a compound containing a flavonol structure in maintaining physiological balance of lactic acid. The present invention provides the use of a compound having a flavonol structure in the manufacture of a product for maintaining the physiological balance of lactic acid in a subject. The compound with the flavonol structure can maintain the physiological balance of the L-lactic acid and the D-lactic acid in blood plasma, and has important significance for developing new medicaments for maintaining the metabolic balance, reducing neurodegenerative diseases, reducing inflammation, delaying aging and the like.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of a compound containing a flavonol structure in maintaining physiological balance of lactic acid.
Background
Lactic acid is a metabolite produced by both physiological and pathological processes, and exists in mammals as both the optical isomers of levorotatory (L-form) and dextrorotatory (D-form). Under normal physiological conditions, the ratio of L-type to D-type lactic acid content in blood is about 100:1. Lactic acid generated by glycolysis is L-lactic acid, and the L-lactic acid accounts for 65% to 20% of the total amount, and a small amount of L-lactic acid is derived from alanine metabolism. In activated immune cells or inflammatory reactions, the L-lactic acid content may increase. D-lactic acid is derived from pathological processes, mainly produced by intestinal bacteria, such as the lactic acid bacterium lactobacilli spp. In the blood of patients suffering from fatigue syndrome, diabetes mellitus, poisoning, the D-lactic acid content is markedly increased. Researchers have found that D-lactic acidotic cattle produce neurological symptoms such as changes in behaviour and posture, eventually coma, and elevated serum D-lactic acid levels. Patients with elevated D-lactic acid levels develop symptoms such as mild cerebellar ataxia, low muscular tension, cognitive dysfunction, hyperuricemia, and gout, indicating that D-lactic acid has a direct neurotoxic effect.
When the amount of lactic acid produced increases and the clearance decreases, acidosis is caused and the severity of clinical symptoms increases. Importantly, severe fluctuations in lactate levels can have profound effects on hemodynamics and can lead to death; blood lactate levels are unbalanced and there is an increased risk of death. In actual clinic, serum or plasma L-lactic acid (L-lactic acid) level is usually used as a risk sign and a treatment evaluation index, so that reasonable content of lactic acid in blood is maintained, and relative balance of L-lactic acid and D-lactic acid content is maintained, and the method has very important significance for body health.
Disclosure of Invention
In a first aspect, the present invention provides the use of a compound having a flavonol structure, a pharmaceutical composition or a pharmaceutical formulation comprising said compound having a flavonol structure for the preparation of a product for maintaining the physiological balance of lactic acid in a subject.
The structural general formula of the compound with the flavonol structure is shown as formula I:
In the formula I, R1 and R2 each independently represent a hydrogen atom, a five-carbon glycosyl group, a six-carbon glycosyl group, a disaccharide group or an oligosaccharide group.
In an embodiment of the present invention, the compound having a flavonol structure is icariin.
In the present invention, the lactic acid is L-lactic acid or D-lactic acid.
In the present invention, the lactic acid is lactic acid derived from at least one of plasma, serum, interstitial fluid and body fluid.
In the present invention, the subject is a mammal, specifically, a human, a mouse, a rat, a pig, or a monkey.
In the invention, the lactic acid physiological balance means that the content ratio of L-lactic acid to D-lactic acid in a subject is within a physiological level range, and the content of L-lactic acid and the content of D-lactic acid are within the physiological level range.
According to the embodiment of the invention, the lactic acid physiological balance means that the content ratio of L-lactic acid to D-lactic acid in a human body is in the range of 90-110, the content of L-lactic acid is in the range of 900-1100 mu M, and the content of D-lactic acid is in the range of 5-20 mu M.
In the present invention, the regulation is to achieve physiological equilibrium of lactic acid levels in a subject by administering a compound having a flavonol structure, a pharmaceutical composition or a pharmaceutical preparation containing the compound having a flavonol structure to the subject.
According to an embodiment of the invention, the regulation is: in the natural aging process of human, the L-lactic acid content in the body is prevented from being lower than physiological level and/or the D-lactic acid content in the body is prevented from being higher than physiological level by administering a compound having a flavonol structure, a pharmaceutical composition or a pharmaceutical preparation containing the compound having a flavonol structure to the human.
In the present invention, the product is selected from one or more of the following group:
(1) A product for the treatment and/or prevention of a disease, disorder, malfunction or symptom caused by abnormal lactic acid content;
Preferably, the lactic acid is D-lactic acid;
Preferably, the disorder, dysfunction or symptom is a disorder, dysfunction or symptom caused by neurotoxic effects of D-lactic acid.
In a specific embodiment, the disorder, dysfunction or symptom comprises mild cerebellum, low muscular tension, cognitive dysfunction.
(2) A product for preventing aging in a subject; preferably, the preventing of aging in a subject is accomplished by maintaining a physiological balance of lactic acid in the subject; more preferably by preventing the level of L-lactic acid in the subject from being below physiological levels and/or preventing the level of D-lactic acid in the subject from being above physiological levels;
(3) A product for maintaining normal expression of a protein associated with a lactate metabolic pathway in a subject;
(4) A product that maintains normal lactoylation modification of a protein in a subject.
In the present invention, in the above (1), the disease includes one or more of metabolic disease, neurodegenerative disease, inflammatory disease.
In the present invention, the compound having a flavonol structure is administered at a dose of:
Dosage for human: 2-14 mg/kg;
equivalent doses for other species converted according to body surface area conversion;
The species include mice, rats, pigs, and monkeys.
According to an embodiment of the invention, the mouse dose: 25-150 mg/kg; rat dose: 12-75 mg/kg.
In the present invention, the dosage form of the pharmaceutical preparation is selected from one of the following: emulsion, oil agent, powder, water agent, suspending agent, tablet, granule, capsule and nanometer preparation.
Compared with the prior art, the invention has the beneficial effects that:
The compound with the flavonol-containing structure can maintain physiological balance of L-lactic acid and D-lactic acid content in a subject, and has important significance for developing new medicaments for maintaining endogenous metabolite balance, relieving neurodegenerative diseases, relieving inflammation and delaying aging.
Drawings
FIG. 1 is a graph showing the relative content of L-lactic acid in plasma of mice with aging models; wherein D-gal refers to D-galactose, 10% DMSO refers to physiological saline containing 10% dimethyl sulfoxide, and ICA refers to icariin.
FIG. 2 is a graph showing the relative content of D-lactic acid in plasma of mice with aging models; wherein D-gal refers to D-galactose, 10% DMSO refers to physiological saline containing 10% dimethyl sulfoxide, and ICA refers to icariin.
FIG. 3 is a graph showing the peak area ratio of D-lactic acid to L-lactic acid in plasma of mice with aging model; wherein D-gal refers to D-galactose, 10% DMSO refers to physiological saline containing 10% dimethyl sulfoxide, and ICA refers to icariin.
FIG. 4 is a total ion flow chromatogram of L-lactic acid and D-lactic acid in plasma of aging model mice.
FIG. 5 is a qualitative analysis mass spectrum of L-lactic acid.
FIG. 6 is a qualitative analytical mass spectrum of D-lactic acid.
Detailed Description
The invention will be further illustrated with reference to the following specific examples, but the invention is not limited to the following examples.
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Reagents, materials, instruments and the like used in the examples described below are commercially available unless otherwise specified.
Mice used in the following examples: balb/C,8 week old, female, 18-20 g, purchased from Shanghai Bikeside Biotechnology Co. Animal license number: SCXK (Shanghai) 2018-0006.
Reagents or starting materials used in the following examples:
d-galactose: purchased from MedChemExpress LLC (Shanghai), cat No. HY-N0210.
Icariin: the structural formula is shown as II, and is purchased from MedChemExpress LLC (Shanghai), and the product number is HY-N0014.
Methoxy amine hydrochloride: purchased from Shanghai Ala Biotechnology Co., ltd., product number M109434.
Pyridine: purchased from Shanghai Ala Biotechnology Co., ltd., product number P111513.
N-methyl-N- (trimethylsilyl) trifluoroacetamide (containing 1% trimethylchlorosilane): purchased from Shanghai Meilin Biochemical technologies Co., ltd., product number N814323.
Methyl parahydroxybenzoate: purchased from Shanghai Source leaf Biotechnology Co., ltd., product number S30305.
High purity helium: purity >99.999%, purchased from Shanghai chlorine Min gas Co.
Test:
1. preparation of aging model mice
The D-galactose was dissolved in physiological saline to obtain an aqueous D-galactose solution. Mice were subcutaneously injected at a dose of 100 mg/kg into the nape of the neck for 5 days a week for nine weeks.
2. Configuration of test reagents
Test agent: icariin is MedChemExpress LLC product with purity of 99.06%.
Icariin 24.0 mg was weighed, dissolved in physiological saline 1.20 mL containing 10% DMSO, and sonicated for 30 min to give a 100 mg/kg dose group.
600. Mu.L of the icariin solution is sucked, 600. Mu.L of 10% DMSO physiological saline is added, and the mixture is uniformly mixed to obtain a 50 mg/kg dose group.
3. Test drug treatment aging mouse model
After half an hour of D-galactose injection, icariin (50 mg/kg dose group and 100 mg/kg dose group) was administered to the model mice by intraperitoneal injection, respectively, at an injection volume of 0.1 mL/20 g body weight. The injection was continued for 5 days a week for nine weeks.
4. Pre-column derivatization treatment of mouse plasma metabolites
50. Mu.L of mouse plasma is taken, 5.0. Mu.L (1 mg/mL) of the internal standard compound methylparaben is added and mixed well. 175. Mu.L of precooled methanol/chloroform (volume ratio v/v=3:1) was added and centrifuged at 20 min (4 ℃,14000 g/min). The supernatant was taken from 200. Mu.L to 1.5 mL EP tube and dried under vacuum. The dried sample was derivatized at 60℃with 50. Mu.L of methoxyamine hydrochloride (20: mg/mL, dissolved in pyridine) to give 1: h. 50 mu L N-methyl N- (trimethylsilyl) trifluoroacetamide (1% trimethylchlorosilane) was added and derivatized at 60℃to 1h. 14000 g/min, centrifuging for 15 min, and sucking supernatant for later use.
5. Test agent for maintaining physiological balance of plasma lactic acid content of aging model mice
A sample of the supernatant from step 4 was taken and injected into a gas phase-mass spectrometer (Clarus SQ8S, perkinelmer, USA) at 1.0. Mu.L.
Gas chromatography conditions: ELITE-5 capillary chromatography column (30 m X0.25 mm X0.25 μm); the temperature of the sample inlet is 280 ℃; heating program: the initial temperature is 50 ℃,3 min is kept, the temperature is increased to 200 ℃ at 8 ℃/min, 0min is kept, the temperature is increased to 300 ℃ at 10 ℃/min, and 5 min is kept; the carrier gas is helium with the flow rate of 1.0 mL/min; the split ratio was 30:1.
Mass spectrometry conditions: an electron bombardment (EI) ion source; electron collision energy 70 eV; the temperature of the ion source is 300 ℃; the temperature of the transmission line is 280 ℃; the mass-to-charge ratio (m/z) of the mass scan range is in the range of 35-602. Scanning by adopting a full scanning mode, and delaying the solvent for 7.16min; the tuning file is auto-tuning.
Qualitative analysis of mass spectrum peaks of the total ion flow chromatogram is carried out by NIST 2020 software; and carrying out relative quantitative analysis on the target metabolite by using the peak area ratio of the target metabolite to the internal standard compound.
The data were analyzed by GraphPad 8.0.1 software. For data conforming to normal distribution, two sample t-test is adopted, and the result is expressed as mean value plus or minus standard deviationSD) and is shown in bar graph. For data that do not fit normal distribution, the comparisons between sets were analyzed using a non-parametric test, and further the pairwise comparisons were tested using Kruskal-WallisH, the results were described in terms of median (25% quantile, 75% quantile) and shown in box-plot. When P <0.05, the difference is considered statistically significant.
The quantitative analysis results are shown in figure 1, figure 2 and figure 3.
The total ion flow chromatogram and the mass spectrum of the lactic acid derivative are shown in figure 4, figure 5 and figure 6.
The experimental conclusion is as follows:
As can be seen from fig. 1, the plasma L-lactic acid content of the aged mice is lower than that of the normal mice (p= 0.0542), and the plasma L-lactic acid content of the aged mice treated with icariin is increased; and the 100 mg/kg dose group was able to significantly restore plasma L-lactate content (p= 0.0119). This demonstrates that in a chemically induced natural aging model, plasma L-lactate levels are reduced; the use of icariin can effectively prevent the reduction of the L-lactic acid content in the aging process.
As can be seen from FIG. 2, the content of D-lactic acid in the plasma of aged mice is higher than that of normal mice, and the content of D-lactic acid in the plasma of aged mice treated by icariin is reduced; and the 100mg/kg dose group was able to significantly reduce the plasma D-lactic acid content (p=0.004). This demonstrates that plasma D-lactic acid levels are elevated in a chemically induced natural aging model; the use of icariin can effectively prevent the increase of the D-lactic acid content in the aging process.
As can be seen from fig. 3, the content ratio of D-lactic acid to L-lactic acid is increased in the chemically induced natural aging model (p= 0.0852); the plasma content ratio of D-lactic acid to L-lactic acid was close to normal in senescent mice treated with icariin, and the 100 mg/kg dose group was able to significantly restore this ratio (p=0.0019). Thus, it is shown that the ratio of the D-lactic acid content to the L-lactic acid content of the blood plasma is abnormal in the natural aging process; the use of icariin can maintain the relative balance of the D-lactic acid and L-lactic acid contents in the blood plasma.
As is clear from FIG. 4, under the above-mentioned gas chromatography conditions, D-lactic acid showed a peak at 9.17 min and L-lactic acid showed a peak at 9.99 min. D-lactic acid and L-lactic acid are isomers, and can be well separated under the gas chromatography condition.
As can be seen from FIG. 5, the mass number of L-lactic acid detected in the test sample is substantially identical to the mass number in the NIST database, and the response intensity is also substantially identical. The peak at 9.99 min was shown to be L-lactic acid.
As can be seen from fig. 6, the mass number of D-lactic acid detected in the test sample is substantially identical to the mass number in the NIST database, and the response intensity is also substantially identical. The peak at 9.17 min was shown to be D-lactic acid.
From the above-described figures 1 to 6, icariin can maintain physiological balance between the levels of plasma L-lactic acid and D-lactic acid, and can be used for treating and/or preventing diseases caused by abnormal levels of lactic acid in a subject, preventing aging in a subject, maintaining the metabolic balance of lactic acid in a subject, maintaining normal expression of related proteins in the metabolic pathway of lactic acid in a subject, or maintaining normal lactoylation modification of proteins in a subject.
In addition, based on the common general knowledge in the art, the person skilled in the art can predict that when R1 and R2 in the formula I are selected from hydrogen atom, penta-glycosyl, di-glycosyl or oligosaccharyl, the compound shown in the formula I also has the function of regulating the physiological balance of lactic acid in the subject.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (10)
1. Use of a compound having a flavonol structure, a pharmaceutical composition or a pharmaceutical formulation comprising said compound having a flavonol structure for the preparation of a product for modulating the physiological balance of lactic acid in a subject;
the structural general formula of the compound with the flavonol structure is shown as formula I:
In the formula I, R1 and R2 each independently represent a hydrogen atom, a five-carbon glycosyl group, a six-carbon glycosyl group, a disaccharide group or an oligosaccharide group.
2. Use according to claim 1, characterized in that the lactic acid is L-lactic acid and D-lactic acid.
3. The use according to claim 1 or 2, wherein the lactic acid is lactic acid from at least one of plasma, serum, interstitial fluid and body fluid.
4. The use according to any one of claims 1-3, wherein the subject is a mammal.
5. The use according to any one of claims 1-4, wherein the lactic acid physiological balance means that the ratio of the content of L-lactic acid to the content of D-lactic acid in the subject is in the physiological level range and the content of L-lactic acid and the content of D-lactic acid are in the physiological level range.
6. The use according to any one of claims 1 to 5, wherein the modulation is such that the level of lactic acid in the subject is brought to physiological equilibrium by administering to the subject a compound having a flavonol structure, a pharmaceutical composition or a pharmaceutical formulation comprising the compound having a flavonol structure.
7. Use according to any one of claims 1-6, wherein the product is selected from one or more of the group:
(1) A product for the treatment and/or prevention of a disease, disorder, malfunction or symptom caused by abnormal lactic acid content;
(2) A product for preventing aging in a subject;
(3) A product for maintaining normal expression of a protein associated with a lactate metabolic pathway in a subject;
(4) A product that maintains normal lactoylation modification of a protein in a subject.
8. The use according to claim 7, wherein the disease in (1) comprises one or more of metabolic disease, neurodegenerative disease and inflammatory disease.
9. The use according to any one of claims 1 to 8, wherein the compound having a flavonol structure is administered at a dose of:
Dosage for human: 2-14 mg/kg;
equivalent dose for other species converted according to body surface area conversion;
The species include mice, rats, pigs, and monkeys.
10. The use according to any one of claims 1 to 9, wherein the dosage form of the pharmaceutical formulation is selected from one of the following: emulsion, oil agent, powder, water agent, suspending agent, tablet, granule, capsule and nanometer preparation.
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