Application of organic metal macrocyclic compound molecule in catalytic improvement of level of oxidized coenzyme I in cells and anti-aging products
By catalyzing the conversion of reducing Coenzyme I in cells into oxidative Coenzyme I through organometallic macrocyclic compound molecules, the problem of oxidative Coenzyme I improvement accompanied by the accumulation of reducing Coenzyme I in the prior art is solved, and the effective improvement of oxidative Coenzyme I levels in cells and the anti-resistance effect of aging is achieved.
Patent Information
- Application Number
- CN202411891837.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-20
- Publication Date
- 2025-04-08
AI Technical Summary
When the prior art increases the level of oxidative Coenzyme I in cells, it is easy to lead to the accumulation of reduced Coenzyme I levels, which in turn causes a series of health problems.
Organometallic macrocyclic compound molecules are used to enter the cell, and the reduced Coenzyme I is converted into oxidative Coenzyme I through one-step catalytic method to enhance the level of oxidative Coenzyme I in the cell.
While reducing the level of reducing Coenzyme I, it can effectively improve the level of oxidative Coenzyme I, improve cell metabolic activity, anti-aging, prolong the lifespan of aging animals, and maintain their physiological health.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of biomedicine technology, and in particular to the use of an organic metal macrocyclic compound molecule in catalyzing and enhancing the level of oxidized coenzyme I in cells and in anti-aging products. Background Art
[0002] Nicotinamide adenine dinucleotide (Coenzyme I) is an important coenzyme in cells, involved in energy metabolism and redox reactions. With age, the level of oxidized Coenzyme I in the body gradually decreases, and this reduction is considered to be one of the key factors in the aging process. As the level of oxidized Coenzyme I decreases, multiple functions of cells will be affected, including DNA repair, mitochondrial energy production, immune system response, cell viability maintenance and epigenetic regulation. The weakening of these functions will lead to the accumulation of DNA damage, decreased mitochondrial activity, decreased immunity, and cells entering a state of aging, which in turn affects the regenerative capacity of tissues and causes organs to gradually degenerate. Therefore, by increasing or maintaining the level of oxidized Coenzyme I, it can help slow down the aging process and reduce age-related health risks to a certain extent.
[0003] There are two main pathways for supplementing oxidized Coenzyme I: the de novo synthesis (DNS) pathway and the salvage pathway. The DNS pathway includes seven enzyme-catalyzed steps to synthesize oxidized Coenzyme I from the substrate tryptophan, a process that is extremely inefficient in cells. In contrast, the salvage pathway uses vitamin B3 derivatives such as nicotinamide (NAM), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) to bypass the synthesis of adenine in cells and synthesize oxidized Coenzyme I in vivo through fewer steps. Studies have found that supplementing oxidized Coenzyme I with tryptophan can effectively improve the health of fruit flies and increase their lifespan (Aging Cell, 2024, 23(4): e14102.). In the salvage pathway, feeding NAM to nematodes, mice, and humans can increase the level of oxidized Coenzyme I in these organisms, thereby improving their age-related muscle aging and degenerative muscle diseases (Cell reports, 2021, 34(3)). The use of NMN and NR has also been shown to increase the level of oxidized coenzyme I in aging mice and prolong their lifespan (Cell metabolism, 2016, 24 (6): 795-806; Science, 2016, 352 (6292): 1436-1443). However, recent studies have found that supplementing precursor substances can also cause an increase in the level of reduced coenzyme I, and excessive reduced coenzyme I can also lead to the occurrence of corresponding diseases (Nature medicine, 2024, 30 (2): 424-434.).
[0004] In summary, both the de novo synthesis pathway and the salvage pathway still need to undergo multiple steps in the cell to be converted into oxidized coenzyme I. The level of oxidized coenzyme I in the body can be significantly increased by precursor supplementation, but it will also lead to the accumulation of reduced coenzyme I in the body. High levels of reduced coenzyme I will cause a series of diseases in the body (such as cardiovascular disease, skin disease, tumors, etc.). Summary of the invention
[0005] In view of the deficiencies in the prior art, the present invention provides an application of an organic metal macrocyclic compound molecule in catalytically increasing the level of oxidized coenzyme I in cells and in anti-aging products. The organic metal macrocyclic compound molecule enters the cell to catalyze the conversion of reduced coenzyme I in the cell into oxidized coenzyme I, and while reducing the level of reduced coenzyme I, the level of oxidized coenzyme I in the cell is efficiently increased through a one-step catalytic method, thereby improving cell metabolic activity, resisting aging, and thereby extending the lifespan of aging animals and maintaining their physiological health.
[0006] In order to solve the above technical problems, the present invention provides an application of an organic metal macrocyclic compound molecule in catalyzing and enhancing the level of oxidized coenzyme I in cells and in anti-aging products.
[0007] Furthermore, the structural formula of the organometallic macrocyclic compound molecule is:
[0008]
[0009] Where M is metal, R 1 -R 12 independently selected from chain alkyl, cyclic alkyl, substituted alkyl, hydrogen or aromatic group, R 13 Selected from hydrogen, hydroxyl, halogen group or oxygen. The organometallic macrocyclic compound molecule may also contain a macrocyclic structure with more than 13 members.
[0010] Furthermore, M is Cu, Fe, Co, Ni, Mn, Zn, Pt, Pb, V, Ag, Sn, Gd, Ga, Cd, Ir, Rh or In.
[0011] Furthermore, the catalytic enhancement of the intracellular oxidized coenzyme I level is specifically: catalytic conversion of the reduced coenzyme I in the cell into oxidized coenzyme I, thereby enhancing the intracellular oxidized coenzyme I level.
[0012] Furthermore, the cells include cardiomyocytes, hepatocytes, lung cells, fibroblasts, epithelial cells and immune cells.
[0013] Furthermore, the immune cells include macrophages, T cells, NK cells and B cells.
[0014] Furthermore, the organometallic macrocyclic compound molecule improves the metabolic function of cell mitochondria by increasing the level of oxidized coenzyme I in cells.
[0015] Furthermore, the mitochondrial function includes ATP synthesis capacity and aerobic respiration capacity.
[0016] Furthermore, the product includes an oxidized coenzyme I supplement.
[0017] Furthermore, the product includes anti-aging medicine or health care product.
[0018] Beneficial effects of the present invention:
[0019] The organic metal macrocyclic compound molecules of the present invention enter cells to catalyze the conversion of reduced coenzyme I in the cells into oxidized coenzyme I. While reducing the level of reduced coenzyme I, the level of oxidized coenzyme I in the cells is efficiently increased through a one-step catalytic method, thereby improving cell activity, resisting aging, and thereby extending the lifespan of aged animals and maintaining their physiological health.
[0020] The organometallic macrocyclic compound molecules of the present invention are applied to oxidized coenzyme I supplements, anti-aging drugs or health care products. Daily use can increase the life span of the aging population and greatly improve their physiological health level. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] In order to more clearly illustrate the technical solution of the present invention, the drawings required for use in the embodiments are briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.
[0022] Figure 1 This is a comparison chart of the dosage concentration of the organometallic macrocyclic compound molecule and the ratio of oxidized coenzyme I / reduced coenzyme I in cells according to Example 1 of the present invention;
[0023] Figure 2 This is a comparison chart of mitochondrial activity of cells before and after administration of the organometallic macrocyclic compound molecule of Example 2 of the present invention;
[0024] Figure 3 This is a comparison chart of the ratio of oxidized coenzyme I / reduced coenzyme I in the liver of mice before and after administration of the organometallic macrocyclic compound molecule of Example 3 of the present invention;
[0025] Figure 4 This is a comparison chart of the life span extension of mice before and after administration of the organometallic macrocyclic compound molecule of Example 4 of the present invention;
[0026] Figure 5This is a comparison chart of the improvement of the health level of mice before and after administration of the organometallic macrocyclic compound molecule of Example 5 of the present invention. DETAILED DESCRIPTION
[0027] The technical solution of the present invention will be described clearly and completely below in conjunction with the specific embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0028] This embodiment provides an application of an organic metal macrocyclic compound molecule in catalyzing and increasing the level of oxidized coenzyme I in cells and in anti-aging products. The structural formula of the organic metal macrocyclic compound molecule is:
[0029]
[0030] Where M is metal, R 1 -R 12 independently selected from chain alkyl, cyclic alkyl, substituted alkyl, hydrogen or aromatic group, R 13 is selected from hydrogen, hydroxyl, a halogen group or oxygen.
[0031] As a specific example, M is Cu, Fe, Co, Ni, Mn, Zn, Pt, Pb, V, Ag, Sn, Gd, Ga, Cd, Ir, Rh or In.
[0032] As a specific example, the catalytic increase of the intracellular oxidized coenzyme I level is specifically: catalytic conversion of the reduced coenzyme I in the cell into oxidized coenzyme I, thereby increasing the intracellular oxidized coenzyme I level; the cells include cardiomyocytes, hepatocytes, lung cells, fibroblasts, epithelial cells and immune cells; the immune cells include macrophages, T cells, NK cells and B cells.
[0033] Specifically, the organometallic macrocyclic compound molecule improves the mitochondrial function of cells by increasing the level of oxidized coenzyme I in cells, and the mitochondrial function includes ATP synthesis capacity and aerobic respiration capacity.
[0034] As specific examples, the products include oxidized coenzyme I supplements, anti-aging drugs or health products.
[0035] The following are specific embodiments.
[0036] Example 1
[0037] This example studies the effect of organometallic macrocyclic compound molecules on increasing the level of intracellular oxidized coenzyme I. Different concentrations of the organometallic macrocyclic compound molecule hemin was incubated with hepatocytes HepG2, and the intracellular reduced coenzyme I and oxidized coenzyme I contents were detected by LC-MS / MS method, and the ratio of oxidized coenzyme I / reduced coenzyme I in each cell was calculated.
[0038] Among them, the method for extracting reduced coenzyme I and oxidized coenzyme I in cells is as follows: remove the surface of the treated cells in the 6-well plate and wash the cells three times with PBS precooled at 4°C. Add 1mL of phosphate buffered saline (PBS) to the 6-well plate, scrape the cells from the bottom of the well plate into PBS with a cell scraper, and transfer the cells to a 1.5mL centrifuge tube after fully mixing them with a pipette. Centrifuge the centrifuge tube containing the cell suspension at 1000rpm for 5min, remove the supernatant, add 50μL of 4°C precooled deionized water, blow the cell pellet evenly, and freeze and thaw repeatedly in liquid nitrogen (3 cycles, 10min each cycle). Mix 50μL of lysate with 200μL of precooled methanol and incubate at -80°C for 20min, then centrifuge at 20000g for 10min at 4°C, and collect the supernatant to obtain the cell lysate. Add 150 μL of methanol extract (-20°C) to the cell pellet, blow the cell pellet evenly with a pipette, centrifuge at 20,000 g for 10 min, collect the supernatant, and mix it with the previous extract. Dry the extract with a nitrogen blow dryer and store it in a -80°C refrigerator for testing.
[0039] Detection method:
[0040] a) Reduced coenzyme I and oxidized coenzyme I: Set the sample injection volume to 5 μL, use a C18 reverse phase column (2.1 mm × 150 mm) for the chromatographic column, and the elution flow rate to 300 μL / min. Mobile phase A: 20 mM ammonium acetate solution, mobile phase B: 100% acetonitrile. The mobile phase gradient for separating the samples is: 98% mobile phase A for isocratic separation for 5 min, the mobile phase A gradient is linearly changed to 10% within 2 min, then the mobile phase A isocratic separation is maintained at 10% for 2 min, and then the mobile phase A gradient is linearly changed to 98% within 0.1 min.
[0041] b) Dihydroxyacetone phosphate: injection volume, chromatographic column and flow rate are consistent with reduced coenzyme I, and the separation gradient is set as follows: 95% mobile phase A isocratic elution for 2 min, mobile phase A gradient linear change to 5% within 6 min, maintain this gradient isocratic elution for 7 min, and finally increase the mobile phase A gradient to 95% within 0.1 min.
[0042] Selective reaction monitoring was used for detection. The parent ion and daughter ion detected in the positron mode were: oxidized coenzyme I (m / z 664.1→136.0) and reduced coenzyme I (m / z 666.2→302.3). The parent ion and daughter ion of dihydroxyacetone phosphate were detected in the negative ion mode: (m / z 168.8→97.3). The LC-MS / MS data were analyzed using Xcalibur 2.0 software. The results are shown in Figure 2. Figure 1 As shown, it can be seen that the organometallic macrocyclic compound molecule hemin can significantly increase the ratio of oxidized coenzyme I / reduced coenzyme I in cells, among which the best effect is when the drug concentration of the organometallic macrocyclic compound molecule hemin is 3 μg / mL.
[0043] Example 2
[0044] This example studies the effect of organometallic macrocyclic compounds on mitochondrial function. Antimycin A was added to the cell culture medium to a final concentration of 1 μM to construct a cell model of mitochondrial damage. The ability of mitochondria to synthesize ATP in cells before and after administration of the organometallic macrocyclic compound hemin was detected (as reflected by the ratio of oxidized coenzyme I / reduced coenzyme I). The results are as follows: Figure 2 As shown, it can be seen that the organometallic macrocyclic compound hemin can restore cellular mitochondrial function.
[0045] Example 3
[0046] This example studies the effect of organometallic macrocyclic compounds on increasing the level of oxidized coenzyme I in the liver of mice. The LC-MS / MS detection technology is used to detect the changes in the level of oxidized coenzyme I in the liver of mice before and 24 hours after a single oral administration of different concentrations of organometallic macrocyclic compounds (ferroheme, hemin and methylcobalamin). Nicotinamide riboside is used for normalization comparison. The results are as follows: Figure 3 As shown, it was confirmed that the organometallic macrocyclic compound molecules can effectively increase the ratio of oxidized coenzyme I / reduced coenzyme I in mouse tissues, among which ferroheme has a better effect.
[0047] Example 4
[0048] This example studies the effect of organometallic macrocyclic compound molecules on the life span of mice. The organometallic macrocyclic compound Ferroheme was dissolved in drinking water and orally administered to 17-month-old male and female mice. The time of death of the mice was then continuously recorded. The results are as follows: Figure 4 As shown, the results showed that the lifespan of old mice administered with organometallic macrocycle molecules was significantly increased.
[0049] Example 5
[0050] This example studies the effect of organometallic macrocyclic compound molecules on improving the health level of mice. The rotarod test is used to examine the muscle endurance and balance of aging mice that have long-term intake of the organometallic macrocyclic compound Ferroheme (at a dosage of about 10 mg / kg) through drinking water for 300 days. The results are as follows Figure 5 As shown, it was confirmed that organometallic macrocyclic compounds can effectively improve the health status of aging mice.
[0051] The present invention has been described in detail above in conjunction with specific implementations and exemplary examples, but these descriptions cannot be understood as limiting the present invention. Those skilled in the art understand that, without departing from the spirit and scope of the present invention, a variety of equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its implementation methods, all of which fall within the scope of the present invention. The scope of protection of the present invention shall be subject to the attached claims.
Claims
1. Application of an organometallic macrocyclic compound molecule in catalyzing and increasing the level of intracellular oxidized coenzyme I and in anti-aging products.
2. The use according to claim 1, characterized in that The structural formula of the organometallic macrocyclic compound molecule is: Among them, M is metal, R1-R 12 independently selected from chain alkyl, cyclic alkyl, hydrogen, aromatic group or functional group containing oxygen, nitrogen or sulfur, R 13 Selected from hydrogen, or functional groups containing oxygen, nitrogen, sulfur, and halogen.
3. The use according to claim 2, characterized in that The M is Cu, Fe, Co, Ni, Mn, Zn, Pt, Pb, V, Ag, Sn, Gd, Ga, Cd, Ir, Rh or In.
4. The use according to claim 1, characterized in that The catalytic enhancement of the intracellular oxidized coenzyme I level specifically includes: catalytically converting the reduced coenzyme I in the cell into oxidized coenzyme I, thereby enhancing the intracellular oxidized coenzyme I level.
5. The use according to claim 1, characterized in that The cells include cardiomyocytes, hepatocytes, lung cells, fibroblasts, epithelial cells and immune cells.
6. The use according to claim 5, characterized in that The immune cells include macrophages, T cells, NK cells and B cells.
7. The use according to claim 1, characterized in that The organometallic macrocyclic compound molecule improves the mitochondrial metabolic function of cells by increasing the level of oxidized coenzyme I in cells.
8. The use according to claim 7, characterized in that The mitochondrial functions include ATP synthesis capacity and aerobic respiration capacity.
9. The use according to claim 1, characterized in that The products include oxidized coenzyme I supplements.
10. The use according to claim 1, characterized in that The products include anti-aging medicines or health products.