CN114632087A - Application of NMN in preparing medicine for preventing and treating vascular endothelial cell senility, vascular aging and vascular atherosclerosis - Google Patents
Application of NMN in preparing medicine for preventing and treating vascular endothelial cell senility, vascular aging and vascular atherosclerosis Download PDFInfo
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Abstract
The invention discloses an application of NMN in preparing a medicament for preventing and treating vascular endothelial cell aging, vascular aging and vascular atherosclerosis. Described in more detail, the NMN can be used to improve vascular endothelial cell senescence induced by any of interleukin-6, oxidized low density lipoprotein, and replication by passage; the NMN can also be used to improve vascular aging and atherosclerosis induced by western high fat diet and/or natural aging models; specifically, the NMN with effective amount of active ingredients and pharmaceutically acceptable carriers are included in the preparation of the drugs, drug mixtures or drug compositions for preventing and treating endothelial cell aging and/or vascular aging and/or atherosclerosis. The invention proves that the NMN can delay the aging of vascular endothelial cells, delay the aging process of blood vessels and inhibit the occurrence of atherosclerosis which is a vascular degenerative disease through in vitro cell experiments and in vivo animal experiments.
Description
Technical Field
The invention relates to the field of medicine application, in particular to application of NMN in preparing medicines for preventing and treating vascular endothelial cell aging, vascular aging and vascular atherosclerosis.
Background
With the increase of the average life span of human beings, the incidence rate of chronic diseases related to vascular aging is remarkably increased, the prevalence rate of atherosclerosis is in a continuously rising stage all the year round, and the death rate of cardiovascular diseases caused by atherosclerosis is still the first place. Age is an independent risk factor for atherosclerotic disease, and for the elderly, many diseases are associated with atherosclerosis. Vascular aging has been found to be a significant cause of atherosclerosis. How to delay vascular aging and prevent and treat the occurrence of atherosclerotic diseases on the basis becomes one of the problems which are commonly faced by all human beings and need to be solved urgently.
Endothelial cells, also known as vascular endothelial cells, generally refer to a single layer of flattened epithelium lining the interior surfaces of the heart, blood vessels, and lymph vessels, which forms the interior walls of blood vessels. They have the function of phagocytizing foreign bodies, bacteria, necrotic and senescent tissues and also participate in the immune activities of the body. Researches show that normal young endothelial cells can carry out energy metabolism by self-synthesis and exogenously capturing a large amount of adenine dinucleotide (NAD +), but the aged endothelial cells have reduced nicotinamide phosphoribosyl transfer (NAMPT) expression, and the NAD + content in the endothelial cells is sharply reduced, so that the endothelial cells have abnormal functions, and the surface adhesion capacity and the permeability of the endothelial cells are increased. Studies have shown that endothelial cell dysfunction may be the initiating factor in vascular aging and degenerative diseases such as atherosclerotic lesions. However, because of the limitation of endothelial cell distribution, research and functional experiments on endothelial cells are still lacking, and how to improve vascular aging and prevent and treat vascular degenerative diseases by delaying endothelial cell aging has important research significance.
NAD + is an important medium in a series of biochemical reactions in human bodies, such as energy metabolism, DNA repair damage and the like. Recent studies have demonstrated that NAD + synthesis capacity in various aging tissues is significantly impaired, but NAD + cannot be taken orally into cells directly due to its large molecular weight. Researches in the years show that Nicotinamide Mononucleotide (NMN) serving as a NAD + precursor can be exogenously supplemented to improve the level of NAD + in vivo and achieve the effect of prolonging the service life.
The good efficacy of NMN at the animal and human levels encouraged us to explore the possible mechanisms that may exist. However, we see that the current NMN research is mostly focused on answering the macroscopic problem of the overall life span of organisms, and the deep research using tissue specificity as a research object is lacking. Vascular aging is the main cause of the decline of the quality of life and the shortened life of people over 65 years old, and accounts for one third of all-cause mortality. The concept of "human co-aging with blood vessels" was proposed by the well-known pathologist William Osler. Concern about vascular aging and delay of vascular aging may be important measures to promote healthy aging, improve the quality of life of the elderly, and reduce social burden. Whether the NMN can delay vascular aging and prevent and treat atherosclerosis is not reported at present.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the application of NMN in preparing the medicines for preventing and treating vascular endothelial cell aging, vascular aging and vascular atherosclerosis.
In order to achieve the purpose, the invention is realized by the following technical scheme:
the invention provides an application of NMN in preparing a medicament for preventing and treating vascular endothelial cell aging and/or vascular atherosclerosis.
The NMN is for improving vascular endothelial cell senescence, wherein the vascular endothelial cells comprise: primary Human Umbilical Vein Endothelial Cells (HUVEC) and endothelial cell line (ea. hy926). Preferably, the NMN treatment of vascular endothelial cells in vitro comprises: HUVEC and ea.hy926 at concentrations ranging from: 0.1-20 Mm.
The NMN is used for improving vascular endothelial cell senescence induced by any one of interleukin-6 (IL-6), oxidized low density lipoprotein (ox-LDL) and a subculture model. Preferably, the NMN is used for improving endothelial cell senescence by: the NMN is capable of reducing the expression of cyclin P53 and P16 in endothelial cells; the NMN is capable of reducing the presence of galactosidase staining deposits in endothelial cells; the NMN is capable of maintaining normal NO secretion capacity in endothelial cells; the NMN is capable of inhibiting abnormal oxidative stress levels in endothelial cells.
The NMN is used for improving vascular aging and atherosclerosis induced by western high fat diet and/or natural aging model. Preferably, the NMN is used for improving vascular aging by: the NMN can inhibit the increase of blood vessel hardness and slow down the pulse wave conduction speed; the NMN is capable of reducing the presence of galactosidase staining deposits in endothelial cells; the NMN can reduce the expression of cyclin P53, P21 and P16 in vascular tissues. Preferably, the NMN is used to improve atherosclerosis by: the NMN can reduce the area, the quantity and the percentage of atherosclerotic plaque lesions after oil red O staining in vascular tissues.
Preferably, the NMN is capable of retarding vascular aging while inhibiting atherosclerotic lesions.
Preferably, an effective amount of the NMN as an active ingredient according to claim 1, together with a pharmaceutically acceptable carrier, is included in the manufacture of a medicament, pharmaceutical mixture or pharmaceutical composition for the prevention and treatment of endothelial cell senescence and/or vascular senescence and/or atherosclerosis.
It is further preferred that the drug, drug mixture or pharmaceutical composition has at least one of the following functions 1) to 4):
1) preventing and/or treating inflammation, cell damage caused by inflammatory factors;
2) preventing and/or treating cellular metabolic abnormalities;
3) reducing free radical increase and oxidative stress caused by inflammation or metabolism disorder;
4) relieving cell mitochondrial membrane depolarization or apoptosis caused by inflammation or metabolic abnormality.
It is further preferred that the medicament, the pharmaceutical mixture or the pharmaceutical composition is in any pharmaceutically acceptable dosage form, including at least one of tablets, capsules, injections, granules, suspensions and solutions.
Further preferably, the drug, drug mixture or pharmaceutical composition is administered by at least one of oral administration, intravenous injection and subcutaneous embedding.
Compared with the prior art, the invention has the following advantages and beneficial effects:
according to the invention, IL-6 and ox-LDL are used for respectively inducing primary human umbilical vein endothelial cells, and NMN is used for intervention, so that the fact that NMN can delay aging of the endothelial cells induced by IL-6 and ox-LDL in vitro is found, and the NMN can inhibit cyclin expression in the endothelial cells and reduce the positive rate of beta-galactosidase staining is shown. After the result that NMN can delay the aging of endothelial cells induced by IL-6 or ox-LDL in a stress type is discovered, the invention uses a probe to mark the cells, and the NMN can inhibit the oxidative stress (ROS) reaction of the endothelial cells and maintain the NO secretion capability of the endothelial cells while delaying the aging of the endothelial cells.
In the invention, ApoE-/-mice are used for feeding the mice with high fat diet for 2 months, and an atherosclerosis model is successfully established. In the experimental process, NMN is used for gastric lavage, and the NMN is found to be capable of effectively preventing and treating the formation of the atherosclerotic plaque of the mice. Meanwhile, PWV is used for detecting aortic blood vessels of mice, and high-fat diet is found to cause atherosclerosis of the mice and increase the hardness of the blood vessels of the mice so as to promote blood vessel aging, NMN can reduce the hardness of the blood vessels of the mice and delay the occurrence and development of the blood vessel aging of the mice. In order to further detect the effectiveness of NMN in delaying vascular aging, the invention uses galactosidase staining to stain the aorta vessels of mice, and the NMN is found to be capable of inhibiting the vascular aging of the mice. The experiments prove that the NMN can effectively prevent and treat atherosclerosis and delay vascular aging.
The invention focuses the NMN anti-aging function on the vascular system for the first time, and verifies the NMN anti-aging function by using a reasonable and scientific experimental mode.
Drawings
FIG. 1 is a graph showing the statistical analysis of the staining of HUVEC cells by beta-galactosidase;
FIG. 2 is a graph showing the result of analyzing the expression gray scale values of cyclin P53 and cyclin P16 in HUVEC cells detected by Western blot assay;
FIG. 3 is a statistical chart of the NO secretion capacity in HUVEC cells detected by a probe experiment;
FIG. 4 is a statistical chart of oxidative stress response in HUVEC cells detected by a probe experiment;
FIG. 5 is a statistical plot of mouse pulse wave velocity (aPWV);
FIG. 6 is a statistical chart of oil red O staining of mouse aortic vascular tissue;
FIG. 7 is a statistical chart of the staining of mouse aortic vascular tissue with beta-galactosidase.
Detailed Description
The blood vessels are used as the largest vascular system of a human body, are not only passages of blood, but also have more important significance in maintaining the normal physiological functions of each organ and even cells of the human body, and the vascular aging is not limited to vascular tissues, can also cause the deterioration of multiple organs of the human body, cause the aging of the system and shorten the service life. Therefore, the research on how to resist vascular aging is of great significance. The aging is a research hotspot in recent years, and the drugs (rapamycin, metformin, senolytics), lifestyle interventions (exercise and caloric restriction), biotechnology (plasma intervention, stem cells) and the like are found to delay the aging and prolong the life. However, most of the above approaches are difficult to transform into clinical practice, and the focus is on prevention rather than treatment against aging.
Compared with the traditional anti-aging mode, the NMN disclosed by the invention exists in various natural vegetables and fruits (on the surface), and can be well absorbed and utilized by a human body. However, the food contains a low amount of NMN, and the mere acquisition of the amount of NMN from the daily diet cannot compensate for the loss of NMN in the aging body, and therefore the NMN intake can be increased by the exogenous supplement. At present, the clinical drug experiments of NMN are being carried out in Japan, Germany, America, France and other countries. Among them, the Japanese studies show that the administration of 250-500mgNMN per day by normal individuals is safe, suggesting that the administration of NMN has less toxic and side effects, and is more suitable for preventive treatment compared with the traditional medicaments such as metformin, rapamycin and the like. The invention further discovers that the NMN can delay the aging of endothelial cells and the occurrence of vascular aging and atherosclerosis, and lays a foundation for the NMN to expand clinical indications and prevent and treat vascular aging.
The present invention will be described in further detail below with reference to the drawings, examples and experimental examples. The test methods or test methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials, unless otherwise indicated, are conventionally obtained commercially or prepared by conventional methods.
Example 1
Preparation of NMN working solution for in vitro experiment
The NMN medicine bottle powder is stored in a dark place at room temperature to avoid moisture, and the powder is light yellow. 835.55mg NMN powder was accurately weighed using a precision balance and placed in a 15ml sterile centrifuge tube. 5ml of high-pressure sterilized water is added into a centrifuge tube filled with NMN powder in a super clean bench by using a micro-sampling gun, and the high-pressure sterilized water is blown and beaten repeatedly by using the gun head until the powder is completely dissolved in the sterilized water, so that the solution is clear, free of particles and impurities and transparent and light yellow. After filtration sterilization using a 0.22 μ M filter, a working solution was obtained at a concentration of 0.5M. The filtered liquid was split charged (10 ul/tube) and stored in an ultra low temperature refrigerator. When in vitro cell intervention is carried out, the packed NMN working solution is taken out from an ultralow temperature refrigerator, is melted at room temperature, is subjected to ultracentrifugation and is placed in an ultraclean bench. The final concentration of interfering cells was 0.5mM, following 1ml complete medium: 1ul of NMN working solution, adding the NMN working solution into the complete culture medium by using a trace sample adding gun, uniformly mixing gun heads, adding the mixture into a cell culture dish, and placing the culture dish into a cell culture box for incubation after the operation is finished.
Example 2
Preparation of NMN working solution for in vivo experiment
The in vivo experiment is carried out by means of intragastric administration, and the intragastric administration volume is 100 ul/day. The weight of 8-week-old male mice was approximately 25. + -. 1.5 g. The concentration of experimental intervention NMN working solution is 300 mg/kg. The content of the gavage liquid was 4ml in terms of mass per 1kg of mass, and 300mg of NMN powder was dissolved to prepare a solution, so that the solubility was 75 mg/ml. According to experimental grouping, 20 mice in total need to be intragastrically infused, and the volume of the working solution required each day is as follows: 20 pieces of the solution were multiplied by 0.1 ml/piece ═ 2ml of the working solution. NMN powder was accurately weighed according to solubility using a precision balance: 2ml × 75mg/ml ═ 150 mg. The weighed powder was dissolved in 2ml of autoclaved water according to the method of example 1, and the solution was used after thoroughly dissolving and sterilizing by filtration. During the gastric perfusion operation, a No. 12 gastric perfusion needle head is prepared, the gastric perfusion needle is matched with a 0.1ml syringe, and after the gastric perfusion needle is fixed by the syringe, NMN working solution is sucked and exhausted upwards for use. The tail of the mouse is pulled by the right hand, the neck and the scalp of the mouse are pulled by the thumb, the index finger and the middle finger of the left hand, in addition, the mouse is grabbed and fixed by the little finger and the tail which is not famously pressed down the mouse, the head, the neck and the body of the mouse are in a straight line, the needle head enters from the mouth corner of the mouse, the tongue is pressed, the needle head pushes the tongue to push the palate carefully inwards, and the medicine can be pushed after the needle head enters the esophagus. After the gavage is finished, the mouse is observed to have no abnormal activity, no liquid and no blood flowing out of the mouth. Mice in the control group and the pure western high fat diet group are subjected to the same method and are perfused with the same volume of autoclaved water.
Experimental example 1
The NMN working solution prepared in example 1 shows good resistance to endothelial cell aging induced by IL-6 or ox-LDL after interfering cells, and can inhibit endothelial cell oxidative stress reaction to promote NO secretion. The specific test process is as follows:
after isolation of primary human umbilical vein endothelial cells, subculture was performed using EGM-2 medium (37 ℃ C., 5% CO)2) Young endothelial cells were selected for the experiment (P3-P8). In the experiment, cells were stimulated and induced by adding IL-6(25ng/ml) or ox-LDL (50ng/ml) to the culture medium for 48 h. Meanwhile, the NMN working solution (0.5M) in example 1 is used for intervening the cells in the drug intervention group, and the cells are maintained for 48 hours. After the induction is finished, intracellular protein is extractedAnd (3) performing western blot experimental analysis, and simultaneously detecting the NO secretion capacity and the oxidative stress level in the cells by using galactosidase staining working solution and a probe.
The test results are shown in the following four aspects:
first, the NMN working solution prepared in example 1 delayed endothelial cell senescence induced by IL-6 or ox-LDL, as shown in FIGS. 1-4.
According to the test results in FIG. 1, it can be seen that: compared with the endothelial cells cultured normally, the expressions of cyclin P53 and P16 in the endothelial cells after the induction of IL-6 and ox-LDL are increased, which indicates that the growth state of the endothelial cells is stagnated and the aging state is presented, and the expression levels of P53 and P16 are reduced after the NMN (0.5M) dry prognosis is used, which indicates that the NMN can resist the aging of the endothelial cells induced by the IL-6 and ox-LDL.
According to the experimental results of fig. 2, it can be known that: the NMN intervention group was able to reduce the presence of intracellular staining deposits compared to the increase of galactosidase staining deposits (green) in endothelial cells following IL-6 and ox-LDL induction in normal cultured endothelial cells. The galactosidase staining method is a currently accepted aging detection method, and the experimental result indicates that NMN can delay aging of endothelial cells induced by IL-6 and ox-LDL, which is consistent with the experimental result of the molecular level in figure 1.
According to the experimental results of fig. 3, it can be known that: endothelial cells have the capacity of secreting NO, which is important for maintaining the function of blood vessels, so that the NO secretion of the endothelial cells under different conditions is detected by using an in-situ loading mode of a NO probe. The normal endothelial cells can secrete a large amount of NO (the green fluorescence intensity reflects the amount of NO secretion), the NO secretion capacity of the endothelial cells is reduced after the induction of IL-6 or ox-LDL, the normal functions of the endothelial cells can be maintained after the intervention of NMN, and the combination of the experimental results shows that the NMN can maintain the normal functions of the endothelial cells while delaying the aging of the endothelial cells, which is consistent with the actual theory.
According to the experimental results of fig. 4, it can be known that: the theory of oxidative stress plays an important role in aging, therefore, the probe is also used for detecting endothelial cells, and the results of the previous experiments show that IL-6 or ox-LD can increase the level of the oxidative stress of the endothelial cells and promote the aging of the endothelial cells; NMN can inhibit abnormal oxidative stress level in cells and delay endothelial cell aging.
Experimental example 2
The NMN working solution prepared in the example 2 has the effect of preventing and treating vascular aging when being used at the animal level. The specific test process is as follows:
the drugs were prepared and mice were intervened as described in example 2. Intervention was performed using SPF-grade APOE knockout mice (male, 8 weeks old). Mice were housed in SPF grade animal rooms, and all mice received free diet and autoclaved water. The method is divided into 3 groups according to experimental requirements: a. a group of normal diets; b. western high fat diet group; c. western high fat diet + NMN intervention group. Each group had 15, 3 per cage. After one week of acclimatization, drug intervention group NMN (300mg/kg) was given for one week of pretreatment. Other groups of mice were intervened with equal volumes of autoclaved water. After one week, western high-fat diet feed is given to the western high-fat diet group and the drug intervention group for feeding, the NMN is used for intervention in the drug intervention group, and the rest groups of mice are also given high-pressure sterilized water for intragastric administration. After 8 weeks of experiment, after anaesthetizing the mouse by using a gas anaesthesia machine, detecting the pulse wave conduction velocity of the mouse by using a small animal PWV detector, and simultaneously recording the electrocardiogram of the mouse. After fully anesthetizing the mice with compound anesthesia, the mice were perfused with PBS to obtain mouse aortic tissues for oil red and galactosidase staining.
From the analysis of the results shown in fig. 5, it can be seen that: the PWV value of the western high fat diet mice is obviously higher than that of the mice in the ordinary diet group, which indicates that the mice in the western high fat diet group are angiosclerosis and thus have increased pulse wave conduction velocity, while the NMN intervention can inhibit the increase of the vascular hardness caused by the western high fat diet and slow down the pulse wave conduction velocity (the ordinary diet group: 2.5307 + -0.29 mm/ms VS western high fat diet group: 3.3085 + -0.53 mm/ms VS NMN intervention group: 2.4389 + -0.24 mm/ms). At present, PWV is a gold index for global detection of vascular aging, which can reflect the condition of vascular aging by detecting the pulse wave conduction velocity, so our experiments suggest that NMN can alleviate western high fat diet-induced in vivo vascular aging conditions.
From the analysis of the results shown in fig. 6 and 7, it can be seen that: compared with the general diet group, western high-fat diet increases the hardness of the blood vessels of the mice and increases the lesion of atherosclerotic plaques in the aorta of the mice, and in fig. 6, the plaques are concentrated near the aortic arch (red), and the NMN intervention can inhibit the lesion of atherosclerosis. Meanwhile, the aortic vascular tissue is stained by using a galactosidase staining working solution, and the aging condition of the blood vessels is detected. The experimental result is shown in fig. 7, the western high-fat diet mice have increased green deposits in aortic tissues, and the condition of NMN intervention mice is obviously improved, which is consistent with the cell experimental result in the experimental example 1, and shows that NMN can inhibit atherosclerotic lesions and delay vascular aging. The current theory holds that the atherosclerosis lesion embodies the specific pathology of vascular aging, and the two are closely separated, so that the experiment is consistent with the theory.
Due to the change of living habits, the dietary structure of most people at present contains a large amount of fat and carbohydrate, so that the risk of cardiovascular diseases is increased, and important factors for the occurrence of the cardiovascular diseases are derived from vascular aging, particularly endothelial cell aging. Our experiments better simulate the vascular aging problem of normal people under the stimulation of diet from the outside and the inside, and find that NMN can effectively delay the aging of endothelial cells, intervene the vascular aging caused by diet and the generation of atherosclerosis of the vascular degenerative disease. Moreover, the safety of the NMN taken by a human body is proved by the clinical test of the NMN disclosed at present, and the experiment provides a theoretical basis for the application of the NMN in preventing and treating the vascular aging in the future.
The above description is only exemplary of the present invention and should not be taken as limiting the invention, as any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
- The application of NMN in preparing medicine for preventing and treating vascular endothelial cell senility and/or vascular atherosclerosis.
- 2. Use according to claim 1, characterized in that: the NMN is used for improving vascular endothelial cell senescence induced by any one of interleukin-6, oxidized low density lipoprotein and a subculture model.
- 3. Use according to claim 1 or 2, characterized in that: the specific expression of the NMN for improving endothelial cell senescence is as follows: the NMN is capable of reducing the expression of cyclin P53 and P16 in endothelial cells; the NMN is capable of reducing the presence of galactosidase staining deposits in endothelial cells; the NMN can maintain the normal NO secretion capacity in endothelial cells; the NMN is capable of inhibiting abnormal levels of oxidative stress in endothelial cells.
- 4. Use according to claim 1, characterized in that: the NMN is used to improve vascular aging and atherosclerosis induced by western high fat diet and/or model of natural aging.
- 5. Use according to claim 1 or 4, characterized in that: the specific expression of the NMN for improving the vascular aging is as follows: the NMN can inhibit the increase of blood vessel hardness and slow down the pulse wave conduction speed; the NMN is capable of reducing the presence of galactosidase staining deposits in endothelial cells; the NMN can reduce the expression of cyclin P53, P21 and P16 in vascular tissues.
- 6. Use according to claim 1 or 4, characterized in that: the specific expression of the NMN for improving atherosclerosis is as follows: the NMN can reduce the area, the quantity and the percentage of atherosclerotic plaque lesions after oil red O staining in vascular tissues.
- 7. Use according to claim 1, characterized in that: in the preparation of a medicament, a pharmaceutical mixture or a pharmaceutical composition for the prevention and treatment of endothelial cell senescence and/or vascular senescence and/or atherosclerosis, an effective amount of the active ingredient NMN according to claim 1, together with a pharmaceutically acceptable carrier.
- 8. Use according to claim 7, characterized in that: the medicine, the medicine mixture or the medicine composition has at least one function of 1) to 4) as follows:1) preventing and/or treating inflammation, cell damage caused by inflammatory factors;2) preventing and/or treating cellular metabolic abnormalities;3) reducing free radical increase and oxidative stress reaction of cells caused by inflammation or metabolism abnormality;4) relieve cell mitochondrial membrane depolarization or apoptosis caused by inflammation or metabolism disorder.
- 9. Use according to claim 7, characterized in that: the medicine, the medicine mixture or the medicine composition is any pharmaceutically acceptable dosage form, and comprises at least one of tablets, capsules, injections, granules, suspensions and solutions.
- 10. Use according to claim 7, characterized in that: the drug, the drug mixture or the drug composition is administered by at least one of oral administration, intravenous injection and subcutaneous embedding.
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