Application of precursor nicotinamide mononucleotide in the preparation of drugs to alleviate acute altitude sickness

Abstract

This invention belongs to the field of biomedical technology, specifically relating to the application of the precursor nicotinamide mononucleotide (NMN) in the preparation of drugs to alleviate acute altitude sickness. In a hypobaric and hypoxic mouse model, administration of the precursor NMN significantly improved metabolic disorders and pathological damage under hypobaric and hypoxic conditions, demonstrating a significant effect in treating acute altitude sickness. Therefore, the application of the precursor NMN in the preparation of drugs to alleviate acute altitude sickness is proposed.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of the precursor nicotinamide mononucleotide in the preparation of drugs to alleviate acute altitude sickness. Background Technology

[0002] High altitude sickness, also known as altitude sickness or mountain sickness, is strictly speaking a subtype of altitude sickness. It refers to various discomfort symptoms that occur when the body rapidly ascends to an altitude of 3000 meters or higher and is exposed to a low-pressure, low-oxygen environment. It is a common illness unique to high-altitude areas. Common symptoms include headache, insomnia, loss of appetite, fatigue, and difficulty breathing. Altitude sickness is divided into two main categories based on the speed of onset: acute and chronic.

[0003] Acute altitude sickness is a series of acute hypoxic reactions caused by the body's inability to adapt to the high-altitude environment. Untreated, it can prolong the duration of altitude sickness and lead to secondary conditions such as high-altitude pulmonary edema and cerebral edema, even endangering life. While methods such as pure oxygen therapy and medication can alleviate these symptoms, they have many limitations, such as the inconvenience of carrying oxygen and the strong side effects of medications. In recent years, exploring new treatment options has become a key focus of high-altitude medicine research, with significant practical implications for people traveling and working in high-altitude areas. Summary of the Invention

[0004] To address the above problems, this invention provides the application of the precursor nicotinamide mononucleotide in the preparation of drugs to alleviate acute altitude sickness.

[0005] Application of precursor nicotinamide mononucleotide in the preparation of drugs to alleviate acute altitude sickness.

[0006] This invention describes the administration of the precursor nicotinamide mononucleotide (NMN) to a hypobaric and hypoxic mouse model, which significantly improved metabolic disorders and pathological damage under hypobaric and hypoxic conditions, and showed a significant effect in treating acute altitude sickness. Therefore, the invention proposes the application of the precursor nicotinamide mononucleotide in the preparation of drugs to alleviate acute altitude sickness.

[0007] Preferably, the drug uses nicotinamide mononucleotide (NMN) as the sole active ingredient to improve metabolic disorders under low-pressure and low-oxygen conditions.

[0008] Preferably, the drug is a precursor nicotinamide mononucleotide as the sole active ingredient, used to improve metabolic disorders and lung pathological damage caused by low pressure and hypoxia.

[0009] Preferably, the drug uses nicotinamide mononucleotide (NMN) as the sole active ingredient to enhance the effect of glucose solution on metabolic disorders and lung pathological damage caused by low pressure and low oxygen.

[0010] Preferably, the drug is a liquid formulation.

[0011] Preferably, the liquid preparation is an oral preparation or a gavage preparation.

[0012] Preferably, the liquid formulation includes pharmaceutically acceptable excipients.

[0013] Preferably, the pharmaceutically acceptable excipients include diluents.

[0014] Preferably, the diluent comprises water.

[0015] Compared with the prior art, the advantages of the present invention are: This invention describes the administration of the precursor nicotinamide mononucleotide (NMN) to a hypobaric and hypoxic mouse model, which significantly improved metabolic disorders and pathological damage under hypobaric and hypoxic conditions, and showed a significant effect in treating acute altitude sickness. Therefore, the application of the precursor nicotinamide mononucleotide in the preparation of drugs to alleviate acute altitude sickness is proposed.

[0016] This invention describes a hypobaric hypoxic mouse model where the precursor nicotinamide mononucleotide (NMN) was administered to a hypoxic mouse model along with glucose solution. The results showed that the combined use of NMN and glucose significantly alleviated pathological damage caused by hypoxia and played a role in metabolic regulation under hypoxic conditions. Therefore, the combined use of NMN and glucose demonstrates a significant effect in treating acute altitude sickness. Attached Figure Description

[0017] Figure 1 PLS-DA plots for high-altitude normal uric acid population (HNU) and low-altitude normal uric acid population (PNU).

[0018] Figure 2 PLS-DA plots for high uric acid populations (HHU) and low uric acid populations (PHU).

[0019] Figure 3 A bubble chart providing an overview of lipid metabolism changes in the HNU and PNU groups.

[0020] Figure 4 A bubble chart to show the overall changes in lipid metabolism in the HHU and PHU groups.

[0021] Figure 5 A violin diagram showing the changes in acylcarnitine levels in the HNU and PNU groups.

[0022] Figure 6 A violin diagram showing the changes in acylcarnitine levels in the HHU and PHU groups.

[0023] Figures 1-6 This study showed characteristic lipid metabolites in clinical serum and their association with altitude.

[0024] Figure 7 The image shows the HE staining results of mouse lungs. In the image, A represents the NC group, B represents the H group, C represents the NH group, D represents the HG group, and E represents the NHG group.

[0025] Figure 8 This is a score bar chart of pathological damage in the lungs of mice.

[0026] Figure 9 The bar chart shows the various indicators in mouse serum and lung tissue. In the bar chart, A-E represent the indicators in serum, and F-G represent the indicators in lung tissue. A represents blood urea nitrogen, B represents creatinine, C represents glucose, D represents lactate dehydrogenase, E represents creatinine kinase, F represents lactate dehydrogenase, and G represents creatinine kinase.

[0027] Figures 7-9 The study demonstrated that supplementation with NMN and glucose alleviated lung damage and restored biochemical parameters in hypobaric mice.

[0028] Figure 10 Volcano diagrams comparing group H and group NC.

[0029] Figure 11 This is a map showing the enrichment of differentially expressed metabolite pathways between group H and group NC.

[0030] Figure 12 Volcanic diagrams comparing the NH group and the H group.

[0031] Figure 13 This is a map showing the enrichment of differential metabolite pathways between the NH group and the H group.

[0032] Figure 14 Volcano diagrams comparing HG group and H group.

[0033] Figure 15 This is a map showing the enrichment of differentially expressed metabolite pathways between the HG group and the H group.

[0034] Figure 16 Volcano diagrams comparing the NHG group and the H group.

[0035] Figure 17 This is a map showing the enrichment of differentially expressed metabolite pathways between the NHG group and the H group.

[0036] Figures 10-17 The study demonstrated the recovery of metabolic disorders in hypobaric and hypoxic mice after NMN and glucose supplementation.

[0037] Figure 18 This is a schematic diagram of a modeling experiment. Detailed Implementation

[0038] The specific embodiments of the present invention are described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention. Unless otherwise specified, the experimental methods described in the embodiments of the present invention are conventional methods.

[0039] This embodiment analyzes the lipidome of a batch of serum samples (four groups in total: high-altitude normal uric acid population (HNU); high-altitude high uric acid population (HHU); low-altitude normal uric acid population (PNU); and low-altitude high uric acid population (PHU)). It found that long-chain acylcarnitine (CAR) including CAR 16:0, CAR 18:0, CAR 18:1, and CAR 18:2 were upregulated, indicating impaired mitochondrial function and inhibited fatty acid oxidation, and this was used as a therapeutic target.

[0040] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the operational steps used herein, such as molecular genetics, nucleic acid chemistry, chemistry, molecular biology, biochemistry, cell culture, microbiology, cell biology, genomics, and recombinant DNA, are all conventional steps widely used in their respective fields. To better understand this invention, definitions and explanations of relevant terms are provided below.

[0041] As used in this article, the term "acute altitude sickness" refers to a series of acute hypoxic reactions caused by the body's failure to adapt to the natural environment of high altitude. Those who are not adapted develop symptoms within 6–24 hours of entering a high-altitude area, experiencing bilateral frontal pain, palpitations, chest tightness, shortness of breath, loss of appetite, nausea, and vomiting. Symptoms usually subside after 24–48 hours at high altitude and disappear after several days. A small number may develop high-altitude pulmonary edema and / or high-altitude cerebral edema.

[0042] As used in this article, the term "lipomics" refers to the discipline that uses modern mass spectrometry techniques to analyze the intrinsic chemical properties of lipids.

[0043] Lipidomics research involves the following: Accurately determine the structure of intracellular lipids, including the number of atoms, the number and location of double bonds, the core structure and head groups of individual fatty acid chains, and the region specificity of each isomer.

[0044] Accurately quantify each lipid in the pathway and discover lipid biomarkers through comparative analysis.

[0045] The interactions between various lipids and other lipids, proteins, and metabolites in the body were measured.

[0046] Disease prevention and intervention can be achieved by revealing nutritional or therapeutic conditions.

[0047] As used herein, the term "subject" refers to mammals, including but not limited to humans, rodents (mice, rats, guinea pigs), dogs, horses, cattle, cats, pigs, monkeys, chimpanzees, etc. In some embodiments, the subject is a human.

[0048] As used in this article, the term "long-chain acylcarnitine" refers to compounds composed of long-chain fatty acids and carnitine, which primarily generate energy through mitochondrial oxidative metabolism. Long-chain acylcarnitine has multiple functions in the human body, the most important of which is its role in fatty acid transport within the mitochondria. When the body needs energy, fatty acids are metabolized to produce acetyl-CoA, and long-chain acylcarnitine helps acetyl-CoA cross the inner mitochondrial membrane into the mitochondria, participating in the tricarboxylic acid cycle to produce ATP energy. Long-chain acylcarnitine also has medical significance. For example, in some cases of inherited fatty acid metabolism disorders, the concentration of long-chain acylcarnitine may be abnormally elevated, which can be diagnosed through blood or urine tests. Furthermore, some studies have found that long-chain acylcarnitine is associated with the occurrence and development of certain diseases, such as metabolic diseases and cardiovascular diseases. In summary, long-chain acylcarnitine plays an important regulatory role in the human body, participating in the regulation of lipid metabolism and energy production, and is also associated with the occurrence and development of some diseases.

[0049] In this invention, the LM (Lipid Maps) number for CAR 16:0 is LMFA07070098; the LM number for CAR 18:0 is LMFA07070051; the LM number for CAR 18:1 is LMFA07070096; the LM number for CAR 18:2 is LMFA07070009; and the LM number for CAR 18:2 is LMFA07070009.

[0050] CAR 16:0 represents palmitoylcarnitine, which has 16 carbon chains.

[0051] CAR 18:0 represents stearoylcarnitine, which has 18 carbon chains.

[0052] CAR 18:1 represents oleoylcarnitine, which has 18 carbon chains with one double bond.

[0053] CAR 18:2 represents linoleic carnitine, which has 18 carbon chains with 2 double bonds.

[0054] Example 1 I. Acquisition of serum lipidome samples from high-altitude normal uric acid population, high-altitude high uric acid population, low-altitude normal uric acid population, and low-altitude high uric acid population. In this embodiment, liquid chromatography-tandem mass spectrometry (LC / MS) was used to investigate the lipid levels in the serum of 296 subjects, including 86 high-altitude normal uric acid (HNU) subjects, 85 high-altitude high uric acid (HHU) subjects, 63 low-altitude normal uric acid (PNU) subjects, and 62 low-altitude high uric acid (PHU) subjects.

[0055] All clinical serum samples used in this experiment were obtained from Beijing 101 Hospital. Collected whole blood was immediately centrifuged to harvest serum, which was then stored at -80°C. The serum was then transported to the laboratory on dry ice for lipid extraction.

[0056] II. Serum Lipidomics Experiments 1. Serum lipid extraction: 1) Accurately extract 50 μL of serum, add 1 mL of pure methanol, vortex for 2 min, transfer to a 5 mL centrifuge tube, and then add 2.5 mL of MTBE (BHT 1 mg / mL).

[0057] 2) Shake at 1000 rpm for 20 min (pre-cooled with nitrogen).

[0058] 3) Add 750 μL of pre-cooled ultrapure water, vortex for 1 min, and let stand for 2 min.

[0059] 4) Centrifuge at 7℃ and 11000g for 15 min, and the liquid surface will show stratification.

[0060] 5) Take 1500 μL of the top organic layer and dispense it into two 1.5 mL centrifuge tubes, 750 μL in each tube.

[0061] 6) Dry the organic layer with nitrogen, add 20 μL of resolvent (dichloromethane:methanol=2:1), vortex for 30s to resolvate the extracted lipids.

[0062] 7) Then add 40 μL of diluent (acetonitrile:isopropanol:water = 65:30:5 5mM ammonium acetate), vortex for 30s to dilute the lipids.

[0063] 8) Centrifuge at 7℃ and 14000g for 10 min, and take 40 μL of the supernatant for LC-MS detection.

[0064] Quality control (QC) samples are prepared by mixing sample extracts and are used to monitor the repeatability of analytical samples under the same processing methods. During instrumental analysis, one QC sample is inserted for every 10 analytical samples to monitor the repeatability of the analytical process.

[0065] 2. Mass spectrometry acquisition conditions: Instrument: Thermo Scientific Orbitrap Exploris 120.

[0066] The ion source parameters are set as shown in Table 1.

[0067] Table 1 Ion source parameter settings 3. Chromatographic conditions: Chromatographic column: C8 column.

[0068] Composition of the mobile phase: Mobile phase A: Acetonitrile:Water = 6:4, 10 mM ammonium acetate; Mobile phase B: Isopropanol:acetonitrile = 9:1 10 mM ammonium acetate.

[0069] The liquid phase gradient is shown in Table 2.

[0070] Table 2 Liquid Phase Gradient Injection volume: 2 μL; Sample tray temperature: 8℃; Column temperature: 55℃.

[0071] III. Experiments on the Hypobaric Hypoxia Mouse Model and Tissue Sampling 1. Establishment of a hypobaric hypoxia mouse model The mouse strain used in this invention was C57BL / 6J. Mice were housed under normoxic conditions in an artificial climate chamber (23℃, 50% humidity) and under hypoxic conditions in a high-altitude low-pressure environment simulation chamber (simulating an altitude of 5000 m, oxygen concentration of approximately 11%) at room temperature. All experimental mice were subject to 12 hours of controlled light and had free access to food and water. Pre-treatment with medication lasted 7 days, followed by 21 days of hypoxic exposure, for a total modeling period of 28 days. The experimental diagram is shown below. Figure 18 .

[0072] After a week of acclimatization to food and water, experimental mice were randomly divided into 5 groups of 6 mice each: normoxic control group (NC), hypoxia model group (H), NMN supplementation group (NH), glucose solution group (HG), and NMN plus glucose solution group (NHG). NMN was administered by gavage at a dose of 500 mg / kg / day for 14 days, including 7 days of pre-treatment and 7 days of treatment during the hypoxia period. Glucose was prepared as an aqueous solution at a dose of 0.2% (2 g / L) and ingested by the mice through their daily drinking water for 21 days starting from the hypoxia treatment. The NC and H groups were administered sterile water by gavage as controls. Both NMN and glucose were prepared by dissolving them in sterile water.

[0073] During the pre-treatment period, the model group continued to be fed under normoxic conditions. After 7 days of pre-treatment, in order to conduct the modeling experiment, the H group and the drug-treated group were simultaneously placed in a hypoxic chamber, while the NC group continued to be fed normally. During the continuous hypoxic exposure period, the mice were weighed daily for the first 10 days, and then the chamber door was opened once every 3 days at 9:00 AM for 20 minutes each time. During this period, the physiological activity of the mice was observed and recorded, and the mice were administered drugs by gavage. The mice's food and drinking water were added, bedding was changed, and their body weight and food intake were measured. Other groups underwent physiological observation and body weight measurement simultaneously.

[0074] 2. Mouse tissue sampling After the hypobaric and hypoxic experiment, the mice were weighed, blood was collected from their eyes, and lung tissue was removed. The left lung was fixed in a centrifuge tube containing 4% paraformaldehyde, while the right lung was frozen in liquid nitrogen in a cryovial and stored at -80°C. The mouse plasma was placed at 4°C for 6 hours, then centrifuged (4°C, 3000 rpm, 20 min), and the supernatant serum was collected and stored at -80°C.

[0075] IV. Mouse pathological sections and HE staining experiment 1) Fixation: The extracted right lung tissue was fixed in 4% paraformaldehyde for more than 48 hours.

[0076] 2) Dehydration: The tissues fixed for more than 8 hours were slowly rinsed with running water and then dehydrated: 50% ethanol (1.5 h) → 75% ethanol (1.5 h) → 85% ethanol (1 h) → 95% ethanol I (1 h) → 95% ethanol II (0.5 h) → 100% ethanol I (1 h) → 100% ethanol II (0.5 h) → 50% xylene (0.5 h) → pure xylene I (0.3 h) → pure xylene II (0.25 h) → paraffin I (2 h) → paraffin II (2 h).

[0077] 3) Paraffin embedding: The dehydrated tissue is placed in liquid paraffin and kept warm. After paraffin embedding is completed, the embedding paraffin is first melted in a paraffin melting box, then poured into the embedding frame to form a block, and placed on a freezing stage to solidify before being taken out for use.

[0078] 4) Sectioning: For the embedded paraffin samples, first place them on ice to pre-cool, then use a paraffin microtome to make continuous sections of 4 μm each, and then place the sections in a 42℃ microtome.

[0079] 5) Baking the slices: After attaching the slices, place them in a baking machine for baking, then place them in an electric oven for baking for 15 minutes. Remove them and store them in a slice box at room temperature.

[0080] 6) HE staining: Remove the sections, place them in a staining rack, and use an automatic HE staining machine for dewaxing and staining. The procedure is as follows: Oven (30 min) → Xylene I (5 min) → Xylene II (5 min) → Anhydrous ethanol (2 min) → 95% ethanol I (1 min) → 95% ethanol II (1 min) → 85% ethanol I (1 min) → 75% ethanol I (1 min) → Distilled water (2 min) → Hematoxylin (3.5 min) → Wash with water (1.5 min) → 1% hydrochloric acid ethanol (15 s) → 1% ammonia water (4 s) → Wash with water (2 min) → Eosin (1.5 min) → Wash with water (10 s) → 75% ethanol II (30 s) → 85% ethanol II (30 s) → 95% ethanol III (1 min) → 100% ethanol I (3 min) → 100% ethanol II (3 min) → Xylene III (4 min) → Xylene IV (4 min).

[0081] 7) Mounting: Apply a drop of neutral resin to the slide, cover with a coverslip to seal, and let it air dry for later use.

[0082] 8) Slide scanning: Place the sealed slide into a fully automatic digital slide scanner for scanning, copy the data into the computer, and use Zen software for observation and subsequent pathological scoring.

[0083] V. Biochemical Indicator Detection Experiment Take 15 mg of lung tissue, add 400 μL of pre-cooled PBS buffer and grind thoroughly (60 Hz, 30 s, 3 times), centrifuge and collect the supernatant (4℃, 13000 rpm, 15 min). Take 50 μL of the homogenate or 25 μL of serum and use a fully automated biochemical analyzer to detect creatinine (CREA), blood urea nitrogen (UREA), total cholesterol (TC), total triglycerides (TG), lactate dehydrogenase (LDH), creatinine kinase (CK), and glucose (Glu). Refer to the instruction manual for specific procedures.

[0084] VI. Metabolomics Experiments 1. Extraction of metabolites (1) Take 10 mg of tissue, add 3 2 mm grinding beads, add 200 μL of pre-cooled ultrapure water, and grind three times at 60 Hz for 3 min.

[0085] (2) Add 800 μL of methanol:acetonitrile = 1:1 (with internal standard), vortex for 30 s, sonicate in an ice bath for 10 min, and incubate in a -20℃ refrigerator for 1 h.

[0086] (3) Centrifuge at 4℃, 14000 g, 15 min, take the supernatant and divide it into two tubes, each containing 400 μL, concentrate and evaporate to dryness at low temperature, and store in a -80℃ refrigerator.

[0087] (4) Redissolve the sample in 50 μL of acetonitrile and ultrapure water at a ratio of 1:1, shake to mix, centrifuge again with the same parameters, take 35 μL of the supernatant and add it to the sample vial for testing.

[0088] (5) Take 50 μL of supernatant from each sample, mix well to prepare total QC, and take 400 μL to dispense into individual QC.

[0089] (6) Reconstitute and dilute in the same way as above, and insert one QC sample for every ten samples before running on the machine.

[0090] 2. Mass spectrometry acquisition conditions The mass spectrometer used in this invention is an Orbitrap Exploris 120, and the chromatograph is a Vanquish Flex System. Key parameters of the whole-component mass spectrometry method are shown in Table 3.

[0091] Table 3 Key parameters of the whole-component mass spectrometry method 3. Chromatographic conditions: Key parameters of the chromatographic method are shown in Table 4, and chromatographic gradients are shown in Table 5.

[0092] Table 4 Key parameters of chromatographic methods Table 5 Chromatographic gradient VII. Data Processing and Statistical Analysis The experiment used TraceFinder 5.1 software for database management, sequence acquisition, data processing, and report template customization and output. Qualitative and quantitative studies were conducted by comparing the retention times of precursor and daughter ions of lipids in the self-built library. Internal standards and QC were used to correct the data.

[0093] In this invention, univariate analysis including fold change analysis (FC) and significant t-test was performed between groups. Among them, 0.01 < p < 0.05 is shown as *, 0.001 < p < 0.01 is shown as **, and p < 0.001 is shown as ***; and multivariate analysis including unsupervised analysis (PCA), clustering analysis, etc. Metabolomics and lipidomics data processing was completed using R 4.1.1 (https: / / www.r-project.org / ), and the heatmap was completed using the software Hiplot (http: / / hiplot.com.cn).

[0094] Results The experimental results of lipidomics are as Figure 1 shown, where Figure 1 and Figure 2 respectively show the PLS-DA plots of high-altitude normal uric acid population (HNU), plain normal uric acid population (PNU), high-altitude hyperuric acid population (HHU), and plain hyperuric acid population (PHU), indicating that there are obvious lipid metabolism differences between high-altitude and plain populations; Figure 3 and Figure 4 respectively show the overview of lipid metabolism changes in the two groups of HNU and PNU, as well as the overview of lipid metabolism changes in the two groups of HHU and PHU. It can be clearly observed that most acylcarnitines (CARs), lysophosphatidylcholines (LPCs), and some fatty acids (FAs) are significantly upregulated after going to the high altitude; Figure 5 and Figure 6 respectively show the changes in the levels of CARs with different carbon chain lengths in the two groups of HNU and PNU, as well as the two groups of HHU and PHU. It is found that the levels of long-chain CARs are significantly accumulated after going to the high altitude, suggesting mitochondrial dysfunction or excessive FA oxidation. Intervening in FA oxidation may be a potential target for promoting adaptation. NAD+ plays an important role in energy conversion and redox balance regulation during β-oxidation and is a key molecule necessary to maintain normal cell function and provide energy. Therefore, this invention supplements NMN, increases the level of NAD+, and promotes fatty acid oxidation, which may help relieve acute altitude reaction. Next, this invention will be further verified in a hypobaric hypoxia mouse model.

[0095] Figure 7 respectively show the HE staining of the lungs of mice in the NC group, H group, NH group, HG group, and NHG group, and it is found that supplementing NMN and glucose significantly alleviates the lung injury caused by hypoxia; Figure 8 shows the scoring of lung injury, which also proves the significant efficacy of NMN and glucose; Figure 9The study presented serum urea nitrogen (UREA), creatinine (CREA), glucose (Glu), lactate dehydrogenase (LDH), and creatinine kinase (CK) levels in mice. It was found that NMN and glucose supplementation reduced these levels compared to group H. Figure 9 The study also demonstrated that LDH and CK levels in mouse lung tissue were reduced by NMN and glucose supplementation compared to group H. In conclusion, the combined use of NMN and glucose has a significant effect in alleviating pathological damage caused by hypoxia.

[0096] Figures 10-17 The study demonstrated the recovery of metabolic disorders in hypobaric and hypoxic mice after NMN and glucose supplementation. Figure 10 Compared with the NC group, the H group showed a significant accumulation of expression levels of organic acids such as 3-hydroxybutyrate (3-HB), indole-3-lactic acid (ILA), and hippuric acid (HA), as well as various N-acetyl amino acids (FC<0.67 or FC>1.5, P<0.05). Figure 11 The study demonstrated that KEGG pathway enrichment analysis of metabolites with significant differences revealed significant upregulation in pathways such as arginine biosynthesis, purine metabolism, and glycine, serine, and threonine metabolism. Figure 12 The results showed that, compared with the H group, the NH group had 27 differentially expressed metabolites that were altered (FC<0.67 or FC>1.5, P<0.05). Figure 13 These metabolites are shown to be primarily involved in the biosynthesis of valine, leucine, and isoleucine, the metabolism of arginine and proline, and the degradation of valine, leucine, and isoleucine. This invention further investigates the effects of glucose supplementation and the metabolic changes in hypoxic mice after the combined use of glucose and NMN. Figure 14 and Figure 15 It was shown that among the 60 metabolites that were upregulated in group H, more than one-third of the metabolites were significantly downregulated after glucose supplementation, including 3-HB, HA, ILA, etc. Figure 16 and Figure 17KEGG pathway enrichment analysis of the downregulated metabolites revealed that they were concentrated in arginine synthesis and purine metabolism, which confounded the upregulation of these metabolic pathways caused by hypoxia. In addition, downregulation was also found in the citric acid cycle, alanine, aspartate, and glutamate metabolism.

[0097] In conclusion, this demonstrates that NMN supplementation with glucose has a certain effect on metabolic regulation under hypoxic conditions.

[0098] It should be noted that when numerical ranges are mentioned in the claims of this invention, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. To avoid redundancy, the present invention describes preferred embodiments.

[0099] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of the invention.

[0100] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. Application of precursor nicotinamide mononucleotide in the preparation of drugs to alleviate acute altitude sickness.

2. Use according to claim 1, characterized in that, The drug uses nicotinamide mononucleotide (NMN) as its sole active ingredient to improve metabolic disorders and lung pathological damage caused by low pressure and hypoxia.

3. The application according to claim 1, characterized in that, The drug uses nicotinamide mononucleotide (NMN) as its sole active ingredient to enhance the effect of glucose solution on metabolic disorders and lung pathological damage caused by low pressure and low oxygen.

4. The application according to claim 1, characterized in that, The drug is a liquid preparation.

5. The application according to claim 4, characterized in that, The liquid preparation is an oral preparation or a gavage preparation.

6. The application according to claim 5, characterized in that, The liquid formulation includes pharmaceutically acceptable excipients.

7. The application according to claim 6, characterized in that, Pharmaceutically acceptable excipients include diluents.

8. The application according to claim 7, characterized in that, The diluent includes water.

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