Application of spermidine in preparation of medicine for relieving copper exposure damage

Abstract

The invention discloses application of spermidine in preparation of a medicine for relieving copper exposure injury, and relates to the field of biological medicine. The invention provides an application of spermidine in preparation of a medicine for relieving copper exposure injury, and the injury is liver injury and / or intestinal injury caused by copper exposure. Spermidine can reduce the copper content in serum and liver, promote the expression of liver copper transporters ATP7B and CTR1, copper death proteins FDX1, LIAS and Lip-DLAT, and reduce the oligomerization of HSP70 and DLAT proteins; meanwhile, transaminase activity in serum and liver and intestinal tissue damage are reduced. The medicine provided by the invention can improve intestinal health, improve liver copper metabolism capability and relieve body injury caused by copper exposure, effectively solves the problem that no reliable medicine exists for related injury caused by copper exposure, and is expected to be developed into a medicine or health food for preventing and treating copper exposure injury.

Description

Technical Field

[0001] The invention relates to the field of biomedicine, and in particular to application of spermidine in preparing a medicine for alleviating copper exposure damage. Background Art

[0002] In today's world, economic growth is closely linked to environmental metal pollution. Rapid urbanization and industrialization have led to an increase in the use of metals and their chemical production, causing environmental pollution, which in turn leads to metal pollution in the food chain. Copper is an essential oxidatively active metal micronutrient in most biological systems. Under normal physiological conditions, copper is absorbed by intestinal cells and reaches the liver for storage, distribution and export to different cells. It is undeniable that despite the physiological need for copper in the human body, the intake of copper exceeding the safe dose is extremely toxic to cells. Metabolically active tissues such as the liver and intestines are more susceptible to metal toxicity.

[0003] The prevalence of copper exposure is steadily increasing worldwide, affecting the food chain by affecting animals, farmland and water sources. Copper in the environment mainly comes from copper mining or processing in industry, agriculture and medicine. Under normal circumstances, the copper content in the atmosphere is less than 200ng / m 3 , the copper content in the soil is 13-24 mg / kg, and the copper content in natural water is 0.004-0.01 mg / L. Over the past few decades, the production and discharge of copper have gradually increased. The widespread discharge of copper reaches 939,000 tons per year, seriously polluting the ecosystem, which may lead to excessive intake of copper by humans and livestock. The appropriate intake of copper for the human body is 0.019-0.027 mg / kg / d. It is reported that the copper exposure of female residents near a copper mining area in a certain place is 0.038-0.067 mg / kg / d, with a median of 0.051 mg / kg / d; the deposition of copper in human hair can reach 2.34-34.36 mg / kg. More seriously, taking metal dietary supplements containing 0.43-0.86 mg / kg / d of copper for three consecutive years can cause liver failure and require a living transplant. Therefore, alleviating the damage of copper exposure through daily diet or medication has been a hot topic of concern in recent years.

[0004] Spermidine is a natural polyamine that exists in all eukaryotic cells and most prokaryotes. The intracellular spermidine content depends on exogenous food intake, intestinal microbial synthesis, cell synthesis, catabolism and excretion. It is reported that spermidine plays a role in cell proliferation and differentiation, maintaining intestinal barrier and liver health, and regulating cell death. At the same time, spermidine is also a natural autophagy inducer, playing an important role in anti-aging, anti-oxidation and other aspects, but there are no reports on the role of spermidine in alleviating the body's copper exposure. Summary of the invention

[0005] In view of the above-mentioned deficiencies in the prior art, the present invention provides the use of spermidine in the preparation of a drug for alleviating copper exposure damage. The drug provided by the present invention can improve intestinal health, enhance the copper metabolism capacity of the liver, and alleviate the body damage caused by copper exposure, thereby effectively solving the problem that there is no reliable drug for related injuries caused by copper exposure.

[0006] To achieve the above-mentioned purpose, the technical solution adopted by the present invention to solve the technical problem is: to provide the use of spermidine in the preparation of a drug for alleviating copper exposure damage.

[0007] Furthermore, the concentration of spermidine in the drug is 2.5-3.5 mmol / L.

[0008] Furthermore, the concentration of spermidine in the drug is 3 mmol / L.

[0009] Furthermore, the drug is administered orally.

[0010] Further, the copper exposure is copper exposure caused by a concentration of 30-40 mg / kg copper.

[0011] Furthermore, the copper exposure is copper exposure caused by a copper concentration of 35 mg / kg.

[0012] Furthermore, the damage is liver damage and / or intestinal damage induced by copper exposure.

[0013] Furthermore, the application is an application in at least one of the following (1)-(5):

[0014] (1) Inhibit the accumulation of copper ions in the body caused by copper exposure;

[0015] (2) inhibiting copper death in the liver caused by copper exposure;

[0016] (3) Improve the liver's ability to metabolize copper;

[0017] (4) Alleviate liver damage caused by copper exposure;

[0018] (5) Alleviate intestinal damage caused by copper exposure.

[0019] A drug for alleviating copper exposure damage comprises spermidine and pharmaceutically acceptable excipients.

[0020] In summary, the present invention has the following beneficial effects:

[0021] The present invention has found a new effective substance for the prevention of copper exposure. Spermidine can be used to alleviate copper exposure damage, can effectively reduce liver and intestinal damage caused by copper exposure, reduce the accumulation of copper ions in serum and liver, reduce the growth of transaminase AST and ALT activity in serum, promote the expression of liver copper transporters ATP7B and CTR1, copper death proteins FDX1, LIAS and Lip-DLAT, and reduce HSP70 and DLAT protein oligomerization. In summary, spermidine has the prospect of being developed as a medicine or health product for preventing and treating copper exposure. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 H&E sections of liver tissues under different treatments;

[0023] Figure 2 The results of serum AST and ALT changes under different treatments are shown in the figure;

[0024] Figure 3 This is a graph showing the changes in copper ion content in liver tissue under different treatments;

[0025] Figure 4 The expression diagram of copper transporter in liver tissue under different treatments;

[0026] Figure 5 Quantification of copper transporter expression in liver tissue under different treatments;

[0027] Figure 6 The expression diagram of DLAT oligomerization protein in liver tissue under different treatments;

[0028] Figure 7 The expression of copper death protein in liver tissue under different treatments;

[0029] Figure 8 The figure is the quantitative result of copper death protein expression in liver tissue under different treatments;

[0030] Fig. 9 The graph shows the changes of polyamine content in liver tissue under different treatment groups;

[0031] Fig.10 H&E staining of small intestinal tissues under different treatments;

[0032] Fig.11 PAS staining images under different treatments;

[0033] Fig.12 The figure shows the effect of spermidine on the ratio of small intestinal villus height to crypt depth and the number of duodenal goblet cells;

[0034] Fig.13 The graphs showing the changes in serum D-lactic acid, IgA and IgG levels under different treatments;

[0035] Fig.14 This is a graph showing the changes in MDA content in the small intestine under different treatments. DETAILED DESCRIPTION

[0036] The principles and features of the present invention are described below, and the examples are only used to explain the present invention and are not used to limit the scope of the present invention. If no specific conditions are specified in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0037] The experimental materials used in the embodiments of the present invention are as follows:

[0038] Experimental animals: 7-week-old C57BL / 6J mice were purchased from Chengdu Dashuo Experimental Animal Co., Ltd. The mice were kept in the small animal room of the Animal Science and Technology College of Sichuan Agricultural University in accordance with the animal welfare and animal husbandry management regulations of Sichuan Agricultural University. All animal experiments and procedures were carried out in strict accordance with the experimental management regulations of Sichuan Agricultural University.

[0039] Main experimental reagents: spermidine (S2626-25, Sigma-Aldrich); 4% tissue cell fixative (P1110, Solarbio); AST detection kit (C010-2-1, Nanjing Jiancheng); ALT detection kit (C009-2-1, Nanjing Jiancheng); copper ion detection kit (E-BC-K300-M, Elabsciece); D-lactic acid detection kit (S0204S, Biyuntian); mouse immunoglobulin A (IgA) ELISA research kit (BL2055-A, Jiangsu Baolai); mouse immunoglobulin A (IgA) ELISA research kit (BL2057-A, Jiangsu Baolai); MD A detection kit (A003-1-2, Nanjing Jiancheng); Anti-CTR1 antibody (1:1000, A0773, ABclonal); Anti-ATP7B antibody (1:500, A5676, ABclonal); Anti-β-actin antibody (1:1000, AC026, ABclonal); Anti-FDX1 antibody (1:1000, T510671, ABmart); Anti-LIAS antibody (1:1000, PH2927, ABmart); Anti-DLAT antibody (1:1000, A8814, ABclonal); Anti-Lipoic Acid (1:6000, ab58724, ABcam); Anti-HSP70 antibody (1:6000, A23457, ABclonal); benzoyl chloride; methanol; perchloric acid; 1,6-hexanediamine; hematoxylin and eosin, etc.

[0040] Example 1 Establishment and treatment of copper exposure model in mice

[0041] (1) Seven-week-old female C57BL / 6J mice were randomly divided into a control group, a copper sulfate (CuSO4) group, a spermidine (SPD) group, and a spermidine + copper sulfate (SPD + CuSO4) group, with 50 mice in each group. After pre-feeding for 1 week, the formal experiment was carried out.

[0042] (2) The control group and the copper sulfate group drank purified water, while the spermidine group and the combined treatment group were fed 3 mmol / L spermidine in their drinking water. The control group and the spermidine group were fed a basal maintenance diet, while the copper sulfate group and the combined treatment group were fed a high-copper feed containing 35 mg / kg. The mice were allowed to eat and drink freely during the feeding period.

[0043] (3) Each time, 300 g of feed and 200 mL of water were added, and the feed and drinking water were replaced every three days. At the same time, the weight of mice in each group, the remaining feed and water were weighed. After continuous feeding for 90 days, the mice were killed, and the liver, intestine and serum were collected for subsequent experiments.

[0044] Example 2 Effects of spermidine on copper exposure-induced liver damage

[0045] (1) Experimental instruments and materials

[0046] Mouse serum and liver samples collected in Example 1; AST detection kit (C010-2-1, Nanjing Jiancheng); ALT detection kit (C009-2-1, Nanjing Jiancheng); ELISA instrument.

[0047] (2) Experimental steps and results

[0048] Take appropriate amount of serum, operate according to the instructions of AST and ALT detection kits, and make standard curves; collect livers for making H&E sections for pathological analysis. The liver tissue H&E sections of the control group, copper sulfate group, spermidine group and copper sulfate + spermidine group are as follows: Figure 1 The results of serum AST and ALT changes in the control group, copper sulfate group, spermidine group and copper sulfate + spermidine group are shown in Figure 2 As shown, Figure 2 In the figure, the left picture shows the result of AST, and the right picture shows the result of ALT.

[0049] Depend on Figure 1-Figure 2 It can be seen that copper exposure has no significant effect on liver tissue structure. However, copper sulfate significantly increased the levels of AST and ALT in serum (P<0.001), and after spermidine treatment, the levels of AST and ALT in serum were significantly reduced (P<0.001). The above results show that copper sulfate can damage liver function, while spermidine can alleviate liver damage.

[0050] Example 3 Effect of spermidine on copper metabolism disorders induced by copper exposure

[0051] (1) Experimental instruments and materials

[0052] Mouse serum and liver samples collected in Example 1; copper ion detection kit (E-BC-K300-M, Elabsciece); CTR1 antibody (1:1000, A0773, ABclonal); ATP7B antibody (1:500, A5676, ABclonal); β-actin antibody (1:1000, AC026, ABclonal); tissue homogenizer; microplate reader.

[0053] (2) Experimental steps and results

[0054] 1 mL PBS was added to every 0.05 g of liver tissue, and the liver was ground with a tissue homogenizer until there was no solid tissue in the liquid; the tissue homogenate was collected, and the protein concentration in the homogenate was detected according to the instructions of the BCA protein detection kit, and the expression of CTR1 and ATP7B proteins was detected by Western Blot. An appropriate amount of liver tissue homogenate and serum were taken, and the copper ion content was detected according to the instructions of the copper ion detection kit. The changes in serum transaminase activity under the treatment of the control group, copper sulfate group, spermidine group and copper sulfate + spermidine group are shown in the figure. Figure 3 As shown (the results are expressed as mean ± standard deviation, * indicates that there is a significant difference between the two groups (P<0.05), where * indicates (P<0.05), ** indicates (P<0.01), *** indicates (P<0.001), and ns indicates that the difference is not significant). Figure 3 In the figure, the left picture shows the copper content in the liver, and the right picture shows the copper concentration in the serum.

[0055] Depend on Figure 3 It can be seen that copper sulfate can significantly increase the copper ion level in serum and liver

[0056] (P<0.001), while after spermidine treatment, the copper ion levels in serum and liver were significantly decreased (P<0.01), indicating that spermidine can effectively alleviate the copper metabolism disorder caused by copper sulfate and reduce copper accumulation.

[0057] At the same time, the effects of spermidine on copper transporter CTR1, ATP7B and β-actin in liver tissue were detected. The expression of copper transporter in liver tissue of control group, copper sulfate group, spermidine group and copper sulfate + spermidine group was shown in the figure. Figure 4 and Figure 5As shown (the results are expressed as mean ± standard deviation, * indicates that there is a significant difference between the two groups (P<0.05), where * indicates (P<0.05), ** indicates (P<0.01), *** indicates (P<0.001), and ns indicates that the difference is not significant). Figure 5 In the figure, the left picture shows the results of CTR1 / β-actin, and the right picture shows the results of ATP7B / β-actin.

[0058] Depend on Figure 4 and Figure 5 It can be seen that copper sulfate significantly inhibited the expression of CTR1 and ATP7B proteins in liver tissue (P<0.05), while spermidine treatment could reverse this change (P<0.05), indicating that spermidine can enhance the copper metabolism capacity of the liver and promote the excretion of accumulated copper in the body, which may be one of its mechanisms of reducing copper accumulation.

[0059] Example 4 Spermidine alleviates copper death in liver tissue

[0060] (1) Experimental instruments and materials

[0061] Mouse liver samples collected in Example 1; Anti-FDX1 antibody (1:1000, T510671, ABmart); Anti-LIAS antibody (1:1000, PH2927, ABmart); Anti-DLAT antibody (1:1000, A8814, ABclonal); Anti-Lipoic Acid (1:6000, ab58724, ABcam); Anti-HSP70 antibody (1:6000, A23457, ABclonal); β-actin antibody (1:1000, AC026, ABclonal); tissue homogenizer; microplate reader.

[0062] (2) Experimental steps and results

[0063] 1 mL PBS was added to every 0.05 g of liver tissue, and the liver was ground using a tissue homogenizer until there was no solid tissue in the liquid; the tissue homogenate was collected and the protein concentration in the homogenate was detected according to the instructions of the BCA protein detection kit. The expression of copper death protein in the liver tissue of the control group, copper sulfate group, spermidine group and copper sulfate + spermidine group was shown in the figure. Figure 6 and Figure 7 As shown, Figure 7 The quantitative results are as follows Figure 8As shown (the results are expressed as mean ± standard deviation, * indicates that there is a significant difference between the two groups (P<0.05), where * indicates (P<0.05), ** indicates (P<0.01), *** indicates (P<0.001), and ns indicates that the difference is not significant). Figure 8 In the figure, from top to bottom and from left to right, they are the results of FDX1 / β-actin, LIAS / β-actin, HSP70 / β-actin, DLAT / β-actin and Lip-DLAT / β-actin.

[0064] Depend on Figure 6-Figure 8 It can be seen that copper sulfate can significantly reduce the protein levels of FDX1, LIAS, DLAT and Lip-DLAT in the liver (P<0.05), while after spermidine treatment, the protein levels of FDX1, LIAS and Lip-DLAT increased significantly (P<0.05). At the same time, copper sulfate treatment significantly increased the oligomerization level of DLAT protein, while spermidine combined treatment alleviated this phenomenon. In addition, copper sulfate and spermidine combined treatment can reduce the level of HSP70 protein in the liver. The above results indicate that copper exposure can cause copper death in the liver, and spermidine can alleviate copper death.

[0065] Example 5 Effect of spermidine on polyamine content in the body

[0066] (1) Experimental instruments and materials

[0067] Mouse serum and liver samples collected in Example 1; benzoyl chloride; methanol; perchloric acid; 1,6-hexanediamine; tissue homogenizer; water bath; HyPURITY C18 chromatographic column (Thermo Fisher Scientific); C18 solid phase extraction column (ThermoFisher Scientific); ASC square solid phase extraction device (Ameritech Scientific Corporation); Agilent 1260 series high performance liquid chromatography analysis system (Agilent Technologies).

[0068] (2) Experimental procedures

[0069] The liver sample was taken out from the -80°C freezer, ground in liquid nitrogen, and 0.1 g of tissue sample was weighed and placed in a 1.5 mL centrifuge tube.

[0070] Add 1mL 5% HClO4 and 10μL 500μg / mL 1,6-hexanediamine as an internal standard to the centrifuge tube, transfer the contents of the centrifuge tube to a glass homogenizer, and grind thoroughly. Centrifuge the homogenate at 12,000g for 10 minutes, extract the supernatant into a 15mL centrifuge tube (protected from light, wrapped in tin foil throughout the experiment), then repeat adding 1mL 5% HClO4 to mix the precipitate, and centrifuge again to extract the supernatant into a 15mL centrifuge tube.

[0071] Add 2 mL of 2.5 mol / L NaOH to the extracted tissue supernatant, then add 10 μL of benzoyl chloride, vortex and derivatize in a 40°C water bath for 30 min.

[0072] Take out the derivative solution and adjust the pH value to 7.0 with 6 mol / mL HCl. Add the derivative solution to a C18 solid phase extraction column activated with 3 mL of methanol and 3 mL of ultrapure water in advance, and filter the derivative solution to separate the polyamines. After filtering the derivative solution, rinse the solid phase extraction column with 15 mL of ultrapure water and 15 mL of 15% methanol in turn to remove impurities. After all the liquids have been filtered, use an ear bulb to blow dry the remaining methanol and water, then elute the sample with 0.5 mL of chromatographic methanol, and then filter the eluate with a 0.22 μm syringe filter. Store the eluate at 4°C in the dark until detection.

[0073] The eluate to be tested was injected with 20 μL of sample, and the chromatographic conditions were as follows: the mobile phase ratio was methanol: water = 62:38 (V / V); the flow rate was 1.0 mL / min; the UV detector detection wavelength was 229 nm; the column temperature was 40°C. The results of the polyamine content changes in the liver tissue of the control group, copper sulfate group, spermidine group and copper sulfate + spermidine group are shown in Fig. 9 As shown (the results are expressed as mean ± standard deviation, * indicates that there is a significant difference between the two groups (P<0.05), where * indicates (P<0.05), ** indicates (P<0.01), *** indicates (P<0.001), and ns indicates that the difference is not significant). Fig. 9 In the figure, from left to right are the results of putrescine, spermidine and spermine content in the liver.

[0074] Depend on Fig. 9 It can be seen that copper sulfate and spermidine treatment alone did not significantly affect the polyamine content in the liver (P>0.05), but in the combined treatment group, the spermidine content increased significantly (P<0.001).

[0075] Example 6 Effects of spermidine on intestinal morphology and structural damage induced by copper exposure

[0076] (1) Experimental instruments and materials

[0077] Mouse intestinal samples collected in Example 1; hematoxylin and eosin; sodium dihydrogen phosphate; disodium hydrogen phosphate; formaldehyde (AR grade); anhydrous ethanol (AR grade); xylene (AR grade); hematoxylin stain; eosin stain; hydrochloric acid (AR grade); neutral gum; rotary slicer; automatic dehydrator; tissue embedding machine.

[0078] (2) Experimental procedures

[0079] Take appropriate amount of duodenum, jejunum and ileum tissue samples, dehydrate, embed and slice in 4% paraformaldehyde solution to make H&E slices. The process of H&E slice preparation is as follows: ① Dehydration reagent: dilute anhydrous ethanol with purified water to make 75vt%, 85vt% and 95vt% ethanol solutions; ② Hydrochloric acid-ethanol differentiation solution: pour 416mL of anhydrous ethanol and 178mL of purified water into a beaker, mix well, then slowly add 6mL of concentrated hydrochloric acid and stir to mix; ③ Dehydrate the fixed tissue in an automatic dehydrator (dehydration time: 75vt% alcohol 1h, 85vt% alcohol 1h, 95vt% alcohol I 50min, 95vt% alcohol II 50min, 100vt% alcohol I 50min) min, 100vt% alcohol II for 50min, 100vt% alcohol: xylene mixed in a ratio of 1:1 for 20min, xylene I for 25min, xylene II for 25min, paraffin I for 1h, paraffin II for 2h, paraffin III for 3h), embedding, sectioning; ④ hematoxylin staining for 10-20min; ⑤ hydrochloric acid alcohol differentiation for 5-10s; ⑥ put in 50℃ warm water or weak alkaline aqueous solution to return to blue until blue appears; ⑦ put in 85% alcohol for 3-5min; ⑧ eosin staining for 3-5min; ⑨ gradient alcohol dehydration; ⑩ neutral gum sealing. Schiff reagent was used for PAS staining in the same way. The slices were imaged using a digital trinocular camera microscope system. Each slice was first observed at low magnification for all tissues, and 100x images were collected in the area to be observed to measure the villus height, crypt depth, and goblet cell number of the small intestine. H&E staining and PAS staining of small intestine tissues in the control group, copper sulfate group, spermidine group, and copper sulfate + spermidine group were shown in Figure 2 Fig.10 and Fig.11 As shown (100X), the effect of spermidine on the ratio of intestinal villus height to crypt depth and the number of duodenal goblet cells is shown in Fig.12 As shown (the results are expressed as mean ± standard deviation, * indicates that there is a significant difference between the two groups (P<0.05), where * indicates (P<0.05), ** indicates (P<0.01), *** indicates (P<0.001), and ns indicates that the difference is not significant). Fig.12 In the figure, from A to D are the results of the villus height to crypt depth ratio of the duodenum, the villus height to crypt depth ratio of the jejunum, the villus height to crypt depth ratio of the ileum, and the goblet cell count.

[0080] Depend on Figure 10-12 It can be seen that copper exposure had no significant effect on the V / C of the duodenum and jejunum (P>0.05). However, copper sulfate significantly reduced the V / C of the ileum and the number of duodenal goblet cells (P<0.05). After spermidine treatment, the V / C of the small intestine and the number of duodenal goblet cells were significantly increased compared with the copper sulfate group (P<0.05), indicating that spermidine can alleviate the intestinal tissue damage caused by copper exposure.

[0081] Example 7 Effects of spermidine on intestinal barrier damage induced by copper exposure

[0082] (1) Experimental instruments and materials

[0083] Mouse serum and intestinal samples collected in Example 1; D-lactic acid detection kit (S0204S, Biyuntian); mouse immunoglobulin A (IgA) ELISA research kit (BL2055-A, Jiangsu Baolai); mouse immunoglobulin A (IgA) ELISA research kit (BL2057-A, Jiangsu Baolai; MDA detection kit (A003-1-2, Nanjing Jiancheng); ELISA instrument.

[0084] (2) Experimental procedures

[0085] Add 1 mL RIPA to every 0.05 g of liver tissue, and grind the liver with a tissue homogenizer until there is no solid tissue in the liquid; collect the tissue homogenate, and detect the protein concentration in the homogenate according to the instructions of the BCA protein detection kit, and use the MDA kit to detect the MDA content in the intestine. Take an appropriate amount of serum and detect the content of the corresponding substances according to the instructions of the D-lactic acid detection kit, IgA and IgG ELISA detection kit. The detection process of the ELISA kit is as follows: ① Move the required reagents to room temperature for 20 minutes; ② Add 50μL of the standard and 50μL of the sample to be tested (10μL sample + 40μL sample diluent) to the ELISA plate, then add 100μL of the detection antibody labeled with horseradish peroxidase to each well, cover with a plate sticker, and incubate at 37℃ for 1h; ③ Discard the liquid in the well, wash the plate 5 times, soaking for 1min each time; ④ Add 50μL of substrate A and B to each well, color at 37℃ in the dark for 15min, then add 50μL of stop solution to terminate the reaction; ⑤ Within 5min after the reaction is terminated, use an ELISA reader to measure the OD value of each well at a wavelength of 450nm. The changes in serum D-lactic acid, IgA and IgG levels in the control group, copper sulfate group, spermidine group and copper sulfate + spermidine group are shown in the figure below. Fig.13 As shown, Fig.13 In the figure, from A to C are the changes in serum D-lactic acid, IgA and IgG levels. The changes in small intestinal MDA content in the control group, copper sulfate group, spermidine group and copper sulfate + spermidine group are shown in the figure. Fig.14 As shown, Fig.14In the figure, A to C are the MDA contents in the duodenum, jejunum and ileum, respectively.

[0086] Depend on Fig.13 and Fig.14 It can be seen that copper sulfate can significantly increase the level of D-lactic acid in serum and the accumulation of MDA in the duodenum and jejunum (P<0.05), while after spermidine treatment, the level of D-lactic acid in serum and the content of MDA in the duodenum and jejunum were significantly reduced (P<0.05). In addition, spermidine significantly increased the levels of IgA and IgG in serum. The above results indicate that spermidine can effectively alleviate the intestinal barrier damage caused by copper sulfate.

[0087] In summary, spermidine can alleviate liver copper death caused by copper explosion and intestinal tissue structure damage caused by copper exposure.

[0088] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. Application of spermidine in the preparation of drugs for alleviating copper exposure damage.

2. The use according to claim 1, characterized in that The concentration of spermidine in the medicine is 2.5-3.5 mmol / L.

3. The use according to claim 1 or 2, characterized in that: The drug is administered orally.

4. The use according to claim 1, characterized in that The copper exposure is copper exposure caused by a concentration of 30-40 mg / kg copper.

5. The use according to claim 1, characterized in that The damage is liver damage and / or intestinal damage induced by copper exposure.

6. The use according to claim 1, characterized in that The application is at least one of the following (1)-(5): (1) Inhibit the accumulation of copper ions in the body caused by copper exposure; (2) inhibiting copper death in the liver caused by copper exposure; (3) Improve the liver's ability to metabolize copper; (4) Alleviate liver damage caused by copper exposure; (5) Alleviate intestinal damage caused by copper exposure.

7. A drug for alleviating copper exposure damage, characterized in that: The invention comprises the spermidine as claimed in claim 1 and pharmaceutically acceptable excipients.

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