Use of maltopentaose in the preparation of a drug for preventing or treating myocardial ischemia-reperfusion injury complicated by diabetes

Abstract

The application discloses application of maltopentaose in preparation of a medicine for preventing or treating diabetes complicated with myocardial ischemia-reperfusion injury, and belongs to the technical field of biological medicine. Research results show that maltopentaose can improve the left ventricular ejection fraction and left ventricular short axis shortening rate of a model mouse, reduce myocardial tissue pathological injury, reduce myocardial infarction area and reduce myocardial cell apoptosis when the maltopentaose is given to the model mouse in the body of the model mouse with diabetes complicated with myocardial ischemia-reperfusion injury, thereby playing a role in prevention and treatment of the diabetes complicated with myocardial ischemia-reperfusion injury. In conclusion, the maltopentaose can be used as an effective component of the medicine for preventing or treating the diabetes complicated with myocardial ischemia-reperfusion injury, and provides a new strategy for preparation of a medicine for preventing and treating dilated cardiomyopathy.

Description

Technical Field

[0001] This invention relates to the application of Maltopentaose in the preparation of drugs for the prevention or treatment of myocardial ischemia-reperfusion injury complicated by diabetes, and belongs to the field of biomedical technology. Background Technology

[0002] Myocardial ischemia-reperfusion injury is caused by impaired cellular metabolism and tissue damage during reperfusion therapy to restore blood supply to ischemic myocardium. Diabetes disrupts cellular protective signals, increasing the myocardium's sensitivity to acute myocardial injury, thus making the damage after ischemia-reperfusion more severe and more difficult to treat. This disease is characterized by myocardial infarction accompanied by decreased ventricular systolic function, reduced left ventricular ejection fraction, and decreased left ventricular fractional shortening. The disease has an acute onset, and death can occur at any stage of the disease.

[0003] Currently, several drugs are being investigated to mitigate myocardial ischemia-reperfusion injury, such as antioxidants, inflammation inhibitors, and apoptosis inhibitors. Cardioprotective procedures, including coronary artery bypass grafting, cardiac hormone injections, and cryotherapy, protect the myocardium by reducing cellular damage caused by ischemia-reperfusion. Researchers are developing new monitoring methods, including myocardial enzyme marker detection, myocardial imaging, and biomarker analysis, to assess the extent of myocardial reperfusion injury and predict patient prognosis. Strategies for preventing myocardial reperfusion injury include improving preoperative management, reducing myocardial ischemia time, and increasing myocardial blood flow and oxygenation levels. In summary, researchers are exploring comprehensive treatment strategies that combine drug therapy, cardioprotective procedures, and reperfusion injury monitoring to minimize myocardial ischemia-reperfusion injury. However, overall, current treatment measures do not meet clinical needs for the prevention and treatment of myocardial ischemia-reperfusion injury in diabetic patients. Finding new therapeutic targets is of significant clinical and scientific importance for the prevention and treatment of myocardial ischemia-reperfusion injury in diabetic patients. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides the application of Maltopentaose in the preparation of drugs for the prevention or treatment of myocardial ischemia-reperfusion injury complicated by diabetes. Maltopentaose is the shortest oligosaccharide among maltodextrins, primarily used in studies of α-lactalbumin glycosylation and phosphorylation, and is currently frequently applied to the regulation of gut microbiota.

[0005] The first objective of this invention is to provide the use of Maltopentaose in the preparation of medicaments for the prevention or treatment of myocardial ischemia-reperfusion injury complicated by diabetes.

[0006] In one embodiment, the Maltopentaose has a CAS number of 34620-76-3 and a structural formula as follows:

[0007]

[0008] In one embodiment, the characteristics of the diabetic myocardial ischemia-reperfusion injury include, but are not limited to, increased oxidative stress, cardiomyocyte apoptosis, and impaired cardiac function.

[0009] In one embodiment, the drug is a drug that reduces oxidative stress, reduces cardiac function impairment, reduces cardiomyocyte apoptosis, reduces myocardial infarction, and reverses myocardial damage.

[0010] In one embodiment, the reduction of impaired cardiac function includes, but is not limited to, reversing the reduction in left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) caused by diabetic myocardial ischemia-reperfusion injury.

[0011] In one embodiment, the reduction of myocardial infarction and reversal of myocardial damage includes, but is not limited to, reducing the levels of CK-MB, LDH, and c-TnL.

[0012] In one embodiment, the drug contains the aforementioned pharmaceutical ingredients and pharmaceutically acceptable excipients.

[0013] In one embodiment, the excipients include any one or a combination of at least two of the following: carrier, diluent, excipient, filler, binder, wetting agent, disintegrant, emulsifier, cosolvent, solubilizer, osmotic pressure regulator, surfactant, coating material, colorant, pH adjuster, antioxidant, antibacterial agent, or buffer.

[0014] In one embodiment, the carrier is one or more of a virus, liposomes, and nanoparticles.

[0015] In one embodiment, the excipient is one or more of mannitol, lactose, fatty acids, and polyethylene glycol.

[0016] In one embodiment, the dosage form of the drug includes any one of drops, oral liquid, tablets, capsules, granules, films, gels, powders, emulsions, pellets, or solutions.

[0017] In one embodiment, the route of administration of the drug includes oral administration, sublingual administration, rectal administration, skin / mucous membrane administration, inhalation administration, or injection administration.

[0018] A second objective of this invention is to provide a medicament for the prevention or treatment of myocardial ischemia-reperfusion injury complicated by diabetes, wherein the active ingredient of the medicament includes Maltopentaose.

[0019] In one embodiment, the drug contains the aforementioned pharmaceutical ingredients and pharmaceutically acceptable excipients.

[0020] In one embodiment, the excipients include any one or a combination of at least two of the following: carrier, diluent, excipient, filler, binder, wetting agent, disintegrant, emulsifier, cosolvent, solubilizer, osmotic pressure regulator, surfactant, coating material, colorant, pH adjuster, antioxidant, antibacterial agent, or buffer.

[0021] In one embodiment, the carrier is one or more of a virus, liposomes, and nanoparticles.

[0022] In one embodiment, the excipient is one or more of mannitol, lactose, fatty acids, and polyethylene glycol.

[0023] In one embodiment, the dosage form of the drug includes any one of drops, oral liquid, tablets, capsules, granules, films, gels, powders, emulsions, pellets, or solutions.

[0024] In one embodiment, the route of administration of the drug includes oral administration, sublingual administration, rectal administration, skin / mucous membrane administration, inhalation administration, or injection administration.

[0025] In one embodiment, the drug of the present invention has at least one or more of the following functions:

[0026] (1) Reverse the decrease in left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) caused by myocardial ischemia-reperfusion injury complicated by diabetes;

[0027] (2) Reduce the levels of CK-MB, LDH, and c-Tnl;

[0028] (3) Reduce cardiomyocyte apoptosis and oxidative damage;

[0029] (4) Reduce oxidative stress and decrease ROS production;

[0030] (5) Reduce the area of ​​myocardial infarction.

[0031] Beneficial effects:

[0032] This invention reveals that Maltopentaose can improve cardiac function in diabetic mice with myocardial ischemia-reperfusion injury, reverse the decrease in left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) caused by diabetic myocardial ischemia-reperfusion injury, reduce cardiomyocyte apoptosis, and decrease the levels of myocardial infarction markers CK-MB, LDH, and c-Tnl, thereby reducing the infarct area. This provides a new target for the preparation of drugs to prevent and treat diabetic myocardial ischemia-reperfusion injury. Attached Figure Description

[0033] Figure 1 Figure 1 shows the effect of Maltopentaose on improving cardiac function in diabetic mice with myocardial ischemia-reperfusion injury. (A) Left ventricular ejection fraction (EF); (B) Left ventricular fractional shortening (FS); (C) Serum levels of myocardial infarction markers CK-MB, LDH, and c-TnL. *p < 0.05 vs. Sham.

[0034] Figure 2 Images showing the effect of Maltopentaose on improving cardiac injury in diabetic mice with myocardial ischemia-reperfusion injury. (A) HE staining of cardiac sections; (B) DHE staining of cardiac sections; (C) PI staining of cardiac sections.

[0035] Figure 3 Image showing the effect of Maltopentaose on improving myocardial infarction level in diabetic mice with myocardial ischemia-reperfusion injury. Left image shows TTC staining; right image shows the statistical distribution of myocardial infarction area. *p < 0.05 vs. Sham. Detailed Implementation

[0036] To further illustrate the technical means and effects adopted by the present invention to achieve its intended purpose, the specific embodiments, structures, features, and effects of the present invention will be described in detail below with reference to the accompanying drawings and preferred embodiments. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available.

[0037] Maltopentaose was purchased from MCE (HY-N1495).

[0038] Example 1: Validating the role of Maltopentaose in diabetic myocardial ischemia-reperfusion injury

[0039] Male C57BL / 6 mice were purchased from Sberford (Beijing) Biotechnology Co., Ltd. All mice were housed in specific pathogen-free microisolation cages with free access to food and water. Animals were housed in a temperature- and humidity-controlled room with a 12-hour light / dark cycle. Male C57BL / 6 mice were divided into three groups. Two groups were induced into diabetic mice by intraperitoneal injection of 0.2% streptozotocin at a dose of 50 mg / kg for 5 consecutive days. Three days after the injection, random blood glucose levels were measured; mice with a blood glucose concentration ≥16.7 mmol / L were considered to have successfully established the model. The normal control group received an equal volume of citrate buffer (Sham group). The two groups of mice with successfully established diabetic models were injected with Maltopentaose (30 mg / kg) and an equal volume of physiological saline, respectively. One day later, the blood supply to the myocardium was blocked by ligation of the left anterior descending coronary artery, causing myocardial ischemia for 30 minutes, followed by reperfusion for 24 hours. These were the DI / R+Maltopentaose group and the DI / R group (diabetic complication of myocardial ischemia-reperfusion model). To test cardiac function, mice were euthanized, and blood samples and heart tissue were collected for biochemical analysis.

[0040] Transthoracic echocardiography was performed on mice using a Vevo 2100 high-resolution imaging system (Visualsonics, Toronto, ON, Canada) and its 30MHz probe. Mice were fully anesthetized with isoflurane and placed on a heated pad, with the chest positioned to expose the probe to the ultrasound. Ultrasound gel was applied to the mouse's chest, and the probe was placed over the gel-coated area. The Vevo 2100 system was then activated for image acquisition. Left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) were measured. Figure 1 AB analysis showed that the ejection fraction (EF) and fulminant ejection fraction (FS) of the normal control group (Sham group) were 74.65±7.30% and 41.68±5.23%, respectively; while the EF and FS of the diabetic myocardial ischemia-reperfusion model mice (DI / R group) were 52.10±6.49% and 26.61±3.56%, respectively, significantly lower than the control group; and the EF and FS of the DI / R+Maltopentaose group were 64.81±4.43% and 35.65±2.03%, respectively, significantly higher than the DI / R group. This indicates that EF and FS were significantly restored in mice with diabetic myocardial ischemia-reperfusion after Maltopentaose administration. These results demonstrate that Maltopentaose can improve left ventricular ejection fraction and left ventricular fractional shortening in mice, thus alleviating cardiac dysfunction.

[0041] Mouse blood samples were left to stand at room temperature for 2 hours, then centrifuged at 3000 rpm for 10 minutes to obtain the supernatant serum. Lactate dehydrogenase (LDH), creatine phosphorylase-isoenzyme MB (CK-MB), and troponin I (c-Tnl) kits were purchased from Nanjing Jiancheng Biotechnology Co., Ltd., and the tests were performed strictly according to the instructions of the corresponding ELISA kits. Figure 1 C indicates that LDH levels in the DI / R group increased 2.4-fold compared to the Sham group, while they decreased by 50% in the DI / R+Maltopentaose group. CK-MB levels in the DI / R group increased 1-fold compared to the Sham group, while they decreased by 40% in the DI / R+Maltopentaose group, approaching the control group level. c-TnL levels in the DI / R group increased 2-fold compared to the Sham group, while they decreased by 40% in the DI / R+Maltopentaose group. In summary, this invention, through ELISA detection of myocardial infarction markers CK-MB, LDH, and c-TnL levels in mouse serum, found that Maltopentaose can reduce the expression levels of these markers.

[0042] like Figure 2 As shown, the hearts of the three groups of mice were taken and subjected to HE (hematologic reaction) analysis. Figure 2 A) DHE( Figure 2 B) and PI staining ( Figure 2 C). HE staining revealed significant pathological damage to the myocardium in the DI / R group mice, while the DI / R+Maltopentaose group improved this myocardial pathological damage. DHE staining showed that, compared to the normal control group, the ROS level in the hearts of diabetic mice with myocardial ischemia-reperfusion model was significantly increased, and ROS levels decreased after Maltopentaose treatment. PI staining relative fluorescence intensity statistics indicated that the number of live cells and the number of dead cells in the hearts of diabetic mice with myocardial ischemia-reperfusion model were reduced, while the number of live cells and the number of dead cells increased in mice treated with Maltopentaose. In summary, this invention found that oxidative stress in cardiomyocytes of diabetic mice with myocardial ischemia-reperfusion model is increased, leading to apoptosis, and that Maltopentaose can improve myocardial pathological damage in the model mice and reduce cardiomyocyte apoptosis and oxidative damage.

[0043] The hearts of the three groups of mice were stained with TTC and statistically analyzed to assess myocardial ischemia damage. Ischemic or necrotic tissue, due to the loss of dehydrogenase activity, was not stained by TTC and appeared pale white. Figure 3 As shown, this invention found that Maltopentaose significantly reduced the myocardial infarction area in diabetic mice with myocardial ischemia-reperfusion injury by approximately 40%.

[0044] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. Application of Maltopentaose in the preparation of drugs for the prevention of myocardial ischemia-reperfusion injury in diabetic patients.

2. The application according to claim 1, characterized in that, The CAS number of Maltopentaose is 34620-76-3, and its structural formula is: 。 3. The application according to claim 1, characterized in that, The characteristics of diabetic myocardial ischemia-reperfusion injury include increased oxidative stress, cardiomyocyte apoptosis, and impaired cardiac function.

4. The application according to claim 1, characterized in that, The drug is in the form of a solution.

5. The application according to claim 1, characterized in that, The drug consists of the active ingredient Maltopentaose and pharmaceutically acceptable excipients.

6. The application according to claim 5, characterized in that, The auxiliary materials include a carrier.

7. The application according to claim 5, characterized in that, The excipients include any one or a combination of at least two of the following: fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, antioxidants, or buffers.

8. The application according to claim 1, characterized in that, The drug can be administered via injection.

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