Application of calcium dobesilate in preparation of medicine for treating and / or preventing indoor conduction block caused by diabetes

Abstract

The invention provides application of calcium dobesilate in preparation of a medicine for treating and / or preventing indoor conduction block caused by diabetes mellitus. The invention provides a non-invasive method capable of actively improving the heart conduction function for treating and / or preventing the indoor conduction block caused by diabetes, and the method is excellent in safety and effectiveness.

Description

Technical Field

[0001] This application relates to the field of biomedical technology, specifically to the use of calcium dobesilate in the preparation of medicaments for the treatment and / or prevention of intraventricular conduction block caused by diabetes. Background Technology

[0002] Diabetes mellitus is a chronic disease characterized primarily by disordered glucose metabolism. Studies have shown that prolonged hyperglycemia can lead to abnormalities in the cardiac electrical conduction system, with intraventricular conduction block being particularly typical. Clinical features of intraventricular conduction block include widened QRS complexes, bundle branch block, or nonspecific intraventricular block. Intraventricular conduction block can cause asynchronous ventricular contraction, significantly worsening cardiac function and substantially increasing the risk of complete atrioventricular block, malignant arrhythmias, and sudden cardiac death.

[0003] Currently, clinical treatments for intraventricular conduction block caused by diabetes are mainly divided into drug therapy and device therapy, but both have significant limitations. First, drug therapy primarily focuses on strict blood glucose control and improving heart failure symptoms. Although novel drugs such as sodium-glucose cotransporter 2 (SGLT-2) inhibitors have shown potential in improving cardiovascular outcomes, these drugs mainly act on metabolic regulation or hemodynamic improvement, lacking the ability to intervene in the specific molecular targets that cause intraventricular conduction block. For existing conduction block, current drugs are unlikely to achieve pathological reversal and cannot effectively prevent its progression. Second, for severe conduction block, implantation of pacemakers or cardiac resynchronization therapy (CRT) is often used clinically. However, these treatments are invasive surgeries with risks such as infection and electrode dislocation, and the equipment is expensive, placing a heavy economic burden on patients and society. More importantly, pacemakers only provide passive electrophysiological support and cannot block the continuous damage to the myocardium and conduction system caused by diabetes at the pathophysiological level.

[0004] Therefore, there is a need for a novel therapeutic drug that can precisely target key proteins in the cardiac conduction system and block the process of intraventricular conduction block caused by diabetes at the molecular level. Summary of the Invention

[0005] In view of this, this application provides the use of calcium dobesilate in the preparation of medicaments for the treatment and / or prevention of intraventricular conduction block caused by diabetes.

[0006] In one aspect, this application provides the use of calcium dobesilate in the preparation of medicaments for the treatment and / or prevention of intraventricular conduction block caused by diabetes.

[0007] Optionally, the calcium dobesilate inhibits O-GlcNAc glycosylation of the XIRP2 protein, treating and / or preventing intraventricular conduction block caused by diabetes.

[0008] Optionally, the calcium dobesilate may be used as a single active ingredient or in combination with other pharmaceutically acceptable active ingredients to constitute the drug for treating and / or preventing intraventricular conduction block caused by diabetes.

[0009] Optionally, the calcium dobesilate content in the drug for treating and / or preventing intraventricular conduction block caused by diabetes is 0.01%-100%.

[0010] Optionally, the medicament for treating and / or preventing intraventricular conduction block caused by diabetes may also include pharmaceutically acceptable carriers and / or excipients.

[0011] Optionally, the carrier may include one or more of solvents, polymers, and liposomes.

[0012] Optionally, the excipients include at least one of a diluent and a stabilizer.

[0013] Optionally, the form of the drug for treating and / or preventing intraventricular conduction block caused by diabetes includes at least one of the following: injection, tablet, granule, capsule, oral liquid, and pill.

[0014] Optionally, the medication for treating and / or preventing intraventricular conduction block caused by diabetes is administered orally or by injection.

[0015] Secondly, this application provides a medicament for treating and / or preventing intraventricular conduction block caused by diabetes, including calcium dobesilate.

[0016] Thirdly, this application provides the use of calcium dobesilate in the preparation of O-GlcNAc glycosylation inhibitors for XIRP2 protein.

[0017] Fourthly, this application provides an O-GlcNAc glycosylation inhibitor for the XIRP2 protein, comprising calcium dobesilate.

[0018] This application provides the use of calcium dobesilate in the preparation of drugs for the treatment and / or prevention of intraventricular conduction block caused by diabetes. It overcomes the shortcomings of existing drugs that lack specificity and the shortcomings of cardiac pacemakers that are invasive and only have a passive support function. It is a new non-invasive therapy that can actively improve cardiac conduction function, which is safer and more effective and is beneficial for the treatment and / or prevention of intraventricular conduction block caused by diabetes. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below. The specific embodiments described herein are merely illustrative of this application and are not intended to limit this application.

[0020] Figure 1 This is a computer simulation of the binding model between calcium dobesilate and the XIRP2 protein.

[0021] Figure 2 Image showing the results of HE staining.

[0022] Figure 3 Image showing the results of staining with arbutin.

[0023] Figure 4 This is a transmission electron microscope (TEM) result image.

[0024] Figure 5 This is a heat conduction diagram.

[0025] Figure 6 This is a graph showing the heart rate monitoring results.

[0026] Figure 7 This is a graph showing the results of the conduction time detection.

[0027] Figure 8 This is a graph showing the results of the conduction velocity test.

[0028] Figure 9 This is a graph showing the results of the dispersion index.

[0029] Figure 10 This is a comparison diagram of field potentials.

[0030] Figure 11 This is a diagram showing the results of the immunoprecipitation. Detailed Implementation

[0031] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0032] This application discloses the use of calcium dobesilate in the preparation of medicaments for the treatment and / or prevention of intraventricular conduction block caused by diabetes. This application provides a new approach to the treatment and / or prevention of intraventricular conduction block caused by diabetes, overcoming the shortcomings of existing drugs lacking specificity and the invasive and passively supportive nature of pacemakers. The administration of calcium dobesilate is a novel, non-invasive therapy that actively improves cardiac conduction function, is safer and more effective, can slow disease progression and reduce reliance on expensive medical devices, and reduces the risk of sudden cardiac death, thus benefiting the treatment and / or prevention of intraventricular conduction block caused by diabetes.

[0033] In some embodiments of this application, calcium dobesilate inhibits O-GlcNAc glycosylation of the XIRP2 protein, treating and / or preventing intraventricular conduction block caused by diabetes. O-GlcNAc glycosylation is a type of glycosylation modification, referring to the O-glycosidic bond between N-acetylglucosamine (GlcNAc) and the hydroxyl group of serine / threonine residues in a protein. Previous studies have found that abnormally elevated levels of O-GlcNAc glycosylation in the XIRP2 protein within cardiomyocytes are a key molecular mechanism leading to intraventricular conduction block. Calcium dobesilate can inhibit excessive O-GlcNAc glycosylation of the XIRP2 protein, blocking the process of intraventricular conduction block caused by diabetes at the molecular level, thus achieving the effect of treating and / or preventing intraventricular conduction block caused by diabetes. This provides precise intervention targeting key pathological links in intraventricular conduction block and offers a new approach for the clinical treatment of intraventricular conduction block caused by diabetes.

[0034] In some embodiments of this application, calcium dobesilate is used as a single active ingredient or in combination with other pharmaceutically acceptable active ingredients to constitute a medicament for treating and / or preventing intraventricular conduction block caused by diabetes. In some embodiments, calcium dobesilate is the sole active ingredient of the medicament for treating and / or preventing intraventricular conduction block caused by diabetes. In other embodiments, calcium dobesilate is used in combination with other pharmaceutically acceptable active ingredients to constitute a medicament for treating and / or preventing intraventricular conduction block caused by diabetes, which is beneficial for treating and / or preventing intraventricular conduction block caused by diabetes through multiple pathways, thereby improving the therapeutic and / or preventive effects of intraventricular conduction block caused by diabetes. The other pharmaceutically acceptable active ingredients have the effect of treating and / or preventing intraventricular conduction block caused by diabetes.

[0035] In this application, the dosage of calcium dobesilate in the drug for treating and / or preventing intraventricular conduction block caused by diabetes is determined based on the drug tolerance and severity of the disease in the recipient. The drug for treating and / or preventing intraventricular conduction block caused by diabetes only needs to contain a therapeutically effective amount of calcium dobesilate. In some embodiments of this application, the mass content of calcium dobesilate in the drug for treating and / or preventing intraventricular conduction block caused by diabetes is 0.01%-100%. For example, the mass content of calcium dobesilate in the drug for treating and / or preventing intraventricular conduction block caused by diabetes can be, but is not limited to, 0.01%, 0.05%, 0.08%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the mass content of calcium dobesilate in drugs for treating and / or preventing intraventricular conduction block caused by diabetes may be 0.1%-90%.

[0036] In some embodiments of this application, the medicament for treating and / or preventing intraventricular conduction block caused by diabetes further includes a pharmaceutically acceptable carrier and / or excipient. The pharmaceutically acceptable carrier and / or excipient are used to transport, stabilize, and dilute calcium dobesilate, enabling calcium dobesilate to exert its intended effect. The carrier, excipient, and calcium dobesilate are compatible and do not affect the activity of calcium dobesilate. Furthermore, the carrier and excipient are non-toxic and do not react with calcium dobesilate to cause toxic side effects.

[0037] In some embodiments of this application, the carrier includes at least one of a solvent, a polymer, and liposomes. Exemplarily, the solvent may include, but is not limited to, water, physiological saline, and at least one of other non-aqueous solvents; the polymer may include, but is not limited to, polylysine, polyethyleneimine and its modified forms, polyamide-amine dendritic polymers and their derivatives, polypropyleneimine and its derivatives, chitosan, polylactic-glycolic acid, polylactic acid, gelatin, cyclodextrin, sodium alginate, albumin, and hemoglobin; the liposomes may be formed by the self-assembly of cationic lipids, neutral accessory lipids, cholesterol, and phospholipids, or by distearate phosphatidylethanolamine-polyethylene glycol intercalating into a phospholipid layer formed by phospholipid molecules. In this application, calcium dobesilate can be dispersed or adsorbed in the above-mentioned carrier to form a dispersion system, or it can be encapsulated by the above-mentioned liposomes and polymers to form a spherical structure, allowing for sustained-release, controlled-release, or targeted release of drugs for treating and / or preventing intraventricular conduction block caused by diabetes.

[0038] In some embodiments of this application, the excipients include at least one of a diluent and a stabilizer. For example, the diluent may include, but is not limited to, at least one of starches, sugars, celluloses, and inorganic salts, such as a binder, filler, disintegrant, or lubricant in tablets; wine, vinegar, or medicinal juice in pills; and the base portion in semi-solid preparations such as ointments and creams. The stabilizer may include, but is not limited to, at least one of preservatives, antioxidants, solubilizers, and emulsifiers.

[0039] In some embodiments of this application, the form of the drug for treating and / or preventing intraventricular conduction block caused by diabetes includes at least one of the following: injection, tablet, granule, capsule, oral liquid, and pill. The specific form of the drug depends on the actual application requirements, such as different forms of sustained-release formulations.

[0040] In some embodiments of this application, the medication for treating and / or preventing intraventricular conduction block caused by diabetes is administered orally or by injection. When administered orally, the dosage form of the medication for treating and / or preventing intraventricular conduction block caused by diabetes can be solid or liquid. In some embodiments, injection can be administered, but is not limited to, intraperitoneal injection, subcutaneous injection, intramuscular injection, or intravenous injection; such as continuous delivery via an implantable sustained-release pump. In other embodiments, the medication for treating and / or preventing intraventricular conduction block caused by diabetes can be dissolved in a solvent, such as water or saline, which facilitates drug injection. In still other embodiments, the medication for treating and / or preventing intraventricular conduction block caused by diabetes can be used via local or systemic administration.

[0041] This application provides a medicament for treating and / or preventing intraventricular conduction block caused by diabetes, comprising calcium dobesilate. The mass content of calcium dobesilate, pharmaceutically acceptable carriers and / or excipients, and the form of the medicament for treating and / or preventing intraventricular conduction block caused by diabetes are as described above and will not be repeated here.

[0042] This application discloses the use of calcium dobesilate in the preparation of an O-GlcNAc glycosylation inhibitor for XIRP2 protein. Calcium dobesilate can specifically target the XIRP2 protein and reduce the O-GlcNAc glycosylation modification level of the XIRP2 protein, and can be used as an O-GlcNAc glycosylation inhibitor for the XIRP2 protein.

[0043] In some embodiments of this application, calcium dobesilate serves as a single active ingredient or constitutes an O-GlcNAc glycosylation inhibitor of the XIRP2 protein, either as a single active ingredient or in combination with other pharmaceutically acceptable active ingredients. In some embodiments, calcium dobesilate serves as the sole active ingredient in the O-GlcNAc glycosylation inhibitor of the XIRP2 protein. In other embodiments, calcium dobesilate, in combination with other pharmaceutically acceptable active ingredients, constitutes an O-GlcNAc glycosylation inhibitor of the XIRP2 protein, which is beneficial for inhibiting O-GlcNAc glycosylation of the XIRP2 protein through multiple pathways. These other pharmaceutically acceptable active ingredients have the effect of inhibiting O-GlcNAc glycosylation of the XIRP2 protein.

[0044] In this application, the amount of calcium dobesilate in the O-GlcNAc glycosylation inhibitor of XIRP2 protein is determined based on the drug tolerance and disease severity of the recipient. The O-GlcNAc glycosylation inhibitor of XIRP2 protein only needs to contain a therapeutically effective amount of calcium dobesilate. In some embodiments of this application, the mass content of calcium dobesilate in the O-GlcNAc glycosylation inhibitor of XIRP2 protein is 0.01%-100%. For example, the mass content of calcium dobesilate in the O-GlcNAc glycosylation inhibitor of XIRP2 protein can be, but is not limited to, 0.01%, 0.05%, 0.08%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the mass content of calcium dobesilate in the O-GlcNAc glycosylation inhibitor of XIRP2 protein can be 0.1%-90%.

[0045] In some embodiments of this application, the O-GlcNAc glycosylation inhibitor of the XIRP2 protein further includes a pharmaceutically acceptable carrier and / or excipient. The pharmaceutically acceptable carrier and / or excipient are used to transport, stabilize, and dilute calcium dobesilate, enabling calcium dobesilate to exert its intended effect. The carrier, excipient, and calcium dobesilate are compatible and do not affect the activity of calcium dobesilate. Furthermore, the carrier and excipient are non-toxic and do not react with calcium dobesilate to cause toxic side effects.

[0046] In some embodiments of this application, the carrier includes at least one of a solvent, a polymer, and liposomes. Exemplarily, the solvent may include, but is not limited to, water, physiological saline, and at least one of other non-aqueous solvents; the polymer may include, but is not limited to, polylysine, polyethyleneimine and its modified forms, polyamide-amine dendritic polymers and their derivatives, polypropyleneimine and its derivatives, chitosan, polylactic-glycolic acid, polylactic acid, gelatin, cyclodextrin, sodium alginate, albumin, and hemoglobin; the liposomes may be formed by the self-assembly of cationic lipids, neutral accessory lipids, cholesterol, and phospholipids, or by distearate phosphatidylethanolamine-polyethylene glycol intercalating into a phospholipid layer formed by phospholipid molecules. In this application, calcium dobesilate can be dispersed or adsorbed in the above-mentioned carrier to form a dispersion system, or it can be encapsulated by the above-mentioned liposomes and polymers to form a spherical structure. The O-GlcNAc glycosylation inhibitor of XIRP2 protein can be released in a sustained, controlled, or targeted manner.

[0047] In some embodiments of this application, the excipients include at least one of a diluent and a stabilizer. For example, the diluent may include, but is not limited to, at least one of starches, sugars, celluloses, and inorganic salts, such as a binder, filler, disintegrant, or lubricant in tablets; wine, vinegar, or medicinal juice in pills; and the base portion in semi-solid preparations such as ointments and creams. The stabilizer may include, but is not limited to, at least one of preservatives, antioxidants, solubilizers, and emulsifiers.

[0048] In some embodiments of this application, the O-GlcNAc glycosylation inhibitor of the XIRP2 protein is in the form of at least one of injections, tablets, granules, capsules, oral liquids, and pills. The specific form of the drug depends on the actual application requirements, such as different forms of sustained-release formulations.

[0049] In some embodiments of this application, the O-GlcNAc glycosylation inhibitor of the XIRP2 protein is administered orally or by injection. When administered orally, the dosage form of the O-GlcNAc glycosylation inhibitor of the XIRP2 protein can be solid or liquid. In some embodiments, injection can be administered, but is not limited to, intraperitoneal injection, subcutaneous injection, intramuscular injection, or intravenous injection; such as continuous delivery via an implantable sustained-release pump. In other embodiments, the O-GlcNAc glycosylation inhibitor of the XIRP2 protein can be dissolved in a solvent, such as water or saline, which facilitates drug injection. In still other embodiments, the O-GlcNAc glycosylation inhibitor of the XIRP2 protein can be used via local or systemic administration.

[0050] This application provides an O-GlcNAc glycosylation inhibitor for the XIRP2 protein, comprising calcium dobesilate. The mass content of calcium dobesilate in the O-GlcNAc glycosylation inhibitor of the XIRP2 protein, the pharmaceutically acceptable carrier and / or excipients, and the form of the drug are as described above and will not be repeated here.

[0051] The following specific examples further illustrate the effects of the technical solution in this application.

[0052] Experiment 1: Drug screening based on virtual molecular docking technology.

[0053] Computer-aided drug design technology was used to screen for drugs targeting the O-GlcNAc modification site of XIRP2, a key pathogenic protein in diabetic intraventricular conduction block. First, a batch of compounds were obtained from the FDA Compound Library and imported into ChemBio3D 14.0 software for batch conformational adjustments and energy optimization calculations. Then, the 3D crystal structure of XIRP2 protein downloaded from the Uniprot database was processed using AutoDock Tools 1.5.6. Water molecules and organic matter in the XIRP2 protein were removed using Pymol 2.6.1, and the XIRP2 protein was then imported into AutoDock Tools 1.5.6 for hydrogenation, charge distribution, and atomic addition. Finally, virtual screening was performed using AutoDock Vina, and the docking results were plotted using Pymol 2.6.1.

[0054] Screening revealed that calcium dobesilate has an excellent binding energy to XIRP2 protein (-6.994 kcal / mol), and calcium dobesilate may also bind to the active capsule of XIRP2 protein. Figure 1 This is a computer-simulated model of the binding between calcium dobesilate and the XIRP2 protein. Calcium dobesilate (blue-green) forms four hydrogen bonds with THR-1517 (threonine at position 1517), CYS-1518 (cysteine ​​at position 1518), and ILE-1519 (isoleucine at position 1519) on the XIRP2 protein (blue). In the diagram, "2.6", "2.9", and "3.2" represent the spatial distance (in Å) between the two atoms at the ends of the yellow dashed lines. These interactions are crucial for the stability between the protein and its ligand and can significantly affect their biological functions.

[0055] Understandably, this application is not limited to classic structure-based docking and specific AutoDock Vina software. Other computational chemistry strategies such as ligand-based drug design (LBDD) can also be used, or different docking software and scoring functions such as Schrödinger (Glide), Gold, or Dock6 can be used for screening. Furthermore, molecular dynamics simulation techniques can be combined to examine the dynamic stability of the binding between the compound and the target.

[0056] Experiment 2: Animal model construction and grouping for drug administration.

[0057] Healthy male SD rats were selected and fed normally until day 7 for modeling. Rats were fasted for 24 hours prior to modeling but allowed free access to water. On the day of modeling, some rats received a single intraperitoneal injection of streptozotocin (STZ)-containing sodium citrate buffer (14 mg / kg), with an injection dose of 55 mg / kg. Rats with a mean random blood glucose level greater than 16.7 mmol / L at 24 and 72 hours after injection were classified as diabetic rats and included in the STZ group. Simultaneously, some rats received a single intraperitoneal injection of the same volume of STZ-free disodium citrate buffer on the day of modeling, serving as the control group (CON group).

[0058] Understandingly, those skilled in the art can also obtain diabetic animal models through other means, such as SD rat models induced by a high-fat diet combined with low-dose STZ injection, or directly using type II diabetes models with spontaneous gene mutations, such as db / db mice (leptin receptor deficient) or ZDF rats. Furthermore, the species of experimental animals are not limited to rats; other mammalian models such as mice (facilitating gene editing) or rabbits or miniature pigs, which are closer to human cardiac physiology, can also be used for validation.

[0059] Rats were randomly divided into four groups: A. Control group (CON-NC): CON group rats were administered an equal volume of physiological saline by gavage; B. Control group treated with calcium dobesilate (CON-CaD): CON group rats were administered an equal volume of calcium dobesilate solution by gavage; C. Diabetic group (STZ-NC): STZ group rats were administered an equal volume of physiological saline by gavage; D. Diabetic group treated with calcium dobesilate (STZ-CaD): STZ group rats were treated with calcium dobesilate solution by gavage. The gavage dose was 100 mg / kg / day, administered for 2 weeks.

[0060] Experiment 3: Staining and electron microscopy.

[0061] After the drug administration cycle was completed, fresh rat myocardial tissue was collected, fixed in 4% paraformaldehyde, and routinely embedded in paraffin to prepare paraffin sections for hematoxylin-eosin (HE) staining. Figure 2 The images show the results of HE staining. The scale bar for the first row is 200 μm, and the scale bar for the second row is 50 μm. Fresh rat myocardial tissue was fixed in 4% paraformaldehyde and embedded in paraffin to prepare paraffin sections, which were then stained with Masson's solution. Figure 3 The images show the results of Masson staining. The scale bar for the first row is 200 μm, and the scale bar for the second row is 50 μm. From... Figure 2 and Figure 3 It can be seen that the staining results of different groups of rats are similar, and no obvious gross histological changes were observed.

[0062] The microscopic pathological features of the myocardium were analyzed using transmission electron microscopy to further assess the ultra-fine changes in cardiomyocytes and intercalated disc structures. Figure 4 The images show the results of transmission electron microscopy. It can be seen that the STZ-NC group exhibits significant abnormalities in the intercalated disk structure, while the intercalated disk structure in the STZ-CaD group is similar to that in the CON-NC and CON-CaD groups, indicating that calcium dobesilate significantly improves the ultrastructure of the damaged intercalated disks.

[0063] Experiment 4: Assessment of cardiac conduction function.

[0064] After the drug administration cycle, rat hearts were harvested and perfused (Langendorff method). Multichannel electrical mapping technology was then used to assess the conduction function of the rat hearts. By recording and analyzing membrane potential signals, the conduction time, conduction velocity, and conduction dispersion of the rat hearts were accurately detected, comprehensively evaluating the intraventricular conduction function. Understandably, other assessment methods, such as standard surface electrocardiography and in vivo cardiac electrophysiological examinations, can also be used to evaluate cardiac conduction function.

[0065] Figure 5 For heat conduction, Figure 6 This is a graph showing the heart rate monitoring results. Figure 7 This is a graph showing the results of the conduction time detection. Figure 8 This is a graph showing the results of the conduction velocity test. Figure 9 The result is a graph of the dispersion index. Figure 10 This is a comparison graph of field potentials, where ns indicates no significant difference. This indicates that p < 0.05. This indicates that p < 0.01. This indicates that p < 0.001. From Figures 5 to 10It can be seen that, compared with the CON-NC group, the heart conduction function of rats in the CON-CaD group was not significantly abnormal, while the STZ-NC group rats showed obvious conduction dysfunction, indicating that diabetes can lead to intraventricular conduction block. Furthermore, after treatment with calcium dobesilate, the conduction function of rats in the STZ-CaD group was significantly improved, with shortened conduction time, increased conduction velocity, reduced conduction dispersion, and shortened ventricular depolarization and repolarization time, thus improving intraventricular conduction block caused by diabetes.

[0066] Experiment 5. Detection of O-GlcNAc modification level of XIRP2 protein.

[0067] To assess the changes in O-GlcNAc modification levels of XIRP2 in the hearts of STZ rats treated with calcium dobesilate, total myocardial protein was extracted from two groups of rats (STZ-NC group and STZ-CaD group) for co-immunoprecipitation (Co-IP) combined with Western blotting (IB) analysis. Each group was further divided into three subgroups: Input group (positive control), IgG group (negative control), and IP group supplemented with O-GlcNAc antibody (RL2). After elution, the immunoprecipitates were analyzed for XIRP2 protein via IB to detect changes in O-GlcNAc modification levels, with tubulin serving as an internal control. It is understood that adjacent-linked immunosorbent assay (ELISA), mass spectrometry-based proteomics analysis, and enzyme-linked immunosorbent assay (ELISA) can also be used to detect O-GlcNAc modification levels of XIRP2 protein.

[0068] Figure 11 The image shows the results of the co-precipitation immunoprecipitation (Co-IP). The Co-IP results are divided into two parts: the Input group (positive control group) and the IP group (immunoprecipitation group). The IP group includes the IgG group and the anti-O-GlcNAc group. The IgG group is the negative control group, and the anti-O-GlcNAc group is the experimental group. It can be seen that compared with the STZ-NC group, the O-GlcNAc modification level of XIRP2 protein in the heart tissue of rats in the STZ-CaD group was significantly reduced, indicating that calcium dobesilate exerts its effect by inhibiting the O-GlcNAc modification level of XIRP2 protein.

[0069] In summary, calcium dobesilate can target the XIRP2 protein and inhibit the O-GlcNAc of the XIRP2 protein, thus serving as an inhibitor of O-GlcNAc glycosylation of the XIRP2 protein. At the same time, calcium dobesilate improves intraventricular conduction block caused by diabetes and can be used in drugs for the treatment and / or prevention of intraventricular conduction block caused by diabetes.

[0070] The above description represents the preferred embodiments of this application, but should not be construed as limiting the scope of this application. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this application, and these improvements and modifications are also considered to be within the scope of protection of this application.

Claims

1. The use of calcium dobesilate in the preparation of drugs for the treatment and / or prevention of intraventricular conduction block caused by diabetes.

2. The application as described in claim 1, characterized in that, The calcium dobesilate inhibits O-GlcNAc glycosylation of XIRP2 protein, treating and / or preventing intraventricular conduction block caused by diabetes.

3. The application as described in claim 1, characterized in that, The calcium dobesilate, either as a single active ingredient or with other pharmaceutically acceptable active ingredients, constitutes the drug for treating and / or preventing intraventricular conduction block caused by diabetes.

4. The application as described in claim 1, characterized in that, The calcium dobesilate content in the drug for treating and / or preventing intraventricular conduction block caused by diabetes is 0.01%-100%.

5. The application as described in claim 1, characterized in that, The medications for treating and / or preventing intraventricular conduction block caused by diabetes also include pharmaceutically acceptable carriers and / or excipients.

6. The application as described in claim 5, characterized in that, The carrier comprises one or more of solvents, polymers, and liposomes; and / or the excipients comprise at least one of diluents and stabilizers.

7. The application as described in claim 1, characterized in that, The form of the medicine for treating and / or preventing intraventricular conduction block caused by diabetes includes at least one of the following: injection, tablet, granule, capsule, oral liquid, and pill; and / or The medication for treating and / or preventing intraventricular conduction block caused by diabetes is administered orally or by injection.

8. A drug for treating and / or preventing intraventricular conduction block caused by diabetes, characterized in that, Including calcium hydroxybenzenesulfonate.

9. Application of calcium dobesilate in the preparation of O-GlcNAc glycosylation inhibitors for XIRP2 protein.

10. An O-GlcNAc glycosylation inhibitor of XIRP2 protein, characterized in that, Including calcium hydroxybenzenesulfonate.

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