Application of PGC-1alpha in preparation of medicine for treating recurrence of lower limb venous ulcer

Abstract

The invention discloses application of a reagent for detecting PGC-1alpha expression in preparation of a product for diagnosing and treating lower limb vein ulcer. The PGC-1alpha is down-regulated in a lower limb vein ulcer case. The invention further discloses application of the PGC-1alpha in preparation of a medicine for treating recurrence of lower limb venous ulcer. Overexpression of the PGC-1alpha can down-regulate expression of inflammatory factors, relieve limb swelling, ulcer healing and pain and relieve tissue edema. According to the application of the PGC-1alpha in preparation of the medicine for treating relapse of the lower limb vein ulcer, expression of the PGC-1alpha protein in patients with the lower limb vein ulcer is reduced, and experiments prove that the PGC-1alpha protein plays an important role in relapse of the ulcer, clinical symptoms, tissue edema and inflammatory response, and the PGC-1alpha protein can be used for preparing the medicine for treating relapse of the lower limb vein ulcer. The PGC-1 alpha protein is expected to become a new target for treating recurrence of the lower limb vein ulcer, and a treatment strategy aiming at the PGC-1 alpha protein possibly becomes an important direction for preventing recurrence of the lower limb vein ulcer in the future.

Description

Technical Field

[0001] The invention belongs to the technical field of biochemistry, and in particular relates to an application of PGC-1α in preparing a medicine for treating recurrent venous ulcer of lower limbs. Background Art

[0002] Chronic venous disease (CVD) of the lower extremities is a common disease in the field of vascular surgery. The prevalence of venous disease of the lower extremities is about 10%, with nearly 100 million patients. Among them, about 1 / 5 have more serious cases such as pigmentation, itching, skin ulcers, and nodules. So far, the largest international epidemiological survey shows that among people over 50 years old, the incidence of CVD is 65%, and venous ulcers account for 10.3%. Venous ulcers of the lower extremities can generally heal after surgery. Some larger ulcers (ulcers with a maximum diameter of more than 3cm) require skin grafting to heal. According to relevant epidemiological surveys, the recurrence rate of venous ulcers of the lower extremities is about 30% in one year and more than 50% in three years. Therefore, how to avoid the recurrence of venous ulcers of the lower extremities is one of the difficulties in the field of vascular surgery.

[0003] PGC-1α is a nuclear receptor transcription factor that regulates mitochondrial biogenesis and energy metabolism. It can activate the transcription of downstream target genes by interacting with peroxisome proliferator-activated receptor γ (PPARγ), thereby participating in processes such as adipocyte differentiation, lipogenesis, and insulin sensitivity. In terms of venous disease, PGC-1α may participate in the pathogenesis of lower extremity venous disease by affecting the function and structure of vascular endothelial cells. Studies have found that PGC-1α can promote the expression of nitric oxide synthase (eNOS) in endothelial cells and increase the production of nitric oxide (NO), thereby playing a role in vasodilation. In addition, PGC-1α can also inhibit endothelial cell apoptosis and inflammatory response, helping to maintain the normal function of vascular endothelial cells. However, the current research on the relationship between PGC-1α and lower extremity venous disease is still limited.

[0004] Given the increasing prevalence of chronic venous disease in the lower extremities, the development of effective therapeutic drugs for this disease is very important. Therefore, it is urgent to find a drug with a completely new pathway of action in drug treatment. Summary of the invention

[0005] The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, the main purpose of the present invention is to provide an application of PGC-1α in the preparation of a drug for treating recurrent venous ulcers of lower limbs, providing a new target for drugs for treating recurrent venous ulcers of lower limbs.

[0006] The objective of the present invention is achieved through the following technical solutions:

[0007] Use of a reagent for detecting PGC-1α expression in the preparation of a product for diagnosing and treating lower extremity venous ulcers.

[0008] Preferably, the expression of PGC-1α is down-regulated in cases of lower extremity venous ulcers.

[0009] Preferably, the product includes a reagent or drug for detecting the expression level of PGC-1α in lower extremity venous ulcers.

[0010] Preferably, the product includes a gene chip, a kit, a test strip, and a high-throughput sequencing platform.

[0011] Use of PGC-1α in the preparation of a drug for treating recurrence of lower extremity venous ulcers.

[0012] Preferably, the drug further includes a pharmaceutically acceptable carrier, and such carriers include (but are not limited to): diluents, buffers, suspensions, emulsions, granules, encapsulants, excipients, fillers, binders, sprays, transdermal absorbents, wetting agents, disintegrants, absorption promoters, surfactants, coloring agents, flavoring agents, or adsorption carriers.

[0013] The drug of the present invention can be prepared into various dosage forms as needed, including but not limited to tablets, solutions, granules, patches, ointments, capsules, aerosols, or suppositories.

[0014] The administration route of the drug of the present invention is not restricted as long as it can exert the desired therapeutic or preventive effect, including but not limited to oral administration, intravenous injection, intramuscular injection, subcutaneous injection, sublingual administration, rectal perfusion, nasal spray, oral spray, topical or systemic transdermal administration on the skin.

[0015] The drug of the present invention can also be used in combination with other drugs for treating lower extremity venous ulcers, and the combined use of multiple drugs can greatly improve the success rate of treatment.

[0016] The sequence of the PGC-1α protein of the present invention can be queried in a public database, and the specific amino acid sequence is shown as SEQ ID NO.1.

[0017] Compared with the prior art, the present invention has at least the following advantages:

[0018] In the present application, it is down-regulated in patients with lower extremity venous ulcers, and through experiments, it has been verified that in the recurrence of ulcers, clinical symptoms, tissue edema, and inflammatory reactions, the PGC-1α protein plays an important role, and it is expected to become a new target for treating the recurrence of lower extremity venous ulcers. The treatment strategy targeting the PGC-1α protein may become an important direction for preventing the recurrence of lower extremity venous ulcers in the future. Brief Description of the Drawings

[0019] In order to more clearly illustrate the specific embodiments of the present invention, the drawings required for use in the specific embodiments or the description of the prior art will be briefly introduced below.

[0020] Figure 1 This is an immunohistochemical staining diagram of PGC-1α in Example 1 of the present invention for patients with venous lower extremity ulcers;

[0021] Figure 2 The effect of PGC-1α on limb swelling, ulcer healing and pain in patients with venous lower limb ulcers in Example 2 of the present invention;

[0022] Figure 3 This is a graph showing changes in peripheral blood inflammatory factors in patients with venous lower extremity ulcers induced by PGC-1α in Example 3 of the present invention;

[0023] Figure 4 This is a graph showing the effect of PGC-1α on edema of peri-ulcer tissue in patients with venous ulcer of lower limbs in Example 4 of the present invention. DETAILED DESCRIPTION

[0024] The present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments. The following embodiments are only illustrative and not restrictive, and the protection scope of the present invention cannot be limited thereto.

[0025] Unless otherwise specified, the professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the described content can also be applied to the present invention. Unless otherwise specified, the technical means and operating methods used in the following examples are conventional means and methods well known to those skilled in the art, and the raw materials used are all commercially available products.

[0026] The technical scheme of the present invention is further described below in conjunction with the accompanying drawings and embodiments. The experimental methods in the following embodiments without specifying specific conditions are usually carried out according to the conditions described in the conventional conditions or according to the conditions recommended by the manufacturer.

[0027] In the following embodiments, the objects and methods of testing are as follows:

[0028] The clinical data of patients who underwent varicose vein surgery for the lower limbs in our department from October 2021 to July 2022 were collected.

[0029] Patient inclusion criteria: 1. Clear diagnosis of varicose veins of the lower limbs; 2. Clear diagnosis of venous ulcers of the lower limbs; 3. Able to tolerate surgical treatment of varicose veins of the lower limbs and no serious cardiopulmonary disease.

[0030] Patient exclusion criteria: 1. Ulcers caused by trauma or other infections; 2. Diabetes, arterial disease, and skin diseases.

[0031] According to the inclusion and exclusion criteria, a total of 68 patients with varicose veins of the lower extremities were enrolled in the study. After a review one year after surgery, they were divided into two groups according to whether the ulcer recurred, namely the experimental group (ulcer recurrence) and the control group (ulcer did not recur). There was no statistical difference between the two groups in terms of gender, age, symptoms, surgical methods, etc. (P values ​​were all greater than 0.05). Detailed data are shown in Table 1:

[0032] Table 1 Detailed information of the trial patients

[0033]

[0034] Note: The surgical methods include intracavitary radiofrequency fusion + sclerosant injection + perforator ligation / high ligation + sclerosant injection + perforator ligation.

[0035] Example 1: Changes in the expression of PGC-1α in patients with recurrent venous ulcers of the lower limbs

[0036] The application of PGC-1α provided in the present application in the preparation of a drug for treating recurrent venous ulcers of the lower extremities, in this embodiment, the ulcer tissues of the aforementioned 68 ulcer patients were taken for immunohistochemical staining during the debridement of varicose vein surgery of the lower extremities, and detailed immunohistochemical staining and immunofluorescence staining belong to the prior art, so they are not described here. After the immunohistochemical staining of the patient was completed, the immunohistochemical score was performed, and the score was scored according to the staining intensity, with negative 0 points, weak positive 1 point, moderate positive 2 points, and strong positive 3 points, and finally the results of the two groups were statistically analyzed.

[0037] The results are as follows Figure 1 As shown in the figure, we can see that in patients without ulcer recurrence, we found that PGC-1α expression was relatively high, while in recurrent patients, PGC-1α expression was low, and the expression levels (P < 0.05) were statistically different, that is, PGC-1α protein expression was downregulated in patients with lower extremity venous ulcers.

[0038] Example 2: Effect of PGC-1α on clinical symptom changes of recurrent venous ulcer of lower extremity

[0039] In this embodiment, the present application performs routine dressing change, anti-infection, thrombosis prevention and other treatments on two groups of patients after surgery, and the patients are discharged from the hospital after their general condition improves. According to the treatment routine, the patients come to the hospital for follow-up two weeks, one month, three months, six months, and one year after surgery. The follow-up items include recording the clinical symptoms of the patients, mainly recording the relief of several groups of clinical symptoms related to venous ulcers of the lower extremities, including limb swelling, ulcer healing, and pain (swelling definition method: comparison of circumference with the healthy ankle; pain: assessment using a pain scale, 5 points or more is recorded as positive; ulcer: skin wound is not completely healed).

[0040] The results are as follows Figure 2As shown in the figure, it can be seen that the three main symptoms of postoperative swelling, pain, and ulcers in the two groups of patients were alleviated. It was found that the PGC-1α high expression group recovered clinical symptoms significantly earlier than the control group, indicating that PGC-1α is significantly correlated with the recovery of clinical symptoms after varicose vein surgery of the lower limbs.

[0041] Example 3: Effect of PGC-1α on the changes of inflammatory factors in patients with recurrent venous ulcers of the lower limbs

[0042] In this embodiment, the present application draws peripheral blood from patients on the 7th day after surgery, observes the changes in peripheral blood inflammatory factors (IL-6, IL-17, PCT, C-reactive protein), draws a change curve, and compares the relationship between inflammatory factors and ulcer changes in the two groups of patients and the changes in chronic venous disease of the lower extremities. Evaluation criteria, taking the preoperative period as a reference, calculate the percentage of decline on the 7th day after surgery.

[0043] The results are as follows Figure 3 As shown in the figure, it can be seen that by comparing the changes of four inflammatory factors commonly used in clinical practice (IL-6, IL-17, PCT, C-reactive protein), it was found that in the high-expression PGC-1α group, the proportion of inflammatory factors decreased more, indicating that PGC-1α can play a promoting role in the absorption of inflammation in chronic venous disease of the lower limbs.

[0044] Example 4: Effect of PGC-1α on the changes in superficial veins and tissue swelling in the medial malleolus region of patients with recurrent venous ulcers of the lower extremities

[0045] In this embodiment, during the follow-up period, we selected 13 groups (13 patients in the experimental group and 13 patients in the control group) and performed 7T magnetic resonance scanning on the medial malleolus area before surgery, two weeks after surgery, and three weeks after surgery, focusing on the superficial veins and tissue swelling in the medial malleolus area, and comparing the organization and absorption of superficial vein thrombosis in the area around the ulcer, in order to clarify the relationship between ulcer healing and organization and absorption of superficial vein thrombosis.

[0046] The results are as follows Figure 4 As shown in the figure, it can be seen that the degree of edema of the tissue around the ulcer in the PGC-1α high expression group is lower than that in the low expression group.

[0047] In summary, in patients with recurrent ulcers, the expression of PGC-1α protein in the ulcer edge tissue is significantly lower than that in patients without recurrence, especially in the dermis. In the group of patients without recurrence of ulcers, PGC-1α protein staining is darker. In addition, by comparing the concentration changes of four inflammatory factors (IL-6, IL-17, PCT, C-reactive protein) in the peripheral venous blood of the two groups of patients before and after surgery, we found that the level of peripheral blood inflammatory factors in the PGC-1α high expression group was lower than that in the PGC-1α low expression group, suggesting that high expression of PGC-1α is associated with lower levels of inflammation.

[0048] Furthermore, by using the most advanced 7T magnetic resonance imaging to observe the tissues around the ulcers in the two groups, we found that the subcutaneous edema in the high-expression PGC-1α group was slightly lighter than that in the control group, while the edema was obvious in the low-expression PGC-1α group. At the same time, we conducted a long-term follow-up of the above patients, observed their postoperative recovery, and focused on recording three common clinical symptoms, including edema, pain, and ulcer healing time. The results showed that in both groups of cases, the ulcer healing time, edema disappearance time, and pain duration in the high-expression PGC-1α group were all lower than those in the control group, indicating that the upregulation of PGC-1α expression may be related to the faster relief of clinical symptoms.

[0049] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. These modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and specification of the present invention.

Claims

1. Application of reagents for detecting PGC-1α expression in the preparation of products for the diagnosis and treatment of lower extremity venous ulcers.

2. The use according to claim 1, characterized in that: The PGC-1α is downregulated in cases of venous leg ulcers.

3. The use according to claim 1 or 2, characterized in that: The product comprises a reagent or a drug for detecting the expression level of PGC-1α in venous ulcers of the lower extremities.

4. The use according to claim 1 or 2, characterized in that: The products include gene chips, test kits, test strips and high-throughput sequencing platforms.

5. Application of PGC-1α in the preparation of drugs for the treatment of recurrent venous ulcers of the lower limbs.

6. The use according to claim 5, characterized in that: The drug further includes a pharmaceutically acceptable carrier.

7. The use according to claim 6, characterized in that: The acceptable carriers include, but are not limited to, diluents, buffers, suspensions, emulsions, granules, encapsulation agents, excipients, fillers, adhesives, sprays, transdermal absorbents, wetting agents, disintegrants, absorption enhancers, surfactants, colorants, flavoring agents or adsorption carriers.

8. The use according to claim 5, characterized in that: The dosage form of the drug includes, but is not limited to, tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories.

9. The use according to claim 5, characterized in that: The administration routes of the drug include, but are not limited to, oral administration, intravenous injection, intramuscular injection, subcutaneous injection, sublingual dissolution, rectal irrigation, nasal spray, oral spray, topical skin administration or systemic transdermal administration.

Images