Application of super enhancer inhibitor JQ-1 in wound healing disorder related diseases

Abstract

The invention provides application of a super enhancer inhibitor JQ-1 in preparation of a medicine for treating wound healing disorder related diseases. Relates to the technical field of biomedicine, the promotion effect of the super enhancer inhibitor JQ-1 in wound healing and repairing is disclosed for the first time, the super enhancer inhibitor JQ-1 is competitively combined with BET protein bromodomain, combination of the super enhancer inhibitor JQ-1 and acetylated histone is blocked, and super enhancer driven gene transcription is inhibited. Skin regeneration can be obviously accelerated, the wound healing time is shortened, and the healing degree is improved. Aiming at the pain point that the existing wound healing therapy is limited in effect, the invention provides a brand-new molecular targeted therapy scheme for people, such as diabetic patients and old people, which are easy to cause abnormal wound healing, can effectively reduce serious sequelae, such as amputation, and provides a scientific basis and a key direction for developing a novel medicine for promoting wound healing; the technical blank in the related treatment field is filled up, and important clinical application value and research and development prospects are achieved.

Description

Technical Field

[0001] This application relates to the field of biomedical technology, and in particular to the application of the super enhancer inhibitor JQ-1 in diseases related to wound healing disorders. Background Technology

[0002] The skin, the largest organ in the human body in terms of surface area, is a crucial structure protecting internal tissues from mechanical damage, microbial infection, ultraviolet radiation, and extreme temperatures, making it extremely vulnerable. Millions of people worldwide suffer from chronic, non-healing wounds each year, significantly impacting patients, healthcare, and the economy.

[0003] Wound healing and repair are among the most complex biological processes in human life. Upon injury, multiple biological pathways are activated. Inflammation is immediately initiated after skin injury; inflammatory cells release inflammatory factors, promoting cell proliferation, migration, and angiogenesis. Following re-epithelialization and new tissue formation, a remodeling phase occurs, requiring apoptosis and the reorganization of matrix proteins such as collagen. This biological process is extremely complex, making patients with diabetes, the elderly, and those with genetic diseases such as sickle cell disease particularly susceptible to abnormal wound healing, leading to long-term sequelae. For example, impaired wound healing in diabetic patients can result in serious adverse consequences such as amputation. Surprisingly, existing interventions have not had a significant impact on the situation. While various therapies exist to promote wound healing, their effectiveness is moderate. Therefore, more effective treatments are needed to promote wound healing. Summary of the Invention

[0004] The purpose of this application is to address the technical problem that existing wound healing therapies do not have a significant impact on the situation.

[0005] To address the aforementioned technical problems, this application provides the following technical solution:

[0006] Application of the super enhancer inhibitor JQ-1 in the preparation of drugs for treating diseases related to impaired wound healing.

[0007] Preferably, the super-enhancer inhibitor JQ-1 is used to promote skin regeneration and accelerate wound healing.

[0008] Preferably, the wound healing disorder-related diseases include one or more of the following: diabetic chronic wound, age-related delayed wound healing, sickle cell disease-related wound non-healing, and post-traumatic persistent wound.

[0009] This application also provides a medicament for treating wound healing disorders, the medicament comprising an effective dose of the super-enhancer inhibitor JQ-1.

[0010] Preferably, the drug further comprises one or more of a pharmaceutically acceptable carrier, diluent, disintegrant, binder, or lubricant.

[0011] Preferably, the dosage form of the drug is selected from one or more of the following: injection, topical ointment, gel, cream, wet dressing for wound, spray, and medical patch.

[0012] Preferably, the drug is used to competitively bind to the bromine domain of the BET protein, blocking its binding to acetylated histones, thereby inhibiting super-enhancer-driven gene transcription.

[0013] Preferably, the bromine domains of the BET protein include BRD2, BRD3, and BRD4.

[0014] Compared with existing technologies, this application reveals for the first time the promoting effect of the super-enhancer inhibitor JQ-1 in wound healing and repair. It inhibits super-enhancer-driven gene transcription by competitively binding to the bromine domains of BET protein (containing BRD2, BRD3, and BRD4) and blocking their binding to acetylated histones. Experiments using a mouse full-thickness skin defect model have confirmed that it can significantly accelerate skin regeneration, shorten wound healing time, and improve the degree of healing. Addressing the limited effectiveness of existing wound healing therapies, this invention provides a novel molecularly targeted treatment option for populations prone to abnormal wound healing, such as diabetic patients and the elderly. It can effectively reduce severe sequelae such as amputation, and at the same time provides a scientific basis and key direction for the development of novel wound healing-promoting drugs, filling a technological gap in related therapeutic areas and possessing significant clinical application value and research prospects. Attached Figure Description

[0015] Figure 1 The image shows the morphology of the wound and the measurement of the wound diameter after a full-thickness skin defect model in mice according to one embodiment of the present invention; the red curve represents the JQ-1 treatment group and the black curve represents the control group. The data was recorded starting from the first day of surgery (d0). On the 8th, 10th and 13th days after surgery, the wound healing speed of the JQ-1 group was significantly faster than that of the control group (*P<0.05; **P<0.01). Detailed Implementation

[0016] This application provides the use of the super enhancer inhibitor JQ-1 in the preparation of a drug for treating diseases related to wound healing disorders. In one embodiment, the super enhancer inhibitor JQ-1 is used to promote skin regeneration and accelerate wound healing.

[0017] The wound healing disorder-related diseases include one or more of the following: diabetic chronic wound, age-related delayed wound healing, sickle cell disease-related wound non-healing, and post-traumatic persistent wound.

[0018] This application also provides a medicament for treating wound healing disorders, the medicament comprising an effective dose of the super-enhancer inhibitor JQ-1. In one embodiment, the medicament further comprises one or more of a pharmaceutically acceptable carrier, diluent, disintegrant, binder, or lubricant.

[0019] The dosage form of the drug is selected from one or more of the following: injection, topical ointment, gel, cream, wet dressing for wound, spray, and medical patch.

[0020] The drug is used to competitively bind to the bromine domain of the BET protein, blocking its binding to acetylated histones, thereby inhibiting super-enhancer-driven gene transcription, wherein the bromine domain of the BET protein includes BRD2, BRD3, and BRD4.

[0021] The above content will be explained in conjunction with specific verification experiments below.

[0022] I. Experimental Materials and Personnel

[0023] 1. The body dissecting microscope was purchased from Olympus.

[0024] 2. The silicone dressings for small animal wounds were purchased from Haide Biotechnology Co., Ltd.

[0025] 3. The transparent dressing was purchased from Smith & Nephew Ltd.;

[0026] 4. Animal feed was purchased from the Animal Experiment Center of Nantong University.

[0027] II. Verification Experiment

[0028] In this application, 8-week-old (22-26 g) male C57BL / 6J mice (from the Animal Center of Nantong University) were used as experimental subjects. The mice were housed in a standard environment of 21°C and 12-hour light-dark cycle, with free access to food and water. The experiment was approved by the Animal Ethics Committee of Nantong University.

[0029] A wound model was constructed in mice, and after the model was completed, the mice were randomly divided into two groups:

[0030] Experimental group (JQ-1 treatment group): JQ-1 was administered via wound instillation.

[0031] Control group (DMSO group): The same amount of DMSO (solvent) was applied to the wound, and the rest of the treatment was the same as that of the experimental group.

[0032] After grouping, on Days 0, 2, 3, 6, 8, 10, and 13, the wound diameter was measured along the X, Y, and Z axes using surgical calipers (average value was taken), and the wound area and healing rate were calculated [healing rate (%) = (original wound area - current wound area) / original wound area × 100%]. At the same time, photomicrographs were taken until the wound was nearly completely healed.

[0033] The results are as follows Figure 1 As shown, compared with the mice in the DMSO injection group, the mice in the JQ-1 treatment group had significantly smaller wound diameters and faster wound healing speeds on days 8, 10, and 13 after surgery; indicating that the super enhancer inhibitor JQ-1 can significantly promote wound healing.

[0034] III. Experimental Methods

[0035] 1. Preparation of anti-shrink silicone pads and transparent dressings

[0036] (1) Draw a 10 mm circle on a 0.5 mm thick silicone sheet, and then make a silicone disc with scissors or a hole punch.

[0037] (2) Place the 5 mm punch head in the center of the 10 mm circle and press it down to form a hole, forming a "donut" shaped disc, which can be used as a clamp.

[0038] (3) Draw a 10 mm circle on the transparent occlusive dressing, and then make a circular dressing with scissors.

[0039] 2. Laboratory animals

[0040] (1) Eight-week-old (22-26 g) male C57BL / 6J mice from the Animal Center of Nantong University were used;

[0041] (2) Mice were kept under standard conditions of 21°C and 12-hour light-dark cycle and had free access to food and water.

[0042] 3. Anesthesia and surgical preparation

[0043] (1) Weigh the mice before surgery, anesthetize the mice with 0.01 mL / g 1% sodium pentobarbital, and place the anesthetized mice in a prone position in front of the operating table;

[0044] (2) Use scissors to cut the hair from the bottom of the neck to the back and between the two shoulder blades for 3 cm to prepare the surgical area; apply hair removal cream lightly for no more than 2 minutes; wipe with a damp gauze to ensure that all hair removal cream and remaining hair are removed;

[0045] (3) Wipe the skin with alcohol and apply 10% povidone-iodine twice.

[0046] 4. Wound excision and splinting

[0047] (1) Use a sterile 4 mm punch to outline two circular patterns of wounds at the shoulder level on both sides of the midline of the mouse.

[0048] (2) Use serrated forceps to lift the skin in the middle of the outline, use iris scissors to make a full-thickness incision, through the subcutaneous tissue, including the fascia and muscle layer, and remove the circular tissue;

[0049] (3) Repeat the process to create a full-thickness wound of the same size on the other side of the midline;

[0050] (4) Remove the plastic protective coating from both sides of the silicone clamp;

[0051] (5) Apply cyanoacrylate adhesive to one side of the silicone splint;

[0052] (6) Place the splint in the center on the wound and fix it with 6-0 nylon sutures to ensure proper positioning;

[0053] (7) Repeat the splinting process on the other wound;

[0054] (8) Cover the wound with a transparent occlusive dressing.

[0055] 5. Postoperative management

[0056] (1) Appropriate analgesia after surgery;

[0057] (2) After the surgery, the animal was kept in a cage alone and on a heating pad until it was fully recovered.

[0058] 6. Wound measurement

[0059] (1) On postoperative Day 0, Day 2, Day 3, Day 6, Day 8, Day 10, and Day 13, the diameter of the wound was measured using surgical calipers (measured three times along the X, Y, and Z axes, and the average value of the measurements was taken).

[0060] (2) Calculate the wound area. The wound closure curve is obtained by calculating the healing rate, i.e., wound healing rate (%) = (original wound area - current wound area) / original wound area × 100%, and take a microscopic photograph until the wound is nearly completely healed.

[0061] Based on the above conclusions, this application reveals for the first time the promoting effect of the super-enhancer inhibitor JQ-1 in wound healing and repair. It inhibits super-enhancer-driven gene transcription by competitively binding to the bromine domains of BET protein (containing BRD2, BRD3, and BRD4) and blocking their binding to acetylated histones. Experiments using a mouse full-thickness skin defect model have confirmed that it can significantly accelerate skin regeneration, shorten wound healing time, and improve the degree of healing. Addressing the limited effectiveness of existing wound healing therapies, this invention provides a novel molecularly targeted treatment option for diabetic patients, the elderly, and other populations prone to abnormal wound healing. It can effectively reduce severe sequelae such as amputation, and simultaneously provides a scientific basis and key direction for the development of novel wound healing-promoting drugs, filling a technological gap in related therapeutic areas and possessing significant clinical application value and research prospects.

Claims

1. Application of the super enhancer inhibitor JQ-1 in the preparation of drugs for treating diseases related to impaired wound healing.

2. The application of the super-enhancer inhibitor JQ-1 according to claim 1 in the preparation of drugs for treating diseases related to wound healing disorders, characterized in that: The super enhancer inhibitor JQ-1 is used to promote skin regeneration and accelerate wound healing.

3. The application of the super-enhancer inhibitor JQ-1 according to claim 1 in the preparation of drugs for treating diseases related to wound healing disorders, characterized in that: The wound healing disorder-related diseases include one or more of the following: diabetic chronic wound, age-related delayed wound healing, sickle cell disease-related wound non-healing, and post-traumatic persistent wound.

4. A drug for treating impaired wound healing, characterized in that: The drug includes an effective dose of the super-enhancer inhibitor JQ-1.

5. A medicament for treating wound healing disorders according to claim 4, characterized in that: The drug also contains one or more of a pharmaceutically acceptable carrier, diluent, disintegrant, binder, or lubricant.

6. The medicament for treating wound healing disorders according to claim 4, characterized in that: The dosage form of the drug is selected from one or more of the following: injection, topical ointment, gel, cream, wet dressing for wound, spray, and medical patch.

7. The medicament for treating wound healing disorders according to claim 4, characterized in that: The drug competitively binds to the bromine domain of the BET protein, blocking its binding to acetylated histones, thereby inhibiting super-enhancer-driven gene transcription.

8. A medicament for treating impaired wound healing according to claim 7, characterized in that: The bromine domains of the BET protein include BRD2, BRD3, and BRD4.

Images