Application of C3aR1 targeted inhibitor in preparation of medicine for preventing or treating anomalous acne

Abstract

The invention discloses an application of a C3aR1 targeted inhibitor in preparation of a medicine for preventing or treating abnormal acne. According to the invention, tamoxifen is injected in the intraperitoneal cavity to induce Ncstn conditional knockout mice, and an abnormal acne model with typical inflammatory characteristics is constructed; after the model is established, intradermal administration of a C3aR1 inhibitor SB290157 is carried out on a mouse, so that a C3a-C3aR1 signal channel is blocked, and skin inflammation is improved. The results show that the C3aR1 inhibitor SB290157 can obviously relieve dermatitis symptoms of mice, and the C3aR1 inhibitor SB290157 is proved to have obvious prevention and treatment effects on abnormal acne.

Description

Technical Field

[0001] This invention relates to the application of C3aR1 targeting inhibitors in the preparation of drugs for the prevention or treatment of atypical acne, and belongs to the field of inflammatory skin disease treatment technology. Background Technology

[0002] Acne paradox (HS) is a chronic, relapsing inflammatory skin disease. Traditional treatments for acne paradox have the following limitations: ① Limited efficacy: Antibiotics and TNF-α inhibitors do not improve the condition of a considerable number of patients and are difficult to achieve long-term stable control; ② Weak targeting: They are difficult to act on the key complement pathway that drives inflammation; ③ High risk: Long-term use of antibiotics can easily lead to drug resistance, and biologics are expensive and accompanied by certain adverse reactions. Summary of the Invention

[0003] The purpose of this invention is to provide the use of C3aR1 targeting inhibitors in the preparation of medicaments for the prevention or treatment of atypical acne.

[0004] The objective of this invention is achieved through the following technical solution: Application of C3aR1 targeting inhibitors in the preparation of drugs for the prevention or treatment of atypical acne.

[0005] Preferably, the C3aR1 targeting inhibitor is SB290157.

[0006] The structural formula of SB290157 is: (2S)-5-(diaminomethyleneamino)-2-[[2-(diphenylmethyl)phenoxy]acetyl]aminovaleric acid trifluoroacetate. Preferably, the SB290157 is administered via intradermal injection.

[0007] Preferably, the dosage of SB290157 is 0.1-3 mg / kg.

[0008] This invention establishes a paradoxical acne model with typical inflammatory characteristics by inducing Ncstn conditional knockout mice through intraperitoneal injection of tamoxifen. After model establishment, mice were administered the C3aR1 inhibitor SB290157 intradermally to block the C3a-C3aR1 signaling pathway and alleviate skin inflammation. Results showed that the C3aR1 inhibitor SB290157 significantly alleviated dermatitis symptoms in mice, confirming its significant preventive and therapeutic effects on paradoxical acne.

[0009] The mechanism of action of the C3aR1 inhibitor SB290157 is as follows: ① Targeting key inflammatory pathways: By blocking the binding of C3a to C3aR1, the core complement inflammatory signaling axis in HS is directly interrupted; ② Regulating macrophage polarization: SB290157 inhibits macrophage M1 polarization, reduces the expression of pro-inflammatory factors, and improves the inflammatory environment of HS lesion tissue.

[0010] Compared with the prior art, the beneficial effects of this application are: This invention significantly improves the skin inflammatory response of paradoxical acne by targeting and blocking the complement C3a-C3aR1 signaling axis, thereby inhibiting macrophage M1 pro-inflammatory polarization at its source. Specifically, it can significantly reduce skin redness, swelling, nodules and tissue damage, and improve the overall degree of inflammation.

[0011] The drug delivery regimen proposed in this invention is simple and effective, and can stably reduce the level of local inflammatory factors and improve the pathological tissue structure.

[0012] This invention can significantly alleviate skin inflammation in HS mice, including redness, swelling, hair loss, and tissue damage, demonstrating superior therapeutic potential compared to traditional anti-inflammatory drugs and providing a new strategy for the precision treatment of paradoxical acne. Attached Figure Description

[0013] Figure 1 Flowchart of mouse paradoxical acne (HS) modeling and C3aR1 inhibitor administration.

[0014] Figure 2 Photographs of the skin appearance on the back of mice and results of weight change monitoring during the experiment.

[0015] Figure 3 HE staining of mouse back skin tissue.

[0016] Figure 4 Results of detection of IL-1β, TNF-α and IL-10 expression levels in mouse dorsal skin tissue. Detailed Implementation

[0017] The present invention will be further described below with reference to the embodiments, but the description of the embodiments does not limit the scope of protection of the present invention in any way.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0019] Unless otherwise specified, all substances or instruments used in the following examples can be obtained from conventional commercial sources.

[0020] The mice used in this invention are Ncstn conditional knockout mice (B6 / JGpt-Tg(KRT14-cre)1Amc / J;Ncstnem1Cflox / Gpt) that were built and stably bred in our laboratory.

[0021] Example 1 Animal preparation: Six- to eight-week-old Ncstn conditional knockout mice (weighing 20 to 25 g) were selected and bred in the laboratory. They were acclimatized for one week and given free access to food and water, with a 12-hour light cycle.

[0022] HS (Hidradenitis Suppurativa) model induction: Tamoxifen was dissolved in corn oil (final concentration 20 mg / mL) and incubated overnight at 37°C in the dark with shaking until completely dissolved; it was then administered intraperitoneally at a dose of 120 mg / kg, once every 24 hours for a total of 7 times, to induce Ncstn gene knockout and generate atypical acne-like skin inflammation. Figure 1 ).

[0023] C3aR1 inhibitor administration: After model induction, the C3aR1 inhibitor SB290157 (dissolved in PBS) was administered intradermally at a dose of 1 mg / kg, once every 24 hours for a total of 7 times, to block the C3a-C3aR1 signaling pathway and improve skin inflammation. Figure 1 ).

[0024] Skin appearance and weight monitoring: Mice were divided into NC group, HS group and C3aRA group.

[0025] 1) NC (Normal Control): Normal control group, without HS modeling and without any drug treatment, used to reflect changes in body surface morphology and body weight of mice under normal physiological conditions; 2) HS (Hidradenitis Suppurativa): HS model group, which was treated with HS modeling and did not receive SB290157 or other interventions, to reflect the effect of the HS disease state itself on the appearance and weight of mice; 3) C3aRA (C3a Receptor Antagonist): HS+C3aR1 antagonist treatment group, with C3aR1 antagonist (i.e. SB290157) administered based on HS modeling, to evaluate the effect of blocking the C3a–C3aR1 pathway on the improvement of HS phenotype.

[0026] During the experiment, the redness, swelling, hair loss, and extent of lesions on the backs of mice were recorded, and the trend of weight changes was monitored. The results are as follows: Figure 2 As shown, the left image is a photograph of the mice on day 14 after modeling and drug administration (the experimental endpoint), and the right image is the mouse's weight statistics. Figure 2 This indicates that C3aR1 antagonists do not only improve local symptoms through general anti-inflammatory effects, but also significantly improve the overall disease phenotype by regulating the systemic inflammatory response associated with HS.

[0027] Skin tissue collection: On day 14, skin tissue from the back of each group of mice was collected and placed in a pre-cooled container; HE staining was used to observe epidermal thickening, inflammatory cell infiltration, and tissue structure destruction. The results were as follows: Figure 3 As shown, C3aR1 mediates key pathological events such as abnormal epidermal proliferation and abnormal recruitment of inflammatory cells in the occurrence and progression of HS. By specifically antagonizing C3aR1, HS-related structural abnormalities can be significantly restored at the histological level while improving surface symptoms.

[0028] Inflammatory factor detection: The regulatory effect of the C3aR1 antagonist SB290157 on the inflammatory microenvironment of anomalous acne was evaluated by detecting the protein expression levels of cytokines such as IL-1β, TNF-α, and IL-10 in skin tissue. The results are as follows: Figure 4 As shown in the figure. The results showed that, compared with the normal control group, the expression levels of pro-inflammatory cytokines IL-1β and TNF-α in the skin tissue of the HS model group were significantly increased, while the expression level of anti-inflammatory cytokine IL-10 was significantly decreased; after treatment with SB290157, the expression levels of IL-1β and TNF-α in the skin tissue of HS mice were significantly decreased, while the expression level of IL-10 was significantly increased. These results indicate that antagonizing C3aR1 can simultaneously inhibit pro-inflammatory responses and promote anti-inflammatory responses, thereby effectively improving the local inflammatory microenvironment of acne paradoxically.

[0029] In summary, the SB290157 treatment group showed significant improvement in skin inflammation, including reduced redness and swelling, less tissue damage, and decreased inflammatory cell infiltration.

[0030] The above embodiments are only for illustrating the technical concept and features of the present invention. Their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be used to limit the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. Application of C3aR1 targeting inhibitors in the preparation of drugs for the prevention or treatment of atypical acne.

2. The application according to claim 1, characterized in that... The C3aR1 targeting inhibitor is SB290157.

3. The application according to claim 2, characterized in that... The administration method of SB290157 is intradermal injection.

4. The application according to claim 3, characterized in that... The dosage of SB290157 is 0.1-3 mg / kg.

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