Use of orceline in preparation of medicine for inhibiting pancreatic fibrosis

Abstract

The application relates to the technical field of traditional Chinese medicine, in particular to application of hypocrellin A in preparation of a medicine for inhibiting pancreatic fibrosis and improving chronic pancreatitis. The application has the advantages that the application finds that the hypocrellin A can inhibit pancreatic fibrosis and treat chronic pancreatitis, and has the characteristics of non-toxicity and high efficiency, and provides a theoretical basis for key effects of anti-inflammation and anti-fibrosis of a traditional Chinese medicine monomer.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of traditional Chinese medicine, in particular, it is Hypocrellin A in the preparation of the application of the drug for inhibiting pancreatic fibrosis and improving chronic pancreatitis. BACKGROUND

[0002] Chronic pancreatitis (CP) is a progressive fibro-inflammatory syndrome, its pathological features are atrophy and destruction of pancreatic parenchyma, interstitial fibrosis hyperplasia and inflammatory immune cell infiltration, etc.; the clinical manifestations are repeated abdominal pain and pancreatic endocrine and exocrine dysfunction, which can be accompanied by pancreatic duct stones, pancreatic parenchyma calcification, pancreatic duct stenosis or irregular dilation, pancreatic pseudocyst, etc., which seriously affects the quality of life of patients. The prevalence of CP is increasing year by year, and the surveys in Europe, the United States and Japan in the past two years suggest that the prevalence of CP is more than 100 / 10 million, and it is estimated that the number of CP patients worldwide is more than 7 million.

[0003] At present, the purpose of clinical treatment of CP is still limited to taking pancreatic enzyme preparations to improve the lack of exocrine function; comprehensive application of drugs, endoscopy and surgery to improve pancreatic duct drainage and relieve abdominal pain and other symptoms to improve the quality of life of patients. Although in recent years, with the progress of endoscopic treatment technology and the improvement of pancreatic surgery, the clinical treatment of CP is more abundant, including various pancreatic duct decompression and drainage surgery and pancreatic resection, but at present, none of the methods can meet the ideal requirements of stopping disease development and preserving pancreatic function, so it is urgent to strengthen the research on the pathogenesis of CP, to find drugs to relieve pancreatic fibrosis and improve pancreatic function, so as to treat CP, and to lay a foundation for clinical transformation and application.

[0004] The application of traditional Chinese medicine has a history of more than 1,000 years, and its efficacy is clear and the side effects are small, but because the composition and mechanism of traditional Chinese medicine compound are complex, its application is limited. Many studies have shown that traditional Chinese medicine exerts a whole body regulation effect on the body through multi-component and multi-target network. Traditional Chinese medicine monomer is the active ingredient in Chinese herbal medicine, which has many medicinal properties, such as anti-inflammatory, antioxidant, anticancer, antibacterial and other effects, and is an important source of new drug development. More than 200 modern drugs are directly or indirectly derived from Chinese herbal medicine. For example, artemisinin, as the best drug for treating drug-resistant malaria, was originally extracted from traditional Chinese medicine Artemisia. Today, scientists continue to discover new compounds in Chinese herbal medicine, which may help develop new therapeutic drugs suitable for Western medicine. SUMMARY

[0005] The present application aims at screening a Chinese medicine monomer-Hypocrellin A which can inhibit pancreatic fibrosis and has no toxicity to normal pancreatic cells, and provides application of Hypocrellin A in drugs for inhibiting pancreatic fibrosis and improving chronic pancreatitis.

[0006] In a first aspect, the present application provides application of Hypocrellin A in preparing a drug for inhibiting pancreatic fibrosis.

[0007] The Hypocrellin A is a Chinese medicine monomer screened from 1771 Chinese medicine monomers in a Chinese medicine monomer compound library, which can inhibit pancreatic fibrosis and has no toxicity to normal pancreatic cells.

[0008] Further, in the application, the Hypocrellin A can be used in preparing a drug for relieving pancreatic tissue fibrosis and improving pancreatic tissue function.

[0009] Further, in the application, the Hypocrellin A can be used in preparing a drug for reducing expression of type I collagen.

[0010] Further, in the drug, the dosage of the Hypocrellin A is 60 mg / kg.

[0011] In a second aspect, the present application provides application of Hypocrellin A in preparing a drug for relieving pancreatic injury.

[0012] In a third aspect, the present application provides application of Hypocrellin A in preparing a drug for treating chronic pancreatitis.

[0013] In a fourth aspect, the present application provides a drug for inhibiting pancreatic fibrosis and treating chronic pancreatitis, which comprises:

[0014] (A) an effective amount of Hypocrellin A; and

[0015] (B) a pharmaceutically or immunologically acceptable carrier or excipient.

[0016] The experiment of the present application proves that:

[0017] After treatment of Hypocrellin A, destruction of acinar cells is reduced, pancreatic lobules are more complete, and fibrosis is relieved, which shows that Hypocrellin A can relieve pancreatic tissue fibrosis of CP mice and improve pancreatic tissue function. Hypocrellin A can dose-dependently reduce expression of type I collagen and relieve pancreatic fibrosis induced by TGF-β1 in vitro. Hypocrellin A administration can relieve pancreatic organoid injury caused by TGF-β1.

[0018] Compared with the prior art, the present application has the following beneficial effects:

[0019] The present application finds that hypocrellin A inhibits pancreatic fibrosis, has a drug effect of treating chronic pancreatitis, and has the characteristics of non-toxicity and high efficiency, and provides a theoretical basis for the key role of anti-inflammatory and anti-fibrosis of a single traditional Chinese medicine. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 . The ratio of mouse pancreatic tissue to body weight. control: control group; CP: chronic pancreatitis group; CP+Hypocrellin A: chronic pancreatitis and hypocrellin A treatment group.

[0021] Figure 2 . Mouse pancreatic tissue HE and Masson staining. control: control group; CP: chronic pancreatitis group; CP+Hypocrellin A: chronic pancreatitis and hypocrellin A treatment group.

[0022] Figure 3 . Hypocrellin A inhibits pancreatic fibrosis in vitro. Col1a1: collagen type Ⅰ a1 chain; β-Tubulin: internal reference protein. TGF-β1(10 ng / mL), hypocrellin A(1-10 μM), 24 hours of action.

[0023] Figure 4 . Mouse pancreatic organoid CCK8. Action concentration: caerulein(100 nM), linoleic acid(100 μM), palmitic acid(100 μM), TGF-β1(10 ng / mL), action time: 120 hours.

[0024] Figure 5 . Hypocrellin A relieves mouse pancreatic organoid injury. control: control group; Hypocrellin A: hypocrellin A administration group. DETAILED DESCRIPTION

[0025] The specific embodiments provided by the present application are described in detail below in conjunction with examples.

[0026] Example 1:

[0027] 1. Materials and methods

[0028] (1) Animal experiment:

[0029] Six-week-old C57BL / 6J mice were selected and divided into three groups: a control group, a CP model group, and a CP model group treated with *Phyllostachys edulis* A. CP modeling was achieved by intraperitoneal injection of *Phyllostachys edulis* A at a dose of 50 μg / kg, administered every other day, three times a week for four consecutive weeks. Two weeks after modeling, the treatment group was administered *Phyllostachys edulis* A by gavage at a dose of 60 mg / kg, while the control and model groups were administered the same amount of the solvent by gavage. Four weeks after modeling, the mice were dissected, and their pancreatic tissue was collected, embedded in paraffin, and stained with HE and Masson staining.

[0030] (2) Cell experiments:

[0031] Human pancreatic stellate cells (HPSCs) were selected and divided into three groups: control group, model group, and bamboo red fungus A-type drug treatment group. The model group and drug treatment group were stimulated with TGF-β1 (10 ng / mL) to simulate pancreatic fibrosis in vitro. The drug treatment group was given bamboo red fungus A-type drug (1, 2, 5, 10 μM) at the same time as the model was created. The control group and model group were given the same amount of solvent. Cell samples were collected after 24 hours and Western blotting was performed to detect changes in fibrosis-related protein indicators.

[0032] Fragments of mouse pancreatic ducts were extracted and mouse pancreatic exocrine organoids were successfully cultured in vitro. Common injury stimuli were applied to stimulate the organoids to establish an organoid injury model. CCK8 assay was used to detect organoid viability.

[0033] 2. Results and Analysis

[0034] (1) Bamboo red fungus A-in alleviated pancreatic tissue fibrosis in CP mice and improved pancreatic tissue function.

[0035] First, this invention investigated the effects of bamboo red fungus extract on alleviating pancreatic fibrosis and improving pancreatic tissue function in mice. Compared with the control group, the pancreatic weight of the CP group mice was significantly reduced, while after administration of bamboo red fungus extract, the pancreatic weight of the mice increased (…). Figure 1 HE staining showed significant acinar cell atrophy in CP group mice, and Masson staining revealed significant collagen hyperplasia and obvious fibrosis in the pancreatic tissue of CP mice. After treatment with baicalein A, acinar cell destruction decreased, pancreatic lobules became more intact, and fibrosis was alleviated. Figure 2 ).

[0036] (2) Bamboo red fungus A-inducing in vitro alleviates TGF-β1-induced pancreatic fibrosis.

[0037] In vitro, this invention uses TGF-β1 to stimulate human pancreatic stellate cells as an in vitro model of pancreatic fibrosis. This invention found that TGF-β1 stimulation increases type I collagen expression, while baicalein can dose-dependently decrease type I collagen expression. Figure 3 ).

[0038] (3) Bamboo red fungus A-in-1 alleviates pancreatic damage in vitro

[0039] This invention extracts fragments of mouse pancreatic ducts and successfully culturees mouse pancreatic exocrine organoids in vitro. The organoids were stimulated for 120 hours with common damage-inducing factors: hygroscopic globulin (100 nM), linoleic acid (100 μM), palmitic acid (100 μM), and TGF-β1 (10 ng / mL). CCK8 assays revealed that TGF-β1 significantly inhibited organoid viability. Figure 4 Therefore, this invention selected TGF-β1-stimulated pancreatic organoids as an in vitro pancreatic injury model. Results showed that 48 hours after organoid inoculation, stimulation with different concentrations of TGF-β1 (0.5, 1, 2 ng / mL) resulted in varying degrees of damage to the organoids after 120 hours. Administration of *Phyllostachys edulis* A (5 μM) alleviated TGF-β1-induced pancreatic organoid damage. Figure 5 ).

[0040] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the embodiments described. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of the present invention, and these equivalent modifications or substitutions are all included within the scope defined by the claims of this application.

Claims

1. Application of bamboo red fungus A in the preparation of drugs that inhibit pancreatic fibrosis.

2. The application of the bamboo red fungus A ingredient according to claim 1 in the preparation of a drug for inhibiting pancreatic fibrosis, characterized in that, Application of bamboo red fungus A in the preparation of drugs that alleviate pancreatic tissue fibrosis and improve pancreatic tissue function.

3. The application of the bamboo red fungus A ingredient according to claim 1 in the preparation of a drug for inhibiting pancreatic fibrosis, characterized in that, Application of bamboo red fungus A in the preparation of drugs that reduce the expression of type I collagen.

4. The application of the bamboo red fungus A ingredient according to claim 1 in the preparation of a drug for inhibiting pancreatic fibrosis, characterized in that, The dosage of bamboo red fungus A is 60 mg / kg.

5. Application of bamboo red fungus A in the preparation of drugs for treating chronic pancreatitis.

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