阅读说明：本技术 西红花醛的新用途 (New application of crocetin ) 是由 徐宏喜 谭红胜 席志超 吕玥 江雪 陈江成 党泽方 于 2019-04-25 设计创作，主要内容包括：本发明公开了西红花醛的新用途,所述的新用途是指以西红花醛或其水合物、药学上可接受的盐、前体化合物中的至少一种作为活性成分用于制备预防或/和治疗前列腺癌的药物或保健品、用于制备预防或/和治疗前列腺癌复发的药物或保健品、用于制备降血脂的药物或保健品或用于制备预防或/和治疗炎症的药物或保健品。实验表明：西红花醛对前列腺癌及前列腺癌复发具备显著的预防和治疗作用,且具有降血脂作用及治疗非酒精性脂肪肝的作用,对炎症也具有显著的治疗作用,可望用于制备预防或/和治疗前列腺癌或前列腺癌复发的药物或保健品、降血脂的药物或保健品、预防或/和治疗炎症的药物或保健品。(The invention discloses a new application of crocetin, which is used for preparing a medicament or health-care product for preventing or/and treating prostatic cancer, a medicament or health-care product for preventing or/and treating prostatic cancer relapse, a medicament or health-care product for reducing blood fat or a medicament or health-care product for preventing or/and treating inflammation by taking at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient. Experiments show that: the saffron aldehyde has obvious effects of preventing and treating the recurrence of the prostate cancer and the recurrence of the prostate cancer, has the effects of reducing blood fat and treating non-alcoholic fatty liver, has obvious effects of treating inflammation, and can be used for preparing medicines or health-care products for preventing or/and treating the recurrence of the prostate cancer or the prostate cancer, medicines or health-care products for reducing the blood fat, and medicines or health-care products for preventing or/and treating the inflammation.)

1. An application of crocetin or at least one of hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient in preparing a medicament or health-care product for preventing or/and treating prostate cancer.

2. An application of crocetin or at least one of hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient in preparing a medicament or health-care product for preventing or/and treating recurrence of prostate cancer.

3. An application of crocetin or at least one of hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient in preparing medicines or health products for reducing blood lipid is provided.

4. Use according to claim 3, characterized in that: at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof is used as an active ingredient for preparing a medicament or health-care product for preventing or/and treating the nonalcoholic fatty liver disease.

5. An application of crocetin or at least one of hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient in preparing a medicament or health-care product for preventing or/and treating inflammation.

6. Use according to claim 5, characterized in that: at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof is used as an active ingredient for preparing a medicament or health-care product for preventing or/and treating inflammation mediated by macrophages.

7. Use according to claim 5, characterized in that: at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof is used as an active ingredient for preparing a medicament or health-care product for preventing or/and treating ulcerative colitis.

Technical Field

The invention relates to a new application of saffron aldehyde, in particular to a new application of saffron aldehyde in preparing a medicament or a health-care product for preventing or/and treating prostatic cancer or prostatic cancer relapse, a medicament or a health-care product for reducing blood fat and a medicament or a health-care product for preventing or/and treating inflammation, and belongs to the technical field of medicines.

Background

Prostate cancer is one of the common tumors threatening the health of men, and 679000 new cases of worldwide issue in 2002 are listed at the 2 nd position of male tumors. The exact cause of prostate cancer is not known and has been rapidly increasing in recent years. Early stage prostate cancer can not have any prognostic symptoms, only serum prostate specific antigen value is found to be increased during screening and/or abnormal prostate change is found in digital rectal examination, and once symptoms appear, the early stage prostate cancer is usually advanced prostate cancer, and the metastatic infiltration phenomenon of cancer cells often appears in prostate patients. At present, the main treatment means of the prostatic cancer are operation, radiotherapy and chemotherapy, and no effective treatment medicine exists.

In the treatment of cancer, the mortality rate of primary cancer and some early cancer patients is continuously reduced due to the continuous progress of surgical treatment and radiotherapy and chemotherapy, and the cancer gradually becomes a chronic disease called "tumor survival". At present, the number of patients with tumors is increasing, and 1200 million patients with tumors exist in the United states alone. However, the overall mortality rate of cancer remains high, and recurrence of cancer is one of the major causes. In clinical practice, people have attracted more and more attention to prevent the recurrence of cancer, but until now, no relevant preventive guidance and no targeted medicine exist.

There is no clear mechanism for the mechanism of cancer recurrence. It is currently the main reason for recurrence of cancer is due to the reentry of Quiescent cancer cells (quiesce cancer cells) into the cell cycle. Quiescent tumor cells are present at various stages of tumor development and also cause a portion of the tumor cells to enter the quiescent stage when the patient receives chemotherapy. The tumor cell enters a resting stage which is a mechanism for self-protection, so that the energy required for the survival of the cancer cell can be reduced, and the sensitivity to drugs is reduced, thereby being beneficial to the survival of the cancer cell. After the change of the organism environment, the resting cancer cells re-enter the cell cycle, and the tumor starts to grow again, thereby causing the recurrence of the cancer. Therefore, if the cancer cells in the stationary phase can be inhibited from reentering the cell cycle, the recurrence of the cancer will be prevented to some extent.

The nonalcoholic fatty liver disease refers to a clinical pathological syndrome which is mainly characterized by fat accumulation and excessive deposition in liver cells caused by alcohol and other definite interference factors, and acquired metabolic stress liver injury closely related to insulin resistance and genetic susceptibility. The incidence of nonalcoholic fatty liver patients is high in the population, and the clinical manifestations of the nonalcoholic fatty liver patients are different along with the progression of the disease course, wherein the nonalcoholic fatty liver patients mainly comprise simple fatty liver, steatohepatitis fibrosis and cirrhosis. At present, the causes of the non-alcoholic fatty liver disease are more, the pathogenesis is not completely clear, and the research considers that obesity, type II diabetes, hyperlipidemia and the like are individually or jointly used as susceptibility factors of the non-alcoholic fatty liver disease, and the susceptibility factors can be related to the following links: 1) abnormal intake of lipids, high-fat diet, hyperlipidemia, and increased peripheral adipose tissue mobilization, promoting increased input of beneficial fatty acids into the liver; 2) mitochondrial dysfunction; 3) free fatty acid and triglyceride synthesis by hepatocytes; 4) inadequate synthesis or reduced secretion of very low density lipoproteins results in reduced transport of triglycerides out of the hepatocytes. Therefore, the current clinical treatment is mainly started from the aspect of reducing blood fat, but no effective treatment medicine for the non-alcoholic fatty liver disease exists at present.

Inflammation, commonly known as "inflammation", is a defense response of the body to stimuli, manifested by redness, swelling, heat, pain, and dysfunction. The inflammation may be infectious inflammation caused by infection or non-infectious inflammation not caused by infection. Normally, inflammation is beneficial and an automatic defense response of the human body, but sometimes, inflammation is also harmful, such as attack on the body's own tissues, inflammation occurring in transparent tissues, and the like.

Ulcerative colitis is a chronic nonspecific inflammatory disease of colon and rectum, the etiology of which is not quite clear, the number of patients with ulcerative colitis in China is over 14 thousands in recent 15 years, and the patients tend to be younger. Ulcerative colitis can lead to a number of lesions such as hematochezia, ulcers and colon cancer. Therefore, it is crucial to find drugs that can treat ulcerative colitis. Currently, 5-aminosalicylic acid drugs, corticosteroids, biologic therapies, immunosuppressive drugs, and the like have been used in the treatment of ulcerative colitis. However, these drugs cause adverse reactions such as vomiting, fever, myocarditis, granulocytopenia, hyperglycemia, and osteoporosis, thereby limiting the use of the drugs. A large number of small molecule compounds from Chinese medicinal materials, such as alkaloids, polyphenols and quinones, have been reported to have anti-inflammatory activity. Therefore, the search for anti-inflammatory active ingredients with less toxic and side effects from traditional Chinese medicines has become a hot spot of current anti-inflammatory research.

In ulcerative colitis, the number of macrophages is significantly increased, and the macrophages infiltrating the intestinal mucosa significantly increase the expression of Pattern Recognition Receptor (PRR) TLR4 on the cell surface to directly recognize intestinal symbionts and antigens passing through the intestinal epithelial barrier, such as Lipopolysaccharide (LPS) which is the product of bacterial cell walls. The interaction of the two can lead to the activation of downstream signal pathways such as NF-kB, MAPKs and the like, so that macrophages can generate various proinflammatory mediators such as NO, IL-6, TNF-alpha and the like, and the inflammatory response is enhanced. In addition, macrophages will present the treated antigen to CD4+ T cells, allowing them to differentiate towards Th2 effector cells. It can be seen that ulcerative colitis is associated with the activation of a variety of immune cells, and macrophage-mediated inflammatory responses play an important role in ulcerative colitis.

With the clinical application of traditional Chinese medicine becoming more and more extensive, the application of traditional Chinese medicine in various diseases also becomes a research hotspot, natural medicines represented by traditional Chinese medicine are huge medicine library resources, and about 50% of the current clinical medicines are derived from natural small molecular compounds, namely traditional Chinese medicine active ingredients. Therefore, the method has very important significance for screening out the high-efficiency and low-toxicity medicines for preventing or/and treating the prostate cancer and the recurrence of the prostate cancer, and reducing the blood fat or inflammation from the traditional Chinese medicines, thereby relieving the pain of patients and improving the life quality.

Saffron (the name of Crocus sativus L.) also known as saffron and Crocus sativus is a perennial flower of Crocus of Iridaceae and is also a common spice. Stigma croci has strong physiological activity, its stigma can be used as medicinal in Asia and Europe, has effects of tranquilizing, eliminating phlegm, and relieving spasm, and can be used for treating gastropathy, regulating menstruation, measles, fever, jaundice, hepatosplenomegaly, etc. Saffron aldehyde (also known as saffron aldehyde, safflower aldehyde and crocin aldehyde) is a monoterpene aldehyde compound extracted from saffron, and has the English name: safranal, molecular formula: C10H14O, molecular weight 150.22, CAS registry number 116-26-7, chemical formula:

at present, saffron aldehyde is mainly used as edible essence, few pharmacological activity researches are carried out, and no research report on the aspects of treating prostatic cancer, prostatic cancer recurrence, reducing blood fat or inflammation and the like is found.

Disclosure of Invention

The invention aims to provide a new application of crocetin to widen the application range of crocetin.

The invention relates to an application of crocetin, which is used for preparing a medicament or health-care product for preventing or/and treating prostatic cancer by taking at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient.

Furthermore, the pharmaceutical composition is used for preparing the drugs or health care products for preventing the prostate cancer by taking at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient.

The other application of the crocetin is that at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof is used as an active ingredient for preparing a medicine or health-care product for preventing or/and treating the recurrence of the prostate cancer.

Furthermore, the pharmaceutical composition is used for preparing a medicament or health-care product for preventing the recurrence of the prostate cancer by taking at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient.

The invention also relates to the use of saffron aldehyde or at least one of its hydrate, pharmaceutically acceptable salt and precursor compound as active component in preparing medicine or health product for reducing blood fat.

Furthermore, the crocetin or at least one of hydrate, pharmaceutically acceptable salt and precursor compound thereof is used as an active ingredient for preparing the medicine or health care product for preventing or/and treating the nonalcoholic fatty liver disease.

The other application of the crocetin is that at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof is used as an active ingredient for preparing a medicament or health-care product for preventing or/and treating inflammation.

Furthermore, the method uses at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient to prepare a medicament or health-care product for preventing or/and treating inflammation mediated by macrophages.

Furthermore, the pharmaceutical composition is used for preparing a medicament or health-care product for preventing or/and treating colitis by using at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient.

Furthermore, the pharmaceutical composition is used for preparing a medicament or health-care product for preventing or/and treating ulcerative colitis by using at least one of crocetin or hydrate, pharmaceutically acceptable salt and precursor compound thereof as an active ingredient.

The crocetin can be obtained by chemical synthesis or extraction from plants; preferably, the saflufenaldehyde is extracted and separated from saffron.

The agents of the present invention may be administered to a patient by a variety of routes of administration, including, but not limited to, oral, transdermal, intramuscular, subcutaneous, and intravenous injection.

The dosage form of the drug of the present invention is not limited, and any dosage form may be used as long as it allows the active ingredient to efficiently reach the body, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches and the like; oral dosage forms are preferred, such as: capsule, tablet, oral liquid, granule, pill, powder, pellet, and unguent.

The medicine of the invention can contain minor ingredients which do not affect the effective components and/or pharmaceutically acceptable carriers and auxiliary materials necessary for various preparations besides the main active components. For example, when the drug is in an oral dosage form, it may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablets may be coated if necessary. Suitable fillers include cellulose, mannitol, lactose and other similar fillers; suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate; suitable lubricants include, for example, magnesium stearate; suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

The terms described in the present invention are defined as follows:

the term "pharmaceutically acceptable salt" refers to salts of the compounds with pharmaceutically acceptable inorganic or organic acids, including but not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; such organic acids include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, 1, 5-naphthalenedisulfonic acid, sulfinic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids; by "pharmaceutically acceptable" is meant a material that is suitable for use in humans without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.

The term "precursor compound" refers to a compound which is inactive in vitro, but can be converted into the active ingredient of the present invention by metabolic or chemical reaction in vivo, thereby exerting its pharmacological effect.

Compared with the prior art, the invention has the following remarkable beneficial effects:

The research results of the invention show that: the saflufenacil can inhibit the proliferation of human prostate cancer cells in a resting stage, can inhibit the re-proliferation of human prostate cancer cells LNCaP in the resting stage, can delay the time for the human prostate cancer cells in the resting stage to re-enter a cell cycle, can influence the expression of LNCaP cell cycle-related proteins in the human prostate cancer in the resting stage, and shows that saflufenacil has remarkable prevention and treatment effects on prostate cancer and recurrence of the prostate cancer; saffron aldehyde can obviously reduce the fat content in liver cells in vitro and can obviously inhibit the formation of non-alcoholic fatty liver of rats, which shows that the saffron aldehyde has the functions of reducing blood fat and treating the non-alcoholic fatty liver; saffron aldehyde can remarkably inhibit macrophage RAW 264.7 mediated inflammatory reaction, which shows that saffron aldehyde has remarkable treatment effect on inflammation; therefore, the crocetin provided by the invention can be expected to be used for preparing medicines or health-care products for preventing or/and treating the prostate cancer or the recurrence of the prostate cancer, medicines or health-care products for reducing blood fat and medicines or health-care products for preventing or/and treating inflammation.

Drawings

FIG. 1 is a graph of a statistical analysis of safinaldehyde (Safranal) inhibition of LNCaP re-proliferation of human prostate cancer cells in the quiescent stage;

FIG. 2 is a graph of flow analysis of safinaldehyde (Safranal) delayed cell cycle re-entry of LNCaP, a human prostate cancer cell in the quiescent state;

FIG. 3 is a graph of an immunoblot analysis of safranil (Safranal) affecting the expression of human prostate cancer LNCaP cell cycle-related protein during the quiescent stage;

FIG. 4 is a graph of the cell viability of safinaldehyde (Safranal) at various concentrations on BRL 3A cells for 24 hours and 48 hours, respectively;

FIG. 5 is a graph showing the TG content in safinaldehyde (Safranal) after 24 hours of exposure to BRL 3A cells;

FIG. 6 is a graph showing the detection of the oil red O content of safranil (Safranal) on BRL 3A cells;

FIG. 7 shows the results of biochemical experiments on serum and liver tissues;

FIG. 8 shows HE staining of rat kidney;

FIG. 9 shows rat liver oil red O staining;

FIG. 10 is a graph of safinaldehyde (Safranal) inhibiting polysaccharide-induced NO production in mouse macrophages;

FIG. 11 is a graph showing that crocetin (Safranal) inhibits protein expression of iNos and COX-2 in polysaccharide-induced mouse macrophages;

FIG. 12 is a graph showing that crocetin (Safranal) inhibits polysaccharide-induced TNF production and protein expression in mouse macrophages;

FIG. 13 is a graph showing that safinaldehyde (Safranal) inhibits the production of IL-6 and protein expression in mouse macrophages induced by polysaccharides;

FIG. 14 is a graph of the NF-B and MAPK signaling pathway in mouse macrophages induced by safinaldehyde (Safranal) inhibitory polysaccharide;

FIG. 15 is a graph of the effect of safranil (Safranal) on body weight of mice with DSS-induced ulcerative colitis;

FIG. 16 is a graph of the effect of safranil (Safranal) on the disease activity index in DSS-induced ulcerative colitis mice;

FIG. 17 is a graph of the effect of safranil (Safranal) on colon length in DSS-induced ulcerative colitis mice.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.