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WO2016115840A1 - Utilisations de 2,3,5,4'-tétrahydroxystilbène-2-o-β-d-glucoside dans la préparation d'inhibiteur pour un système immunitaire inné tlr4 - Google Patents

Utilisations de 2,3,5,4'-tétrahydroxystilbène-2-o-β-d-glucoside dans la préparation d'inhibiteur pour un système immunitaire inné tlr4 Download PDF

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Publication number
WO2016115840A1
WO2016115840A1 PCT/CN2015/083448 CN2015083448W WO2016115840A1 WO 2016115840 A1 WO2016115840 A1 WO 2016115840A1 CN 2015083448 W CN2015083448 W CN 2015083448W WO 2016115840 A1 WO2016115840 A1 WO 2016115840A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
ester
tlr4
use according
acceptable salt
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Ceased
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PCT/CN2015/083448
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English (en)
Chinese (zh)
Inventor
俞捷
赵荣华
顾雯
林佩
陆建美
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Yunnan University of Traditional Chinese Medicine TCM
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Yunnan University of Traditional Chinese Medicine TCM
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Publication of WO2016115840A1 publication Critical patent/WO2016115840A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin

Definitions

  • the present invention relates to pharmacological activity studies, and in particular to the inhibitory effect of stilbene glycoside on the innate immune system of TLR4.
  • liver-gut-axis With the increasing understanding of homology, metabolic interaction, and immune association between liver and intestinal anatomy, the concept of liver-gut-axis has been proposed and accepted. The concept of "liver-gut axis" was officially proposed by Marshall in 1998. It clarifies the close relationship between substances, cells, cytokines, etc. between the liver and the intestine through the inherent portal vein system. Depicts the anatomical and functional interactions between the two organs of the liver and the intestine, especially the cytokines and the hepatoenteral circulation of the cells.
  • liver-gut axis can partially explain the cause of nonalcoholic fatty liver disease (NAFLD).
  • NAFLD nonalcoholic fatty liver disease
  • Intestinal flora disorder and intestinal mucosal barrier damage activate liver innate immunity, destroy liver homeostasis and aggravate liver inflammation. Frasinariu OE and others believe that food can change the intestinal flora and increase the intestinal flora and its products through the portal vein translocation to the liver.
  • Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) activate Toll-like receptor-4 (TLR4), and TLRs-mediated signaling induces innate immune responses such as cytokines and IFN- ⁇ .
  • PAMPs Pathogen-associated molecular patterns
  • DAMPs damage-associated molecular patterns
  • TLR4 Toll-like receptor-4
  • cytokines Excessive production of cytokines is associated with elevated levels of LPS-binding proteins produced by endotoxin stimulation in the plasma, promoting endotoxin binding to the CD14/TLR4 complex.
  • the LPS/TLR4 pathway promotes the release of TGF- ⁇ from liver Kupffer cells by sensing the signals produced by transforming growth factor- ⁇ (TGF- ⁇ ) in hepatic stellate cells, leading to the development of liver fibrosis.
  • TGF- ⁇ transforming growth factor- ⁇
  • Stilbene glycoside (2,3,5,4'-tetrahydroxystilbene-2-O- ⁇ -D-glucoside, TSG) has been widely demonstrated to improve liver lipid accumulation and to reduce serum, The content of AST and ALT in liver tissue homogenate has a certain inhibitory effect on inflammation.
  • Zeng Cheng The effect of stilbene glycoside on inflammatory bowel disease: induction of PPAR- ⁇ and inhibition of NF- ⁇ B inflammatory pathway
  • Ph.D. Huazhong University of Science and Technology
  • the inventors have found through experiments that stilbene glycoside and its pharmaceutically acceptable salt or ester can act as inhibitors of the TLR4 innate immune system. This discovery has good prospects for development.
  • the pharmaceutically acceptable salt is selected from various inorganic or organic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, Malay. Acid salts, fumarates, mandelates and oxalates; various inorganic or organic base salts such as sodium hydroxide, trishydroxymethylaminomethane and N-methyl-glucosamine.
  • various inorganic or organic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, Malay. Acid salts, fumarates, mandelates and oxalates
  • various inorganic or organic base salts such as sodium hydroxide, trishydroxymethylaminomethane and N-methyl-glucosamine.
  • the pharmaceutically acceptable ester is selected from a C1-C6 alkyl ester or a benzyl ester.
  • stilbene glucoside and a pharmaceutically acceptable salt or ester thereof may be used singly or in the form of a pharmaceutical composition.
  • the pharmaceutical composition includes stilbene glycoside as an active ingredient and its pharmaceutically acceptable Accepted salt or ester, and one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients include, but are not limited to, fillers such as starch, sucrose, dextrin, lactose, compressible starch, microcrystalline cellulose, sorbitol, etc.; binders such as cellulose derivatives (methyl fibers) , ethyl cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose), sodium alginate, gelatin, polyvinylpyrrolidone, etc.; wetting agents such as water, ethanol, glycerin, etc.; disintegrating agents such as Dry starch, sodium carboxymethyl starch, hypromellose, crospovidone, effervescent disintegrant, agar, calcium carbonate, sodium hydrogencarbonate, etc.; absorption enhancer such as quaternary ammonium compound; surfactant such as ten Hexadecanol; adsorption carrier such as kaolin and soap clay; lubricants such as talc, calcium stearate, magnesium
  • the content of the stilbene glycoside and the pharmaceutically acceptable salt or ester thereof in the pharmaceutical composition is from 0.1 to 99.9% by weight, preferably from 1 to 90% by weight, from 5 to 80% by weight, 10 -70% by weight, 20-60% by weight or 30-50% by weight.
  • the stilbene glucoside and a pharmaceutically acceptable salt or ester thereof and the pharmaceutical composition can be administered by enteral or parenteral route.
  • the administration preparations include tablets, capsules, granules, injections, creams, ointments, patches, sprays, dropping pills, and the like.
  • Routes of administration include subcutaneous, intradermal, intraarterial, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial injection or infusion, or oral, topical, rectal, menstrual Nasal, buccal, vaginal, sublingual, intradermal, mucosal, tracheal, urethral administration, or by inhalation of aerosol or implant accumulation or acupuncture.
  • the preparation may be prepared according to a conventional production method in the pharmaceutical field, for example, by mixing the active ingredient with one or more carriers, and then preparing the desired dosage form.
  • the stilbene glycoside and a pharmaceutically acceptable salt or ester thereof are administered at a daily dose 0.01-200 mg/kg, preferably 0.1-100 mg/kg, 1-80 mg/kg or 10-50 mg/kg, further preferably 12-15 mg/kg, 22-25 mg/kg or 45-50 mg/kg; Treat with medication or combination therapy.
  • the invention induces SD rat model by high-fat diet, induces simultaneous administration of aqueous solution of stilbene, and analyzes the expression of main signal molecules of TLR4 pathway by liver whole gene scanning technology, including CD14 and myeloid differentiation factor 88 (My D88).
  • IL-1 related protein kinases IL-1 related protein kinases
  • IRAKs tumor necrosis factor receptor activating factor 6
  • TGF- ⁇ tumor growth factor- ⁇
  • IFN interferon
  • FIG. 1 Statistical diagram of key gene data in the TLR4 innate immune response system.
  • FIG. 4 Stilbene glycoside against fetuin A (FetA), type 4 Toll-like receptor (TLR4), NF-excellentB, tumor necrosis factor TNF- ⁇ , interleukin-1 alpha (IL-1 alpha), interleukin-6 ( Effects of IL-6) and interleukin-10 (IL-10) levels: *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 compared with the normal group, #p ⁇ compared with the model group 0.05, ##p ⁇ 0.01, ###p ⁇ 0.001.
  • mice Twenty-one SD rats, weighing 180-200 g, were randomly divided into three groups: normal control group (CON), high fat model group (MOD), and stilbene glycoside (24.28 mg/kg) administration group (TSG.).
  • CON normal control group
  • MOD high fat model group
  • TSG stilbene glycoside
  • each group was fed a high-fat diet (cholesterol 1%, lard 10%, cooked egg yolk 10%) for 12 weeks until the end of the experiment.
  • a high-fat diet cholesterol 1%, lard 10%, cooked egg yolk 10%
  • the rat liver was removed, weighed, washed with 0.9% saline, and part of the liver was cut into a cryotube and quickly stored in liquid nitrogen for whole-genome detection.
  • the data analysis results of the invention are all adopted Expressed and used one-way analysis of variance (ANOVA).
  • Agilent's rat 4x44K gene expression chip was used to perform whole-genome scanning on the liver tissues of three groups of rats.
  • the main expression genes in the TLR4 innate immune response system were selected, and the key gene expression clustering tree and corresponding standardized signal values were obtained.
  • Figure 2, 3 The results showed that the bacterial lipopolysaccharide brought by the high-fat diet for 12 weeks in SD rats was used as an exogenous ligand or fetuin secreted by the liver as an endogenous ligand, which increased the expression of CD14 and TLR4 signals and promoted the distribution.
  • the complex which causes the recruitment of downstream signaling molecules, is mainly expressed in the protein kinase-binding protein Tab2, transforming growth factor- ⁇ (Tgfb1), IL-1 ⁇ , IL-6 and interferon, which cause tumor necrosis factor Tnf and ⁇ transforming growth factor activation.
  • Tgfb1 transforming growth factor- ⁇
  • IL-1 ⁇ IL-1 ⁇
  • IL-6 interferon
  • TSG group administered with aqueous solution of stilbene, it is better to inhibit LR4 activation of leucine-rich region expression (Tril), down-regulate the expression of CD14 and TLR4 signaling molecules, and effectively inhibit the signal expression of downstream cytokines, among which IL -6.
  • Tgfb1 signaling molecules is significant, which inhibits the TLR4 innate immune response system.
  • the aqueous solution of stilbene was given to reduce the content of TLR4 by 56% compared with the model group, increase the content of IL-10, and inhibit the protein content of FetA and NF-excellentB to some extent, thereby inhibiting the release of related inflammatory factors. It shows that stilbene glycoside has a certain inhibitory effect on TLR4 innate immune response system.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des utilisations de 2,3,5,4'-tétrahydroxystilbène-2-O-β-D-glucoside et un sel ou ester pharmaceutiquement acceptable de ce dernier dans la préparation d'un inhibiteur pour un système immunitaire inné TLR4. Le 2,3,5,4'-tétrahydroxystilbène-2-O-β-D-glucoside peut soulager un système de réponse immunitaire inné TLR4. Un résultat de détection de protéine ELISA montre que le 2,3,5,4'-tétrahydroxystilbène-2-O-β-D-glucoside peut réduire la teneur en TLR4 de 56 % et réduire l'expression de NF-κB de 23 % par comparaison avec ceux d'un groupe témoin et, par conséquent, empêche efficacement la libération de facteurs inflammatoires.
PCT/CN2015/083448 2015-01-21 2015-07-07 Utilisations de 2,3,5,4'-tétrahydroxystilbène-2-o-β-d-glucoside dans la préparation d'inhibiteur pour un système immunitaire inné tlr4 Ceased WO2016115840A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510029335.0A CN104546874A (zh) 2015-01-21 2015-01-21 二苯乙烯苷在制备tlr4固有免疫系统的抑制剂中的应用
CN201510029335.0 2015-01-21

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WO2016115840A1 true WO2016115840A1 (fr) 2016-07-28

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CN105726508B (zh) * 2016-01-12 2019-02-15 中国人民解放军第四军医大学 新型二苯乙烯苷缓控释制剂及其制备方法

Citations (1)

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CN102321129A (zh) * 2011-07-14 2012-01-18 中国人民解放军第四军医大学 一种二苯乙烯苷注射剂及其制备工艺

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CN103385967A (zh) * 2013-07-19 2013-11-13 苏州市天灵中药饮片有限公司 一种包含何首乌的中药及其制备方法

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CN102321129A (zh) * 2011-07-14 2012-01-18 中国人民解放军第四军医大学 一种二苯乙烯苷注射剂及其制备工艺

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZENG, CHENG;: "Beneficial Effects of THSG on Acetic Acid-induced Experimental Colitis: Involvement of Upregulating PPAR-y and Inhabiting NF-kappaB Inflammatory Pathway", MEDICINE & PUBLIC HEALTH, CHINA DOCTORAL DISSERTATIONS FULL-TEXT DATABASE (ELECTRONIC JOURNALS, 15 July 2012 (2012-07-15), pages E057 - 22, ISSN: 1674-022X *

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