WO2023065478A1 - Utilisation d'icariside i - Google Patents

Utilisation d'icariside i Download PDF

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Publication number
WO2023065478A1
WO2023065478A1 PCT/CN2021/135559 CN2021135559W WO2023065478A1 WO 2023065478 A1 WO2023065478 A1 WO 2023065478A1 CN 2021135559 W CN2021135559 W CN 2021135559W WO 2023065478 A1 WO2023065478 A1 WO 2023065478A1
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Prior art keywords
icariside
fermented
epimedium extract
epimedium
extract
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PCT/CN2021/135559
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English (en)
Chinese (zh)
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李慧灵
黄佳俊
陈川
张利民
罗冬章
林育成
周金林
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广东金骏康生物技术有限公司
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Publication of WO2023065478A1 publication Critical patent/WO2023065478A1/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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/29—Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
    • A61K36/296—Epimedium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/80—Vectors or expression systems specially adapted for eukaryotic hosts for fungi
    • C12N15/81—Vectors or expression systems specially adapted for eukaryotic hosts for fungi for yeasts
    • C12N15/815—Vectors or expression systems specially adapted for eukaryotic hosts for fungi for yeasts for yeasts other than Saccharomyces
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
    • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/14—Preparation of compounds containing saccharide radicals produced by the action of a carbohydrase (EC 3.2.x), e.g. by alpha-amylase, e.g. by cellulase, hemicellulase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/10—Plasmid DNA
    • C12N2800/102—Plasmid DNA for yeast

Definitions

  • the invention relates to the field of medicine, in particular to the application of icariside I.
  • Osteoporosis is a disease characterized by decreased bone mass, changes in the microstructure of bone tissue, and an increased risk of fracture. Osteoblast proliferation inhibition and reduced differentiation are important causes of osteoporosis.
  • the clinical manifestations of osteoporosis are low back pain, limb weakness, and bone pain. Because of its high incidence and great harm in middle-aged and elderly people, it has been highly valued by the society and the medical field.
  • the treatment of osteoporosis mainly uses estrogen, calcium, active vitamin D, calcitonin and fluoride as commonly used drugs. Although it has a certain effect, it has the disadvantages of large adverse reactions and patients cannot tolerate it for a long time. .
  • icariside I is a trace flavonoid glycoside compound in the Chinese herbal medicine Epimedium.
  • epimedium drugs can increase the blood flow of cardiovascular and cerebrovascular, promote hematopoietic function, immune function and bone metabolism, and also have the functions of nourishing kidney and strengthening yang, anti-aging and so on.
  • Icariside I as the main metabolite of icariin, has little research on the anti-osteoporosis.
  • the technical problem to be solved by the present invention is to provide a new application of icariside I, i.e. the application in the preparation of medicines or health products for the prevention and/or treatment of osteoporosis.
  • the medicine can be made into any dosage form, exemplified by tablets, capsules, granules, soft capsules, dripping pills, syrups or injections, but not limited thereto.
  • the daily dosage of icariside I is 5-50 mg/kg ⁇ BW (body weight).
  • the icariside I is obtained by fermenting the epimedium extract with Pichia pastoris engineering bacteria GS115-KA; the icariside I in the fermented epimedium extract The content is greater than or equal to 1%; wherein, the Pichia pastoris engineering strain GS115-KA is a rhamnosidase TpeRha-K579A gene mutant.
  • the specific amino acid sequence and nucleotide sequence of the rhamnosidase TpeRha-K579A mutant refer to the applicant's previous application CN113136378B.
  • the preparation method of Pichia pastoris engineered bacteria GS115-KA is:
  • the preparation method of fermented Epimedium extract is:
  • icariside I is obtained by enzymatically hydrolyzing the epimedium extract with rhamnosidase TpeRha-K579A enzyme, and enzymatically hydrolyzing the content of icariside I in the epimedium extract The content is greater than or equal to 1%.
  • this application also discloses the use of fermented Epimedium extract in the preparation of medicines or health products for the prevention and/or treatment of osteoporosis; wherein, the content of icariside I in the fermented Epimedium extract The content is greater than or equal to 1%.
  • this application also discloses the use of the enzymatically hydrolyzed Epimedium extract in the preparation of medicines or health products for the prevention and/or treatment of osteoporosis; wherein, the enzymatically hydrolyzed Epimedium extract contains The content of I is greater than or equal to 1%.
  • the medicine can be made into any dosage form, exemplified by tablets, capsules, granules, soft capsules, dripping pills, syrups or injections, but not limited thereto.
  • the daily dosage of icariside I is 5-50 mg/kg BW (body weight).
  • the present invention shows that icariside I can be used for treating osteoporosis through pharmacological experiments. Specifically, the results of in vitro experiments show that icariside I can significantly promote the proliferation of osteoblasts, and the results of in vivo experiments show that icariside I can significantly increase the bone density of mice and promote the formation of osteoblasts. Inhibits osteoclast formation. Moreover, it has been proved by in vivo experiments that when the dose ranges from 5-50 mg/kg ⁇ BW, it has the best therapeutic effect, and at high doses (200 mg/kg ⁇ BW), there is no therapeutic effect. In addition, the present invention uses the fermented or enzymatically hydrolyzed Epimedium extract to add pharmaceutically acceptable carriers to prepare various preparations. The preparations have low toxic and side effects and make up for the disadvantages of long-term use of the commercially available drugs.
  • Fig. 1 is the impact diagram of each test group on mouse liver weight in embodiment 2;
  • Fig. 2 is the liver slice figure of Sham group mouse in embodiment 2;
  • Fig. 3 is the liver section figure of OVX group mouse in embodiment 2;
  • Fig. 4 is the liver slice figure of ALN group mouse in embodiment 2;
  • Fig. 5 is the L group mouse liver slice figure among the embodiment 2;
  • Fig. 6 is the liver section figure of group M mice in embodiment 2;
  • Fig. 7 is the liver section figure of group H mice in embodiment 2;
  • Fig. 8 is the figure of influence of each test group on total bone density in embodiment 2;
  • Fig. 9 is the impact diagram of each test group on cortical bone density in embodiment 2.
  • Fig. 10 is the impact diagram of each test group on the bone density content of cancellous bone in embodiment 2;
  • Fig. 11 is the impact diagram of each test group on mouse osteocalcin in embodiment 2;
  • Fig. 12 is the figure of the influence of each test group on the activity of ALP in rBMSCs cells in embodiment 3;
  • Fig. 13 is the impact diagram of each test group on ALP mRNA expression in rBMSCs cells in embodiment 3;
  • Fig. 14 is a diagram showing the influence of each test group on the expression of Run ⁇ 2 mRNA in rBMSCs cells in Example 3.
  • This implementation provides a preparation method of fermented Epimedium extract, which includes:
  • the rhamnosidase TpeRha-K579A gene was connected to the plasmid pPIC9K, and the plasmid was transformed into Pichia pastoris GS115 to obtain engineering bacteria GS115-KA;
  • the volume of the fermentation medium is 3.5L
  • the medium formula is: 85% (w/v) H 3 PO 4 26.7ml/L, CaSO 4 0.93g/L, K 2 SO 4 18.2g/L, KOH 4.13g/L, MgSO 4 7H 2 O 14.9g/L, glycerin 40g/L, yeast extract 5g/L, peptone 5g/L, trace element PTM1 4.4ml/L, defoaming oil 15mL, 30mL ammonia water to adjust the pH to 5.0.
  • mice that underwent surgery without ovariectomy were used as the sham operation group (SHAM), and the mouse osteoporosis model made in step (1) was randomly divided into the control group (OVX), the A Lunronate sodium intervention group (ALN), fermented or enzymatically hydrolyzed Epimedium extract (based on 1 dose of icariin) low, middle and high dose groups L, M, and H, a total of 6 groups, with three mice in each group.
  • OVX control group
  • Epimedium extract based on 1 dose of icariin
  • FIG. 1 is a graph showing the influence of each test group on the mouse liver weight by each test group. It can be seen from Figure 1 that the livers of the mice in the Sham group and the ALN group were normal and not affected, the livers of the mice in the model group were affected, and the liver anatomy and morphology of the mice were normal under the three doses of low, medium and high.
  • FIGS 2 to 7 are liver slices of mice in each test group. From the pictures, after taking the fermented icariin extract, the liver of the mice returned to normal, indicating that the fermented icariin extract has low toxicity , or may have the effect of repairing the liver.
  • Figures 8 to 10 are diagrams showing the influence of each test group on bone density. It can be seen from the figure that compared with OVX after 4 weeks of administration, the low-dose group (L) and the middle-dose group (M) have improved bone mineral density, and the low-dose group (L) has the best effect , low dose (L) and middle dose group (M) compared with the drug alendronate sodium group, the effect is better than the alendronate sodium group (ALN), and the high dose group (H) has no improvement effect. It shows that the daily dosage of 5-50 mg/kg ⁇ bw in mice does not improve the bone density in a dose-dependent manner, and the high dosage has the opposite effect.
  • Figure 11 is a diagram of the influence of each test group on mouse osteocalcin. It can be seen from the figure that after 4 weeks of administration, in the blood of mice, the content of osteocalcin in the Sham group is the highest, which is the expression of normal mice. Osteocalcin in the OVX group was the lowest, indicating that the bone loss of the mice was severe after ovariectomy, which also indicated that the osteoporosis model was successfully established.
  • the treatment effect of the L group was the best, strong
  • the treatment effect of M group is not as good as that of L group, but it also has a certain effect, which is better than that of OVX group. It has an effect at a dose of 5-50 mg/kg ⁇ BW, the optimal dose is 5 mg/kg ⁇ BW, and there will be opposite results at high doses. Cannot reach the effect of treating osteoporosis.
  • rBMSCs rat bone marrow mesenchymal stem cells
  • ALP alkaline Phosphatase
  • Control group basic culture medium: DMEM+10mL/dL fetal bovine serum (containing 100U/ml penicillin and streptomycin), fermented Epimedium extract Intervention group: basic culture medium+fermented or enzymolyzed Epimedium Husk extract 1 ⁇ 10 -5 mol/L, 1 ⁇ 10 -6 mol/L, 1 ⁇ 10 -7 mol/L, 1 ⁇ 10 -8 mol/L, 1 ⁇ 10 -9 mol/L, 1 ⁇ 10 -10 mol/L.
  • Figure 12 is a diagram showing the influence of each test group on the ALP activity in rBMSCs cells. It can be seen from the figure that the ALP activity of different concentrations of fermented Epimedium extract intervened in rBMSCs was higher than that of the control group, and at 1 ⁇ 10 -7 mol/L, 1 ⁇ 10 -8 mol/L, 1 ⁇ 10 -9 mol/L, 1 ⁇ 10 -10 mol/L have the most significant effect.
  • Figure 13 is a graph showing the influence of each test group on the expression of ALP mRNA in rBMSCs cells; it can be seen from the graph that the expression level of ALP mRNA significantly increased at a concentration of 1 ⁇ 10 -6 mol/L.
  • Figure 14 is a diagram of the influence of each test group on the expression of Run ⁇ 2 mRNA in rBMSCs cells; it can be seen from the figure that the expression level of Run ⁇ 2 mRNA at a concentration of 1 ⁇ 10 -7 mol/L is much higher than that of the control group.
  • Run ⁇ 2 is a specific transcription factor for osteoblasts and a key regulator of osteoblast differentiation, and is an important transcription factor for activating and initiating the differentiation of BMSCs into osteoblasts and regulating the maturation of osteoblasts during bone development.
  • the fermented Epimedium extract can promote the proliferation of primary osteoblasts. And in the range of 1 ⁇ 10 -6 -1 ⁇ 10 -10 mol/L, it can promote the proliferation of primary osteoblasts very well.
  • the present invention proves that the fermented Epimedium extract has little toxic effect on the host through safety experiments; through in vivo experiments on osteoporosis mice, it is proved that the fermented Epimedium extract can increase the bone density of mice, It can promote proliferation of osteoblasts and inhibit osteoclasts. Moreover, icariside I has an effect on the treatment of osteoporosis at a dose of 5-50 mg/kg ⁇ BW, and a high dose will have the opposite result, and the effect of treating osteoporosis cannot be achieved. Through in vitro experiments, it has been proved that the fermented epimedium extract has a proliferative effect on osteoblasts. According to the above examples, it is proved that icariside I and fermented epimedium extract can be used as medicine for treating osteoporosis.

Abstract

L'invention concerne l'utilisation d'icariside I. Des expériences montrent que l'icariside I peut améliorer significativement la densité osseuse d'une souris, favoriser la formation d'ostéoblastes et inhiber la formation d'ostéoclastes, de telle sorte que l'icariside I peut être utilisé dans la préparation d'un médicament ou d'un produit de soins de santé pour prévenir et/ou traiter l'ostéoporose.
PCT/CN2021/135559 2021-10-18 2021-12-04 Utilisation d'icariside i WO2023065478A1 (fr)

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