WO2020192232A1 - Application de l'andrographolide dans l'inhibition de la formation et de l'activation des ostéoclastes - Google Patents

Application de l'andrographolide dans l'inhibition de la formation et de l'activation des ostéoclastes Download PDF

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WO2020192232A1
WO2020192232A1 PCT/CN2019/130829 CN2019130829W WO2020192232A1 WO 2020192232 A1 WO2020192232 A1 WO 2020192232A1 CN 2019130829 W CN2019130829 W CN 2019130829W WO 2020192232 A1 WO2020192232 A1 WO 2020192232A1
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andrographolide
bone
osteoclasts
osteoclast
group
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PCT/CN2019/130829
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Chinese (zh)
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管敏
黄童龄
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深圳先进技术研究院
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • 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

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  • the invention belongs to the technical field of biomedicine, and specifically relates to an application of andrographolide in inhibiting the formation and activation of osteoclasts.
  • Bone supports the body's muscles or organs and protects them from external shocks by surrounding the internal organs. Bone is an important part of the human body, which not only stores calcium in the body, but also stores necessary inorganic substances such as phosphorus or magnesium. The old bone matrix of the adult is removed and replaced with a new bone matrix. Through repeated resorption and destruction processes, that is, bone remodeling, the balance of bone production is maintained.
  • osteoblasts responsible for building bone
  • osteoclasts responsible for destroying bone. That is, under normal conditions, the formation and maintenance of bone homeostasis depends on the dynamic balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. In the life process of an individual, this dynamic balance is affected by genetics, immunity, endocrine, metabolism and nutrition at the overall level; at the tissue cell level, it is affected by the functions of stem cells, osteoblasts, osteoclasts, and bone cells. State regulation; at the molecular level, it is regulated by key signaling molecular pathways. Under physiological conditions, all levels and links are interconnected and regulated to maintain bone homeostasis together. Any problem in any link may cause bone instability, decrease in bone density, and ultimately lead to osteoporosis.
  • the clinical treatment of osteoporosis is mainly divided into two types: promoting bone formation and inhibiting bone resorption.
  • the drugs that promote bone formation mainly include parathyroid hormone and its similar compounds, vitamin D and its derivatives, strontium salts, etc.; drugs that inhibit bone resorption include estrogen, calcitonin, and bisphosphonates.
  • drugs that inhibit bone resorption include estrogen, calcitonin, and bisphosphonates.
  • the main side effects currently found include venous thrombosis, hypocalcemia, hyperthyroidism, esophageal and digestive tract side effects. The treatment brought great pain to the patient both physically and mentally.
  • Andrographis paniculata (Burm.f.) Nees is a dry aerial part of the Acanthaceae plant. It is a commonly used traditional Chinese medicine. It has the effects of clearing heat and detoxification, cooling blood and reducing swelling. It is clinically used for upper respiratory tract infections, acute dysentery, and gastrointestinal Treatment of inflammation, cold and fever. Andrographolide is one of the main chemical components of Andrographis paniculata. However, there are no reports about the use of andrographolide in the prevention and treatment of bone loss diseases.
  • the purpose of the present invention is to overcome the above-mentioned shortcomings of the prior art, and to provide an application of andrographolide as an inhibitor of osteoclast formation and/or activation and preparation of drugs for the prevention/treatment of bone diseases to solve
  • Andrographis paniculata is often used to clear away heat and detoxify, cool blood and reduce swelling, and the effects of existing drugs for treating osteoporosis are not particularly satisfactory, and there are many technical problems with side effects.
  • one aspect of the present invention provides an application method of andrographolide.
  • Application of the andrographolide as an inhibitor of osteoclast formation and/or activation.
  • Another aspect of the present invention provides the application of andrographolide in the preparation of drugs for the prevention/treatment of bone diseases.
  • a medicine for preventing/treating bone diseases includes andrographolide in effective dose.
  • a method for inhibiting the formation of osteoclasts includes the step of contacting an effective dose of andrographolide or the drug for preventing/treating bone diseases of the present invention with osteoclast precursor cells.
  • the method for inhibiting the activity of the GLS promoter induced by ERRa/PGC1- ⁇ includes the step of contacting cells with an effective amount of andrographolide or the drug for preventing/treating bone diseases of the present invention.
  • the andrographolide has a relatively strong function of inhibiting at least one of osteoclast formation and activation. Therefore, after the andrographolide is used as an inhibitor of osteoclast formation and/or activation, it can It can effectively inhibit the differentiation, formation and activation of osteoclasts.
  • the andrographolide of the present invention is used in the preparation of drugs for the prevention/treatment of bone diseases, and the drugs for prevention/treatment of bone diseases prepared based on its application can be used to inhibit the differentiation and maturation of osteoclasts, and can significantly reduce The expression of genes related to osteoclast differentiation can improve bone loss, and ultimately play a role in preventing bone loss diseases such as osteoporosis.
  • andrographolide is a natural substance, it has good curative effect and small side effects.
  • Figure 1 shows the stained photos and histograms of osteoclast numbers after different concentrations of andrographolide inhibited the osteoclast differentiation of mouse bone marrow monocytes.
  • Figure 1-A is the negative control group after TRAP staining on the 5th day of induction. (Control group), positive control group (RANKL group), andrographolide 0.5 ⁇ M, 1 ⁇ M, 2 ⁇ M and 5 ⁇ M group photos;
  • Figure 1-B is a histogram of the number of osteoclasts on the 5th day of induction; and Figure 1-B ***P ⁇ 0.001vs Control, ##P ⁇ 0.01vs RANKL;
  • Figure 2 is a graph showing the level of andrographolide inhibiting the expression of genes related to osteoclast differentiation.
  • Figure 2-A is a bar graph showing the expression levels of osteoclast ERRa genes in the negative control group, positive control group and 0.2 ⁇ m andrographolide group.
  • Figure 2-B is a histogram of the expression levels of osteoclast PGC-1 ⁇ gene in the negative control group, positive control group and 0.2 ⁇ m andrographolide group
  • Figure 2-C is the negative control group, positive control group and 0.2 ⁇ m andrographolide The histogram of the expression level of osteoclast GLS gene in the lactone group
  • Figure 2-D is the histogram of the expression level of osteoclast TRAP gene in the negative control group, the positive control group and the 0.2 ⁇ m andrographolide group
  • Figure E is negative The histogram of the control group, the positive control group and the 0.2 ⁇ m andrographolide group on the expression level of osteoclast CTSK gene
  • Figure 3 is a bar graph of andrographolide inhibiting ERRa/PGC1- ⁇ -induced GLS promoter activity, where ***P ⁇ 0.001vs Con, #P ⁇ 0.05,##P ⁇ 0.01,## #P ⁇ 0.001vs DMSO;
  • Figure 4 shows the enzyme activity of andrographolide on osteoporotic bone loss, bone density, and serum type 1 collagen carboxy-terminal peptide in male mice induced by high-fat diet
  • Figure 4-A is the normal group (CD) , High-fat group (HFD) and high-fat plus andrographolide group (HFD+AP) mouse bone photos
  • Figure 4-B is the normal group (CD), high-fat group (HFD) and high-fat plus andrographolide group (HFD+AP) Bone density, bone volume fraction, number of bone trabeculae and separation of trabecular bone in mice
  • Figure 4-C is the normal group (CD), high fat group (HFD) and high fat plus andrographis The enzyme activity diagram of type 1 collagen carboxyl terminal peptide in the serum of ester group (HFD+AP) mice; and in Figure 4-AC (*P ⁇ 0.05, **P ⁇ 0.01 vs CD, #P ⁇ 0.05 vs HFD)
  • Figure 5 is a graph showing the effects of andrographolide on ovarian removal-induced osteoporotic bone loss, bone density, and enzyme activity of type 1 collagen carboxy-terminal peptide in serum;
  • Figure 4-A shows the sham operation group (sham) , Ovarian removal group (OVX) and ovarian removal plus andrographolide group (OVX+AP) mouse bone photos;
  • Figure 4-B is the sham operation group (sham), ovarian removal group (OVX) and ovarian removal plus andrographolide Group (OVX+AP) mice bone density, bone volume fraction, bone trabecular bone number and bone trabecular separation diagram;
  • Figure 4-C is the sham operation group (sham), ovarian removal group (OVX) and ovarian removal plus Enzyme activity diagram of type 1 collagen carboxyl terminal peptide in serum of andrographolide group (OVX+AP) mice; and (**P ⁇ 0.01,***P ⁇ 0.001vs sham,#P ⁇ in Figure 5-
  • Osteoclast also known as bone-resorbing cells, OC: is a kind of bone-resorbing cells, derived from the mononuclear macrophage lineage, is a multinucleated giant cell with bone resorption function, and is the only bone in the human body Absorb cells to perform the function of bone resorption. Insufficiency or increase in its quantity and activity can lead to osteosclerosis, osteoporosis and other osteolytic diseases, respectively. Highly expressed tartrate resistant acid phosphatase and cathepsin K are the main signs of osteoclasts.
  • ERR ⁇ It belongs to estrogen-related receptors, a type of orphan nuclear hormone receptor with continuous activation transcription activity.
  • Glutaminase Located in the cytoplasm, mitochondrial matrix and mitochondrial membrane, it is the first catalytic enzyme in the main metabolic pathway of glutamine. It requires inorganic phosphate and ammonium ions as activators to catalyze the hydrolysis of glutamine It becomes glutamic acid and ammonia, and then is converted into ⁇ -ketoglutarate to enter the tricarboxylic acid cycle. It is completely oxidized to generate a large amount of ATP, which becomes the other required substrates and the carbon source of fat in the TCA cycle.
  • the inventors of the present invention have discovered based on a large number of studies that andrographolide has the ability to inhibit the formation and activation of osteoclasts. Based on this, the embodiments of the present invention provide applications of andrographolide in the following related aspects.
  • the embodiments of the present invention provide the use of andrographolide as an inhibitor of osteoclast formation and/or activation. According to related experiments constructed by the inventor, as an active ingredient, the andrographolide can effectively inhibit the formation and activation of osteoclasts.
  • the andrographolide has the function of inhibiting the differentiation and maturation of osteoclasts. Therefore, the andrographolide can be used as an inhibitor of osteoclast formation, and further can be used for Preparation of related drugs to inhibit the formation of osteoclasts. This effectively inhibits the differentiation and maturation of osteoclasts, thereby balancing osteoclasts and osteocytes, thereby improving corresponding bone diseases.
  • the andrographolide has the function of inhibiting the expression of genes related to osteoclast differentiation. Therefore, the andrographolide can be used for osteoclast differentiation genes TRAP, CTSK, ERRa, PGC-1 ⁇ , Gls expression inhibitor, and further can be used to prepare drugs for inhibiting the expression of osteoclast differentiation genes TRAP, CTSK, ERRa, PGC-1 ⁇ , and Gls. This effectively inhibits the differentiation of osteoclasts, thereby balancing osteoclasts and bone cells, thereby improving the corresponding bone diseases.
  • the andrographolide has the function of inhibiting the activity of the GLS promoter induced by ERRa/PGC1- ⁇ .
  • ERR ⁇ is currently considered to mainly interact with peroxisome proliferator receptor ⁇ coactivator 1 ⁇ , 1 ⁇ (PGC-1 ⁇ , PGC-1 ⁇ ) to jointly regulate the transcription of genes in the oxidative phosphorylation pathway, thereby Regulates the balance of energy metabolism.
  • POC-1 ⁇ , PGC-1 ⁇ peroxisome proliferator receptor ⁇ coactivator 1 ⁇ , 1 ⁇
  • Recent studies have also shown that ERR ⁇ may have an important regulatory role in the process of osteoclast formation and bone resorption.
  • Glutaminase can not only catalyze the hydrolysis of glutamine into glutamate and ammonia, and then convert it into ⁇ -ketoglutarate to enter the tricarboxylic acid cycle, complete oxidation to generate a large amount of ATP, and become other requirements in the TCA cycle
  • the metabolites produced in the process of glutamine metabolism can be used as an important material basis for cell proliferation and differentiation.
  • ERRa can regulate bone by regulating the expression of GLS.
  • the role of GLS in the process of osteoclast differentiation is not yet known.
  • the andrographolide can be used as an inhibitor of ERRa/PGC1- ⁇ -induced GLS promoter activity signal pathway, and further can be used to prepare related drugs that inhibit osteoclast formation. This effectively inhibits the differentiation and maturation of osteoclasts, thereby balancing osteoclasts and osteocytes, thereby improving corresponding bone diseases.
  • the andrographolide has the function of inhibiting the activation of osteoclasts. Therefore, the andrographolide can be used to inhibit osteoclast activation inhibitors, and further can be used to prepare related drugs that inhibit osteoclast activation. This effectively inhibits the activation of osteoclasts, thereby inhibiting the bone absorption effect of osteoclasts, thereby improving the corresponding bone diseases.
  • andrographolide can be used in the preparation of drugs for the prevention/treatment of bone diseases.
  • the andrographolide is an effective ingredient that inhibits the formation or/and activation of osteoclasts, which can inhibit the formation of osteoclasts, including differentiation and maturation, thereby achieving Balance between bone cells and osteoclasts, thereby improving the corresponding bone diseases; or directly inhibit the activation of osteoclasts, thereby inhibiting the bone resorption of osteoclasts, thereby improving the corresponding bone diseases.
  • the bone diseases described above include primary osteoporosis, secondary osteoporosis, rheumatoid arthritis, multiple myeloma, Paget's disease, and hypercalcemia of malignant tumors. At least one of osteogenesis imperfecta and alveolar bone loss.
  • the andrographolide in the above embodiments can be extracted from the original medicinal material of Andrographis paniculata according to the existing conventional methods.
  • a new extraction method can also be designed to extract from the original medicinal material of Andrographis paniculata.
  • embodiments of the present invention also provide a medicine for preventing/treating bone diseases.
  • the medicine includes an effective amount of active ingredients for preventing/treating bone diseases.
  • the active ingredient includes andrographolide.
  • the active ingredient may also include other active ingredients that can effectively inhibit osteoclast-related properties.
  • the "effective” mentioned here refers to the prevention or treatment of bone diseases alone.
  • the clinically effective component can also be a component that can improve andrographolide to prevent or treat bone diseases after being compounded with andrographolide.
  • the "effective dose” refers to an effective amount capable of preventing or treating bone diseases, and refers to an amount of andrographolide sufficient to show benefits or clinical significance to an individual.
  • the effective dose of andrographolide is 30 mg/kg-100 mg/kg, specifically, the effective dose for mouse clinical experiments is 30 mg/kg-100 mg/kg.
  • the drug for preventing/treating bone diseases may further include a pharmaceutically acceptable carrier component of andrographolide.
  • the carrier component of the pharmaceutically acceptable andrographolide may be a corresponding carrier of a corresponding dosage form prepared according to the administration mode of the drug for treating tumors.
  • the carrier includes but not only corn oil. As long as it is a carrier that can support the andrographolide and facilitate its stability and absorption, it is within the scope of the disclosure of the present invention. Therefore, according to the choice of the carrier, the dosage form of the drug may be at least one of an oral dosage form, an injection dosage form and an external dosage form.
  • the drug for preventing/treating bone diseases contains the above andrographolide, the drug can effectively inhibit the formation and activation of osteoclasts.
  • the andrographolide can significantly inhibit the differentiation and maturation of osteoclasts; inhibit the expression of osteoclast differentiation genes TRAP, CTSK, ERRa, PGC-1 ⁇ , and Gls; inhibit ERRa/PGC1- ⁇ Induced GLS promoter activity; In addition, it can directly inhibit the activation of osteoclasts, thereby inhibiting the bone resorption of osteoclasts, improving bone loss, and ultimately preventing osteoporosis.
  • andrographolide is a natural substance, it has good curative effect, small side effects and safety.
  • the embodiment of the present invention provides a method for inhibiting the formation of osteoclasts.
  • the method includes the step of contacting an effective dose of the andrographolide or the drug for preventing/treating bone diseases described above with osteoclast precursor cells.
  • the method can effectively inhibit the differentiation and maturation of osteoclast precursor cells into osteoclasts.
  • the osteoclast precursor cells can be but not only monocytes.
  • the embodiment of the present invention provides a method for inhibiting the activity of GLS promoter induced by ERRa/PGC1- ⁇ .
  • the method includes the step of contacting cells with an effective dose of andrographolide or the drug for preventing/treating bone diseases described above.
  • the method can effectively inhibit the expression of genes related to osteoclast differentiation, thereby inhibiting the formation of osteoclasts.
  • Example 1 The effect of andrographolide on the osteoclast differentiation of mouse bone marrow monocytes
  • the experimental method is as follows:
  • Figure 1-A shows the negative control group (Control group), positive control group (RANKL group), andrographolide 0.5 ⁇ M, 1 ⁇ M, 2 ⁇ M and 5 ⁇ M after TRAP staining on the 5th day of induction.
  • Figure 1-B is a histogram of the number of osteoclasts on the fifth day of induction. It can be seen from Figure 1 that within the effective dose concentration, andrographolide concentration-dependently inhibits the differentiation of monocytes into osteoclasts.
  • the experimental method is as follows:
  • mice primary monocytes were extracted for osteoclast differentiation, and the cells were seeded in a 24-well plate at 4 ⁇ 10 5 /mL.
  • the experiment was grouped as follows: the negative control group (Control group) only added 40ng /mL M-CSF, 40ng/mL M-CSF and 100ng/mL RANKL were added to the positive control group (RANKL group) and the drug group, and 2 ⁇ M andrographolide was added to the drug group at the same time. Each group had 3 replicate holes. After induction for 3 days , Discard the medium, wash with PBS, add Trizol to lyse the cells, extract the total RNA in the cells, and prepare cDNA by reverse transcription. The system is shown in the following expression 1:
  • Realtime PCR uses a 20 ⁇ l reaction system, and prepare the PCR reaction solution according to the components in Table 2 (the reaction solution is prepared on ice).
  • the primer sequence is shown in Table 3 below:
  • the experimental method is as follows:
  • the experimental method is as follows:
  • mice Six-week-old male C57BL/6 mice were divided into 3 groups, ordinary group (CD), high-fat group (HFD) and high-fat plus andrographolide group (HFD+AP).
  • the general group was given regular feeding, and the high-fat group and the high-fat drug group were given a high-fat diet.
  • the high-fat medicated group was given a high-fat diet and andrographolide 50 mg/kg was administered daily.
  • the mice were sacrificed, and blood and bone samples were collected for testing.
  • the imaging characteristics of the mice were analyzed by MicroCT, and the results are shown in Figure 4. It can be seen from Figure 4 that andrographolide can reverse the bone loss of osteoporosis induced by high-fat diet, as shown in Figure 4-A.
  • the experimental method is as follows:
  • mice Seven-week-old female C57BL/6 mice were randomly divided into 3 groups, sham operation group (sham), ovarian removal group (OVX) and ovarian removal plus andrographolide group (OVX+AP). After bilateral incisions were made on the back of the mice, the ovarian removal group and the ovarian removal plus medicine group had their ovaries removed, and the sham operation group only had bilateral incisions. Two weeks after the operation, the ovarian removal plus medicine group was given andrographolide 30 mg/kg per day. Three weeks later, the mice were sacrificed, and blood and bone samples were collected for testing. The imaging characteristics of the mice were analyzed by MicroCT, and the results are shown in Figure 5.

Abstract

L'invention concerne l'application d'un agent et d'une médication inhibiteurs de la formation et/ou de l'activation des ostéoclastes, ainsi qu'un médicament contenant une dose efficace d'andrographolide, un procédé d'inhibition de la formation des ostéoclastes, et un procédé d'inhibition de l'activité d'un promoteur GLS induit par ERRa/PGC1-β. L'andrographolide peut inhiber la formation et l'activation des ostéoclastes, réduire la perte de masse osseuse, et finalement obtenir l'effet de prévention et de traitement de maladies liées à une perte osseuse telles que l'ostéoporose. De plus, l'andrographolide est une substance naturelle, et présente ainsi un bon effet thérapeutique et peu d'effets secondaires.
PCT/CN2019/130829 2019-03-25 2019-12-31 Application de l'andrographolide dans l'inhibition de la formation et de l'activation des ostéoclastes WO2020192232A1 (fr)

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