32 results about "RANKL" patented technology

The invention discloses a bifidobacterium animalis subsp. Lactis BA-C53 and an application of the bifidobacterium animalis subsp. Lactis BA-C53 in products for improving bone health. The bifidobacterium animalis subsp. Lactis BA-C53 is classified and named as bifidobacterium animalis subsp. Lactis Bifidobacterium animalis subsp. Lactis BA-C53, the preservation number is CCTCC NO: M 2024460, the preservation unit is China Center for Type Culture Collection, and the preservation time is March 11, 2024. The bifidobacterium animalis subsp. Lactis BA-C53 can effectively improve the steady state of intestinal flora of a mouse with osteoporosis induced by estrogen deficiency, so that the relative abundance of phylum firmicalis and phylum actinomycetes is increased, the relative abundance of phylum bacteroides is reduced, and then short-chain fatty acid is generated to activate intestinal immunity and maintain the integrity of an intestinal barrier, so that the osteoporosis caused by estrogen deficiency is inhibited. Meanwhile, osteoclast differentiation can be inhibited by regulating NFATC1, RANKL and OPG pathways, then osteoporosis is relieved, and the compound can be widely applied to preparation of food and drugs.

The invention provides a polyketone compound and application thereof in preparation of an osteoclast differentiation inhibitor, and relates to the technical field of marine natural products. The compound is obtained by separation and purification from a fermentation culture of a marine fungus talaromyces sp. GMIMD 02524 (the preservation number is GDMCC No. 66968), the compound is named as talaromyces furanone A, and the structure of the compound is as shown in the formula (I) in the specification. The compound can effectively inhibit RANKL-induced osteoclast differentiation by inhibiting an NF-kappa B signal channel in vitro, and has no obvious cytotoxicity at an effective concentration. Therefore, the compound talaromyfuranone A can be used for developing medicines for preventing and treating osteoclast-related osteolytic diseases such as osteoporosis and the like, and has a good application prospect.

The invention discloses application of a compound with a benzo-aza structure in preparation of a medicine for inhibiting osteoclast formation, the structure of the compound is shown as a formula (1), and R substituent is one of H, OCH3, Br, F and i-Pr. Cell experiments prove that the compound with the benzo-aza structure has a remarkable inhibiting effect on RANKL-induced osteoclast differentiation and marker gene expression, can be used as a candidate medicine which is novel in structure and is used for inhibiting osteoclast formation, and is used for targeting osteoclast to treat osteoporosis related diseases.

In one aspect, the disclosure relates to a method for treating clonal hematopoiesis of indeterminate potential (CHIP) in a subject, the method including at least the step of administering to the subject a therapeutically effective amount of an inhibitor of receptor activator of nuclear factor κB ligand (RANKL), such as denosumab, a therapeutically effective amount of an anti-inflammatory agent, such as colchicine, or both. In a further aspect, performing the method reduces growth of one or more clones or causes the size of one or more clones to remain constant. In another aspect, each month of performing the method can result in a further reduction of annual clonal growth rate. In a still further aspect, performing the method further treats or prevents a cardiometabolic disease, a cardiovascular disease, or a myeloproliferative disease or disorder. Also disclosed are methods for reducing or maintaining clonal hematopoiesis risk score (CHRS) in a subject.

The invention discloses an anti-osteoporosis drug screening kit, and belongs to the technical field of drug screening, the anti-osteoporosis drug screening kit comprises a device base, one side of the top of the device base is fixedly connected with a constant temperature supporting mechanism, the center of the constant temperature supporting mechanism is provided with a rotation continuous mechanism, and the rotation continuous mechanism is provided with a rotation mechanism. A plurality of microporous RANK protein detection plates are placed on the rotary continuous mechanism, an RANKL solution temporary storage refrigerating box is arranged in the center of the top of the constant-temperature supporting mechanism, a source plate temporary storage mechanism is arranged on one side of the front end of the top of the device base, and a multidirectional driving mechanism is arranged at the top of the device base. And a cleaning mechanism is mounted on one side of the multidirectional driving mechanism. By designing the constant-temperature supporting mechanism and the rotating continuous mechanism, multiple groups of compounds can be screened in sequence, circulating continuous operation is achieved, the time utilization rate is greatly increased, and then the compound screening efficiency is improved.

The invention discloses an osteoclast culture method as well as a culture medium and application thereof, the culture method is based on primary monocyte extraction, inoculation is performed according to a specific density, then quantitative M-CSF is added, and culture is performed overnight; on the second day, when the cell confluence degree of the mononuclear bone marrow hematopoietic stem cells is 5-30%, supplementing quantitative RANKL into each hole, continuously culturing for 2-4 days, then changing the solution, and obtaining mature osteoclasts on the sixth-seventh day. According to the invention, the optimization relationship among the cell activity, the cell density and the culture medium in the primary culture process of the osteoclast is deeply studied, and from the perspective of cost reduction and efficiency improvement, the use cost of cell factors is remarkably reduced, the number of times of liquid change is reduced, and the traditional culture time of 10-12 days (calculated from cell extraction) is shortened to 6-7 days. The average diameter of the mature osteoclast cultured by the method is larger, the number of fused cell nucleuses is larger, the space proportion of the mature osteoclast is not less than 80%, and the cell quality is obviously higher than that in the prior art.

The invention belongs to the technical field of biological medicine, and particularly relates to a new Spp1 + Carmil1 + and Spp1 + Cav1 + macrophage subgroup, a screening method and application in diagnosis and treatment of rheumatoid arthritis (RA). Aiming at the function limitation of a traditional M1 / M2 classification model, the invention proves the following new subgroup pathological interaction mechanism: osteoclast (ACP5 +) specifically releases TNFSF11 (RANKL), and is co-localized with Spp1 + Carmil1 + and Spp1 + Cav1 + subgroup space; the Spp1 + Carmil1 + subgroup secretes IL-18, and space interaction exists between the Spp1 + Carmil1 + subgroup and Treg (Foxp3 +) and Th17 (Il17a +) cells. The invention provides a novel cell marker and a targeted treatment strategy for accurate diagnosis and treatment of RA.

The present application relates to a kind of RANKL / NLRP3 dual-target inhibitor and its preparation method and application, belong to the field of pharmaceutical chemistry and biomedical technology.The indole compound, its optical isomer, pharmaceutically acceptable salt and hydrate provided by the present application have RANKL and NLRP3 dual-target inhibition activity, can be inhibited by inhibiting RANKL-RANK interaction, and inhibit inflammasome NLRP3 activity, regulate RANKL activity in osteoclast precursor cell, inhibit the formation of osteoclast, thereby reduce bone resorption, and improve the inflammatory response caused by rheumatoid arthritis, is expected to play the prevention and treatment of bone metabolic disease.

This invention relates to the application of 5-(tetradecoxy)-2-furoic acid (TOFA) in the preparation of drugs that inhibit osteoclast differentiation and function. Using a RANKL-induced mouse bone marrow macrophage osteoclast differentiation model, experiments demonstrated that TOFA can effectively inhibit osteoclast differentiation and function by inhibiting ROS and downregulating the expression of key osteoclast differentiation and function proteins such as Nfatc1, Src, and Ctsk. Furthermore, TOFA at concentrations of 40 μM and below showed no significant cytotoxicity, proving that TOFA can serve as a candidate compound for developing drugs that inhibit osteoclast differentiation and function, and for treating diseases caused by excessive activation of osteoclasts, thus possessing significant clinical application value. Additionally, by constructing a mouse ovariectomized osteoporosis model, the preventive and therapeutic effects of TOFA on estrogen-deficiency-induced osteoporosis were demonstrated.

The invention provides application of wogonoside in preparation of a medicine for preventing and treating inflammatory osteolysis, and belongs to the technical field of bone disease treatment, wogonoside has an inhibiting effect on RANKL-induced osteoclast generation and bone resorption, and MAPK and NF-kB signal channels related to osteoclast differentiation are detected through WB and PCR experiments. The wogonoside has an inhibiting effect on osteoclast differentiation, bone resorption function and bone loss of LPS-induced inflammatory osteolysis mice, and the effect is possibly related to inhibition of RANKL-mediated ROS level and a downstream MAPK signal channel. Therefore, the invention possibly provides a new treatment thought for preventing inflammatory osteolysis diseases.

The invention discloses a drug for combined treatment of breast cancer bone metastasis, the drug comprises two active components, namely a first active component and a second active component, the first active component is Bufalin and its pharmaceutically acceptable salt, prodrug and derivative, and the second active component is RANKL targeted drug; bufalin and a derivative thereof are combined with an RANKL targeted drug for use, the Bufalin and the derivative thereof are synergistically complementary, and the Bufalin is used for regulating and controlling a tumor microenvironment, reducing secretion of high bone metastatic breast cancer cells HMGB1 and inhibiting differentiation of mononuclear / macrophages in bone marrow to osteoclasts, so that occurrence and development of breast cancer bone metastasis are inhibited; the RANKL targeted drug can specifically block an OPG / RANK / RANKL signal channel, inhibit osteoclast activation, reduce bone destruction and block vicious circle of bone metastasis; when the two active ingredients are combined for use, the effect of inhibiting breast cancer bone metastasis is obviously better than that of single use of any active ingredient, the occurrence of breast cancer bone metastasis can be effectively prevented and delayed, the progress of bone metastasis focus is controlled, and the occurrence risk of bone related events is reduced.

Disclosed herein are methods and compositions of RANKL-binding switch receptors and engineered immune cell comprising said switch receptors, wherein the switch receptor comprises a RANKL-binding ectodomain, transmembrane domain and a costimulatory endodomain.

The invention relates to the field of biological medicine, relates to a bifunctional fusion protein and application thereof, and more specifically relates to a polypeptide construct containing an antigen binding domain capable of specifically binding to RANKL and PTH peptide, and related application of the polypeptide construct in disease treatment.

The present invention relates to the field of biomedicine. More specifically, the present invention relates to a polypeptide construct comprising an antigen binding domain capable of specifically binding to RANKL, and a PTH peptide, and a related use thereof for disease treatment.

The invention discloses a radionuclide-labeled small-molecule inhibitor targeting RANKL, a precursor compound thereof, a preparation method and application, and belongs to the technical field of nuclear medicine. The invention discloses a precursor compound with a structure as shown in a formula I or pharmaceutically acceptable salt thereof, and a radionuclide-labeled small-molecule inhibitor targeting RANKL with a structure as shown in a formula II or pharmaceutically acceptable salt thereof. The invention also discloses a preparation method of the compounds as shown in the formula I and the formula II, and application of the compounds in preparation of tumor imaging agents. Or / and application in preparation of drugs for treating tumors. According to the invention, a chelating agent DOTA is creatively combined with a small molecule compound to synthesize a novel compound as shown in a formula I; according to the present invention, the nuclide-labeled compound represented by the formula I can effectively provide the RANKL / RANK signal pathway targeting potential, and can be used for imaging and treatment of related diseases.

The application discloses a furan coumarin compound and application thereof in preparation of a drug for treating osteoporosis, and belongs to the technical field of drug research and development. 50 The furan coumarin compound has an IC of 37.86 nM, has no obvious cytotoxicity and systemic toxicity, can inhibit a key path of RANKL-induced osteoclast differentiation, and can be used for preparing the drug for treating osteoporosis.

The invention discloses a 2, 4, 6-trisubstituted pyrimidine compound as well as a preparation method, a pharmaceutical composition and application thereof. The structure of the compound is shown in a formula (I), and the derivative of the compound comprises pharmaceutically acceptable salt of the compound. The compound and the pharmaceutical composition thereof can effectively inhibit the activity level of RANKL in osteoclast precursor cells by regulating and controlling an OPG-RANKL-RANK signal channel (the signal channel is one of key channels for converting the osteoclast precursor cells into osteoclasts), so that bone resorption is inhibited. The 2, 4, 6-trisubstituted pyrimidine compound or the pharmaceutically acceptable salt thereof disclosed by the invention is expected to play a role in preventing and treating bone metabolic diseases, and has an important treatment value for patients with bone metabolic diseases.

The invention discloses application of a diaryl-substituted alpha-carbonyl amide compound. The diaryl-substituted alpha-carbonyl amide compound can be used for preparing medicines for treating osteoporosis, tumor bone metastasis or inflammatory bone destruction. Cell experiments prove that the diaryl-substituted alpha-carbonyl amide compound Z1-Z4 provided by the invention has a remarkable inhibition effect on osteoclast differentiation and bone resorption induced by RANKL, has no obvious cytotoxicity, and can be used as a candidate drug with a novel structure for inhibiting osteoclast differentiation and bone resorption; the method is used for targeting osteoclast to treat bone mass loss related diseases.

The present application relates to a kind of 3-amido-β-carboline compound, its preparation method and purposes, specifically related to 3-amido-β-carboline compound represented by general formula P, its optical isomer, pharmaceutically acceptable salt and hydrate, its preparation method, pharmaceutical composition comprising it and its pharmaceutical purposes.The 3-amido-β-carboline compound of the present application, its optical isomer, pharmaceutically acceptable salt and hydrate can be inhibited by RANKL-RANK interaction, intervene OPG-RANKL-RANK signal system, regulate RANKL activity in osteoclast precursor cell and inhibit the formation of osteoclast, thereby reducing bone absorption.The compound of the present application, its optical isomer, pharmaceutically acceptable salt and hydrate are expected to play the role of preventing and treating bone metabolism disease.

This invention relates to the field of pharmaceutical technology, specifically disclosing the application of sea buckthorn extract in the preparation of products for the prevention and treatment of periodontitis. The invention uses network pharmacology to predict the potential molecular mechanisms of sea buckthorn extract in preventing and treating periodontitis, and validates these mechanisms in vivo using a rat model of experimental periodontitis. Results show that sea buckthorn extract significantly improves periodontal probing depth and gingival bleeding index in rats with periodontitis, reduces the expression levels of IL-6, TNF-α, IL-1β, and MMP-9 in serum and gingival tissue, and alleviates periodontal inflammation. Simultaneously, sea buckthorn extract upregulates the expression of RUNX2, OCN, OPG, and ALP, downregulates the expression of RANKL and COX-2, inhibits osteoclast formation, improves alveolar bone resorption, and regulates bone homeostasis. This invention provides a new medical application for sea buckthorn extract, which can be used to prepare products for the prevention and / or treatment of periodontitis.

The invention discloses a long-acting parathyroid hormone receptor stimulant fusion protein and application thereof. The fusion protein can inhibit the activity of RANKL and promote PTHR-mediated bone anabolism, and comprises a first arm and a second arm, the first arm comprises a functional region targeting RANKL and an Fc region, and the second arm comprises a functional region capable of activating PTHR and an Fc region. The long-acting parathyroid hormone receptor stimulant fusion protein has the advantages of better drug effect, more lasting effect, better safety, higher structural stability, higher expression quantity and the like, and the comprehensive performance of the long-acting parathyroid hormone receptor stimulant fusion protein is superior to that of the existing or potential treatment means such as teriparatide, PEG-PTH, anti-RANKL monoclonal antibody, romomonoclonal antibody or a control sample synPTH-alpha RANKL-1.

This invention provides monoclonal antibodies against RANKL, particularly high-affinity humanized RANKL monoclonal antibodies. It also provides functional monoclonal antibodies that cross-react with RANKL in humans, cynomolgus monkeys, and mice. Furthermore, this invention provides the amino acid sequence of the antibodies of this invention, cloning or expression vectors, host cells, methods for expressing or isolating the antibodies, and identification of antibody epitopes. It also provides therapeutic compositions comprising the antibodies of this invention. Finally, this invention provides methods for treating cancer and other diseases with anti-RANKL antibodies.

The present invention provides monoclonal antibodies to RANKL, in particular high affinity humanized monoclonal antibodies to RANKL. The present invention also provides functional monoclonal antibodies that cross-react with RANKL of human, cynomolgus monkey and mouse. The present invention further provides amino acid sequences of antibodies of the present invention, cloning or expression vectors, host cells and methods for expressing or isolating antibodies, identifying epitopes of antibodies. Therapeutic compositions comprising antibodies of the present invention are also provided. The present invention also provides methods of treating cancer and other diseases with anti-RANKL antibodies.

The invention relates to the technical field of osteoclast differentiation inhibitors, and discloses application of a quinoxalinone compound in preparation of an osteoclast differentiation inhibitor. The quinoxalinone compound with the R group being the aliphatic nitrogen heterocyclic ring has no obvious cytotoxicity, can significantly inhibit expression of Trap and Ctsk genes in cells, and has a significant inhibition effect on formation of RANKL-induced osteoclasts. On the basis, the invention provides application of the quinoxalinone compound in preparation of an osteoclast differentiation inhibitor and a medicine for treating osteoporosis. Validation shows that the inhibiting effect is dose-dependent.

The application discloses a 2,3,4,9-tetrahydro-1H-pyridine [3,4-b] indole compound and a preparation method and application thereof. The 2,3,4,9-tetrahydro-1H-pyridine [3,4-b] indole compound is prepared from 3-hydroxy-4-methoxybenzaldehyde and 1-(chloromethyl)-2,6-difluorobenzene as starting materials through two-step reactions. The 1-(3-((2,6-difluorophenyl)oxy)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyridine [3,4-b] indole provided by the application has a significant inhibitory effect on RANKL-induced osteoclast differentiation and has no obvious cytotoxicity, and can be used as a novel candidate drug for inhibiting osteoclast differentiation and for targeted osteoclast treatment of bone mass loss related diseases.

Cytoablative treatments lead to severe damages on thymic epithelial cells (TECs), which result in delayed de novo thymopoïesis and a prolonged period of T-cell immunodeficiency. Understanding the mechanisms that govern thymic regeneration is of paramount interest for the recovery of a functional immune system notably after bone marrow transplantation (BMT). Here, the inventors show that administration of RANK ligand (RANKL) after total body irradiation and BMT boosts thymic regeneration. Notably, this treatment is also beneficial upon BMT in aged individuals. The inventors show that RANKL can improve thymopoiesis in aged individuals affected by thymic involution. Finally, the inventors show that RANK receptor is conserved in the human thymus. Accordingly, one aspect of the present invention relates to a method of boosting thymic regeneration in a patient suffering from a thymic injury comprising administering to the subject a therapeutically effective amount of a RANKL polypeptide.

The invention provides application of ginkgetin in preparation of a medicine for treating osteoporotic diseases, and belongs to the technical field of medicines, according to the regulation and control effect of ginkgetin on bone loss caused by overactivity of osteoclasts, firstly, it is found that ginkgetin inhibits formation of RANKL-induced osteoclasts through TRAP staining; bone resorption experiments and oxyntobutin discover that the biflavone inhibits the bone resorption and oxyntobutin functions of osteoclasts. Through PCR detection, it is found that ginkgo biflavone inhibits expression of specific genes of osteoclast differentiation. Meanwhile, according to transcriptome sequencing analysis and WB experiment clarification of a basic molecular mechanism, it is found that ginkgo biflavone inhibits generation and differentiation of osteoclasts by regulating and controlling streak OXPHOS. In addition, a femoral artery ligation mouse model is constructed to simulate occurrence of hypoxia osteoporosis, and Hamp is scanned through CT; according to E staining and TRAP staining, the bone destruction degree and the number of osteoclasts are analyzed, and compared with FAL group mice, the ginkgo biflavone treatment group obviously reduces the number of osteoclasts in bone tissues.

The invention discloses a method for preparing an anti-osteoporosis medicine for inhibiting bone resorption by adjusting NFIA for the first time. The invention finds that NFIA inhibits osteoclast differentiation and bone resorption activity by inhibiting transcription of RANKL. The cancellous bone mass of the mouse of which the NFIA gene is specifically knocked out in osteogenic precursor cells and mesenchymal cells is reduced; the ovariectomized mouse bone loss induced by ovariectomized mouse bone loss can be relieved by performing caudal vein injection on the adeno-associated virus overexpressing the The medicine prepared according to the invention has the effect of preventing and treating osteoporosis by enhancing NFIA expression or enhancing the protein function of NFIA, inhibiting osteoclast differentiation, reducing bone resorption and increasing body bone mass.

The present invention provides monoclonal antibodies to RANKL, in particular high affinity humanized monoclonal antibodies to RANKL. The present invention also provides functional monoclonal antibodies that cross-react with RANKL of human, cynomolgus monkey and mouse. The present invention further provides amino acid sequences of antibodies of the present invention, cloning or expression vectors, host cells and methods for expressing or isolating antibodies, identifying epitopes of antibodies. Therapeutic compositions comprising antibodies of the present invention are also provided. The present invention also provides methods of treating cancer and other diseases with anti-RANKL antibodies.

Bispecific antibodies that target both human RANKL and sclerostin are provided. Also provided herein are polynucleotides encoding the bispecific antibodies, pharmaceutical compositions comprising the bispecific antibodies, and methods of producing the bispecific antibodies. Medical uses of the bispecific antibodies described herein are also disclosed.