CN113908260A - Application of musclin in preparation of medicine for inhibiting muscle adiposis, fibrosis and atrophy - Google Patents
Application of musclin in preparation of medicine for inhibiting muscle adiposis, fibrosis and atrophy Download PDFInfo
- Publication number
- CN113908260A CN113908260A CN202111198047.XA CN202111198047A CN113908260A CN 113908260 A CN113908260 A CN 113908260A CN 202111198047 A CN202111198047 A CN 202111198047A CN 113908260 A CN113908260 A CN 113908260A
- Authority
- CN
- China
- Prior art keywords
- musclin
- muscle
- fibrosis
- atrophy
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 102100040556 Osteocrin Human genes 0.000 title claims abstract description 98
- 101710089325 Osteocrin Proteins 0.000 title claims abstract description 98
- 210000003205 muscle Anatomy 0.000 title claims abstract description 63
- 206010016654 Fibrosis Diseases 0.000 title claims abstract description 32
- 230000004761 fibrosis Effects 0.000 title claims abstract description 32
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 24
- 206010003694 Atrophy Diseases 0.000 title claims abstract description 17
- 230000037444 atrophy Effects 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims description 8
- 208000008589 Obesity Diseases 0.000 title abstract description 5
- 210000004027 cell Anatomy 0.000 claims abstract description 52
- 239000002243 precursor Substances 0.000 claims abstract description 45
- 230000002293 adipogenic effect Effects 0.000 claims abstract description 42
- 210000002950 fibroblast Anatomy 0.000 claims abstract description 42
- 230000011759 adipose tissue development Effects 0.000 claims abstract description 28
- 230000006907 apoptotic process Effects 0.000 claims abstract description 28
- 230000035755 proliferation Effects 0.000 claims abstract description 24
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 201000000585 muscular atrophy Diseases 0.000 abstract description 33
- 206010028289 Muscle atrophy Diseases 0.000 abstract description 22
- 230000020763 muscle atrophy Effects 0.000 abstract description 20
- 230000000694 effects Effects 0.000 abstract description 19
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 8
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 229920001184 polypeptide Polymers 0.000 abstract description 7
- 230000009471 action Effects 0.000 abstract description 6
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- 230000003387 muscular Effects 0.000 abstract description 2
- 230000017423 tissue regeneration Effects 0.000 abstract description 2
- 230000001276 controlling effect Effects 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 21
- 210000000663 muscle cell Anatomy 0.000 description 20
- 206010048654 Muscle fibrosis Diseases 0.000 description 19
- 241000699670 Mus sp. Species 0.000 description 14
- 238000001727 in vivo Methods 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 230000000903 blocking effect Effects 0.000 description 12
- 230000008595 infiltration Effects 0.000 description 11
- 238000001764 infiltration Methods 0.000 description 11
- 210000001789 adipocyte Anatomy 0.000 description 10
- 101000783356 Naja sputatrix Cytotoxin Proteins 0.000 description 9
- 239000002340 cardiotoxin Substances 0.000 description 9
- 231100000677 cardiotoxin Toxicity 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- KPKZJLCSROULON-QKGLWVMZSA-N Phalloidin Chemical compound N1C(=O)[C@@H]([C@@H](O)C)NC(=O)[C@H](C)NC(=O)[C@H](C[C@@](C)(O)CO)NC(=O)[C@H](C2)NC(=O)[C@H](C)NC(=O)[C@@H]3C[C@H](O)CN3C(=O)[C@@H]1CSC1=C2C2=CC=CC=C2N1 KPKZJLCSROULON-QKGLWVMZSA-N 0.000 description 8
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 7
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 7
- 241000283074 Equus asinus Species 0.000 description 7
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 7
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 210000002744 extracellular matrix Anatomy 0.000 description 7
- 230000001737 promoting effect Effects 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 6
- 238000004393 prognosis Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 102000001406 Perilipin Human genes 0.000 description 4
- 108060006002 Perilipin Proteins 0.000 description 4
- 108010009711 Phalloidine Proteins 0.000 description 4
- 150000001413 amino acids Chemical group 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000008929 regeneration Effects 0.000 description 4
- 238000011069 regeneration method Methods 0.000 description 4
- JGVWCANSWKRBCS-UHFFFAOYSA-N tetramethylrhodamine thiocyanate Chemical compound [Cl-].C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=C(SC#N)C=C1C(O)=O JGVWCANSWKRBCS-UHFFFAOYSA-N 0.000 description 4
- 102100036912 Desmin Human genes 0.000 description 3
- 108010044052 Desmin Proteins 0.000 description 3
- 206010020880 Hypertrophy Diseases 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 210000005045 desmin Anatomy 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000835 fiber Substances 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 238000013115 immunohistochemical detection Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 210000001665 muscle stem cell Anatomy 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 2
- 108010022452 Collagen Type I Proteins 0.000 description 2
- 102000016911 Deoxyribonucleases Human genes 0.000 description 2
- 108010053770 Deoxyribonucleases Proteins 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- 102000019298 Lipocalin Human genes 0.000 description 2
- 108050006654 Lipocalin Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 210000004292 cytoskeleton Anatomy 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 210000000651 myofibroblast Anatomy 0.000 description 2
- 210000001087 myotubule Anatomy 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- XIHHLOVIGNFBCR-HVTMNAMFSA-N Ala-Val-Asp-His Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 XIHHLOVIGNFBCR-HVTMNAMFSA-N 0.000 description 1
- 108090000672 Annexin A5 Proteins 0.000 description 1
- 102000004121 Annexin A5 Human genes 0.000 description 1
- PHHRSPBBQUFULD-UWVGGRQHSA-N Arg-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)N PHHRSPBBQUFULD-UWVGGRQHSA-N 0.000 description 1
- IXIWEFWRKIUMQX-DCAQKATOSA-N Asp-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O IXIWEFWRKIUMQX-DCAQKATOSA-N 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- JFOKLAPFYCTNHW-SRVKXCTJSA-N Gln-Arg-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N JFOKLAPFYCTNHW-SRVKXCTJSA-N 0.000 description 1
- IGOYNRWLWHWAQO-JTQLQIEISA-N Gly-Phe-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 IGOYNRWLWHWAQO-JTQLQIEISA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- BTKUIVBNGBFTTP-WHFBIAKZSA-N Ser-Ala-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)NCC(O)=O BTKUIVBNGBFTTP-WHFBIAKZSA-N 0.000 description 1
- CRJZZXMAADSBBQ-SRVKXCTJSA-N Ser-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO CRJZZXMAADSBBQ-SRVKXCTJSA-N 0.000 description 1
- MQUZANJDFOQOBX-SRVKXCTJSA-N Ser-Phe-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O MQUZANJDFOQOBX-SRVKXCTJSA-N 0.000 description 1
- FKYWFUYPVKLJLP-DCAQKATOSA-N Ser-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FKYWFUYPVKLJLP-DCAQKATOSA-N 0.000 description 1
- YDPFWRVQHFWBKI-GVXVVHGQSA-N Val-Glu-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N YDPFWRVQHFWBKI-GVXVVHGQSA-N 0.000 description 1
- 210000003489 abdominal muscle Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 108010024078 alanyl-glycyl-serine Proteins 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940096422 collagen type i Drugs 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002638 denervation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 235000019581 fat taste sensations Nutrition 0.000 description 1
- 230000003352 fibrogenic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 108010018006 histidylserine Proteins 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000037257 muscle growth Effects 0.000 description 1
- 230000009756 muscle regeneration Effects 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
Abstract
The invention relates to the technical field of polypeptide medicines, in particular to application of Musclin in preparing medicines for inhibiting muscle adiposis, fibrosis and atrophy, wherein the amino acid sequence of the Musclin is shown as SEQ ID No. 1. According to the scheme, the Musclin can inhibit muscle adipogenesis and fibrosis by regulating and controlling proliferation and apoptosis of fibroblast/adipogenic precursor cells, so that the action target of the Musclin is expanded, and further the muscle atrophy prevention and treatment effect can be achieved. Musclin can be used as a polypeptide drug in the medical practice of resisting muscular atrophy, and can also be independently used in the practice of muscle tissue repair resisting muscular adiposity or fibrosis.
Description
Technical Field
The invention relates to the technical field of polypeptide medicines, in particular to application of Musclin in preparing medicines for inhibiting muscle adiposis, fibrosis and atrophy.
Background
Muscle atrophy (muscular atrophy) can be caused by a variety of causes including hereditary, denervation, senile, traumatic, disuse, etc., and its main pathological features are a decrease in the number of muscle fibers and a decrease in the volume of muscle fibers, resulting in a state of decreased muscle mass, often accompanied by decreased muscle strength. Meanwhile, a large amount of fat cell infiltration and fiber deposition can occur in atrophied muscle, so that muscle regeneration is hindered, the progress of the condition of the muscular atrophy is further promoted, usually, the fat cell infiltration and the fiber deposition are both chronic progressive development, no effective means is available for radical treatment, the muscular atrophy treatment is difficult, and the patient is difficult to recover. At present, methods for treating muscular atrophy include physical therapy, nutrition enhancement and exercise, surgical treatment, drug therapy, and the like.
US20190270785A1(Musclin peptides and methods of use of thermoof) discloses a method of using polypeptide Musclin to promote muscle growth and improve muscle health, which has certain promoting effect on preventing muscle atrophy due to improved growth and performance of muscle cells. However, this patent does not mention other effects of Musclin except for promotion of hypertrophy of muscle cells, and the medicinal value of Musclin is not sufficiently developed, resulting in limitation of the range of application of Musclin.
Disclosure of Invention
The invention aims to provide the application of the Musclin in preparing the medicines for inhibiting muscle adiposity, fibrosis and atrophy so as to solve the technical problem that the action target of the polypeptide Musclin is not fully explored.
In order to achieve the purpose, the invention adopts the following technical scheme:
use of Musclin in the manufacture of a medicament for inhibiting muscle adipogenesis, fibrosis and atrophy.
Adopt above-mentioned technical scheme's principle and beneficial effect:
musclin is a bioactive factor secreted by skeletal muscle, and has regulating effect on metabolism of organism. In addition to the effects of inhibiting degeneration during muscular atrophy, the inventors found that Musclin also has the effects of inhibiting muscle adipogenesis and fibrosis, thereby preventing and treating muscular atrophy. Musclin can be used as a polypeptide drug in the medical practice of muscle tissue repair and muscular atrophy resistance. The Musclin not only can directly treat the atrophy of muscle cells, but also can relieve the adverse reaction generated after the atrophy of the muscle cells, thereby expanding the application of the Musclin. In the actual treatment of patients, Musclin can be used for treatment according to the specific conditions of the patients, and the administration mode, the administration amount and the administration timing are selected according to the target treatment targets of the treatment scheme. In addition, as the present protocol finds the role of Musclin in inhibiting muscle adipogenesis and fibrosis, Musclin may also be used in the treatment of muscle adipogenesis and fibrosis caused by other factors including muscle atrophy.
Among them, the muscular adipogenesis refers to a phenomenon of fat cell infiltration occurring during the degenerative process of muscle tissue. Muscle fibrosis refers to the phenomenon that extracellular matrix is deposited in muscle tissues during muscle degeneration, resulting in muscle fibrosis. The inventor discovers through in vivo experiments and in vitro experiments that Musclin can act on precursor cells in muscles causing muscle adiposity, directly promotes apoptosis of fat precursor cells, and realizes the inhibition effect on muscle adiposity through the acting target. Fibrosis is one of typical pathological changes of muscle atrophy, muscle cells become small after muscle atrophy, a part of reserved space is occupied by fibrous tissues, regeneration of muscle stem cells is inhibited, regeneration of the muscle stem cells is hindered, and the muscle atrophy is further promoted by the atrophy of the muscle cells. In the scheme, the inventor finds that the Musclin can directly act on precursor cells causing fibrosis through in vivo and in vitro experiments, and further inhibits the progress of muscle fibrosis, so that the therapeutic effect on muscle atrophy is realized.
In summary, although the prior art suggests that Musclin has the efficacy of promoting hypertrophy of muscle cells, we found that Musclin can inhibit muscle fibrosis and adipogenesis by regulating fibroblast/adipogenic precursor cell (FAP), thereby improving pathological degeneration of muscle atrophy. Since muscle fibrosis and adiposity are not only present in muscle wasting diseases, the present invention expands the indications of Musclin and can be applied to other diseases with muscle fibrosis and adiposity phenomena.
Further, the amino acid sequence of Musclin is shown in SEQ ID NO. 1. The protein with the amino acid sequence shown as SEQ ID NO.1 consists of 80 th-112 th amino acids of whole Musclin protein, and has obvious effect of inhibiting muscle adiposis and fibrosis.
Further, the Musclin is an apoptosis promoter of fibroblast/adipogenic precursor cells.
Further, the Musclin is an inhibitor of proliferation of fibroblast/adipogenic precursor cells.
The inventor researches and discovers that under the action of Musclin, the proliferation of muscle fibroblast/adipogenic precursor cells (FAP) is inhibited and the apoptosis process of the FAP is promoted, and the phenomenon that the space between muscle cells is filled by fat cells and extracellular matrix is relieved. Therefore, besides directly acting on muscle cells, the Musclin also acts on fibroblast/adipogenic precursor cells, and achieves the effects of inhibiting muscle adipogenesis and fibrosis by inhibiting proliferation of the fibroblast/adipogenic precursor cells and promoting apoptosis of the fibroblast/adipogenic precursor cells, thereby further promoting the treatment of muscle atrophy. Furthermore, the properties of Musclin to inhibit proliferation and promote apoptosis of fibroblast/adipogenic precursor cells may also be applied to the treatment of muscle adipogenesis and fibrosis caused by other causes.
Drawings
FIG. 1 is a graph showing statistics of the protein concentration of Musclin in the muscle of a Musclin overexpressing mouse and a control mouse according to example 1 of the present invention.
FIG. 2 is a graph showing the results of the fluorescence immunohistochemical detection of fat infiltration in example 1 of the present invention.
FIG. 3 is a graph showing the results of the fluorescence immunohistochemical muscle fibrosis assay of example 2 of the present invention.
FIG. 4 is a graph showing the results of the experiment for detecting degeneration of atrophic muscle by fluorescence immunohistochemistry in example 3 of the present invention.
FIG. 5 is a graph showing the effect of Muscin according to example 4 of the present invention on fibroblast proliferation and apoptosis in vitro.
FIG. 6 is a graph showing the effect of Musclin according to example 4 of the present invention on the proliferation and apoptosis of fibroblasts/adipogenic precursor cells in vivo (CTX-induced muscle fibrosis model).
FIG. 7 is a graph showing the effect of Musclin according to example 4 of the present invention on the proliferation and apoptosis of fibroblast/adipogenic precursor cells in vivo (glycerol-induced muscle adipogenesis model).
FIG. 8 is a graph showing the effect of Musclin according to example 4 of the present invention on the proliferation and apoptosis of fibroblasts/adipogenic precursor cells in vivo (muscle atrophy model).
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, the technical means used in the following examples are conventional means well known to those skilled in the art; the experimental methods used are all conventional methods; the materials, reagents and the like used are all commercially available.
Example 1: study of the action of Musclin in inhibiting muscle adipogenesis
The Musclin used in this protocol was purchased from shanghai gill polypeptide Ltd (GL Biochem co., Ltd), sequence: NH (NH)2-SFSGFGSPLDRLSAGSVEHRGKQRKAVDHSKKR-COOH (SEQ ID NO.1), which is a partial sequence of amino acids 80 to 112.
Construction of Musclin overexpressing mice: the Muscin recombinant protein was dissolved in 1% BSA solution at 80. mu.g/mL, the Muscin solution was intraperitoneally injected continuously for 5 days, once daily, 100. mu.L each time, and the control group was injected with an equal amount of 1% BSA solution. ELISA experiments prove that the muscle concentration of the mouse is obviously increased compared with that of a control group (the experimental results are shown in figure 1, the right side is a group injected with the Muscin protein, and the left side is a group injected with 1% BSA solution), and the method can effectively promote the protein concentration of the Muscin in the muscle.
Constructing a muscle fat infiltration mouse model: fat infiltration was induced by injecting 50 μ L of 50% (v/v) glycerol solution into the tibioanterior muscle belly of mice (either Musclin overexpressing mice or controls injected with 1% BSA).
Preparing a specimen: (1) fixing the tibialis anterior muscle on the 10 th day after glycerol injection in 4% paraformaldehyde for 12 hours, and dehydrating with 30% sucrose solution overnight; (2) the dehydrated tibialis anterior tissue is prepared into frozen sections by a freezing microtome according to the thickness of 8-10 μm.
Fluorescence immunohistochemical detection of fat infiltration: (1) re-warming the frozen section to room temperature; (2) rehydrating in PBS; (3) blocking the sample with blocking solution for 1 hour at 37 deg.C (blocking solution composition: 10% donkey serum, 3% BSA); (4) the blocking solution was decanted and primary antibody was added: rabbit anti-mouse Perilipin antibody (1:200, Abcam), incubated overnight at 4 ℃; (5) excess primary antibody was washed out with PBS, secondary antibody was added: AF 488-labeled donkey anti-rabbit IgG antibody (1:200, Jackson ImmunoResearch); TRITC-labeled phalloidin (1:200, saint next biotechnology (shanghai) gmbh); incubating for 30 minutes at room temperature in dark; (6) washing the excess secondary antibody with PBS, adding Hoechst 33342(1:500), and incubating for 15 minutes at room temperature in a dark place; (7) washing off the redundant dye liquor; (8) and sealing the film, and observing and taking a picture by a confocal microscope.
The results are shown in fig. 2 (left mice were not treated with Musclin and right mice were treated with Musclin), the green part in fig. 2 is labeled with Perilipin (lipocalin) to show adipocyte infiltration, and the red part is TRITC-labeled phalloidin, showing the tissue cytoskeleton; the blue part is labeled Hoechst 33342, showing the nuclei. From the experimental results of fig. 2, it is known that increasing the level of Musclin in the mouse body can reduce the fat infiltration of muscle tissue, and thus, the effect of inhibiting the muscle adipogenesis is achieved.
Example 2: study of the Effect of Musclin on inhibition of muscle fibrosis
The process for constructing a Musclin overexpression mouse is the same as in example 1.
Constructing a muscle fibrosis mouse model: muscle fibrosis was induced in mice (either Musclin overexpressing mice or controls injected with 1% BSA) by injecting 50 μ L Cardiotoxin (CTX) solution (10 μ M) into the tibiomyo.
Preparing a specimen: (1) fixing the tibialis anterior muscle on the 15 th day after cardiotoxin injection in 4% paraformaldehyde for 12 hours, and then dehydrating with 30% sucrose solution overnight; (2) the dehydrated tibialis anterior tissue is prepared into frozen sections by a freezing microtome according to the thickness of 8-10 μm.
Fluorescence immunohistochemical detection of fibrosis: (1) re-warming the frozen section to room temperature; (2) rehydrating in PBS; (3) blocking the sample with blocking solution at 37 ℃ for 1 hour (blocking solution composition: 10% donkey serum, 3% BSA); (4) the blocking solution was decanted and primary antibody was added: mouse anti-mouse Desmin antibody (1:50, Santa Cruz), incubated overnight at 4 ℃; (5) excess primary antibody was washed off with PBS, secondary antibody was added: AF 488-labeled donkey anti-mouse IgG antibody (1:200, Jackson ImmunoResearch); incubating for 30 minutes at room temperature in dark; (6) washing the excess secondary antibody with PBS, adding Hoechst 33342(1:500), and incubating for 15 minutes at room temperature in a dark place; (7) washing off the redundant dye liquor; (8) and sealing the film, and observing and taking a picture by a confocal microscope.
The results are shown in FIG. 3 (left mice were not treated with Muscin and right mice were treated with Muscin), in which the green part is labeled with Desmin (Desmin) and shows the degree of fibrosis, and the blue part is labeled with Hoechst 33342 and shows the nucleus. From the experimental results, it is clear that the mice with muscle fibrosis treated with Musclin had less extracellular matrix deposition and slower progression of muscle fibrosis, and that Musclin acts to inhibit muscle fibrosis.
Example 3: study of the Effect of Musclin on the treatment of muscular atrophy
Constructing a muscle atrophy model: after the mice were anesthetized with 0.5% pentobarbital sodium, the sciatic nerve and the tibialis anterior muscle tendon of one hind limb were cut off, sutured and sterilized.
Musclin treatment: from the model construction, 100. mu.L of Musclin recombinant protein (80. mu.g/mL) was intraperitoneally injected every other day for the time point of sampling (up to 42 days).
Preparing a specimen: (1) taking the atrophic tibialis anterior at a specified time point, fixing in 4% paraformaldehyde for 12 hours, and dehydrating with 30% sucrose solution overnight; (2) the dehydrated tibialis anterior tissue is prepared into frozen sections by a freezing microtome according to the thickness of 8-10 μm.
Fluorescence immunohistochemistry detection of degenerative conditions of atrophic muscles: (1) re-warming the frozen section to room temperature; (2) rehydrating in PBS; (3) blocking the sample with blocking solution at 37 ℃ for 1 hour (blocking solution composition: 10% donkey serum, 3% BSA); (4) the blocking solution was decanted and primary antibody was added: rabbit anti-mouse Perilipin antibody (1:200, Abcam) or mouse anti-mouse type I collagen antibody (1:50, Santa Cruz), incubated overnight at 4 ℃; (5) excess primary antibody was washed off with PBS, secondary antibody was added: an AF 488-labeled donkey anti-rabbit IgG antibody (1:200, Jackson ImmunoResearch) or a Cy 3-labeled donkey anti-mouse IgG antibody (1:200, Jackson ImmunoResearch); TRITC-labeled phalloidin (1:200, saint next biotechnology (shanghai) gmbh); incubating for 30 minutes at room temperature in dark; (6) washing off excessive secondary antibody by PBS, adding Hoechst 33342(1:500), and incubating for 15 minutes at room temperature in a dark place; (7) washing off excessive dye liquor; (8) and sealing the film, and observing and taking a picture by a confocal microscope.
The results of the experiment are shown in fig. 4, in the upper two panels of fig. 4, the red part is labeled with collagen type I antibody, showing extracellular matrix; the blue part is labeled Hoechst 33342, showing the nuclei. In the lower two panels of fig. 4, the green part is Perilipin (lipocalin) labeled and the red part is TRITC labeled phalloidin, showing the tissue cytoskeleton; the blue part is labeled Hoechst 33342, showing the nuclei. Experimental results show that in a muscle atrophy model mouse, due to the reduction of the volume of muscle cells), certain space is formed among the muscle cells, and the space is easily filled by adipose tissues and extracellular matrix, so that the proliferation and differentiation of muscle stem cells are hindered, and the regeneration of muscle tissues is finally hindered. However, after treatment with Musclin, extracellular matrix content decreased (upper two panels of fig. 4) and muscle adipogenesis decreased (lower two panels of fig. 4). Therefore, the Musclin protein can be used for the treatment of muscle atrophy. The target of action of Musclin is not only on the muscle cells themselves (which have been reported in the prior art to promote muscle cell hypertrophy), but also on the fibroblasts/adipogenic precursor cells of the muscle, directly affecting adipogenesis and fibrosis. Muscle adipogenesis and fibrosis are symptoms which are accompanied after the atrophy of muscle cells, and the adipogenesis and fibrosis can block the regeneration of the muscle cells and promote the progress of the atrophic disease, so that the Musclin not only directly treats the atrophy of the muscle cells, but also can relieve the adverse reaction generated after the atrophy of the muscle cells, and the application of the Musclin is expanded. In the actual treatment of patients, Musclin can be used for treatment according to the specific conditions of the patients, and the administration mode, the administration amount and the administration timing are selected according to the target treatment targets targeted by the treatment scheme. In addition, as the present protocol finds the effect of Musclin on inhibiting muscle adipogenesis and fibrosis, Musclin may also be used in the treatment of muscle adipogenesis and fibrosis caused by non-muscle atrophy.
Example 4:
in mechanistic studies, we found that Musclin reduces the degree of adipogenesis and fibrosis by inhibiting proliferation of adipogenic/fibroblast precursor cells, promoting apoptosis and reducing abnormal accumulation of such cells.
Musclin promotes apoptosis of fibroblast/adipogenic precursor cell in vitro and inhibits proliferation
Intervention conditions are as follows: muscle primary fibroblasts/adipogenic precursor cells were sorted by flow cytometric fluorescence sorting (FACS), cultured in vitro, and after the cells had entered the logarithmic growth phase, the cells were treated with Musclin (1 μ M) for 48 hours with an equivalent amount of solvent (1% BSA) as a control.
And (3) proliferation: BrdU solution (1. mu.L) was added 3 hours before sampling and incubated for 3 hours. The medium was aspirated, washed with PBS, and the cells were collected into 1.5mLEP and subjected to Phase-FlowTMFITC BrdU Kit (Biolegend), fixed according to the instructions, permeabilized the cell sample, DNase at 37 ℃ for 1 hour, adding AF 488-labeled BrdU antibody, incubation for 30 minutes in the absence of light, washing away unbound antibody, and detecting the sample on the machine.
Apoptosis: and (3) sucking the culture medium of the cells treated by the Musclin, collecting the cells in a 1.5mLEP tube, adding 400 mu Lannexin binding agent according to the specification method of the Annexin V/PI apoptosis detection kit, incubating for 10 minutes, adding PI staining solution, incubating for 5 minutes, and detecting the sample on a computer.
The results of the experiments are detailed in fig. 5, where fig. 5a shows the effect of Musclin on fibroblast/adipogenic precursor cell proliferation in vitro, and the right statistical plot suggests that the Musclin-treated group inhibited fibroblast/adipogenic precursor cell proliferation in vitro compared to the Vehicle group (Vehicle group). Figure 5b shows the effect of Musclin on apoptosis of fibroblasts/adipogenic precursors in vitro, and the right statistical figure suggests that the Musclin-treated group promotes apoptosis of fibroblasts/adipogenic precursors compared to the Vehicle group (Vehicle group). It is suggested that proliferation of fibroblast/adipogenic precursor cell is inhibited and apoptosis is promoted by the Musclin, which may lead to decrease of the number of adipocyte and myofibroblast formed by fibroblast/adipogenic precursor cell in the process of muscular atrophy in vivo, and alleviate the phenomenon that the intercellular space formed by decrease of muscle cell volume is filled with adipocyte and extracellular matrix, thereby inhibiting the fattiness and fibrosis of muscle.
Secondly, the Musclin promotes the apoptosis of fibroblast/adipogenic precursor cells in vivo and inhibits the proliferation
1. Construction of Musclin overexpressing mice: the Muscin recombinant protein was dissolved in 1% BSA solution at 80. mu.g/mL, the Muscin solution was injected intraperitoneally for 5 consecutive days, once daily, 100. mu.L each, and the control group was injected with an equal amount of 1% BSA solution.
2. Constructing a muscle fibrosis mouse model: muscle fibrosis was induced by injecting 50 μ L Cardiotoxin (CTX) solution (10 μ M) into the abdominal muscle of the tibialis anterior of mice.
3. Constructing a muscle fat infiltration mouse model: mice were injected with 50 μ L of 50% (v/v) glycerol solution to the tibialis anterior muscle abdomen to induce fat infiltration.
4. Flow cytometry to detect the ratio of fibroblasts/adipogenic precursor cells in damaged muscle: shearing muscle tissue, digesting with 0.2% type II collagenase for 1 hr, centrifuging, discarding supernatant, re-suspending tissue precipitate, filtering, centrifuging filtrate, re-suspending, lysing erythrocytes with erythrocyte lysate, centrifuging, re-suspending, adding flow antibody, labeling fibroblast/adipogenic precursor cell, and detecting cell ratio change with flow cytometer.
Detection of cell proliferation by the BrdU method: cell suspensions were prepared and labeled fibrogenic/adipogenic according to step 4Precursor cells, then using Phase-FlowTMFITC BrdU Kit (Biolegend), fixed according to the instructions, permeabilized the cell sample, treated with DNase at 37 ℃ for 1 hour, added with PE-labeled BrdU antibody, incubated for 30 minutes in the dark, washed free of unbound antibody, and tested on the machine.
6. Detecting apoptosis in vivo: preparation of cell suspensions and labelling of fibroblast/adipogenic precursor cells according to step 4 Using VybrantTMFAM Caspase-3and-7Assay Kit (Invitrogen) detected apoptosis of fibroblasts/adipogenic precursor cells, incubated with FAM-labeled DEVD-FMK complex (FLICA) at 37 ℃ for 1 hour, and the samples were tested on-machine.
The experimental results are shown in detail in fig. 6 and 7. Figure 6a shows the in vivo detection of proliferation of fibroblasts/adipogenic precursor cells after Musclin stem prognosis in a CTX-induced muscle fibrosis model. In the histogram on the right, the bars on the left are blank control groups and the bars on the right are Musclin treatment groups. Figure 6b shows the in vivo detection of Musclin Stem prognosis apoptosis of fibroblasts/adipogenic precursor cells in a model of CTX-induced muscle fibrosis. In the histogram on the right, the left panel is a blank control group and the right panel is a Musclin treatment group. Figure 7a shows the in vivo detection of proliferation of fibroblast/adipogenic precursor cells after Musclin stem prognosis in a model of glycerol-induced muscle adipogenesis. In the histogram on the right, the left panel is a blank control and the right panel is a Musclin treatment. Figure 7b shows the in vivo detection of fibroblast/adipogenic precursor cell apoptosis following Musclin intervention in a glycerol-induced muscle adipogenesis model. In the histogram on the right, the left panel is a blank control group and the right panel is a Musclin treatment group. From the experimental results, it is known that Musclin can inhibit proliferation of fibroblast/adipogenic precursor cells, promote apoptosis of the precursor cells, prevent proliferation of excessive adipocytes and formation of excessive intercellular matrix, and further inhibit muscle adipogenesis and fibrosis in a CTX-induced muscle fibrosis model and a glycerol-induced muscle adipogenesis model.
Thirdly, Musclin promotes the apoptosis of fibroblast/adipogenic precursor cells in a muscle atrophy model and inhibits the proliferation
1, constructing a muscle atrophy model according to the previous method; and periodic treatment with Musclin (see example 3 for details);
2, the muscle was collected and the cells were extracted according to the same method as described above, and BrdU and apoptosis were detected according to the same method as described above ("two" in this example).
Results of the experiment as shown in figure 8, figure 8a demonstrates the in vivo detection of proliferation of fibroblast/adipogenic precursor cells in muscle atrophy models after Musclin stem prognosis. Figure 8b demonstrates the in vivo detection of Musclin stem prognosis apoptosis of fibroblasts/adipogenic precursor cells in a muscle atrophy model. From the data in the figure, it is known that in the course of the muscular atrophy, as the muscle cell volume becomes smaller, gaps are formed between the cells, and fat cells and intercellular matrix accumulate in the gaps, while the use of Musclin can inhibit proliferation of fibroblast/adipogenic precursor cells, reduce formation of fat cells and myofibroblasts, reduce accumulation of intercellular fibers, and further inhibit adipogenesis and fibrosis of the muscle, and finally achieve the effect of treating muscular atrophy.
In summary of the above experimental results, the Musclin acts directly on the muscle cells, and the target of action is the fibroblast/adipogenic precursor cells, and the effects of inhibiting the adipogenesis and the fibrogenesis of the muscle are achieved by inhibiting the proliferation of the fibroblast/adipogenic precursor cells and promoting the apoptosis of the fibroblast/adipogenic precursor cells, thereby further promoting the treatment of muscle atrophy.
The foregoing is merely an example of the present invention and common general knowledge in the art of designing and/or characterizing particular aspects and/or features is not described in any greater detail herein. It should be noted that, for those skilled in the art, without departing from the technical solution of the present invention, several variations and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the exclusive utility. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.
SEQUENCE LISTING
<110> first subsidiary hospital of China civil liberation army, military and medical university
<120> use of Musclin for the preparation of a medicament for inhibiting muscle adipogenesis, fibrosis and atrophy
<130> 2021.10.11
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 33
<212> PRT
<213> Artificial sequence
<400> 1
Ser Phe Ser Gly Phe Gly Ser Pro Leu Asp Arg Leu Ser Ala Gly Ser
1 5 10 15
Val Glu His Arg Gly Lys Gln Arg Lys Ala Val Asp His Ser Lys Lys
20 25 30
Arg
Claims (4)
- Use of Musclin for the preparation of a medicament for inhibiting muscle adipogenesis, fibrosis and atrophy.
- 2. Use of Musclin according to claim 1 for the preparation of a medicament for inhibiting muscle adipogenesis, fibrosis and atrophy, wherein the amino acid sequence of Musclin is shown in SEQ ID No. 1.
- 3. Use of Musclin according to claim 1 for the preparation of a medicament for inhibiting muscle adiposity, fibrosis and atrophy, wherein: the Musclin is an apoptosis promoter for fibroblast/adipogenic precursor cells.
- 4. Use of Musclin according to claim 1 for the preparation of a medicament for inhibiting muscle adiposity, fibrosis and atrophy, wherein: the Musclin is a proliferation inhibitor of fibroblast/adipogenic precursor cells.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111198047.XA CN113908260A (en) | 2021-10-14 | 2021-10-14 | Application of musclin in preparation of medicine for inhibiting muscle adiposis, fibrosis and atrophy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111198047.XA CN113908260A (en) | 2021-10-14 | 2021-10-14 | Application of musclin in preparation of medicine for inhibiting muscle adiposis, fibrosis and atrophy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113908260A true CN113908260A (en) | 2022-01-11 |
Family
ID=79240557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111198047.XA Pending CN113908260A (en) | 2021-10-14 | 2021-10-14 | Application of musclin in preparation of medicine for inhibiting muscle adiposis, fibrosis and atrophy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113908260A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180194824A1 (en) * | 2016-12-14 | 2018-07-12 | University Of Iowa Research Foundation | Musclin peptides and methods of use thereof |
| CN110028570A (en) * | 2018-10-31 | 2019-07-19 | 华中科技大学 | A kind of expression of muscle element and its application in metabolic disease |
-
2021
- 2021-10-14 CN CN202111198047.XA patent/CN113908260A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180194824A1 (en) * | 2016-12-14 | 2018-07-12 | University Of Iowa Research Foundation | Musclin peptides and methods of use thereof |
| CN110028570A (en) * | 2018-10-31 | 2019-07-19 | 华中科技大学 | A kind of expression of muscle element and its application in metabolic disease |
Non-Patent Citations (1)
| Title |
|---|
| ANDREA D. RE CECCONI, ET AL.: "Musclin, A Myokine Induced by Aerobic Exercise, Retards Muscle Atrophy During Cancer Cachexia in Mice", CANCERS, pages 1 - 27 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Mittal et al. | Genetic ablation of TWEAK augments regeneration and post-injury growth of skeletal muscle in mice | |
| US20020028762A1 (en) | Medicament and method for treating renal disease | |
| Takahashi et al. | Endothelin in chronic renal failure | |
| JPH07504650A (en) | Inhibition of transforming growth factor β to prevent extracellular matrix accumulation | |
| Yang et al. | Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance | |
| EP1034185B1 (en) | Pharmaceutical compositions containing the long pentraxin ptx3 | |
| Wang et al. | Inhibition of elevated hippocampal CD24 reduces neurogenesis in mice with traumatic brain injury | |
| WO2022027953A1 (en) | Use of c188-9, venetoclax, and bumetanide in drug for fibrotic diseases | |
| CN113372435A (en) | Polypeptide for promoting angiogenesis and pharmaceutical application thereof | |
| CN113908260A (en) | Application of musclin in preparation of medicine for inhibiting muscle adiposis, fibrosis and atrophy | |
| CN113616792B (en) | Application of reagent for increasing expression level of smurf1 protein in preparation of medicine for preventing and treating calcified aortic valve diseases | |
| CN109223737B (en) | Application of alkannin compound in preparing medicine for promoting TRAIL antineoplastic activity | |
| CN116555174A (en) | Joint repair protein composition, preparation method and application thereof | |
| WO2021169812A1 (en) | Use of pax4 inhibitor in preparation of drug for inhibiting fibrosis | |
| Descalzi Cancedda et al. | Ex-FABP, extracellular fatty acid binding protein, is a stress lipocalin expressed during chicken embryo development | |
| CN110590929B (en) | Application of TDGF-1 truncated body small molecule polypeptide in anti-hepatic fibrosis | |
| JP4177436B2 (en) | Hepatocyte replication promoter and insulin resistance improver | |
| CN111568916A (en) | Use of LncRNAGAGAS 5 in treating primary osteoporosis | |
| Su et al. | TNF‐α‐Induced KAT2A Impedes BMMSC Quiescence by Mediating Succinylation of the Mitophagy‐Related Protein VCP | |
| CN112351791A (en) | Glycosaminoglycan inhibitors and promoters | |
| CN111701021B (en) | Application of NIPA2 as drug target in preparation of drug for treating type 2 diabetes osteoporosis | |
| CN100445297C (en) | Amolops loloensis insulin release promoting peptide and use in producing medicine | |
| CN115808527A (en) | Application of LAMP2A in ankylosing spondylitis | |
| JP2024046128A (en) | Osteogenesis promoting agent | |
| CN115040637A (en) | Application of RCN2 recombinant protein in preparation of drugs for preventing and/or treating osteoporosis and improving immunity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220111 |