CN116509853B - Application of dehydrogenated harmine derivatives in improving organ fibrosis - Google Patents
Application of dehydrogenated harmine derivatives in improving organ fibrosis Download PDFInfo
- Publication number
- CN116509853B CN116509853B CN202310690547.8A CN202310690547A CN116509853B CN 116509853 B CN116509853 B CN 116509853B CN 202310690547 A CN202310690547 A CN 202310690547A CN 116509853 B CN116509853 B CN 116509853B
- Authority
- CN
- China
- Prior art keywords
- hmd
- carboline
- beta
- organ fibrosis
- butyl
- 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.)
- Active
Links
- 206010016654 Fibrosis Diseases 0.000 title claims abstract description 37
- 230000004761 fibrosis Effects 0.000 title claims abstract description 37
- 210000000056 organ Anatomy 0.000 title claims abstract description 35
- BXNJHAXVSOCGBA-UHFFFAOYSA-N Harmine Chemical class N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C BXNJHAXVSOCGBA-UHFFFAOYSA-N 0.000 title abstract description 16
- RAYHOJDYVGUYQQ-UHFFFAOYSA-N 7-methoxy-1-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indol-8-amine;hydrochloride Chemical compound [Cl-].C1CNC(C)C2=C1C1=CC=C(OC)C([NH3+])=C1N2 RAYHOJDYVGUYQQ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 208000009366 Echinococcosis Diseases 0.000 claims abstract description 15
- 206010014096 Echinococciasis Diseases 0.000 claims abstract description 14
- 210000004185 liver Anatomy 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 230000001447 compensatory effect Effects 0.000 claims abstract description 5
- 244000045947 parasite Species 0.000 claims abstract description 4
- 210000004072 lung Anatomy 0.000 claims description 36
- 229940079593 drug Drugs 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- VDTQIHDOWKFVDA-UHFFFAOYSA-N 9-butyl-n-(2-hydroxyethyl)-1-methylpyrido[3,4-b]indole-3-carboxamide Chemical compound OCCNC(=O)C1=NC(C)=C2N(CCCC)C3=CC=CC=C3C2=C1 VDTQIHDOWKFVDA-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- DXYICJBVZYMJJG-UHFFFAOYSA-N 1-ethyl-9H-pyrido[3,4-b]indole-3-carboxamide Chemical compound C(C)C1=NC(=CC2=C1NC1=CC=CC=C21)C(=O)N DXYICJBVZYMJJG-UHFFFAOYSA-N 0.000 abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- 208000005069 pulmonary fibrosis Diseases 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000006378 damage Effects 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000014674 injury Diseases 0.000 abstract description 4
- 208000027418 Wounds and injury Diseases 0.000 abstract description 3
- 208000019425 cirrhosis of liver Diseases 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000001125 extrusion Methods 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 40
- 210000001519 tissue Anatomy 0.000 description 35
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 18
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 18
- 229960002591 hydroxyproline Drugs 0.000 description 18
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 18
- 102000008186 Collagen Human genes 0.000 description 13
- 108010035532 Collagen Proteins 0.000 description 13
- 229920001436 collagen Polymers 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 108020004999 messenger RNA Proteins 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 238000010186 staining Methods 0.000 description 10
- PSFDQSOCUJVVGF-UHFFFAOYSA-N harman Chemical compound C12=CC=CC=C2NC2=C1C=CN=C2C PSFDQSOCUJVVGF-UHFFFAOYSA-N 0.000 description 9
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 8
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 8
- 230000008021 deposition Effects 0.000 description 8
- 210000003456 pulmonary alveoli Anatomy 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 5
- 210000005228 liver tissue Anatomy 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 210000004879 pulmonary tissue Anatomy 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 102000003945 NF-kappa B Human genes 0.000 description 4
- 108010057466 NF-kappa B Proteins 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 230000008595 infiltration Effects 0.000 description 4
- 238000001764 infiltration Methods 0.000 description 4
- 210000004969 inflammatory cell Anatomy 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012188 paraffin wax Substances 0.000 description 4
- RERZNCLIYCABFS-UHFFFAOYSA-N Harmaline hydrochloride Natural products C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000004043 dyeing Methods 0.000 description 3
- VJHLDRVYTQNASM-UHFFFAOYSA-N harmine Natural products CC1=CN=CC=2NC3=CC(=CC=C3C=21)OC VJHLDRVYTQNASM-UHFFFAOYSA-N 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000003753 real-time PCR Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000012398 clinical drug development Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000037390 scarring Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- XOSXWYQMOYSSKB-LDKJGXKFSA-L water blue Chemical compound CC1=CC(/C(\C(C=C2)=CC=C2NC(C=C2)=CC=C2S([O-])(=O)=O)=C(\C=C2)/C=C/C\2=N\C(C=C2)=CC=C2S([O-])(=O)=O)=CC(S(O)(=O)=O)=C1N.[Na+].[Na+] XOSXWYQMOYSSKB-LDKJGXKFSA-L 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- IWAQARWDGPHWGI-UHFFFAOYSA-N C1(=CC=CC=C1)C1=NC=CC=2C3=CC=CC=C3N(C1=2)CCCC Chemical compound C1(=CC=CC=C1)C1=NC=CC=2C3=CC=CC=C3N(C1=2)CCCC IWAQARWDGPHWGI-UHFFFAOYSA-N 0.000 description 1
- 241001247197 Cephalocarida Species 0.000 description 1
- 201000003808 Cystic echinococcosis Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000012868 Overgrowth Diseases 0.000 description 1
- 238000009004 PCR Kit Methods 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 240000005523 Peganum harmala Species 0.000 description 1
- 235000005126 Peganum harmala Nutrition 0.000 description 1
- 108010009736 Protein Hydrolysates Proteins 0.000 description 1
- 101100347655 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) NAB3 gene Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- -1 methyl- Chemical group 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
- 229960003073 pirfenidone Drugs 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000001950 radioprotection Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses an application of a harmine derivative (Hydroharminederivatives, HMD) in improving organ fibrosis, belonging to the field of compound application. The harmine derivatives disclosed in the present invention include 1- (2-chloro) phenyl-9-butyl-beta-carboline (HMD 3) and/or 9-butyl-1-methyl-N- (2-hydroxy) ethyl-beta-carboline-3-carboxamide (HMD 4). Animal experiments show that the traditional Chinese medicine composition can remarkably improve the problem of compensatory formation of liver and lung fibrosis caused by parasite extrusion and injury in echinococcosis, thereby being used for treating related diseases of tissue and organ fibrosis, having lower toxic and side effects and providing theoretical basis for clinical medicine development for improving and treating organ fibrosis.
Description
Technical Field
The invention relates to the field of compound application, in particular to application of harmine derivatives in improving organ fibrosis.
Background
Fibrosis is a pathological process characterized by scarring of tissue, which can be caused by trauma and a variety of diseases, manifesting as overgrowth, scarring or sclerosis of tissue, and can occur in almost all organs within the human body, thereby damaging tissue structure and function, with light persons becoming organ fibrosis, and heavy persons developing organ sclerosis, severely threatening the health and life of humans. Numerous studies have elucidated the key role of the mechanism of overactivation of transforming growth factor-beta (TGF-beta) signaling as a core in organ fibrosis, and drugs such as pirfenidone, imatinib and the like developed for the above research results have been marketed for treating fibrosis diseases such as idiopathic pulmonary fibrosis, but the problems of poor curative effect and serious adverse drug reactions still exist at present.
The harmine (Harmine, HM) is a natural alkaloid extracted from seed of Peganum harmala L of Tribulaceae, and has various beneficial effects such as anti-bag worm effect, antibacterial effect, antiinflammatory effect, broad antitumor activity, central nervous system effect, and radioprotection. In recent years, research on derivatives of compounds has become a hot spot, and it has been reported that harmine derivatives can be used for treating cystic echinococcosis, and chemical modification of harmine has also been reported that the obtained derivatives can enhance antitumor activity, however, there is no report that harmine derivatives can improve organ fibrosis diseases. Therefore, intensive research on whether the harmine derivatives can improve the organ fibrosis diseases is conducted, which is beneficial to expanding the pharmaceutical application of the harmine derivatives and providing a new direction for improving the organ fibrosis diseases.
Disclosure of Invention
The object of the present invention is to provide the use of harmine derivatives for improving organ fibrosis, solving the problems of the prior art as described above. The invention discovers that the harmine derivative can obviously improve the problem of compensatory formation of liver and lung fibrosis caused by parasite extrusion and injury in echinococcosis, thereby being used for treating related diseases of tissue and organ fibrosis and providing theoretical basis for clinical drug development for improving and treating organ fibrosis.
In order to achieve the above object, the present invention provides the following solutions:
The invention provides an application of a harmine derivative (Hydroharmine derivatives, HMD) in preparing a medicine for improving and/or treating organ fibrosis.
Further, the harmine derivative comprises one or more of 1- (2-chloro) phenyl-9-butyl-beta-carboline (HMD 3) and/or 9-butyl-1-methyl-N- (2-hydroxy) ethyl-beta-carboline-3-carboxamide (HMD 4);
the chemical structural formula of the 1-methyl-9- (3-pyridine) methyl-beta-carboline is as follows:
the chemical structural formula of the 1- (4-methoxy) phenyl-9-butyl-beta-carboline is as follows:
the chemical structural formula of the 1- (2-chlorine) phenyl-9-butyl-beta-carboline is as follows:
the chemical structural formula of the 9-butyl-1-methyl-N- (2-hydroxy) ethyl-beta-carboline-3-formamide is as follows:
Further, the organ fibrosis includes organ fibrosis caused by echinococcosis.
Further, the organ fibrosis caused by echinococcosis includes organ fibrosis due to compensatory formation after being squeezed and damaged by parasites.
Further, the organ includes a lung and a liver.
The invention also provides a medicine for improving and/or treating organ fibrosis, which comprises any combination of more than one of the harmine derivatives.
Further, the medicine also comprises common excipients, auxiliary materials and other pharmaceutically acceptable salts.
The application of the pharmaceutical preparation containing the harmine derivative in preparing medicaments for improving and/or treating organ fibrosis.
The invention discloses the following technical effects:
The harmine derivative disclosed by the invention can obviously improve the problem of compensatory formation of liver and lung fibrosis due to parasitic extrusion and injury in echinococcosis, thereby being used for treating related diseases of tissue and organ fibrosis and providing a theoretical basis for clinical drug development for improving and treating organ fibrosis.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph of HE staining of lung tissue sections of mice in each group;
FIG. 2 is a graph of HE staining of liver tissue sections of mice in each group;
FIG. 3 is a map of Masson staining of lung tissue sections of mice in each group;
FIG. 4 is a map of Masson staining of lung tissue sections of mice in each group;
FIG. 5 shows the expression levels of TGF-. Beta.1 (A), smad3 (B) and NF-. Kappa. B P65 (C) mRNA in lung tissue of mice in each group (** P <0.01 compared to the normal control group; #P<0.05,## P <0.01 compared to the model group).
FIG. 6 shows the hydroxyproline content in the lung tissue of mice, wherein A is the hydroxyproline content in the lung tissue of mice in the control group, the model group and the HMD1-HMD4 treatment group, B is the hydroxyproline content in the lung tissue of mice in the control group, the model group and the HMD1 low/high dose group and the HMD2 low/high dose group, and C is the hydroxyproline content in the lung tissue of mice in the control group, the model group and the HMD3 low/high dose group (** P <0.01 compared with the normal control group; #P<0.05,## P <0.01 compared with the model group).
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples of the present invention are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
The harmine derivative used in the embodiment of the invention has the following chemical structural formula:
HM derivative (HMD 1) 1-methyl-9- (3-pyridine) methyl-beta-carboline having the chemical structural formula:
HM derivative (HMD 2), 1- (4-methoxy) phenyl-9-butyl-beta-carboline, having the chemical structural formula:
HM derivative (HMD 3) 1- (2-chloro) phenyl-9-butyl-beta-carboline having the chemical structural formula:
HM derivative (HMD 4) butyl-1-methyl-N- (2-hydroxy) ethyl-beta-carboline-3-carboxamide having the formula:
The invention adopts the mode of intraperitoneal injection of echinococcosis to establish a mouse model infected by the artemia, and the establishment, grouping and administration of the animal model are as follows:
Female Kunming mice (provided by laboratory animal center of Xinjiang medical university) of 8 weeks old are selected, fresh sheep livers which naturally infect echinococcosis granulosa are collected from Xinjiang Urufimbriae slaughterhouse, and echinococcosis in liver cysts is collected under aseptic condition, so that activity of the echinococcosis is ensured to be more than or equal to 95%. About 1000 echinococci granulosa/mouse were intraperitoneally injected to establish a model of echinococcosis infected mice. Mice not injected with echinococci granulosa were a blank control group. Mice successfully modeled were divided into model groups and harmine derivative treatment groups 1-4 (50 mg/kg) in a completely randomized manner, 10 mice per group, wherein the above HM derivatives (HMD 1) - (HMD 4) were administered to each of the harmine derivative treatment groups 1-4. The medicine is prepared into corresponding concentration and then is administrated by lavage for 1 time/d and is continuously administrated for 28d.
EXAMPLE 1HE staining to observe pathological changes in pulmonary tissue and Masson staining to observe collagen deposition in pulmonary tissue
1. Mouse lung and liver tissue specimen collection and slicing preparation
After 28d, each group of mice is killed by cervical dislocation, the lungs and livers of the mice are dissected, part of the mice is fixed by 4% paraformaldehyde, the mice are dehydrated by gradient ethanol, are transparent, are embedded by paraffin, are sectioned (the thickness is 4 mu m), and the rest of the lung tissues are frozen in a refrigerator at the temperature of-80 ℃ for later use.
HE staining for the observation of pathological changes in pulmonary tissue
And (3) baking paraffin slices in a 65 ℃ oven, dewaxing and rehydrating, then placing the paraffin slices in hematoxylin dye liquor for dyeing for 1min, washing for 3 times, differentiating with ethanol hydrochloride for 2s, returning PBS (pH 7.2) to blue, washing with water, dyeing with eosin dye liquor for 1min, washing with water, dehydrating, naturally airing after transparency, sealing with neutral resin, and carrying out microscopic examination.
As a result, the mice in the blank group had a substantially normal lung tissue structure, a uniform alveolar size, no inflammatory exudates and no pulmonary fibrosis. The pulmonary tissue fibrosis degree of the model group mice infected by the echinococcosis granulosa is obviously increased, the pulmonary alveolus structure is seriously damaged, a large number of red blood cells are visible in part of pulmonary alveolus cavities, the pulmonary alveolus interval is obviously thickened, a large number of inflammatory cells are generated, and the inflammatory infiltration condition is serious. The lung tissue inflammation change of mice in the 1- (2-chloro) phenyl-9-butyl-beta-carboline (HMD 3) or 9-butyl-1-methyl-N- (2-hydroxy) ethyl-beta-carboline-3-carboxamide (HMD 4) treatment group is obviously reduced compared with that in the same-period model group, the pulmonary alveolus structure is complete, the size is uniform, the hyperemia condition in the pulmonary alveolus cavity is improved, the pulmonary alveolus space thickening is reduced, the infiltration of surrounding inflammatory cells is reduced, and the fibrosis degree is obviously reduced. The improvement effect of the lung tissue inflammation of mice in the treatment group of 1-methyl-9- (3-pyridine) methyl-beta-carboline (HMD 1) and 1- (4-methoxy) phenyl-9-butyl-beta-carboline (HMD 2) was not obvious compared with the synchronous model group (FIG. 1 lung HE staining).
The model group mice have serious pathological damage to liver tissues, edema, necrosis, inflammatory cell infiltration, irregular hepatic chordae arrangement, disordered hepatic lobular structure, increased intercellular matrix and excessive deposition of blue collagen among the hepatocytes. Compared with the model group, the liver tissue inflammation of mice in the treatment group (1- (2-chloro) phenyl-9-butyl-beta-carboline (HMD 3) or 9-butyl-1-methyl-N- (2-hydroxy) ethyl-beta-carboline-3-carboxamide (HMD 4)) is obviously reduced compared with the model group, the nucleus structure, the cell arrangement and the liver plate structure condition are improved, the thickening of the matrix among liver cells is reduced, the infiltration of surrounding inflammatory cells is reduced, the fibrosis degree is reduced, and the liver tissue inflammation of mice in the treatment group (1-methyl-9- (3-pyridine) methyl-beta-carboline (HMD 1) and 1- (4-methoxy) phenyl-9-butyl-beta-carboline (HMD 2) is not obviously improved compared with the model group in the same period (liver HE staining in figure 2).
Masson staining for observing collagen deposition in pulmonary tissue
According to the operation steps of the Masson trichromatic dyeing kit, paraffin sections are baked in a 65 ℃ oven, dewaxed and rehydrated, hematoxylin dyed for 8min, washed, differentiated for 10s, washed by distilled water, returned to blue by aqueous ammonia solution for 4min, washed by distilled water, ponceau dyed for 8min, washed by weak acid working solution, phosphomolybdic acid differentiated for 2min, washed by distilled water, aniline blue dyed for 2min, and washed by weak acid working solution to remove redundant aniline blue dyed liquid, dehydrated conventionally, dried naturally, sealed by neutral resin and subjected to microscopic examination.
As a result, the lung tissue structure of the mice in the blank group is normal, the size of alveoli is uniform and has no obvious change, and a small amount of blue collagen deposition can be seen at the alveoli interval. Blue collagen staining in the lung tissue of the mice in the model group is increased compared with that in the normal control group, and a great amount of proliferated blue collagen fibers can be seen in the alveolus space and the alveolus wall. The fibrotic area was reduced in the (1- (2-chloro) phenyl-9-butyl- β -carboline (HMD 3) or 9-butyl-1-methyl-N- (2-hydroxy) ethyl- β -carboline-3-carboxamide (HMD 4)) mice compared to the model group, the alveolar structure remained more intact than the model group, the extent of alveolar septal collagen deposition proliferation was reduced, the harmine derivative treatment group 1-methyl-9- (3-pyridine) methyl- β -carboline (HMD 1), the 1- (4-methoxy) phenyl-9-butyl- β -carboline (HMD 2) treatment group mice did not significantly differ from the model group in terms of changes in the pulmonary fibrotic area, alveolar structure and alveolar septal collagen deposition proliferation (fig. 3 lung Masson staining).
The model group mice are blue in staining of liver cell nuclei and proliferated collagen fibers, and red in staining of cytoplasm, muscle and red blood cells. The blue matrix collagen deposition was reduced and the degree of fibrosis was reduced in the (1- (2-chloro) phenyl-9-butyl- β -carboline (HMD 3) or 9-butyl-1-methyl-N- (2-hydroxy) ethyl- β -carboline-3-carboxamide (HMD 4)) treated group compared to the model group, and none of the mice in the harmine derivative treated group 1-methyl-9- (3-pyridine) methyl- β -carboline (HMD 1), 1- (4-methoxy) phenyl-9-butyl- β -carboline (HMD 2) treated group were significantly improved compared to the model group (fig. 4 liver Masson staining).
EXAMPLE 2 real-time fluorescent quantitative PCR detection of lung tissue TGF-beta 1 mRNA, smad3mRNA and NF-kappa B p65mRNA expression levels
In this example, the real-time fluorescent quantitative PCR assay for detecting TGF-beta 1 mRNA, smad3mRNA and NF-kappa B p mRNA expression levels of lung tissue mainly comprises the following steps:
Trizol method is used for extracting total RNA of mouse lung tissue, a nucleic acid quantitative analyzer is used for measuring the total RNA concentration, and PRIMESCRIPT KITTM RTREAGENT KIT kit is used for reverse transcription to synthesize cDNA. Primers were synthesized by biological engineering (Shanghai) Inc., and the primer sequences are shown in Table 1. Assays were performed using TakaRa (RR 030A) PCR kit, and 3 wells were made in parallel for each sample tested. The reaction system: Premix Ex-TaqTMII. Mu.L, cDNA 1. Mu.L, forward Primer 0.4. Mu.L, REVERSE PRIMER 0.4.4. Mu.L, ddH2O 3. Mu.L, ROX fluorescent label 0.2. Mu.L, and total volume 10. Mu.L. The reaction conditions were 95℃for 30s,95℃for 5s,60℃for 34s, for a total of 40 cycles. The amplification results were analyzed by the 2 -ΔΔCt method and are shown in Table 2 and FIG. 5.
TABLE 1
TABLE 2
The results of the real-time fluorescence quantitative PCR detection of the expression levels of the TGF-beta 1 mRNA, the Smad3mRNA and the NF-kappa B P mRNA in the lung tissues of the mice show a significant increase (F values are 37.641,39.914 and 362.290, respectively, and P < 0.01) compared with a blank control group, the expression levels of the TGF-beta 1 mRNA, the Smad3mRNA and the NF-kappa B P mRNA in the lung tissues of the mice show a significant decrease (P < 0.01) compared with the model group, the expression levels of the TGF-beta 1 mRNA and the Smad3mRNA in the lung tissues of the mice show a significant decrease (1- (2-chloro) phenyl-9-butyl-beta-carboline (HMD 3) or 9-butyl-1-methyl-N- (2-hydroxy) ethyl-beta-carboline (HMD 4)) compared with the model group, and the expression levels of the TGF-beta 5257 mRNA and the Smad3mRNA in the control group 1-methyl-9- (3-pyridine) methyl-beta-carboline (HMD 1), the 1- (4-methoxy) phenyl-9-butyl-beta-carboline (HMD 2) have no significant changes compared with the model mRNA expression levels of the control group and the Smad3mRNA and the K-beta 5365 mRNA.
Example 3 effect of HMD on hydroxyproline content in mouse lung tissue
To investigate the effect of different doses of HMD on hydroxyproline content in lung tissue of mice, mice successfully modeled according to the present invention were dosed with the HM derivatives (HMD 1) - (HMD 4) at a dose of 25mg/kg, respectively, in the (HMD 1) - (HMD 4) high dose groups, indicated as (HMD 1) - (HMD 4) low dose groups, and lung tissue of mice was collected as in example 1.
In this embodiment, the experiment for determining the hydroxyproline content in the lung tissue of the mouse mainly comprises the following steps:
Thawing at room temperature, weighing about 80mg of lung tissue specimen, placing in a test tube, shearing, adding 1mL of hydrolysate, mixing, detecting the content of Hydroxyproline (HYP) in lung tissue by using a detection kit of Hydroxyproline (HYP) of Nanjing institute of biological engineering, and measuring absorbance of each tube by taking supernatant at 550nm, 1cm optical path, double steaming for zeroing.
Pulmonary fibrosis is characterized by abnormal deposition of extracellular matrix, eventually leading to a significant increase in collagen fibers, while HYP is a unique amino acid of the body, mainly found in collagen. Hydroxyproline is therefore a general indicator for evaluating collagen fibers in pulmonary fibrosis.
As a result, the content of hydroxyproline in the lung tissue of the model mice was significantly increased as compared with the control group, and the content of hydroxyproline in the lung tissue of the mice was significantly decreased as compared with the model group (see FIG. 6A), in the harmine derivative group (1-methyl-9- (3-pyridine) methyl-. Beta. -carboline (HMD 1)), (1- (4-methoxy) phenyl-9-butyl-. Beta. -carboline (HMD 2)), (1- (2-chloro) phenyl-9-butyl-. Beta. -carboline (HMD 3)) or 9-butyl-1-methyl-N- (2-hydroxy) ethyl-. Beta. -carboline-3-carboxamide (HMD 4)), the harmine derivative group (1- (2-chloro) phenyl-9-butyl-. Beta. -carboline (HMD 3) or 9-butyl-1-methyl-N- (2-hydroxy) ethyl-. Beta. -carboline-3-carboxamide (HMD 4)) was low, the high dose group can significantly reduce the content of hydroxyproline (P < 0.01) (see C of figure 6), the content of hydroxyproline in the lung tissues of mice in the low dose group of the harmine derivative group (1-methyl-9- (3-pyridine) methyl-beta-carboline (HMD 1)) and the low dose group of the (1- (4-methoxy) phenyl-9-butyl-beta-carboline (HMD 2)) is not significantly changed, and the content of hydroxyproline in the lung tissues of mice in the high dose group of the harmine derivative group (1-methyl-9- (3-pyridine) methyl-beta-carboline (HMD 1)) and the (1- (4-methoxy) phenyl-9-butyl-beta-carboline (HMD 2)) treatment group of the high dose group of the mice is reduced, but the difference is not obvious (see B of figure 6).
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310690547.8A CN116509853B (en) | 2023-06-12 | 2023-06-12 | Application of dehydrogenated harmine derivatives in improving organ fibrosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310690547.8A CN116509853B (en) | 2023-06-12 | 2023-06-12 | Application of dehydrogenated harmine derivatives in improving organ fibrosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116509853A CN116509853A (en) | 2023-08-01 |
| CN116509853B true CN116509853B (en) | 2025-01-28 |
Family
ID=87401324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310690547.8A Active CN116509853B (en) | 2023-06-12 | 2023-06-12 | Application of dehydrogenated harmine derivatives in improving organ fibrosis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116509853B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105998014A (en) * | 2016-06-08 | 2016-10-12 | 新疆医科大学第附属医院 | Application of harmine derivative to preparation of drugs for treating cystic echinococcosis |
| CN113181177A (en) * | 2020-12-30 | 2021-07-30 | 新疆医科大学第一附属医院 | Application of harmine derivative in preparation of drugs for treating or preventing cystic echinococcosis |
| CN113559098A (en) * | 2021-07-06 | 2021-10-29 | 中国人民解放军陆军特色医学中心 | Application of harmine in improving organ fibrosis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112135613A (en) * | 2018-03-20 | 2020-12-25 | 西奈山伊坎医学院 | Kinase inhibitor compounds and compositions and methods of use |
| CN111714638A (en) * | 2020-06-23 | 2020-09-29 | 新疆医科大学第一附属医院 | Composition, preparation method and application of DNA damage-inducing compound combined with DNA damage repair inhibitor |
| CN114133390B (en) * | 2021-12-20 | 2023-10-27 | 新疆医科大学 | Harmine derivative as well as preparation method and application thereof |
| CN114191432A (en) * | 2021-12-31 | 2022-03-18 | 新疆医科大学第一附属医院 | Application of harmine derivative in preparation of anti-hydatid insecticide |
-
2023
- 2023-06-12 CN CN202310690547.8A patent/CN116509853B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105998014A (en) * | 2016-06-08 | 2016-10-12 | 新疆医科大学第附属医院 | Application of harmine derivative to preparation of drugs for treating cystic echinococcosis |
| CN113181177A (en) * | 2020-12-30 | 2021-07-30 | 新疆医科大学第一附属医院 | Application of harmine derivative in preparation of drugs for treating or preventing cystic echinococcosis |
| CN113559098A (en) * | 2021-07-06 | 2021-10-29 | 中国人民解放军陆军特色医学中心 | Application of harmine in improving organ fibrosis |
Non-Patent Citations (1)
| Title |
|---|
| 去氢骆驼蓬碱对细粒棘球蚴感染致小鼠肺纤维化的作用;吾斯曼江•艾麦提等;《中国病原生物学杂志》;20211231;第16卷(第12期);1414-1419 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116509853A (en) | 2023-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2769446C1 (en) | Use of chiglitazar and related compounds | |
| CN112138159A (en) | Application of lactate dehydrogenase in the treatment of tissue inflammation and fibrosis | |
| CN116509853B (en) | Application of dehydrogenated harmine derivatives in improving organ fibrosis | |
| US20230057861A1 (en) | Use of corydalis saxicola bunting and formulation thereof in preparation of drug for treating non-alcoholic fatty liver diseases | |
| EP3834834B1 (en) | Drug used for treating tissue necrosis or for improving cardiac function | |
| CN109223818A (en) | Application of the miR-3158-3p in preparation diagnosis, prevention and/or treatment atopic dermatitis product | |
| CN107913273B (en) | The application of mesaconine | |
| CN109985180B (en) | Application of traditional Chinese medicine compound composition in preparation of anti-hepatic fibrosis medicine | |
| CN111568937A (en) | Application of pien Tze Huang and preparation thereof in preparation of medicine for promoting healing of refractory wound | |
| CN118766887B (en) | Application of arachidonic acid in the preparation of medicine for treating burns | |
| CN115645449B (en) | Processing method and application of double-auxiliary wine honey pulp | |
| CN118976019B (en) | Application of β,β-dimethylacryloyl akanin in the preparation of drugs for treating atherosclerosis | |
| CN112138029B (en) | A kind of bacteroides ovatus is used for the purposes of preparing anti-renal fibrosis medicine | |
| CN116172989B (en) | Application of schisandrin in preparation of medicines for treating cancer embolism | |
| CN120392726A (en) | Application of dronedarone in the preparation of anti-tumor drugs | |
| CN112294851B (en) | A kind of Bacteroides fragilis is used for the purposes of preparing anti-renal fibrosis medicine | |
| CN108938633A (en) | A kind of pharmaceutical composition for treating kidney region fibrosis | |
| CN106727916A (en) | Application of Basil polysaccharide extract in preparation of medicine for treating pulmonary fibrosis | |
| WO2024153254A1 (en) | Use of ovatodiolide derivative and pharmaceutical composition thereof in prevention and treatment of peritoneal fibrosis | |
| CN102631351A (en) | Application of oleanolic acid in pharmacy | |
| CN118001265A (en) | Application of suramin in preparation of products for relieving myocardial fibrosis after myocardial infarction | |
| US20210046043A1 (en) | Use of daphnetin in improving function of aortic endothelial cell | |
| CN119097713A (en) | Application of a BCAT1 inhibitor in the preparation of a drug for treating fibrotic diseases | |
| CN119909066A (en) | Use of T-5224 for preparing a drug for preventing and treating doxorubicin-induced cardiotoxicity | |
| CN119868368A (en) | Application of gefitinib in preparation of medicines for treating or preventing keloids |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |