CN116531374A - Application of pioglitazone and pioglitazone salt in preparation of product for treating systemic lupus erythematosus - Google Patents
Application of pioglitazone and pioglitazone salt in preparation of product for treating systemic lupus erythematosus Download PDFInfo
- Publication number
- CN116531374A CN116531374A CN202310426497.2A CN202310426497A CN116531374A CN 116531374 A CN116531374 A CN 116531374A CN 202310426497 A CN202310426497 A CN 202310426497A CN 116531374 A CN116531374 A CN 116531374A
- Authority
- CN
- China
- Prior art keywords
- pioglitazone
- lupus erythematosus
- systemic lupus
- mice
- use according
- 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
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 229960005095 pioglitazone Drugs 0.000 title claims abstract description 52
- 201000000596 systemic lupus erythematosus Diseases 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000003814 drug Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 241000699670 Mus sp. Species 0.000 claims description 44
- 239000000243 solution Substances 0.000 claims description 12
- 108090000623 proteins and genes Proteins 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 10
- 102000004169 proteins and genes Human genes 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 claims description 8
- 210000005259 peripheral blood Anatomy 0.000 claims description 8
- 239000011886 peripheral blood Substances 0.000 claims description 8
- 229960002827 pioglitazone hydrochloride Drugs 0.000 claims description 6
- 230000036541 health Effects 0.000 claims description 5
- 230000002485 urinary effect Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000002674 ointment Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 238000012827 research and development Methods 0.000 abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 210000003491 skin Anatomy 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 210000002700 urine Anatomy 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 230000008021 deposition Effects 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 210000003734 kidney Anatomy 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 238000007789 sealing Methods 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 5
- 239000002285 corn oil Substances 0.000 description 5
- 235000005687 corn oil Nutrition 0.000 description 5
- 206010040882 skin lesion Diseases 0.000 description 5
- 231100000444 skin lesion Toxicity 0.000 description 5
- 210000002469 basement membrane Anatomy 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000001434 glomerular Effects 0.000 description 4
- 230000008595 infiltration Effects 0.000 description 4
- 238000001764 infiltration Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 201000001474 proteinuria Diseases 0.000 description 4
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-N 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- 238000008157 ELISA kit Methods 0.000 description 3
- 108010016731 PPAR gamma Proteins 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- 230000003460 anti-nuclear Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 210000002510 keratinocyte Anatomy 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 230000037380 skin damage Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 108010051219 Cre recombinase Proteins 0.000 description 2
- 102100038595 Estrogen receptor Human genes 0.000 description 2
- 102000000536 PPAR gamma Human genes 0.000 description 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 210000003855 cell nucleus Anatomy 0.000 description 2
- 230000035617 depilation Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 210000005069 ears Anatomy 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 230000001861 immunosuppressant effect Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000013011 mating Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000008807 pathological lesion Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000007480 spreading Effects 0.000 description 2
- 238000003892 spreading Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000004018 waxing Methods 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 102000002227 Interferon Type I Human genes 0.000 description 1
- 108010014726 Interferon Type I Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 101150037996 KRT5 gene Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000034527 Retinoid X Receptors Human genes 0.000 description 1
- 108010038912 Retinoid X Receptors Proteins 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000001039 kidney glomerulus Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003818 metabolic dysfunction Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000006492 vascular dysfunction Effects 0.000 description 1
- 238000009423 ventilation 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of pioglitazone and a salt thereof in preparing a product for treating systemic lupus erythematosus, and the pioglitazone is used as an old medicine for clinically treating diabetes, and has small toxic and side effects. The first study of the invention shows that pioglitazone has a certain potential in treating systemic lupus erythematosus, and the new use of the pioglitazone as an old medicine can greatly shorten the research and development cost and the research and development risk. The invention explores the effect of pioglitazone on treating the systemic lupus erythematosus for the first time, and provides an experimental basis for treating the systemic lupus erythematosus.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to a novel application of thiazolidinedione-selective PPAR gamma (peroxisome proliferator-activated receptor) agonist pioglitazone in preparing a product for treating systemic lupus erythematosus, in particular to an application of pioglitazone and a salt thereof.
Background
Systemic lupus erythematosus (systemic lupus erythematosus, SLE) is a complex autoimmune disease with diverse clinical manifestations characterized by excessive production of type I Interferons (IFNs) and autoantibodies. SLE pathogenesis is not clear, genetic susceptibility, environmental inducement and hormone level interaction together promote the occurrence and development of diseases. In recent years, SLE incidence rate is rising worldwide, global incidence rate is 43.7/10 ten thousand people, human health is seriously endangered, and even life is threatened.
SLE is well developed in women of childbearing age, the main treatment means are glucocorticoid and immunosuppressant, most of patients can be in stable or low activity state, but the SLE can not be thoroughly cured, and meanwhile, the problems of low responsiveness to drugs, no response and large side effects of long-term administration of the drugs exist. Thus, treatment for SLE has been a major concern and difficulty of research.
Pioglitazone (Pioglitazone) acts as a selective ppary (peroxisome proliferator-activated receptor) agonist and binds with high affinity to the ppary ligand binding domain, and activated ppary forms heterodimers with retinoid X receptors, which bind to the target gene promoter DNA and thereby modulate target gene expression to produce a biological effect. Pioglitazone is used for clinical treatment of type 2 diabetes and has been shown to alleviate nonalcoholic fatty liver and restore skin barrier function in eczema patients. Furthermore, studies and clinical trials have shown that pioglitazone can ameliorate vascular and metabolic dysfunction in SLE mice and patients, but the effect of pioglitazone on SLE disease itself has not been elucidated.
Disclosure of Invention
The invention aims to: aiming at the problem of large side effect of the traditional SLE therapeutic drug, the invention provides a new application of pioglitazone drug in treating SLE, and provides an experimental basis and a new therapeutic means for SLE treatment.
The invention provides application of pioglitazone and salt thereof in preparing a product for treating systemic lupus erythematosus for the first time. Specifically, the systemic lupus erythematosus is an autoimmune disease characterized by immune disorder and the generation of a large amount of autoantibodies, and is different from other types of lupus erythematosus.
External treatment of SLE model mice is carried out by using pioglitazone and pioglitazone salt, and the pioglitazone can obviously reduce the contents of anti-dsDNA, ANA and urine protein in the peripheral blood of the mice, and reduce the generation of autoantibodies. Pathological staining of skin tissue showed significantly reduced inflammatory cell infiltration and tissue injury compared to the untreated drug group, and kidney and skin immunofluorescence showed significantly reduced deposition of glomeruli and basement membrane band IgG. Experimental results show that pioglitazone can reduce the generation of autoantibodies, protect kidneys and exert the treatment effect of SLE.
Wherein, when in use, the pioglitazone and the salt thereof are used as active ingredients of medicines for treating systemic lupus erythematosus.
In particular, the product is a medicine and a health product.
The invention further proposes the use of a pharmaceutical composition comprising pioglitazone or a salt thereof for the preparation of a product for the treatment of systemic lupus erythematosus.
Further, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or adjuvant.
Wherein the product is a medicine or a health product.
Preferably, the pharmaceutical composition is selected from the following dosage forms: solution, gel, paste, powder, tablet, injection, capsule or oral liquid, wherein the solution is a medicine solution for external application coated on skin lesions.
The above pharmaceutical compositions may be formulated in known ways for administration to a subject using routes including, but not limited to: parenteral, oral, topical, intradermal, intramuscular, intraperitoneal, subcutaneous, intravenous, and the like.
Preferably, the pharmaceutical composition is pioglitazone hydrochloride solution.
The beneficial effects are that: at present, the main treatment means of SLE are glucocorticoid and immunosuppressant, most of patients can be in a stable or low activity state, but the patients cannot be thoroughly cured, and the problems of low responsiveness, no response and large side effect of long-term administration of medicines exist. Pioglitazone is used as an old medicine for clinically treating diabetes, and has small toxic and side effects. The first study of the invention shows that pioglitazone has a certain potential in treating SLE, and the new use of the pioglitazone as an old medicine can greatly shorten the research and development cost and the research and development risk. The invention explores the effect of pioglitazone on treating the systemic lupus erythematosus for the first time, and provides an experimental basis for treating the systemic lupus erythematosus.
Drawings
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings and detailed description.
Figure 1 is a topical pioglitazone for the treatment of mouse SLE, wherein figure a shows pioglitazone can alleviate SLE mouse skin loss severity; panel B shows that pioglitazone can reduce urine protein and ANA content of SLE mice and peripheral blood anti-dsDNA; panel C shows that pioglitazone can relieve skin pathological damage of SLE mice; panel D shows pioglitazone can reduce deposition of IgG immune complexes on kidney glomeruli and skin basement membrane of SLE mice. Detailed Description
The present invention will be further described with reference to the following examples, but it should not be construed that the scope of the present invention is limited to the examples. Various substitutions and alterations are made according to the general technical knowledge and the conventional methods in the field without departing from the technical idea of the present invention, and all such substitutions and alterations are included in the protection scope of the present invention.
Examples topical pioglitazone was used to treat mouse SLE.
1. Experimental materials
1.1 drugs and reagents for experiments: pioglitazone hydrochloride (MedChemExpress), DMSO (Sigma-Aldrich), tamoxifen (Sigma-Aldrich), corn oil (beyotide), proteinuria test paper (ulite), urine protein quantification kit (Nanjing Jiancheng Bioengineering Institute), anti-nuclear and anti-double stranded DNA antibody ELISA kit (Cusabio), 4% paraformaldehyde (Biosharp), OCT embedding medium (Sakura), goat anti-mouse IgG-FITC (abcam).
1.2 laboratory animals
The mice used in this experiment were Krt5-CreERT2+/-PPARγflox/flox-/-SLE mice. The mice were about 6-12 weeks old and had a weight of 20-30g, which was offered by Shanghai, nannon model Biotech Co., ltd.
Specifically, krt5-CreERT2+/-PPARγflox/flox-/-SLE mice were constructed by the following method:
(1) Preparation of Krt5-CreERT2+/-PPARγflox/flox-/-mice: mating a Krt5-CreERT2 mouse with a PPARγflox/flox mouse containing loxP flanking sequences to generate offspring mice with genotypes of Krt5-CreERT2+/-PPARγflox/flox +/-and Krt5-CreERT2+/-PPARγflox/flox-/-and reserving PPARγflox/flox +/-Krt5-CreERT2 +/-mice, and mutually mating and breeding heterozygote mice to obtain mice with genotypes of PPARγflox/flox-/-Krt5-CreERT2 +/-; among them, PPARγflox/flox and Krt5-CreERT2 mice were supplied by Shanghai Nannon model Biotech Co. Krt5-CreERT2 mice are able to express the CreERT2 fusion protein targeted in keratinocytes by means of the endogenous promoter/enhancer element of the Krt5 locus. The CreERT2 fusion protein consists of a ligand binding region mutant (ERT) of the estrogen receptor (estrogen receptor, ER) and a Cre recombinase protein. PPARγflox/flox mice, i.e., PPARγ conditional knockout mice, have a loxP site inserted at both ends of the specific exon of the PPARγ gene, which can be cleaved by the active Cre recombinase.
(2) Specific knockout of keratinocyte pparγ: 50mg of 4-hydroxy tamoxifen was mixed in 1ml of DMSO, 9ml of corn oil was added, the suspension was thoroughly mixed using a vortexer, and sonicated in an ultrasonic bath at 37℃for 20 minutes to prepare a 4-hydroxy tamoxifen solution (5 mg/ml) ready for use. Then, 50ul of 5mg/ml of 4-hydroxy tamoxifen solution is smeared on two ears of a Krt5-CreERT2+/-PPARγflox/flox-/-mouse, the corresponding solution is smeared on two ears continuously for 5 days, and the phenotype of the mouse is observed, so that the Krt5-CreERT2+/-PPARγflox/flox-/-SLE mouse is obtained.
Mice were observed for skin lesions weekly and photographed with a camera for survival. The mice were periodically cleaned of midrange urine and urine protein was detected using a test paper for detection of ulide proteinuria. The urinary protein content of mice was quantified using CBB. The content of peripheral blood serum antinuclear antibodies and anti-double-stranded DNA antibodies was detected using ELISA kit (Cusabio).
On day 17, mice were sacrificed after anesthesia for cervical dislocation. Binaural skin of the same portion of the three groups of mice was cut with a sharp scalpel and ophthalmology, approximately 0.5 cm x 0.5 cm, spread on tinfoil, and snap frozen with liquid nitrogen or fixed to 4% paraformaldehyde. And (5) after fixation, dehydrating, waxing and embedding. And (3) slicing the tissue block, spreading, baking, dewaxing, hematoxylin and eosin staining, sealing, taking a view picture by using a microscope, and analyzing inflammatory cell infiltration in the skin damage of the mice.
After the skin tissue or kidney subjected to liquid nitrogen quick freezing is embedded by OCT, the skin tissue or kidney is placed on a frozen section mould, the frozen section mould is used for slicing, OCT is washed off, a goat anti-mouse IgG-FITC (1:200) is added after the immune fluorescence sealing liquid (Beyotime) is sealed for 1 hour at 37 ℃ for incubation at 4 ℃ overnight, the cell nucleus is stained with DAPI working liquid at room temperature for 10 minutes after PBS is cleaned, the sealing sheet is cleaned by PBS, and the skin and glomerular IgG deposition is observed by a fluorescence microscope imaging.
The results show that the constructed Krt5-CreERT2+/-PPARγflox/flox-/-SLE mice can efficiently, stably and spontaneously show SLE-like phenotypes such as immune cell disorder, inflammatory skin damage and dehairing, proteinuria, obvious elevation of peripheral blood dsDNA and ANA autoantibodies, skin basal membrane bands, glomerular IgG deposition and the like after activating PPARγgene knockout in local keratinocytes.
Feeding conditions: the room temperature is 18-20 ℃, the humidity is 50-60%, the brightness is alternate (12 hours), the luminosity is moderate, and the ventilation is clean. All experiments were approved and conducted as directed by the ethical committee of the dermatology hospital of the national academy of medical science (the dermatology institute of the national academy of medical science).
2. Experimental method
2.1 administration to mice
SLE mice were grouped as required: control group (corn oil+dmso), pioglitazone hydrochloride group, 5-8 per group. 120mg of pioglitazone hydrochloride was mixed in 1ml of DMSO, 9ml of corn oil was added, the suspension was thoroughly mixed using a vortexer, and sonicated in an ultrasonic bath at 37℃for 20 minutes to prepare pioglitazone hydrochloride solution (12 mg/ml) for use. The control group was applied with corn oil containing 10% DMSO and the pioglitazone hydrochloride group was applied with 50ul 12mg/ml pioglitazone hydrochloride solution. Two groups of mice were double-applied with the corresponding solution 1 time per day.
2.2 mouse skin lesions, urine proteins and autoantibody monitoring
Mice were observed for skin lesions weekly and photographed with a camera for survival. The mice were periodically cleaned of midrange urine and urine protein was detected using a test paper for detection of ulide proteinuria. The urinary protein content of mice was quantified using CBB. The content of peripheral blood serum antinuclear antibodies and anti-double-stranded DNA antibodies was detected using ELISA kit (Cusabio).
2.3 histopathology
On day 18, mice were sacrificed after anesthesia for cervical dislocation. Binaural skin of the same portion of the three groups of mice was cut with a sharp scalpel and ophthalmology, approximately 0.5 cm x 0.5 cm, spread on tinfoil, and snap frozen with liquid nitrogen or fixed to 4% paraformaldehyde. And (5) after fixation, dehydrating, waxing and embedding. And (3) slicing the tissue block, spreading, baking, dewaxing, hematoxylin and eosin staining, sealing, taking a view picture by using a microscope, and analyzing inflammatory cell infiltration in the skin damage of the mice.
2.4 immunofluorescent staining
After the skin tissue or kidney subjected to liquid nitrogen quick freezing is embedded by OCT, the skin tissue or kidney is placed on a frozen section mould, the frozen section mould is used for slicing, OCT is washed off, a goat anti-mouse IgG-FITC (1:200) is added after the immune fluorescence sealing liquid (Beyotime) is sealed for 1 hour at 37 ℃ for incubation at 4 ℃ overnight, the cell nucleus is stained with DAPI working liquid at room temperature for 10 minutes after PBS is cleaned, the sealing sheet is cleaned by PBS, and the skin and glomerular IgG deposition is observed by a fluorescence microscope imaging.
3. Experimental results
Figure 1A pioglitazone can alleviate SLE mice skin injury severity. On day 18 of treatment, the control mice showed significant depilation and inflammatory lesions, with less depilation in the overlying scale and less lesions in the pioglitazone mice. Pioglitazone is indicated to alleviate skin lesions in SLE mice.
FIG. 1B pioglitazone can reduce SLE mouse urine protein, peripheral blood anti-dsDNA and ANA content. Compared with the control group, the pioglitazone group urine protein (control group vs pioglitazone group: 67.26+/-20.70 mg/dl vs 30.30+/-7.73 mg/dl, P < 0.001), the peripheral blood autoantibody anti-dsDNA (control group vs pioglitazone group: 18.40+/-5.00 ng/ml vs 12.66+/-3.74 ng/ml, P < 0.05) and ANA (control group vs pioglitazone group: 37.58+/-4.46 ng/ml vs 23.03+/-7.53 ng/ml, P < 0.001) are obviously reduced. The results show that pioglitazone can significantly reduce SLE mouse urine protein and autoantibodies.
Fig. 1C pioglitazone can alleviate skin pathological lesions in SLE mice. HE histopathological staining is carried out on the skin of the mice, and the skin of the control group has hyperkeratosis, thickening of the acantha layer, liquefaction and denaturation of basal cells and infiltration of dermal layer immune cells. Pioglitazone group mice showed significantly reduced skin inflammatory changes at the same site. The above results again demonstrate that pioglitazone can alleviate skin pathological lesions in SLE mice.
Figure 1D pioglitazone can reduce SLE mice kidney glomerulus and skin basement membrane with IgG immune complex deposition. Tissue frozen sections indicated IgG deposition in the basal membrane band and glomeruli of the skin of the control group. Pioglitazone group mice had significantly reduced skin basal membrane band and glomerular IgG deposition at the same site. Pioglitazone is shown to reduce deposition of IgG immune complexes on kidney glomeruli and skin basement membrane of SLE mice.
The results show that pioglitazone can treat SLE mice by external application.
The invention provides ideas and methods for the application of pioglitazone in preparing medicaments for treating systemic lupus erythematosus, and the method and the way for realizing the technical scheme are numerous, the above description is only a preferred embodiment of the invention, and it should be pointed out that a plurality of improvements and modifications can be made by those skilled in the art without departing from the principle of the invention, and the improvements and modifications are also considered as the protection scope of the invention. The components not explicitly described in this embodiment can be implemented by using the prior art.
Claims (10)
1. The use of pioglitazone and its salts for the preparation of a product for the treatment of systemic lupus erythematosus.
2. The use according to claim 1, wherein pioglitazone and its salts reduce the content of anti-dsDNA, ANA and urinary proteins in the peripheral blood of mice, reducing the production of autoantibodies.
3. Use according to claim 1, characterized in that pioglitazone and its salts are used as active ingredient of a medicament for the treatment of systemic lupus erythematosus.
4. Use according to any one of claims 1-3, wherein the salt is the hydrochloride salt.
5. The use according to claim 1, wherein the products are pharmaceutical and health products.
6. Use of a pharmaceutical composition for the preparation of a product for the treatment of systemic lupus erythematosus, characterized in that the composition comprises pioglitazone or a salt thereof.
7. The use according to claim 6, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier or adjuvant.
8. The use according to claim 6, wherein the products are pharmaceutical and health products.
9. The use according to claim 6, wherein the pharmaceutical composition is selected from the following dosage forms: solutions, gels, ointments, pastes, powders, tablets, injections, capsules or oral liquids.
10. The use according to claim 6, wherein the pharmaceutical composition is pioglitazone hydrochloride solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310426497.2A CN116531374A (en) | 2023-04-20 | 2023-04-20 | Application of pioglitazone and pioglitazone salt in preparation of product for treating systemic lupus erythematosus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310426497.2A CN116531374A (en) | 2023-04-20 | 2023-04-20 | Application of pioglitazone and pioglitazone salt in preparation of product for treating systemic lupus erythematosus |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116531374A true CN116531374A (en) | 2023-08-04 |
Family
ID=87444445
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310426497.2A Pending CN116531374A (en) | 2023-04-20 | 2023-04-20 | Application of pioglitazone and pioglitazone salt in preparation of product for treating systemic lupus erythematosus |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116531374A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0108087D0 (en) * | 2001-03-30 | 2001-05-23 | Novartis Ag | Organic compounds |
| CN1413105A (en) * | 1999-04-15 | 2003-04-23 | 史密丝克莱恩比彻姆有限公司 | Novel method of treatment |
| US20090082260A1 (en) * | 2005-03-01 | 2009-03-26 | Jonathan Robert Lamb | Combination of an immunosuppressant and a ppar gamma agonist for the treatment of an undesirable immune response |
| EP2301539A1 (en) * | 2009-09-07 | 2011-03-30 | Rheinische Friedrich-Wilhelms Universität | PPAR gamma agonists for treating illnesses with pathophysiological participation of TH17 lymphocytes |
-
2023
- 2023-04-20 CN CN202310426497.2A patent/CN116531374A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1413105A (en) * | 1999-04-15 | 2003-04-23 | 史密丝克莱恩比彻姆有限公司 | Novel method of treatment |
| GB0108087D0 (en) * | 2001-03-30 | 2001-05-23 | Novartis Ag | Organic compounds |
| US20090082260A1 (en) * | 2005-03-01 | 2009-03-26 | Jonathan Robert Lamb | Combination of an immunosuppressant and a ppar gamma agonist for the treatment of an undesirable immune response |
| EP2301539A1 (en) * | 2009-09-07 | 2011-03-30 | Rheinische Friedrich-Wilhelms Universität | PPAR gamma agonists for treating illnesses with pathophysiological participation of TH17 lymphocytes |
Non-Patent Citations (4)
| Title |
|---|
| S MOHAMMADI等: "Immunomodulation in systemic lupus erythematosus: induction of M2 population in monocyte-derived macrophages by pioglitazone.", 《LUPUS . 》, vol. 26, no. 12, pages 1318 - 1327 * |
| TAMAR R APRAHAMIAN等: "Peroxisome proliferator-activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus", 《IMMUNOLOGY . 》, vol. 142, no. 3, pages 363 - 373, XP055381116, DOI: 10.1111/imm.12256 * |
| WENPU ZHAO等: "The peroxisome-proliferator activated receptor-γ agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus", 《CLIN IMMUNOL.》, vol. 149, no. 1, pages 119 - 132, XP028731164, DOI: 10.1016/j.clim.2013.07.002 * |
| 孙文萍: "免疫复合物对人血管内皮细胞和单核细胞的活化作用及其机制研究", 医药卫生科技辑, pages 065 - 29 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Chojkier | Inhibition of albumin synthesis in chronic diseases: molecular mechanisms | |
| Ouellette | IV. Paneth cell antimicrobial peptides and the biology of the mucosal barrier | |
| Bahn | Graves' ophthalmopathy | |
| Liu et al. | Transcriptional and post-translational regulation of adiponectin | |
| Wakamatsu et al. | Effect of a small molecule inhibitor of nuclear factor-κB nuclear translocation in a murine model of arthritis and cultured human synovial cells | |
| Lipton | Modulation of host defense by the neuropeptide alpha-MSH. | |
| Lhamyani et al. | miR-21 mimic blocks obesity in mice: A novel therapeutic option | |
| He et al. | Severe hypertriglyceridemia and hypercholesterolemia accelerating renal injury: a novel model of type 1 diabetic hamsters induced by short-term high-fat/high-cholesterol diet and low-dose streptozotocin | |
| Yoneda et al. | Estrogen deficiency accelerates murine autoimmune arthritis associated with receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis | |
| CA2518199A1 (en) | Pharmaceutical preparations containing thiazolidinediones showing new therapeutic indications | |
| JP4521748B2 (en) | Islet cell production and insulin delivery | |
| CN102151337B (en) | Compositions and methods for regulated protein expression in gut | |
| Wilson et al. | PANcreatic-DERived factor: novel hormone PANDERing to glucose regulation | |
| Palin et al. | The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFα-induced sickness behavior | |
| Padrutt et al. | Effects of the glucagon-like peptide-1 (GLP-1) analogues exenatide, exenatide extended-release, and of the dipeptidylpeptidase-4 (DPP-4) inhibitor sitagliptin on glucose metabolism in healthy cats | |
| Ikeda et al. | Obesity and insulin resistance in human growth hormone transgenic rats | |
| Pittenger et al. | Intramuscular injection of islet neogenesis-associated protein peptide stimulates pancreatic islet neogenesis in healthy dogs | |
| Aharon-Hananel et al. | Antidiabetic effect of interleukin-1β antibody therapy through β-cell protection in the Cohen diabetes-sensitive rat | |
| CN116548385B (en) | Construction method and application of animal model of self-onset systemic lupus erythematosus | |
| CN116531374A (en) | Application of pioglitazone and pioglitazone salt in preparation of product for treating systemic lupus erythematosus | |
| Blumenthal | From insulin and insulin-like activity to the insulin superfamily of growth-promoting peptides: a 20th-century odyssey | |
| Yamada et al. | Intensification therapy with anti-parathyroid hormone-related protein antibody plus zoledronic acid for bone metastases of small cell lung cancer cells in severe combined immunodeficient mice | |
| Leff et al. | Peroxisome Proliferator‐Activated Receptor‐γ and Its Role in the Development and Treatment of Diabetes | |
| TW201522629A (en) | Micro-organs providing sustained delivery of a therapeutic polypeptide and methods of use thereof | |
| AU2018290320A1 (en) | Garcinol compositions for therapeutic management of endoplasmic reticulum stress |
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 |