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WO2023036117A1 - Application de l-glutamine dans le traitement de l'ostéoarthrite - Google Patents

Application de l-glutamine dans le traitement de l'ostéoarthrite Download PDF

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Publication number
WO2023036117A1
WO2023036117A1 PCT/CN2022/117211 CN2022117211W WO2023036117A1 WO 2023036117 A1 WO2023036117 A1 WO 2023036117A1 CN 2022117211 W CN2022117211 W CN 2022117211W WO 2023036117 A1 WO2023036117 A1 WO 2023036117A1
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WO
WIPO (PCT)
Prior art keywords
gln
nkila
tgf
osteoarthritis
glutamine
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PCT/CN2022/117211
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English (en)
Chinese (zh)
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程文丹
马潇
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安徽医科大学第二附属医院
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Publication of WO2023036117A1 publication Critical patent/WO2023036117A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the field of biomedicine, more specifically, it relates to the application of L-glutamine in the treatment of osteoarthritis.
  • Osteoarthritis is the most common joint disease. It is the degeneration of articular cartilage caused by many factors such as strain, trauma, aging, congenital abnormalities of joints, and joint deformities. It is mainly characterized by the destruction of articular cartilage. Including synovial and chondrocyte inflammation, osteophyte formation and subchondral bone sclerosis and other pathological changes; the clinical manifestations are slowly developing joint pain, stiffness, joint swelling, limited mobility and joint deformity. Approximately 10%-20% of adults suffer from OA, thus imposing a huge socioeconomic burden.
  • Non-drug treatment includes weight loss, aerobic training and physical therapy, etc., and is not aimed at the pathological state of the disease.
  • Drug therapy is expected to improve the symptoms of patients and delay the pathological process of the disease.
  • the current drugs for treating osteoarthritis are mainly anti-inflammatory and analgesic drugs, such as non-steroidal anti-inflammatory drugs, acetaminophen and tramadol, etc., which relieve symptoms but cannot delay the pathological process of osteoarthritis, but only delay the final operation time.
  • DMOADs disease-modifying osteoarthritis drugs
  • Its representative drugs include strontium ranelate, hydroxychloroquine, and tumor necrosis factor alpha blockers, etc., but these drugs are basically in the preclinical research stage, and their clinical efficacy is still uncertain and expensive.
  • the object of the present invention is to provide the application of L-glutamine in the treatment of osteoarthritis.
  • the technical purpose of the present invention is achieved through the following technical solutions: the application of L-glutamine in the preparation of medicines for treating osteoarthritis.
  • the L-glutamine regulates the up-regulation of lncRNA NKILA gene expression through the TGF- ⁇ 1 signaling pathway to treat osteoarthritis.
  • the expression of the lncRNA NKILA gene is up-regulated to reduce chondrocyte inflammatory damage by inhibiting NF- ⁇ B activation.
  • the L-glutamine is combined with at least one of the alanine residue 230, leucine residue 278 and lysine residue 232 of TGF- ⁇ 1.
  • the TGF- ⁇ 1 acts on the membrane receptor TGF- ⁇ R, it activates the downstream Smad2 and Smad3 signaling proteins, and the Smad2 and Smad3 signaling proteins enter the nucleus and bind to the NKILA promoter region to increase the expression of NKILA to prevent NF- ⁇ B activation and translocation into the nucleus.
  • the lncRNA NKILA gene is located on human chromosome 20p13.
  • the present invention has the following beneficial effects:
  • the present invention uses L-Gln to treat rat OA animal models, and systematically evaluates the direct curative effect of L-Gln on OA from multiple aspects such as inflammatory response, extracellular matrix secretion, chondrocyte survival, and cartilage regeneration; combined with NKILA gene silencing And TGF- ⁇ receptor blockers and other methods revealed the molecular mechanism of L-Gln in the treatment of OA, and verified that L-Gln can up-regulate the expression of NKILA through the TGF- ⁇ 1 pathway, thereby inhibiting the activation of NF- ⁇ B and reducing the inflammation of chondrocytes damage, promote extracellular matrix secretion and cartilage repair, and provide a new theoretical basis for the prevention and treatment of OA; thus, L-Gln can be used as a new, cheap and more effective drug for improving osteoarthritis disease, not only can Relieve the pain caused by the patient's disease, and fundamentally improve the damaged cartilage structure, thereby delaying the progress of the disease.
  • Fig. 1 is the knee joint KSS scoring result figure after L-Gln treatment in the embodiment of the present invention
  • Fig. 2 is the expression spectrum of lncRNAs detected in human normal cartilage and OA cartilage by high-throughput sequencing method in the embodiment of the present invention
  • Fig. 3 is the result figure of lncRNAs expression in OA cartilage and OA chondrocyte detected by Real-time PCR in the embodiment of the present invention
  • Fig. 4 is a Docking result diagram of TGF- ⁇ 1, a potential target of L-glutamine in an example of the present invention.
  • L-glutamine (L-glutamine, L-Gln) (trade name xinmaglin), the molecular formula is C5H10N2O3, it is a non-essential amino acid mainly concentrated in plasma and skeletal muscle, and plays an important role in human metabolism important regulatory role. Its structural formula is as follows:
  • the knee joint OA models of rabbits and rats were established by anterior cruciate ligament resection, and the expression of NKILA in chondrocytes was detected by Real-time PCR, and it was found that NKILA was not expressed in rabbit chondrocytes , while the expression of rat chondrocytes, and the difference is roughly the same as the expression of human chondrocytes; finally, Real-time PCR was used to detect the expression of NKILA in rat OA chondrocytes cultured in vitro, and it was found that it was significantly lower than that of normal cartilage. The expression level of L-Gln was significantly increased after 10mM L-Gln.
  • A is the expression of lncRNA in human OA chondrocytes cultured in vitro and its expression after adding L-Gln
  • B is the expression of NKILA in human OA cartilage and rat OA cartilage
  • C is the expression of human OA cartilage in vitro
  • the experimental conditions are: 20mM PB, 100mM NaCl, 5% DMSO, pH 8.0, 18°C.
  • concentrations of TGF- ⁇ 1 and L-Gln were 50 ⁇ M and 1000 ⁇ M, respectively.
  • L-Gln exothermic after adding TGF- ⁇ 1, but did not reach saturation.
  • DMSO was dropped into protein.
  • L-Gln the exotherm continued, and the exotherm did not reach saturation.
  • the present invention proposes for the first time that L-Gln up-regulates the expression of NKILA through the TGF- ⁇ 1 signaling pathway, thereby inhibiting the activation of the NF- ⁇ B signaling pathway, finally inhibiting the inflammatory injury and apoptosis of chondrocytes, promoting the secretion of extracellular matrix, and repairing damaged cells. Damaged articular cartilage to achieve the purpose of treating OA.
  • the present invention respectively constructs OA cell models and animal models corresponding to NKILA gene silencing and TGF- ⁇ 1 blocking, revealing the molecular mechanism of L-Gln treating OA.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Une application de la L-glutamine dans le traitement de l'ostéoarthrite, qui concerne le domaine de la biomédecine, est divulguée. La présente invention utilise la L-Gln pour traiter un modèle animal de rat d'OA, et évalue systématiquement l'efficacité directe de la L-Gln sur l'OA en termes de réponse inflammatoire, de sécrétion de la matrice extracellulaire, de survie des chondrocytes, et de régénérescence du cartilage. En combinaison aux procédés tels que le silençage de gène NKILA et des agents bloquants le TGF-β, la L-Gln s'est montrée comme régulant à la hausse l'expression de NKILA par l'intermédiaire de la voie TGF-β1, inhibant ainsi l'activation du NF-κB, réduisant les dégâts inflammatoires des chondrocytes, et favorisant la sécrétion de la matrice extracellulaire et la réparation de cartilage. La L-Gln, comme nouveau médicament, bon marché, et plus efficace pour améliorer l'ostéoarthrite, non seulement soulage la douleur causée par la maladie, mais améliore également fondamentalement les structures du cartilage endommagé, ralentissant ainsi la progression de la maladie.
PCT/CN2022/117211 2021-09-07 2022-09-06 Application de l-glutamine dans le traitement de l'ostéoarthrite WO2023036117A1 (fr)

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CN202111043698.1A CN113768912A (zh) 2021-09-07 2021-09-07 L-谷氨酰胺在治疗骨关节炎中的应用
CN202111043698.1 2021-09-07

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CN113768912A (zh) * 2021-09-07 2021-12-10 安徽医科大学第二附属医院 L-谷氨酰胺在治疗骨关节炎中的应用
CN114796178A (zh) * 2022-03-10 2022-07-29 李亚兰 L-谷氨酰胺用于缓解银环蛇伤的潜在治疗用途

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CN113768912A (zh) * 2021-09-07 2021-12-10 安徽医科大学第二附属医院 L-谷氨酰胺在治疗骨关节炎中的应用

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EP1663283B1 (fr) * 2003-09-12 2012-05-23 University of Colorado Glutamine pour le traitement de lesion

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CN113768912A (zh) * 2021-09-07 2021-12-10 安徽医科大学第二附属医院 L-谷氨酰胺在治疗骨关节炎中的应用

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Title
FUJITA SHINYA, ARAI YUJI, NAKAGAWA SHUJI, TAKAHASHI KENJI A., TERAUCHI RYU, INOUE ATSUO, TONOMURA HITOSHI, HIRAOKA NOBUYUKI, INOUE: "Combined microwave irradiation and intraarticular glutamine administration-induced HSP70 expression therapy prevents cartilage degradation in a rat osteoarthritis model", JOURNAL OF ORTHOPAEDIC RESEARCH, ORTHOPAEDIC RESEARCH SOCIETY, US, vol. 30, no. 3, 18 August 2011 (2011-08-18), US , pages 401 - 407, XP093045601, ISSN: 0736-0266, DOI: 10.1002/jor.21535 *
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YANG, K. C. ET AL.: "L-glutamine regulates the expression of matrix proteins, pro-inflammatory cytokines and catabolic enzymes in interleukin-1beta-stimulated human chondrocytes", PROCESS BIOCHEMISTRY, vol. 51, 19 December 2015 (2015-12-19), XP029422123, DOI: 10.1016/j.procbio.2015.12.010 *

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