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1.
Clin Immunol ; 264: 110255, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38763433

ABSTRACT

Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Cell Movement , Cell Proliferation , Fibroblasts , Succinates , Synoviocytes , Animals , Synoviocytes/drug effects , Synoviocytes/metabolism , Cell Movement/drug effects , Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Cell Proliferation/drug effects , Succinates/pharmacology , Rats , Fibroblasts/drug effects , Fibroblasts/metabolism , Male , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Mice , Mice, Knockout , Cells, Cultured , Mice, Inbred DBA , Citric Acid Cycle/drug effects
2.
Arthritis Rheumatol ; 75(3): 411-423, 2023 03.
Article in English | MEDLINE | ID: mdl-36098515

ABSTRACT

OBJECTIVE: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiorgan dysfunction. Neuropsychiatric SLE (NPSLE) occurs in 30-40% of lupus patients and is the most severe presentation of SLE, frequently resulting in limitation of daily life. Recent studies have shown that microglia, tissue-resident macrophages in the central nervous system, are involved in the pathogenesis of NPSLE. This study was undertaken to explore new therapeutic targets for NPSLE focusing on microglia. METHODS: RNA sequencing of microglia in MRL/lpr, lupus-prone mice, as well as that of microglia cultured in vitro with cytokines were performed. A candidate gene, which could be a therapeutic target for NPSLE, was identified, and its role in microglial activation and phagocytosis was investigated using specific inhibitors and small interfering RNA. The effect of intracerebroventricular administration of the inhibitor on the behavioral abnormalities of MRL/lpr was also evaluated. RESULTS: Transcriptome analysis revealed the up-regulation of Ikbke, which encodes the inhibitor of NF-κB kinase subunit ɛ (IKBKε) in both microglia from MRL/lpr mice and cytokine-stimulated microglia in vitro. Intracerebroventricular administration of an IKBKε inhibitor ameliorated cognitive function and suppressed microglial activation in MRL/lpr mice. Mechanistically, IKBKε inhibition reduced glycolysis, which dampened microglial activation and phagocytosis. CONCLUSION: These findings suggest that IKBKε plays a vital role in the pathogenesis of NPSLE via microglial activation, and it could serve as a therapeutic target for NPSLE.


Subject(s)
Lupus Erythematosus, Systemic , Microglia , Mice , Animals , NF-kappa B , Depression/psychology , Mice, Inbred MRL lpr , Cytokines
3.
J Stroke Cerebrovasc Dis ; 31(8): 106601, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35717718

ABSTRACT

OBJECTIVES: Complement component 6 (C6) deficiency is a very rare genetic defect that leads to significantly diminished synthesis, secretion, or function of C6. In the current report, we demonstrate a previously undescribed, homozygous missense mutation in exon 17 of the C6 gene (c.2545A>G p.Arg849Gly) in a 35-year-old Japanese woman with moyamoya disease and extremely low levels of CH50 (<7.0 U/mL). MATERIALS AND METHODS: The complement gene analysis using hybridization capture-based next generation sequencing was performed. CH50 was determined in patient's plasma mixed with plasma from a healthy donor or purified human C6 protein. Western blot was performed on patient's plasma using polyclonal antibodies against C6, with healthy donor's plasma and purified human C6 protein as positive controls while C6-depleted human serum as a negative control. The carriage of ring finger protein 213 variant (c.14576G>A p.Arg4859Lys), a susceptibility gene for moyamoya disease, was examined by direct sequencing. RESULTS: CH50 mixing test clearly showed a deficiency pattern, being rescued by addition of only 1% healthy donor's plasma or 1 µg/mL purified human C6 protein (1/50-1/100 of physiological concentration). Western blot revealed the absence of C6 protein in the patient's plasma, confirming a quantitative deficiency of C6. The ring finger protein 213 variant was not detected. CONCLUSIONS: Our data implies that unrecognized complement deficiencies would be harbored in cerebrovascular diseases with unknown etiologies.


Subject(s)
Complement C6 , Moyamoya Disease , Adult , Complement C6/deficiency , Complement C6/genetics , Female , Hereditary Complement Deficiency Diseases , Humans , Moyamoya Disease/complications , Moyamoya Disease/genetics , Pedigree
4.
Eur J Intern Med ; 96: 109-110, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34998666

Subject(s)
Spleen , Thrombocytosis , Humans
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