ABSTRACT
BACKGROUND: Fibroblast-like synoviocytes (FLSs) are involved in osteoarthritis (OA) pathogenesis through pro-inflammatory cytokine production. TAK-242, a TLR4 blocker, has been found to have a significant impact on the gene expression profile of pro-inflammatory cytokines such as IL1-ß, IL-6, TNF-α, and TLR4, as well as the phosphorylation of Ikßα, a regulator of the NF-κB signaling pathway, in OA-FLSs. This study aims to investigate this effect because TLR4 plays a crucial role in inflammatory responses. MATERIALS AND METHODS: Ten OA patients' synovial tissues were acquired, and isolated FLSs were cultured in DMEM in order to assess the effectiveness of TAK-242. The treated FLSs with TAK-242 and Lipopolysaccharides (LPS) were analyzed for the mRNA expression level of IL1-ß, IL-6, TNF-α, and TLR4 levels by Real-Time PCR. Besides, we used western blot to assess the protein levels of Ikßα and pIkßα. RESULTS: The results represented that TAK-242 effectively suppressed the gene expression of inflammatory cytokines IL1-ß, IL-6, TNF-α, and TLR4 which were overexpressed upon LPS treatment. Additionally, TAK-242 inhibited the phosphorylation of Ikßα which was increased by LPS treatment. CONCLUSION: According to our results, TAK-242 shows promising inhibitory effects on TLR4-mediated inflammatory responses in OA-FLSs by targeting the NF-κB pathway. TLR4 inhibitors, such as TAK-242, may be useful therapeutic agents to reduce inflammation and its associated complications in OA patients, since traditional and biological treatments may not be adequate for all of them.
Subject(s)
Cytokines , Interleukin-1beta , Interleukin-6 , Lipopolysaccharides , NF-kappa B , Signal Transduction , Sulfonamides , Synoviocytes , Toll-Like Receptor 4 , Tumor Necrosis Factor-alpha , Humans , Signal Transduction/drug effects , Synoviocytes/drug effects , Synoviocytes/metabolism , NF-kappa B/metabolism , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Toll-Like Receptor 4/metabolism , Cytokines/metabolism , Interleukin-6/metabolism , Interleukin-1beta/metabolism , Tumor Necrosis Factor-alpha/metabolism , Lipopolysaccharides/pharmacology , Fibroblasts/metabolism , Fibroblasts/drug effects , Osteoarthritis/metabolism , Osteoarthritis/drug therapy , Cells, Cultured , Phosphorylation , RNA, Messenger/metabolism , Male , Female , Middle AgedABSTRACT
BACKGROUND: Mild cognitive impairment (MCI) is a state between normal cognition and dementia. However, MCI diagnosis does not necessarily guarantee the progression to dementia. Since no previous study investigated brain positron emission tomography (PET) imaging of MCI-- to-normal reversion, we provided PET imaging of MCI- to-normal reversion using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. METHODS: We applied comprehensive neuropsychological criteria (NP criteria), consisting of memory, language, and attention/executive function domains, to include patients with a baseline diagnosis of MCI (n=613). According to the criteria, the year 1 status of the patients was categorized into three groups (reversion: n=105, stable MCI: n=422, conversion: n=86). Demographic, neuropsychological, genetic, CSF, and cognition biomarker variables were compared between the groups. Additionally, after adjustment for confounding variables, the deposition pattern of amyloid-ß and cerebral glucose metabolism were compared between three groups via AV45- and FDG-PET modalities, respectively. RESULTS: MCI reversion rate was 17.1% during one year of follow-up. The reversion group had the lowest frequency of APOE ε4+ subjects, the highest CSF level of amyloid-ß, and the lowest CSF levels of t-tau and p-tau. Neuropsychological assessments were also suggestive of better cognitive performance in the reversion group. Patients with reversion to normal state had higher glucose metabolism in bilateral angular and left middle/inferior temporal gyri, when compared to those with stable MCI state. Meanwhile, lower amyloid-ß deposition at baseline was observed in the frontal and parietal regions of the reverted subjects. On the other hand, the conversion group showed lower cerebral glucose metabolism in bilateral angular and bilateral middle/inferior temporal gyri compared to the stable MCI group, whereas the amyloid-ß accumulation was similar between the groups. CONCLUSION: This longitudinal study provides novel insight regarding the application of PET imaging in predicting MCI transition over time.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Cognitive Dysfunction/diagnosis , Disease Progression , Fluorodeoxyglucose F18 , Humans , Longitudinal Studies , Positron-Emission Tomography/methodsABSTRACT
BACKGROUND: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. Although a significant proportion of the population with MCI experience reversion to normal cognition, it is still poorly understood. OBJECTIVE: This study was designed to extend the present evidence regarding the difference between stable and reverting MCI by including whole brain atrophy measures as possible parameters involved. METHODS: 405 patients diagnosed with MCI at baseline were selected. After one-year follow-up period, 337 patients (83.2%) were categorized as stable MCI and 68 patients (16.8%) reverted to cognitively normal status (reversion group). Several baseline biomarkers including cerebrospinal fluid (CSF) biomarkers of AD, including Aß42, t-tau, and p-tau and MRI-based atrophy measurements were compared. RESULTS: Participants with stable MCI demonstrated greater brain atrophy as well as lower Aß and higher tau proteins in the CSF. The atrophy rate was found to be associated with CSF biomarkers merely in the stable group, after adjustment for confounding variables. CONCLUSION: These findings provide novel evidence regarding the biological perspective of the reversion phenomenon in individuals with MCI.
