Browsing by Subject "FACTOR-KAPPA-B"

Sort by: Order: Results:

Now showing items 1-4 of 4
  • Taavitsainen-Wahlroos, Eveliina; Miettinen, Ilkka; Kortesoja, Maarit; Reigada, Inés; Savijoki, Kirsi; Nyman, Tuula Anneli; Hanski, Leena (2022)
    Chlamydia pneumoniae is a ubiquitous intracellular bacterium which infects humans via the respiratory route. The tendency of C. pneumoniae to persist in monocytes and macrophages is well known, but the underlying host-chlamydial interactions remain elusive. In this work, we have described changes in macrophage intracellular signaling pathways induced by C. pneumoniae infection. Label-free quantitative proteome analysis and pathway analysis tools were used to identify changes in human THP-1-derived macrophages upon C. pneumoniae CV6 infection. At 48-h postinfection, pathways associated to nuclear factor kappa B (NF-kappa B) regulation were stressed, while negative regulation on cell cycle control was prominent at both 48 h and 72 h. Upregulation of S100A8 and S100A9 calcium binding proteins, osteopontin, and purine nucleoside hydrolase, laccase domain containing protein 1 (LACC1) underlined the proinflammatory consequences of the infection, while elevated NF-kappa B2 levels in infected macrophages indicates interaction with the noncanonical NF-kappa B pathway. Infection-induced alteration of cell cycle control was obvious by the downregulation of mini chromosome maintenance (MCM) proteins MCM2-7, and the significance of host cell cycle regulation for C. pneumoniae replication was demonstrated by the ability of a cyclin-dependent kinase (CDK) 4/6 inhibitor Palbociclib to promote C. pneumoniae replication and infectious progeny production. The infection was found to suppress retinoblastoma expression in the macrophages in both protein and mRNA levels, and this change was reverted by treatment with a histone deacetylase inhibitor. The epigenetic suppression of retinoblastoma, along with upregulation of S100A8 and S100A9, indicate host cell changes associated with myeloid-derived suppressor cell (MDSC) phenotype.
  • Loppi, S.; Kolosowska, N.; Kärkkäinen, O.; Korhonen, P.; Huuskonen, M.; Grubman, A.; Dhungana, H.; Wojciechowski, S.; Pomeshchik, Y.; Giordano, M.; Kagechika, H.; White, A.; Auriola, S.; Koistinaho, J.; Landreth, G.; Hanhineva, K.; Kanninen, K.; Malm, T. (2018)
    Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.
  • Loppi, Sanna; Korhonen, Paula; Bouvy-Liivrand, Maria; Caligola, Simone; Turunen, Tiia A.; Turunen, Mikko P.; de Sande, Ana Hernandez; Kolosowska, Natalia; Scoyni, Flavia; Rosell, Anna; Garcia-Berrocoso, Teresa; Lemarchant, Sighild; Dhungana, Hiramani; Montaner, Joan; Koistinaho, Jari; Kanninen, Katja M.; Kaikkonen, Minna U.; Giugno, Rosalba; Heinäniemi, Merja; Malm, Tarja (2021)
    Ischemic stroke, the third leading cause of death in the Western world, affects mainly the elderly and is strongly associated with comorbid conditions such as atherosclerosis or diabetes, which are pathologically characterized by increased inflammation and are known to influence the outcome of stroke. Stroke incidence peaks during influenza seasons, and patients suffering from infections such as pneumonia prior to stroke exhibit a worse stroke outcome. Earlier studies have shown that comorbidities aggravate the outcome of stroke, yet the mediators of this phenomenon remain obscure. Here, we show that acute peripheral inflammation aggravates stroke-induced neuronal damage and motor deficits specifically in aged mice. This is associated with increased levels of plasma proinflammatory cytokines, rather than with an increase of inflammatory mediators in the affected brain parenchyma. Nascent transcriptomics data with mature microRNA sequencing were used to identify the neuron-specific miRNome, in order to decipher dysregulated miRNAs in the brains of aged animals with stroke and co-existing inflammation. We pinpoint a previously uninvestigated miRNA in the brain, miR-127, that is highly neuronal, to be associated with increased cell death in the aged, LPS-injected ischemic mice. Target prediction tools indicate that miR-127 interacts with several basally expressed neuronal genes, and of these we verify miR-127 binding to Psmd3. Finally, we report reduced expression of miR-127 in human stroke brains. Our results underline the impact of peripheral inflammation on the outcome of stroke in aged subjects and pinpoint molecular targets for restoring endogenous neuronal capacity to combat ischemic stroke.
  • Torregrosa-Munumer, Ruben; Vara, Elena; Fernandez-Tresguerres, Jesus Angel; Gredilla, Ricardo (2021)
    Purpose Aging is known to play a critical role in the etiopathogenesis of several diseases. Among them, cardiovascular disorders are especially relevant since they are becoming the first cause of death in western countries. Resveratrol is a polyphenolic compound that has been shown to exert beneficial effects at different levels, including neuronal and cardiovascular protection. Those effects of resveratrol are related, at least in part, to its antioxidant and anti-inflammatory properties. In the current investigation we were interested in exploring whether the positive effects of resveratrol at cardiac level were taking place even when the supplementation started in already old animals. Methods Old male rats were supplemented with resveratrol during 10 weeks. Using RT-PCR, we analyzed the effects of resveratrol supplementation on the expression of different genes related to inflammation, oxidative stress and apoptosis in rat heart. Results Resveratrol reverted age-related changes in inflammatory, oxidative and apoptotic markers in the rat heart. Among others, the expression of two major inflammatory markers, INF-gamma and TNF-alpha and two oxidative markers, heme oxygenase-1 and nitric oxide synthase, were increased with aging, and resveratrol supplementation reduced the level of some of these to those observed in the heart of young animals. Moreover, age-related changes in apoptotic markers in rat heart tend to be also reverted by resveratrol treatment. Conclusion Our results suggest that resveratrol might exert beneficial effects as an anti-aging compound to revert age-related changes in cardiac function.