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- Di Martino, E, et al.
(författare)
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Defining a Time Window for Neuroprotection and Glia Modulation by Caffeine After Neonatal Hypoxia-Ischaemia
- 2020
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Ingår i: Molecular neurobiology. - : Springer Science and Business Media LLC. - 1559-1182 .- 0893-7648. ; 57:5, s. 2194-2205
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxic-ischemic (HI) brain injury remains an important cause of brain damage in neonates with potential life-long consequences. Caffeine, which is a competitive inhibitor of adenosine receptors, is commonly used as treatment for preterm apnoea in clinical settings. In the current study, we investigated the effects of caffeine given at 0 h, 6 h, 12 h or 24 h after HI in P10 mouse pups. Open field and rotarod behavioural tests were performed 2 weeks after injury, and brain morphology was then evaluated. Gene expression and immunohistological analyses were assessed in mice 1- and 5-day post-HI. A single dose of caffeine directly after HI resulted in a reduction of the lesion in the grey and white matter, judged by immunostaining of MAP2 and MBP, respectively, compared to PBS-treated controls. In addition, the number of amoeboid microglia and apoptotic cells, the area covered by astrogliosis, and the expression of pro-inflammatory cytokines were significantly decreased. Behavioural assessment after 2 weeks showed increased open-field activity after HI, and this was normalised if caffeine was administered immediately after the injury. Later administrations of caffeine did not change the outcomes when compared to the vehicle group. In conclusion, caffeine only yielded neuroprotection and immunomodulation in a neonatal model of brain hypoxia ischaemia if administered immediately after injury.
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| 2. |
- Mukai, T, et al.
(författare)
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Umbilical cord-derived mesenchymal stromal cells immunomodulate and restore actin dynamics and phagocytosis of LPS-activated microglia via PI3K/Akt/Rho GTPase pathway
- 2021
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Ingår i: Cell death discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 7:1, s. 46-
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Tidskriftsartikel (refereegranskat)abstract
- Microglia are the immune cells in the central nervous system surveying environment and reacting to various injuries. Activated microglia may cause impaired synaptic plasticity, therefore modulating and restoring them to neutral phenotype is crucial to counteract a pro-inflammatory, neurotoxic state. In this study, we focused on elucidating whether human umbilical cord (UC) -derived mesenchymal stromal cells (MSCs) can exert immunomodulatory effect and change the phenotype of activated microglia. Primary culture of microglia was activated by lipopolysaccharide (LPS) and was co-cultured with three lots of MSCs. We investigated immunomodulation, actin dynamics and phagocytic capacity of activated microglia, and examined change of Rho GTPase in microglia as the mechanism. MSCs suppressed the expression of IL-1β and pNFκB in LPS-activated microglia, and conversely elevated the expression of IL-1β in resting-surveying microglia with lot-to-lot variation. Morphological and phagocytotic analyses revealed that LPS stimulation significantly increased active Rho GTPase, Rac1, and Cdc42 levels in the microglia, and their morphology changed to amoeboid in which F-actin spread with ruffle formation. The F-actin spreading persisted after removal of LPS stimulation and reduced phagocytosis. On the other hand, MSC co-culture induced bimodal increase in active Rac1 and Cdc42 levels in LPS-activated microglia. Moreover, extended ruffles of F-actin shrinked and concentrated to form an actin ring, thereby restoring phagocytosis. We confirmed inhibition of the PI3K/Akt pathway attenuated F-actin dynamics and phagocytosis restored by MSCs. Overall, we demonstrated that MSCs immunomodulated microglia with lot-to-lot variation, and changed the phenotype of LPS-activated microglia restoring actin dynamics and phagocytosis by increase of active Rho GTPase.
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