Browsing by Subject "Matricellular protein"

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    Cerebrovascular pathophysiology of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Suzuki, Hidenori; Kanamaru, Hideki; Kawakita, Fumihiro; Asada, Reona; Fujimoto, Masashi; Shiba, Masato
    Aneurysmal subarachnoid hemorrhage (SAH) remains a serious cerebrovascular disease. Even if SAH patients survive the initial insults, delayed cerebral ischemia (DCI) may occur at 4 days or later post-SAH. DCI is characteristics of SAH, and is considered to develop by blood breakdown products and inflammatory reactions, or secondary to early brain injury, acute pathophysiological events that occur in the brain within the first 72 hours of aneurysmal SAH. The pathology underlying DCI may involve large artery vasospasm and/or microcirculatory disturbances by microvasospasm, microthrombosis, dysfunction of venous outflow and compression of microvasculature by vasogenic or cytotoxic tissue edema. Recent clinical evidence has shown that large artery vasospasm is not the only cause of DCI, and that both large artery vasospasm-dependent and -independent cerebral infarction causes poor outcome. Animal studies suggest that mechanisms of vasospasm may differ between large artery and arterioles or capillaries, and that many kinds of cells in the vascular wall and brain parenchyma may be involved in the pathogenesis of microcirculatory disturbances. The impairment of the paravascular and glymphatic systems also may play important roles in the development of DCI. As pathological mediators for DCI, glutamate and several matricellular proteins have been investigated in addition to inflammatory molecules. Glutamate is involved in excitotoxicity contributing to cortical spreading ischemia and epileptic activity-related events. Microvascular dysfunction is an attractive mechanism to explain the cause of poor outcomes independently of large cerebral artery vasospasm, but needs more studies to clarify the pathophysiologies or mechanisms and to develop a novel therapeutic strategy.
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    Phenytoin activates SMAD3 phosphorylation and periostin expression in drug-induced gingival enlargement
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Kim, Shawna S.; Nikoloudaki, Georgia; Darling, Mark; Rieder, Michael J.; Hamilton, Douglas W.
    Drug-induced gingival enlargement (DIGE) is a fibrotic condition associated with systemic administration of the anti-epileptic drug, phenytoin. We have previously demonstrated that periostin, which is transforming growth factor-beta (TGF-β) inducible gene, is upregulated in various fibrotic conditions including gingival enlargement associated with nifedipine. The objective of this study was to assess periostin expression in phenytoin-induced gingival enlargement (PIGE) tissues and to investigate the mechanisms underlying periostin expression. Human PIGE tissues were assessed using Masson’s trichrome, with cell infiltration and changes in extracellular matrix composition characterized through labeling with antibodies to periostin, phospho-SMAD 3, TGF-β, as well as the macrophage markers CD68 and RM3/1. Using human gingival fibroblasts (HGFs) in vitro, we examined the pathways through which phenytoin acts on fibroblasts. In PIGE tissues, which demonstrate altered collagen organization and increased inflammatory cell infiltration, periostin protein was increased compared with healthy tissues. p-SMAD2/3, the transcription factor associated with canonical TGF-β signaling, is localized to the nuclei in both gingival fibroblasts and oral epithelial cells in PIGE tissues, but not in healthy tissue. In vitro culture of HGFs with 15 and 30 μg/ml of phenytoin increased periostin protein levels, which correlated with p-SMAD3 phosphorylation. Inhibition of canonical TGF-β signaling with SB431542 significantly reduced phenytoin induction of SMAD3 phosphorylation and periostin expression in HGFs. Analysis of PIGE tissues showed a subset of CD68 stained macrophages were TGF-β positive and that RM1/3 regenerative macrophages were present in the tissues. Our results demonstrate that phenytoin up-regulates periostin in HGFs in a TGF-β-dependent manner.