The American journal of pathology
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We previously reported that ethanol consumption affects morbidity and mortality after traumatic brain injury (TBI) by accelerating brain edema via oxidative stress after TBI. Aquaporin-4 (AQP4), a water channel, is involved in brain edema formation. In this study, we found that acute ethanol administration increased AQP4 expression after TBI, leading to severe brain edema in rats. ⋯ Acetazolamide treatment improved the survival rate to 100% and decreased brain edema and AQP4 in ethanol-pretreated rats. These findings suggest that ethanol induces up-regulation of AQP4, leading to brain edema. The accumulation of AQP4 may play an important role in the augmentation of brain edema after TBI under ethanol consumption.
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Neuroglobin is an endogenous neuroprotectant for retinal ganglion cells against glaucomatous damage.
Neuroglobin (NGB), a newly discovered member of the globin superfamily, may regulate neuronal survival under hypoxia or oxidative stress. Although NGB is greatly expressed in retinal neurons, the biological functions of NGB in retinal diseases remain largely unknown. We investigated the role of NGB in an experimental model of glaucoma, a neurodegenerative disorder that usually involves elevation of intraocular pressure (IOP). ⋯ Moreover, overexpression of NGB attenuated ocular hypertension-induced superoxide production and the associated decrease in ATP levels in mice, suggesting that NGB acts as an endogenous neuroprotectant to reduce oxidative stress and improve mitochondrial function, thereby promoting RGC survival. Thus, NGB may modulate RGC susceptibility to glaucomatous neural damage. Manipulating the expression and bioactivity of NGB may represent a novel therapeutic strategy for glaucoma.
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Idiopathic pulmonary fibrosis (IPF) is a prevalent, progressive, and incurable fibroproliferative lung disease. The phenotype of IPF fibroblasts is characterized by their ability to elude the proliferation-suppressive properties of polymerized type I collagen. The mechanism underlying this pathological response is incompletely understood but involves aberrant activation of the phosphatidylinositol 3-kinase-Akt signaling pathway owing to inappropriately low phosphatase and tensin homolog phosphatase activity. ⋯ In contrast, the expression of dominant-negative FoxO3a augmented control fibroblast proliferation. IHC examination of fibroblastic foci in IPF lung tissue demonstrates the presence of inactive FoxO3a in cells within fibroblastic foci. These data indicate that the ability of IPF fibroblasts to circumvent the proliferation-suppressive properties of polymerized collagen involves inactivation of FoxO3a by high Akt activity, resulting in down-regulation of p27.
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Idiopathic pulmonary fibrosis (IPF) may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 (MMP-3) in the pathogenesis of IPF through i) determination of MMP-3 expression in patients with IPF, ii) in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii) in vitro experiments to elucidate possible mechanisms of action. ⋯ In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the β-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss and cognitive impairment. Neuroinflammation, including the extensive production of pro-inflammatory molecules and the activation of microglia, has been implicated in the disease process. Tumor necrosis factor (TNF)-α, a prototypic pro-inflammatory cytokine, is elevated in AD, is neurotoxic, and colocalizes with amyloid plaques in AD animal models and human brains. ⋯ These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg-AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced amyloid-β phagocytic marker expression and phagocytosis activity, indicating that intact TNF-α receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-β peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-α inhibitors for the treatment of AD.