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High mobility group box 1 protein (HMGB1) is potentially triggered by Aβ oligomers and other sterile injuries, and is a non-histone DNA binding nuclear protein with roles in neural development and neurodegeneration, which contribute to memory impairment and chronic neuroinflammation in the brain. However, the exact molecular mechanisms of HMGB1 activation in Alzheimer's disease (AD) were previously unknown. The present study aimed to elucidate the effects of HMGB1 in Aβ25-35-induced neuroinflammation in hippocampal neuron cultures. RNA interference (RNAi) HMGB1 treatment significantly reduced Aβ25-35-induced HMGB1 expression by almost 70% in primary hippocampal neurons. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay (ELISA) demonstrated that short hairpin RNA (shRNA) for HMGB1 ameliorated Aβ25-35-treated neuroinflammation, including activation of advanced glycosylation end product-specific receptor (RAGE), toll-like receptor 4 (TLR4), and nuclear factor-kappa B (NF-κB)-p65, as well as induced the release of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IL-6, and HMGB1 in primary hippocampal neurons and the culture supernatant. In addition, pretreatment with HMGB1-shRNA dramatically reduced both the degree of nuclear-cytoplasmic HMGB1 translocation of HMGB1 and NF-κB DNA binding. Together, the data indicate that HMGB1 mediates the pathogenesis of AD by activating RAGE/TLR4 signaling and that shRNA targeting HMGB1 may be a promising therapeutic strategy for treating AD.

Because of a lack of markers for predicting prognosis and an underlying mechanism, patients with primary brainstem hemorrhage (PBH) are currently treated with multiple strategies, but most of them have poor outcomes in a comparison with patients with supratentorial intracranial hemorrhage. Recently, it has been reported that the neutrophil-to-lymphocyte ratio (NLR) represents a novel composite inflammatory marker to predict the prognosis of patients with intracranial hemorrhage, a majority of whom have supratentorial hemorrhage. In this report, we aim to assess the potential predictive value of NLR in patients with PBH. In addition, other available laboratory parameters, including platelet-to-lymphocyte ratio (PLR), and admission blood glucose level (ABG), will be also investigated as markers for prognosis in patients with PBH.This study retrospectively enrolled 225 patients with acute PBH who were admitted West China Hospital from January 2012 to December 2016. ABG and absolute numbers of neutrophils, lymphocytes, white blood cells, and platelets were extracted from electronic medical records. ABG, NLR, and PLR were calculated and further assessed using multivariable logistic regression analysis for understanding the associations of treatment outcomes. The comparison of predictive power of independent predictors was evaluated using receiver operating characteristic.Of 225 inpatients, NLR (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.24-2.62, P0.01), PLR (OR, 1.43; 95% CI, 1.11-2.36; P = 0.013), and ABG (OR, 6.57; 95% CI, 2.78-15.52; P 0.01) were independently associated with 90-day status in 112 patients with unfavorable outcomes. All 3 parameters also correlated with admission Glasgow Coma Scale score (r = -0.244, P 0.001; r = -0.292, P0.001; r = -0.661, P0.01) and absolute neutrophil counts (r = 0.645, P0.001; r = 0.347, P0.001; r = 0.695, P0.01). Meanwhile, NLR exhibits a comparable predictive power by comparing with PLR (area under the curve [AUC], 0.694; 95% CI, 0.626-0.764; P0.001; versus AUC, 0.662; 95% CI, 0.596-0.724; P0.001). In addition, ABG shows a positive predictive value (AUC, 0.784; 95% CI, 0.725-0.832; P0.001). The best independent predictive cutoff points were 6.65, 59.3, and 7.81 mmol/L for NLR, PLR, and ABG, respectively. Nevertheless, a combination of 3 parameters shows the best predictive ability (AUC, 0.835; 95% CI, 0.781-0.883; P0.001).NLR, PLR, and ABG can be used to independently predict 90-day functional outcome in patients after PBH. When combined, they have better predictive power in identifying PBH patients with a poor prognosis. To our knowledge, this study is the first to reveal the associations between NLR, PLR, and hyperglycemia and the functional outcomes of patient with PBH. In associating with previously studies on hemorrhage site, our results provide a good opportunity to elucidate the underlying mechanisms of PBH.