Scientific reports
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Protein allostery is essential for vital activities. Allosteric regulation of human hemoglobin (HbA) with two quaternary states T and R has been a paradigm of allosteric structural regulation of proteins. It is widely accepted that oxygen molecules (O2) act as a "site-specific" homotropic effector, or the successive O2 binding to the heme brings about the quaternary regulation. ⋯ Our simulation results revealed that the solution environment of high O2 partial pressure enhances the quaternary change from T to R without binding to the heme, suggesting an additional "non-site-specific" allosteric effect of O2. The latter effect should play a complementary role in the quaternary change by affecting the intersubunit contacts. This analysis must become a milestone in comprehensive understanding of the allosteric regulation of HbA from the molecular point of view.
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Lipopolysaccharide (LPS), an endotoxin derived from gram-negative bacteria, promotes the secretion of proinflammatory cytokines and mediates endotoxemia through activation of mitogen activated protein kinases, NF-κB, and interferon regulatory factor-3. Silent information regulator transcript-1 (SIRT1), an NAD-dependent deacetylase, mediates NF-κB deacetylation, and inhibits its function. SIRT1 may affect LPS-mediated signaling pathways and endotoxemia. ⋯ We also demonstrate that interferon β increases SIRT1 expression by activating the Janus kinase--signal transducer and activator of transcription (JAK-STAT) pathway in mouse bone marrow derived macrophages. In vivo treatment of interferon β protects against lethal endotoxic and septic shock, which is abrogated by infection with dominant negative SIRT1-expressing adenovirus. Our work suggests that both SIRT1 and SIRT1-inducing cytokines are useful targets for treating patients with sepsis.
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The role of amyloid-β (Aβ) neuropathology and its significant changes in biofluids after traumatic brain injury (TBI) is still debated. We used ultrasensitive digital ELISA approach to assess amyloid-β1-42 (Aβ42) concentrations and time-course in cerebrospinal fluid (CSF) and in plasma of patients with severe TBI and investigated their relationship to injury characteristics, neurological status and clinical outcome. We found decreased CSF Aβ42 levels in TBI patients acutely after injury with lower levels in patients who died 6 months post-injury than in survivors. ⋯ A trend analysis showed that both CSF and plasma Aβ42 levels strongly correlated with mortality. A positive correlation between changes in CSF Aβ42 concentrations and neurological status as assessed by Glasgow Coma Scale (GCS) was identified. Our results suggest that determination of Aβ42 may be valuable to obtain prognostic information in patients with severe TBI as well as in monitoring the response of the brain to injury.
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This study assessed the potential antinociceptive effects of liquiritigenin, a plant-derived compound with transient receptor potential melastatin 3 blocking activity in a rat model of persistent neuropathic pain. Chronic constriction injury (CCI) to the sciatic nerve was induced in male Sprague-Dawley rats to model human peripheral neuropathic pain. Liquiritigenin (1, 3, or 9 mg/kg) was administered intraperitoneally to examine the effects on mechanical, thermal, and cold hyperalgesia using the von Frey test, plantar test, and cold plate test, respectively. ⋯ In addition, daily repeated treatment with liquiritigenin did not demonstrate significant antinociceptive tolerance in the measures of hyperalgesia. Within the doses studied, liquiritigenin did not significantly affect motor performance. These results suggest that liquiritigenin may be potentially useful novel treatments for neuropathic pain.
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Meta Analysis
Decompressive craniectomy for the treatment of malignant infarction of the middle cerebral artery.
Early decompressive craniectomy (DC) has been shown to reduce mortality in malignant middle cerebral artery (MCA) infarction, whereas efficacy of DC on functional outcome is inconclusive. Here, we performed a meta-analysis to estimate the effects of DC on malignant MCA infarction and investigated whether age of patients and timing of surgery influenced the efficacy. We systematically searched PubMed, Medline, Embase, Cochrane library, Web of Science update to June 2014. ⋯ In the subgroup analysis stratified by age, early DC improved outcome both in younger and older patients. However, later DC (after 48h after stroke onset) might not have a benefit effect on lowering mortality or improving outcome in patients with malignant infarction. Together, this study suggested that decompressive surgery undertaken within 48 h reduced mortality and increased the number of patients with a favourable outcome in patients with malignant MCA infarction.