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Stroke is one of the highest incidence neurological disorder with great morbidity and mortality rate. The secondary neuroinflammation contributed by microglial activation is a consequential response observed in the pathogenesis of stroke. High-mobility group box 1, a non-histone nuclear protein, interacts with immune cells, such as microglia, and leads to a cascade amplification of the secondary neuroinflammatory responses, which are related to neuronal damage later. Melatonin is a neurohormone, well-known as its anti-oxidative and anti-inflammatory effects. However, until now, more findings are required for better understanding about anti-inflammatory effect of melatonin on HMGB1 and HMGB1-triggered pathway in LPS-induced microglial activation. Melatonin effect on the viability of BV2 microglial cells was measured by CCK-8 assay; mRNA levels of HMGB1 and other inflammatory cytokines were determined by quantitative real-time polymerase chain reaction assay or enzyme-linked immunosorbent assays; the protein expression levels of TLR4/MyD88/NF-κB and SIRT1 were detected by Western blot, and HMGB1 translocation and release from BV2 microglial cells were examined by immunofluorescence assay. The results of this study demonstrated that melatonin suppressed LPS-triggered BV2 microglial activation-mediated inflammation by inhibiting high expression and release of HMGB1 and moderating the activation of subsequent TLR4/MyD88/NF-κB signaling pathway, which was activated by SIRT1 elevation. Furthermore, LPS-induced expression of pro-inflammatory cytokines (i.e., TNF-α, IL-6, and IL-1β) was notably reversed by melatonin pre-treatment. In summary, our findings suggest that melatonin may act as a promising therapeutic agent for reducing post-stroke neuroinflammation by targeting HMGB1 and the subsequent signaling axis.

Cognitive impairment can seriously affect the quality of life of Parkinson's disease (PD) patients. Although numerous studies showed that N200, P300 latency and amplitude are correlated with cognitive functions, there is a sufficient amount of controversial results. Therefore, it is necessary to conduct a meta-analysis of N200, P300 latency and amplitude data of event-related potential (ERP) in PD.We systematically searched on PubMed and Web of Science for PD-related ERP studies published before December 2021. Standard mean difference (SMD) and 95% confidence interval (CI) estimates of N200 and P300 components were compared among PD patients, PD dementia (PDD) patients, PD non-dementia (PDND) patient, and healthy control (HC).Our meta-analysis showed prolonged N200 latency at the Fz, Cz electrode sites, prolonged P300 latency at the Fz sites in PD patients, compared to HC; prolonged N200 latency at the Cz, Pz electrode sites in PDND patients, compared to HC; prolonged P300 latency at the Cz site in PDD patients, compared to PDND patients; and reduced P300 amplitude at the Fz electrode site in PDND patients, compared to HC.N200 and P300 component may be potential electrophysiological biomarkers of early cognitive impairment in PD patients. Future studies are needed to confirm this conclusion. Estimates of N200 and P300 component can be a valuable support for clinicians in diagnosis of early cognitive impairment in PD patients due to the simplicity and non-invasiveness of the procedure.

Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats. Mechanistically, 8C reduced I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes and inhibited cardiomyocyte (CM) apoptosis. Furthermore, we elucidated that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a, suggesting that 8C dramatically improves cardiac function mainly through metabolic acetyl-CoA-mediated histone acetylation. Therefore, our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury.

Hippocampal dysfunction related to cognitive impairment and emotional disorders in young children and adolescents caused by neonatal hypoxic-ischemic brain injury (HIBI) has attracted increasing attention in recent years. Crosstalk between the nervous and immune systems organized by hypoxia-ischemia (HI) insult may contribute to hippocampal dysfunction after HIBI. Extracellular HMGB1 functions as a damage-associated molecular pattern to instigate and amplify inflammatory responses, but whether this molecule is correlated with hippocampal dysfunction after HIBI is largely unknown. Therefore, this study examined hippocampal function after HMGB1 inhibition in an experimental HIBI model to verify the hypothesis that HMGB1 is a key mediator of hippocampal neuropathology in neonatal HIBI. By administering different doses of the HMGB1-specific inhibitor glycyrrhizin (GLY), we first found that GLY reversed the HI insult-induced loss of neurons and myelin in the hippocampal region and neurobehavioral impairments, partially in a dose-dependent manner, and based on this, we determined the optimal drug concentration to be 50 mg/kg. Subsequent analysis found that this neuroprotective effect was achieved through the inhibition of HMGB1 expression and nucleocytoplasmic translocation, a reduction in the abnormal expression of proteins associated with the downstream signaling pathway of HMGB1, a decrease in the inflammatory response, the suppression of increases in microglia/astrocytes, and the inhibition of hippocampal cell apoptosis. Collectively, our discoveries contribute to the rising appreciation of the role of HMGB1 in the neuropathology of hippocampal dysfunction and related behavioral outcomes following HIBI.

Background Epigenetic histone acetylation is a major event controlling cell functions, such as metabolism, differentiation and repair. Here, we aim to determine whether Valproic acid (VPA), a FDA approved inhibitor of histone deacetylation for bipolar disease, could protect heart against myocardial infarction (MI) injury and elucidate key molecular pathways. Methods VPA was administrated to MI rats at different time points, onset and after MI injury. Echocardiography, histology, serum biology assays, and gene expression, inhibition, and over-expression were performed to characterize the systolic function, infarct size, gene and signaling pathways. Findings VPA treatment reduced the infarct size by ~50% and preserved the systolic function of heart after acute MI in rats. Even 60 min after infarction, VPA treatment significantly decreased infarct size. Furthermore, long-term treatment of VPA markedly improved myocardial performance. VPA regulated gene expression essential for cell survival and anti-inflammatory response. Consequently, oxidative stress and cell death were notably reduced after VPA treatment. Moreover, Foxm1 was identified as a potential key target of VPA. Overexpression of Foxm1 provided similar heart protective effect to VPA treatment. Particularly, both VPA treatment and Foxm1 over-expression repressed inflammatory response after MI for heart protection. In contrast, inhibition of Foxm1 activity abolished the cardiac protective effect of VPA. VPA mediated CM protection through Foxm1 upregulation was also identified in a human ESC derived CM hypoxia/reperfusion system. Interpretation VPA treatments significantly reduce cardiac damage after MI and the cardioprotective effect of VPA is likely mediated via Foxm1 pathway. Fund This work was mainly supported by 1R01HL109054.

OBJECTIVES Inflammation plays a key role in the pathogenesis and progression of ischemic stroke (IS). The high mobility group box 1 (HMGB1) nucleoprotein is involved in the amplification of inflammatory responses during acute ischemic injury. HMGB1 levels in patients with active disease are higher than those in healthy controls. We performed a meta-analysis to assess currently published data pertaining to circulating blood HMGB1 levels in IS and the relationship with stroke severity. METHODS We systematically searched for studies investigating the circulating blood HMGB1 levels in patients with IS in PubMed/Medline, Embase, the Cochrane Library, Web of science and China National Knowledge Infrastructure (CNKI). Two independent researchers used the Cochrane Collaboration tools for data extraction and quality assessment. Extracted data were analyzed by Review Manager version 5.3. RESULTS A total of 28 studies were included with a total of 4497 participants, including 2671 IS patients and 1826 matched controls. The meta-analysis revealed that compared with control, IS patients had higher circulating blood HMGB1 levels (n = 4497, standardized mean difference (SMD) = 5.70, 95%confidence interval (CI) = 4.79 to 6.62, Z = 12.23, P

Background Mainly based on evidence of success in adults, various medications are commonly used to prevent pediatric migraines. Topiramate has been approved for migraine prevention in children as young as 12 years of age. In this meta-analysis, we aimed to assess the currently published data pertaining to the efficacy of topiramate for migraine prevention in patients less than 18 years of age. Methods We searched PubMed/Medline, Embase and the Cochrane Library (from inception to April 2017) for randomized controlled trials (RCTs) published in English. Two independent investigators performed data extraction and quality evaluation using the Cochrane Collaboration’s tool. The data extracted were analyzed by Review Manager 5.3 software. Results A total of four RCTs matching the inclusion criteria were included, with an aggregate of 465 patients. Of these patients, 329 were included in the topiramate group, and 136 were included in the placebo group. This meta-analysis revealed that compared with placebo, topiramate failed to decrease the number of patients experiencing a ≥ 50% relative reduction in headache frequency (n = 465, RR = 1.26, 95% CI = [0.94,1.67], Z = 1.55, P = 0.12) or the number of headache days (n = 465, MD = −0.77, 95% CI = [−2.31,0.76], Z = 0.99, P = 0.32) but did reduce PedMIDAS scores (n = 205, MD = −9.02, 95% CI = [−17.34, −0.70], Z = 2.13, P = 0.03). Higher rates of side effects and adverse events in the topiramate group than in the placebo group were observed in the included trials. Conclusions Topiramate may not achieve a more effective clinical trial endpoint than placebo in the prevention of migraines in patients less than 18 years of age, and topiramate may lead to more side effects or adverse events in the included patients.

The paper studies the bird strike against composite material tail leading edge under Chinese HB7084-94 condition, including material failure process, by using explicit finite element method. SPH grid free method is taken to describe birds splashing during the strike. The calculation results show that, the original design composite structure could not meet the requirements of standard HB7084-94 towards the aircraft vertical tail anti-bird impact performance. The optimized design increases the ply number of the leading edge from 6 to 22. With a weight cost of 2.957Kg, the optimized design could meet the standard.

The research of alternative treatment for ischemic stroke and degenerative diseases has always been a priority in neurology. 3-N-Butylphthalide (NBP), a family of compounds initially isolated from the seeds ofApium graveolensLinn., has shown significant neuroprotective effects. Previous extensive studies have demonstrated that NBP promotes a better poststroke outcome and exerts a multitargeted action on several mechanisms, from oxidative stress to mitochondrial dysfunction to apoptosis to inflammation. Additionally, recent findings on several neurological disorders have shown that NBP’s beneficial effects extend beyond the management of stroke. However, despite the increasing number of studies toward a better understanding and the rapid advances made in therapeutic options, to date, dl-3-N-butylphthalide, a synthetic variation of l-3-N-butylphthalide, remains the only clinically approved anti-ischemic agent in China, stressing the difficulties for a viable and effective transition from experimental to clinical practice. Events indicate that NBP, due to its multitargeted effect and the adaptability of its basic structure, can be an important game changer and a precursor to a whole new therapeutic approach to several neurological conditions. The present review discusses recent advances pertaining to the neuroprotective mechanisms of NBP-derived compounds and the possibility of their clinical implementation in the management of various neurological conditions.