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Neurocognitive dysfunction is a major clinical consequence in patients with obstructive sleep apnea syndrome (OSAS). The effects of continuous positive airway pressure (CPAP) treatment, as the gold standard of treatment in OSAS, on this major complication are controversial. The duration and compliance of CPAP are thought to be important factors but evidence is lacking. This study is designed to evaluate the effects of immediate (one night), long-term (3 months) influence and the compliances of CPAP treatment on the neurocognitive function in OSAS patients. We enrolled newly diagnosed severe OSAS patients. Neurocognitive function test battery, CANTAB (Cambridge Neuropsychological Test Automated Battery), was performed before, one night and 3 months of CPAP treatment. Patients with CPAP compliance rate ≥ 70 % and < 50 % were grouped into good and poor adherence subjects, respectively. Fourteen patients were enrolled in final analyses. Six of them were in poor compliant group. Improvements in attention domain were found in all subjects after one-night treatment and maintained till three-month follow-up. Additional improvements in some attention performances and visual memory performances were gained only after three-month treatment. Significant changes of decision-making and response control function were found between good and poor compliance groups after three-month treatment. CPAP can improve some neurocognitive function at the very first day used. Longer treatment of CPAP can additionally improve some other neurocognitive functions. Compliance of CPAP has influence on the recovery of neurocognitive functions in patients with severe OSAS.

Excluding tracheostomy, maxillomandibular advancement (MMA) is the most effective surgical treatment for obstructive sleep apnoea (OSA). However, the anticipated facial changes may prevent acceptance of this procedure by patients with bimaxillary protrusion, a common feature of Asian faces. We therefore developed a modified MMA technique for such cases, consisting of anterior segmental osteotomies together with standard Le Fort I and bilateral sagittal split osteotomies. A prospective study of 20 consecutive Taiwanese adults with moderate-to-severe OSA who underwent modified MMA and postsurgical orthodontics was undertaken to evaluate the efficacy with regard to OSA and the postoperative facial appearance and dental occlusion. After modified MMA, the mean apnoea-hypopnoea index decreased from 41.6±19.2 n/h to 5.3±4.0 n/h (P<0.001). All patients had a successful outcome. No patient was dissatisfied with their postoperative facial appearance. The mean Peer Assessment Rating score decreased from 21.9±14.3 to 1.7±1.6 (P=0.001). The data suggest that the modified MMA is effective in treating patients with moderate-to-severe OSA without negatively affecting facial appearance or dental occlusion. To achieve a better outcome, surgical-orthodontic integration is warranted. The surgery-first approach can achieve early improvement., (Copyright © 2014 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Extracorporeal membrane oxygenation (ECMO) can be used as a salvage therapy, but the effectiveness is controversial. The aim of this study was to investigate the predictors of mortality and the influence of organ dysfunction scores in severe acute respiratory distress syndrome (ARDS) patients treated with ECMO., Methods: The records of adult severe ARDS patients receiving ECMO support from May 2006 to December 2011 at Chang Gung Memorial Hospital were retrospectively analyzed., Results: The records of 65 patients with severe ARDS who received venovenous ECMO were analyzed. The hospital survival rate was 47.7%. Survivors were younger than nonsurvivors (41.4 ± 15.4 versus 54.1 ± 16.9 years, respectively; p = 0.002) and had shorter duration of mechanical ventilation before ECMO (52.7 ± 51.1 versus 112.1 ± 101.0 hours, respectively; p = 0.01). Before ECMO, Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction scores were significantly lower for survivors than for nonsurvivors. Mortality rate increased with rising predictive score. During 7 days of ECMO use, organ dysfunction scores were significantly lower for survivors than nonsurvivors., Conclusions: Severe ARDS patients who are younger, have shorter duration of mechanical ventilation, and lower organ dysfunction scores before ECMO initiation have more favorable survival outcome. Early application of ECMO, especially if predictive score is below 2, may improve survival. Organ dysfunction scores before and during ECMO support are correlated with survival., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Polygalasaponin F (PS-F), an oleanane-type triterpenoid saponin extracted from Polygala japonica, decreases the release of the inflammatory cytokine tumor necrosis factor α (TNFα), but the precise molecular mechanisms by which this event occurs are not fully understood. To study the anti-neuroinflammatory mechanisms of PS-F, enzyme-linked immunosorbent assay was used to detect the secretion of TNFα from BV-2 microglial cells. Nuclear proteins extracted from BV-2 microglial cells stimulated by lipopolysaccharide (LPS) and pretreated with/without inhibitors were measured by Western blotting, and cell viability was evaluated by MTT analysis. The results indicated that inhibition of toll-like receptor (TLR) 4 (CLI-095 1 μg/ml), phosphatidylinositol 3-kinase (PI3K) (Ly294002 10 μM) or IκBα phosphorylation (Bay11-7082 10 μM) completely prevents the release of TNFα induced by LPS without affecting cell viability and attenuated the nuclear translocation of p65 stimulated by LPS. In addition, PS-F exhibited a similar trend regarding TNFα release, AKT phosphorylation and NF-κB translocation. These results suggest that PS-F reduces neuroinflammatory cytokine secretion through the regulation of the TLR4-PI3K/AKT-NF-κB signaling pathway.

Background: Obstructive sleep apnea (OSA) is known to be a risk factor of coronary artery disease. The chemotaxis and adhesion of monocytes to the endothelium in the early atherosclerosis is important. This study aimed to investigate the effect of intermittent hypoxia, the hallmark of OSA, on the chemotaxis and adhesion of monocytes., Methods: Peripheral blood was sampled from 54 adults enrolled for suspected OSA. RNA was prepared from the isolated monocytes for the analysis of C-C chemokine receptor 2 (CCR2). The effect of intermittent hypoxia on the regulation and function of CCR2 was investigated on THP-1 monocytic cells and monocytes. The mRNA and protein expression levels were investigated by RT/real-time PCR and western blot analysis, respectively. Transwell filter migration assay and cell adhesion assay were performed to study the chemotaxis and adhesion of monocytes., Results: Monocytic CCR2 gene expression was found to be increased in severe OSA patients and higher levels were detected after sleep. Intermittent hypoxia increased the CCR2 expression in THP-1 monocytic cells even in the presence of TNF-α and CRP. Intermittent hypoxia also promoted the MCP-1-mediated chemotaxis and adhesion of monocytes to endothelial cells. Furthermore, inhibitor for p42/44 MAPK or p38 MAPK suppressed the activation of monocytic CCR2 expression by intermittent hypoxia., Conclusions: This is the first study to demonstrate the increase of CCR2 gene expression in monocytes of severe OSA patients. Monocytic CCR2 gene expression can be induced under intermittent hypoxia which contributes to the chemotaxis and adhesion of monocytes.

The title compound [systematic name: 3β-hy-droxy-lup-20(29)-en-28-oic acid methanol monosolvate], C30H48O3·CH3OH, is a solvent pseudopolymorph of a naturally occurring plant-derived lupane-type penta-cyclic triterpenoid, which was isolated from the traditional Chinese medicinal plant Syzygium jambos (L.) Alston. The dihedral angle between the planes of the carb-oxy-lic acid group and the olefinic group is 12.17 (18)°. The A/B, B/C, C/D and D/E ring junctions are all trans-fused. In the crystal, O-H⋯O hydrogen bonds involving the hy-droxy and carb-oxy-lic acid groups and the methanol solvent mol-ecule give rise to a two-dimensional network structure lying parallel to (001).

Mitochondria dysfunction is implicated in diverse conditions, including metabolic and neurodegenerative disorders. Mitochondrial dynamics has attracted increasing attention as to its relationship with mitochondria autophagy, also known as mitophagy, which is critical for degradation of dysfunctional mitochondria maintaining mitochondrial homeostasis. Mitochondrial fission and its role in clearance of injured mitochondria in acute ischemic injury, however, have not been elucidated yet. Here we showed that hypoxic/ischemic conditions led to fragmentation of mitochondria and induction of mitophagy in permanent middle cerebral artery occlusion (pMCAO) rats and oxygen-glucose deprivation (OGD) PC12 cells. Inhibition of Drp1 by pharmacologic inhibitor or siRNA resulted in accumulation of damaged mitochondria mainly through selectively blocking mitophagy without affecting mitochondrial biogenesis and non-selective autophagy. Drp1 inhibitors increased the infarct volume and aggravated the neurological deficits in a rat model of pMCAO. We demonstrated that the devastating role of disturbed mitochondrial fission by inhibiting Drp1 contributed to the damaged mitochondria-mediated injury such as ROS generation, cyt-c release and activation of caspase-3. Taken together, we proved that under hypoxic/ischemic stress a Drp1-dependent mitophagy was triggered which was involved in the removal of damaged mitochondria and cellular survival at the early stage of hypoxic/ischemic injury. Thus, Drp1 related pathway involved in selective removal of dysfunctional mitochondria is proposed as an efficient target for treatment of cerebral ischemia., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Clausena lansium Skeels, a member of the Rutaceae, is a shrub or small tree with grapelike fruits. Several parts of this plant have been used in folk medicine. A bioactive constituent investigation of the stems of C. lansium herein resulted in isolation of four furanocoumarins, claucoumarins A-D, and 13 known analogs. Their structures were elucidated on the basis of spectroscopic analyses, including UV, IR, MS, and NMR experiments, and their absolute configurations were determined by CD experiments. Using an in vitro system, several of these compounds showed selective neuroprotective effects at a concentration of 10μM., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Chemokine-like factor 1 (CKLF1), a newly cloned chemotactic cytokine, plays an essential role in immune cell migration. However, the potential role of CKLF1 in the cortical neuronal migration remains unclear. In the present research, by measuring the distance between the margin of brain slices and the leading population of migrating cells, we showed that the extent of cell migration was markedly enhanced in response to CKLF1 treatment, which was significantly inhibited by the simultaneous addition of anti-CKLF1 antibody. By immunofluorescence staining, it was found that CKLF1 induced actin polymerization in primary cerebral cortical neurons. By wound-healing assays, it was found that CKLF1 stimulated the migration of cortical neurons in a dose-dependent manner. In conclusion, our data suggest that CKLF1 promotes the migration of rat primary cerebral cortical neurons by the induction of actin polymerization.

Lactate is an abundant metabolite, produced by host tissues and commensal organisms, and it represents an important potential carbon source for bacterial pathogens. In the case of Neisseria spp., the importance of the lactate permease in colonization of the host has been demonstrated, but there have been few studies of lactate metabolism in pathogenic Neisseria in the postgenomic era. We describe herein the characterization of genome-annotated, respiratory, and substrate-level lactate dehydrogenases (LDHs) from the obligate human pathogen Neisseria gonorrhoeae. Biochemical assays using N. gonorrhoeae 1291 wild type and isogenic mutant strains showed that cytoplasmic LdhA (NAD(+)-dependent D-lactate dehydrogenase) and the membrane-bound respiratory enzymes, LdhD (D-lactate dehydrogenase) and LldD (L-lactate dehydrogenase) are correctly annotated. Mutants lacking LdhA and LdhD showed greatly reduced survival in neutrophils compared with wild type cells, highlighting the importance of D-lactate metabolism in gonococcal survival. Furthermore, an assay of host colonization using the well-established human primary cervical epithelial cell model revealed that the two respiratory enzymes make a significant contribution to colonization of and survival within the microaerobic environment of the host. Taken together, these data suggest that host-derived lactate is critical for the growth and survival of N. gonorrhoeae in human cells., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Parkinson's disease (PD) is pathologically characterized by selective loss of dopaminergic neurons in the midbrain and the existence of intracellular protein inclusions termed Lewy bodies, largely composed of α-synuclein. Genetic studies have revealed that rare point mutations in the gene encoding α-synuclein including A30P, A53T, and E46K are associated with familial forms of PD, indicating a pathological role for mutant α-synuclein in PD etiology. However, the mechanisms underlying the neuronal toxicity of mutant α-synuclein are still to be elucidated. Growing evidence has suggested a deleterious effect of mutant α-synuclein on the autophagy-lysosome pathway. In this study, we discovered that overexpression of human E46K mutant α-synuclein impaired macroautophagy in mammalian cells. Our data showed that overexpression of E46K mutant α-synuclein impaired autophagy at an early stage of autophagosome formation via the c-Jun N-terminal kinase 1 (JNK1)-Bcl-2 but not the mammalian target of rapamycin (mTOR) pathway. Overexpressed E46K mutant α-synuclein inhibited JNK1 activation, leading to a reduced Bcl-2 phosphorylation and increased association between Bcl-2 and Beclin1, further disrupting the formation of Beclin1/hVps34 complex, which is essential for autophagy initiation. Furthermore, overexpression of E46K mutant α-synuclein increased the vulnerability of differentiated PC12 cells to rotenone treatment, which would be partly due to its inhibitory effects on autophagy. Our findings may shed light on the potential roles of mutant α-synuclein in the pathogenesis of PD.

Oxidative stress is a condition of imbalance between reactive oxygen species (ROS) formation and antioxidant capacity as a result of dysfunction of the antioxidant system. ROS can be served as a second messenger at low or moderate concentration, while excessive amount of ROS under oxidative stress condition would destroy macromolecules like proteins, DNA, and lipids, finally leading to cell apoptosis or necrosis. Changes in these macromolecules are involved in various pathological changes and progression of diseases, especially neurodegenerative diseases. Neurodegenerative diseases are morphologically featured by progressive neuronal cell loss, accompanied with inclusions formed by protein aggregates in neurons or glial cells. Neurons have always received much more attention than glial cells in neurodegenerative diseases. Actually, glial cells might play a key role in the functioning of neurons and cellular survival through an antioxidant way. Additionally, neurons can modulate the activities of glia either. Herein, the main purposes of this review are to mention the connection between Huntington's disease (HD) and oxidative stress, to summarize the characteristics and functions of glial cells in HD, to state the cross talk between neurons and glial cells, and to emphasize the conclusive role of activation of Keap1-Nrf2-ARE pathway in glial cells against oxidative stress in HD.

Chemokine-like factor 1 (CKLF1) is a novel C-C chemokine, and plays important roles in immune response and brain development. In previous study, we have found that the expression of CKLF1 increased after focal cerebral ischemia and inhibition of CKLF1 using antagonist C19 peptide protected against cerebral ischemia. However, few studies have focused on the role of CKLF1 on neuronal apoptosis. The objective of present study is to investigate the role of CKLF1 on neuronal apoptosis by applying anti-CKLF1 antibodies in rat focal cerebral ischemia and reperfusion model. Antibodies against CKLF1 was applied to the right cerebral ventricle immediately after transient middle cerebral artery occlusion (MCAO), and infarct volume, neurological score, glucose metabolism and apoptosis-related protein were measured. Treatment with anti-CKLF1 antibody decreased infarct volume and neurological score, and inhibited neuronal apoptosis in a dose-dependent manner at 24h after reperfusion. Anti-CKLF1 antibody also reduced the level of phosphorylation of Akt (P-Akt), and led to decrease of pro-apoptotic protein Bcl-2 associated X protein (Bax) and increase of anti-apoptotic protein B cell lymphoma-2 protein (Bcl-2) and the ratio of Bcl-2/Bax, and inhibited caspase-3 at last. In addition, positron emission tomography (PET) indicated that anti-CKLF1 antibody increased glucose metabolism in ischemic hemisphere. These results suggest that CKLF1 is associated with neuronal apoptosis after cerebral ischemia and reperfusion. Neutralization of CKLF1 with antibodies shows neuroprotective effects against cerebral ischemia, which may be involved in inhibition of Akt pathway, regulation of apoptosis-related protein expression, and improvement glucose metabolism in ischemic hemisphere. Therefore, CKLF1 may be a novel target for the treatment of stroke., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: To investigate the anti-fibrosis effects of ginsenoside Rg1 on alcohol- and CCl4-induced hepatic fibrosis in rats and to explore the mechanisms of the effects., Methods: Rats were given 6% alcohol in water and injected with CCl4 (2 mL/kg, sc) twice a week for 8 weeks. Rg1 (10, 20 and 40 mg/kg per day, po) was administered in the last 2 weeks. Hepatic fibrosis was determined by measuring serum biochemical parameters, HE staining, Masson's trichromic staining, and hydroxyproline and α-SMA immunohistochemical staining of liver tissues. The activities of antioxidant enzymes, lipid peroxidation, and Nrf2 signaling pathway-related proteins (Nrf2, Ho-1 and Nqo1) in liver tissues were analyzed. Cultured hepatic stellate cells (HSCs) of rats were prepared for in vitro studies., Results: In the alcohol- and CCl4-treated rats, Rg1 administration dose-dependently suppressed the marked increases of serum ALT, AST, LDH and ALP levels, inhibited liver inflammation and HSC activation and reduced liver fibrosis scores. Rg1 significantly increased the activities of antioxidant enzymes (SOD, GSH-Px and CAT) and reduced MDA levels in liver tissues. Furthermore, Rg1 significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes. Treatment of the cultured HSCs with Rg1 (1 μmol/L) induced Nrf2 translocation, and suppressed CCl4-induced cell proliferation, reversed CCl4- induced changes in MDA, GPX, PCIII and HA contents in the supernatant fluid and α-SMA expression in the cells. Knockdown of Nrf2 gene diminished these actions of Rg1 in CCl4-treated HSCs in vitro., Conclusion: Rg1 exerts protective effects in a rat model of alcohol- and CCl4-induced hepatic fibrosis via promoting the nuclear translocation of Nrf2 and expression of antioxidant enzymes.

Objective: To explore the protective effect of baicalin against rotenone-induced injury on PC12 cells, and the po-tential mechanism of action action was also explored., Method: PC12 cells were injured by rotenone and were treated with different concentrations (0.1, 1, 10 μmol x L(-1)) of baicalin at the same time. Cell viability was analyzed by MTT, and morphology was observed by phase-contrast microscopy. The cell apoptosis was detected by flow cytometry by Annexin V-FITC/PI staining. The intracellular ROS level was determined by fluorescence microscope with DCF-DA staining. The expression of Bcl-2, Bax and Caspase-3 was analyzed by Western blot., Result: The viability of PC12 cells exposure to rotenone for 24 hour was gradually decreased with dose escalating and 1.5 μmol x L was adopted to do the following experiment. Baicalin increased cell viability, improved cell morphology and decreased intracellular ROS level. Moreover, FACS indicated baicalin attenuated the apoptosis induced by rotenone significantly. Western blot showed that Bcl-2, Bax and Caspase-3 expression in rotenone-induced PC12 cells was reversed by baicalin., Conclusion: This study has demonstrated that baicalin protects PC12 cells against rotenone-induced apoptosis, at least in part, by scavenging excessive ROS and inhibiting the mitochondrion-dependent apoptotic pathway.

Stroke and especially its complications are a leading cause of death. Despite reduced morbidity in some developed countries, mortality in stroke patients is still high worldwide. In the past decades, treatment of acute stroke has focused on early intervention, such as revascularization and cerebral edema prevention. However, long-term clinical observations indicate that poststroke pneumonia, cardiovascular complications, and vascular embolism are the major reasons for the increased death rate after stroke. Few evidence-based data are available currently to guide the management of these complications. Thus, systematic studies of these adverse events are essential and urgent to improve survival after stroke.

Therapeutic strategies designed to inhibit the activation of microglia may lead to significant advancement in the treatment of most neurodegenerative diseases. 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin (IMM-H004) is a novel compound and has been reported exerting potent neuroprotective effects which may be related to anti-inflammation. In the present study, the anti-inflammatory effects of IMM-H004 were investigated in lipopolysaccharide (LPS)-treated BV2 microglia. Our observations indicated that treatment with IMM-H004 significantly inhibited BV2 microglia activation, protected PC12 cells and primary neurons against indirect toxicity mediated by exposure to conditioned medium (CM) from LPS-treated BV2 cells. Additionally, IMM-H004 significantly suppressed the release of TNF-α, IL-1β and NO, and suppressed the expression of pro-inflammatory mediators and cytokines such as iNOS, COX-2, and IL-6 in LPS-stimulated BV2 microglia. The nuclear translocation of NF-κB and the phosphorylation level of JNK and p38 MAPK pathways were also inhibited by IMM-H004 in LPS-treated BV2 microglia. Moreover, IMM-H004 also was a strong selective OH scavenger whose effect was similar with vitamin C. Overall, our findings suggested that IMM-H004 might be a promising therapeutic agent for alleviating the progress of neurodegenerative diseases associated with microglia activation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

α-Synuclein (α-syn), a 14 kDa pre-synaptic protein, is widely involved in the Parkinson's disease (PD) pathogenesis. Recent studies have shown that the nuclear accumulation of α-syn might have a toxic effect. The main purpose of the present study was to explore which amino acid residues in α-syn are associated with its nuclear accumulation, the molecule(s) mediated the nuclear import of α-syn, and the role of α-syn accumulated in the nucleus. It has been noted that the nuclear import of α-syn may be mediated by importin α and that both the amino acid residues 1-60 and 103-140 of α-syn were indispensable for its nuclear import. After imported into the nucleus, the accumulated α-syn played a toxic role in both the PC12 cells and the C57 mice. Furthermore, α-syn-nuclear localization signal-injected mice showed behavioral symptoms associated with PD. Further studies performed in vitro showed that the toxicity of α-syn in the nucleus might be due to an interference of the cell cycle. Thus, it can be concluded that α-syn can accumulate in nucleus, which is mediated by importin α, and promote neurotoxicity by accelerating the cell cycle., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Inflammation plays a key role in the pathophysiology of ischemic stroke. Some proinflammatory mediators, such as cytokines and chemokines, are produced in stroke. Chemokine-like factor 1 (CKLF1), as a novel C-C chemokine, displays chemotactic activities in a wide spectrum of leukocytes and plays an important role in brain development. In previous studies, we have found that the expression of CKLF1 increased in rats after focal cerebral ischemia and treatment with the CKLF1 antagonist C19 peptide decreased the infarct size and water content. However, the role of CKLF1 in stroke is still unclear. The objective of the present study was to ascertain the possible roles and mechanism of CKLF1 in ischemic brain injury by applying anti-CKLF1 antibody., Methods: Male Sprague-Dawley rats were subjected to one-hour middle cerebral artery occlusion. Antibody to CKLF1 was applied to the right cerebral ventricle immediately after reperfusion; infarct volume and neurological score were measured at 24 and 72 hours after cerebral ischemia. RT-PCR, Western blotting and ELISA were utilized to characterize the expression of adhesion molecules, inflammatory factors and MAPK signal pathways. Immunohistochemical staining and myeloperoxidase activity was used to determine the extent of neutrophil infiltration., Results: Treatment with anti-CKLF1 antibody significantly decreased neurological score and infarct volume in a dose-dependent manner at 24 and 72 hours after cerebral ischemia. Administration with anti-CKLF1 antibody lowered the level of inflammatory factors TNF-α, IL-1β, MIP-2 and IL-8, the expression of adhesion molecules ICAM-1 and VCAM-1 in a dose-dependent manner. The results of immunohistochemical staining and detection of MPO activity indicated that anti-CKLF1 antibody inhibited neutrophil infiltration. Further studies suggested MAPK pathways associated with neutrophil infiltration in cerebral ischemia., Conclusions: Selective inhibition of CKLF1 activity significantly protects against ischemia/reperfusion injury by decreasing production of inflammatory mediators and expression of adhesion molecules, thereby reducing neutrophils recruitment to the ischemic area, possibly via inhibiting MAPK pathways. Therefore, CKLF1 may be a novel target for the treatment of stroke.

Background: Over decades, improvements in presymptomatic screening and awareness of surgical benefits have changed the presentation and management of primary hyperparathyroidism (PHPT). Unrecognized multiglandular disease (MGD) remains a major cause of operative failure. We hypothesized that during parathyroid surgery the initial finding of a mildly enlarged gland is now frequent and predicts both MGD and failure., Methods: A prospective database was queried to examine the outcomes of initial exploration for sporadic PHPT using intraoperative PTH monitoring (IOPTH) over 15 years. All patients had follow-up ≥6 months (mean = 1.8 years). Cure was defined by normocalcemia at 6 months and microadenoma by resected weight of <200 mg., Results: Of the 1,150 patients, 98.9 % were cured and 15 % had MGD. The highest preoperative calcium level decreased over time (p < 0.001) and varied directly with adenoma weight (p < 0.001). Over time, single adenoma weight dropped by half (p = 0.002) and microadenoma was increasingly common (p < 0.01). MGD risk varied inversely with weight of first resected abnormal gland. Microadenoma required bilateral exploration more often than macroadenoma (48 vs. 18 %, p < 0.01). When at exploration the first resected gland was <200 mg, the rates of MGD (40 vs. 11 %, p = 0.001), inadequate initial IOPTH drop (67 vs. 79 %, p = 0.002), operative failure (6.6 vs. 0.7 %, p < 0.001), and long-term recurrence (1.6 vs. 0.3 %, p = 0.007) were higher., Conclusions: Single parathyroid adenomas are smaller than in the past and require more complex pre- and intraoperative management. During exploration for sporadic PHPT, a first abnormal gland <200 mg should heighten suspicion of MGD and presages a tenfold higher failure rate.

Background: Minimally invasive surgeries of the soft palate have emerged as a less-invasive treatment for habitual snoring. To date, there is only limited information available comparing the effects of snoring sound between different minimally invasive surgeries in the treatment of habitual snoring., Objective: To compare the efficacy of palatal implant and radiofrequency surgery, in the reduction of snoring through subjective evaluation of snoring and objective snoring sound analysis., Patients and Method: Thirty patients with habitual snoring due to palatal obstruction (apnea-hypopnea index ≤15, body max index ≤30) were prospectively enrolled and randomized to undergo a single session of palatal implant or temperature-controlled radiofrequency surgery of the soft palate under local anesthesia. Snoring was primarily evaluated by the patient with a 10 cm visual analogue scale (VAS) at baseline and at a 3-month follow-up visit and the change in VAS was the primary outcome. Moreover, life qualities, measured by snore outcomes survey, and full-night snoring sounds, analyzed by a sound analytic program (Snore Map), were also investigated at the same time., Results: Twenty-eight patients completed the study; 14 received palatal implant surgery and 14 underwent radiofrequency surgery. The VAS and snore outcomes survey scores were significantly improved in both groups. However, the good response (postoperative VAS ≤3 or postoperative VAS ≤5 plus snore outcomes survey score ≥60) rate of the palatal implant group was significantly higher than that of the radiofrequency group (79% vs. 29%, P = 0.021). The maximal loudness of low-frequency (40-300 Hz) snores was reduced significantly in the palatal implant group. In addition, the snoring index was significantly reduced in the radiofrequency group., Conclusions: Both palatal implants and a single-stage radiofrequency surgery improve subjective snoring outcomes, but palatal implants have a greater effect on most measures of subjective and objective snoring. Multi-stage radiofrequency surgery was not tested., Trial Registration: ClinicalTrials.gov NCT01955083.

α-Synuclein (α-syn) is a presynaptic protein that is widely implicated in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons and the formation of Lewy bodies. Evidence suggests that α-syn could be imported into the nucleus and subsequently disrupt normal neuronal function. The existence of α-syn in the nucleus provides the possibility of interaction with DNA leading to gene transcript regulation. Thus, CD spectra were used to determine the specific DNA sequence with which α-syn is most likely to interact. Our results indicated that α-syn was prone to preferentially interact with the GC-box-like sequence in vitro at a ratio of 2:1 or less (α-syn: the GC-box-like sequence).

Hyperglycemia is considered to be associated with poor outcomes of ischemic stroke. However, it is controversial about the blood glucose-lowering therapy in patients with stroke. According to the current reports, hyperglycemia is an indicator of severe stroke and cannot increase cerebral glucose content but promotes further ischemia in brain. Consequently, cerebral glucose control is significant to maintain the energy homeostasis. Compared with blood glucose level, the cerebral glucose content, controlled by glucose transporters (GLUTs), is more directly and important to maintain the energy supply in brain, especially to the patients with ischemic stroke. Some active materials, such as Glucagon-like peptide-1, progesterone, tPA and N-acetylcysteine, have been found to ameliorate ischemic stroke by regulating GLUTs expression. Therefore, this review discusses the significance of cerebral glucose level and GLUTs. Additionally, cerebral GLUTs and their actions in ischemic stroke are detailed in order to promote research on GLUTs as a possible therapeutic target for ischemic stroke., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Maxillomandibular advancement (MMA) is effective in the treatment of obstructive sleep apnoea. We aimed to assess changes in the calibre of the upper airway, facial skeleton, and surrounding structural position after MMA and their association with improvement in symptoms. Sixteen consecutive adults with moderate-to-severe apnoea were treated by primary MMA. Polysomnography and computed tomography (CT) of the head and neck were done before and at least 6 months after MMA. The calibre of the upper airway, the facial skeleton, and the surrounding structures were measured with image analysis software. After MMA, patients had a significant reduction in their apnoea-hypopnoea index (31.2 (18.8)number of events (n)/hour (h)). The mean (SD) volume of the airway increased significantly in the velopharynx (p<0.01), oropharynx (p=0.001), and hypopharynx (p<0.001) (by 2.3 (2.4), 2.1 (2.6), and 1.7 (1.1)cm(3), respectively) and the length of the airway was significantly decreased (by 3.1 (3.5)mm p<0.01). The soft palate (p<0.001), tongue (p<0.001), and hyoid (p=0.001) moved significantly anteriorly (by 4.4 (2.0), 7.5 (2.8), and 5.7 (5.0)mm, respectively), and these movements were related to the MMA (r=0.6-0.8). The improvement in the apnoea-hypopnoea index was associated with both maxillary advancement and anterior movements of the soft palate and hyoid (r=0.6-0.7). The results of this study suggest that MMA increases the volume in the upper airway and reduces its length. Improvement in obstructive sleep apnoea is associated with the extent of the anterior movements of the maxilla, soft palate, and hyoid., (Copyright © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

CKLF1, which exhibits chemotactic activities on a wide spectrum of leukocytes, is up-regulated during the progress of asthma. It plays a vital role in the pathogenesis of pulmonary disease. Here, we report that CKLF1 has the capability to activate the NF-κB signaling pathway leading to the pathological change in the lung. The HEK293-CCR4 cell line, which expressed CCR4 stably, was established and screened. Western blot analysis was performed to determine the expression of NF-κB in HEK293-CCR4 and A549 cells following the C27 (10μg/ml) added in each well at different times. These results showed that C27 (10μg/ml) time-dependently induced the accumulation of NF-κB in the nucleus of HEK293-CCR4 and A549 cells. In addition, CKLF1 plasmid (100μg) injection and electroporation led to the asthmatic change in the lung in mice as shown by HE and PAS staining. Furthermore, it was confirmed that CKLF1 significantly up-regulated the p-IκB expression, decreased the IκB expression, and suppressed the NF-κB expression in the cytoplasm of pulmonary tissue in vivo study. Intriguingly, an enhanced nuclear accumulation of NF-κB was observed in the lung of pCDI-CKLF1 electroporated mice, compared to that in the sham group. Therefore, the NF-κB signaling pathway was involved in the asthmatic change induced by CKLF1, among which CCR4 might play a crucial role., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Hemagglutinin (HA) is essential for Influenza A virus infection, but its diversity of subtypes presents an obstacle to developing broad-spectrum HA inhibitors. In this study, we investigated the molecular mechanisms by which poly-galloyl glucose (pGG) analogs inhibit influenza hemagglutinin (HA) in vitro and in silico. We found that (1) star-shaped pGG analogs exhibit HA-inhibition activity by interacting with the conserved structural elements of the receptor binding domain (RBD); (2) HA inhibition depends on the number of galloyl substituents in a pGG analog; the best number is four; and when PGG binds with two HA trimers at their conserved receptor binding domains (loop 130, loop 220, and 190-α-helix), PGG acts as a molecular glue by aggregating viral particles so as to prevent viral entry into host cells (this was revealed via an in silico simulation on the binding of penta-galloyl-glucose (PGG) with HA). pGGs are also effective on a broad-spectrum influenza A subtypes (including H1, H3, H5, H7); this suggests that pGG analogs can be applied to most influenza A subtypes as a prophylactic against influenza viral infections.

Objectives: To investigate the effect of sedative music on the different stages of the sleep cycle in young adults with various sleep latencies by using polysomnography (PSG)., Design: Prospective, randomized, controlled, crossover study., Setting: Sleep center of a teaching hospital., Participants: Young adults with different sleep latencies. Poor sleepers (Pittsburgh Sleep Quality Index score ≥5) were excluded., Interventions: Each participant stayed one night in the sleep center for adaptation and on each of the following two nights was assigned to (1) music and (2) control (without music) conditions in random order. In the music condition, sedative music composed by certified music therapists was played on a compact disc player for the first hour the participant was in bed., Outcome Measures: Sleep measures recorded with PSG, including sleep latency and durations of sleep stages., Results: Twenty-four young adults (mean±standard deviation, 24.5±2.6 years) participated. They were classified into the short sleep latency (SL) group if the baseline SL of the adaptation night was shorter than 10 minutes or into the long SL group if the baseline SL was 10 minutes or longer. Sedative music did not alter the SL in either group. Sedative music reduced stage II sleep in both SL groups (main effect of music, p=0.03; interaction effect, p=0.87) but increased the duration of deep sleep (stages III and IV) only in the long SL group (main effect of music, p=0.15; interaction effect, p=0.02)., Conclusions: In participants with long SL, sedative music improved the quality of sleep by prolonging the duration of deep sleep. This effect provides an alternative and noninvasive way to improve sleep in selected persons experiencing sleep problems.

The accumulation of misfolded a-synuclein is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other alpha-synucleinopathies. However, how alpha-synuclein causes neurodegeneration is unresolved. Several studies have supported the involvement of dynein, the major motor for retrograde axonal transport in alpha-synuclein-dependent neurodegeneration, especially in the nigrostriatal system. Therefore, we examined the nigrostriatal dyneins in transgenic mice that overexpress human A53T alpha-synuclein and recapitulate key features of a PD-like neuronal synucleinopathy. Age-matched nontransgenic littermates were used as controls. The results demonstrated that the protein level of dynein was decreased in the striatum, whereas it was elevated in the substantia nigra. Double immunostaining results revealed that the reduction in dynein level was associated with aggregation of A53T a-synuclein in the striatum. Furthermore, we performed a quantitative analysis of motor behaviors in A53T alpha-synuclein transgenic mice and controls using a modified open field test. We demonstrated that the protein level of dynein in the striatum was significantly correlated with the motor behaviors. Together, our data indicate that dynein changes in the nigrostriatal system of A53T alpha-synuclein transgenic mice may contribute to their severe movement disorder.

Background: Obstructive sleep apnea (OSA) syndrome is a complicated disease involving several pathogenic mechanisms. Microarray technology provides a high-throughput means of identifying differentially expressed genes in patients with OSA., Methods: An Affymetrix U133A gene chip was used to globally analyze the transcriptome of peripheral blood mononuclear cells (PBMC) in patients with OSA and nonapneic control participants after overnight polysomnography., Results: Several genes were differentially expressed in patients with OSA compared with control participants. These genes included disintegrin and metalloproteinase domain 29 (ADAM29), solute carrier family 18 (vesicular acetylcholine) member 3 (SLC18A3), cyclin-dependent kinase inhibitor 2C (CDKN2C), and fibronectin-like domain-containing leucine-rich transmembrane protein 2 (FLRT2). Among these genes, the expression levels of ADAM29 (p = 0.00003), FLRT2 (p < 0.0001), and SLC18A3 (p = 0.0006) were found to be possible markers of severe OSA [respiratory disturbance index (RDI) > 30]., Conclusion: Our data suggest that PCMC expression of ADAM29, FLRT2, and SLC18A3 could be assessed as part of a routine screen to help identify individuals at risk of severe OSA in Asian populations.

Six novel iridal-type triterpenoids with a previously unreported 3,6-dihydro-2H-pyran moiety, named spirioiridotectals A-F (1-6), were isolated from the ethanol extract of the rhizomes of Iris tectorum. Their structures were elucidated on the basis of extensive spectroscopic analysis. Furthermore, in in vitro bioactivity assays, compounds 1, 2, and 6 exhibited neuroprotective activities against serum-deprivation-induced PC12 cell damage.

7-Hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin (IMM-H004) is a novel coumarin derivative synthesized in our laboratory. The purpose of the current study was to determine the neuroprotective effects of IMM-H004 on PC12 cells and its potential mechanism of action. PC12 cells were subject to oxygen and glucose deprivation (OGD) followed by the restoration of oxygen and glucose (R), which mimics ischemia and reperfusion in vivo. Cell viability was determined by MTT assay. DNA fragmentation was analyzed by DNA ladder. ROS and mitochondrial membrane potential were measured by fluorescent microscope and quantified by Image-Pro Express 6.0 software. ATP was measured by luciferin-luciferase assay. The activation of signal-regulated molecules was assessed by the Western blot analysis. OH formation was determined using the Electron Spin Resonance (ESR) trapping technique in combination with 5, 5-dimethyl-1-pyrroline-N-oxide. OGD/R reduced cell viability and induced cell apoptosis, which were both dose-dependently attenuated by IMM-H004. The accumulation of intracellular reactive oxygen species (ROS) and reduced mitochondrial membrane potential observed in PC12 cells treated with OGD/R, which switch on the mitochondrion-dependent apoptotic pathway, were reversed by IMM-H004. ATP production in OGD/R-treated PC12 cells was elevated by IMM-H004, which suggests that it restored the functions of the mitochondria. OGD/R-induced cytochrome c release from the mitochondria reduced the ratio of apoptotic proteins, Bcl-2/Bax, and induced caspase-3 activation and DNA fragmentation. These changes were significantly inhibited by IMM-H004. IMM-H004 also significantly inhibited OH formation, determined by electron spin resonance, which indicates that it is a potent free-radical scavenger. This study has demonstrated that IMM-H004 protects PC12 cells against OGD/R-induced apoptosis, at least in part, by scavenging excessive ROS and inhibiting the mitochondrion-dependent apoptotic pathway., (© 2013 Published by Elsevier B.V.)

To investigate the protective effect and the underlying mechanism of polygalasaponin F (PS-F) against rotenone-induced PC12 cells, the cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. The cell apoptosis rate was analyzed using flow cytometry. The reactive oxygen species was examined using 2',7'-dichlorofluorescin diacetate, and the adenosine triphosphate depletion was examined using a luciferase-coupled quantification assay. JC-1 staining was used to detect the mitochondrial membrane potential. Western blotting analysis was used to determine cytochrome c, p53, Bax, Bcl-2, and caspase-3. Treatment of PC12 cells with rotenone (1-10 μmol/l) significantly reduced the cell viability in a concentration-dependent manner. Treatment with PS-F (0.1, 1, and 10 μmol/l) increased the viability of rotenone-induced PC12 cells, decreased rotenone-induced apoptosis, restored rotenone-induced mitochondrial dysfunction, and suppressed rotenone-induced protein expression. PS-F showed a dose-dependent manner in all the treatments. PS-F protects PC12 cells against rotenone-induced apoptosis via ameliorating the mitochondrial dysfunction. Thus, PS-F may be a potential bioactive compound for the treatment of Parkinson's disease.

Depression is the most common non-motor symptom of Parkinson's disease (PD). Recent clinical trials have evaluated the effectiveness of traditional Chinese medicine (TCM) in the treatment of depression in PD (dPD). However, the results are conflicting rather than conclusive. To investigate the effectiveness of TCM for the treatment of dPD, a systematic review was conducted. Literature searches and collections were performed to identify studies addressing the treatment of TCM for dPD. The methodological quality and risk of bias in all studies included were evaluated. Weighted mean difference (WMD) with 95% confidence interval (CI) was used as the effect measure. Finally, a total of 10 studies involving 582 patients were identified. The pooled results revealed that TCM combined with conventional drugs significantly improved the total scores of the unified Parkinson's disease rating scale (WMD = -7.35, 95% CI: -11.24 to -3.47) and the score of the Hamilton rating scale for depression (HAM-D) (WMD = -4.19, 95% CI: -5.14 to -3.24) compared with conventional drug, respectively. Conclusively, there is evidence that TCM may be beneficial to the treatment of dPD in spite of the methodological weakness of the included studies.

To study the anti-neuroinflammatory mechanisms of polygalasaponin F (PS-F), ELISA method was used to detect the secretion of inflammatory cytokines. Western blot was used to detect the protein expression and phosphorylation levels. Immunofluorescence assay was used to observe the NF-κB nuclear translocation. PS-F could inhibit the release of inflammatory cytokines TNF-α and NO induced by lipopolysaccharides (LPS) and reduce the expression of inducible nitric oxide synthases (iNOS). As for MAPK-signaling pathway, PS-F could only inhibit the phosphorylation levels of p38 MAPK, but did not significantly affect the phosphorylation levels of JNK and ERK1/2 protein kinases. PS-F could inhibit NF-κB nuclear translocation in a dose-dependent manner. The results of Western blot assay were consistent with immunofluorescence assays. Meanwhile, p38-specific inhibitor SB203580 (20 μM) and p65-specific inhibitor PDTC (100 μM) were, respectively, administered as a positive control. In addition, PS-F could significantly inhibit the cytotoxicity of conditioned medium prepared by LPS-stimulated BV-2 microglia (LPS conditioned media) to neuronal PC12 cells and improve cell viability. PS-F inhibits the secretions of neuroinflammatory cytokines by the regulation of NF-κB-signaling pathway.

Aim: To study the effects of Claulansine F (Clau F), a carbazole alkaloid isolated from the stem of Clausena lansium (Lour) Skeels, on neuritogenesis of PC12 cells, and to elucidate the mechanism of action., Methods: Neuritogenesis of PC12 cells was quantified under an inverted microscope. Expression of the neurite outgrowth marker GAP-43 was detected using immunofluorescence. GAP-43 transcription was measured using RT-PCR. Cell viability was evaluated with MTT assay. The levels of phosphor-ERK1/2, phosphor-CREB, phosphor-AKT and acetylate-p53 in the cells were examined using Western blotting analyses., Results: Clau F (10-100 μmol/L) significantly increased the percentage of PC12 cells bearing neurites. Clau F markedly increased the expression of GAP-43 in the cells. The efficiency of Clau F (10 μmol/L) in increasing neuritogenesis and GAP-43 expression was comparable to that of nerve growth factor (50 ng/mL). In addition, Clau F completely blocked the proliferation of PC12 cells within 7 d of incubation, whereas it did not cause cell death in cultured rat cortical neurons. Treatment of PC12 cells with Clau F activated both ERK and AKT signaling pathways. Co-treatment of PC12 cells with the specific ERK inhibitor PD98059, but not the specific PI3K inhibitor LY294002, blocked Clau F-induced neuritogenesis and GAP-43 upregulation., Conclusion: Clau F promotes neuritogenesis in PC12 cells specifically via activation of the ERK signaling pathway.

Seven new sesquiterpenoid glycosides, consisting of one thapsan-type (1), two capnellane-type (2 and 3), four floridanolide sesquiterpene glycosides (4-7), and one new azulene-type sesquiterpene (8), along with six known sesquiterpenes (9-14) were isolated from the roots of Illicium henryi. The structures of 1-8 were elucidated by extensive spectroscopic analyses and chemical methods. The absolute configurations of 1, 2, and 8 were determined based on Rh2(OCOCF3)4-induced CD, Mo2(OAc)4-induced CD data, and calculated electronic circular dichroism (ECD), respectively. Compound 1 was found to exhibit weak neurotoxicant activity., (Georg Thieme Verlag KG Stuttgart · New York.)

Microglia activation is the major component of inflammation that constitutes the characteristic of neurodegenerative disease. A large amount of researches have demonstrated that inflammation involved in the pathogenesis of PD process activated microglia acting on the neurons through the release of a variety of inflammatory factors. However, the molecular mechanism underlying how it does work on neurons is still unclear. Here, we show that intracerebral injections of LPS induced Parkinson's disease pathology in C57BL/6J mice. Furthermore, study on the dynamic changes in Synaptic vesicle-associated protein and axonal transport Protein in this process. The results indicated that after administration of LPS in the brain, the inflammatory levels of TNF- α and IL-1 β both are elevated, and have a time-dependent.

Background/purpose: To examine trajectories of change in sleep during the acute phase of traumatic brain injury (TBI), and whether specific demographic and disease characteristics predicted the initial levels of sleep and the trajectories of change in sleep parameters., Methods: This was a prospective observational study. Fifty-two patients with first-ever TBI were enrolled. Sleep parameters were measured using actigraphy for 7 consecutive days after admission. Hierarchical linear modeling was used for data analyses in 52 TBI patients and in a subgroup of mild TBI patients (n = 31)., Results: Participants had significant lower sleep efficiency, longer wake time after sleep onset, and longer 24-hour total sleep time (TST) than the normative data (all p < 0.05). Seventy-two percent of participants experienced prolonged 24-hour TST. Both daytime and 24-hour TST showed a significant downward trend across the study period. An initial Glasgow Coma Scale score < 11 significantly predicted the slope of change of daytime TST over time. Without initial loss of consciousness and age < 40 years were independent predictors of the change pattern of 24-hour TST over time. In the mild TBI subgroup, 24-hour TST significantly and gradually declined over time. Gender significantly predicted the trajectory of 24-hour sleep duration., Conclusion: Poor sleep efficiency and longer sleep duration are common symptoms in acute TBI patients. Both head injury severity and age predicted the trajectories of daytime and 24-hour sleep duration during the acute phase of TBI, whereas gender predicted the trajectories of 24-hour sleep duration in the mild TBI subgroup., (Copyright © 2013. Published by Elsevier B.V.)

Study Objective: To explore the profile of patients who visit a sleep center with symptoms that fulfill the four essential criteria for restless legs syndrome (RLS)., Design: A prospective study., Setting: Outpatients from one sleep disorders clinic in Taiwan., Participants: 1,200 consecutive patients visit sleep disorders clinic with any sleep complaints., Interventions: After completing a history and physical examination, all participants answered the RLS questionnaire. Subjects who fulfilled the four essential criteria for RLS were referred to a special clinic. A work-up including blood tests, polysomnography, and specialized neurological tests etc. was performed to make the final diagnosis., Measurements and Results: A total of 1,185 participants were enrolled, and, of these, 131(11.1%) fulfilled the four essential criteria for RLS, and 121 completed the supplemental work-up. Their mean age was 47.6±13.3 and 52.9% were male. Insomnia and snoring were the most common chief complaints. Obstructive sleep apnea syndrome and other diseases were found in 103 patients. Only 18 (14.9%) patients had no comorbid condition and were diagnosed with primary RLS., Conclusions: Symptoms of RLS are common in patients with sleep complaints. Even in a sleep clinic, using a questionnaire approach for identification of RLS has a low positive predictive value. Clinicians should pay attention to the limitations of the 4-item questionnaire in diagnosis of RLS and also the importance of a careful differential diagnosis to identify possible secondary causes of RLS.

Aims: Obstructive sleep apnea is known to be a risk factor of coronary artery disease. Matrix metalloproteinases (MMPs) contribute to the instability and rupture of atherosclerotic plaque and acute coronary syndrome. The present study aimed to determine the correlation of MMPs including MMP-1, -2, -3 and -9 with the severity of obstructive sleep apnea (OSA)., Main Methods: Peripheral blood was sampled before and after overnight polysomnography study from OSA patients. Plasma was processed for ELISA and zymography. Monocytes were isolated from peripheral blood and RNA was prepared for RT/real-time PCR., Key Findings: The plasma level of MMP-9, but not MMP-1, -2, and -3 and TIMP-1 was remarkably increased in OSA patients. The plasma MMP-9 level was considerably higher after sleep and the net difference was most significant in patients with severe OSA. The plasma MMP-9 activity was also demonstrated to be significantly higher after sleep. The mRNA expression of MMP-9 in monocytes not only correlated well to the plasma MMP-9 level in the patients, but also was found to be significantly higher in patients with severe OSA., Significance: This study for the first time proves that the increase of plasma MMP-9 level in OSA patients is likely due to the up-regulated MMP-9 mRNA expression of monocytes in the peripheral blood., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a common neurodegenerative disease, and its etiology remains obscure. Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in increasing the risk of developing PD and inflammation is the early incident during the process of PD. In this study, we measure the pro-inflammatory cytokines by enzyme-linked immunosorbnent assay and RT-PCR methods; analyze the reactive oxygen species by DCFH-DA; detected nuclear factor κB (NFκB) translocation by western blot and immunofluorescence methods; and analyze the phosphorylation of mitogen-activated protein (MAP) kinase and protein level of Nurr1 by western blot. Results showed that rotenone could induce tumor neurosis factor α (TNFα) and interleukin 1β (IL-1β) release from BV-2 cells, enhance TNFα and IL-1β mRNA levels in substantia nigra lesioned by rotenone; also, rotenone could increase the phosphorylation of inhibitor of κB (IκB), extracellular regulated protein kinase , c-Jun N-terminal kinase, p38 MAP kinases and promote p65 subunit of NFκB translocation to nuclear; at the same time, rotenone could decrease the protein level of Nurr1 in nuclear. So, rotenone exerted toxicity through activating microglia, and its mechanism might be associated with NFκB signal pathway.

This study is to investigate the amelioration effect of glucocorticoid receptor (GR) antagonist mifepristone on the changes of learning and memory abilities in rat model of depression. In the present study, a 35-day rat chronic unpredictable stress (CUS) model was used to observe both depression-like behaviors with sucrose preference test and open-field test and learning and memory-associated behaviors with Morris water maze test. A total of 45 male adult Sprague-Dawley rats were randomly assigned to three groups of equal size: control group (CON); CUS group (CUS); CUS + mifepristone group (CM). Animals in CM group were first exposed to CUS for 14 days, and then were administered with 50 mg x kg(-1) x d(-1) of mifepristone with continued CUS procedure. Corticosterone EIA Kit was used to detect the concentration of plasma corticosterone (CORT). Nissl staining was used to observe the structure of hippocampus. The results demonstrated that CUS exposure induced both depressive-like and learning and memory-associated behaviors and these deficits were reversed by mifepristone. Compared to CON group, the concentration of plasma CORT increased significantly in CUS group. CUS exposure damaged the structure of hippocampus, whereas mifepristone had an amelioration effect. Together, the structural deficits of hippocampus resulting from long-term stress exposure, which could contribute to the impairment of learning and memory in depression, are reversed by the GR receptor antagonist mifepristone.

We have investigated the effect of IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-2H-chromen-2-one), a coumarin derivative, on the amyloid beta (Aβ)-induced neurotoxicity in primary culture cortical neurons and pheochromocytoma (PC12) cells. Our results showed that treatment with IMM-H004 markedly reduced the number of apoptotic cells after exposure to Aβ25-35 or Aβ1-42, determined by MTT, TUNEL staining and Flow cytometry. Further study indicated that IMM-H004 significantly inhibited Aβ-induced cytotoxicity and apoptosis by reversing Aβ-induced mitochondrial dysfunction, including MMP (mitochondrial membrane potential) decrease, reactive oxygen species production, and mitochondrial release of cytochrome c. IMM-H004 can regulate the interaction between Bax and Bcl-2, decreased levels of p53 and active caspase-3 protein induced by Aβ25-35. Furthermore, IMM-H004 also reduced translocation of AIF (apoptosis-inducing factor) induced by Aβ25-35. These results demonstrated that IMM-H004 was capable of protecting neuronal cells from Aβ-induced degeneration through a mitochondrial-dependent apoptotic pathway. The results of this study lend further credence to the notion that IMM-H004 is a 'multipotent therapeutic agrent' that reduces toxic levels of brain Aβ, and holds the potential to protect neuronal mitochondrial function in Alzheimer's disease., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Stroke is a leading cause of permanent disability and death. A complex series of biochemical and molecular mechanisms (e.g. the release of ROS/NOS, proapoptotic proteins and proinflammatory cytokine; neuronal depolarization, Ca2+ accumulation and so on) impair the neurologic functions of cerebral ischemia and stroke. We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. The principal mammalian estrogen (17β estradiol or E2) is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However the incidence of stroke in women is lower than in men until decades past menopause, suggesting that factors beyond sex hormone contribute to these epidemiological sex differences. So a new concept is emerging: both sex steroids and biologic sex are important factors in clinical and experimental strokes. In this review, we will address sex steroids and gender differences in influencing the mechanisms and outcomes of brain ischemia stroke. These sex differences need to be identified which could help future translation to human neuroprotection., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Glucosamine (GlcN), like N-acetylglucosamine (GlcNAc), is salvaged into the hexosamine pathway and is converted to UDP-GlcNAc. Golgi N-glycan branching enzymes produce N-glycans, using UDP-GlcNAc as a substrate, which attach to the T cell receptor (TCR) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). These findings suggest that GlcN exerts the immunoregulation through TCR signalling, which could be involved not only in cytokine production but also activated T cell apoptosis. In fact, a preliminary study showed that GlcN reduced the number of CD3+ T cells of NC/Nga mice with AD-like skin lesions. Therefore, whether apoptosis of T cells would be one of the potential molecular mechanisms of GlcN-induced immunosuppression was investigated. Cultured human primary along with Jurkat T cells and purified T cells from NC/Nga mice with or without Df-induced AD-like skin lesion were used for the study. Glucosamine treatment increased the number of T cells expressing β1,6GlcNAc-branched N-glycans, with reduced ZAP-70 phosphorylation and enhanced CTLA-4 expression. Glucosamine treatment reduced the number of activated T cells from both the human primary and Jurkat cells and the dermatitis-induced mice. The expression of FasL and activated caspases, particularly caspase-3, was increased, whereas the phosphorylation of PI3K, Akt and NF-κB was decreased by GlcN treatment. Therefore, in addition to down-regulating TCR signalling and promoting CTLA-4 expression, GlcN may also suppress T cell function by enhancing apoptosis of activated T cells, through both extrinsic and intrinsic apoptotic signalling pathways, which were regulated by the inhibition of PI3K/Akt and NF-κB phosphorylation., (© 2013 John Wiley & Sons Ltd.)

To observe the effect of various doses of oil of Piper longum unsaponifiable matter (OPUM) to cholesterol gallstones in experimental mice. C57BL/6 mice (n = 60) were randomly divided into 6 groups: control group, model group, OPUM (15, 30 and 60 mg x kg(-1)) group and ursodeoxycholic acid (UDCA, 60 mg x kg(-1)) group, administered for 10 weeks. The level of serum lipid and liver function enzymes were tested. The gallbladder was removed and bile was obtained by centrifugation. Next, the levels of the bile total cholesterol (TC), phospholipid (PL) and bile acid (TBA) were measured. The indicators of lipid peroxidation were determined and cholesterol saturation index (CSI) was calculated. The liver histological changes were observed by HE staining. The results showed that serum TC, TG (triglycerides) and AST (aspartate transaminase) contents, gallbladder cholesterol crystallization and CSI increased significantly (P < 0.05). In addition, the activity of SOD decreased significantly and MDA content increased significantly in liver (P < 0.05). HE staining results showed that the hepatic cord disorder and intracellular lipid droplets increased significantly. All results indicate that lithogenic diet lead to the formation of cholesterol gallstones. In OPUM (30 and 60 mg x kg(-1)) group, serum TC, TG and AST content, gallbladder cholesterol crystallization and CSI decreased significantly, the activity of SOD increased significantly and MDA content decreased significantly. HE staining results showed that OPUM can improve the morphology of liver cell, reduce the degree of hepatic cord disorders and restore the cell morphology close to normal. The cause of OPUM prevents cholesterol gallstone formation maybe due to protect the integrity of the liver cells, lower CSI, and reduce cholesterol crystal formation and hence prevent cholesterol gallstone formation.

Reactive oxygen species (ROS) are known to be involved in many neurodegenerative diseases. This study assessed the effect of Claulansine F, a new carbazole isolated from Clausena lansium, on sodium nitroprusside (SNP)-treated rat pheochromocytoma PC12 cells. First, it was found that Claulansine F showed more potential on inhibiting the programmed death of PC12 cells than edaravone by cell viability, morphologic observation, and flow cytometric analysis. Further results also showed that Claulansine F attenuated the production of total intracellular ROS formation and lipid peroxidation in PC12 cells, inhibited the mitochondrial membrane potential (MMP) loss, and prevented the programmed cell death event via the P53/Bcl-2 family pathway. Its protective effect was likely medicated by the hydroxyl radical (·OH) scavenging ability, as it appeared to be not involved in the natural antioxidant system. These results suggested a promising potential for Claulansine F as a ROS scavenger in pathologies, where an oxidative stress is involved.

Ginsenoside Rg1, one of the major active ingredients isolated from Panax Ginseng, has been shown notable neuroprotective effects in memory impairment animals. However, the role of ginsenoside Rg1 on cognition capacity damaged by neurofibrillary tangles (NFTs) is still poorly understood, and the underlying mechanism remain to be fully elucidated. Okadaic acid (OKA), a potent phosphatase inhibitor, often apply to imitate Alzheimer's disease-like symptom damaged by neurofibrillary tangles, was used to investigate the effects of ginsenoside Rg1 on memory impairment and the related mechanisms in Sprague Dawley (SD) rats. The anti-dementic drug donepezil was used as a positive contrast. The results showed that OKA intracerebroventricular (i.c.v.) injection induced memory impairment, including changes in the ability of orientation navigate, spatial probe and relearning memory in behavioral test of Morris water maze (MWM). However, treatment with Rg1 and donepezil remarkably alleviated these changes. Also OKA treated rats showed memory impairment including increasing of phospho-tau, decreasing of phospho-GSK3β and the formation of β-amyloid in special brain regions, which were reversed by Rg1 (20 mg/kg) and donepezil (1 mg/kg) administration. All these indicating that ginsenoside Rg1 protects rats against OKA-induced neurotoxicity. The possible neuroprotective mechanism may be that Rg1 decreases OKA-induced memory impairment through GSK3β/tau signaling pathway and/or attenuating Aβ formation. Thus, these studies indicate that ginsenoside Rg1 might be a potential preventive drug for Alzheimer's disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In an aging society, the incidence of brain ischemia increases dramatically. Despite progress in pathophysiology mechanisms, the medical therapy for brain ischemia has not been satisfactory. Recanalization using tissue plasminogen activator only modestly improves patient outcome, and inhibiting excitotoxicity has shown no clinical benefit. Both do not provide an adequate time window for effective stroke therapy in clinical practice. A more reasonable therapeutic window, and hence a greater potential for clinical success, is likely to be attained by placing emphasis on ameliorating the effects of the synergistic processes of programmed cell death (PCD) that is active for hours to days after ischemia. It is necessary to identify molecular mediators of ischemic neuroprotection suitable for translation to human clinical trials. In this review, the mechanisms of cell death/survival signaling pathways after ischemia and the potential therapeutic targets will be discussed.