Variations of plasma oxidative stress levels in male patients with chronic schizophrenia. Correlations with psychopathology and matrix metalloproteinase-9: a case-control study.

BACKGROUND: Accumulating evidence has indicated that oxidative stress (OS) and matrix metalloproteinase-9 (MMP-9) may contribute to the mechanism of schizophrenia. In the present study, we aimed to evaluate the associations of OS parameters and MMP-9 levels with psychopathological symptoms in male chronic schizophrenia patients. METHODS: This study was an observational, cross-sectional, retrospective case-control study. Plasma hydrogen peroxide (H2O2), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), serum matrix metalloproteinase-9 (MMP-9), and tissue inhibitors of metalloproteinases-1 (TIMP-1) levels were assayed in 80 male patients with chronic schizophrenia and 80 matched healthy controls. Schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS). Multivariate regression was used to analyze relationships between OS parameters and MMP-9, and clinical symptoms. RESULTS: Our results demonstrated that levels of antioxidant enzymes, SOD, GSH-Px, H2O2, and MDA were significantly decreased, whereas CAT and MMP-9 levels were increased in patients with schizophrenia, when compared with healthy controls (all P < 0.05). In schizophrenia patients, correlation analyses showed that H2O2 levels were significantly and positively correlated with PANSS positive scores, CAT and MDA levels were significant negatively correlated with PANSS negative scores and PANSS total scores, and MDA levels were significantly positively correlated with MMP-9 levels (all P < 0.05). However, we did not find that MMP-9 played an interaction role between OS parameters and PANSS total scores and subscales scores (all P > 0.05). CONCLUSIONS: Our results showed that alterations of plasma OS parameters in male patients with chronic schizophrenia were associated with psychopathology and MMP-9, suggesting that OS and neuroinflammation may play important role in the mechanism of schizophrenia.

Systemic inflammatory biomarkers in Schizophrenia are changed by ECT administration and related to the treatment efficacy.

Immune inflammation has long been implicated in the pathogenesis of schizophrenia. Despite as a rapid and effective physical therapy, the role of immune inflammation in electroconvulsive therapy (ECT) for schizophrenia remains elusive. The neutrophils to lymphocytes (NLR), platelets to monocytes (PLR) and monocytes to lymphocytes (MLR) are inexpensive and accessible biomarkers of systemic inflammation. In this study, 70 schizophrenia patients and 70 age- and sex-matched healthy controls were recruited. The systemic inflammatory biomarkers were measured before and after ECT. Our results indicated schizophrenia had significantly higher peripheral NLR, PLR and MLR compared to health controls at baseline, while lymphocytes did not differ. After 6 ECT, the psychiatric symptoms were significantly improved, as demonstrated by the Positive and Negative Syndrome Scale (PANSS). However, there was a decline in cognitive function scores, as indicated by the Mini-Mental State Examination (MMSE). Notably, the neutrophils and NLR were significantly reduced following ECT. Although lymphocytes remained unchanged following ECT, responders had significantly higher lymphocytes compared to non-responders. Moreover, the linear regression analyses revealed that higher lymphocytes served as a predictor of larger improvement in positive symptom following ECT. Overall, our findings further highlighted the presence of systemic inflammation in schizophrenia patients, and that ECT may exert a therapeutic effect in part by attenuating systemic inflammation. Further research may therefore lead to new treatment strategies for schizophrenia targeting the immune system.

The association between inflammation and kynurenine pathway metabolites in electroconvulsive therapy for schizophrenia: Implications for clinical efficacy.

The kynurenine pathway (KP) of tryptophan has been implicated in the pathogenesis of schizophrenia and its interaction with the immune system has been suggested to play a role. In this study, 28 schizophrenia patients and 25 healthy controls were recruited and divided into different inflammatory subgroups using a two-step recursive clustering analysis. Cytokine gene expression and plasma KP metabolites were measured before, during and after treatment. Our findings indicated that schizophrenia patients had lower levels of Tryptophan (TRP), N-formylkynurenine (NFK), xanthinic acid (XA), quinolinic acid (QA), kynurenic acid (KYNA), KYNA/KYN and QA/KYNA, but higher levels of IL-18 mRNA, KYN/TRP compared to healthy controls (all p < 0.05). After electroconvulsive therapy (ECT), patients with low inflammation achieved better clinical improvement (PANSS scores) compared to those with high inflammation (F = 5.672, P = 0.025), especially in negative symptoms (F = 6.382, P = 0.018, η2 = 0.197). While IL-18 mRNA (F = 32.910, P < 0.0001) was significantly decreased following ECT, the KYN/TRP (F = 3.455, p = 0.047) and KYNA/TRP (F = 4.264, P = 0.026) only significantly decreased in patients with low inflammation. Correlation analyses revealed that baseline IL-18 gene expression significantly correlated with pre- (r = 0.537, p = 0.008) and post-KYNA/TRP (r = 0.443, p = 0.034), post-KYN/TRP (r = 0.510, p = 0.013), and post-negative symptoms (r = 0.525, p = 0.010). Moreover, baseline TRP (r = -0.438, p = 0.037) and XA (r = -0.516, p = 0.012) were negatively correlated with baseline PANSS, while post-KYN (r = -0.475, p = 0.022), 2-AA (r = -0.447, p = 0.032) and KYN/TRP (r = -0.566, p = 0.005) were negatively correlated with Montreal Cognitive Assessment (MoCA) following ECT. Overall, these findings suggested that the association between inflammation and kynurenine pathway plays an essential role in mechanism of ECT for schizophrenia and that the regulation of ECT on KP is influenced by inflammatory characteristics, which may relate to clinical efficacy in schizophrenia.

2-BFI Provides Neuroprotection Against Fluorosis by Stabilizing Endoplasmic Reticulum-Mitochondria Contact Sites and Inhibiting Activation of the NLRP3 Inflammasome.

2-(2-benzofu-ranyl)-2-imidazoline (2-BFI) is a drug that has attracted much attention in recent years. It has a therapeutic effect on brain diseases in animal models such as Alzheimer's disease and cerebral infarction. However, whether 2-BFI affords neuroprotection against the toxicity of fluoride, which can cross the blood-brain barrier and cause neurological dysfunction is not known. We investigated the cell viability and apoptosis of SH-SY5Y cells and primary cultures of cortical neurons exposed to fluoride, and 2-BFI was used to protect both two kinds of cells against the effects of fluoride. We found that 2-BFI can provide neuroprotection on SH-SY5Y cells and primary cultures of cortical neurons upon fluorosis by maintaining the stability of endoplasmic reticulum-mitochondria contact sites and inhibiting activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. This study may provide a new method for protecting against the neurotoxicity induced by fluoride exposure.

The Predictive Value of Monocyte/High-Density Lipoprotein Ratio (MHR) and Positive Symptom Scores for Aggression in Patients with Schizophrenia.

Background and Objectives: Schizophrenia with aggression often has an inflammatory abnormality. The monocyte/high-density lipoprotein ratio (MHR), neutrophil/high-density lipoprotein ratio (NHR), platelet/high-density lipoprotein ratio (PHR) and lymphocyte/high-density lipoprotein ratio (LHR) have lately been examined as novel markers for the inflammatory response. The objective of this study was to assess the relationship between these new inflammatory biomarkers and aggression in schizophrenia patients. Materials and Methods: We enrolled 214 schizophrenia inpatients in our cross-sectional analysis. They were divided into the aggressive group (n = 94) and the non-aggressive group (n = 120) according to the Modified Overt Aggression Scale (MOAS). The severity of schizophrenia was assessed using the Positive and Negative Syndrome Scale (PANSS). The numbers of platelets (PLT), neutrophils (NEU), lymphocytes (LYM), monocytes (MON) and the high-density lipoprotein (HDL) content from subjects were recorded. The NHR, PHR, MHR and LHR were calculated. We analyzed the differences between those indexes in these two groups, and further searched for the correlation between inflammatory markers and aggression. Results: Patients with aggression had higher positive symptom scores (p = 0.002). The values of PLT, MON, MHR and PHR in the aggressive group were considerably higher (p < 0.05). The NHR (r = 0.289, p < 0.01), LHR (r = 0.213, p < 0.05) and MHR (r = 0.238, p < 0.05) values of aggressive schizophrenia patients were positively correlated with the total weighted scores of the MOAS. A higher MHR (ß = 1.529, OR = 4.616, p = 0.026) and positive symptom scores (ß = 0.071, OR = 1.047, p = 0.007) were significant predictors of aggression in schizophrenia patients. Conclusions: The MHR and the positive symptom scores may be predictors of aggressive behavior in schizophrenia patients. The MHR, a cheap and simple test, may be useful as a clinical tool for risk stratification, and it may direct doctors' prevention and treatment plans in the course of ordinary clinical care.

Altered intrinsic default mode network functional connectivity in patients with remitted geriatric depression and amnestic mild cognitive impairment.

OBJECTIVES: Patients with geriatric depression exhibit a spectrum of symptoms ranging from mild to severe cognitive impairment which could potentially lead to the development of Alzheimer's disease (AD). The aim of the study is to assess the alterations of the default mode network (DMN) in remitted geriatric depression (RGD) patients and whether it could serve as an underlying neuropathological mechanism associated with the risk of progression of AD. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 154 participants, comprising 66 RGD subjects (which included 27 patients with comorbid amnestic mild cognitive impairment [aMCI] and 39 without aMCI [RGD]), 45 aMCI subjects without a history of depression (aMCI), and 43 matched healthy comparisons (HC), were recruited. MEASUREMENTS: All participants completed neuropsychological tests and underwent resting-state functional magnetic resonance imaging (fMRI). Posterior cingulate cortex (PCC)-seeded DMN functional connectivity (FC) along with cognitive function were compared among the four groups, and correlation analyses were conducted. RESULTS: In contrast to HC, RGD, aMCI, and RGD-aMCI subjects showed significant impairment across all domains of cognitive functions except for attention. Furthermore, compared with HC, there was a similar and significant decrease in PCC-seed FC in the bilateral medial superior frontal gyrus (M-SFG) in the RGD, aMCI, and RGD-aMCI groups. CONCLUSIONS: The aberrations in rsFC of the DMN were associated with cognitive deficits in RGD patients and might potentially reflect an underlying neuropathological mechanism for the increased risk of developing AD. Therefore, altered connectivity in the DMN could serve as a potential neural marker for the conversion of geriatric depression to AD.

Effects of chronic fluorosis on the brain.

This article reviews the effects of chronic fluorosis on the brain and possible mechanisms. We used PubMed, Medline and Cochraine databases to collect data on fluorosis, brain injury, and pathogenesis. A large number of in vivo and in vitro studies and epidemiological investigations have found that chronic fluorosis can cause brain damage, resulting in abnormal brain structure and brain function.Chronic fluorosis not only causes a decline in concentration, learning, and memory, but also has mental symptoms such as anxiety, tension, and depression. Several possible mechanisms that have been proposed: the oxidative stress and inflammation theory, neural cell apoptosis theory, neurotransmitter imbalance theory, as well as the doctrine of the interaction of fluorine with other elements. However, the specific mechanism of chronic fluorosis on brain damage is still unclear. Thus, a better understanding of the mechanisms via which chronic fluorosis causes brain damage is of great significance to protect the physical and mental health of people in developing countries, especially those living in the endemic areas of fluorosis. In brief, further investigation concerning the influence of fluoride on the brain should be conducted as the neural damage induced by it may bring about a huge problem in public health, especially considering growing environmental pollution.

Effect of a group-based acceptance and commitment therapy programme on the mental health of clinical nurses during the COVID-19 sporadic outbreak period.

AIM: To develop and implement of a group-based acceptance and commitment therapy programme in helping clinical nurses with mental health problems during the sporadic COVID-19 outbreak period. BACKGROUND: In the face of the continuing COVID-19 pandemic, clinical nurses have a high risk of mental health issues. METHODS: A quasi-experimental design was used. Two hundred twenty-six nurses were recruited from four general hospitals to receive 10 sessions of acceptance and commitment therapy programme. The Symptom Checklist-90, Perceived Stress Scale and Connor-Davidson Resilience Scale were used to assess nurses' mental health symptom, perceived stress and psychological resilience at pre-intervention and 4-week post-intervention. RESULTS: The mean attendance sessions was 5.78. The Symptom Checklist-90 score was significantly lower at post-intervention than pre-intervention (P < 0.01), and there were no significant changes of perceived stress and psychological resilience. There were significant correlations among the changed rates of mental health, perceived stress and psychological resilience (P < 0.01). CONCLUSION: The acceptance and commitment therapy programme was effective in relieving mental health symptoms for clinical nurses and could protect clinical nurses' perceived stress and psychological resilience. However, a randomized controlled trial is needed to confirm the findings. IMPLICATION FOR NURSING MANAGEMENT: To facilitate clinical nurses' psychological health in crisis situation, nursing management team should provide and allocated appropriate resources to support the healthcare providers.

Schizophrenia and Alarmins.

Schizophrenia, consisting of a group of severe psychiatric disorders with a complex etiology, is a leading cause of disability globally. Due to the lack of objective indicators, accurate diagnosis and selection of effective treatments for schizophrenia remain challenging. The association between schizophrenia and alarmins levels has been proposed for many years, but without solid evidence. Alarmins are prestored molecules that do not require processing and can be released upon cell death or damage, making them an ideal candidate for an early initiator of inflammation. Immunological biomarkers seem to be related to disease progression and treatment effectiveness. Several studies suggest strong associations among the high-mobility group box 1 protein (HMGB1), interleukin-1α, interleukin-33, S100B, heat-shock proteins, and uric acid with schizophrenic disorders. The purpose of this review is to discuss the evidence of central and peripheral immune findings in schizophrenia, their potential causes, and the effects of immunomodulatory therapies on symptoms and outline potential applications of these markers in managing the illness. Although there are currently no effective markers for diagnosing or predicting treatment effects in patients with schizophrenia, we believe that screening immune-inflammatory biomarkers that are closely related to the pathological mechanism of schizophrenia can be used for early clinical identification, diagnosis, and treatment of schizophrenia, which may lead to more effective treatment options for people with schizophrenia.

Target-Triggered Nanomaterial Self-Assembly Induced Electromagnetic Hot-Spot Generation for SERS-Fluorescence Dual-Mode In Situ Monitoring MiRNA-Guided Phototherapy.

A multifunctional theranostic nanosystem that integrates dynamic monitoring and therapeutic functions is necessary for precision tumor medicine. Herein, an entropy-driven self-assembly nanomachine is developed that overcomes the mechanism differences of different diagnostic modes and is applied to miRNA surface-enhanced Raman scattering (SERS)-fluorescence dual-mode dynamic monitoring and synergy phototherapy. It is worth noting that the activated dual-mode theranostic nanosystem (DTN) is capable of tumor in situ fluorescence imaging and SERS absolute quantification of the target. After being internalized into tumor cells, the DTN nanosystem is activated by the DNA cascade chain displacement of the target miR-21, resulting in the secondary release of fluorophores and the assembly of core-satellite structures (CS structures). The coupling of localized surface plasmon resonances (LSPRs) in the CS structure results in the formation of numerous enhanced electric fields (hot spot) in the nanogap of the CS structure. Then the DTN nanosystem greatly improves the sensitivity and repeatability of Raman detection by converting trace targets into numerous adenines residing in the electromagnetic hot spot of the CS structure. Meanwhile, the CS structure and the loaded photosensitizer are used for synergy phototherapy under the guidance of fluorescence imaging. This proposed strategy is confirmed by in vivo and in vitro results, and it provides new ideas for tumor SERS-fluorescence dual-mode diagnosis and effective tumor therapy.

Gold-Bipyramid-Based Nanothernostics: FRET-Mediated Protein-Specific Sialylation Visualization and Oxygen-Augmenting Phototherapy against Hypoxic Tumor.

Despite several attempts, incorporating biological detection that supplies necessary biological information into therapeutic nanotheranostics for hypoxic tumor treatments is considered to be in its infancy. It is therefore imperative to consolidate biological detection and desirable phototherapy into a single nanosystem for maximizing theranostic advantages. Herein, we develop a versatile nanoprobe through combined fluorescence resonance energy transfer (FRET) and oxygen-augmenting strategy, namely APT, which enables glycosylation detection, O2 self-sufficiency, and collaborative phototherapy. Such APT nanoprobes were constructed by depositing platinum onto gold nano-bipyramids (Au NBPs), linking FITC fluorophore-labeled AS1411 aptamers for introducing FRET donors, and by conjugating G-quadruplex intercalated with TMPyP4 to their surfaces via the SH-DNA chain. By installing FRET acceptors on the glycan of targeted EpCAM glycoprotein using the metabolic glycan labeling and click chemistry, FRET signals appear on the cancerous cell membranes, not normal cells, when donors and acceptors are within an appropriate distance. This actualizes protein-specific glycosylation visualization while revealing glycan-based changes correlated with tumor progression. Interestingly, the deposited platinum scavenges excessive H2O2 as artificial nanoenzymes to transform O2 that alleviates tumor hypoxia and simultaneously elevates singlet oxygen (1O2) for inducing cancer cell apoptosis. Notably, the significant hyperthermia devastation was elicited via APT nanoprobes with phenomenal photothermal therapy (PTT) efficiency (71.8%) for thermally ablating cancer cells, resulting in synergistically enhanced photodynamic-hyperthermia therapy. Consequently, APT nanoprobes nearly actualized thorough tumor ablation while demonstrating highly curative biosafety. This work offers a new paradigm to rationally explore a combined FRET and oxygen-augmenting strategy with a focus on nanotheranostics for hypoxic tumor elimination.

The cognitive impairment and risk factors of the older people living in high fluorosis areas: DKK1 need attention.

OBJECTIVE: To evaluate cognitive impairment and risk factors of elders in high fluoride drinking water areas and investigate whether DKK1 is involved in this disorder. METHODS: MoCA-B and AD-8 were used to measure the cognitive functions of 272 and 172 subjects over the age of 60 came from the high and normal fluoride drinking water areas respectively, general information and peripheral blood were collected, the level of SOD, GSH and MDA were measured, mRNA level of DKK1, the concentration of blood fluoride and the polymorphism of APOE were tested. RESULTS: The blood fluoride concentration, mRNA level of DKK1 and ratio of abnormal cognitive function of subjects in high fluorine drinking water areas were higher than those in normal areas. The level of SOD of subjects in high fluorine drinking water was low compared with those in normal areas. The level of MDA and GSH had no difference between the two crowds in different fluorine drinking water areas. There were differences in cigarette smoking, education, dental status, hypertension, hyperlipidaemia and APOE results between the two crowds in different fluorine drinking water areas. The mRNA level of DKK1 and the level of cognitive function showed a positive correlation and DKK1 was one of five risk factors involved in cognitive impairment of older people living in high fluorosis areas. CONCLUSIONS: The cognitive functions could be impaired in the older people living in high fluoride drinking water areas, and DKK1 may as a potential intervention point of this brain damage process need attention.

Carbon Nanohorns/Pt Nanoparticles/DNA Nanoplatform for Intracellular Zn2+ Imaging and Enhanced Cooperative Phototherapy of Cancer Cells.

Superfluous zinc ion (Zn2+) in living cells has been identified as a potential tumor biomarker for early cancer diagnosis and cancer progression monitoring. In this paper, we developed a novel carbon nanohorns/Pt nanoparticles/DNA (CNHs/Pt NPs/DNA) nanoplatform based on the clamped hybridization chain reaction (c-HCR) process for intracellular Zn2+ imaging and enhanced cooperative phototherapy of cancer cells. Cross-shaped DNAzyme (c-DNAzyme), hairpin DNA1, hairpin DNA2, and aptamer DNA were adsorbed onto the surfaces of CNHs/Pt NPs, and the fluorescence of carboxytetramethyl-rhodamine was also quenched. After entering the living cells, the c-DNAzyme was cleaved to output trigger DNA in the existence of intracellular Zn2+ and initiate the c-HCR process for fluorescence amplification. Compared with the single HCR process triggered by a single DNAzyme, the c-HCR process could further improve the amplification efficiency and sensitivity. In addition, such a nanoprobe possesses a catalysis-enhanced photodynamic effect by Pt NP generation of oxygen in a tumor microenvironment and increases the photothermal effect by loading of Pt NPs on CNHs, indicating that this is a promising biological method for cancer diagnosis and cancer cell therapy.

The role of DKK1 in Alzheimer's disease: A potential intervention point of brain damage prevention?

Dickkopf-1 (DKK1), a secretory glycoprotein discovered for 'inducing generation of head', is an endogenous inhibitor of the canonical Wnt/ß-catenin signaling pathway. It was found to be involved in many pathophysiological processes in vivo. Abnormal expression of DKK1 will alter expressions of related proteins and genes not only in canonical Wnt/ß-catenin signaling pathway but also in other signaling pathways. Previous studies of DKK1 focused on its function in tumors. In recent years, a large number of studies have shown that it plays an important role in embryonic development, neural regeneration, synaptogenesis and so on. Therefore, its role in neuropsychiatric disorders, such as neurodysplasia, cognitive impairment and emotional disorder, has attracted increasing attention. At present, the role of DKK1 in Alzheimer's disease (AD) is one of the research hot topics. This article reviewed the research progress of its role in AD in order to provide new ideas and directions for further studies on the pathogenesis and treatment of AD.

Attenuation of hyperalgesia responses via the modulation of 5-hydroxytryptamine signalings in the rostral ventromedial medulla and spinal cord in a 6-hydroxydopamine-induced rat model of Parkinson's disease.

Background Although pain is one of the most distressing non-motor symptoms among patients with Parkinson's disease, the underlying mechanisms of pain in Parkinson's disease remain elusive. The aim of the present study was to investigate the role of serotonin (5-hydroxytryptamine) in the rostral ventromedial medulla (RVM) and spinal cord in pain sensory abnormalities in a 6-hydroxydopamine-treated rat model of Parkinson's disease. Methods The rotarod test was used to evaluate motor function. The radiant heat test and von Frey test were conducted to evaluate thermal and mechanical pain thresholds, respectively. Immunofluorescence was used to examine 5-hydroxytryptamine neurons and fibers in the rostral ventromedial medulla and spinal cord. High-performance liquid chromatography was used to determine 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels. Results The duration of running time on the rotarod test was significantly reduced in 6-hydroxydopamine-treated rats. Nociceptive thresholds of both mechanical and heat pain were reduced compared to sham-treated rats. In addition to the degeneration of cell bodies and fibers in the substantia nigra pars compacta, the number of rostral ventromedial medulla 5-hydroxytryptamine neurons and 5-hydroxytryptamine fibers in the spinal dorsal horn was dramatically decreased. 5-Hydroxytryptamine concentrations in both the rostral ventromedial medulla and spinal cord were reduced. Furthermore, the administration of citalopram significantly attenuated pain hypersensitivity. Interestingly, Intra-rostral ventromedial medulla (intra-RVM) microinjection of 5,7-dihydroxytryptamine partially reversed pain hypersensitivity of 6-hydroxydopamine-treated rats. Conclusions These results suggest that the decreased 5-hydroxytryptamine contents in the rostral ventromedial medulla and spinal dorsal horn may be involved in hyperalgesia in the 6-hydroxydopamine-induced rat model of Parkinson's disease.

The p38/CYLD Pathway is Involved in Necroptosis Induced by Oxygen-glucose Deprivation Combined with ZVAD in Primary Cortical Neurons.

Recently, necroptosis, a form of programmed necrosis, has been widely studied. It has previously been shown that knockout of lysine 63 deubiquitinase CYLD significantly inhibits necroptosis in other cell lines, and serum response factor (SRF) could regulate CYLD gene expression through p38 mitogen-activated protein kinase (p38 MAPK). In the following study, we show oxygen-glucose deprivation (OGD) combined with a caspase inhibitor, ZVAD (OGD/ZVAD), induced CYLD protein expression in a time-dependent manner. Immunofluorescence studies showed that CYLD was localized strongly to the nucleus and weakly to the cytoplasm of neurons. The expression of CYLD in the cytoplasm, but not in the nucleus, was increased significantly upon OGD treatment. SB203580 (a p38 MAPK inhibitor) protected against neuronal injury induced by OGD/ZVAD treatment. More importantly, SB203580 decreased CYLD protein levels by inhibiting SRF phosphorylation and indirectly prevented SRF from binding to a CYLD promoter. We also found that cells with knockdown of SRF by short interfering RNA in a lentivirus vector tolerated OGD/ZVAD-induced necroptosis, when the expression of CYLD protein decreased. The results show that SB203580 prevented necroptosis induced by OGD/ZVAD injury by blocking a p38/CYLD dependent pathway.

EGb-761 Attenuates the Anti-proliferative Activity of Fluoride via DDK1 in PC-12 Cells.

EGb-761 is commonly used as a treatment for ischemic brain injury, neurodegenerative diseases and some types of tumors (Christen and Maixent, in Cell Mol Biol 48(6):601-611, 2002). However, it is unclear whether EGb-761 affects the proliferation of cells exposed to fluoride. In this study, the proliferation and apoptosis of PC-12 cells exposed to fluoride were investigated and EGb-761 was used to protect PC-12 cells against the effects of fluoride. We found that the canonical Wnt signaling pathway was involved in the anti-proliferation of PC-12 cells exposed to fluoride. Furthermore, the results also showed that EGb-761 could attenuate the anti-proliferative activity of fluoride via DDK1 in PC-12 cells. This study may provide a new method for protecting against the inhibition of cell proliferation induced by fluoride.

Neuroprotective Effects of Paeoniflorin on 6-OHDA-Lesioned Rat Model of Parkinson's Disease.

Paeoniflorin (PF) is the main active component extracted from the roots of Paeonialactiflora, a traditional Chinese medicine used for the treatment of neurodegenerative disorders, especially Parkinson's disease (PD). The degeneration of dopaminergic (DA-) neurons in PD may be caused by pathological activation of acid-sensing ion channels (ASICs). Thus, we designed a series of experiments to evaluate the therapeutic effects of PF and to test whether its effects are related to its inhibitory effect on ASIC1a. We found that systemic administration of PF or ASICs blockers (psalmotoxin-1 and amiloride) improved behavioral symptoms, delayed DA-neuronal loss and attenuated the reduction of dopamine (DA) and its metabolites in a rat model of 6-hydroxydopamine (6-OHDA)-induced PD. In addition, our data showed that PF, like ASICs blockers, regulated the expression of ASIC1a, decreased the level of α-synuclein (α-SYN), and improved autophagic dysfunction. Further experiments showed that ASIC1a knockdown down-regulated the α-SYN level and alleviated the autophagic injury in the 6-OHDA-treated ASIC1a-silenced PC12 cells. In summary, these findings indicate that PF enhanced the autophagic degradation of α-SYN and, thus, protected DA-neurons against the neurotoxicity caused by 6-OHDA. These findings also provide experimental evidence that PF may be a neuroprotectant for PD by acting on ASIC1a and that ASIC1a may be involved in the pathogenesis of PD.

Tardive intermittent massive vaginal bleeding from abnormal blood vessels within cesarean scar: Two more new cases should bring our attention to a new entity.

The two cases in this report had intermittent massive vaginal bleeding with a distant history of cesarean delivery. Such severe bleeding was life-threating but was eventually cured by surgical management. To the best of our knowledge, this is the second report of cases of tardive vaginal bleeding caused by abnormal blood vessels embedded within cesarean scars. The two new cases in this report suggest a novel cause of tardive vaginal bleeding, which should bring our special attention to post-cesarean clinical practice.

[eIF3a gene polymorphism and chemo-sensitivity to platinum-based drugs in ovarian cancer].

OBJECTIVE: To investigate the relationship between the eukaryotic initiation factor 3a (eIF3a)polymorphisms and chemo-sensitivity to platinum-based drug in ovarian cancer.
 METHODS: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis was performed to detect 57 cases of eIF3a polymorphic genotypes (rs3824830, rs77382849, rs10787899 and rs3740556) after platinum-based chemotherapy drugs up to 6 cycles in primary ovarian cancer. The association between these gene sites was analyzed.
 RESULTS: There were 3 genotypes for eIF3a rs3824830, named AA, GA and GG. The frequency distribution for them was 43.86%, 36.84% and 15.79% (2 cases did not detect the genotype, 3.51%), respectively. There were 2 genotypes for eIF3a rs77382849, named CC and TC. The frequency distribution for them was 85.96% and 12.28%(1 case did not detect the genotype, 1.76%), respectively. There were 3 genotypes for eIF3a rs10787899, named GG, GA and AA, respectively. The frequency distribution for them was 26.32%, 47.36% and 26.32%, respectively. There were significant difference in different genotypes between age group and FIGO stage (P<0.05). The genotype of eIF3a rs10787899 GA was easier to resist platinum drug compared with the GG genotype and the odds ratio could be increased by 2.676 (95%CI: 0.544-13.159). The genotype of eIF3a rs10787899 AA was easier to resist platinum drug compared with the GG genotype and the odds ratio could be increased by 5.419(95%CI: 0.964-30.471). Rebalanced by age and FIGO stage, there was no significant difference (P>0.05) among these genotype groups. In all blood samples, there was only one genotype for eIF3a rs3740556, named GG.
 CONCLUSION: There is no mutation genotype in eIF3a rs3740556 loci. Polymorphism in the eIF3a rs3824830, rs77382849 and rs10787899 doesn't affect the response of ovarian cancer to platinum-based chemotherapy.