HnRNPK is involved in stress-induced depression-like behavior via ERK-BDNF pathway in mice.

As a ubiquitous RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) interacts with numerous nucleic acids and proteins and is involved in various cellular functions. Available literature indicates that it can regulate dendritic spine density through the extracellular signal-regulating kinase (ERK) - brain-derived neurotrophic factor (BDNF) pathway, which is crucial to retain the synaptic plasticity in patients with major depressive disorder (MDD) and mouse depression models. However, ERK upstream regulatory kinase has not been fully elucidated. Furthermore, it remains unexplored whether hnRNPK may impact the depressive condition via the ERK pathway. The present study addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing. We found that hnRNPK in the brain was mainly distributed in the hippocampal neurons; that it was significantly downregulated in mice that displayed stress-induced depression-like behaviors; and that the level of hnRNPK markedly decreased in MDD patients from the GEO database. Further in vivo and in vitro analyses revealed that the changes in the expressions of BDNF and PSD95 and in the phosphorylation of ERK (Thr202/Tyr204) paralleled the variation of hnRNPK levels in the ventral hippocampal neurons in mice with depression-like behaviors. Finally, esketamine treatment significantly increased the level of hnRNPK in mice. These findings evidence that hnRNPK involved in the pathogenesis of depression via the ERK-BDNF pathway, pinpointing hnRNPK as a potential therapeutic target in treating MDD patients.

Ginsenoside Rb1 selectively inhibits the activity of L-type voltage-gated calcium channels in cultured rat hippocampal neurons.

AIM: To investigate the effect of ginsenoside Rb1 on voltage-gated calcium currents in cultured rat hippocampal neurons and the modulatory mechanism. METHODS: Cultured hippocampal neurons were prepared from Sprague Dawley rat embryos. Whole-cell configuration of the patch-clamp technique was used to record the voltage-gated calcium currents (VGCCs) from the hippocampal neurons,and the effect of Rb1 was examined. RESULTS: Rb1 (2-100 µmol/L) inhibited VGCCs in a concentration-dependent manner, and the current was mostly recovered upon wash-out. The specific L-type Ca(2+) channel inhibitor nifedipine (10 µmol/L) occluded Rb1-induced inhibition on VGCCs. Neither the selective N-type Ca(2+) channel blocker ω-conotoxin-GVIA (1 µmol/L), nor the selective P/Q-type Ca(2+) channel blocker ω-agatoxin IVA (30 nmol/L) diminished Rb1-sensitive VGCCs. Rb1 induced a leftward shift of the steady-state inactivation curve of I(Ca) to a negative potential without affecting its activation kinetics or reversal potential in the I-V curve. The inhibitory effect of Rb1 was neither abolished by the adenylyl cyclase activator forskolin (10 µmol/L), nor by the PKA inhibitor H-89 (10 µmol/L). CONCLUSION: Ginsenoside Rb1 selectively inhibits the activity of L-type voltage-gated calcium channels, without affecting the N-type or P/Q-type Ca(2+) channels in hippocampal neurons. cAMP-PKA signaling pathway is not involved in this effect.

[Analysis of CLCN1 gene mutations in 2 patients with myotonia congenita].

OBJECTIVE: To investigate chloride channel 1 (CLCN1) gene mutation and clinical features of 2 Chinese patients with myotonia congenita. METHODS: Clinical data of a patient from a family affected with myotonia congenita in addition with a sporadic patient from Fujian province were analyzed. Exons of CLCN1 gene were amplified and sequenced. RESULTS: The proband from the affected family was found to carry a c.1024G>A heterozygous missense mutation in exon 8, whilst the sporadic patient has carried a c.1292C>T heterozygous missense mutation in exon 11. CONCLUSION: Detection of CLCN1 gene mutation is an effective method for the diagnosis of myotonia congenita. Exon 8 of CLCN1 gene may be a mutational hotspot in Chinese patients with myotonia congenita.

Generation of an induced pluripotent stem cell line, FJMUUHi001-A, from a hereditary Parkinson's disease patient with homozygous mutation of c.189dupA in PARK7.

PARK7 mutations are accountable for the inherited Parkinson's disease. An induced pluripotent stem cell (iPSC) line FJMUUHi001-A was generated by expressing five reprogramming factors, OCT3/4, SOX2, c-MYC, KLF4 and BCL-XL, in peripheral blood mononuclear cells from a 32-year old patient carrying a homozygous mutation of c.189dupA in PARK7. The iPSCs with a normal karyotype had the abilities to differentiate into three germ layers and expressed pluripotency markers without detectable residual plasmids. The cell line FJMUUHi001-A carrying the truncating protein PARK7 could be a useful tool to help comprehend the function of PARK7 in the iPSCs and differentiated cells from them.

Tripchlorolide protects neuronal cells from microglia-mediated beta-amyloid neurotoxicity through inhibiting NF-kappaB and JNK signaling.

Recent research has focused on soluble oligomeric assemblies of beta-amyloid peptides (Abeta) as the proximate cause of neuroinflammation, synaptic loss, and the eventual dementia associated with Alzheimer's disease (AD). In this study, tripchlorolide (T4), an extract of Tripterygium wilfordii Hook. F (TWHF), was studied as a novel agent to suppress neuroinflammatory process in microglial cells and to protect neuronal cells against microglia-mediated oligomeric Abeta toxicity. T4 significantly attenuated oligomeric Abeta(1-42)-induced release of inflammatory productions such as tumor necrosis factor-alpha, interleukin-1beta, nitric oxide (NO), and prostaglandin E2. It also downregulated the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in microglial cells. Further molecular mechanism study demonstrated that T4 inhibited the nuclear translocation of nuclear factor-kappaB (NF-kappaB) without affecting I-kappaBalpha phosphorylation. It repressed Abeta-induced JNK phosphorylation but not ERK or p38 MAPK. The inhibition of NF-kappaB and JNK by T4 is correlated with the suppression of inflammatory mediators in Abeta-stimulated microglial cells. These results suggest that T4 protects neuronal cells by blocking inflammatory responses of microglial cells to oligomeric Abeta(1-42) and that T4 acts on the signaling of NF-kappaB and JNK, which are involved in the modulation of inflammatory response. Therefore, T4 may be an effective agent in modulating neuroinflammatory process in AD.

Sleep fragmentation as an important clinical characteristic of sleep disorders in Parkinson's disease: a preliminary study.

BACKGROUND: Sleep disorders are one of the earliest non-motor symptoms of Parkinson's disease (PD). Sleep disorders could, therefore, have value for recognition and diagnosis in PD. However, no unified classification and diagnostic criteria exist to evaluate sleep disorders by polysomnography (PSG). Utilizing PSG to monitor sleep processes of patients with PD and analyze sleep disorder characteristics and their relationship with demographic parameters could aid in bridging this gap. This preliminary study aimed to evaluate the clinical characteristic of sleep disorders in PD using PSG. METHODS: PSG was used to evaluate sleep disorders in 27 patients with PD and 20 healthy volunteers between August 2015 and July 2018 in Fujian Medical University Union Hospital. Total sleep time (TST), sleep efficiency (SE), total wake time, and other parameters were compared between the two groups. Finally, the correlation between sleep disorders and age, disease duration, Unified Parkinson's Disease Rating Scale-III scores, Hoehn-Yahr stage, and levodopa dose were analyzed. The main statistical methods included Chi-square test, two independent samples t test, Fisher exact test, and Pearson correlation. RESULTS: Sleep fragmentation in the PD group was significantly increased (74.1%) while difficulty falling asleep and early awakening were not, as compared to healthy controls. No significant differences were found in time in bed, sleep latency (SL), non-rapid eye movement (NREM) stage 1 (N1), N1%, N2, N2%, N3%, and NREM% between PD and control groups; but TST (327.96 ±â€Š105.26 min vs. 414.67 ±â€Š78.31 min, P = 0.003), SE (63.26% ±â€Š14.83% vs. 76.8% ±â€Š11.57%, P = 0.001), R N3 (20.00 [39.00] min vs. 61.50 [48.87] min, P = 0.001), NREM (262.59 ±â€Š91.20 min vs. 337.17 ±â€Š63.47 min, P = 0.003), rapid-eye-movement (REM) (32.50 [33.00] min vs. 85.25 [32.12] min, P < 0.001), REM% (9.56 ±â€Š6.01 vs. 15.50 ±â€Š4.81, P = 0.001), REM sleep latency (157.89 ±â€Š99.04 min vs. 103.47 ±â€Š71.70 min, P = 0.034) were significantly reduced in PD group. CONCLUSION: This preliminary study supported that sleep fragmentation was an important clinical characteristic of sleep disorders in PD. Whether sleep fragmentation is a potential quantifiable marker in PD needs to be further investigated in the future study.

Increased DJ-1 and α-Synuclein in Plasma Neural-Derived Exosomes as Potential Markers for Parkinson's Disease.

The diagnosis of PD might be in difficulty, especially in the early stages. Therefore, the identification of novel biomarkers is imperative for the diagnosis and monitoring disease progression in PD. DJ-1 and α-synuclein, are two proteins that are critically involved in the pathogenesis of PD, and they have been examined as disease biomarkers in studies. However, no study exists regarding DJ-1 in plasma neural-derived exosomes. In the present study, the levels of DJ-1 and α-synuclein in plasma neural-derived exosomes were studied together in order to investigate novel biomarkers for PD. DJ-1 and α-synuclein in plasma and plasma neural-derived exosomes of the patients with PD and controls were quantified by ELISAs. The data revealed that the levels of DJ-1 and α-synuclein in plasma neural-derived exosomes and the ratio of plasma neural-derived exosomal DJ-1 to total DJ-1 were significantly higher in patients with PD, compared with controls, while levels of the two proteins in plasma exhibited no difference between the patients with PD and controls. However, no relationship was identified between biomarkers and disease progression. In addition, significant positive correlations between DJ-1 and α-synuclein in plasma neural-derived exosomes were found in the patients with PD and in healthy individuals. We hypothesize that DJ-1 in plasma neural-derived exosomes may be used as a potential biomarker as α-synuclein in PD and they might participate in the mechanism of PD together.

Abnormal resting-state functional connectivity in posterior cingulate cortex of Parkinson's disease with mild cognitive impairment and dementia.

OBJECTIVE: To investigate changes in the functional connectivity (FC) pattern in the posterior cingulate cortex (PCC) of Parkinson's disease (PD) patients with mild cognitive impairment and dementia by employing resting-state functional magnetic resonance imaging (RS-fMRI). METHODS: Twenty-seven PD patients with different cognitive status and 9 healthy control subjects (control group) were enrolled for RS-fMRI. The RS-fMRI data were analyzed with DPARSF and REST software. Regions with changed functional connectivity were determined by the seed-based voxelwise method and compared between groups. Correlation between the intensity of FC and the MoCA scores of PD group was analyzed. RESULTS: Parametric maps showed statistical increases in PCC functional connectivity in PD-MCI patients and decreases in PCC connectivity in PDD patients. The latter group of patients also showed evidence for increased connectivity between prefrontal cortices and posterior cerebellum. A significant positive correlation was found between the MoCA scores and the strength of PCC connectivity in the angular gyrus and posterior cerebellum and a negative correlation between MoCA scores and PCC connectivity in all other brain regions. CONCLUSION: When patients transition from PD-NCI to PD-MCI, there appears to be an increase in functional connectivity in the PCC, suggesting an expansion of the cortical network. Another new network (a compensatory prefrontal cortical-cerebellar loop) later develops during the transition from PD-MCI to PDD.

[Effect of the oil from ganoderma lucidum spores on pathological changes in the substantia nigra and behaviors of MPTP-treated mice].

OBJECTIVE: To investigate the oil from the spores of ganoderma lucidum, a rare Chinese herb, on the behaviors and pathological changes in the substantia nigra pars compacta (SNpc) in mouse models of Parkinson's disease (PD) induced by MPTP. METHODS: C57BL mice were divided into 3 groups, and the ganoderma spores oil + MPTP group were treated with ganoderma spores oil for 8 days, together with subcutaneous injection of MPTP (30 mg/kg) starting on the third day for 6 days; MPTP group were pretreated with normal saline before subcutaneous MPTP injection, and the normal control group received pretreatment with normal saline before subcutaneous normal saline injection. The behavioral changes of the mice in different groups were observed by pole test, dopamine and its metabolic products in the striatum determined by HPLC, tyrosine hydroxylase (TH) positive cells detected by immunofluorescence method, and expression of TH protein by Western blotting. RESULTS: The mice in the ganoderma spores oil + MPTP group presented significantly less involuntary movement of the limbs in the pole test than the mice in MPTP group. The levels of dopamine and DOPAC in the striatum of ganoderma spores oil-treated mice were increased as compared with those in MPTP group. The number of surviving TH-positive neurons in SNpc of mice in ganoderma spores oil + MPTP group was significantly greater than that in MPTP group, with also significantly increased TH protein expression. CONCLUSION: Ganoderma spores oil has neuroprotective effect for preventing doparminergic neuron from impairment by MPTP.

Microglial phagocytosis induced by fibrillar ß-amyloid is attenuated by oligomeric ß-amyloid: implications for Alzheimer's disease.

BACKGROUND: Reactive microglia are associated with ß-amyloid (Aß) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear Aß deposits although they mainly exist in an "activated" state. Oligomeric Aß (oAß), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar Aß (fAß). However, the role of the different Aß forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear. RESULTS: We demonstrated that Aß(1-42) fibrils, not Aß(1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oAß(1-42) not only attenuated fAß(1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fAß(1-42). Compared with the fAß(1-42) treatment, the oAß(1-42) treatment resulted in a rapid and transient increase in interleukin 1ß (IL-1ß) level and produced higher levels of tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fAß(1-42)-induced microglia was decreased by IL-1ß, lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-κB (NF-κB) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oAß-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oAß(1-42) stimulation reduced the mRNA expression of CD36, integrin ß1 (Itgb1), and Ig receptor FcγRIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oAß(1-42) or the inflammatory and oxidative milieu (IL-1ß, LPS or t-BHP) significantly downregulated the fAß(1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 receptors in microglial cells. CONCLUSION: These results imply that Aß oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of Aß fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.

A neurofibromatosis type 1 patient with thoracic encapsulated fluid and intracranial hypotension syndrome: a case report.

INTRODUCTION: Spinal meningoceles are uncommon entities, mostly associated with neurofibromatosis type 1 (NF-1). Their intrusion into the thoracic cavity, which compresses lung tissue, is quite often mistaken as a "pleural effusion." The withdrawal of a large amount of "pleural effusion" can lead to the intracranial hypotension syndrome (IHS), herniation, or even death. CASE REPORT: A 43-year-old woman, with NF-1 and a large "pleural effusion" which compressed lung tissue, was admitted to the Thoracic Department due to the patient's shortness of breath during her physical activities. The patient complained of headache shortly after withdrawal of about 250 mL of "pleural effusion." She was diagnosed with IHS according to the typical symptoms of postural headache, low cerebrospinal fluid (CSF) pressure and magnetic resonance imaging findings of diffuse pachymeningeal gadolinium enhancement. The "pleural effusion" was examined and found to be CSF. CONCLUSION: The reported case is the first 1 in the literature in which the intrusion of the NF-1 patient's spinal meningoceles into the thoracic cavity was diagnosed as a "pleural effusion" and large CSF withdrawal led to IHS. We highlight the possibility that thoracic meningoceles can coexist with a thoracic spinal deformity and the caution that needs to be taken when cases with similar symptoms are subjected to withdrawal of fluid.

Neuroprotective role of tripchlorolide on inflammatory neurotoxicity induced by lipopolysaccharide-activated microglia.

A large body of evidence has suggested a strong association between neuroinflammation and the pathogenesis of many neurodegenerative diseases. Therefore, it is a good target for therapeutic treatment. So far, studies have proven anti-inflammatory herbal medicine and its constituents to be effective in slowing down the neurodegenerative process. The present study tested tripchlorolide, an extract of Tripterygium wilfordii Hook F (TWHF), as a novel agent to suppress inflammatory process in microglia. It showed this novel agent to be cytotoxic at a dose of 20-40 nM to primary microglia and BV-2 microglial cells but not to primary cortical neurons and Neuro-2A cells in vitro. Moreover, tripchlorolide protected primary cortical neurons and Neuro-2A cells from neuroinflammatory toxicity induced by the conditioned media from lipopolysaccharide (LPS)-stimulated microglia, which resulted in a significant decrease in their cell survival. The changes of the inflammatory mediators in this process were further investigated. In the LPS-stimulated microglia, the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), nitric oxide (NO), prostaglandin E(2) (PGE(2)), and intracellular superoxide anion (SOA) was markedly attenuated by tripchlorolide at a dose of 1.25-10 nM in a dose-dependent manner. Furthermore, the production of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was also significantly inhibited by tripchlorolide in both mRNA and protein levels. These results suggest that tripchlorolide can protect neuronal cells via a mechanism involving inhibition of inflammatory responses of microglia to pathological stimulations. Therefore, it is potentially a highly effective therapeutic agent in treating neuroninflammatory diseases.