Renal dysfunction in AQP4 NMOSD and MS; a potential predictor of relapse and prognosis.

OBJECTIVE: This study aimed to explore the association between kidney function and the risk of relapse as well as prognosis in patients with aquaporin-4 (AQP4)-immunoglobulin G (IgG)-seropositive neuromyelitis optica spectrum disorder (NMOSD). METHODS: We focused on patients experiencing their first onset of AQP4-IgG-seropositive NMOSD. Data on demographics, disease characteristics, and kidney function were collected, with the primary assessment utilizing the estimated glomerular filtration rate (eGFR). Associations between eGFR and relapse risk were examined using multivariate Cox proportional hazards regression models. Additionally, logistic regression models were employed to evaluate the impact of eGFR on clinical prognosis. RESULTS: Our analysis revealed glomerular hyperfiltration and impaired urine concentrating ability in patients with AQP4-IgG-seropositive NMOSD. Multivariate Cox proportional hazards regression demonstrated a positive correlation between eGFR and the risk of relapse. Logistic regression analysis further identified higher eGFR as an independent predictor of disease relapse and prognosis in AQP4-IgG-seropositive NMOSD patients. CONCLUSIONS: The eGFR of patients with AQP4-IgG-seropositive NMOSD emerges as a potential diagnostic biomarker for this condition, indicating its significance in predicting both relapse risk and clinical prognosis.

Associations between sarcopenia and circulating branched-chain amino acids: a cross-sectional study over 100,000 participants.

BACKGROUND: Emerging evidence suggests that alterations in BCAA metabolism may contribute to the pathogenesis of sarcopenia. However, the relationship between branched-chain amino acids (BCAAs) and sarcopenia is incompletely understood, and existing literature presents conflicting results. In this study, we conducted a community-based study involving > 100,000 United Kingdom adults to comprehensively explore the association between BCAAs and sarcopenia, and assess the potential role of muscle mass in mediating the relationship between BCAAs and muscle strength. METHODS: Multivariable linear regression analysis examined the relationship between circulating BCAAs and muscle mass/strength. Logistic regression analysis assessed the impact of circulating BCAAs and quartiles of BCAAs on sarcopenia risk. Subgroup analyses explored the variations in associations across age, and gender. Mediation analysis investigated the potential mediating effect of muscle mass on the BCAA-muscle strength relationship. RESULTS: Among 108,017 participants (mean age: 56.40 ± 8.09 years; 46.23% men), positive associations were observed between total BCAA, isoleucine, leucine, valine, and muscle mass (beta, 0.56-2.53; p < 0.05) and between total BCAA, leucine, valine, and muscle strength (beta, 0.91-3.44; p < 0.05). Logistic regression analysis revealed that increased circulating valine was associated with a 47% reduced sarcopenia risk (odds ratio = 0.53; 95% confidence interval = 0.3-0.94; p = 0.029). Subgroup analyses demonstrated strong associations between circulating BCAAs and muscle mass/strength in men and individuals aged ≥ 60 years. Mediation analysis suggested that muscle mass completely mediated the relationship between total BCAA, and valine levels and muscle strength, partially mediated the relationship between leucine levels and muscle strength, obscuring the true effect of isoleucine on muscle strength. CONCLUSION: This study suggested the potential benefits of BCAAs in preserving muscle mass/strength and highlighted muscle mass might be mediator of BCAA-muscle strength association. Our findings contribute new evidence for the clinical prevention and treatment of sarcopenia and related conditions involving muscle mass/strength loss.

Mutations in ARHGEF15 cause autosomal dominant hereditary cerebral small vessel disease and osteoporotic fracture.

Cerebral small vessel disease (CSVD) is a prominent cause of ischemic and hemorrhagic stroke and a leading cause of vascular dementia, affecting small penetrating vessels of the brain. Despite current advances in genetic susceptibility studies, challenges remain in defining the causative genes and the underlying pathophysiological mechanisms. Here, we reported that the ARHGEF15 gene was a causal gene linked to autosomal dominant inherited CSVD. We identified one heterozygous nonsynonymous mutation of the ARHGEF15 gene that cosegregated completely in two families with CSVD, and a heterozygous nonsynonymous mutation and a stop-gain mutation in two individuals with sporadic CSVD, respectively. Intriguingly, clinical imaging and pathological findings displayed severe osteoporosis and even osteoporotic fractures in all the ARHGEF15 mutation carriers. In vitro experiments indicated that ARHGEF15 mutations resulted in RhoA/ROCK2 inactivation-induced F-actin cytoskeleton disorganization in vascular smooth muscle cells and endothelial cells and osteoblast dysfunction by inhibiting the Wnt/ß-catenin signaling pathway in osteoblast cells. Furthermore, Arhgef15-e(V368M)1 transgenic mice developed CSVD-like pathological and behavioral phenotypes, accompanied by severe osteoporosis. Taken together, our findings provide strong evidence that loss-of-function mutations of the ARHGEF15 gene cause CSVD accompanied by osteoporotic fracture.

circCELF1 Induces the Apoptosis and Autophagy of Astrocytes in Ischemic Stroke via Upregulating NFAT5.

INTRODUCTION: Ischemic stroke, an abrupt blockage of artery, accounting for the most cases of stroke, causes high neurological mortality across the world. Recent evidence has uncovered that circular RNAs (circRNAs) highly engage in ischemic stroke-related neuronal injury. This study concentrated on a novel circRNA hsa_circ_0000304 (termed as circCELF1), trying to unveil its role and underlying mechanism in ischemic stroke. METHODS: RT-qPCR and Western blot assays were conducted to detect the expression levels of RNA and protein, respectively. Functional analysis was performed to evaluate the influences of circCELF1 expression on astrocyte apoptosis and autophagy. Multiple mechanism assays were performed to probe the molecular mechanism underlying circCELF1 regulation. The oxygen-glucose deprivation/reoxygenation (OGD/R)-induced astrocytes model and transient middle cerebral artery occlusion (tMCAO) mouse model were constructed. RESULTS: circCELF1 was found to be upregulated in OGD/R-induced astrocytes, relative to normal astrocytes. circCELF1 knockdown repressed the apoptosis and autophagy of astrocytes. The in vivo study conducted with the tMCAO model also revealed that circCELF1 or NFAT5 deficiency contributed to the suppression of neural injury. Further, circCELF1 was uncovered to elevate NFAT5 expression via recruiting DDX54, functionally promoting astrocyte apoptosis and autophagy. CONCLUSION: circCELF1 recruits DDX54 to upregulate NFAT5, by which astrocyte apoptosis and autophagy are stimulated.

MRI-visible enlarged perivascular spaces: imaging marker to predict cognitive impairment in older chronic insomnia patients.

OBJECTIVE: Perivascular spaces (PVS), components of the glymphatic system in the brain, have been known to be important conduits for clearing metabolic waste, and this process mainly increases during sleep. Sleep disruption might result in PVS dysfunction and cognitive impairment. In this study, we aim to explore whether MRI-visible enlarged perivascular spaces (EPVS) could be imaging markers to predict cognitive impairment in chronic insomnia patients. METHOD: We obtained data from 156 patients with chronic insomnia and 79 age-matched healthy individuals. Using T2-weighted MRI images, visible EPVS in various brain regions were measured and analyzed. The associations between EPVS numbers and cerebrospinal fluid (CSF) ß-amyloid 42 (Aß42), total tau (t-tau), and phosphorylated tau (p-tau) level in chronic insomnia patients were evaluated. RESULT: Our results showed that MRI-visible EPVS in the frontal cortex, centrum semiovale, basal ganglia, and hippocampus of chronic insomnia patients with impaired cognition (ICG) significantly increased than that in normal cognition (NCG) patients. The increased MRI-visible EPVS in the frontal cortex, centrum semiovale, and basal ganglia were also associated with the increased CSF Aß42, t-tau, and p-tau level in ICG patients. MRI-visible EPVS in the basal ganglia and centrum semiovale had high sensitivity and specificity in distinguishing ICG chronic insomnia patients from those with NCG. CONCLUSION: Our study indicated that MRI-visible EPVS in the basal ganglia and centrum semiovale might be valuable imaging markers to predict cognitive impairment in chronic insomnia patients. It will be meaningful to discern those cognitive decline patients in preclinical stage and take some measures to prevent disease progression. KEY POINTS: • Increased MRI-visible EPVS were associated with the increased CSF Aß42, t-tau, and p-tau level in older chronic insomnia patients with impaired cognition.

Phloretin enhances autophagy by impairing AKT activation and inducing JNK-Beclin-1 pathway activation.

Phloretin is a type of dihydrochalcone that is primarily found in apples and has been reported to possess various potent biological activities, such as anticancer, antioxidant and anti-inflammatory effects. Our previous study has shown that phloretin induces apoptosis in human glioblastoma. In this study, we found that phloretin induced autophagy in SH-SY5Y cells by decreasing p-AKT and p-mTOR levels in the AKT/mTOR pathway and increasing the activation of JNK, the phosphorylation of c-Jun and the expression of Beclin-1. Moreover, the upregulation of Beclin-1 was decreased by SP600125 or a siRNA against c-Jun. Furthermore, SP600125 and siRNAs against c-Jun and Beclin-1 inhibited phloretin-induced autophagy. In addition, inhibition of phloretin-induced autophagy by cotreatment with phloretin and 3-MA decreased phloretin-induced cytotoxicity to SH-SY5Y cells. In conclusion, our results suggest that the AKT/mTOR pathway and JNK-mediated Beclin-1 expression are involved in phloretin-induced autophagy. Phloretin can be used to protect neurons during phloretin treatment of glioblastoma.

Autophagy-lysosome dysfunction is involved in gastric ischemia-reperfusion injury by promoting microglial activation in the paraventricular nucleus.

The hypothalamic paraventricular nucleus (PVN) is a specific center in the brain that regulates gastric mucosal injury following gastric ischemia-reperfusion (GI-R) injury. This study aimed to investigate whether autophagy-lysosome dysfunction in the PVN tissues of GI-R rats is involved in the gastric injury, and the underlying molecular mechanisms. The rat model of GI-R was established by clamping the celiac artery for 30 min and reperfusion for different hours (1, 3, and 6 h). The gastric injury was evaluated by hematoxylin and eosin staining of the stomach and the gastric mucosal index. The autophagy-lysosome dysfunction in the PVN was evaluated by the protein levels of LC3 II and Beclin-1 (markers for autophagosome activity) and the activity of acid phosphatase (a representative lysosomal enzyme). Immunohistochemical staining of ionized calcium-binding adaptor molecule 1 in the PVN was performed to evaluate microglial activation. Reactive oxygen species (ROS) content and phosphorylated γ-aminobutyric acid B receptor (p-GABAB R) expression in the PVN were also examined. The results revealed that, in GI-R rats, the shorter the reperfusion duration, the more severe the gastric mucosal damage. The autophagy-lysosome dysfunction exhibited by GI-R rats further enhanced microglial activation, ROS production, p-GABAB R expression, and gastric injury. In addition, activating microglial cells increased ROS production, p-GABAB R expression, and gastric injury in GI-R rats, while inhibiting microglial activation resulted in the opposite results. Taken together, autophagy-lysosome dysfunction induced by GI-R aggravated the gastric injury by inducing microglia activation.

An ischemia-homing bioengineered nano-scavenger for specifically alleviating multiple pathogeneses in ischemic stroke.

BACKGROUND: Ischemic stroke is one of the most serious global public health problems. However, the performance of current therapeutic regimens is limited due to their poor target specificity, narrow therapeutic time window, and compromised therapeutic effect. To overcome these barriers, we designed an ischemia-homing bioengineered nano-scavenger by camouflaging a catalase (CAT)-loaded self-assembled tannic acid (TA) nanoparticle with a M2-type microglia membrane (TPC@M2 NPs) for ischemic stroke treatment. RESULTS: The TPC@M2 NPs can on-demand release TA molecules to chelate excessive Fe2+, while acid-responsively liberating CAT to synergistically scavenge multiple ROS (·OH, ·O2-, and H2O2). Besides, the M2 microglia membrane not only can be served as bioinspired therapeutic agents to repolarize M1 microglia into M2 phenotype but also endows the nano-scavenger with ischemia-homing and BBB-crossing capabilities. CONCLUSIONS: The nano-scavenger for specific clearance of multiple pathogenic elements to alleviate inflammation and protect neurons holds great promise for combating ischemic stroke and other inflammation-related diseases.

Association of neutrophil-to-lymphocyte ratio (NLR) with the prognosis of first attack neuromyelitis optica spectrum disorder (NMOSD): a retrospective cohort study.

BACKGROUND: To investigate the relationship between the neutrophil-to-lymphocyte ratio (NLR) and prognosis after the first attack of optic neuromyelitis optica spectrum disorder (NMOSD). METHODS: In this retrospective study, we included the medical records of 324 patients with first episode NMOSD and collected data on clinical parameters. Follow-up extended disability status scale (EDSS) score and relapse rate were analyzed using logistic regression models to determine the independent effect of NLR on outcomes; receiver operating characteristic (ROC) curves were applied to analyze the predictive value of NLR for the prognosis of NMOSD. Interaction and stratification analyses were used to explore the association between NLR and prognosis of patients with NMOSD, and Kaplan-Meier analysis was used to investigate the relationship between NLR and outcome. The association between NLR level with relapse rate and poor recovery was assessed by a Cox regression analysis. RESULTS: Patients in the high-NLR group had significantly higher EDSS scores and relapse rates at follow-up (both, P < 0.001) than did those in the low-NLR group. Univariate analysis showed revealed that NLR was significantly associated with relapse (odds ratio [OR] = 1.28, 95% confidence interval [CI]: 1.16-1.41, P < 0.001) and poor recovery (OR = 1.32, 95% CI: 1.20-1.46, P < 0.001), and these associations remained significant, even after multifactorial analysis (OR = 1.33, 95% CI: 1.11-1.59, P = 0.002; OR = 1.23, 95% CI: 1.06-1.43, P = 0.007, respectively). Stratified analysis showed that sex, platelet-to-lymphocyte ratio (PLR) level, and lymphocyte-to-monocyte technical ratio (LMR) level were strongly associated with relapse owing to elevated NLR; Kaplan-Meier survival curve analysis showed that the median time to relapse was significantly lower in the high-NLR group than in the low-NLR group (P < 0.001). A multivariate analysis showed a significant relationship between NLR level with relapse (HR = 1.07, 95%CI: 1.03-1.10, P = 0.001) and poor recovery (HR = 1.08, 95%CI: 1.04-1.11, P = 0.001). CONCLUSIONS: NLR may be used as a prognostic indicator for first onset NMOSD, and a high NLR may be significantly associated with high relapse rates and poor recovery.

MicroRNA-130a regulates neurological deficit and angiogenesis in rats with ischaemic stroke by targeting XIAP.

MicroRNAs (miRNAs) have already been proposed to be implicated in the development of ischaemic stroke. We aim to investigate the role of miR-130a in the neurological deficit and angiogenesis in rats with ischaemic stroke by regulating X-linked inhibitor of apoptosis protein (XIAP). Middle cerebral artery occlusion (MCAO) models were established by suture-occluded method, and MCAO rats were then treated with miR-130a mimics/inhibitors or/and altered XIAP for detection of changes of rats' neurological function, nerve damage and angiogenesis in MCAO rats. The oxygen-glucose deprivation (OGD) cellular models were established and respectively treated to determine the roles of miR-130a and XIAP in neuronal viability and apoptosis. The expression levels of miR-130a and XIAP in brain tissues of MCAO rats and OGD-treated neurons were detected. The binding site between miR-130a and XIAP was verified by luciferase activity assay. MiR-130a was overexpressed while XIAP was down-regulated in MCAO rats and OGD-treated neurons. In animal models, suppressed miR-130a improved neurological function, alleviated nerve damage and increased new vessels in brain tissues of rats with MCAO. In cellular models, miR-130a inhibition promoted neuronal viability and suppressed apoptosis. Inhibited XIAP reversed the effect of inhibited miR-130a in both MCAO rats and OGD-treated neurons. XIAP was identified as a target of miR-130a. Our study reveals that miR-130a regulates neurological deficit and angiogenesis in rats with MCAO by targeting XIAP.

Long noncoding MIAT acting as a ceRNA to sponge microRNA-204-5p to participate in cerebral microvascular endothelial cell injury after cerebral ischemia through regulating HMGB1.

This study is applied to the investigation of the long noncoding RNA myocardial infarction associated transcript's (MIAT's) role in regulating the expression of high-mobility group box 1 (HMGB1) in cerebral microvascular endothelial cell (CMEC) injury after cerebral ischemia by serving as a competitive endogenous RNA (ceRNA) to sponge microRNA-204-5p (miR-204-5p). The cerebral ischemia model of middle cerebral artery occlusion (MCAO) in rats was established by the suture method, in which rats were injected with empty plasmids and MIAT siRNA plasmids. The cerebral ischemia injury model in vitro was established through oxygen glucose deprivation (OGD) in primary cultured CMECs in rats. The cells were transfected with empty plasmids and MIAT siRNA plasmids. The MIAT/miR-204-5p/HMGB1 axis' function in damage and angiogenesis of CMECs were explored. The binding site between MIAT and miR-204-5p along with that between miR-204-5p and HMGB1 was determined. MIAT was overexpressed in MCAO rats' brain tissue and inhibited MIAT attenuated the injury of brain tissue in MCAO rats. Inhibition of MIAT promoted angiogenesis, promoted miR-204-5p expression and inhibited HMGB1 expression in brain tissue of MCAO rats. Inhibition of MIAT reduced CMEC damage, induced angiogenesis of CMECs, increased the number of surviving neurons, promoted miR-204-5p expression and inhibited HMGB1 expression in CMECs treated with OGD. MIAT promoted HMGB1 expression by competitive binding to miR-204-5p to regulate the injury of CMECs after cerebral ischemia. Our study showed that MIAT promoted HMGB1 expression by competitively binding to miR-204-5p to regulate the injury of CMECs after cerebral ischemia.

Long-read sequencing identified intronic repeat expansions in SAMD12 from Chinese pedigrees affected with familial cortical myoclonic tremor with epilepsy.

BACKGROUND: The locus for familial cortical myoclonic tremor with epilepsy (FCMTE) has long been mapped to 8q24 in linkage studies, but the causative mutations remain unclear. Recently, expansions of intronic TTTCA and TTTTA repeat motifs within SAMD12 were found to be involved in the pathogenesis of FCMTE in Japanese pedigrees. We aim to identify the causative mutations of FCMTE in Chinese pedigrees. METHODS: We performed genetic linkage analysis by microsatellite markers in a five-generation Chinese pedigree with 55 members. We also used array-comparative genomic hybridisation (CGH) and next-generation sequencing (NGS) technologies (whole-exome sequencing, capture region deep sequencing and whole-genome sequencing) to identify the causative mutations in the disease locus. Recently, we used low-coverage (~10×) long-read genome sequencing (LRS) on the PacBio Sequel and Oxford Nanopore platforms to identify the causative mutations, and used repeat-primed PCR for validation of the repeat expansions. RESULTS: Linkage analysis mapped the disease locus to 8q23.3-24.23. Array-CGH and NGS failed to identify causative mutations in this locus. LRS identified the intronic TTTCA and TTTTA repeat expansions in SAMD12 as the causative mutations, thus corroborating the recently published results in Japanese pedigrees. CONCLUSIONS: We identified the pentanucleotide repeat expansion in SAMD12 as the causative mutation in Chinese FCMTE pedigrees. Our study also suggested that LRS is an effective tool for molecular diagnosis of genetic disorders, especially for neurological diseases that cannot be positively diagnosed by conventional clinical microarray and NGS technologies.

The effect of early growth response 1 on levels of Amyloid-ß 40 peptide in U87MG cells.

A recent study has shown that early growth response 1 (EGR1) plays a critical role in the ß-amyloid cascade and tau hypotheses. In addition, evidence has suggested that EGR1 can regulate levels of amyloid-beta peptides, key molecules in the pathogenesis of Alzheimer's disease (AD). However, whether EGR1 is a deleterious or protective factor in the AD is still controversial. In this present study, we constructed an overexpression plasmid, CMV-EGFP-EGR1-Kanamycin, and transfected it into U87MG cells to investigate the effects of EGR1 expression on amyloid-ß (1-40) peptide (Aß40) levels. U87MG cells transfected by CMV-EGFP-EGR1-Kanamycin and CMV-EGFP-Kanamycin were assigned, respectively, to experimental and control groups. Fluorescence microscopy was used to observe transfection efficiencies of the plasmids after 6 hours. EGR1 messenger RNA levels were measured by quantitative reverse transcription polymerase chain reaction. Aß40 secretion was analyzed by enzyme-linked immunosorbent assay. Expression of the amyloid precursor protein, beta-secretase enzyme, and presenilin 1 proteins were analyzed by Western blot analysis. The results showed that EGR1 overexpression increased Aß40 secretion in vitro, possibly through increasing BACE1 expression. Based on these results, EGR1 might be a promising therapeutic target for the AD.

Role of XIAP gene overexpressed bone marrow mesenchymal stem cells in the treatment of cerebral injury in rats with cerebral palsy.

BACKGROUND: This study is performed to investigate the effects of adenovirus-mediated X-linked inhibitor of apoptosis protein (XIAP) overexpressed bone marrow mesenchymal stem cells (BMSCs) on brain injury in rats with cerebral palsy (CP). METHODS: Rat's BMSCs were cultured and identified. The XIAP gene of BMSCs was modified by adenovirus expression vector Ad-XIAP-GFP. The rat model of CP with ischemia and anoxia was established by ligating the left common carotid artery and anoxia for 2 h, and BMSCs were intracerebroventricularly injected to the modeled rats. The mRNA and protein expression of XIAP in brain tissue of rats in each group was detected by RT-qPCR and western blot analysis. The neurobehavioral situation, content of acetylcholine (Ach), activity of acetylcholinesterase (AchE), brain pathological injury, apoptosis of brain nerve cells and the activation of astrocytes in CP rats were determined via a series of assays. RESULTS: Rats with CP exhibited obvious abnormalities, increased Ach content, decreased AchE activity, obvious pathological damage, increased brain nerve cell apoptosis, as well as elevated activation of astrocyte. XIAP overexpressed BMSCs improved the neurobehavioral situation, decreased Ach content and increased AchE activity, attenuated brain pathological injury, inhibited apoptosis of brain nerve cells and the activation of astrocytes in CP rats. CONCLUSION: Our study demonstrates that XIAP overexpressed BMSCs can inhibit the apoptosis of brain nerve cells and the activation of astrocytes, increase AchE activity, and inhibit Ach content, so as to lower the CP caused by cerebral ischemia and hypoxia in rats.

Inhibition of Calcium/Calmodulin-Dependent Protein Kinase IIα Suppresses Oxidative Stress in Cerebral Ischemic Rats Through Targeting Glucose 6-Phosphate Dehydrogenase.

Ischemic stroke is a leading cause of mortality and morbidity worldwide, and oxidative stress plays a significant role in the ischemia stage and reperfusion stage. Previous studies have indicated that both calcium/calmodulin-dependent protein kinase II (CaMKII) and glucose 6-phosphate dehydrogenase (G6PD) are involved in the oxidative stress. Thus, the aim of this study was to investigate the roles of CaMKIIα, an important isoform of CaMKII, and G6PD in a rat model of middle cerebral artery occlusion (MCAO). Intracerebroventricular injection of small interfering ribonucleic acid (siRNA) for CaMKIIα was performed at 48 h pre-MCAO surgery. Immunofluorescence Staining and western blot were performed to detect the expression of p-CaMKIIα and G6PD in the cortices. 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining was performed to investigate the infarct volume. In addition, neurological deficit, reactive oxygen species (ROS), ratio of reduced-to-oxidized glutathione (GSH/GSSG) and ratio of reduced-to-oxidized oxidized nicotinamide adenine dinucleotide phosphate (NADPH/NADP+) were assessed. The results indicated that both p-CaMKIIα and G6PD were widely located in the neurons and astrocytes, and their expression was gradually increased in the cortices after MCAO, which was accompanied by increased level of ROS and decreased levels of GSH/GSSG and NADPH/NADP+. However, after treatment with siRNA for CaMKIIα, p-CaMKIIα expression was decreased and G6PD expression was increased. Moreover, inhibition of CaMKIIα improved the neurological deficit, reduced the infarct volume, decreased the level of ROS and increased the levels of GSH/GSSG and NADPH/NADP+. The results suggested that CaMKIIα inhibition exerted neuroprotective effects through regulating G6PD expression, which provides a new target for prevention and treatment of stroke.

Free thyroxine level is associated with both relapse rate and poor neurofunction in first-attack Neuromyelitis Optica Spectrum Disorder (NMOSD) patients.

BACKGROUND: To investigate whether the serum free thyroxine (FT4) level is a prognostic factor for the first-attack neuromyelitis optica spectrum disorders (NMOSD). METHODS: This retrospective study enrolled 109 patients with first-attack NMOSD. The Expanded Disability Status Scale (EDSS) and the relapse rate were used to evaluate the outcomes. The logistic regression model was used to analyze the independent effects of FT4 on relapse and final EDSS. Kaplan-Meier analysis, scatter plot smoothing method, and two-phase piecewise linear regression model were used to investigate the relationship between the FT4 level and the relapse rate. RESULTS: Multivariate analysis revealed that serum FT4 level might be a risk factor for both final EDSS (ß = 0.17; 95% confidence interval: 0.03-0.32) and the relapse rate (HR = 1.18; 95% confidence interval: 1.05-1.32). Furthermore, 1400 days after the onset, nearly 100% of patients in the high-FT4 group relapsed, while only 40% of the patients in the low-FT4 group relapsed. Finally, we found that the relationship between the FT4 level and the NMOSD relapse rate was nonlinear. The risk of NMOSD relapse increased with the FT4 level up to the inflection point of 12.01 pmol/L (HR = 1.45; 95% confidence interval: 1.06-1.98). When the FT4 level was > 12.01 pmol/L, there was no correlation between the FT4 level and the risk of NMOSD relapse (HR = 1.05; 95% confidence interval: 0.78-1.41). CONCLUSION: Serum FT4 level may be a prognostic indicator for the first-attack in patients with NMOSD. High FT4 levels are associated with poor neurofunctions and a high relapse rate in patients with the first-attack in patients with NMOSD.

MicroRNA-182 inhibits HCMV replication through activation of type I IFN response by targeting FOXO3 in neural cells.

Human cytomegalovirus (HCMV) has led to kinds of clinical disorders and great morbidity worldwide, such as sensorineural hearing loss (SNHL), mental retardation, and developmental delays in immunocompromised individuals. Congenital HCMV infection is a leading cause of birth defects, primarily manifesting as neurological disorders. Previous studies reported that HCMV has evolved a variety of mechanisms to evade the immune system, such as dysregulation of miRNAs. However, reports concerning the role of miRNA in HCMV infection in neural cells are limited. Here, we reported that a host microRNA, miR-182, was significantly up-regulated by HCMV infection in U-251MG and NPCs cells. Subsequently, our results of in vitro and in vivo experiments demonstrated that miR-182 was a positive regulator of interferon regulatory factor 7 (IRF7) by directly targeting FOXO3, resulting in the induction of IFN-I response and suppression of HCMV replication in neural cells. Taken together, our findings provide detailed molecular mechanisms of the antiviral function of miR-182 against HCMV infection in neural cells, and suggest an intrinsic anti-HCMV therapeutic target.

Pretreatment of glial cell-derived neurotrophic factor and geranylgeranylacetone ameliorates brain injury in Parkinson's disease by its anti-apoptotic and anti-oxidative property.

The aim of the present study was to determine the combined effects of glial cell-derived neurotrophic factor (GDNF) and geranylgeranylacetone (GGA) on neuron apoptosis and oxidative stress in Parkinson's disease (PD). A mouse MPTP model of PD and cellular models of H2 O2 and MPP+ -treated PC12 cells were established. Swimming, pole, and traction tests were used to detect behavioral impairment. Tyrosine hydroxylase (TH) immunohistochemistry was used to evaluate the neuron loss. TUNEL and flow cytometer method were used to identify the neuron apoptosis. MDA levels and activities of antioxidant enzymes were used to detect the oxidative damage. The PD model of mice received GDNF and GGA exhibited a significant recovery in their swim, pole, and traction scores. Moreover, the combined treatment significantly reduced the neuron apoptosis in the substantia nigra (SN) of PD mice or in H2 O2 or MPP+ -induced PC12 cells compared with the single drug group. In addition, significant reduction of MDA levels and improvement of activities of CAT, SOD, and GSH-px were observed after GDNF and GGA treatment in the PD model and H2 O2 or MPP+ -induced PC12 cells. The combination of GDNF and GGA ameliorated neural apoptosis and oxidative damage in PD.

Ultrasound-triggered effects of the microbubbles coupled to GDNF- and Nurr1-loaded PEGylated liposomes in a rat model of Parkinson's disease.

The purpose of this study was to investigate ultrasound-triggered effects of the glial cell line-derived neurotrophic factor (GDNF) + nuclear receptor-related factor 1 (Nurr1)-polyethylene glycol (PEG)ylated liposomes-coupled microbubbles (PLs-GDNF + Nurr1-MBs) on behavioral impairment and neuron loss in a rat model of Parkinson's disease (PD). The unloaded PEGylated liposomes-coupled microbubbles (PLs-MBs) were characterized for zeta potential, particle size, and concentration. 6-hydroxydopamine (6-OHDA) was used to establish the PD rat model. Rotational, climbing pole, and suspension tests were used to detect behavioral impairment. The immunohistochemical staining of tyrosine hydroxylase (TH) and dopamine transporter (DAT) was used to assess the neuron loss. Western blot and quantitative real-time PCR (qRT-PCR) analysis were used to measure the expression levels of GDNF and Nurr1. The particle size of PLs-MBs was gradually increased, while the concentration and absolute zeta potential were gradually decreased as the time prolongs. 6-OHDA increased amphetamine-induced rotations and loss of dopaminergic neurons as compared to sham group. Interestingly, PLs-GDNF-MBs or PLs-Nurr1-MBs decreased rotations and increased the TH and DAT immunoreactivity. Combined of both genes resulted in a robust reduction in the rotations and a greater increase of the dopaminergic neurons. The delivery of PLs-GDNF + Nurr1-MBs into the brains using magnetic resonance imaging (MRI)-guided focused ultrasound may be more efficacious for the treatment of PD than the single treatment.

Ginsenoside Rb1 Protects the Brain from Damage Induced by Epileptic Seizure via Nrf2/ARE Signaling.

BACKGROUND/AIMS: Ginsenoside Rb1 (Rb1) has been reported to have varieties of neuroprotective effects. This study aimed to evaluate the effects of Rb1 on pentylenetetrazol (PTZ)-induced rat brain injury and Mg2+ free-induced neuron injury and analyzed the detailed molecular mechanisms in vivo and in vitro. METHODS: Seizure duration and latency were measured in epilepsy kindled rat. The cognitive impairment was assessed by Morris water maze (MWM) test. Oxidative stress parameters, malondialdehyde (MDA) and glutathione (GSH) were measured by the 2-thiobarbituric acid methods and the DTNB-GSSG reductase recycling methods. Neuronal damage was assessed by hematoxylin and eosin (H&E) and Nissl staining. Neuronal apoptosis was measured by Annexin V-FITC and propidium iodide (PI) staining. Immunohistochemistry and immunofluorescence staining were performed to evaluate Nrf2 and HO-1 expressions. Expression of Nrf2, HO-1, Bcl-2, iNOS and LC3 were evaluated by western blot. RESULTS: The PTZ-injured rats presented longer seizure duration and shorter seizure latency. Rb1 ameliorated these effects, as well as the cognitive deficits caused by PTZ exposure. Besides, Rb1 dose-dependently increased GSH levels, decreased MDA levels and alleviated neuronal damage in PTZ-treated rats. In vitro, Rb1 increased cell viability and decreased neuronal apoptosis in a dose-dependent manner under Mg2+ free condition. Moreover, in vivo and in vitro, Rb1 enhanced both the Nrf2 and HO-1 expressions. Furthermore, upregulation of the expression of Bcl-2 and downregulation of the expression of iNOS and LC3 were observed. However, knockdown of Nrf2 adversely affected the protective effects of Rb1 in epileptic hippocampal neurons. CONCLUSION: Rb1 conferred neuroprotective effects against PTZ-induced brain damage and Mg2+ free-induced neuron injury by activating Nrf2/ARE signaling.