The neutrophil extracellular traps in neurological diseases: An update.

Neutrophil extracellular traps released by neutrophils are web-like DNA structures adhered to granulin proteins with bactericidal activity and can be an important mechanism for preventing pathogen dissemination or eliminating microorganisms. However, they also play important roles in diseases of other systems, such as the central nervous system. We tracked the latest advances and performed a review based on published original and review articles related to neutrophil extracellular traps and neurological diseases. Generally, neutrophils barely penetrate the blood-brain barrier into the brain parenchyma, but when pathological changes such as infection, trauma, or neurodegeneration occur, neutrophils rapidly infiltrate the central nervous system to exert their defensive effects. However, neutrophils may adversely affect the host when they uncontrollably release neutrophil extracellular traps upon persistent neuroinflammation. This review focused on recent advances in understanding the mechanisms and effects of neutrophil extracellular traps release in neurological diseases, and we also discuss the role of molecules that regulate neutrophil extracellular traps release in anticipation of clinical applications in neurological diseases.

Community identified characteristics related to illegal dumping; a mixed methods study to inform prevention.

Illegal dumping is a public health burden for communities suffering from historical disinvestment. We conducted a mixed methods study to answer: 1) What are stakeholder perspectives on social/environmental determinants of illegal dumping? and 2) Do these or other characteristics predict known locations of illegal dumping? We employed an exploratory sequential design in which we collected and analyzed in-depth interviews (n=12) with service providers and residents and subsequently collected and analyzed data from multiple secondary sources. Stakeholders endorsed nine determinants of illegal dumping: Economic Decline, Scale of Vacancy, Lack of Monitoring, Poor Visibility, Physical Disorder, Illegal Activity, Norms, Accessibility, and Seclusion. Results demonstrate important community-identified, modifiable, social, and environmental characteristics related to illegal dumping with the potential to inform effective prevention.

Subcutaneous etonogestrel implant combined with endometrial ablation for the treatment of adenomyosis: two case reports.

Adenomyosis is a common disease that affects many premenopausal women. Two patients with adenomyosis, aged 51 and 42 years, presented with dysmenorrhea and increased menstrual volume. They refused laparoscopy or laparotomy surgery and were not eligible for the levonorgestrel-releasing intrauterine system (LNG-IUS). The first patient underwent endometrial ablation and subcutaneous etonogestrel (ENG)-releasing implant placement at the same time. Her symptoms of dysmenorrhea and heavy menstruation improved significantly. When serum follicle-stimulating hormone (FSH) and estradiol (E2) levels suggested menopause, the ENG-releasing implant was removed. However, her abdominal pain recurred and was relieved by medication. For the second patient, an ENG-releasing implant was placed first, and her dysmenorrhea and heavy menstrual volume were relieved. However, the bleeding pattern changed from regular bleeding to prolonged bleeding, which troubled the patient. Endometrial ablation was performed 4 months later to solve the problem. Both patients had improved symptoms and were satisfied with the treatment. For patients with adenomyosis who refuse surgery and are not candidates for the use of LNG-IUS, an ENG-releasing implant combined with endometrial ablation may be an effective alternative.

Platelet-rich fibrin accelerates skin wound healing in pressure injuries: a rat model.

OBJECTIVE: Platelet-rich fibrin (PRF) plays a role in promoting wound healing by releasing cytokines, chemokines and growth factors, and by inducing proliferation and activation of cells. A pressure injury (PI) is a treatable but serious and costly disease with adverse outcomes for the patient. However, traditional PI treatments are time-consuming, with limited effectiveness. Thus, we aimed to investigate the effects and mechanisms of PRF on skin wound healing in PIs in vivo in a rat model. METHOD: PRF was prepared from the blood of male Wistar rats. A rat model for PI ischaemia/reperfusion injury was established by placing a magnet onto the back skin, where a magnetic steel plate had been previously implanted. The rats were randomised into two groups: the control group was treated with sterile gauze dressings and the iPRF group received additional PRF. Skin wound healing rate was calculated and a CD31/Masson's trichrome stain performed. RESULTS: In this study, 16 rats were allocated to the two groups (n=8 in each group). PRF improved the skin wound healing rate of PIs in the rats; haematoxylin and eosin staining and CD31 staining showed that the number of capillaries increased significantly in the wound. However, Masson's trichrome staining showed no increase in fibrotic tissues after PRF treatment. CONCLUSION: In this in vivo rat model for PI, PRF accelerated skin wound healing by increasing angiogenesis in the wound.

Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model.

Background: Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods: To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results: Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-ß and NMDAR2-α subtypes as well as their downstream signaling proteins ß-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of ß-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-ß association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions: These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.

Anion-Coordination-Assisted Assembly of Supramolecular Charge-Transfer Complexes Based on Tris(urea) Ligands.

Charge-transfer (CT) complexes, formed by noncovalent bonding between electron-rich (donor, D) and electron-deficient (acceptor, A) molecules (or moieties) have attracted considerable attention due to their fascinating structures and potential applications. Herein, we demonstrate that anion coordination is a promising strategy to promote CT complex formation between anion-binding, electron-rich tris(urea) donor ligands (D) and electron-deficient viologen cation acceptors (A), which form co-crystals featuring infinite ⋅⋅⋅DADA⋅⋅⋅ or discrete (circular DADA or three-decker DAD) π-stacking interactions. These CT complexes were studied by X-ray diffraction, UV/Vis spectroscopy, electric conductivity measurements, charge displacement curve (CDC) calculations, and DFT computations.

Quercetin alleviates neonatal hypoxic-ischemic brain injury by inhibiting microglia-derived oxidative stress and TLR4-mediated inflammation.

OBJECTIVE AND DESIGN: Microglia stimulated by oxygen glucose deprivation (OGD) were treated with quercetin to investigate the effect on oxidative stress and the inflammatory response and to explore whether toll-like receptor 4 (TLR4) signaling was involved. In addition, the effect of quercetin on the neurological functions of neonatal mice with hypoxic-ischemic brain injury (HIBI) was examined. MATERIALS AND SUBJECTS: Mouse BV2 microglial cells and postnatal day 7 neonatal mice were used. TREATMENT: A predetermined concentration of quercetin was used in cell experiments. Quercetin was injected i.p. (50 mg/kg) at three time points after HI insult: 0, 24, and 48 h. METHODS: Cell viability assay, Western blotting, qRT-RCR, ELISA, HIBI model construction and behavioral tests. RESULTS: This study first showed that quercetin protected BV2 cells from OGD-induced damage and reversed the changes in microglial oxidative stress-related molecules. Second, quercetin inhibited OGD-induced expression of inflammatory factors in BV2 cells and suppressed TLR4/MyD88/NF-κB signaling. Finally, quercetin was disclosed to be effective in mitigating cerebral infarct volume and cognitive and motor function deficits in HIBI mice. CONCLUSION: These results suggest that the neuroprotective effect of quercetin in HIBI mice is partially due to the inhibition of oxidative stress and TLR4-mediated inflammatory responses in activated microglia.

Overexpression of Mesothelin in Pancreatic Ductal Adenocarcinoma (PDAC).

Purpose: Pancreatic ductal adenocarcinoma (PDAC) with difficulty in early diagnosis does not respond well to conventional treatments and has not occurred significant improvement in the overall 5-year survival rates. Mesothelin (MSLN) is a tumor differentiation antigen expressed in several solid neoplasms and a limited number of healthy tissues. Its selective expression on malignant cells makes it an interesting candidate for investigation as a diagnostic and prognostic biomarker and as a therapeutic target. In this study, we detected the expression of MSLN in PDAC and analyzed the correlation between the expression of MSLN and clinicopathological data, so as to provide more theoretical basis for the role of MSLN in the diagnosis and treatment of PDAC. Patients and methods: Cancer and para-cancer tissues of 24 cases with PDAC were assessed by standardized immunohistochemical (IHC) detection with two kinds of anti-MSLN antibodies (EPR4509 and EPR19025-42) to detect their positive expression rates and study the correlation between the expression of MSLN and the clinicopathological data. Results: The two anti-MSLN antibodies of cancer tissues showed positive expression with tan yellow or tan brown granules diffusely distributed on the cell membrane in 22 of 24 cases with PDAC (positive rate of 91.67%), and the positive expression of the two antibodies EPR4509 and EPR19025-42 was completely consistent in all tissue samples. No expression of the two anti-MSLN antibodies was found in para-cancer tissues and the difference was statistically significant (χ2=40.615, p=0.000, p<0.05) when compared with PDAC tissues. There was no significant correlation between MSLN expression and clinicopathological data, such as gender, tumor size, location, pathological stage, differentiation degree and lymph node metastasis (p>0.05). Conclusion: MSLN was highly expressed in PDAC tissues, but not in paracancerous tissues. There was no significant correlation between MSLN expression and clinicopathological factors. The overexpression of MSLN may have promising prospects in diagnosis, targeted therapy and immunotherapy of PDAC.

Hypoxia-inducible factor-prolyl hydroxylase inhibitor ameliorates myopathy in a mouse model of chronic kidney disease.

Muscle wasting and diminished physical performance contribute to the morbidity and mortality of chronic kidney disease (CKD), for which no curative therapy exists. Accumulating evidence indicates that impaired angiogenesis occurs in the muscles of CKD models. Therefore, proangiogenesis therapy is considered a potentially effective strategy for limiting CKD-associated myopathy. Hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF and enhances muscle angiogenesis during acute ischemia; however, little evidence was available from CKD models. Here, we assessed whether pharmacological activation of HIF by MK-8617 (MK), a novel orally active HIF-PHI, improves CKD-associated myopathy. Mice were divided into sham or CKD groups, and CKD mice were subdivided into CKD + vehicle or MK treatment groups (1.5, 5, or 12.5 mg/kg for 12 wk). In CKD mice, skeletal muscle mass, mitochondrial amount, and exercise capacity decreased compared with sham mice. Compared with the CKD + vehicle group, low (1.5 mg/kg) and medium (5 mg/kg) doses of MK, but not the high dose (12.5 mg/kg), significantly restored these changes and was accompanied by incremental increases in HIF-1α. Furthermore, increased capillary density and area were observed in a MK dose-dependent manner, which is likely related to an improved VEGF response in the skeletal muscle of CKD mice. In addition, macrophage and proinflammatory cytokines, including monocyte chemoattractant protein 1, TNF-α, and IL-6, significantly increased in the high-dose MK group. These results indicate that HIF-PHI provides a potential therapeutic strategy to improve CKD-associated myopathy.

Chronic Unexpected Mild Stress Destroys Synaptic Plasticity of Neurons through a Glutamate Transporter, GLT-1, of Astrocytes in the Ischemic Stroke Rat.

Background and Objective: Chronic unexpected mild stress (CUMS) destroys synaptic plasticity of hippocampal regenerated neurons that may be involved in the occurrence of poststroke depression. Astrocytes uptake glutamate at the synapse and provide metabolic support for neighboring neurons. Currently, we aim to investigate whether CUMS inhibits synaptic formation of regenerated neurons through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. Method: We exposed the ischemic stroke rats to ceftriaxone, during the CUMS intervention period to determine the effects of GLT-1 on glutamate circulation by immunofluorescence and mass spectrometry and its influences to synaptic plasticity by western blot and transmission electron microscopy. Result: CUMS evidently reduced the level of astroglial GLT-1 in the hippocampus of the ischemic rats (p < 0.05), resulting in smaller amount of glutamate being transported into astrocytes surrounding synapses (p < 0.05), and then expression of synaptophysin was suppressed (p < 0.05) in hippocampal dentate gyrus. The ultrastructures of synapses in dentate gyrus were adversely influenced including decreased proportion of smile synapses, shortened thickness of postsynaptic density, reduced number of vesicles, and widened average distance of the synaptic cleft (all p < 0.05). Moreover, ceftriaxone can promote glutamate circulation and synaptic plasticity (all p < 0.05) by raising astroglial GLT-1 (p < 0.05) and then improve depressive behaviors of the CUMS-induced model rats (p < 0.05). Conclusion: Our study shows that CUMS destroys synaptic plasticity of regenerated neurons in the hippocampus through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. This may indicate one potential pathogenesis of poststroke depression.

Scale-up cultivation enhanced arachidonic acid accumulation by red microalgae Porphyridium purpureum.

The present study attempts to cultivate Porphyridium purpureum under different scale-up conditions for further development and commercialization of microalgae-derived PUFAs such as ARA and EPA. Different temperatures (25, 30, and 35 °C) and light intensities (70, 165, and 280 µmol/m2s) were applied to the 50 L pilot-scale cultivation of P. purpureum in ASW. The cultivation under the light intensity of 280 µmol/m2s at 35 °C obtained biomass concentration up to 9.52 g/L, total fatty acid content to 56.82 mg/g, and ARA content to 22.29 mg/g. While the maximum EPA content of 7.00 mg/g was achieved under the light intensity of 280 µmol/m2s at 25 °C and the highest ratio of UFAs to TFAs of 74.66% was also obtained in this trial. Both biomass concentration and TFAs content were improved by increasing light intensity and temperature. Moreover, the ratio of ARA to EPA was enhanced by increasing cultivation temperature under the light intensity of 280 µmol/m2s. In contrast with flask culture, the conversion of linoleic acid (C18:2) to ARA was enhanced in scale-up culture, leading to more ARA content. Phosphate limitation enhanced the synthesis of lipid and LPUFAs. Moreover, the biomass concentration and biosynthesis of palmitic acid were preferred by sufficient C (NaHCO3).

Is topiramate effective for migraine prevention in patients less than 18 years of age? A meta-analysis of randomized controlled trials.

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

[Research on the Pre-Processing Methods of Wheat Hardness Prediction Model Based on Visible-Near Infrared Spectroscopy].

Grain hardness is an important quality parameter of wheat which has great influence on the classification, usage and composition research of wheat. To achieve rapid and accurate detection of wheat hardness, radial basis function (RBF) neural network model was built to predict the hardness of unknown samples on the basis of analyzing the absorptive characteristics of the composition of wheat grain in infrared, besides, the effects of different spectral pretreatment methods on the predictive accuracy of models were emphatically analyzed. 111 wheat samples were collected from major wheat-producing areas in China; then, spectral data were obtained by scanning samples. Mahalanobis distance method was used to identify and eliminated abnormal spectra. The optimized method of sample set partitioning based on joint X-Y distance (SPXY) was used to divide sample set with the number of calibration set samples being 84 and prediction set samples being 24. Successive projections algorithm (SPA) was employed to extract 47 spectral features from 262. SPA, first derivatives, second derivatives, standard normal variety (SNV) and their combinations were applied to preprocess spectral data, and the interplay of different prediction methods was analyzed to find the optimal prediction combination. Radial basis function (RBF) was built with preprocessed spectral data of calibration set being as inputs and the corresponding hardness data determined via hardness index (HI) method being as outputs. Results showed that the model got the best prediction accuracy when using the combination of SNV and SPA to preprocess spectral data, with the discriminant coefficient (R2), standard error of prediction (SEP) and ratio of performance to standard deviate (RPD) being 0.844, 3.983 and 2.529, respectively, which indicated that the RBF neural network model built based on visible-near infrared spectroscopy (Vis-NIR) could accurately predict wheat hardness, having the advantages of easy, fast and nondestructive compared with the traditional method. It provides a more convenient and practical method for estimating wheat hardness.

Alternative splicing as a biomarker and potential target for drug discovery.

Alternative splicing is a key process of multi-exonic gene expression during pre-mRNA maturation. In this process, particular exons of a gene will be included within or excluded from the final matured mRNA, and the resulting transcripts generate diverse protein isoforms. Recent evidence demonstrates that approximately 95% of human genes with multiple exons undergo alternative splicing during pre-mRNA maturation. Thus, alternative splicing plays a critical role in physiological processes and cell development programs, and.dysregulation of alternative splicing is highly associated with human diseases, such as cancer, diabetes and neurodegenerative diseases. In this review, we discuss the regulation of alternative splicing, examine the relationship between alternative splicing and human diseases, and describe several approaches that modify alternative splicing, which could aid in human disease diagnosis and therapy.

Salvia Miltiorrhiza Bge.f.alba Ameliorates the Progression of Monocrotaline-Induced Pulmonary Hypertension by Protecting Endothelial Injury in Rats.

Pulmonary hypertension (PH) is a life-threatening disease that is characterized by elevated pulmonary blood pressure, abnormally thickened pulmonary arteries, and right ventricular hypertrophy. Monocrotaline (MCT) has been used to generate an experimental model of PH in rats, with PH initiated from injuries of lung vascular endothelium. Salvia Miltiorrhiza Bge.f.alba is a widely used traditional herb in China, known to exert protective effects on vascular endothelial cell injury in animal experiments. However, the role of Salvia Miltiorrhiza Bge.f.alba in PH remains unclear. Thus, we investigated the effects of the aqueous extract of Salvia Miltiorrhiza Bge.f.alba (AESM) on MCT-induced PH and explored the pertinent mechanism. PH was induced in rats by a single subcutaneous injection of MCT (60 mg/kg body weight). Low or high dose (4.6 g/kg or 14 g/kg body weight) of AESM was then administered orally for 21 days to PH rats. Hemodynamic study showed that AESM reduced mean pulmonary artery pressure and improved right ventricle function. Lung pathological analysis revealed that AESM reduced wall thickness and lumen stenosis of pulmonary vessels. Also AESM ameliorated right ventricular hypertrophy. Measurement of biochemical parameters indicated that AESM decreased endothelin-1 and thromboxane A2 in plasma and increased nitrogen monoxide and prostacyclin in the plasma and reduced the increase of transforming growth factor ß1 in lung tissue. Our results suggest that AESM may ameliorate the progression of MCT-induced PH in rats, at least in part by its protective effect on endothelial injury. Therefore, Salvia Miltiorrhiza Bge.f.alba could be useful in the treatment of PH.

Effect of single and combined median nerve stimulation and repetitive transcranial magnetic stimulation in patients with prolonged disorders of consciousness: a prospective, randomized, single-blinded, controlled trial.

Objective: To investigate the efficacy of median nerve stimulation (MNS) combined with repetitive transcranial magnetic stimulation (rTMS), MNS alone, and rTMS alone in elevating the level of consciousness in patients with prolonged disorders of consciousness (pDOC). Participants and methods: We enrolled 75 eligible inpatients suffering from pDOC as a result of traumatic or non-traumatic brain injury. Participants were randomly assigned to one of the following three treatment groups: (1) rTMS+sham-MNS; (2) MNS + sham-rTMS; or (3) MNS + rTMS. The rTMS protocol involved stimulation above the left dorsolateral prefrontal cortex at a 10 Hz frequency and 90% resting motor threshold. The MNS protocol involved the delivery of a 15-20 mA current at the median nerve point 2 cm from the wrist crease of the right distal forearm. The primary outcome was the change from baseline of the Coma Recovery Scale-Revised (CRS-R) score after treatment. Secondary outcomes included post-treatment changes from baseline of the Glasgow Coma Scale (GCS) score, awaken ratio, electroencephalography (EEG) scores, and the latency and amplitude of N20 on somatosensory evoked potentials. Results: Before the intervention, there were no significant differences between groups in the CRS-R, GCS scores, age, duration of pDOC, clinical diagnosis, EEG scores, latency and amplitude of N20, sex, job, marital status, education level, or disease etiology. Within the three groups, the total CRS-R, GCS scores and amplitude of N20 on both side significantly increased and latency of N20 on poor side significantly decreased post-intervention. Significantly greater improvement in CRS-R, GCS total scores, amplitude of N20 on both side and latency of N20 on the poor side were observed in the MNS + TMS group compared to those of the groups receiving rTMS alone or MNS alone. The patients receiving TMS and MNS intervention showed a greater EEG activity improvement, and the EEG activity improved ratio significantly differ between groups, while there were no significant differences in the awakening ratios between the three groups. Conclusion: The combination of MNS + rTMS was more efficacious in improving the level of consciousness than MNS alone or rTMS alone in patients with pDOC.

Model for predicting prognosis and immunotherapy based on CD+8 T cells infiltration in neuroblastoma.

BACKGROUND: Neuroblastoma (NBL) is an extracranial malignant tumor in children deriving from the neural crest in the sympathetic nervous system. Although various immunotherapy interventions have made significant breakthroughs in many adult cancers, the efficacy of these immunotherapies was still limited in NBL. NBL has low immunogenicity which results in a lack of tumor-infiltrating T lymphocytes in the tumor microenvironment (TME). Moreover, tumor cells can wield many immune evasion strategies both in the TME and systemically to impede lymphocyte infiltration and activation. All these factors hamper the anti-tumor effects of CD8+ T cells during immunotherapy and the levels of infiltrating CD8+ T cells correlate with therapy response. MATERIALS AND METHODS: In this study, we utilized multidimensional bioinformatic methods to establish a risk model based on CD8+ T cells -related genes (CD8+ TRGs). RESULTS: We obtained 33 CD8+ TRGs with well-predictive ability for prognosis in both GSE49711 and E-MTAB-8248 cohorts. Then, 12 CD8+ TRGs including HK2, RP2, HPSE, ELL2, GFI1, SLC22A16, FCGR3A, CTSS, SH2D1A, RBP5, ATF5, and ADAM9 were finally identified for risk model construction and validation. This model revealed a stable performance in prognostic prediction of the overall survival (OS) and event-free survival (EFS) in patients with NBL. Additionally, our research indicated that the immune and stromal scores, immune-related pathways, immune cell infiltration, the expression of major histocompatibility complex (MHC) and immune checkpoint molecules, immunotherapy response, and drug susceptibility revealed significant differences between high and low-risk groups. CONCLUSIONS: According to our analyses, the constructed CD8+ TRGs-based risk model may be promising for the clinical prediction of anti-tumor therapy responses and prognoses in NBL.

RCC2 promotes prostate cancer cell proliferation and migration through Hh/GLI1 signaling pathway and cancer stem-like cells.

BACKGROUND: Regulator of chromosome condensation 2 (RCC2) was a telophase disk-binding protein on mitosis, and functions as an oncogene in many human cancers. However, its role on prostate cancer (PCa) was unknown. The goal of this study is to explore the function of RCC 2 on PCa development. METHODS: The expression of RCC2 and its methylation level, its correlation with lymph node metastasis or disease-free survival (DFS) was analyzed using TCGA database. The effect of RCC2 on PCa cell proliferation, migration and invasion were detected using CCK-8, cell colony formation, Transwell and wood healing assays. RNA-seq and GSEA analysis were used to search the downstream genes and pathways of RCC2 in mediated PCa progression. Western blot was used to detect the proteins in PCa cells transfected with indicated siRNAs or plasmids. RESULTS: RCC2 had high expression and low promoter methylation level in PCa, and its expression was correlated with regional node metastasis and disease-free survival. Cell proliferation, migration, invasion and EMT of PCa cells in vitro were greatly enhanced after RCC2 overexpression, while the RCC2 knockdown suppressed these processes. RNA-seq and GSEA results showed the Hedgehog signaling regulator Gli1 and Gli3 were involved in RCC2 knockdown DU145 cells. Gli1 was also a marker of cancer stem-like cells (CSCs). Mechanistically, RCC2 induced cell growth, EMT, CSCs markers through Gli1; inhibiting Gli1 expression using siGli1 or GLI inhibitor suppressed cell progression in vitro and tumor growth in vivo. CONCLUSION: In summary, RCC2 promoted PCa development through Hh/Gli1 signaling pathway via regulating EMT and CSCs.

PI(4,5)P2-dependent regulation of endothelial tip cell specification contributes to angiogenesis.

Dynamic positioning of endothelial tip and stalk cells, via the interplay between VEGFR2 and NOTCH signaling, is essential for angiogenesis. VEGFR2 activates PI3K, which phosphorylates PI(4,5)P2 to PI(3,4,5)P3, activating AKT; however, PI3K/AKT does not direct tip cell specification. We report that PI(4,5)P2 hydrolysis by the phosphoinositide-5-phosphatase, INPP5K, contributes to angiogenesis. INPP5K ablation disrupted tip cell specification and impaired embryonic angiogenesis associated with enhanced DLL4/NOTCH signaling. INPP5K degraded a pool of PI(4,5)P2 generated by PIP5K1C phosphorylation of PI(4)P in endothelial cells. INPP5K ablation increased PI(4,5)P2, thereby releasing ß-catenin from the plasma membrane, and concurrently increased PI(3,4,5)P3-dependent AKT activation, conditions that licensed DLL4/NOTCH transcription. Suppression of PI(4,5)P2 in INPP5K-siRNA cells by PIP5K1C-siRNA, restored ß-catenin membrane localization and normalized AKT signaling. Pharmacological NOTCH or AKT inhibition in vivo or genetic ß-catenin attenuation rescued angiogenesis defects in INPP5K-null mice. Therefore, PI(4,5)P2 is critical for ß-catenin/DLL4/NOTCH signaling, which governs tip cell specification during angiogenesis.

Resveratrol Improves Synaptic Plasticity in Hypoxic-Ischemic Brain Injury in Neonatal Mice via Alleviating SIRT1/NF-κB Signaling-Mediated Neuroinflammation.

Neonatal hypoxic-ischemic encephalopathy (HIE) is an obstinate disease that troubles neonatologists. At present, cognitive impairment after HIE has received increasing attention. Synaptic plasticity determines the development of cognitive function, so it is urgent to develop new drugs that can improve HIE-induced cognitive impairment. Hypoxia-ischemia (HI)-induced neuroinflammation affects synaptic plasticity. As a SIRT1 agonist, resveratrol has a powerful anti-inflammatory effect, but whether it has an effect on impaired synaptic plasticity in HIE and the potential mechanism remain unclear. In the present study, resveratrol was used to intervene in hypoxic-ischemic brain injury (HIBI) mice, and the effects on hippocampal synaptic plasticity and further mechanisms were explored through performing neurobehavioral, morphological observations, Golgi sliver staining, western blotting, and quantitative real-time polymerase chain reaction experiments. We first found that resveratrol improves HI-induced long-term cognitive and memory deficits, and then we found that resveratrol reduces hippocampal neuronal damage and increases dendritic spine density and the expression of synaptic proteins. Finally, we found that this effect may be exerted by regulating the neuroinflammatory response mediated by the SIRT1/NF-κB axis. This study provides a new theoretical basis for resveratrol to prevent long-term neurological dysfunction following HIBI.