Regulation of Toll-like receptor-mediated inflammatory response by microRNA-152-3p-mediated demethylation of MyD88 in systemic lupus erythematosus.

OBJECTIVE: microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE. METHODS: We determined the miR-152-3p expression profiles in CD4+ T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4+ T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88). RESULTS: The obtained findings revealed that miR-152-3p was highly-expressed in CD4+ T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4+ T cells and but also to restrain their cellular inflammation, which were also validated in vivo. CONCLUSION: Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4+ T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.

miR-34c inhibits PDGF-BB-induced HAVSMCs phenotypic transformation and proliferation via PDGFR-ß/SIRT1 pathway.

The purpose of this study was to explore the effect of miR-34c on PDGF-BB-induced HAVSMCs phenotypic transformation and proliferation via PDGFR-ß/SIRT1 pathway, so as to find a new method for early diagnosis and treatment of cardiovascular disease. HA-VSMCs were treated with platelet-derived growth factor-BB (PDGF-BB) at 0 h, 12 h, 24 h, 48 h or 36 h to explore the optimal time for phenotypic transformation of VSMCs. And then, PDGF-BB-induced HA-VSMCs were transfected with miR-34c mimics/mimics NC and pcDNA3.1-PDGFR-ß/pcDNA3.1-NC to observe cell biological behaviour. CCK8 was used to detect cell proliferation activity. Transwell chamber assay was used to detect cell invasion. Early apoptosis was analyzed by flow cytometry. The expression of α-SMA and Smemb was detected by immunofluorescence staining. The expressions of PDGFR-ß, IRF9, Acetyl-NF-κB/p65, Acetyl-p53 and CyclinD1 were analyzed by Western blot analysis. The expression of miR-34a, miR-34b and miR-34c was detected by RT-PCR, and the targeting relationship between miR-34c and PDGFR-ß was detected by luciferase reporting assay. The results indicated the proliferation and migration of PDGF-BB-induced HA-VSMCs significantly increased, and apoptosis significantly decreased. Besides, α-SMA decreased significantly, while Smemb increased significantly. Furthermore, expressions of PDGFR-ß, IRF9, Acetyl-NF-κB/p65, Acetyl-p53 and CyclinD1 increased significantly, and SIRT1 decreased significantly. Experimental results showed that, miR-34c mimics significantly inhibited cell proliferation and migration, and promoted cell apoptosis, and miR-34c inhibitor had the opposite effects. MiR-34c mimics significantly increased α-SMA expression and decreased Smemb expression, while the opposite effects were reflected after transfection with miR-34c inhibitor. Moreover, miR-34c mimics significantly decreased the expressions of PDGFR-ß, IRF9, Acetyl-NF-κB/p65, Acetyl-p53 and CyclinD1, and significantly increased the expression of SIRT1, while miR-34c inhibitor had the opposite effects. Luciferase assay confirmed that PDGFR-ß was a potential target of miR-34c. Subsequently, PDGF-BB-induced HA-VSMCs were co-transfected with miR-34c mimics and pcDNA3.1-PDGFR-ß. The results indicated that PDGFR-ß reversed the biological function of miR-34c mimic. The results revealed the potential application value of miR-34c as a marker molecule of phenotypic transformation, providing a potential target for improving phenotypic transformation.

The role of FOXOs and autophagy in cancer and metastasis-Implications in therapeutic development.

Autophagy is a highly conserved intracellular degradation process that plays a crucial role in cell survival and stress reactions as well as in cancer development and metastasis. Autophagy process involves several steps including sequestration, fusion of autophagosomes with lysosomes and degradation. Forkhead box O (FOXO) transcription factors regulate the expression of genes involved in cellular metabolic activity and signaling pathways of cancer growth and metastasis. Recent evidence suggests that FOXO proteins are also involved in autophagy regulation. The relationship among FOXOs, autophagy, and cancer has been drawing attention of many who work in the field. This study summarizes the role of FOXO proteins and autophagy in cancer growth and metastasis and analyzes their potential roles in cancer disease management.

Pristimerin-induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway.

Uveal melanoma (UM) is a highly invasive intraocular malignancy with high mortality. Presently, there is no FDA-approved standard for the treatment of metastatic UM. Pristimerin is a natural quinine methide triterpenoid compound with anti-angiogenic, anti-cancer and anti-inflammatory activities. However, Pristimerin potential cytotoxic effect on UM was poorly investigated. In the present study, we found the migration and invasion of UM-1 cells were inhibited by Pristimerin which also caused a rapid increase of ROS, decreased mitochondrial membrane potential, induced the accumulation of cells in G0/G1 phase, ending with apoptotic cell death. Pristimerin inhibited Akt and FoxO3a phosphorylation and induced nuclear accumulation of FoxO3a in UM-1 cells, increased the expression of pro-apoptotic proteins Bim、p27Kip1 , cleaved caspase-3, PARP and Bax, and decreased the expression of Cyclin D1 and Bcl-2. LY294002 or Akt-siRNA inhibited the PI3K/Akt/FoxO3a pathway and promoted the Pristimerin-induced apoptosis, while Pristimerin effects were partially abolished in FoxO3a knockdown UM-1 cell cultures. Taken together, present results showed that Pristimerin induced apoptotic cell death through inhibition of PI3K/Akt/FoxO3a pathway in UM-1 cells. These findings indicate that Pristimerin may be considered as a potential chemotherapeutic agent for patients with UM.

Monensin inhibits glioblastoma angiogenesis via targeting multiple growth factor receptor signaling.

Glioblastoma is characterized by the extensive vascularization with poor prognosis. Targeting both tumor cell and angiogenesis may present an effective therapeutic strategy for glioblastoma. Monensin, a polyether ionophore antibiotic, has been recently recognized as promising anticancer drug candidate due to its potent and selective anti-tumor activities. However, little is known on the effects of monensin on tumor angiogenesis. In this work, we investigated the effects and underlying mechanisms of monensin on glioblastoma angiogenesis and growth. We show that monensin at nanomolar concentrations inhibits early stages of capillary network formation of glioblastoma endothelial cell. Monensin inhibited multiple endothelial cellular events, including migration, growth and survival, without affecting adhesion to Matrigel. We further demonstrate that monensin acts on endothelial cells via suppressing VEGFR- and EGFR-mediated signaling pathways. Monensin also inhibits proliferation and induces apoptosis in a panel of glioblastoma cells. However, monensin is more effective in targeting endothelial cells than tumor cells. Using glioblastoma growth xenograft mice model, we show that monensin at tolerable dose effectively inhibits glioblastoma growth. Of note, there is a significant decreased tumor vascularization from monensin-treated mice. Our work clearly demonstrates the anti-angiogenic activity of monensin and its ability in suppressing multiple tyrosine kinase receptor-mediated pathways. Our findings suggest that is a useful addition to the treatment armamentarium for glioblastoma.

Metformin protects PC12 cells and hippocampal neurons from H2 O 2 -induced oxidative damage through activation of AMPK pathway.

Metformin, a first line anti type 2 diabetes drug, has recently been shown to extend lifespan in various species, and therefore, became the first antiaging drug in clinical trial. Oxidative stress due to excess reactive oxygen species (ROS) is considered to be an important factor in aging and related disease, such as Alzheimer's disease (AD). However, the antioxidative effects of metformin and its underlying mechanisms in neuronal cells is not known. In the present study, we showed that metformin, in clinically relevant concentrations, protected neuronal PC12 cells from H2 O2 -induced cell death. Metformin significantly ameliorated cell death due to H2 O2 insult by restoring abnormal changes in nuclear morphology, intracellular ROS, lactate dehydrogenase, and mitochondrial membrane potential induced by H2 O2 . Hoechst staining assay and flow cytometry analysis revealed that metformin significantly reduced the apoptosis in PC12 cells exposed to H2 O2 . Western blot analysis further demonstrated that metformin stimulated the phosphorylation and activation of AMP-activated protein kinase (AMPK) in PC12 cells, while application of AMPK inhibitor compound C, or knockdown of the expression of AMPK by specific small interfering RNA or short hairpin RNA blocked the protective effect of metformin. Similar results were obtained in primary cultured hippocampal neurons. Taken together, these results indicated that metformin is able to protect neuronal cells from oxidative injury, at least in part, via the activation of AMPK. As metformin is comparatively cheaper with much less side effects in clinic, our findings support its potential to be a drug for prevention and treatment of aging and aging-related diseases.

LIM and SH3 protein 1 regulates cell growth and chemosensitivity of human glioblastoma via the PI3K/AKT pathway.

BACKGROUND: LIM and SH3 protein 1 (LASP1) is upregulated in several types of human cancer and implicated in cancer progression. However, the expression and intrinsic function of LASP1 in glioblastoma (GBM) remains unclear. METHOD: Oncomine and The Cancer Genome Atlas (TCGA) database was analyzed for the expression and clinical significance of LASP1 in GBM. LASP1 mRNA and protein level were measured by qRT-PCR and western blotting. The effect of LASP1 on GBM proliferation was examined by MTT assay and colony formation assay, the effect of LASP1 on sensitivity of Temozolomide was measured by flow cytometry and subcutaneous tumor model. The association between LASP1 and PI3K/AKT signaling was assessed by western blotting. RESULTS: Oncomine GBM dataset analysis indicated LASP1 is significantly upregulated in GBM tissues compared to normal tissues. GBM dataset from The Cancer Genome Atlas (TCGA) revealed that high LASP1 expression is related to poor overall survival. LASP1 mRNA and protein in clinical specimens and tumor cell lines are frequently overexpressed. LASP1 knockdown dramatically suppressed U87 and U251 cell proliferation. Silencing LASP1 potentiated cell chemosensitivity to temozolomide in vitro, LASP1 knockdown inhibited tumor growth and enhanced the therapeutic effect of temozolomide in vivo. TCGA dataset analysis indicated LASP1 was correlated with PI3K/AKT signaling pathway, and LASP1 deletion inhibited this pathway. Combination treatment with PI3K/AKT pathway inhibitor LY294002 dramatically accelerated the suppression effect of temozolomide. CONCLUSION: LASP1 may function as an oncogene in GBM and regulate cell proliferation and chemosensitivity in a PI3K/AKT-dependent mechanism. Thus, the LASP1/PI3K/AKT axis is a promising target and therapeutic strategy for GBM treatment.

Enterprise stent-assisted coiling for wide-necked intracranial aneurysms during ultra-early (48hours) subarachnoid hemorrhage: a single-center experience in 59 consecutive patients.

BACKGROUND AND OBJECTIVE: Accumulated experience and improvement of stents dedicated to intracranial use have significantly widened the applicability of stent-assisted coiling (SAC) to ruptured wide-necked aneurysms. This retrospective study was designed to evaluate the safety and efficacy of SAC using the Enterprise stent for ruptured wide-necked intracranial aneurysms during ultra-early subarachnoid hemorrhage. METHOD: We reviewed data from 59 consecutive patients with ruptured wide-necked aneurysms who had SAC using the Enterprise stent performed within 48hours of onset. Data collected and analyzed included: patient demographics; morphologic features of the aneurysm; treatment results and follow-up results. Clinical outcomes were evaluated by modified Rankin Scale (mRS). RESULTS: In all 59 cases, SAC using the Enterprise stent was performed successfully, with no significant technical difficulties. Initial angiographic results were: complete occlusion in 38 cases; near occlusion in 17; and partial occlusion in four. Angiographic follow-up of 48 patients showed that 46 (95.8%) remained stable or improved, without regrowth, while regrowth was imaged in two patients. Medium-term clinical follow-up of 54 patients (mean, 26.9months) showed that 88.9% had a good outcome (mRS: 0 in 34; 1 in eight; and 2 in six), and 11.1% poor outcomes (mRS: 3 in four; and 4 in two). CONCLUSION: Enterprise SAC is a safe and viable option for treatment of ruptured wide-necked aneurysms within 48hours of ictus.

Impact of hypertension and smoking on the rupture of intracranial aneurysms and their joint effect.

BACKGROUND: In general population, the prevalence of intracranial aneurysm reaches as high as three percent. The goal of the study was to analyze retrospectively the independent risk factors for the rupture of intracranial aneurysms and their joint effect. METHODS: The records and angiographies of continuous 519 intracranial aneurysm patients treated at our center between February 2013 and July 2014 were retrospectively analyzed. Ruptured group and unruptured group were included in the study according to their clinical and imaging information. Univariate analysis and multivariate logistic regression analysis was used to identified independent risk factors for the rupture of intracranial aneurysms. We assessed the joint effect of independent risk factors for the rupture of intracranial aneurysms with an additional logistic regression analysis. RESULTS: The results of multivariate analysis show that hypertension (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.05-2.18) and smoking (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.06-2.33) were independent risk factors for rupture of intracranial aneurysms. The joint risk of hypertension and smoking was higher (OR, 2.28; 95% CI, 1.29-4.02) than the risks of hypertension (OR, 1.74; 95% CI, 1.11-2.72) and smoking (OR, 1.86; 95% CI, 1.05-3.29) independently. CONCLUSIONS: Hypertension and smoking increase of the rupture risk of intracranial aneurysms. And the joint risk of hypertension and smoking was higher than the risks of hypertension and smoking independently.

Onyx embolization of cavernous sinus dural arteriovenous fistulas via direct transorbital puncture under the guidance of three-dimensional reconstructed skull image (reports of six cases).

BACKGROUND: Because of complex angioarchitecture, the transarterial or venous pathway is not feasible for some cavernous sinus dural arteriovenous fistulas (CS DAVFs). We present six cases in which onyx embolization of a CS DAVFs was made possible through direct transorbital puncture. METHODS: In the present study, all patients were penetrated through one third of the medial-lateral of the inferior orbital rim under the guidance of fluoroscopy superimposed on the three-dimensional reconstructed skull image to complete embolization (onyx with or without coils). The records of patient demographics, clinical manifestation, fistula features, procedures, clinical outcome and angiographic outcome were reviewed and analyzed. RESULTS: In our series of six patients, the immediate angiographic result showed complete occlusion in all patients. The six patients experienced retrobulbarhematoma and eye swelling right after embolization, while the swelling significantly subsided after 3-5 days of conservative treatment. During the postoperative angiography and clinical follow-up (4-10 months), one of the patients had decreased visual acuity; the other five patients did not have neurological dysfunction. CONCLUSIONS: Onyx embolization via direct transorbital puncture provides a method to be considered to treat CS DAVFs when the conventional transvenous approaches are inaccessible.

[Hemodynamic analyses of large intracranial aneurysms].

OBJECTIVE: To simulate the computational hemodynamics of large intracranial aneurysms and analyze the hemodynamics of three types of large intracranial aneurysms. METHODS: A total of 32 patient-specific models of large intracranial aneurysms were constructed with the data of DSA (digital subtraction angiography). According to the location of outflow vessel, plane of main vortex and impact zone, large intracranial aneurysms were classified into type A (outflow vessel in the plane of main vortex), type B1 (outflow vessel out of plane of main vortex, impact zone at the lateral wall of aneurysm) and type B2 (outflow vessel out of plane of main vortex, impact zone at the dome of aneurysm). Blood flow was assumed to be laminar and incompressible and blood Newtonian fluid. The time-dependent pulsatile boundary condition was deployed at inlet. CFD ICEM and Fluent software packages were used to simulate the computational hemodynamics of large intracranial aneurysms. RESULTS: The distributions of hemodynamic variables during the cardiac cycle were analyzed for wall shear stress, velocity and streamlines. The velocity ratio (ratio of aneurysmal flow velocity to parent artery flow velocity) of type A, B1 and B2 was 0.186 ± 0.019, 0.706 ± 0.077 and 0.208 ± 0.041 respectively. The wall shear stress ratio (ratio of aneurysmal wall shear stress to parent artery wall shear stress) of types A, B1 and B2 was 0.081 ± 0.029, 1.019 ± 0.139 and 0.103 ± 0.031 respectively. The flow velocity and wall shear stress were the highest in type B1 group, followed by those in type B2 group and the lowest in type A group. CONCLUSION: As reflected by the location of impact zone, the location of outflow vessel and inflow-angle can influence the level of blood flow in aneurysm sac.

[Pathophysiological roles of matrix metalloproteinases and nitric oxide synthase in cerebral aneurysm].

OBJECTIVE: To explore the expressions of matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9) and inducible nitric oxide synthase (iNOS) in cerebral aneurysms, compare them with normal brain vessels tissue so as to gain a better understanding of the pathogenesis of cerebral aneurysms. METHODS: Twelve samples of cerebral aneurysms were obtained during operations and 10 cortical arteries as controls during surgery for temporal lobe epilepsy from 2009 to 2012 at Inner Mongolia People's Hospital and Beijing Tiantan Hospital. The activities of MMP-2, MMP-9 and iNOS in specimens were detected with spectrophotometry and substrate gel zymography. RESULTS: The MMP-2 and MMP-9 levels in cerebral aneurysm group were (199 598 ± 125 288) gray scale area × mg⁻¹ × L⁻¹ and (719 253 ± 376 519) gray scale area × mg⁻¹ × L⁻¹. Both in cerebral aneurysm group were significantly higher than that in control group (P < 0.05) . The TNOS and iNOS levels in cerebral aneurysm group were (23.6 ± 6.6) and (11.4 ± 2.6) U/mgprot. The difference of TNOS level was not significant between aneurysm and control groups (P > 0.05) while the levels of iNOS and iNOS/TNOS in cerebral aneurysm group were significantly higher than that in control group (P < 0.05). CONCLUSION: MMP-2, MMP-9 and iNOS are closely correlated with cerebral aneurysm.

Scientific evidence of acupuncture for post-stroke motor impairment: protocol for an overview of systematic reviews and meta-analyses.

INTRODUCTION: Several systematic reviews and meta-analyses (SRs/MAs) of clinical trials showed the efficacy of acupuncture for post-stroke motor impairment. To systematically estimate and synthesise these results, we aimed to conduct an overview of SRs/MAs to summarise the evidence and evaluate the methodological quality regarding the effectiveness and safety of acupuncture for post-stroke motor impairment. METHODS AND ANALYSIS: This is a protocol for an overview of SRs/MAs. A literature search will be conducted in PubMed, Embase, Web of Science and Cochrane Central Registry of Controlled Trials from the construction of the database to March 2024. SRs/MAs evaluating the efficacy of acupuncture in post-stroke motor impairment patients will be included. Two independent investigators will screen and evaluate related SRs/MAs back-to-back. We will extract data into a predefined form designed to summarise the key characteristics of each study. The evaluation of methodological quality of the included SRs/MAs will be assessed using AMSTAR-2, the PRISMA 2020 checklist and the GRADE grading system. ETHICS AND DISSEMINATION: Ethics approval is not required for this overview as we will only analyse published literature. The results will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42024502006.

Prediction model of malnutrition in hospitalized patients with acute stroke.

OBJECTIVE: The prognosis of stroke patients is greatly threatened by malnutrition. However, there is no model to predict the risk of malnutrition in hospitalized stroke patients. This study developed a predictive model for identifying high-risk malnutrition in stroke patients. METHODS: Stroke patients from two tertiary hospitals were selected as the objects. Binary logistic regression was used to build the model. The model's performance was evaluated using various metrics including the receiver operating characteristic curve, Hosmer-Lemeshow test, sensitivity, specificity, Youden index, clinical decision curve, and risk stratification. RESULTS: A total of 319 stroke patients were included in the study. Among them, 27% experienced malnutrition while in the hospital. The prediction model included all independent variables, including dysphagia, pneumonia, enteral nutrition, Barthel Index, upper arm circumference, and calf circumference (all p < 0.05). The AUC area in the modeling group was 0.885, while in the verification group, it was 0.797. The prediction model produces greater net clinical benefit when the risk threshold probability is between 0% and 80%, as revealed by the clinical decision curve. All p values of the Hosmer test were > 0.05. The optimal cutoff value for the model was 0.269, with a sensitivity of 0.849 and a specificity of 0.804. After risk stratification, the MRS scores and malnutrition incidences increased significantly with escalating risk levels (p < 0.05) in both modeling and validation groups. CONCLUSIONS: This study developed a prediction model for malnutrition in stroke patients. It has been proven that the model has good differentiation and calibration.

[Multiple factors related with intracranial hemorrhage of dural arteriovenous fistula: clinical analysis].

OBJECTIVE: To discuss the relevant predicative factors of dural arteriovenous fistula (dAVF) in intracranial hemorrhage. METHODS: A total of 144 consecutive patients with dAVFs were recruited for a retrospective analysis from 1996 to 2006. The relevant factors of gender, age, fistula flow rate, arterial supply, lesion and venous drainage pattern were analyzed to evaluate the outcome of intracranial hemorrhage. RESULTS: Univariate analysis showed that gender, lesion and venous drainage pattern were statistical significant for intracranial hemorrhage of DAVF (P < 0.05). However, only venous drainage pattern was significant in the predication of intracranial hemorrhage (P < 0.05). CONCLUSION: Only venous drainage pattern is significant in the predication of dural arteriovenous fistulas in intracranial hemorrhage. Both gender and lesion may be confounding factors.

Transcription factor YY1 mediates self-renewal of glioblastoma stem cells through regulation of the SENP1/METTL3/MYC axis.

Glioma is a primary brain tumor with limited treatment approaches and glioblastoma stem cells (GSCs) are manifested with the self-renewal capability and high tumorigenic capacity. This study was performed to investigate the regulatory effect of the SUMO-specific protease 1 (SENP1)/methyltransferase-like 3 (METTL3)/MYC axis on the self-renewal of GSCs mediated by transcription factor Yin Yang 1 (YY1). Following bioinformatics analysis and clinical and cellular experiments, we found that YY1 was highly expressed in GBM tissues and cells, while silencing its expression reduced the self-renewal ability of GSCs. Functionally, YY1 promoted the transcriptional expression of SENP1 by binding to the promoter region of SENP1, while the deSUMOase SENP1 facilitated the methylase activity of m6A through deSUMOylation of the methylase METTL3, thereby promoting the m6A modification of MYC mRNA via METL3 and promoting the expression of MYC. A nude mouse xenograft model of GBM was also constructed to examine the tumorigenicity of GSCs. The obtained findings demonstrated that YY1 promoted tumorigenicity of GSCs by promoting the expression of MYC in vivo. Conclusively, YY1 can transcriptionally upregulate the SUMOylase SENP1 and enhance the methylase activity of METTL3, resulting in the increased m6A modification level of MYC mRNA, thereby promoting the self-renewal of GSCs.

Apolipoprotein E Polymorphism Impacts White Matter Injury Through Microglial Phagocytosis After Experimental Subarachnoid Hemorrhage.

Apolipoprotein E (apoE, protein; APOE, gene), divided into three alleles of E2, E3 and E4 in humans, is associated with the progression of white matter lesion load. However, mechanism evidence has not been reported regarding the APOE genotype in early white matter injury (WMI) under subarachnoid hemorrhage (SAH) conditions. In the present study, we investigated the effects of APOE gene polymorphisms, by constructing microglial APOE3 and APOE4-specific overexpression, on WMI and underlying mechanisms of microglia phagocytosis in a mice model of SAH. A total of 167 male C57BL/6J mice (weight 22-26 g) were used. SAH and bleeding environment were induced by endovascular perforation in vivo and oxyHb in vitro, respectively. Multi-technology approaches, including immunohistochemistry, high throughput sequencing, gene editing for adeno-associated viruses, and several molecular biotechnologies were used to validate the effects of APOE polymorphisms on microglial phagocytosis and WMI after SAH. Our results revealed that APOE4 significantly aggravated the WMI and decreased neurobehavioral function by impairing microglial phagocytosis after SAH. Indicators negatively associated with microglial phagocytosis increased like CD16, CD86 and the ratio of CD16/CD206, while the indicators positively associated with microglial phagocytosis decreased like Arg-1 and CD206. The increased ROS and aggravating mitochondrial damage demonstrated that the damaging effects of APOE4 in SAH may be associated with microglial oxidative stress-dependent mitochondrial damage. Inhibiting mitochondrial oxidative stress by Mitoquinone (mitoQ) can enhance the phagocytic function of microglia. In conclusion, anti-oxidative stress and phagocytosis protection may serve as promising treatments in the management of SAH.

Psychological symptoms and correlates of Chinese healthcare professionals in the intensive care unit before and after the COVID-19 outbreak: A comparison of two cross-sectional studies.

BACKGROUND: The outbreak of COVID-19 disarranged lives across mainland China. No study has examined changes in psychological symptoms of healthcare professionals in the intensive care unit (ICU) before and after the outbreak of COVID-19. The aim of this study was to estimate changes in psychological symptoms of ICU healthcare professionals before and after the COVID-19 outbreak, and to analyze factors related to psychological symptoms. METHODS: Two waves' administrations were implemented between December 13 and December 14, 2018, and between April 5 and April 7, 2020, respectively. The symptom checklist-90 (SCL-90) were used to evaluate psychological symptoms. Multiple logistical regression was used to reveal the risk of psychological symptoms. RESULTS: A total of 3902 and 3908 ICU healthcare professionals took part in the first and second surveys. The mean total score of the SCL-90 was 179.27 (70.02) at wave 1 and 147.75 (58.40) at wave 2, respectively. The proportion of psychological symptoms was 55.6 % (95%CI = 54.0-57.1) at wave 1. But rates of psychological symptoms decreased to 36.6 % (95%CI = 35.1-38.2) at wave 2. ICU healthcare professionals with western economic belt and 6-10 years of work were more likely to develop psychological symptoms, while ICU healthcare professionals with the later survey and doctoral degree were less likely to develop psychological symptoms. CONCLUSION: Although COVID-19 period benefited psychological symptoms of ICU healthcare professionals, psychological symptoms still had a related high prevalence. Regular screening and appropriate interventions should still be implemented to decrease the risk for psychological symptoms among Chinese ICU healthcare professionals.

Assessment of mental health status among Chinese nursing staff in the intensive care unit: a network analysis.

Backgrounds: Nursing is the key group to provide healthcare services, and it is easy for nursing staff to develop mental health problems. Aims: The study aimed to evaluate prevalence of psychological symptoms in nurses working in an intensive care unit (ICU) and the inter-relationship of associations of psychological symptoms using network analysis. Methods: This study is a cross-sectional design study. The Chinese version of the Symptom Check List-90 (SCL-90) was used to measure the psychological status of ICU nurses. The network structure of psychological symptoms was characterised, and indices of 'Expected influence' were used to identify symptoms central to the network. Network stability was examined using a case-dropping bootstrap procedure. Results: Multiple logistic regression analysis found those who had worked more than 15 years were less likely to experience positive psychological symptoms, whereas nurses working in emergency ICU and other ICUs, nurses working in departments with over 16 beds were more likely to develop psychological symptoms. In addition, 'Anxiety', 'Mental degeneration' and 'Depression' were central symptoms in the network. Conclusions: ICU nurses reported a high level of psychological symptoms, which may affect the quality of their work and worsen public health problems.

Preclinical anti-angiogenic and anti-cancer activities of BAY1143269 in glioblastoma via targeting oncogenic protein expression.

Glioblastoma angiogenesis is critical for tumor growth, making it an appealing target for treatment development. BAY1143269 is a novel inhibitor of mitogen-activated protein kinase interacting serine/threonine-protein kinase 1 (MKN1) and has potent anti-cancer activity. We identified BAY1143269 as an angiogenesis inhibitor, by in vitro and in vivo glioblastoma angiogenesis models. BAY1143269 inhibited the capillary network formation of glioblastoma microvascular endothelial cells (GMECs), particularly the early stage of tubular structure formation. It also inhibited migration and proliferation, and induced apoptosis of GMECs isolated from glioblastoma patients. We found that BAY1143269 acted on GMECs by suppressing the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E-mediated expression of oncogenic proteins, including those involved in cell cycle, epithelial-mesenchymal transition (EMT), and pro-survival. In addition, BAY1143269 suppressed eIF4E phosphorylation, inhibited proliferation, and induced apoptosis of glioblastoma cells. Interestingly, it reduced vascular endothelial growth factor (VEGF) level in tumor cells and culturing medium, demonstrating the inhibitory effect of BAY1143269 on tumor proangiogenic microenvironment. We finally challenged BAY1143269 on the glioblastoma xenograft mice model and observed a significant tumor growth reduction without toxicity in mice receiving oral BAY1143269. Immunoblotting analysis demonstrated significantly less phosphorylated-eIF4E (p-eIF4E), cluster of differentiation 31 (CD31) (microvascular endothelial cell marker), and VEGF in tumors from drug-treated mice. In summary, the inhibition of glioblastoma angiogenesis with BAY1143269 may provide an alternative approach for anti-glioblastoma therapy.