Quetiapine Attenuates Glial Activation and Proinflammatory Cytokines in APP/PS1 Transgenic Mice via Inhibition of Nuclear Factor-κB Pathway

Background:

In Alzheimer’s disease, growing evidence has shown that uncontrolled glial activation and neuroinflammation may contribute independently to neurodegeneration. Antiinflammatory strategies might provide benefits for this devastating disease. The aims of the present study are to address the issue of whether glial activation and proinflammatory cytokine increases could be modulated by quetiapine in vivo and in vitro and to explore the underlying mechanism.

Methods:

Four-month–old amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic and nontransgenic mice were treated with quetiapine (5mg/kg/d) in drinking water for 8 months. Animal behaviors, total Aβ levels, and glial activation were evaluated by behavioral tests, enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot accordingly. Inflammatory cytokines and the nuclear factor kappa B pathway were analyzed in vivo and in vitro.

Results:

Quetiapine improves behavioral performance, marginally affects total Aβ₄₀ and Aβ₄₂ levels, attenuates glial activation, and reduces proinflammatory cytokines in APP/PS1 mice. Quetiapine suppresses Aβ_1-42-induced activation of primary microglia by decresing proinflammatory cytokines. Quetiapine inhibits the activation of nuclear factor kappa B p65 pathway in both transgenic mice and primary microglia stimulated by Aβ_1–42.

Conclusions:

The antiinflammatory effects of quetiapine in Alzheimer’s disease may be involved in the nuclear factor kappa B pathway. Quetiapine may be an efficacious and promising treatment for Alzheimer’s disease targeting on neuroinflammation.     

Fluoxetine Regulates Neurogenesis In Vitro Through Modulation of GSK-3β/β-Catenin Signaling

Background:

It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis.

Methods:

The aim of this study was to determine whether GSK-3β/β-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine’s regulation of GSK-3β/β-catenin signaling pathway were also examined.

Results:

Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilized β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced up-regulation of both phosphorylation of Ser9 on GSK-3β and nuclear β-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT_1A) receptor antagonist WAY-100635.

Conclusions:

The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3β/β-catenin signaling pathway that links postsynaptic 5-HT_1A receptor activation.     

Prognostic value of aldo-keto reductase family 1 member B10 (AKR1B10) in digestive system cancers: A meta-analysis

Background:Numbers of studies have reported that the expression of aldo-keto reductase family 1 member B10 (AKR1B10) is abnormal in digestive system cancers, and could be used as a prognostic biomarker. However, the results are argued. Therefore, we conduct a meta-analysis to comprehensively evaluate the prognostic value of high AKR1B10 expression for overall survival (OS), disease specific survival (DSS), and disease-free survival/recurrence-free survival (DFS/PFS) in digestive system cancers.Methods:Hazard ratios (HRs) with its 95% confidence intervals (CIs) were calculated to assess the prognostic value of AKR1B10 by using the random effects model. The STATA version 12.0 software were used to perform all the analyses.Results:Eleven articles including 1428 patients involved in this meta-analysis. The pooled analysis suggested that high AKR1B10 expression was not associated with OS (HR: 1.18; 95% CI: 0.69–2.00) and DFS/PFS (HR: 1.08, 95% CI: 0.67–1.76) in digestive system cancers. However, Further analysis revealed that high AKR1B10 expression indicated poor OS in oral squamous cell carcinomas (OSCC) (HR: 2.92, 95% CI: 1.86–4.58) and favorable DSS in hepatocellular carcinoma (HCC) (HR: 0.71, 95% CI: 0.52–0.97).Conclusions:The prognostic value of high AKR1B10 expression varied in different types of digestive system cancers. Further studies exploring the prognostic role of AKR1B10 in digestive system cancers are needed.     

The meta-analysis of the effect of 68Ga-PSMA-PET/CT diagnosis of prostatic cancer compared with bone scan

Background:⁶⁸Ga-PSMA-PET/CT (positron emission tomography/computed tomography) is a promising method for prostate cancer (PC) detection. However, the ability of ⁶⁸Ga-PSMA-PET/CT to detect malignant bone lesions, and whether this method is superior to the existing bone imaging methods are still lack of systematic analysis.Purpose:To evaluate the value of ⁶⁸Ga-PSMA-PET/CT and bone scan in clinical diagnosis of prostatic cancer from the perspective of evidence-based medicine.Methods:PubMed, The Cochrane Library, EMBASE, Springer Link, Sinomed, CNKI, Wanfang database, and CQVIP database were searched to find the satisfactory studies that needed systematic review of trials and compared the value of 68Ga-PSMA-PET/CT and bone scan. All studies published from inception to March 31, 2020. According to the inclusion and exclusion criteria, 2 reviewers independently evaluated and extracted the literature. Review Manager 5.3 was applied to evaluate the included literature quality. The heterogeneity of the included literature was tested by Meta Disc 1.4, and the effect model was selected according to the heterogeneity test results, and the sensitivity (SEN), specificity (SPE), PLR, NLR and diagnostic odds ratio (DOR) were analyzed. After testing the heterogeneity results of literature by using the 95% confidence interval and the forest map.Results:A total of 4 studies were eligible for inclusion in the meta-analysis, which included 318 patients, 120 cases with bone metastasis and 198 cases without bone metastasis. The results of summary evaluation for ⁶⁸Ga-PSMA-PET/CT and bone scan in diagnosis of prostatic cancer as follow respectively: The SEN were 0.97 and 0.86; the SPE were 1.00 and 0.87; the DOR were 1468.33 and 36.23; PLR were 88.45 and 6.67; NLR were 0.05 and 0.19; and the area under curve (AUC) and 95% CI were 0.9973 (1.0000–0.9927) and 0.8838 (0.9584–0.8092).Conclusion:By comparing the diagnostic results of ⁶⁸Ga-PSMA-PET/CT and bone scan imaging diagnosis methods, the ⁶⁸Ga-PSMA-PET/CT has a higher SEN and SPE than bone scan, and it has a higher diagnostic efficiency for prostate cancer bone metastasis, which is worthy of clinical application.     

Correlation between 25-hydroxyvitamin D level and arterial elasticity in middle-aged and elderly cadres in Guiyang,China: A retrospective observational study

There is evidence that serum 25-hydroxyvitamin D [25-(OH) D] levels may be associated with cardiovascular disease and its risk factors. This study aimed to investigate the relationship between 25-(OH) D levels and blood pressure (BP), blood lipids, and arterial elasticity in middle-aged and elderly cadres in China.In this retrospective study, we included 401 civil servants and cadres aged >42 years who underwent medical examinations at Guiyang Municipal First People''s Hospital, China in 2018. The participants were assigned to deficiency (≤20 ng/mL), insufficiency (20–30 ng/mL), and sufficiency (≥30 ng/mL) groups according to 25-(OH) D levels in their blood. Demographics, brachial–ankle pulse wave velocity (baPWV), BP, ankle–brachial index (ABI), and blood lipids were compared among groups. The associations between 25-(OH) D and other parameters were evaluated using linear regression analysis.Median (range) 25-(OH) D levels in the deficiency (n = 162), insufficiency (n = 162), and sufficiency (n = 77) groups were 15.32 (2.93–19.88), 25.12 (20.07–29.91), and 33.91 (30.23–82.42) ng/mL, respectively. There were significant differences in systolic BP, pulse pressure, baPWV (left and right sides), ABI (left side), high-density lipoprotein-cholesterol, and triglycerides (TGs; all P < .05) among groups. Multivariate linear regression revealed that TG, left baPWV, and right baPWV were significantly negatively correlated with 25-(OH) D levels (all P < .05).In this study, 25-(OH) D levels were found to be associated with TG, left baPWV, and right baPWV values. 25-(OH) D deficiency may be associated with reduced arterial elasticity.     

The exosome of platelet endothelial cell adhesion molecule-1 (PECAM1) protein: A potential risking star in high blood pressure patients (HBPP)

A number of studies have demonstrated that exosomes were involved in important physiological and pathological processes through cell-to-cell communication in cardiovascular disease, which contained nucleic acids, proteins, and lipid contents. In our study, we found that the protein platelet endothelial cell adhesion molecule-1 (PECAM1) was an extracellular vesicle in the blood of high blood pressure patients (HBPP).Isolated the vesicles from the blood of HBPP and health examiners and detected its size and morphology with nanoparticle tracking analysis, then we identified its surface protein CD63, CD81, and the protein expression of PECAM1 in the exosome with western blot. Furthermore, we analyzed the correlation between the expression of PECAM1 and the high blood degree with linear regression analysis.Our results showed that the morphology of extracellular vesicles was more evident in high blood pressure groups than healthy controls, and the protein expression of PECAM1 was also abundant in the vesicles of HBPP, however, there were no extracellular vesicles in the blood samples of healthy controls. Besides, linear regression showed the linear correlation coefficient R = 0.901, P < .01 between the expression of PECAM1 and the systolic blood pressure of the high blood patients. Therefore, the exosome of protein of PECAM1 was a potential risking star in HBPP.     

Efficacy of warming needle moxibustion in the treatment of ankylosing spondylitis: A protocol of a randomized controlled trial

Background:Ankylosing spondylitis is a recurrent autoimmune disease, which has a high disability rate and seriously affects patients’ daily life. Conventional treatment cannot effectively solve the clinical problems of patients, and long-term medication is accompanied by adverse reactions. The evidence shows that warming needle moxibustion has advantages in the treatment of ankylosing spondylitis, but there is still a lack of clinical studies on warm acupuncture alone and long-term follow-up.Methods:This is a prospective randomized controlled trial to study the efficacy and safety of needle warming through moxibustion in the treatment of ankylosing spondylitis. It was approved by the Ethics Committee of Clinical Research of our hospital. Patients were randomly assigned to an observation group or a control group. The patients were followed up for 6 months after 30 days of treatment. Observation indicators include; activity index, functional ability, Bath Ankylosing Spondylitis Metrology Index, inflammatory indicators, adverse reactions, and so on. Finally, SPASS 22.0 software is used for statistical analysis of the data.Discussion:This study will evaluate the clinical efficacy of warming needle moxibustion in the treatment of ankylosing spondylitis. The results of this study will provide a reference basis for the clinical use of warm needle moxibustion in the treatment of ankylosing spondylitis.Trial registration:OSF Registration number: DOI 10.17605/OSF.IO/GWPX3     

Risk factors of infection after transarterial chemoembolization for hepatocellular carcinoma: A protocol for systematic review and meta-analysis

Background:Transarterial chemoembolization (TACE) has the characteristics of minimally invasive, strong repeatability, and good curative effect, so it is commonly used in the nonoperative treatment of hepatocellular carcinoma (HCC). However, infection will occur after TACE, which not only increases the hospitalization time and medical expenses, but also affects the efficacy of TACE treatment. At present, there is a lack of analysis of the risk factors of infection after TACE of patients with HCC. In this study, meta-analysis was used to further explore the risk factors of postoperative infection in patients with HCC after TACE, and to provide strategies for infection prevention and intervention.Methods:To search the literatures about the influencing factors of post-TACE infection in patients with HCC published from the establishment of PubMed, Embase, The Cochrane Library, Web of Science, China Biology Medicine Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, and WANFANG to April 2021. Screening was carried out according to inclusion criteria and exclusion criteria. A meta-analysis was performed using RevMan 5.3 software.Results:We disseminated the findings of this systematic review and meta-analysis via publications in peer-reviewed journals.Conclusion:This study systematically reviewed the existing evidence and determined the incidence and predictors of infection after TACE of patients with HCC.Ethics and dissemination:The private information from individuals will not be published. This systematic review also should not damage participants’ rights. Approval from an ethics committee is not required for this study. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.OSF Registration number:DOI 10.17605/OSF.IO/26P5X     

Nutlin-3-induced redistribution of chromatin-bound IFI16 in human hepatocellular carcinoma cells in vitro is associated with p53 activation

Aim:

Interferon-γ inducible protein 16 (IFI16), a DNA sensor for DNA double-strand break (DSB), is expressed in most human hepatocellular carcinoma cell (HCC) lines. In this study we investigated the re-localization of chromatin-bound IFI16 by Nutlin-3, a DNA damage agent, in HCC cells in vitro, and the potential mechanisms.

Methods:

Human HCC SMMC-7721 (wild-type TP53), Huh-7 (mutant TP53), Hep3B (null TP53) and normal fetal liver L02 cell lines were examined. DSB damage in HCC cells was detected via γH2AX expression and foci formation assay. The expression of IFI16 and IFNB mRNA was measured using RT-PCR, and subcellular localization and expression of the IFI16 protein were detected using chromatin fractionation, Western blot analysis, and fluorescence microscopy.

Results:

Treatment of SMMC-7721 cells with Nutlin-3 (10 μmol/L) or etoposide (40 μmol/L) induced significant DSB damage. In SMMC-7721 cells, Nutlin-3 significantly increased the expression levels of IFI16 and IFNB mRNA, and partially redistributed chromatin-bound IFI16 protein to the cytoplasm. These effects were blocked by pretreatment with pifithrin-α, a p53 inhibitor. Furthermore, Nutlin-3 did not induce ectopic expression of IFI16 protein in Huh-7 and Hep3B cells. Moreover, the association of IFI16 with chromatin and Nutlin-3-induced changes in localization were not detected in L02 cells.

Conclusion:

Nutlin-3 regulates the subcellular localization of IFI16 in HCC cells in vitro in a p53-dependent manner.     

Predicting in-hospital mortality in ICU patients with sepsis using gradient boosting decision tree

Sepsis is a leading cause of mortality in the intensive care unit. Early prediction of sepsis can reduce the overall mortality rate and cost of sepsis treatment. Some studies have predicted mortality and development of sepsis using machine learning models. However, there is a gap between the creation of different machine learning algorithms and their implementation in clinical practice.This study utilized data from the Medical Information Mart for Intensive Care III. We established and compared the gradient boosting decision tree (GBDT), logistic regression (LR), k-nearest neighbor (KNN), random forest (RF), and support vector machine (SVM).A total of 3937 sepsis patients were included, with 34.3% mortality in the Medical Information Mart for Intensive Care III group. In our comparison of 5 machine learning models (GBDT, LR, KNN, RF, and SVM), the GBDT model showed the best performance with the highest area under the receiver operating characteristic curve (0.992), recall (94.8%), accuracy (95.4%), and F1 score (0.933). The RF, SVM, and KNN models showed better performance (area under the receiver operating characteristic curve: 0.980, 0.898, and 0.877, respectively) than the LR (0.876).The GBDT model showed better performance than other machine learning models (LR, KNN, RF, and SVM) in predicting the mortality of patients with sepsis in the intensive care unit. This could be used to develop a clinical decision support system in the future.