miR-146a-5p regulates autophagy and NLRP3 inflammasome activation in epithelial barrier damage in the in vitro cell model of ulcerative colitis through the RNF8/Notch1/mTORC1 pathway

Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon that can be influenced by microRNAs (miRNAs). This study aims to investigate the impact of miR-146a-5p on lipopolysaccharide (LPS)-induced Caco-2/HT-29 cell autophagy and NLRP3 inflammasome activation and the underlying mechanism, with the aim of identifying potential therapeutic targets. We used LPS to establish Caco-2/HT-29 cell models and measured cell viability by CCK-8. The levels of miR-146a-5p, RNF8, markers of NLRP3 inflammasome activation and autophagy, proteins involved in the Notch1/mTORC1 pathway, and inflammatory factors were assessed by RT-qPCR, Western blot, and ELISA. Intestinal epithelial barrier function was evaluated by measuring transepithelial electrical resistance. Autophagic flux was measured using tandem fluorescent-labeled LC3. miR-146a-5p was highly-expressed in LPS-induced Caco-2/HT-29 cells, and autophagy flux was blocked at the autolysosomal stage after LPS induction. Inhibition of miR-146a-5p suppressed NLRP3 inflammasome activation, reduced intestinal epithelial barrier damage, and facilitated autophagy inhibition in LPS-induced Caco-2/HT-29 cells. The autophagy inhibitor NH4Cl partially nullified the inhibitory effects of miR-146a-5p inhibition on NLRP3 inflammation activation. miR-146a-5p targeted RNF8, and silencing RNF8 partly abrogated the action of miR-146a-5p inhibition on promoting autophagy and inhibiting NLRP3 inflammasome activation. miR-146a-5p inhibition suppressed the Notch1/mTORC1 pathway activation by upregulating RNF8. Inhibition of the Notch1/mTORC1 pathway partially nullified the function of silencing RNF8 on inhibiting autophagy and bolstering NLRP3 inflammasome activation. In conclusion, miR-146a-5p inhibition may be a potential therapeutic approach for UC, as it facilitates autophagy of LPS-stimulated Caco-2/HT-29 cells, inhibits NLRP3 inflammasome activation, and reduces intestinal epithelial barrier damage by upregulating RNF8 and suppressing the Notch1/mTORC1 pathway.     

S100P as a marker for poor survival and advanced stage in gallbladder carcinoma

AimsGallbladder carcinomas usually present in advanced stages and has a dismal prognosis despite modern imaging techniques and aggressive surgical intervention. Identification of biologic markers for early diagnosis and improved therapeutic strategies is thus of paramount importance. S100P has been identified in a variety of malignant neoplasms of the gastrointestinal and pancreaticobiliary systems, but it is not yet known if S100P expression is associated with clinically-relevant characteristics of gall bladder carcinoma. The aims of the present study were: 1) to investigate the relationship between S100P expression and histological type, grade, tumor-node-metastasis stage, presence of vascular invasion, perineural invasion and necrosis; and 2) to evaluate for any S100P-defined difference in the risk for tumor recurrence or death.MethodImmunostains for S100P were performed on 4 tissue microarray blocks containing 91 cases of gall bladder carcinoma.ResultThe intensity of S100P staining was significantly associated with pathological T stage 4 (p = 0. 0238). Staining intensity ≥3 in ≥25% tumor cells was associated with pathological T stage 4 (p = 0.0005). A higher S100P immunoreactivity score (IRS) was significantly associated with higher TNM stage (p = 0.0341). Age (p = 0.0485), presence of vascular invasion (p = 0.0359), pathological T stage (p = 0.0291) and TNM stage (p = 0.0153) were significantly associated with tumor recurrence. Intense S100P reactivity was associated with decreased overall survival [hazard ratio = 9.614; 95% confidence interval (CI), 1.873–49.338; p = 0.0067].ConclusionOur findings indicate that S100P over-expression is a potential prognostic marker for gall bladder carcinoma and is significantly associated with advanced tumor stage and poorer survival.     

The utility of inflammatory and endothelial factors in the prognosis of severe dengue

BackgroundSevere dengue is associated with a considerable risk of mortality, and there is currently a lack of appropriate prognostic biomarkers to predict its severity. Pathogenesis of severe dengue is characterized by overt inflammation, endothelial activation, and increased vascular permeability. The current study investigates the utility of endothelial, inflammatory, and vascular permeability factors as biomarkers to identify dengue severity, which could improve disease prognosis and management.MethodsThe dengue-positive subjects were classified based on seropositivity for NS1, IgM, and IgG. The samples in each group were quantified for basic clinical investigations. The levels of Interleukin-6 (IL-6), Tumor necrosis factor receptor 1 (TNFR1), EOTAXIN, Monocyte chemoattractant protein-1 (MCP-1), Monokine induced by interferon-gamma (MIG), Intercellular adhesion molecule-1 (ICAM-1), Vascular cell adhesion molecule-1 (VCAM-1), Thrombomodulin, and Angiopoietin-2 were estimated in all serum samples using the multiplex bead-based assay.ResultsIgG seropositive dengue patients showed abnormal laboratory characteristics and severe dengue symptoms. Among the studied markers, only IL-6, TNFR1, ICAM-1, VCAM-1, Thrombomodulin, and Angiopoietin-2 were significantly elevated in IgG seropositive patients compared to healthy controls. Increased IL-6 and TNFR1 levels were associated with decreased platelet count and elevated Hematocrit levels in IgG seropositive patients. Furthermore, ROC curve analysis indicated that IL-6, TNFR1, Thrombomodulin, and Angiopoietin-2 showed good potential for predicting dengue severity.ConclusionInflammatory markers IL-6 and TNFR1, and endothelial factors Angiopoietin-2 and Thrombomodulin, could serve as prognostic markers for severe dengue. These findings also encourage the future study of these biomarkers in the pathogenesis of severe dengue infection.     

Prevalence of overweight and obesity among nurses in Scotland: A cross-sectional study using the Scottish Health Survey

BackgroundIncreasing prevalence of overweight and obesity represents a global pandemic. As the largest occupational group in international healthcare systems nurses are at the forefront of health promotion to address this pandemic. However, nurses own health behaviours are known to influence the extent to which they engage in health promotion and the public's confidence in advice offered. Estimating the prevalence of overweight and obesity among nurses is therefore important. However, to date, prevalence estimates have been based on non-representative samples and internationally no studies have compared prevalence of overweight and obesity among nurses to other healthcare professionals using representative data.ObjectivesTo estimate overweight and obesity prevalence among nurses in Scotland, and compare to other healthcare professionals and those working in non-heath related occupations.DesignCross-sectional study using a nationally representative sample of five aggregated annual rounds (2008–2012) of the Scottish Health Survey.SettingScotland.Participants13,483 adults aged 17–65 indicating they had worked in the past 4 weeks, classified in four occupational groups: nurses (n = 411), other healthcare professionals (n = 320), unqualified care staff (n = 685), and individuals employed in non-health related occupations (n = 12,067).Main outcome measuresPrevalence of overweight and obesity defined as Body Mass Index ≥ 25.0.MethodsEstimates of overweight and obesity prevalence in each occupational group were calculated with 95% confidence intervals (CI). A logistic regression model was then built to compare the odds of being overweight or obese with not being overweight or obese for nurses in comparison to the other occupational categories. Data were analysed using SAS 9.1.3.Results69.1% (95% CI 64.6, 73.6) of Scottish nurses were overweight or obese. Prevalence of overweight and obesity was higher in nurses than other healthcare professionals (51.3%, CI 45.8, 56.7), unqualified care staff (68.5%, CI 65.0, 72.0) and those in non-health related occupations (68.9%, CI 68.1, 69.7). A logistic regression model adjusted for socio-demographic composition indicated that, compared to nurses, the odds of being overweight or obese was statistically significantly lower for other healthcare professionals (Odds Ratio [OR] 0.45, CI 0.33, 0.61) and those in non-health related occupations (OR 0.78, CI 0.62, 0.97).ConclusionsPrevalence of overweight and obesity among Scottish nurses is worryingly high, and significantly higher than those in other healthcare professionals and non-health related occupations. High prevalence of overweight and obesity potentially harms nurses’ own health and hampers the effectiveness of nurses’ health promotion role. Interventions are therefore urgently required to address overweight and obesity among the Scottish nursing workforce.     

Evaluation of adalimumab biosimilar candidate (HS016) in Chinese patients with active ankylosing spondylitis based on a health survey: sub-analysis of a phase 3 study

Clinical Rheumatology - The equivalence of the biosimilar HS016 to adalimumab (Humira) for the treatment of active ankylosing spondylitis (AS) patients has been previously validated. The aim was to...     

Non-invasive assessment of cerebrospinal fluid flow dynamics using phase-contrast magnetic resonance imaging in communicating hydrocephalus

This work aims to evaluate the changes in cerebrospinal fluid (CSF) hydrodynamics in patients diagnosed with communicating hydrocephalus. Besides, we establish the relationship between CSF flow dynamic parameters on the midbrain aqueduct and intracranial pressure (ICP). CSF hydrodynamics analysis was performed using Phase-Contrast Magnetic Resonance Imaging (PC‐MRI) techniques on the midbrain aqueduct of 41 patients diagnosed with communicating hydrocephalus and 22 healthy volunteers. The correlation between CSF average flow in the midbrain aqueduct and intracranial pressure measured by Lumbar Puncture (LP) was assessed in patients with hydrocephalus. Pearson correlation coefficient was used to establish the correction between the average CSF flow of midbrain aqueduct and ICP. CSF dynamic parameters of the midbrain aqueduct in hydrocephalus patients, including peak positive velocity (7.348 cm/s), average velocity (0.623 cm/s), average flow (50.799 mm³/s), and regions of interest (ROI) area (9.978 mm²) were significantly higher than in the healthy controls (p < 0.05). This was after adjusting the age, gender, heart rate, systolic blood pressure, diastolic blood pressure, and body mass index. However, only the peak negative velocity of the midbrain aqueduct did not significantly differ between the groups (p = 0.209). A positive correlation was noted between the average flow (AF) of the midbrain aqueducts and ICP in hydrocephalus patients (y (AF) = 0.386× (ICP)−33.738, r = 0.787, p < 0.05). Reference data of CSF flow dynamic parameters was obtained through the PC-MRI in middle-aged healthy volunteers and communicating hydrocephalus patients. Although the sample size was constrained, this study has significant contributions. For instance, a significant correlation was noted between the average CSF flow of the aqueduct and ICP. This therefore provides a reference for clinicians to monitor ICP in patients with hydrocephalus.     

Sulforaphane enhances the activity of the Nrf2–ARE pathway and attenuates inflammation in OxyHb-induced rat vascular smooth muscle cells

Aim

A growing body of evidence indicates that the nuclear factor erythroid 2-related factor 2–antioxidant response element (Nrf2–ARE) pathway plays a protective role in many physiological stress processes such as inflammatory damage, oxidative stress, and the accumulation of toxic metabolites, which are all involved in the cerebral vasospasm following subarachnoid hemorrhage (SAH). We hypothesized that the Nrf2–ARE pathway might have a protective role in cerebral vasospasm following SAH.

Materials and methods

In our study, we investigate whether the oxyhemoglobin (OxyHb) can induce the activation of the Nrf2–ARE pathway in vascular smooth muscle cells (VSMCs), and evaluate the modulatory effects of sulforaphane (SUL) on OxyHb-induced inflammation in VSMCs.

Results

As a result, both the protein level and the mRNA level of the nuclear Nrf2 were significantly increased, while the mRNA levels of two Nrf2-regulated gene products, both heme oxygenase-1 and NAD(P)H: quinone oxidoreductase-1, were also up-regulated in VSMCs induced with OxyHb. A marked increase of inflammatory cytokines such as IL-1β, IL-6 and TNF-α release was observed at 48 h after cells were treated with OxyHb. SUL enhanced the activity of the Nrf2–ARE pathway and suppressed cytokine release.

Conclusions

Our results indicate that the Nrf2–ARE pathway was activated in OxyHb-induced VSMCs. SUL suppressed cytokine release via the activation of the Nrf2–ARE pathway in OxyHb-induced VSMCs.