Alpha-tocopherylquinone-mediated activation of the Aryl Hydrocarbon Receptor regulates the production of inflammation-inducing cytokines and ameliorates intestinal inflammation.

This study investigated the role of Alpha-tocopherylquinone (TQ) in regulating the intestinal immune system and the underlying mechanisms. In the experimental dextran sodium sulfate and T cell-mediated colitis models, TQ significantly reduced the mRNA levels of interleukin (IL)-6, IL-1ß, IL-17A, IL-23, and tumor necrosis factor (TNF)-α and the abundance of proinflammatory macrophages, T helper (Th)17 cells, and ILC3s in the colons of wild-type mice. TQ also prevented lipopolysaccharide (LPS)-induced activation of NFκB and signal transducer and activator of transcription (Stat)-3 pathways in the human macrophage U937 cells. Pharmacological inhibition or CRISPR-Cas-9-mediated knockout of Aryl hydrocarbon Receptor (AhR) prevented the anti-inflammatory effects of TQ in the LPS-treated U937 cells. Furthermore, TQ reduced the mRNA levels of the LPS-induced pro-inflammatory cytokines in the WT but not Ahr-/- mice splenocytes. TQ also reduced IL-6R protein levels and IL-6-induced Stat-3 activation in Jurkat cells and in vitro differentiation of Th17 cells from wild-type but not Ahr-/- mice naive T cells. Additionally, TQ prevented the pro-inflammatory effects of LPS on macrophages and stimulation of T cells in human PBMCs and significantly reduced the abundance of tumor necrosis factor-α, IL-1ß, and IL-6hi inflammatory macrophages and Th17 cells in surgically resected Crohn's disease (CD) tissue. Our study shows that TQ is a naturally occurring, non-toxic, and effective immune modulator that activates AhR and suppresses the Stat-3-NFκB signaling.

Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways.

Defects in intestinal epithelial tight junctions (TJs) allow paracellular permeation of noxious luminal antigens and are important pathogenic factors in inflammatory bowel disease (IBD). We show that alpha-tocopherylquinone (TQ), a quinone-structured oxidation product of vitamin E, consistently enhances the intestinal TJ barrier by increasing barrier-forming claudin-3 (CLDN3) and reducing channel-forming CLDN2 in Caco-2 cell monolayers (in vitro), mouse models (in vivo), and surgically resected human colons (ex vivo). TQ reduces colonic permeability and ameliorates colitis symptoms in multiple colitis models. TQ, bifunctionally, activates both aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Genetic deletion studies reveal that TQ-induced AhR activation transcriptionally increases CLDN3 via xenobiotic response element (XRE) in the CLDN3 promoter. Conversely, TQ suppresses CLDN2 expression via Nrf2-mediated STAT3 inhibition. TQ offers a naturally occurring, non-toxic intervention for enhancement of the intestinal TJ barrier and adjunct therapeutics to treat intestinal inflammation.

Autophagy Reduces the Degradation and Promotes Membrane Localization of Occludin to Enhance the Intestinal Epithelial Tight Junction Barrier against Paracellular Macromolecule Flux.

BACKGROUND AND AIMS: Functional loss of the gut epithelium's paracellular tight junction [TJ] barrier and defective autophagy are factors potentiating inflammatory bowel disease [IBD]. Previously, we showed the role of autophagy in enhancing the intestinal TJ barrier via pore-forming claudin-2 degradation. How autophagy regulates the TJ barrier-forming proteins remains unknown. Here, we investigated the role of autophagy in the regulation of occludin, a principal TJ component involved in TJ barrier enhancement. RESULTS: Autophagy induction using pharmacological activators and nutrient starvation increased total occludin levels in intestinal epithelial cells, mouse colonocytes and human colonoids. Autophagy induction enriched membrane occludin levels and reduced paracellular permeability of macromolecules. Autophagy-mediated TJ barrier enhancement was contingent on the presence of occludin as OCLN-/- nullified its TJ barrier-enhancing effect against macromolecular flux. Autophagy inhibited the constitutive degradation of occludin by preventing its caveolar endocytosis from the membrane and protected against inflammation-induced TJ barrier loss. Autophagy enhanced the phosphorylation of ERK-1/2 and inhibition of these kinases in Caco-2 cells and human colonic mucosa prevented the macromolecular barrier-enhancing effects of autophagy. In vivo, autophagy induction by rapamycin enhanced occludin levels in wild-type mouse intestines and protected against lipopolysaccharide- and tumour necrosis factor-α-induced TJ barrier loss. Disruption of autophagy with acute Atg7 knockout in adult mice decreased intestinal occludin levels, increasing baseline colonic TJ permeability and exacerbating the effect of experimental colitis. CONCLUSION: Our data suggest a novel role of autophagy in promoting the intestinal TJ barrier by increasing occludin levels in an ERK1/2 mitogen-activated protein kinase-dependent mechanism.

Long-Term Use of Proton Pump Inhibitors Disrupts Intestinal Tight Junction Barrier and Exaggerates Experimental Colitis.

BACKGROUND: Proton pump inhibitors [PPIs] are widely used to treat a number of gastro-oesophageal disorders. PPI-induced elevation in intragastric pH may alter gastrointestinal physiology. The tight junctions [TJs] residing at the apical intercellular contacts act as a paracellular barrier. TJ barrier dysfunction is an important pathogenic factor in inflammatory bowel disease [IBD]. Recent studies suggest that PPIs may promote disease flares in IBD patients. The role of PPIs in intestinal permeability is not clear. AIM: The aim of the present study was to study the effect of PPIs on the intestinal TJ barrier function. METHODS: Human intestinal epithelial cell culture and organoid models and mouse IBD models of dextran sodium sulphate [DSS] and spontaneous enterocolitis in IL-10-/- mice were used to study the role of PPIs in intestinal permeability. RESULTS: PPIs increased TJ barrier permeability via an increase in a principal TJ regulator, myosin light chain kinase [MLCK] activity and expression, in a p38 MAPK-dependent manner. The PPI-induced increase in extracellular pH caused MLCK activation via p38 MAPK. Long-term PPI administration in mice exaggerated the increase in intestinal TJ permeability and disease severity in two independent models of DSS colitis and IL-10-/- enterocolitis. The TJ barrier disruption by PPIs was prevented in MLCK-/- mice. Human database studies revealed increased hospitalizations associated with PPI use in IBD patients. CONCLUSIONS: Our results suggest that long-term use of PPIs increases intestinal TJ permeability and exaggerates experimental colitis via an increase in MLCK expression and activity.

Myocardial fibrosis in Type 2 Diabetes is associated with functional and metabolomic parameters.

AIMS: To identify biomarkers of cardiomyopathy in patients with type 2 diabetes mellitus (T2DM) using cardiovascular magnetic resonance (CMR) and to identify associations between functional status, metabolomic profile and myocardial fibrosis. METHODS: In this prospective case control study, patients (n = 49) with T2DM without significant coronary artery disease, and matched controls (n = 18) underwent CMR, cardiopulmonary exercise testing, and plasma metabolomic analyses. RESULTS: Patients with T2DM (n = 49, median [interquartile range] age 61 [56-63] years, 61% male, diabetes duration 11 [7-20] years), historical HbA1c 7.6% (60 mmol/mol) (6.9-8.6) and matched controls (n = 18) were examined. Study patients had increased myocardial extracellular volume (ECV) (26.9 [23.8-30.0] vs 23.4 [22.4-25.5) %, p < 0.001). Increased ECV was associated with male sex (p = 0.04), time with T2DM (p = 0.02), reduced peak VO2 (R2 = 0.48, p = 0.01), increased circulating choline (p = 0.002) and cysteamine (p = 0.002) both of which were also associated with reduced peak VO2 (p < 0.025 and 0.014 respectively). CONCLUSIONS: Patients with well-controlled T2DM without significant coronary disease exhibit focal and diffuse myocardial fibrosis and diffuse myocardial fibrosis is associated with reduced exercise tolerance and metabolites. Plasma metabolites may provide mechanistic insights into diffuse myocardial fibrosis, and cardiopulmonary fitness.

Utilisation of telehealth for outpatient diabetes management during COVID-19 pandemic: how did the patients fare?

BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, many outpatient services at public hospitals, including diabetes services, had adopted telehealth appointments for their clinic patients. There was concern that patients' glycaemic control may worsen during the pandemic. AIM: To assess glycaemic control of patients with diabetes attending telehealth consultations in 2020, compared to face-to-face reviews prior to pandemic. METHODS: We conducted a retrospective review of patients with diabetes managed by telehealth consultations over 5 months at two metropolitan hospitals in Sydney. Their attendance rate, glycaemic control and unplanned admissions to hospital were assessed, and these were compared with the same period 12 months prior when patients were reviewed via face-to-face appointments. RESULTS: Between April and September 2020, the attendance rate for telehealth consultation at the diabetes services at the two hospitals was 88.9% (884 out of 994), which was higher than in 2019 (85.2%; 818 out of 959; P = 0.016) when patients attended via face-to-face appointments. Of the 629 patients reviewed via telehealth in 2020 and who had been with our service for over 12 months, glycaemic control was better in 2020 (HbA1c 7.8 ± 1.4% (62 ± 15 mmol/mol)) compared with 12 months earlier (8.2 ± 1.7% (66 ± 19 mmol/mol); P < 0.001). There was no difference in the number of unplanned admissions for this cohort in 2020 (n = 58; 9.2%) compared with 2019 (n = 75; 11.9%; P = 0.100). CONCLUSIONS: The present study showed that for patients with diabetes who received care via telehealth consultations during the COVID-19 lockdown, their glycaemic control was slightly better, and unplanned admission rates were not higher compared with those in the pre-COVID-19 period. Telehealth consultation offers an important care delivery option in the management of patients with diabetes under these circumstances.

Standard versus ultrasound-guided radial and femoral access in coronary angiography and intervention (SURF): a randomised controlled trial.

AIMS: This study aimed to compare outcomes in unselected patients undergoing cardiac catheterisation via transradial versus transfemoral access and standard versus ultrasound-guided arterial access. METHODS AND RESULTS: This was a prospective, randomised (radial vs. femoral and standard vs. ultrasound), 2x2 factorial trial of 1,388 patients undergoing coronary angiography and percutaneous coronary intervention. The primary outcome was a composite of ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) major bleeding, MACE (death, stroke, myocardial infarction or urgent target lesion revascularisation) and vascular complications at 30 days. Transradial access reduced the primary outcome (RR 0.37, 95% CI: 0.17-0.81; p=0.013), mostly driven by ACUITY major bleeding (RR 0.343, 95% CI: 0.123-0.959; p=0.041) when compared with the transfemoral approach. There was no difference in the primary outcome between standard and ultrasound guidance (p=0.76). Ultrasound guidance, however, reduced mean access time (93 sec vs. 111 sec; p=0.009), attempts (1.47 vs. 1.9; p<0.0001), difficult accesses (4.5% vs. 9.2%; p=0.0007), venepuncture (4.1% vs. 9.2%; p<0.0001) and improved first-pass success (73% vs. 59.7%; p<0.0001). CONCLUSIONS: Transradial access significantly reduced the composite outcome compared to transfemoral access. Ultrasound guidance did not reduce the primary outcome compared to the standard technique, but significantly improved the efficiency and overall success rate of arterial access.

Social anxiety and peer helping in adolescent addiction treatment.

BACKGROUND: The developmental need to fit in may lead to higher alcohol and other drug use among socially anxious youths which exacerbates the drink/trouble cycle. In treatment, youths with social anxiety disorder (SAD) may avoid participating in therapeutic activities with risk of negative peer appraisal. Peer-helping is a low-intensity, social activity in the 12-step program associated with greater abstinence among treatment-seeking adults. This study examined the influence of SAD on clinical severity at intake, peer-helping during treatment, and outcomes in a large sample of adolescents court-referred to residential treatment. METHODS: Adolescents (N = 195; 52% female, 30% Black) aged 14 to 18 were prospectively assessed at treatment admission, treatment discharge, and 6 months after treatment discharge. Data were collected using rater-administered assessments, youth reports, clinician reports, medical charts, and electronic court records. The influence of SAD on peer-helping and outcomes was examined using hierarchical linear regression and event history methods. RESULTS: Forty-two percent of youths reported a persistent fear of being humiliated or scrutinized in social situations, and 15% met current diagnostic criteria for SAD. SAD onset preceded initial use for two-thirds of youths with SAD and substance dependency. SAD youths presented for treatment with greater clinical severity in terms of earlier age of first use (p < 0.01), greater lifetime use of heroin and polysubstance use (p < 0.05), incarceration history (p < 0.01), and lifetime trauma (p < 0.001). Twelve-step participation patterns during treatment did not differ between youths with and without SAD except for peer-helping, which was associated with reduced risk of relapse (p < 0.01) and incarceration (p < 0.05) in the 6 months posttreatment. CONCLUSIONS: This study found evidence of an association between SAD and earlier age of first use, greater lifetime use of heroin, incarceration history, and lifetime trauma. SAD was associated with higher service participation during treatment, which was associated with reduced risk of relapse and incarceration in the 6 months posttreatment. Findings indicate the benefits of service participation for juveniles with SAD which provides a nonjudgmental, task-focused venue for developing sober networks in the transition back into the community.