The marine compound and elongation factor 1A1 inhibitor, didemnin B, provides benefit in western diet-induced non-alcoholic fatty liver disease.

Inhibition of eukaryotic elongation factor 1A1 (EEF1A1) with the marine compound didemnin B decreases lipotoxic HepG2 cell death in vitro and improves early stage non-alcoholic fatty liver disease (NAFLD) in young genetically obese mice. However, the effects of didemnin B on NAFLD in a model of long-term diet-induced obesity are not known. We investigated the effects of didemnin B on NAFLD severity and metabolic parameters in western diet-induced obese mice, and on the cell types that contribute to liver inflammation and fibrosis in vitro. Male 129S6 mice were fed either standard chow or western diet for 26 weeks, followed by intervention with didemnin B (50 µg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. Moreover, didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a). In vitro, didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1ß secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. Thus, didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver. Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro. These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD.

Two-Week Isocaloric Time-Restricted Feeding Decreases Liver Inflammation without Significant Weight Loss in Obese Mice with Non-Alcoholic Fatty Liver Disease.

Prolonged, isocaloric, time-restricted feeding (TRF) protocols can promote weight loss, improve metabolic dysregulation, and mitigate non-alcoholic fatty liver disease (NAFLD). In addition, 3-day, severe caloric restriction can improve liver metabolism and glucose homeostasis prior to significant weight loss. Thus, we hypothesized that short-term, isocaloric TRF would improve NAFLD and characteristics of metabolic syndrome in diet-induced obese male mice. After 26 weeks of ad libitum access to western diet, mice either continued feeding ad libitum or were provided with access to the same quantity of western diet for 8 h daily, over the course of two weeks. Remarkably, this short-term TRF protocol modestly decreased liver tissue inflammation in the absence of changes in body weight or epidydimal fat mass. There were no changes in hepatic lipid accumulation or other characteristics of NAFLD. We observed no changes in liver lipid metabolism-related gene expression, despite increased plasma free fatty acids and decreased plasma triglycerides in the TRF group. However, liver Grp78 and Txnip expression were decreased with TRF suggesting hepatic endoplasmic reticulum (ER) stress and activation of inflammatory pathways may have been diminished. We conclude that two-week, isocaloric TRF can potentially decrease liver inflammation, without significant weight loss or reductions in hepatic steatosis, in obese mice with NAFLD.

The role of heart rate variability in predicting delirium: A systematic review and meta-analysis.

Brain and heart interact through multiple ways. Heart rate variability, a non-invasive measurement is studied extensively as a predicting model for various health conditions including subarachnoid hemorrhage, cancer, and diabetes. There is limited evidence to predict delirium, an acute fluctuating disorder of brain dysfunction, as it poses a significant challenge in the intensive care unit (ICU) and post-operative setting. In this systematic review of 9 articles, heart rate variability indices were used to investigate the occurrence of post-operative and ICU delirium. This systematic review and meta-analysis reveal evidence of a strong predilection between postoperative and intensive care unit delirium and alterations in the heart rate variability, measured by mean differences for standard deviation of NN-intervals. Other heart rate variability indices [root mean squares of successive differences, low-frequency (LF), high-frequency (HF), and LF:HF ratio] showed lack of or very weak association. A non-invasive tool of brain and heart interaction may refine diagnostic predictions for acute brain dysfunctions like delirium in such population and would be an important step in delirium research.

Efficacy and Safety of Different Dosing Regimens of Rivaroxaban in Patients With Atrial Fibrillation for Stroke Prevention: A Systematic Review and Meta-Analysis.

Atrial fibrillation (AF) poses a substantial risk of stroke, necessitating effective anticoagulation therapy. This systematic review and meta-analysis (SRMA) evaluates the efficacy and safety of different dosing regimens of rivaroxaban in patients with AF. A comprehensive search of relevant databases, focusing on studies published from 2017 onward, was conducted. Inclusion criteria comprised randomized controlled trials (RCTs) and observational studies comparing standard and reduced dosing of rivaroxaban in AF. Data extraction and risk of bias (ROB) assessment were performed, and a meta-analysis was conducted for relevant outcomes. A total of 21 studies fulfilled the inclusion criteria. Standard dosing demonstrates a slightly lower risk of composite effectiveness outcomes and safety outcomes (HR: 0.79, 95% CI: 0.66-0.94, P=0.01) compared to reduced dosing (HR: 0.83, 95% CI: 0.71-0.97, P=0.02). Notable differences in major bleeding, gastrointestinal bleeding (GIB), and intracranial bleeding favored standard dosing. Hemorrhagic stroke and all-cause stroke rates differed significantly, with standard dosing showing a more favorable profile for ischemic stroke prevention. This study highlights the pivotal role of personalized anticoagulation therapy in AF. Standard dosing of rivaroxaban emerges as a preferred strategy for stroke prevention, balancing efficacy and safety. Clinical decision-making should consider individual patient characteristics and future research should delve into specific subpopulations and long-term outcomes to further refine treatment guidelines. The study bridges evidence from clinical trials to real-world practice, offering insights into the evolving landscape of AF management.