Exploring interleukin-6, lipopolysaccharide binding protein and brain-derived neurotrophic factor following 12 weeks of adjunctive minocycline treatment for depression

Objective: This study aimed to explore effects of adjunctive minocycline treatment on inflammatory and neurogenesis markers in major depressive disorder (MDD). Methods: Serum samples were collected from a randomised, placebo-controlled 12-week clinical trial of minocycline (200mg/day, added to treatment as usual) for adults (n=71) experiencing MDD to determine changes in interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) and brain derived neurotrophic factor (BDNF). General Estimate Equation modelling explored moderation effects of baseline markers and exploratory analyses investigated associations between markers and clinical outcomes. Results: There was no difference between adjunctive minocycline or placebo groups at baseline or week 12 in the levels of IL-6 (week 12; placebo 2.06±1.35 pg/ml; minocycline 1.77±0.79 pg/ml; p=0.317), LBP (week 12; placebo 3.74±0.95 µg/ml; minocycline 3.93±1.33 µg/ml; p=0.525) or BDNF (week 12; placebo 24.28±6.69 ng/ml; minocycline 26.56±5.45 ng/ml; p=0.161). Higher IL-6 levels at baseline were a predictor of greater clinical improvement. Exploratory analyses suggested that the change in IL-6 levels were significantly associated with anxiety symptoms (HAMA; p=0.021) and quality of life (Q-LES-Q-SF; p=0.023) scale scores. No other clinical outcomes were shown to have this mediation effect, nor did the other markers (LBP or BDNF) moderate clinical outcomes. Conclusion: There were no overall changes in IL-6, LBP or BDNF following adjunctive minocycline treatment. Exploratory analyses suggest a potential role of IL-6 on mediating anxiety symptoms with MDD. Future trials may consider enrichment of recruitment by identifying several markers or a panel of factors to better represent an inflammatory phenotype in MDD with larger sample size.

Platelet Toll-Like Receptor 4–Related Innate Immunity Potentially Participates in Transfusion Reactions Independent of ABO Compatibility: An Ex Vivo Study

The role of platelet TLR4 in transfusion reactions remains unclear. This study analyzed platelet TLR4 and certain damage-associated molecular patterns (DAMPs) and evaluated how ABO compatibility affected TLR4 expression after a simulated ex vivo transfusion. A blood bank was the source of donor red blood cells. Blood from patients undergoing cardiac surgery was processed to generate a washed platelet suspension to which the donor blood was added in concentrations 1, 5, and 10% (v/v). Blood-mixing experiments were performed on four groups: a 0.9% saline control group (n = 31); a matched-blood-type mixing group (group M, n = 20); an uncross-matched ABO-specific mixing group (group S, n = 20); and an ABO-incompatible blood mixing group (group I, n = 20). TLR4 expression in the platelets was determined after blood mixing. We evaluated levels of TLR4-binding DAMPs (HMGB1, S100A8, S100A9, and SAA), lipopolysaccharide-binding protein, and endpoint proteins in the TLR4 signaling pathway. In the M, S, and I groups, 1, 5, and 10% blood mixtures significantly increased TLR4 expression (all p < 0.001) in a concentration-dependent manner. Groups M, S, and I were not discovered to have significantly differing TLR4 expression (p = 0.148). HMGB1, S100A8, and S100A9 levels were elevated in response to blood mixing, but SAA, lipopolysaccharide-binding protein, TNF-α, IL-1β, and IL-6 levels were not. Blood mixing may elicit innate immune responses by upregulating platelet TLR4 and DAMPs unassociated with ABO compatibility, suggesting that innate immunity through TLR4-mediated signaling may induce transfusion reactions.

Shift Work Predicts Increases in Lipopolysaccharide-Binding Protein, Interleukin-10, and Leukocyte Counts in a Cross-Sectional Study of Healthy Volunteers Carrying Low-Grade Systemic Inflammation

The disruption of inflammatory responses is a potential mechanism behind the harmful effects of shift work and is associated with increased risk of hypertension, stroke, obesity, diabetes, and cancer. These responses are linked to the proliferation of leukocytes in shift workers, suggesting a systemic signal as a potential mediator. The purpose of this study was to assess the relationship between systemic inflammation, leukocyte counts, and systemic endotoxemia in samples from a diverse cohort of day workers and shift workers. Participants (normothermic and normotensive) were healthy volunteers, non-smoking, and drug- and medication-free. The following outcomes were measured: C-reactive protein, TNF-α, IL-6, IL-1β, IL-10, leukocyte counts (monocytes, lymphocytes, and neutrophils), and lipopolysaccharide-binding protein (LBP). Risk factors that increase systemic inflammation, such as blood pressure, sleep loss, and cortisol, were also assessed. The results indicated that shift workers slept significantly less than day workers and had significantly increased concentrations of all of the cytokines measured as well as plasma cortisol. Regression models found that after controlling for covariates, shift-work exposure predicted the significant increase observed in IL-10, leukocyte counts, and LBP. Our results suggest that acute increases in low-grade systemic endotoxemia are unresolved during chronic shift-work exposure. This ongoing immune challenge may underlie the disrupted inflammatory responses characteristic of shift-work-related pathologies. Systemic endotoxemia may represent a novel target to investigate the early effects of exposure to shift-work schedules.

Effect of Time Restricted Feeding on Anthropometric Measures, Body Composition, Eating Behavior, Stress, Brain Derived Neurotrophic Factor (BDNF) and Lipopolysaccharide Binding Protein (LBP) Levels in Food Addicted Over Weight and Obese Women: A Study Protocol for a RRandomized Clinical Trial

Background: Food addiction, the desire to eat compulsively and excessively palatable foods, is one of the behavioral factors that plays an important role in pathogenesis of obesity. Food addiction, like drug addiction, changes the dopaminergic system in rewards region of brain, but at lower levels. There are evidence suggesting brain-derived neurotrophic factor (BDNF) is synthesized in dopaminergic pathways in the reward regions of the brain and is involved in regulating food intake and body weight. BDNF is also associated with eating disorders in humans and hyperphagia in mice. On the other hand, it has been shown that the intestinal microbiome is effective in eating behavior through the production of neuronal and hormonal mediators, including BDNF. Intestinal microbiome changes greatly under the influence of diet. It has been shown that a time-restricted feeding (TRF) has been able to maintain fluctuations in the intestinal microbiome in response to the body's circadian rhythm. Furthermore, increased pathogens in the gut are associated with increased release of polysaccharides from the bacterial wall, resulting in increased levels of lipopolysaccharide binding protein (LBP). This study will aim to evaluate the effect of TRF on anthropometric measures, body composition, eating behavior, stress level, BDNF and LBP levels in over weight and obese women with food addiction.Methods/design: we will carry on a randomized clinical trial for 8 weeks to evaluate the effect of a TRF on anthropometric measures, body composition, eating behavior, stress level, BDNF and LBP levels in obese and overweight women with food addiction.Discussion: Given the effect of BDNF on regulating eating behavior and body weight and the effect of dietary restrictions on BDNF and the gut microbiome, the TRF diet could possibly be a new way to successfully manage weight through modifying BDNF in people with eating disorders, including food addiction.Trial Registration: Iranian Registry of Clinical Trials. IRCT20131228015968N7. Registered on 2020-10-25.

CD14 and LBP as Novel Biomarkers for Sarcoidosis by Proteomics of Extracellular Vesicles

Sarcoidosis is an inflammatory granulomatous multi-organ disease of unknown cause. The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. Extracellular vesicles (EVs) play important roles in intercellular communication. Isolated serum EVs from seven patients with sarcoidosis and five control subjects were subjected to non-targeted proteomics analysis. Then 2,292 proteins were detected; 42 proteins were upregulated in patients with sarcoidosis relative to control subjects, and 324 proteins were downregulated. The protein signature of EVs from patients with sarcoidosis reflected disease characteristics such as antigen presentation and immunological disease. Candidate biomarkers were further verified by targeted proteomics analysis in 46 patients and 10 control subjects. CD14 and lipopolysaccharide-binding protein (LBP) were validated by targeted proteomics analysis and upregulation of them was confirmed by immunoblotting. Their expression was also upregulated in macrophages of lung granulomatous lesions. Consistent with these findings, CD14 levels were increased in lipopolysaccharide-stimulated macrophages during multinucleation, concomitant with increased levels of CD14 and LBP in EVs. The area under the curve values of CD14 and LBP were 0.81 and 0.84, respectively. Thus CD14 and LBP in serum EVs, which are associated with granulomatous pathogenesis, can improve the diagnostic accuracy in patients with sarcoidosis.

Chronic Oral Administration of Mineral Oil Compared With Corn Oil: Effects on Gut Permeability and Plasma Inflammatory and Lipid Biomarkers

We investigated the effects of chronic oral administration of mineral oil, versus corn oil as control, on intestinal permeability, inflammatory markers, and plasma lipids in APOE*3-Leiden.CETP mice. Mice received mineral oil or corn oil 15 or 30 μL/mouse/day for 16 weeks (15 mice/group). Intestinal permeability was increased with mineral versus corn oil 30 µL/day, shown by increased mean plasma FITC-dextran concentrations 2 h post-administration (11 weeks: 1.5 versus 1.1 μg/ml, p = 0.02; 15 weeks: 1.7 versus 1.3 μg/ml, p = 0.08). Mean plasma lipopolysaccharide-binding protein levels were raised with mineral versus corn oil 30 µL/day (12 weeks: 5.8 versus 4.4 μg/ml, p = 0.03; 16 weeks: 5.8 versus 4.5 μg/ml, p = 0.09), indicating increased intestinal bacterial endotoxin absorption and potential pro-inflammatory effects. Plasma cholesterol and triglyceride concentrations were decreased with mineral oil, without affecting liver lipids among treated groups. Fecal neutral sterol measurements indicated increased fecal cholesterol excretion with mineral oil 30 µL/day (+16%; p = 0.04). Chronic oral administration of mineral oil in APOE*3-Leiden.CETP mice increased intestinal permeability, with potential pro-inflammatory effects, and decreased plasma cholesterol and triglyceride levels. Our findings may raise concerns about the use of mineral oil as a placebo in clinical studies.