Miconazole Suppresses 27-Hydroxycholesterol-induced Inflammation by Regulating Activation of Monocytic Cells to a Proinflammatory Phenotype

Miconazole is effective in treating inflammatory skin conditions and has well-established antifungal effects. To elucidate the underlying mechanisms mediating its additional beneficial effects, we assessed whether miconazole influences the inflammation induced by 27-hydroxycholesterol (27OHChol), an oxygenated cholesterol derivative with high proinflammatory activity, using THP-1 monocytic cells. Miconazole dose-dependently inhibited the expression of proinflammatory markers, including CCL2 and CCR5 ligands such as CCL3 and CCL4, and impaired the migration of monocytic cells and CCR5-positive T cells. In the presence of 27OHChol, miconazole decreased CD14 surface levels and considerably weakened the lipopolysaccharide response. Furthermore, miconazole blocked the release of soluble CD14 and impaired the transcription of the matrix metalloproteinase-9 gene and secretion of its active gene product. Additionally, it downregulated the expression of ORP3 and restored the endocytic function of THP-1 cells. Collectively, these findings indicate that miconazole regulates the 27OHChol-induced expression of proinflammatory molecules in monocytic cells, thereby suppressing inflammation in an oxysterol-rich milieu.

Elevated plasma von Willebrand factor levels are associated with subsequent ischemic stroke in persons with treated HIV infection

Background We assessed whether key biomarkers of endothelial activation and hemostasis/thrombosis were elevated in individuals receiving effective antiretroviral therapy (ART) in the year before ischemic stroke. Methods We conducted a case-control study nested in the CNICS cohort, comparing 42 adjudicated cases with ischemic stroke to 83 controls matched for ART regimen. Angiopoietin-1, angiopoietin-2, C-reactive protein, interleukin-6, plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, ICAM-1, VCAM-1, apolipoprotein A1, ADAMTS13, and von Willebrand factor (VWF) were measured in stored plasma collected before the stroke event. We used conditional logistic regression to identify associations with ischemic stroke, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores. Results After adjustment for age and sex, higher plasma viral load and higher angiopoeitin-2, soluble CD14, and VWF were associated with increased odds of ischemic stroke; higher nadir CD4 count was associated with decreased odds of ischemic stroke. VWF remained associated with subsequent ischemic stroke after adjustment for ASCVD score (adjusted odds 1.74, 95%CI 1.01–2.98 per log2 increment). In a separate model adjusting for VACS score, only VWF (adjusted odds 1.80, 95% CI 1.04–3.12 per log2 increment) was associated with subsequent ischemic stroke. In a sensitivity analysis excluding participants with viral load ≥400 copies/mL, associations between VWF and ischemic stroke were attenuated, with risk estimates ranging from 1.59–1.64 per log2 increment. Conclusions Endothelial activation and related release and attachment of VWF may play an important role in ischemic stroke among persons living with treated HIV infection.

Bacterial Translocation Associates With Aggression in Schizophrenia Inpatients

Objective: Accumulating evidence indicates that inflammation abnormalities may contribute to aggression behaviors in psychotic patients, however, the possible sources of inflammation remain elusive. We aimed to evaluate the associations among aggression, inflammation, and bacterial translocation (BT) in aggression-affected schizophrenia (ScZ) inpatients with 2 weeks of antipsychotics discontinuation.Methods: Serum specimens collected from 112 aggression and 112 non-aggression individuals with ScZ and 56 healthy adults were used for quantifications of inflammation- or BT-related biomarkers. Aggression severity was assessed by Modified Overt Aggression Scale (MOAS).Results: Proinflammation phenotype dominated and leaky gut-induced BT occurred only in cases with ScZ with a history of aggression, and the MOAS score positively related to levels of C-reactive protein, interleukin (IL)-6, IL-1β, and tumor necrosis factor-α. Furthermore, serum levels of BT-derived lipopolysaccharide (LPS), as well as LPS-responded soluble CD14, were not only positively correlated with levels of above proinflammation mediators but also the total MOAS score and subscore for aggression against objects or others.Conclusion: Our results collectively demonstrate the presence of leaky gut and further correlate BT-derived LPS and soluble CD14 to onset or severity of aggression possibly by driving proinflammation response in inpatients with ScZ, which indicates that BT may be a novel anti-inflammation therapeutic target for aggression prophylaxis.

sCD14 Level in Saliva of Children and Adolescents with and without Dental Caries, a Hurdle Model

Objective: Soluble CD14 (sCD14) plays an important role in the innate immune response of the oral cavity. The investigation of this biomarker for detection of carious lesions is an even more actual procedure due to its non-invasiveness and the ease of withdrawal. The purpose of the present observational case-control study was to evaluate whether the quantification of sCD14 in children and adolescent’s saliva can discriminate healthy subjects from those suffering from tooth decay. Materials and Methods: 164 subjects (6 to 17 years) were selected and divided into 2 groups: those with at least 1 decayed tooth were assigned to group Decayed (n = 82) and those free from dental caries to group Healthy (n = 82). The amount of salivary soluble CD14 was quantified. Results: Mean salivary soluble CD14 was 28.3 ± 10.8 μg/mL in the Healthy group and 22 ± 9.6 μg/mL in the Decayed group. A hurdle model was applied to the data to estimate both the probability of having carious lesions and their number in relation to sCD14 levels. sCD14 was strongly associated (p < 0.01) with an inverse relation to both the probability of having caries and their number (falling rate of 5% per unit CD14 μg/mL). Conclusions: This data confirms the relationship between sCD14 and the presence of dental caries. However, there is no clear cut off level between healthy and unhealthy subjects, so it is currently not possible to use sCD14 as a biomarker to determine the risk of decays.

The macrophage reprogramming ability of antifolates reveals soluble CD14 as a potential biomarker for methotrexate response in rheumatoid arthritis

The physio-pathological relevance of the one-carbon metabolism (OCM) is illustrated by the chemotherapeutic and anti-inflammatory effects of the antifolates Pemetrexed (PMX) and Methotrexate (MTX) in cancer and rheumatoid arthritis (RA). We report that OCM determines the functional and gene expression profile of human macrophages. PMX induces the acquisition of a p53-dependent proinflammatory gene signature in human monocyte-derived macrophages (GM-Mθ). Indeed, OCM blockade reprograms GM-Mθ towards a state of LPS-tolerance at the signaling and functional levels, an effect abolished by folinic acid. Importantly, OCM blockade led to reduced expression of membrane-bound and soluble CD14 (sCD14), whose exogenous addition restores LPS sensitivity. The therapeutic relevance of these results was confirmed in early RA patients, as MTX-responder RA patients exhibit lower sCD14 serum levels, with baseline sCD14 levels predicting MTX response. Our results indicate that OCM is a metabolic circuit that critically mediates the acquisition of innate immune tolerance, and positions sCD14 as a valuable tool to predict MTX-response in RA patients.

Soluble CD14 Levels in the Jackson Heart Study: Associations With Cardiovascular Disease Risk and Genetic Variants

Objective: sCD14 (soluble CD14) is a circulating pattern recognition receptor involved in inflammatory signaling. Although it is known that sCD14 levels vary by race, information on the genetic and cardiovascular disease (CVD) risk relationships of sCD14 in Black participants is limited. Approach and Results: We measured sCD14 in plasma at the baseline exam from n=3492 Black participants from the JHS (Jackson Heart Study). We evaluated associations between sCD14 and subclinical CVD measures, incident CVD events, and mortality under 3 levels of covariate adjustment. We used whole-genome sequence data from the Trans-Omics for Personalized Medicine program to identify genetic associations with sCD14. Adjusting for CVD risk factors and C-reactive protein, higher sCD14 was significantly associated with increased risk of mortality (hazard ratio, 1.25 [95% CI, 1.17–1.32]), incident coronary heart disease (hazard ratio, 1.28 [95% CI, 1.11–1.47]), and incident heart failure (hazard ratio, 1.27 [95% CI, 1.15–1.41]), but not stroke (hazard ratio, 0.96 [95% CI, 0.84–1.09]). Some of these relationships differed by age or sex: the association between sCD14 and heart failure was only observed in females; there was an association between sCD14 and stroke only at younger ages (in the lowest tertile of age, <49.4 years). We replicated the association between sCD14 levels with African ancestry-specific allele (rs75652866) on the CD14 region of chromosome 5q31. We additionally identified 2 novel statistically distinct genetic associations with sCD14 represented by index variants rs770147646 and rs57599368, also in the chromosome 5q31 region. Conclusions: sCD14 independently predicts CVD-related outcomes and mortality in Black participants.

An assessment of potential biomarkers of environment enteropathy and its association with age and microbial infections among children in Bangladesh

Interventional studies targeting environment enteropathy (EE) are impeded by the lack of appropriate, validated, non-invasive biomarkers of EE. Thus, we aimed to validate the association of potential biomarkers for EE with enteric infections and nutritional status in a longitudinal birth cohort study. We measured endotoxin core antibody (EndoCab) and soluble CD14 (sCD14) in serum, and myeloperoxidase (MPO) in feces using commercially available enzyme-linked immunosorbent assay (ELISA) kits. We found that levels of serum EndoCab and sCD14 increase with the cumulative incidence of enteric infections. We observed a significant correlation between the fecal MPO level in the children at 24 months of age with the total number of bacterial and viral infections, the total number of parasitic infections, and the total number of diarrheal episodes and diarrheal duration. We observed that the levels of serum EndoCab, sCD14, and fecal MPO at 3 months of age were significantly associated with whether children were malnourished at 18 months of age or not. Biomarkers such as fecal MPO, serum EndoCab and sCD14 in children at an early age may be useful as a measure of cumulative burden of preceding enteric infections, which are predictive of subsequent malnutrition status and may be useful non-invasive biomarkers for EE.