The severity of COVID-19 upon hospital admission is associated with plasma omega-3 fatty acids.

Fatty acids are precursors of inflammatory oxylipins. In the context of COVID-19, an excessive production of pro-inflammatory cytokines is associated with disease severity. The objective was to investigate whether the baseline omega 3/omega 6 fatty acids ratio and the oxylipins were associated with inflammation and oxidative stress in unvaccinated patients with COVID-19, classified according to the severity of the disease during hospitalization. This Prospective population-based cohort study included 180 hospitalized patients with COVID-19. The patients were classified into five groups according to the severity of their disease. Group 1 was the least severe and Group 5 was the most severe. Three specific types of fatty acids-eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)-as well as their enzymatic and non-enzymatic oxylipins were determined using chromatography coupled mass spectrometry. There was no difference in the ratio of omega-3 to omega-6 fatty acids between the groups (p = 0.276). However, the EPA/AA ratio was lower in Group 4 compared to Group 1 (p = 0.015). This finding was associated with an increase in both C-Reactive Protein (p < 0.001) and Interleukin-6 (p = 0.002). Furthermore, the concentration of F2-Isoprostanes was higher in Group 4 than in Group 1 (p = 0.009), while no significant changes were observed for other oxylipins among groups. Multivariate analysis did not present any standard of biomarkers, suggesting the high complexity of factors involved in the disease severity. Our hypothesis was confirmed in terms of EPA/AA ratio. A higher EPA/AA ratio upon hospital admission was found to be associated with lower concentration of C-Reactive Protein and Interleukin-6, leading to a better prognosis of hospitalized SARS-CoV-2 patients. Importantly, this beneficial outcome was achieved without any form of supplementation. The trial also provides important information that can be further applied to reduce the severity of infections associated with an uncontrolled synthesis of pro-inflammatory cytokines.Trial registration: https://clinicaltrials.gov/study/NCT04449718 -01/06/2020. ClinicalTrials.gov Identifier: NCT04449718.

An integrative multi-omics approach to characterize interactions between tuberculosis and diabetes mellitus.

Tuberculosis-diabetes mellitus (TB-DM) is linked to a distinct inflammatory profile, which can be assessed using multi-omics analyses. Here, a machine learning algorithm was applied to multi-platform data, including cytokines and gene expression in peripheral blood and eicosanoids in urine, in a Brazilian multi-center TB cohort. There were four clinical groups: TB-DM(n = 24), TB only(n = 28), DM(HbA1c ≥ 6.5%) only(n = 11), and a control group of close TB contacts who did not have TB or DM(n = 13). After cross-validation, baseline expression or abundance of MMP-28, LTE-4, 11-dTxB2, PGDM, FBXO6, SECTM1, and LINCO2009 differentiated the four patient groups. A distinct multi-omic-derived, dimensionally reduced, signature was associated with TB, regardless of glycemic status. SECTM1 and FBXO6 mRNA levels were positively correlated with sputum acid-fast bacilli grade in TB-DM. Values of the biomarkers decreased during the course of anti-TB therapy. Our study identified several markers associated with the pathophysiology of TB-DM that could be evaluated in future mechanistic investigations.

Effect of Dysglycemia on Urinary Lipid Mediator Profiles in Persons With Pulmonary Tuberculosis.

Background: Oxidized lipid mediators such as eicosanoids play a central role in the inflammatory response associated with tuberculosis (TB) pathogenesis. Diabetes mellitus (DM) leads to marked changes in lipid mediators in persons with TB. However, the associations between diabetes-related changes in lipid mediators and clearance of M. tuberculosis (Mtb) among persons on anti-TB treatment (ATT) are unknown. Quantification of urinary eicosanoid metabolites can provide insights into the circulating lipid mediators involved in Mtb immune responses. Methods: We conducted a multi-site prospective observational study among adults with drug-sensitive pulmonary TB and controls without active TB; both groups had sub-groups with or without dysglycemia at baseline. Participants were enrolled from RePORT-Brazil (Salvador site) and RePORT-South Africa (Durban site) and stratified according to TB status and baseline glycated hemoglobin levels: a) TB-dysglycemia (n=69); b) TB-normoglycemia (n=64); c) non-TB/dysglycemia (n=31); d) non-TB/non-dysglycemia (n=29). We evaluated the following urinary eicosanoid metabolites: 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (major urinary metabolite of prostaglandin E2, PGE-M), tetranor-PGE1 (metabolite of PGE2, TN-E), 9α-hydroxy-11,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (metabolite of PGD2, PGD-M), 11-dehydro-thromboxane B2 (11dTxB2), 2,3-dinor-6-keto-PGF1α (prostaglandin I metabolite, PGI-M), and leukotriene E4 (LTE4). Comparisons between the study groups were performed at three time points: before ATT and 2 and 6 months after initiating therapy. Results: PGE-M and LTE4 values were consistently higher at all three time-points in the TB-dysglycemia group compared to the other groups (p<0.001). In addition, there was a significant decrease in PGI-M and LTE4 levels from baseline to month 6 in the TB-dysglycemia and TB-normoglycemia groups. Finally, TB-dysglycemia was independently associated with increased concentrations of PGD-M, PGI-M, and LTE4 at baseline in a multivariable model adjusting for age, sex, BMI, and study site. These associations were not affected by HIV status. Conclusion: The urinary eicosanoid metabolite profile was associated with TB-dysglycemia before and during ATT. These observations can help identify the mechanisms involved in the pathogenesis of TB-dysglycemia, and potential biomarkers of TB treatment outcomes, including among persons with dysglycemia.

Haloperidol Interactions with the dop-3 Receptor in Caenorhabditis elegans.

Haloperidol is a typical antipsychotic drug commonly used to treat a broad range of psychiatric disorders related to dysregulations in the neurotransmitter dopamine (DA). DA modulates important physiologic functions and perturbations in Caenorhabditis elegans (C. elegans) and, its signaling have been associated with alterations in behavioral, molecular, and morphologic properties in C. elegans. Here, we evaluated the possible involvement of dopaminergic receptors in the onset of these alterations followed by haloperidol exposure. Haloperidol increased lifespan and decreased locomotor behavior (basal slowing response, BSR, and locomotion speed via forward speed) of the worms. Moreover, locomotion speed recovered to basal conditions upon haloperidol withdrawal. Haloperidol also decreased DA levels, but it did not alter neither dop-1, dop-2, and dop-3 gene expression, nor CEP dopaminergic neurons' morphology. These effects are likely due to haloperidol's antagonism of the D2-type DA receptor, dop-3. Furthermore, this antagonism appears to affect mechanistic pathways involved in the modulation and signaling of neurotransmitters such as octopamine, acetylcholine, and GABA, which may underlie at least in part haloperidol's effects. These pathways are conserved in vertebrates and have been implicated in a range of disorders. Our novel findings demonstrate that the dop-3 receptor plays an important role in the effects of haloperidol.

Repeated measures of urinary oxidative stress biomarkers and preterm birth in Puerto Rico.

BACKGROUND: Preterm birth (PTB; gestational age <37 weeks), the leading cause of infant morbidity and mortality worldwide, is of particular concern in Puerto Rico. Rates of PTB in Puerto Rico peaked at 20% in 2006, which are historically some of the highest in the world. Oxidative stress and inflammation have been implicated as contributors to adverse birth outcomes, including PTB, and these associations have not been explored in Puerto Rico. Our objective was to examine associations between urinary oxidative stress biomarkers and PTB in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) pregnancy cohort (N = 469). METHODS: 8-iso-prostaglandin F2α (8-iso-PGF2α), its primary metabolite, and prostaglandin F2α (PGF2α) were included as biomarkers of oxidative stress or inflammation. Biomarkers were measured in urine samples collected at up to 3 timepoints across pregnancy (mean 18, 24, 28 weeks gestation). We quantified the proportion of 8-iso-PGF2α originating from oxidative stress and inflammation pathways with a formula based on the ratio of 8-iso-PGF2α to PGF2α. Logistic regression models were used to calculate adjusted odds ratios (OR) for associations between average biomarker concentrations from each woman (visits 1-3) and PTB. Associations between biomarker concentrations at each study visit and PTB were analyzed in separate models. RESULTS: Averaged levels of 8-iso-PGF2α, its primary metabolite, and PGF2α were associated with increased odds of PTB (OR = 1.64, 95% confidence interval [CI] = 1.07-2.54; OR = 1.79, 95% CI = 1.14-2.84; OR = 1.98, 95% CI = 1.32-3.02, respectively). Odds ratios for PTB were greater in magnitude in association with oxidative stress biomarkers measured later in pregnancy. The fraction of 8-iso-PGF2α derived from inflammation was associated with PTB (OR = 1.73, 95% CI = 1.09, 2.93), while the fraction of 8-iso-PGF2α derived from oxidative stress was not associated with PTB (OR = 1.17, 95% CI = 0.90, 1.54). CONCLUSIONS: Our results suggest that oxidative stress and inflammation, as measured by these biomarkers, may be important contributors to PTB. Further research is needed to improve our understanding of the role these biomarkers may play in the causal pathway between environmental factors and PTB.

Associations between socioeconomic status, psychosocial stress, and urinary levels of 8-iso-prostaglandin-F2α during pregnancy in Puerto Rico.

BACKGROUND: Lower socioeconomic status (SES) and psychosocial stress during pregnancy have been associated with adverse birth outcomes. While hypothalamic-pituitary-axis activation is thought to be the primary driver, oxidative stress may also be involved mechanistically. We used data from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort (N=476) to examine associations between self-reported psychosocial stress measures, SES indicators, and urinary oxidative stress biomarker concentrations, hypothesizing that women with lower SES and increased psychosocial stress would have elevated oxidative stress biomarkers. METHODS: Maternal age, education, marital status, insurance status, alcohol use and smoking status were obtained via self-reported questionnaires and were used as indicators of SES. Perceived stress, depression, negative life experiences, neighborhood perceptions, and social support were self-reported in questionnaires administered during pregnancy. Responses were grouped into tertiles for analysis, where the highest tertile corresponded to highest level of psychosocial stress. Urinary concentrations of 8-iso-prostaglandin F2α (8-iso-PGF2α) and its primary metabolite were measured at three study visits (median 18, 24, 28 weeks gestation) and averaged to reflect oxidative stress across pregnancy. Linear models were used to examine associations between SES indicators, tertiles of psychosocial stress and oxidative stress biomarkers. RESULTS: Average levels of 8-iso-PGF2α and the 8-iso-PGF2α metabolite were higher among pregnant women who were younger, who had public compared to private insurance, and who were unemployed compared to employed. However, no associations were observed between psychosocial stress measures and biomarker concentrations in adjusted analyses. CONCLUSIONS: Psychosocial stress during pregnancy, as indicated by self-reported questionnaire measures, was not associated with biomarkers of oxidative stress in the PROTECT study. However, results suggest that these biomarkers are elevated among women of lower SES, which is typically associated with stress. Notably, compared to other populations, self-reported psychosocial stress measures were lower in PROTECT compared to other populations.

Oxidative stress in relation to diet and physical activity among premenopausal women.

Higher levels of oxidative stress, as measured by F2-isoprostanes, have been associated with chronic diseases such as CVD and some cancers. Improvements in diet and physical activity may help reduce oxidative stress; however, previous studies regarding associations between lifestyle factors and F2-isoprostane concentrations have been inconsistent. The aim of this cross-sectional study was to investigate whether physical activity and intakes of fruits/vegetables, antioxidant nutrients, dietary fat subgroups and alcohol are associated with concentrations of F2-isoprostane and the major F2-isoprostane metabolite. Urinary F2-isoprostane and its metabolite were measured in urine samples collected at enrolment from 912 premenopausal women (aged 35-54 years) participating in the Sister Study. Physical activity, alcohol consumption and dietary intakes were self-reported via questionnaires. With adjustment for potential confounders, the geometric means of F2-isoprostane and its metabolite were calculated according to quartiles of dietary intakes, alcohol consumption and physical activity, and linear regression models were used to evaluate trends. Significant inverse associations were found between F2-isoprostane and/or its metabolite and physical activity, vegetables, fruits, vitamin C, α-carotene, vitamin E, ß-carotene, vitamin A, Se, lutein+zeaxanthin and long-chain n-3 fatty acids. Although trans fats were positively associated with both F2-isoprostane and its metabolite, other dietary fat subgroups including SFA, n-6 fatty acids, n-3 fatty acids, MUFA, PUFA, short-chain n-3 fatty acids, long-chain n-3 fatty acids and total fat were not associated with either F2-isoprostane or its metabolite. Our findings suggest that lower intake of antioxidant nutrients and higher intake of trans fats may be associated with greater oxidative stress among premenopausal women.

The effect of HIV and HPV coinfection on cervical COX-2 expression and systemic prostaglandin E2 levels.

Human immunodeficiency virus (HIV-1) infection causes chronic inflammation. COX-2-derived prostaglandin E(2) (PGE(2)) has been linked to both inflammation and carcinogenesis. We hypothesized that HIV-1 could induce COX-2 in cervical tissue and increase systemic PGE(2) levels and that these alterations could play a role in AIDS-related cervical cancer. Levels of cervical COX-2 mRNA and urinary PGE-M, a biomarker of systemic PGE(2) levels, were determined in 17 HIV-negative women with a negative cervical human papilloma virus (HPV) test, 18 HIV-infected women with a negative HPV test, and 13 HIV-infected women with cervical HPV and high-grade squamous intraepithelial lesions on cytology. Cervical COX-2 levels were significantly associated with HIV and HPV status (P = 0.006 and 0.002, respectively). Median levels of urinary PGE-M were increased in HIV-infected compared with uninfected women (11.2 vs. 6.8 ng/mg creatinine, P = 0.02). Among HIV-infected women, urinary PGE-M levels were positively correlated with plasma HIV-1 RNA levels (P = 0.003). Finally, levels of cervical COX-2 correlated with urinary PGE-M levels (P = 0.005). This study shows that HIV-1 infection is associated with increased cervical COX-2 and elevated systemic PGE(2) levels. Drugs that inhibit the synthesis of PGE(2) may prove useful in reducing the risk of cervical cancer or systemic inflammation in HIV-infected women.