Common Supplements Found To Lower Circulating Inflammation Levels

Glucosamine and chondroitin are popular non-vitamin dietary supplements used for osteoarthritis. Long-term use is associated with lower incidence of colorectal and lung cancers and with lower mortality; however, the mechanism underlying these observations is unknown. In vitro and animal studies show that glucosamine and chondroitin inhibit NF-kB, a central mediator of inflammation, but no definitive trials have been done in healthy humans.We conducted a randomized, double-blind, placebo-controlled, cross-over study to assess the effects of glucosamine hydrochloride (1500 mg/d) plus chondroitin sulfate (1200 mg/d) for 28 days compared to placebo in 18 (9 men, 9 women) healthy, overweight (body mass index 25.0-32.5 kg/m2) adults, aged 20-55 y. We examined 4 serum inflammatory biomarkers: C-reactive protein (CRP), interleukin 6, and soluble tumor necrosis factor receptors I and II; a urinary inflammation biomarker: prostaglandin E2-metabolite; and a urinary oxidative stress biomarker: F2-isoprostane. Plasma proteomics on an antibody array was performed to explore other pathways modulated by glucosamine and chondroitin.Serum CRP concentrations were 23% lower after glucosamine and chondroitin compared to placebo (P = 0.048). There were no significant differences in other biomarkers. In the proteomics analyses, several pathways were significantly different between the interventions after Bonferroni correction, the most significant being a reduction in the "cytokine activity" pathway (P = 2.6 x 10-16), after glucosamine and chondroitin compared to placebo.Glucosamine and chondroitin supplementation may lower systemic inflammation and alter other pathways in healthy, overweight individuals. This study adds evidence for potential mechanisms supporting epidemiologic findings that glucosamine and chondroitin are associated with reduced risk of lung and colorectal cancer.ClinicalTrials.gov NCT01682694

Cruciferous vegetable feeding alters UGT1A1 activity: diet- and genotype-dependent changes in serum bilirubin in a controlled feeding trial.

Chemoprevention by isothiocyanates from cruciferous vegetables occurs partly through up-regulation of phase-II conjugating enzymes, such as UDP-glucuronosyl-transferases (UGT). UGT1A1 glucuronidates bilirubin, estrogens, and several dietary carcinogens. The UGT1A1*28 polymorphism reduces transcription compared to the wild-type, resulting in decreased enzyme activity. Isothiocyanates are metabolized by glutathione-S-transferases (GST); variants may alter isothiocyanate clearance, such that response to crucifers may vary by genotype. We evaluated, in a randomized, controlled, cross-over feeding trial in humans (n=70), 3 test diets, (single- and double-“dose” cruciferous and cruciferous plus apiaceous) compared to a fruit-and-vegetable-free basal diet. We measured serum bilirubin concentrations on days 0, 7, 11 and 14 of each 2-week feeding period to monitor UGT1A1 activity, and determined effects of UGT1A1*28 and GSTM1/GSTT1-null variants on response. Aggregate bilirubin response to all vegetable-containing diets was statistically significantly lower compared to the basal diet (p<0.03 for all). Within each UGT1A1 genotype, lower bilirubin concentrations were seen in: *1/*1 in both single and double-dose cruciferous diets compared to basal (p<0.03 for both); *1/*28 in double-dose cruciferous and cruciferous plus apiaceous compared to basal, and cruciferous plus apiaceous compared to single-dose cruciferous (p<0.02 for all); and *28/*28 in all vegetable-containing diets compared to basal (p<0.02 for all). Evaluation of the effects of diet stratified by GST genotype revealed some statistically significant genotypic differences however, the magnitude was similar and not statistically significant between genotypes. These results may have implications for altering carcinogen metabolism through dietary intervention, particularly among UGT1A1*28/*28 individuals

Modulation of human serum glutathione S-transferase-A1/2 concentration by cruciferous vegetables in a controlled feeding study is influenced by GSTM1 and GSTT1 genotypes

Glutathione S-transferases (GST) detoxify a wide range of carcinogens. Isothiocyanates (ITC), from cruciferous vegetables, are substrates for, and inducers of GST. GST variants may alter ITC clearance such that response to crucifers varies by genotype. In a randomized cross-over trial, we tested the hypothesis that changes in serum GSTA1/2 concentration in response to cruciferous vegetable feeding depends on GSTM1/GSTT1 genotype. Thirty-three men and 34 women (age 20-40 yr), ate four 14-day controlled diets: basal (vegetable-free), basal supplemented with 2 different doses of crucifers, (single-“dose” and double-“dose”) and single-dose cruciferous-plus-apiaceous vegetables, fed per kg body weight. Fasting bloods from days 0, 7, 11, and 14 of each diet period were analyzed for serum GSTA1/2 by ELISA. GSTA1/2 increased with single- and double-dose cruciferous compared to basal diet (10% and 13%, respectively; P = 0.02 and 0.004), but cruciferous-plus-apiaceous did not differ from basal (P = 0.59). Overall, GSTA1/2 was higher in GSTM1-null/GSTT1-null than GSTM1+/GSTT1+ individuals (4198 ± 338 and 3372 ± 183 pg/ml; P = 0.03). The formal interaction of genotype-by-diet was not statistically significant, but the GSTA1/2 increase during the single-dose cruciferous diet was among GSTM1-null/GSTT1-null individuals (by 28%; P = 0.008), largely explained by GSTM1-null/GSTT1-null men (by 41%; P = 0.01). GSTA1/2 increased during the double-dose cruciferous diet in both GSTM1-null/GSTT1-null men (by 35 %; P = 0.04) and GSTM1+/GSTT1+ men (by 26%; P = 0.01), but not in women. In summary, cruciferous vegetable supplementation increased GSTA1/2, but the effect was most marked in GSTM1-null/GSTT1-null men

The clinical relevance of oliguria in the critically ill patient : Analysis of a large observational database

Funding Information: Marc Leone reports receiving consulting fees from Amomed and Aguettant; lecture fees from MSD, Pfizer, Octapharma, 3 M, Aspen, Orion; travel support from LFB; and grant support from PHRC IR and his institution. JLV is the Editor-in-Chief of Critical Care. The other authors declare that they have no relevant financial interests. Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Urine output is widely used as one of the criteria for the diagnosis and staging of acute renal failure, but few studies have specifically assessed the role of oliguria as a marker of acute renal failure or outcomes in general intensive care unit (ICU) patients. Using a large multinational database, we therefore evaluated the occurrence of oliguria (defined as a urine output 16 years) patients in the ICON audit who had a urine output measurement on the day of admission were included. To investigate the association between oliguria and mortality, we used a multilevel analysis. Results: Of the 8292 patients included, 2050 (24.7%) were oliguric during the first 24 h of admission. Patients with oliguria on admission who had at least one additional 24-h urine output recorded during their ICU stay (n = 1349) were divided into three groups: transient - oliguria resolved within 48 h after the admission day (n = 390 [28.9%]), prolonged - oliguria resolved > 48 h after the admission day (n = 141 [10.5%]), and permanent - oliguria persisting for the whole ICU stay or again present at the end of the ICU stay (n = 818 [60.6%]). ICU and hospital mortality rates were higher in patients with oliguria than in those without, except for patients with transient oliguria who had significantly lower mortality rates than non-oliguric patients. In multilevel analysis, the need for RRT was associated with a significantly higher risk of death (OR = 1.51 [95% CI 1.19-1.91], p = 0.001), but the presence of oliguria on admission was not (OR = 1.14 [95% CI 0.97-1.34], p = 0.103). Conclusions: Oliguria is common in ICU patients and may have a relatively benign nature if only transient. The duration of oliguria and need for RRT are associated with worse outcome.publishersversionPeer reviewe

Modulation of Gut Microbiota by Glucosamine and Chondroitin in a Randomized, Double-Blind Pilot Trial in Humans

Glucosamine and chondroitin (G&amp;C), typically taken for joint pain, are among the most frequently used specialty supplements by US adults. More recently, G&amp;C have been associated with lower incidence of colorectal cancer in human observational studies and reduced severity of experimentally-induced ulcerative colitis in rodents. However, little is known about their effects on colon-related physiology. G&amp;C are poorly absorbed and therefore metabolized by gut microbiota. G&amp;C have been associated with changes in microbial structure, which may alter host response. We conducted a randomized, double-blind, placebo-controlled crossover trial in ten healthy adults to evaluate the effects of a common dose of G&amp;C compared to placebo for 14 days on gut microbial community structure, measured by 16S rRNA gene sequencing. Linear mixed models were used to evaluate the effect of G&amp;C compared to placebo on fecal microbial alpha and beta diversity, seven phyla, and 137 genera. Nine genera were significantly different between interventions (False Discovery Rate &lt; 0.05). Abundances of four Lachnospiraceae genera, two Prevotellaceae genera, and Desulfovibrio were increased after G&amp;C compared to placebo, while Bifidobacterium and a member of the Christensenellaceae family were decreased. Our results suggest that G&amp;C affect the composition of the gut microbiome which may have implications for therapeutic efficacy

Pharmacometabonomic Prediction of Busulfan Clearance in Hematopoietic Cell Transplant Recipients

Intravenous (IV) busulfan doses are often personalized to a concentration at steady state (Css) using the patient’s clearance, which is estimated with therapeutic drug monitoring. We sought to identify biomarkers of IV busulfan clearance using a targeted pharmacometabonomics approach. A total of 200 metabolites were quantitated in 106 plasma samples, each obtained before IV busulfan administration in hematopoietic cell transplant (HCT) recipients. Both univariate linear regression with false discovery rate (FDR) and pathway enrichment analyses using the Global test were performed. In the univariate analysis, glycine, <i>N-</i>acetylglycine, 2-hydroxyisovaleric acid, creatine, serine, and tyrosine were statistically significantly associated with IV busulfan clearance at <i>P</i> < 0.05, with the first three satisfying the FDR of <i>q</i> < 0.1. Using pathway enrichment analysis, the glycine, serine, and threonine metabolism pathway was statistically significantly associated with IV busulfan clearance at <i>P</i> < 0.05 and <i>q</i> < 0.1, and a pathway impact >0.1. Glycine is a component of glutathione, which is conjugated with busulfan via glutathione transferase enzymes. These results demonstrate the potential utility of pharmacometabonomics to inform IV busulfan dosing. Future studies are required to validate these findings

Reliability of serum biomarkers of inflammation from repeated measures in healthy individuals.

BACKGROUND: Biomarkers of low-grade systemic inflammation are used to study the associations of inflammation with chronic diseases, including cancer. However, relatively little is known about the intra-individual variability of most of these measures. METHODS: Fasting serum samples, collected at baseline and the end of ≥3 week washout periods in a 4-diet crossover feeding trial, were used to measure the inflammatory markers high sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-8 and soluble TNF receptor (sTNFR) I and II. Participants included 62 men and women for analyses of IL-6 and CRP and 56 for analyses of IL-8, TNF-α, and sTNFRs, aged 20-40, who were free of factors known to influence inflammation, e.g., chronic disease, medication use, heavy alcohol use, smoking and obesity (body mass index >30 kg/m2). Intraclass correlations (ICC) were estimated using random effects ANOVA, across all 4 time points (~6 weeks apart). RESULTS: ICCs for TNF-α and sTNFRI and II were very high: ICC=0.92, (95% CI: 0.89-0.96); 0.92, (95% CI: 0.88-0.95); and 0.90, (95% CI: 0.85-0.94), respectively. ICCs for IL-8 and hsCRP were 0.73 (95% CI: 0.63-0.83) and 0.62 (95% CI: 0.49-0.75), respectively. The ICC for IL-6 was considerably lower, ICC=0.48, (95% CI: 0.36-0.62). Three measures of IL-6 would be needed to achieve a reliability coefficient (Cronbach's alpha) of 0.75. CONCLUSIONS: With the exception of IL-6, reliability of all inflammatory markers in our panel was high. Impact: This suggests that a single measure accurately captures the short-term (e.g., 4-6 months) variability within an individual