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Aims/hypothesisInterventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D3 and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes.MethodsThis study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D3 (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years.ResultsA total of 333 participants were randomised to vitamin D3 and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D3, 370 to vitamin D3 and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D3 had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index.Conclusions/interpretationAmong adults with type 2 diabetes, supplementation with vitamin D3 or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years.Trial registrationClinicalTrials.gov NCT01684722FundingThe study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases.

•In a subsample within VITAL, a double-blind randomized controlled trial of adults randomized to n-3 fatty acids or placebo, we identified reductions in proinflammatory n-3 fatty acid-derived lipid mediators and increases in n-3 fatty acid-derived lipid proresolving mediators in those receiving n-3 fatty acids after 1 y.•Larger 1-y lipid biomarker changes were seen in patients with reported low (<1 serving/mo) vs. high (≥3.9 servings/wk) fish intake at baseline.•Analyses did not reveal significant multiplicative interactions between low vs. high baseline fish intake and randomization to n-3 fatty acids for 1 y upon the change in concentration of lipid mediators. We assessed the joint effects of omega (n)-3 fatty acid supplementation and dietary fish intake on systemic lipid mediators of inflammation among adults. Within VITAL, a double-blind randomized controlled trial, adults were randomized to ω-3 fatty acids (460 mg EPA + 380 mg DHA/d) or placebo. We selected participants who reported low (<1 serving/mo) baseline dietary fish intake and matched them by age, sex, race, and trial arm to participants with self-reported highest fish intake (≥3.9 servings/wk). Baseline and 1-y plasma samples were tested for 9 ω-3 fatty acid-derived lipid mediators. Multivariable linear models assessed lipid mediator changes and joint effects of ω-3 fatty acid supplementation and dietary fish intake. Forty-eight participants with low baseline fish intake were matched to 48 with high fish intake. Mean age was 64.6 (±7.26), 50% were female, and 85% non-Hispanic white. One-year lipid mediator changes in expected directions were observed in those receiving ω-3 fatty acids versus placebo: reductions in proinflammatory mediators, PGD2, 5-HETE, and 12-HETE; increases in proresolving mediators, EPA and DHA. Larger 1-y lipid biomarker changes were seen in those with low baseline fish intake randomized to active ω-3 fatty acids for DHA, EPA, PGD2, Resolvin D1, and Resolvin D4 were observed, although no significant multiplicative interactions were detected. Beneficial changes in circulating proresolving and proinflammatory mediators were found with 1-y of ω-3 fatty acid supplementation versus placebo for all participants, with a trend toward larger effects among those with low baseline fish intake, although interactions were not significant.

Identify relationships and evaluate effects of long chain polyunsaturated fatty acids (LCPUFA) on frailty and physical performance. Design: Randomized, double blind pilot study. University General Clinical Research Center. 126 postmenopausal women. 2 fish oil (1.2g eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or 2 placebo (olive oil) capsules per day for 6 months. All participants received calcium and vitamin D supplements. Fatty acid levels, frailty assessment, hand grip strength, 8 foot walk, body composition, medical history and co-morbidities, nutrient intake, and inflammatory biomarkers taken at baseline and 6 months. At baseline, those with greater red blood cell (RBC) DHA and DHA/arachidonic acid (AA) presented with less frailty (r=−0.242, p=0.007 and r=−0.254, p=0.004, respectively). Fish oil supplementation resulted in higher RBC DHA and lower AA compared to baseline and placebo (p<0.001) and an improvement in walking speed compared to placebo (3.0±16 vs. −3.5±14, p=0.038). A linear regression model included age, antioxidant intake (selenium and vitamin C), osteoarthritis, frailty phenotype, and tumor necrosis factor alpha (TNFα). The model explained 13.6% of the variance in the change in walking speed. Change in DHA/AA (p=0.01) and TNFα (p=0.039), and selenium intake (p=0.031) had the greatest contribution to change in walking speed. Physical performance, measured by change in walking speed, was significantly affected by fish oil supplementation. Dietary intake of antioxidants (selenium and vitamin C) and changes in TNFα also contributed to change in walking speed suggesting LCPUFA may interact with antioxidants and inflammatory response to impact physical performance.

Two trials separately measured the bioavailability and impact on inflammation of a supplement taken daily containing 510 mg Docosahexaenoic acid (DHA), 344 mg Eicosapentaenoic acid (EPA), and 1000 IU of vitamin D (25-hydroxyvitamin D; 25(OH)D), for healthy and Crohn’s disease (CD) populations. Both trials were double blinded, randomized, placebo-controlled with cross-over. Participants were randomly allocated to groups A (placebo then supplement) or B (supplement then placebo). Both included a washout. Fatty acid (N-3 PUFAs) and vitamin D serum levels, plasma C-reactive protein (CRP), and stool calprotectin were measured before and after each treatment period. Outcome measures were analyzed using generalized linear mixed models, including terms for treatment, period, and a treatment-by-period interaction. The supplement significantly increased serum levels in healthy and CD groups for EPA (p < 0.001 and p < 0.001, respectively), Docosapentaenoic acid (p < 0.001 and 0.005), DHA (p < 0.001 and 0.006), the omega-3 index (p < 0.001 and 0.001), and (vitamin D (p < 0.001 and 0.027). CRP and calprotectin measures showed no evidence of a treatment effect on inflammation; however, model estimation was imprecise for both outcomes, hence further research is required to elucidate potential inflammation effects. The nutrient supplement increased serum levels of key N-3 PUFAs and vitamin D in both populations, showing the preparation was readily bioavailable.

Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenodesoxycholic acid and lower levels of l-acetylcarnitine, creatinine, l-asparagine, l-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, l-serine, oleic acid, myo-inositol, dodecanoic acid, l-methionine, hypoxanthine, palmitic acid, l-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls. l-tryptophan and kynurenic acid were consistently downregulated in MDD patients, regardless of antidepressant exposure. Depression rating scores were negatively associated with decreased levels of l-tryptophan. Pathway and network analyses revealed altered amino acid metabolism and lipid metabolism, especially for the tryptophan–kynurenine pathway and fatty acid metabolism, in the peripheral system of MDD patients. Taken together, our integrated results revealed that metabolic changes in the peripheral blood were associated with MDD, particularly decreased l-tryptophan and kynurenic acid levels, and alterations in the tryptophan–kynurenine and fatty acid metabolism pathways. Our findings may facilitate biomarker development and the elucidation of the molecular mechanisms that underly MDD.

L -Amino acids are the building blocks for proteins synthesized in ribosomes in all kingdoms of life, but d -amino acids ( d -aa) have important non-ribosome-based functions 1 . Mammals synthesize d -Ser and d -Asp, primarily in the central nervous system, where d -Ser is critical for neurotransmission 2 . Bacteria synthesize a largely distinct set of d -aa, which become integral components of the cell wall and are also released as free d -aa 3 , 4 . However, the impact of free microbial d -aa on host physiology at the host–microbial interface has not been explored. Here, we show that the mouse intestine is rich in free d -aa that are derived from the microbiota. Furthermore, the microbiota induces production of d -amino acid oxidase (DAO) by intestinal epithelial cells, including goblet cells, which secrete the enzyme into the lumen. Oxidative deamination of intestinal d -aa by DAO, which yields the antimicrobial product H 2 O 2 , protects the mucosal surface in the small intestine from the cholera pathogen. DAO also modifies the composition of the microbiota and is associated with microbial induction of intestinal sIgA. Collectively, these results identify d -aa and DAO as previously unrecognized mediators of microbe–host interplay and homeostasis on the epithelial surface of the small intestine. The mouse gut microbiota produce free d -amino acids and induce the production of d -amino acid oxidase by intestinal epithelial cells. Oxidative deamination of d -amino acids yields H 2 O 2 , which protects the mucosa from Vibrio cholera e.

The peptidoglycan layer of the bacterial cell wall typically contains d -alanine ( d -Ala) and d -glutamic acid ( d -Glu), and also various non-canonical d -amino acids that have been linked to peptidoglycan remodeling, inhibition of biofilm formation, and triggering of biofilm disassembly. Bacteria produce d -amino acids when adapting to environmental changes as a common survival strategy. In our previous study, we detected non-canonical d -amino acids in Escherichia coli grown in minimal medium. However, the biosynthetic pathways of non-canonical d -amino acids remain poorly understood. In the present study, we identified amino acid racemases in E. coli MG1655 (YgeA) and Bacillus subtilis (RacX) that produce non-canonical d -amino acids other than d -Ala and d -Glu. We characterized their enzymatic properties, and both displayed broad substrate specificity but low catalytic activity. YgeA preferentially catalyzes the racemization of homoserine, while RacX preferentially racemizes arginine, lysine, and ornithine. RacX is dimeric, and appears not to require pyridoxal 5′-phosphate (PLP) as a coenzyme as is the case with YgeA. To our knowledge, this is the first report on PLP-independent amino acid racemases possessing broad substrate specificity in E. coli and B. subtilis .

Hypovitaminosis C and D are highly prevalent in acutely hospitalized patients, but the clinical significance of these biochemical abnormalities is not known. Because deficiencies of vitamin C and D have been linked to psychologic abnormalities, vitamin C or D provision could improve the mood state of acutely hospitalized patients. Double-blind clinical trial of the effect of vitamin C (500 mg twice daily) or vitamin D (1000 IU twice daily) on mood, as assessed with a validated instrument, the Profile of Mood States. Vitamin C therapy increased plasma ( P < 0.0001) and mononuclear leukocyte ( P = 0.014) vitamin C concentrations and was associated with a 34% reduction in mood disturbance ( P = 0.013). Vitamin D therapy increased plasma 25-hydroxyvitamin D concentrations ( P = 0.0004), but had no significant effect on mood. Treatment of hypovitaminosis C improves the mood state of acutely hospitalized patients.

D-Amino acid oxidase (DAAO) is a FAD-containing flavoenzyme that catalyzes the oxidative deamination of D-isomers of neutral and polar amino acids. This enzymatic activity has been identified in most eukaryotic organisms, the only exception being plants. In the various organisms in which it does occur, DAAO fulfills distinct physiological functions: from a catabolic role in yeast cells, which allows them to grow on D-amino acids as carbon and energy sources, to a regulatory role in the human brain, where it controls the levels of the neuromodulator D-serine. Since 1935, DAAO has been the object of an astonishing number of investigations and has become a model for the dehydrogenase-oxidase class of flavoproteins. Structural and functional studies have suggested that specific physiological functions are implemented through the use of different structural elements that control access to the active site and substrate/product exchange. Current research is attempting to delineate the regulation of DAAO functions in the contest of complex biochemical and physiological networks.

Breast cancer patients are characterized by the oncobiotic transformation of multiple microbiome communities, including the gut microbiome. Oncobiotic transformation of the gut microbiome impairs the production of antineoplastic bacterial metabolites. The goal of this study was to identify bacterial metabolites with antineoplastic properties. We constructed a 30-member bacterial metabolite library and screened the library compounds for effects on cell proliferation and epithelial-mesenchymal transition. The metabolites were applied to 4T1 murine breast cancer cells in concentrations corresponding to the reference serum concentrations. However, yric acid, glycolic acid, d-mannitol, 2,3-butanediol, and trans-ferulic acid exerted cytostatic effects, and 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, and vanillic acid exerted hyperproliferative effects. Furthermore, 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, 2,3-butanediol, and hydrocinnamic acid inhibited epithelial-to-mesenchymal (EMT) transition. We identified redox sets among the metabolites (d-mannitol—d-mannose, 1-butanol—butyric acid, ethylene glycol—glycolic acid—oxalic acid), wherein only one partner within the set (d-mannitol, butyric acid, glycolic acid) possessed bioactivity in our system, suggesting that changes to the local redox potential may affect the bacterial secretome. Of the nine bioactive metabolites, 2,3-butanediol was the only compound with both cytostatic and anti-EMT properties.