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1.
Br J Nutr ; 122(3): 262-273, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31397239

RESUMO

Kidney function affects amino acid metabolism and vitamin status. The aims of the present study were to investigate urine and plasma concentrations of amino acids as well as plasma vitamin status in rats with impaired renal function (Zucker fa/fa rats) and in rats with normal kidney function (Long-Evans rats), and to explore the effects of salmon intake on these parameters and potential biomarkers of salmon intake in both rat strains. Male rats were fed diets with casein as sole protein source (control diet) or 25 % protein from baked salmon and 75 % casein for 4 weeks. Urine concentrations of markers of renal function and most amino acids and plasma concentrations of most vitamins were higher, and plasma concentrations of several amino acids including arginine, total glutathione and most tryptophan metabolites were lower in Zucker fa/fa rats compared with Long-Evans rats fed the control diet. Concentrations of kidney function markers were lower after salmon intake only in Zucker fa/fa rats. A trend towards lower urine concentrations of amino acids was seen in both rat strains fed the salmon diet, but this was more pronounced in Long-Evans rats and did not reflect the dietary amino acid content. Urine 1-methylhistidine, 3-methylhistidine, trimethylamineoxide and creatine concentrations, and plasma 1-methylhistidine and creatine concentrations were higher after salmon intake in both rat strains. To conclude, concentrations of amino acids in urine and plasma as well as vitamin status were different in Zucker fa/fa and Long-Evans rats, and the effects of salmon intake differed by rat strain for some of these parameters.

2.
Eur J Nutr ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401679

RESUMO

PURPOSE: To identify biomarkers to assess participants' compliance in an intervention study with high intake of cod or salmon, compared to a fish-free diet. METHODS: In this randomised clinical trial, 62 healthy overweight/obese participants consumed 750 g/week of either cod (N = 21) or salmon (N = 22) across 5 weekly dinners, or were instructed to continue their normal eating habits but avoid fish intake (Control group, N = 19) for 8 weeks. RESULTS: After cod intake, serum concentrations of trimethylamine N-oxide (TMAO, p = 0.0043), creatine (p = 0.024) and 1-methylhistidine (1-MeHis, p = 0.014), and urine concentrations (relative to creatinine) of TMAO (p = 2.8 × 10-5), creatine (p = 8.3 × 10-4) and 1-MeHis (p = 0.016) were increased when compared to Control group. After salmon intake, serum concentrations of 1-MeHis (p = 2.0 × 10-6) and creatine (p = 6.1 × 10-4), and urine concentrations (relative to creatinine) of 1-MeHis (p = 4.2 × 10-6) and creatine (p = 4.0 × 10-5) were increased when compared to Control group. Serum and urine concentrations of TMAO were more increased following cod intake compared to salmon intake (p = 0.028 and 2.9 × 10-4, respectively), and serum and urine 1-MeHis concentrations were more increased after salmon intake compared to cod intake (p = 8.7 × 10-5 and 1.2 × 10-4, respectively). Cod and salmon intake did not affect serum and urine concentrations of 3-methylhistidine, and only marginally affected concentrations of free amino acids and amino acid metabolites. CONCLUSION: TMAO measured in serum or urine is a potential biomarker of cod intake, and 1-MeHis measured in serum or urine is a potential biomarker of salmon intake.

3.
Brain Stimul ; 12(5): 1135-1142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31176607

RESUMO

BACKGROUND: Prior studies suggest that activation of the tryptophan catabolism via the kynurenine pathway by proinflammatory cytokines may be involved in the pathophysiology of depression. Electroconvulsive therapy (ECT) is an effective treatment for major depression (MD) with immunomodulation as one of the proposed modes of action. OBJECTIVE: The aim of this study was to investigate serum concentrations of tryptophan and kynurenine pathway metabolites in MD patients and healthy controls, and to explore the effect of ECT on components of the kynurenine pathway. METHODS: The study included 27 moderately to severely depressed patients referred to ECT. Blood samples were collected prior to treatment and after the completed ECT-series. Baseline samples were also collected from 14 healthy, age- and sex-matched controls. Serum concentrations of tryptophan, kynurenine, 3-hydroxykynurenine (HK), kynurenic acid (KA), xanthurenic acid (XA), anthranilic acid (AA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA), picolinic acid (Pic), pyridoxal 5'-phosphat (PLP), riboflavin, neopterin and cotinine were measured. RESULTS: Patients with MD had lower levels of neuroprotective kynurenine-pathway metabolites (KA, XA and Pic) and lower metabolite ratios (KA/Kyn and KA/QA) reflecting reduced neuroprotection compared to controls. The concentration of the inflammatory marker neopterin was increased after ECT, along with Pic and the redox active and immunosuppressive metabolite HAA. CONCLUSION: In this pilot study, we found increased concentrations of inflammatory marker neopterin and putative neuroprotective kynurenine metabolites HAA and Pic in MD patients after ECT. Further research in larger cohorts is required to conclude whether ECT exerts its therapeutic effects via changes in the kynurenine pathway.

4.
Am J Clin Nutr ; 109(5): 1239-1250, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31051508

RESUMO

BACKGROUND: Replacing dietary saturated fatty acids (SFAs) with polyunsaturated fatty acids (PUFA) reduces the plasma low-density lipoprotein (LDL) cholesterol and subsequently the risk of cardiovascular disease. However, beyond changes in LDL cholesterol, we lack a complete understanding of the physiologic alterations that occur when improving dietary fat quality. OBJECTIVES: The aim of this study was to gain knowledge of metabolic alterations paralleling improvements in the fat quality of the diet. METHODS: We recently conducted an 8-wk, double-blind, randomized controlled trial replacing SFAs with PUFAs in healthy subjects with moderate hypercholesterolemia (n = 99). In the present substudy, we performed comprehensive metabolic profiling with multiple platforms (both nuclear magnetic resonance- and mass spectrometry-based technology) (n = 99), and analyzed peripheral blood mononuclear cell gene expression (n = 95) by quantitative real-time polymerase chain reaction. RESULTS: A large number of lipoprotein subclasses, myristoylcarnitine and palmitoylcarnitine, and kynurenine were reduced when SFAs were replaced with PUFAs. In contrast, bile acids, proprotein convertase subtilisin/kexin type 9, acetate, and acetoacetate were increased by the intervention. Some amino acids were also altered by the intervention. The mRNA levels of LXRA and LDLR were increased, in addition to several liver X receptor α target genes and genes involved in inflammation, whereas the mRNA levels of UCP2 and PPARD were decreased in peripheral blood mononuclear cells after replacing SFAs with PUFAs. Partial least squares-discriminant analysis showed that the 30 most important variables that contributed to class separation spanned all classes of biomarkers, and was in accordance with the univariate analysis. CONCLUSIONS: Applying metabolomics in randomized controlled dietary intervention trials has the potential to extend our knowledge of the biological and molecular effects of dietary fat quality. This study was registered at clinicaltrials.gov as NCT01679496.

5.
Diabetes Care ; 42(7): 1225-1233, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31036547

RESUMO

OBJECTIVE: Altered plasma amino acid levels have been implicated as markers of risk for incident type 2 diabetes; however, amino acids are also related to established diabetes risk factors. Therefore, potential for confounding and the impact from competing risks require evaluation. RESEARCH DESIGN AND METHODS: We prospectively followed 2,519 individuals with coronary artery disease but without diabetes. Mixed Gaussian modeling identified potential for confounding. Confounding, defined as a change in effect estimate (≥10%), was investigated by comparing amino acid-incident diabetes risk in a Cox model containing age and sex with that in models adjusted for potential confounders (BMI, estimated glomerular filtration rate, HDL cholesterol, triacylglycerol, C-reactive protein), which were further adjusted for plasma glucose, competing risks, and multiple comparisons (false discovery rate = 0.05, Benjamini-Hochberg method). Finally, component-wise likelihood-based boosting analysis including amino acids and confounders was performed and adjusted for competing risks in order to identify an optimal submodel for predicting incident diabetes. RESULTS: The mean age of the source population was 61.9 years; 72% were men. During a median follow-up of 10.3 years, 267 incident cases of diabetes were identified. In age- and sex-adjusted models, several amino acids, including the branched-chain amino acids, significantly predicted incident diabetes. Adjustment for confounders, however, attenuated associations. Further adjustment for glucose and multiple comparisons rendered only arginine significant (hazard ratio/1 SD 1.21 [95% CI 1.07-1.37]). The optimal submodel included arginine and asparagine. CONCLUSIONS: Adjustment for relevant clinical factors attenuated the amino acid-incident diabetes risk. Although these findings do not preclude the potential pathogenic role of other amino acids, they suggest that plasma arginine is independently associated with incident diabetes. Both arginine and asparagine were identified in an optimal model for predicting new-onset type 2 diabetes.

6.
Eur J Nutr ; 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30972484

RESUMO

PURPOSE: To examine whether supplementation with low doses of fish or milk proteins would affect glucose regulation and circulating lipid concentrations in overweight healthy adults. METHODS: Ninety-three overweight adults were assigned to receive 2.5 g protein/day from herring (HER), salmon (SAL), cod (COD) or milk (CAS, a casein-whey mixture as positive control) as tablets for 8 weeks. RESULTS: Seventy-seven participants were included in the analyses. HER and SAL did not affect glucose and insulin concentrations. COD significantly reduced within-group changes in 90 and 120 min postprandial glucose concentrations but changes were not different from HER and SAL groups. CAS supplementation significantly reduced the area under the curve for glucose concentrations (- 7%), especially when compared to SAL group, and reduced postprandial insulin c-peptide concentration (- 23%). Reductions in acetoacetate (- 24%) and ß-hydroxybutyrate (- 29%) serum concentrations in HER group were more prominent compared to SAL and COD groups, with no differences between fish protein groups for α-hydroxybutyrate. Serum concentrations of α-hydroxybutyrate (- 23%), acetoacetate (- 39%) and ß-hydroxybutyrate (- 40%) were significantly reduced within CAS group, and the decreases were significantly more pronounced when compared to SAL group. Serum lipid concentrations were not altered in any of the intervention groups. CONCLUSION: Findings indicate that 2.5 g/day of proteins from fish or milk may be sufficient to improve glucose regulation in overweight adults. The effects were most pronounced after supplementation with proteins from cod, herring and milk, whereas salmon protein did not affect any of the measurements related to glucose regulation. CLINICAL TRAIL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT01641055.

7.
Brain Behav Immun ; 75: 155-162, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30675874

RESUMO

INTRODUCTION: Tryptophan, its downstream metabolites in the kynurenine pathway and neopterin have been associated with inflammation and dementia. We aimed to study the associations between plasma levels of these metabolites and cognitive function in community-dwelling, older adults. METHODS: This cross-sectional study included 2174 participants aged 70-72 years of the community-based Hordaland Health Study. Tryptophan, kynurenine, neopterin and eight downstream kynurenines were measured in plasma. Kendrick Object Learning Test (KOLT), Digit Symbol Test (DST) and the Controlled Oral Word Association Test (COWAT) were all outcomes in standardized Zellner's regression. The Wald test of a composite linear hypothesis of an association with each metabolite was adjusted by the Bonferroni method. Age, body mass index, C-reactive protein, depressive symptoms, diabetes, education, glomerular filtration rate, hypertension, previous myocardial infarction, prior stroke, pyridoxal 5'phosphate, sex and smoking were considered as potential confounders. RESULTS: Higher levels of the kynurenine-to-tryptophan ratio (KTR) and neopterin were significantly associated with poorer, overall cognitive performance (p < 0.002). Specifically, KTR was negatively associated with KOLT (ß -0.08, p = 0.001) and COWAT (ß -0.08, p = 0.001), but not with DST (ß -0.03, p = 0.160). This pattern was also seen for neopterin (KOLT: ß -0.07; p = 0.001; COWAT: ß -0.06, p = 0.010; DST: ß -0.01, p = 0.800). The associations were not confounded by the examined variables. No significant associations were found between the eight downstream kynurenines and cognition. CONCLUSION: Higher KTR and neopterin levels, biomarkers of cellular immune activation, were associated with reduced cognitive performance, implying an association between the innate immune system, memory, and language.

8.
Int J Cancer ; 145(5): 1221-1231, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30665271

RESUMO

Colorectal cancer is known to arise from multiple tumorigenic pathways; however, the underlying mechanisms remain not completely understood. Metabolomics is becoming an increasingly popular tool in assessing biological processes. Previous metabolomics research focusing on colorectal cancer is limited by sample size and did not replicate findings in independent study populations to verify robustness of reported findings. Here, we performed a ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) screening on EDTA plasma from 268 colorectal cancer patients and 353 controls using independent discovery and replication sets from two European cohorts (ColoCare Study: n = 180 patients/n = 153 controls; the Colorectal Cancer Study of Austria (CORSA) n = 88 patients/n = 200 controls), aiming to identify circulating plasma metabolites associated with colorectal cancer and to improve knowledge regarding colorectal cancer etiology. Multiple logistic regression models were used to test the association between disease state and metabolic features. Statistically significant associated features in the discovery set were taken forward and tested in the replication set to assure robustness of our findings. All models were adjusted for sex, age, BMI and smoking status and corrected for multiple testing using False Discovery Rate. Demographic and clinical data were abstracted from questionnaires and medical records.

9.
Int J Cancer ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30499135

RESUMO

Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer aetiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5,183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ]= 1.08, 95%CI= 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer. This article is protected by copyright. All rights reserved.

10.
J Neuroinflammation ; 15(1): 327, 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30470234

RESUMO

BACKGROUND: The host response to intruders in the central nervous system (CNS) may be beneficial but could also be harmful and responsible for neurologic symptoms and sequelae in CNS infections. This immune response induces the activation of the kynurenine pathway (KP) with the production of neuroactive metabolites. Herein, we explored cytokine and KP responses in cerebrospinal fluid (CSF) and serum in patients with encephalitis, aseptic, and bacterial meningitis. METHODS: Cytokines were measured in CSF and serum by multiplex assay in adult patients with encephalitis of infectious, autoimmune or unknown etiology (n = 10), aseptic meningitis (ASM, n = 25), acute bacterial meningitis (ABM, n = 6), and disease control patients with similar symptoms but without pleocytosis in CSF (n = 42). Liquid chromatography-tandem mass spectrometry (LC-MS/ MS) was used to measure KP metabolites in CSF and serum. RESULTS: A characteristic pattern of increasing cytokine levels and KP metabolites was found in CSF from encephalitis to ASM, with the highest levels in ABM. In ASM and ABM, most inflammatory mediators, including IL-6, IL-8, and IFN-inducible protein-10 (IP-10), showed markedly elevated levels in CSF compared with serum, indicating production within the CNS. In contrast to most mediators, the highest level of IP-10 was found in the ASM group, suggesting a potential role for IP-10 in aseptic/viral meningitis. Neopterin and IP-10 were associated with marked changes in KP metabolites in CSF with increasing kynurenine/tryptophan ratio reflecting indoleamine 2,3-dioxygenase activity. Neopterin, a marker of IFN-γ activity, was associated with an unfavorable balance between neuroprotective and neurotoxic tryptophan metabolites. CONCLUSION: We show that parenchymal and meningeal inflammations in CNS share a characteristic cytokine profile with a general immune response in the CSF with limited influence from the systemic circulation. IFN-γ activity, assessed by neopterin and IP-10 levels, may play a role in the activation of the KP pathway in these patients, potentially mediating neurotoxic effects.

11.
PLoS One ; 13(10): e0205558, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30312323

RESUMO

BACKGROUND: Preterm birth and low birth weight are associated with reduced nephron numbers and increased risk of hypertension and kidney disease in later life. AIMS: We tested the hypothesis that extremely preterm birth and intrauterine growth restriction is associated with decreased renal function in mid childhood. METHODS: At 11 years of age the following measures were obtained in a regional cohort of children born extremely premature (EP, i.e. < 28 weeks gestational age-GA) or with extremely low birth weight (ELBW, i.e. BW < 1000 grams) and in matched controls born at term with appropriate BW (AGA): Height, weight, abdominal circumference, triceps and subscapular skin fold thicknesses, blood pressure, plasma levels of creatinine, cystatin C and symmetric dimethyl arginine (SDMA). Small for gestational age (SGA) was defined as a BW < 10th percentile for GA. Glomerular filtration rate (GFR) was estimated according to the equations by Schwartz, Zappitelli and Gao. RESULTS: Fifty-seven of 61 eligible EP/ELBW children, 20 (35%) born SGA, and 54 controls, were assessed. Estimated GFR decreased while plasma SDMA increased from the children born AGA at term through those born preterm AGA to preterm SGA. Systolic BP was correlated to fat mass indices (p<0.03), but not to renal function (p>0.2) and did not differ between the groups. CONCLUSIONS: Children born EP/ELBW, particularly those born SGA, had impaired renal function at age 11 years as judged from estimated GFRs and plasma levels of SDMA. Since reduced renal function is associated with an increased risk of later disease, these children should be followed in order to minimize additional risk factors.

12.
Sci Rep ; 8(1): 12217, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111829

RESUMO

Estrogen is a potent vasodilator through activation of endothelial nitric oxide synthase (eNOS). Arginine and its homologue homoarginine are substrates for NOS, while asymmetric dimethylarginine (ADMA) is a NOS inhibitor. Healthy, never-pregnant women aged 18 to 40 years (n = 158) were categorized according to use of hormonal contraception into non-users (n = 76), users of estrogen contraceptives (EC-users, n = 58) and users of progestins-only contraceptives (PC-users, n = 24). Plasma homoarginine, arginine, ADMA and SDMA concentrations were assayed using a LC-MS/MS method. Compared to non-users, EC users had higher plasma homoarginine (median (interquartile range) 1.63 (1.24, 2.04) vs. 2.39 (2.05, 2.85) µmol/L, p < 0.001), lower arginine (80.8 (72.4, 94.3) vs. 72.1 (62.9, 85.1) µmol/L, p = 0.008) and ADMA (0.52 (0.46, 0.59) vs. 0.48 (0.42, 0.54) µmol/L, p = 0.003) concentrations. The lowest median plasma homoarginine concentration (1.34 (0.92, 1.75) µmol) was seen in PC-users. No differences were seen in SDMA concentrations according to use of hormonal contraception. In healthy, never-pregnant women aged 18 to 40 years, use of estrogen containing contraception was associated with significantly higher plasma concentrations of homoarginine and lower plasma concentrations of arginine and ADMA as compared to non-users, while the lowest plasma homoarginine concentrations were seen in progestin-only users. Whether the observed changes in relation to use of hormonal contraception have an impact on cardiovascular status, should be evaluated in an intervention study.

13.
Br J Nutr ; 120(7): 740-750, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30156176

RESUMO

Obesity increases the risk for developing kidney disease, and protection of kidneys through changes in diet should be investigated. Fish intake has been associated with reduced risk of developing kidney disease; therefore, we wanted to investigate whether cod protein intake could prevent or delay the development of kidney damage in an obese rat model that spontaneously develops proteinuria and focal segmental glomerulosclerosis. The aim of the study was to investigate any effects of cod protein intake on established markers of kidney function, amino acid composition, protein utilisation and growth in obese Zucker fa/fa rats in the early stage of decreased renal function. Male obese Zucker fa/fa rats (HsdOla:Zucker-Lepr) were fed cod muscle proteins in an amount corresponding to 25 % of dietary protein, with the remaining protein from a casein/whey mixture (COD diet). A control group was fed a diet with a casein/whey mixture as the only protein source (CAS diet). The intervention started when rats were 9-10 weeks old, and the rats were fed these diets for 4 weeks. At the end of the study, rats fed the COD diet had lower urine concentration of cystatin C, T-cell immunoglobulin mucin-1 (TIM-1), amino acids, carbamide, uric acid and ammonium and higher concentrations of creatine, trimethylamine N-oxide, 1-methylhistidine and 3-methylhistidine, lower kidney concentration of TIM-1 and showed better growth when compared with the CAS group. To conclude, cod protein may have the potential to delay the development of kidney damage in young obese Zucker rats and to improve protein utilisation and growth.

14.
Int J Epidemiol ; 47(6): 1760-1771, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29901778

RESUMO

Background: Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine-a nicotine metabolite and biomarker of recent tobacco exposure-provides additional information on lung cancer risk. Methods: The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnostic serum cotinine concentrations were measured in one laboratory on 5364 lung cancer cases and 5364 individually matched controls. We used conditional logistic regression to evaluate the association between circulating cotinine and lung cancer, and assessed if cotinine provided additional risk-discriminative information compared with self-reported smoking (smoking status, smoking intensity, smoking duration), using receiver-operating characteristic (ROC) curve analysis. Results: We observed a strong positive association between cotinine and lung cancer risk for current smokers [odds ratio (OR ) per 500 nmol/L increase in cotinine (OR500): 1.39, 95% confidence interval (CI): 1.32-1.47]. Cotinine concentrations consistent with active smoking (≥115 nmol/L) were common in former smokers (cases: 14.6%; controls: 9.2%) and rare in never smokers (cases: 2.7%; controls: 0.8%). Former and never smokers with cotinine concentrations indicative of active smoking (≥115 nmol/L) also showed increased lung cancer risk. For current smokers, the risk-discriminative performance of cotinine combined with self-reported smoking (AUCintegrated: 0.69, 95% CI: 0.68-0.71) yielded a small improvement over self-reported smoking alone (AUCsmoke: 0.66, 95% CI: 0.64-0.68) (P = 1.5x10-9). Conclusions: Circulating cotinine concentrations are consistently associated with lung cancer risk for current smokers and provide additional risk-discriminative information compared with self-report smoking alone.

15.
Sci Rep ; 8(1): 6725, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29712976

RESUMO

HIV infection and type 2 diabetes are associated with altered gut microbiota, chronic inflammation, and increased cardiovascular risk. We aimed to investigate the combined effect of these diseases on gut microbiota composition and related metabolites, and a potential relation to endothelial dysfunction in individuals with HIV-infection only (n = 23), diabetes only (n = 16) or both conditions (n = 21), as well as controls (n = 24). Fecal microbiota was analyzed by Illumina sequencing of the 16 S rRNA gene. Markers of endothelial dysfunction (asymmetric dimethylarginine [ADMA]), tryptophan catabolism (kynurenine/tryptophan [KT]-ratio), and inflammation (neopterin) were measured by liquid chromatography-tandem mass spectrometry. The combination of HIV and type 2 diabetes was associated with reduced gut microbiota diversity, increased plasma KT-ratio and neopterin. Microbial genes related to tryptophan metabolism correlated with KT-ratio and low alpha diversity, in particular in HIV-infected with T2D. In multivariate analyses, KT-ratio associated with ADMA (ß = 4.58 [95% CI 2.53-6.63], p < 0.001), whereas microbiota composition per se was not associated with endothelial dysfunction. Our results indicate that tryptophan catabolism may be related to endothelial dysfunction, with a potentially detrimental interaction between HIV and diabetes. The potential contribution of gut microbiota and the impact for cardiovascular risk should be further explored in prospective studies powered for clinical end points.

16.
Nutrients ; 10(5)2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29783689

RESUMO

Cobalamin and folate are crucial micronutrients during infancy and they are required for growth and cognitive development. Due to the monotonous and predominantly vegetarian-based complementary feeding and poor maternal micronutrient status, infants from low- and middle-income countries are susceptible to cobalamin deficiency. However, data on plasma cobalamin and folate and the functional markers methylmalonic acid and total homocysteine from breastfed infants in Nepal are still needed. We collected plasma samples from 316 6⁻11-month-old breastfed infants with a length-for-age of less than minus one z-score and analyzed blood for plasma folate, cobalamin, methylmalonic acid and total homocysteine concentrations. Cobalamin deficiency (plasma cobalamin 10 µmol/L) and methylmalonic acid (>0.28 µmol/L) indicating functional cobalamin deficiency were found among 53% and 75% of the infants, respectively. Based on a combined indicator of cobalamin status, 58% were found to have low cobalamin status. However, folate deficiency (.


Assuntos
Aleitamento Materno , Ácido Fólico/sangue , Fenômenos Fisiológicos da Nutrição do Lactente , Vitamina B 12/sangue , Biomarcadores/sangue , Estudos Transversais , Feminino , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/diagnóstico , Homocisteína/sangue , Humanos , Lactente , Masculino , Ácido Metilmalônico/sangue , Nepal , Estado Nutricional , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/diagnóstico
17.
PLoS One ; 13(4): e0196233, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29694444

RESUMO

Disturbances in one-carbon metabolism, intracellular reactions involved in nucleotide synthesis and methylation, likely increase the risk of colorectal cancer (CRC). However, results have been inconsistent. To explore whether this inconsistency could be explained by intertumoral heterogeneity, we evaluated a comprehensive panel of one-carbon metabolism biomarkers and some single nucleotide polymorphisms (SNPs) in relation to the risk of molecular subtypes of CRC defined by mutations in the KRAS and BRAF oncogenes. This nested case-control study included 488 CRC cases and 947 matched controls from two population-based cohorts in the Northern Sweden Health and Disease Study. We analyzed 14 biomarkers and 17 SNPs in prediagnostic blood and determined KRAS and BRAF mutation status in tumor tissue. In a multivariate network analysis, no variable displayed a strong association with the risk of specific CRC subtypes. A non-synonymous SNP in the CTH gene, rs1021737, had a stronger association compared with other variables. In subsequent univariate analyses, participants with variant rs1021737 genotype had a decreased risk of KRAS-mutated CRC (OR per allele = 0.72, 95% CI = 0.50, 1.05), and an increased risk of BRAF-mutated CRC (OR per allele = 1.56, 95% CI = 1.07, 2.30), with weak evidence for heterogeneity (Pheterogeneity = 0.01). This subtype-specific SNP association was not replicated in a case-case analysis of 533 CRC cases from The Cancer Genome Atlas (P = 0.85). In conclusion, we found no support for clear subtype-specific roles of one-carbon metabolism biomarkers and SNPs in CRC development, making differences in CRC molecular subtype distributions an unlikely explanation for the varying results on the role of one-carbon metabolism in CRC development across previous studies. Further investigation of the CTH gene in colorectal carcinogenesis with regards to KRAS and BRAF mutations or other molecular characteristics of the tumor may be warranted.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Cistationina gama-Liase/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Carbono/metabolismo , Estudos de Casos e Controles , Neoplasias Colorretais/metabolismo , Feminino , Redes Reguladoras de Genes , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Suécia
18.
Anal Chem ; 90(5): 3366-3373, 2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29420882

RESUMO

Circulating proteins are widely used as biomarkers in clinical applications for the diagnosis, prediction, and treatment of numerous diseases. Immunoassays are the most common technologies for quantification of protein biomarkers and exist in various formats. Traditional immunoassays offer sensitive and fast analyses but cannot differentiate between proteoforms. Protein microheterogeneity, mainly due to post-translational modification, has been recognized as a fingerprint for different pathologies, and knowledge about proteoforms is an important step toward personalized medicine. Mass spectrometry (MS) has emerged to be a powerful technique for the characterization and quantification of proteoforms. We have established a novel four-plex immunoassay based on Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight (MALDI-TOF) MS for the targeted quantification of the inflammatory markers C-reactive protein (CRP), serum amyloid A (SAA), and calprotectin (S100A8/9) and the kidney function marker cystatin C (CysC). Antibodies were covalently bound to superparamagnetic beads, which delivered robust and fast sample processing. Polyhistidine-tagged recombinant target proteins were used as internal standards for quantification. Our method identified a number of proteoforms for SAA ( n = 11), S100A8/9 ( n = 4) and CysC ( n = 4). The assay was characterized by low limits of detection (0.01-0.06 µg/mL) and low coefficients of variation (3.8-9.4%). Method validation demonstrated good between-assay agreement with immuno-turbidimetry ( R2 = 0.963 for CRP), ELISA ( R2 = 0.958 for SAA; R2 = 0.913 for S100A8/9), and nephelometry ( R2 = 0.963 for CysC). The low sample consumption of 20 µL and the high sample throughput of 384 samples per day make this targeted immuno-MALDI approach suited for assessment of inflammatory and renal status in large cohort studies based on precious biobanks samples.

19.
J Clin Endocrinol Metab ; 103(3): 1161-1170, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325121

RESUMO

Context and Objective: Vitamin D status may affect cardiovascular disease (CVD) development and survival. We studied the relationship between concentrations of the circulating biomarker 25-hydroxyvitamin D (25OHD) and all-cause and cardiovascular mortality risk. Design, Setting, Participants, and Main Outcome Measures: 25OHD, the sum of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2, was analyzed in plasma samples from 4114 white patients suspected of having stable angina pectoris and was adjusted for seasonal variation. Hazard ratios (HRs) for all-cause and cardiovascular mortality were estimated by using multivariable Cox models with 25OHD as the main exposure variable, with adjustment for study site, age, sex, smoking, body mass index, estimated glomerular filtration rate, and systolic blood pressure. Results: A total of 895 (21.8%) deaths, including 407 (9.9%) from CVD causes, occurred during a mean ± standard deviation follow-up of 11.9 ± 3.0 years. Compared with the first 25OHD quartile, HRs in the second, third, and fourth quartiles were 0.64 [95% confidence interval (CI), 0.54 to 0.77], 0.56 (95% CI, 0.46 to 0.67), and 0.56 (95% CI, 0.46 to 0.67) for all-cause mortality and 0.70 (95% CI, 0.53 to 0.91), 0.60 (95% CI, 0.45 to 0.79), and 0.57 (95% CI, 0.43 to 0.75) for cardiovascular mortality, respectively. Threshold analysis demonstrated increased all-cause and CVD mortality in patients with 25OHD concentrations below ∼42.5 nmol/L. Moreover, analysis suggested increased all-cause mortality at concentrations >100 nmol/L. Conclusion: Plasma 25OHD concentrations were inversely associated with cardiovascular mortality and nonlinearly (U-shaped) associated with all-cause mortality.


Assuntos
Angina Estável/sangue , Angina Estável/mortalidade , Vitamina D/análogos & derivados , Idoso , Angina Estável/complicações , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Causas de Morte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Estações do Ano , Vitamina D/sangue
20.
J Natl Cancer Inst ; 110(1)2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28922778

RESUMO

Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown. Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models. Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups. Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.


Assuntos
Ácido Fólico/sangue , Neoplasias Pulmonares/epidemiologia , Metionina/sangue , Vitamina B 6/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Ásia/epidemiologia , Austrália/epidemiologia , Estudos de Casos e Controles , Cotinina/sangue , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Proteção , Fatores de Risco , Fatores Sexuais , Fumar/sangue , Fumar/epidemiologia , Estados Unidos/epidemiologia
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