HK:XA ratio

@article{pmid37444500,

title = {Higher Plasma Creatinine Is Associated with an Increased Risk of Death in Patients with Non-Metastatic Rectal but Not Colon Cancer: Results from an International Cohort Consortium},

author = {Jennifer Ose and Biljana Gigic and Stefanie Brezina and Tengda Lin and Anita R Peoples and Pauline P Schobert and Andreas Baierl and Eline van Roekel and Nivonirina Robinot and Audrey Gicquiau and David Achaintre and Augustin Scalbert and Fränzel J B van Duijnhoven and Andreana N Holowatyj and Tanja Gumpenberger and Petra Schrotz-King and Alexis B Ulrich and Arve Ulvik and Per-Magne Ueland and Matty P Weijenberg and Nina Habermann and Pekka Keski-Rahkonen and Andrea Gsur and Dieuwertje E Kok and Cornelia M Ulrich},

doi = {10.3390/cancers15133391},

issn = {2072-6694},

year  = {2023},

date = {2023-06-01},

journal = {Cancers (Basel)},

volume = {15},

number = {13},

abstract = {Colorectal cancer (CRC) is increasingly recognized as a heterogeneous disease. No studies have prospectively examined associations of blood metabolite concentrations with all-cause mortality in patients with colon and rectal cancer separately. Targeted metabolomics (Biocrates Absolute p180) and pathway analyses (MetaboAnalyst 4.0) were performed on pre-surgery collected plasma from 674 patients with non-metastasized (stage I-III) colon ( = 394) or rectal cancer ( = 283). Metabolomics data and covariate information were received from the international cohort consortium MetaboCCC. Cox proportional hazards models were computed to investigate associations of 148 metabolite levels with all-cause mortality adjusted for age, sex, tumor stage, tumor site (whenever applicable), and cohort; the false discovery rate (FDR) was used to account for multiple testing. A total of 93 patients (14%) were deceased after an average follow-up time of 4.4 years (60 patients with colon cancer and 33 patients with rectal cancer). After FDR adjustment, higher plasma creatinine was associated with a 39% increase in all-cause mortality in patients with rectal cancer. HR: 1.39, 95% CI 1.23-1.72, p = 0.03; but not colon cancer: p = 0.96. Creatinine is a breakdown product of creatine phosphate in muscle and may reflect changes in skeletal muscle mass. The starch and sucrose metabolisms were associated with increased all-cause mortality in colon cancer but not in rectal cancer. Genes in the starch and sucrose metabolism pathways were previously linked to worse clinical outcomes in CRC. In summary, our findings support the hypothesis that colon and rectal cancer have different etiological and clinical outcomes that need to be considered for targeted treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37084480,

title = {Metabolic role of the hepatic valine/3-hydroxyisobutyrate (3-HIB) pathway in fatty liver disease},

author = {Mona Synnøve Bjune and Laurence Lawrence-Archer and Johnny Laupsa-Borge and Cathrine Horn Sommersten and Adrian McCann and Robert Clay Glastad and Iain George Johnston and Matthias Kern and Matthias Blüher and Gunnar Mellgren and Simon N Dankel},

doi = {10.1016/j.ebiom.2023.104569},

issn = {2352-3964},

year  = {2023},

date = {2023-05-01},

journal = {EBioMedicine},

volume = {91},

pages = {104569},

abstract = {BACKGROUND: The valine (branched-chain amino acid) metabolite 3-hydroxyisobutyrate (3-HIB), produced by 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH), is associated with insulin resistance and type 2 diabetes, but implicated tissues and cellular mechanisms are poorly understood. We hypothesized that HIBCH and 3-HIB regulate hepatic lipid accumulation.nnMETHODS: HIBCH mRNA in human liver biopsies ("Liver cohort") and plasma 3-HIB ("CARBFUNC" cohort) were correlated with fatty liver and metabolic markers. Human Huh7 hepatocytes were supplemented with fatty acids (FAs) to induce lipid accumulation. Following HIBCH overexpression, siRNA knockdown, inhibition of PDK4 (a marker of FA β-oxidation) or 3-HIB supplementation, we performed RNA-seq, Western blotting, targeted metabolite analyses and functional assays.nnFINDINGS: We identify a regulatory feedback loop between the valine/3-HIB pathway and PDK4 that shapes hepatic FA metabolism and metabolic health and responds to 3-HIB treatment of hepatocytes. HIBCH overexpression increased 3-HIB release and FA uptake, while knockdown increased cellular respiration and decreased reactive oxygen species (ROS) associated with metabolic shifts via PDK4 upregulation. Treatment with PDK4 inhibitor lowered 3-HIB release and increased FA uptake, while increasing HIBCH mRNA. Implicating this regulatory loop in fatty liver, human cohorts show positive correlations of liver fat with hepatic HIBCH and PDK4 expression (Liver cohort) and plasma 3-HIB (CARBFUNC cohort). Hepatocyte 3-HIB supplementation lowered HIBCH expression and FA uptake and increased cellular respiration and ROS.nnINTERPRETATION: These data implicate the hepatic valine/3-HIB pathway in mechanisms of fatty liver, reflected in increased plasma 3-HIB concentrations, and present possible targets for therapeutic intervention.nnFUNDING: Funding was provided by the Research Council of Norway (263124/F20), the University of Bergen, the Western Norway Health Authorities, Novo Nordisk Scandinavia AS, the Trond Mohn Foundation and the Norwegian Diabetes Association.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37031691,

title = {The effect of vitamin B12 supplementation during pregnancy on infant growth and development in Nepal: a community-based, double-blind, randomised, placebo-controlled trial},

author = {Ram K Chandyo and Ingrid Kvestad and Manjeswori Ulak and Suman Ranjitkar and Mari Hysing and Merina Shrestha and Catherine Schwinger and Adrian McCann and Per M Ueland and Sudha Basnet and Laxman Shrestha and Tor A Strand},

doi = {10.1016/S0140-6736(23)00346-X},

issn = {1474-547X},

year  = {2023},

date = {2023-05-01},

journal = {Lancet},

volume = {401},

number = {10387},

pages = {1508--1517},

abstract = {BACKGROUND: Vitamin B12 is required for healthy infant growth and development, but low and marginal vitamin B12 status is endemic in low-income and middle-income countries. We aimed to measure the effect of vitamin B12 supplementation from early pregnancy until 6 months post partum on infant growth and neurodevelopment.nnMETHODS: In this community-based, double-blind, placebo-controlled trial, we randomly assigned (1:1) 800 pregnant women (aged 20-40 years) who were up to 15 weeks pregnant-recruited from home visits and outpatient departments at three hospitals in Nepal-to daily supplementation with 50 μg oral vitamin B12 or placebo until 6 months postpartum. Independent scientists generated the list that linked allocation to participants' study identification number. Participants were masked to group assignment and all investigators were masked until data cleaning was completed. The primary outcomes were length-for-age Z score (LAZ) at age 12 months and the cognitive composite score of the Bayley Scales of Infant and Toddler Development (3rd edition) at age 6 months and 12 months. The primary and secondary outcomes, including adverse events, were assessed in the intention-to-treat population, for all participants with available outcome data. This trial is registered with ClinicalTrials.gov, NCT03071666.nnFINDINGS: 800 eligible pregnant women were enrolled in the trial between March 28, 2017, and Oct 15, 2020, with 400 women randomly assigned to each group. Follow-up was completed on May 18, 2022. At baseline, 569 (71%) of 800 women had plasma vitamin B12 indicating low or marginal status (<221 pmol/L). We found no effect of vitamin B12 on the primary outcomes. The mean LAZ at age 12 months were -0·57 (SD 1·03) in the B12 group and -0·55 (1.03) in the placebo group (366 infants in the vitamin B12 group vs 363 infants in the placebo group) with a mean difference of -0·02 (95% CI -0·16 to 0·13). The mean cognitive composite scores were 97·7 (SD 10·5) in the B12 group and 97·1 (10·2) in the placebo group, with a mean difference of 0·5 (95% CI -0·6 to 1·7) measured in 364 and 361 infants. Stillbirths or infant deaths occurred in three (1%) of 374 women in the vitamin B12 group and nine (2%) of 379 women in the placebo group.nnINTERPRETATION: Although vitamin B12 deficiency was prevalent in our study population and vitamin B12 supplementation from early pregnancy substantially improved vitamin B12 status, supplementation did not improve infant growth or neurodevelopment. Our findings support the current WHO recommendations of no routine vitamin B12 supplementation during pregnancy.nnFUNDING: Research Council of Norway.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37198607,

title = {Healthy Nordic diet and associations with plasma concentrations of metabolites in the choline oxidation pathway: a cross-sectional study from Northern Sweden},

author = {André Hesselink and Anna Winkvist and Bernt Lindahl and Per M Ueland and Jörn Schneede and Ingegerd Johansson and Therese Karlsson},

doi = {10.1186/s12937-023-00853-w},

issn = {1475-2891},

year  = {2023},

date = {2023-05-01},

journal = {Nutr J},

volume = {22},

number = {1},

pages = {26},

abstract = {BACKGROUND: The choline oxidation pathway and metabolites involved have been linked to diseases including cardiovascular disease, type 2 diabetes and cancer. A healthy Nordic diet is a recently defined dietary pattern associated with decreased risk for these diseases. Our aim was to explore associations between adherence to a healthy Nordic diet and plasma concentrations of metabolites of the choline oxidation pathway.nnMETHODS: The Healthy Nordic Food Index (HNFI) and Baltic Sea Diet Score (BSDS) were applied to cross-sectional data (n = 969) from the Västerbotten Intervention Programme in Northern Sweden to score adherence to a healthy Nordic diet. Data included responses to a dietary questionnaire and blood sample analyses (1991-2008). Associations of diet scores with plasma concentrations of metabolites of the choline oxidation pathway and total homocysteine (tHcy), seven metabolites in total, were evaluated with linear regression, adjusting for age, BMI, education and physical activity.nnRESULTS: HNFI scores showed linear relationships with plasma choline (β = 0.11), betaine (β = 0.46), serine (β = 0.98) and tHcy (β =  - 0.38), and BSDS scores with betaine (β = 0.13) and tHcy (β =  - 0.13); unstandardized beta coefficients, all significant at P < 0.05. The regression models predicted changes in plasma metabolite concentrations (± 1 SD changes in diet score) in the range of 1-5% for choline, betaine, serine and tHcy. No other statistically significant associations were observed.nnCONCLUSIONS: A healthy Nordic diet was associated with plasma concentrations of several metabolites of the choline oxidation pathway. Although relationships were statistically significant, effect sizes were moderate. Further research is warranted to explore the underlying mechanisms and associations with health outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36611247,

title = {Systemic Activation of the Kynurenine Pathway in Graves Disease With and Without Ophthalmopathy},

author = {Hans Olav Ueland and Arve Ulvik and Kristian Løvås and Anette S B Wolff and Lars Ertesvåg Breivik and Ann-Elin Meling Stokland and Eyvind Rødahl and Roy Miodini Nilsen and Eystein Husebye and Grethe Åstrøm Ueland},

doi = {10.1210/clinem/dgad004},

issn = {1945-7197},

year  = {2023},

date = {2023-05-01},

journal = {J Clin Endocrinol Metab},

volume = {108},

number = {6},

pages = {1290--1297},

abstract = {CONTEXT: Graves disease (GD) is one of the most common autoimmune disorders. Recent literature has shown an immune response involving several different inflammatory related proteins in these patients.nnOBJECTIVE: This work aimed to characterize the kynurenine pathway, activated during interferon-γ (IFN-γ)-mediated inflammation and cellular (T-helper type 1 [Th1] type) immunity, in GD patients with and without thyroid eye disease (TED).nnMETHODS: We analyzed 34 biomarkers by mass spectrometry in serum samples from 100 patients with GD (36 with TED) and 100 matched healthy controls. The analytes included 10 metabolites and 3 indices from the kynurenine pathway, 6 microbiota-derived metabolites, 10 B-vitamers, and 5 serum proteins reflecting inflammation and kidney function.nnRESULTS: GD patients showed significantly elevated levels of 7 biomarkers compared with healthy controls (omega squared [ω2] > 0.06; P < .01). Of these 7, the 6 biomarkers with the strongest effect size were all components of the kynurenine pathway. Factor analysis showed that biomarkers related to cellular immunity and the Th1 responses (3-hydroxykynurenine, kynurenine, and quinolinic acid with the highest loading) were most strongly associated with GD. Further, a factor mainly reflecting acute phase response (C-reactive protein and serum amyloid A) showed weaker association with GD by factor analysis. There were no differences in biomarker levels between GD patients with and without TED.nnCONCLUSION: This study supports activation of IFN-γ inflammation and Th1 cellular immunity in GD, but also a contribution of acute-phase reactants. Our finding of no difference in systemic activation of the kynurenine pathway in GD patients with and without TED implies that the local Th1 immune response in the orbit is not reflected systemically.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36682040,

title = {Plasma methylmalonic acid predicts risk of acute myocardial infarction and mortality in patients with coronary heart disease: A prospective 2-cohort study},

author = {Indu Dhar and Vegard Lysne and Arve Ulvik and Gard F T Svingen and Eva R Pedersen and Espen Ø Bjørnestad and Thomas Olsen and Robert Borsholm and Johnny Laupsa-Borge and Per M Ueland and Grethe S Tell and Rolf K Berge and Gunnar Mellgren and Kaare H Bønaa and Ottar K Nygård},

doi = {10.1111/joim.13610},

issn = {1365-2796},

year  = {2023},

date = {2023-04-01},

journal = {J Intern Med},

volume = {293},

number = {4},

pages = {508--519},

abstract = {BACKGROUND: Elevated plasma methylmalonic acid (MMA) is reported in patients with established coronary heart disease (CHD) and is considered a marker of vitamin B12 deficiency. Moreover, MMA-dependent reactions have been linked to alterations in mitochondrial energy metabolism and oxidative stress, key features in the pathophysiology of cardiovascular diseases (CVDs).nnOBJECTIVES: We examined whether plasma MMA prospectively predicted the long-term risk of acute myocardial infarction (AMI) and mortality.nnMETHODS AND RESULTS: Using Cox modeling, we estimated hazard ratios (HRs) for endpoints according to per 1-SD increment of log-transformed plasma MMA in two independent populations: the Western Norway Coronary Angiography Cohort (WECAC) (patients evaluated for CHD; n = 4137) and the Norwegian Vitamin Trial (NORVIT) (patients hospitalized with AMI; n = 3525). In WECAC and NORVIT, 12.8% and 18.0% experienced an AMI, whereas 21.8% and 19.9% died, of whom 45.5% and 60.3% from CVD-related causes during follow-up (range 3-11 years), respectively. In WECAC, age- and gender-adjusted HRs (95% confidence interval) were 1.18 (1.09-1.28), 1.25 (1.18-1.33), and 1.28 (1.17-1.40) for future AMI, total mortality, and CVD mortality, respectively. Corresponding risk estimates were 1.19 (1.10-1.28), 1.22 (1.14-1.31), and 1.30 (1.19-1.42) in NORVIT. These estimates were only slightly attenuated after multivariable adjustments. Across both cohorts, the MMA-risk association was stronger in older adults, women, and non-smokers.nnCONCLUSIONS: Elevated MMA was associated with an increased risk of AMI and mortality in patients with suspected or verified CHD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36881945,

title = {The serum kynurenine pathway metabolic profile is associated with overweight and obesity in multiple sclerosis},

author = {Marie Kupjetz and Nadine Patt and Niklas Joisten and Per Magne Ueland and Adrian McCann and Roman Gonzenbach and Jens Bansi and Philipp Zimmer},

doi = {10.1016/j.msard.2023.104592},

issn = {2211-0356},

year  = {2023},

date = {2023-04-01},

journal = {Mult Scler Relat Disord},

volume = {72},

pages = {104592},

abstract = {BACKGROUND: Overweight and obesity increase multiple sclerosis (MS) susceptibility, disease severity, and disability progression. Kynurenine pathway (KP) dysregulation is present in overweight and obesity, and in MS. Since the effect of overweight and obesity on KP dysregulation in persons with MS (pwMS) remains to be established, this study primarily aims to explore the effect of overweight and obesity on the serum KP metabolic profile in pwMS.nnMETHODS: This cross-sectional study represents a secondary analysis of a randomized clinical trial at Valens rehabilitation clinic, Switzerland. Registration was performed on 22 April 2020 at clinicaltrials.gov (NCT04356248, https://clinicaltrials.gov/ct2/show/NCT04356248). The first participant was enrolled on 13 July 2020. Based on body mass index (BMI), 106 MS inpatients (Expanded Disability Status Scale (EDSS) score ≤ 6.5) were dichotomised to a lean group (LG, BMI < 25 kg/m), and an overweight/obese group (OG, BMI ≥ 25 kg/m). Targeted metabolomics (LC-MS/MS) was performed to determine serum concentrations of tryptophan (TRP), KP downstream metabolites, and neopterin (Neopt). Correlations between BMI, kynurenine-to-TRP ratio (KTR), and serum concentrations of TRP, KP downstream metabolites, and Neopt were calculated. ANCOVA was used to determine differences in KTR, and serum concentrations of TRP, KP downstream metabolites and Neopt between OG and LG, and across MS phenotypes.nnRESULTS: Higher BMI correlated with higher KTR (r = 0.425, p <0.001) and serum concentrations of most KP downstream metabolites, but not with EDSS score. Higher KTR (r = 0.470, p < .001) and serum concentrations of most KP downstream metabolites correlated with a higher serum concentration of Neopt. The OG (n = 44, 59% female, 51.68 (9.98) years, EDSS: 4.71 (1.37)) revealed higher KTR (0.026 (0.007) vs. 0.022 (0.006), p=.001) and serum concentrations of most KP downstream metabolites than the LG (n = 62, 71% female, 48.37 (9.63) years, EDSS: 4.60 (1.29)). KP metabolic profiles did not differ between MS phenotypes.nnCONCLUSION: Overweight and obesity are associated with a systemic elevation of KP metabolic flux and an accumulation of most KP downstream metabolites in pwMS. Further research is needed to clarify if KP involvement serves as a mechanism linking overweight and obesity with symptom expression, disease severity, and disability progression in pwMS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36318283,

title = {Assessment of vitamin B6 status in never-pregnant, pregnant and postpartum women and their infants},

author = {Anne-Lise Bjørke-Monsen and Kristin Varsi and Sunniva Todnem Sakkestad and Arve Ulvik and Per Magne Ueland},

doi = {10.1007/s00394-022-03033-4},

issn = {1436-6215},

year  = {2023},

date = {2023-03-01},

journal = {Eur J Nutr},

volume = {62},

number = {2},

pages = {867--878},

abstract = {PURPOSE: Pyridoxal 5´-phosphate (PLP) is the main form of vitamin B6 in humans and functions a coenzyme for more than 160 different enzymatic reactions. The purpose of the study was to find plasma PLP concentrations, which ensure an optimal vitamin B6 status determined by a metabolic marker, in never-pregnant, pregnant and lactating women and their infants.nnMETHODS: In an observational, prospective study, plasma PLP and the metabolic marker, HKr (hydroxykynurenine/(kynurenic acid + anthranilic acid + xanthurenic acid + hydroxyanthranilic acid) were assessed in women (n = 114) from pregnancy week 18 to 6 months postpartum and related to infant status. Never-pregnant women 18-40 years (n = 127) were included as controls.nnRESULTS: Compared to controls, plasma PLP decreased during pregnancy and increased postpartum, while HKr increased from week 18 to 6 weeks postpartum, indicating maternal vitamin B6 insufficiency during this period. In never-pregnant women, HKr increased gradually with plasma PLP < 100 nmol/L, and in pregnancy week 28 a sharp increase in HKr was seen at plasma PLP < 30 nmol/L. Despite correcting for maternal vitamin B6 status, infant median plasma PLP decreased with months of exclusive breastfeeding.nnCONCLUSIONS: Plasma PLP and kynurenine concentrations differ substantially between never-pregnant, pregnant and postpartum women and infants. A plasma PLP concentration in the range of 50-100 nmol/L seems to ensure an optimal vitamin B6 status for never-pregnant women, whereas a plasma PLP > 30 nmol/L in pregnancy week 28 ensures an adequate vitamin B6 status during pregnancy and lactation. Infant vitamin B6 status at age 6 months is inversely correlated to number of months of exclusive breastfeeding.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36830760,

title = {A Vegetarian Diet Significantly Changes Plasma Kynurenine Concentrations},

author = {Anne-Lise Bjørke-Monsen and Kristin Varsi and Arve Ulvik and Sunniva Todnem Sakkestad and Per Magne Ueland},

doi = {10.3390/biom13020391},

issn = {2218-273X},

year  = {2023},

date = {2023-02-01},

journal = {Biomolecules},

volume = {13},

number = {2},

abstract = {Tryptophan is an essential amino acid and a precursor of a number of physiologically important metabolites, including serotonin, melatonin, tryptamine, and kynurenines. We assessed tryptophan, kynurenines, and vitamin B2 and B6, as well as biomarkers of liver function and inflammation, in a group of 158 female omnivores and vegetarians aged 18-40 years. The majority of women were omnivores, and 22% were vegetarians. Vegetarians had 25% lower serum ALT, significantly higher pyridoxal concentrations, and significantly lower plasma concentrations of most kynurenines, varying from 8% lower concentrations of median plasma kynurenine to 42% lower concentrations of plasma xanthurenic acid, compared to omnivores. No significant differences were observed in vitamin B2 status or in inflammation markers, C-reactive protein and neopterin between the groups. Vegetarians had lower levels of several plasma kynurenines compared to omnivores. The reason for this is unknown; however, lower ALT concentrations, suggesting a better liver status, and a more favourable vitamin B6 status might be contributing factors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36087137,

title = {Stable isotope ratios of nitrogen and carbon as biomarkers of a vegan diet},

author = {Jutta Dierkes and Stefan Dietrich and Klaus Abraham and Bernhard H Monien and Adrian McCann and Katrine Borgå and Cornelia Weikert},

doi = {10.1007/s00394-022-02992-y},

issn = {1436-6215},

year  = {2023},

date = {2023-02-01},

journal = {Eur J Nutr},

volume = {62},

number = {1},

pages = {433--441},

abstract = {PURPOSE: Dietary biomarkers can potentially overcome the limitations of self-reported dietary data. While in ecology and archaeology, stable isotope ratios of carbon and nitrogen are widely used as biomarkers, this is not the case in nutrition research. Since the abundance of the 13C and the 15N isotope differ in food sources from plant and animal origin, stable isotope ratios of carbon and nitrogen (δ13C and δ15N) may differ in human biological material. Here, we investigated the stable isotope ratios of nitrogen and carbon in serum and urine from vegans and omnivores.nnMETHOD: Measurement of δ15N and δ13C in serum and 24 h urine was performed by Elemental Analyzer-Isotope Ratio Mass Spectrometer in the cross-sectional study "Risks and Benefits of a Vegan Diet". The study included 36 vegans and 36 omnivores with a median age of 37.5 years (matched for age and sex), who adhered to their diet for at least 1 year.nnRESULTS: Both δ15N and δ13C were significantly lower in both the serum and 24 h urine of vegans compared to omnivores. δ15N either in serum or urine had 100% specificity and sensitivity to discriminate between vegans and omnivores. Specificity of δ13C was also > 90%, while sensitivity was 93% in serum and 77% in urine.nnCONCLUSION: δ15N both in serum and urine was able to accurately identify vegans and thus appears to be a promising marker for dietary habits.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37523604,

title = {The Association Between Serum Riboflavin and Flavin Mononucleotide With Pancreatic Cancer: Findings From a Prospective Cohort Study},

author = {Pedram Paragomi and Renwei Wang and Joyce Y Huang and Øivind Midttun and Arve Ulvik and Per M Ueland and Woon-Puay Koh and Jian-Min Yuan and Hung N Luu},

doi = {10.1097/MPA.0000000000002220},

issn = {1536-4828},

year  = {2023},

date = {2023-02-01},

journal = {Pancreas},

volume = {52},

number = {2},

pages = {e127--e134},

abstract = {OBJECTIVES: Vitamin B2 (riboflavin) has a prime role in metabolic reactions imperative to cell cycle and proliferation. We investigated the associations between serum concentrations of riboflavin flavin mononucleotide with the risk of pancreatic cancer in a nested case-control study involving 58 cases and 104 matched controls.nnMETHODS: The Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese Singaporeans. Conditional logistic regression method was used to evaluate these associations with adjustment for potential confounders including the level of education, body mass index, smoking status, alcohol consumption, history of diabetes, serum cotinine and pyridoxal 5'-phosphate, estimated glomerular filtration rate, and total methyl donors (ie, the sum of serum choline, betaine, and methionine).nnRESULTS: The risk of pancreatic cancer increased with increasing level of serum riboflavin in a dose-dependent manner, especially in men (Ptrend = 0.003). The odds ratio (95% confidence intervals) of pancreatic cancer for the second and third tertiles of serum riboflavin, compared with the lowest tertile, were 9.92 (1.65-59.77) and 25.59 (3.09-212.00), respectively. This positive association was stronger in individuals with a longer follow-up period (≥7 years).nnCONCLUSIONS: The findings suggest a potential role of riboflavin in the development of pancreatic cancer, especially in men.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35641553,

title = {Pregnancy homocysteine and cobalamin status predict childhood metabolic health in the offspring},

author = {Alejandra Rojas-Gómez and Pol Solé-Navais and Pere Cavallé-Busquets and Gemma Ornosa-Martin and Carme Grifoll and Carla Ramos-Rodriguez and Joan Fernandez-Ballart and Luis Masana and Mónica Ballesteros and Per Magne Ueland and Michelle M Murphy},

doi = {10.1038/s41390-022-02117-5},

issn = {1530-0447},

year  = {2023},

date = {2023-02-01},

journal = {Pediatr Res},

volume = {93},

number = {3},

pages = {633--642},

abstract = {BACKGROUND: Inadequate pregnancy cobalamin status has been associated with adverse offspring metabolic health in Indian and Nepalese studies. Studies of pregnancy cobalamin status and mid-childhood health outside of Asia are scarce.nnMETHODS: Associations between pregnancy fasting plasma total homocysteine (tHcy), cobalamin status (plasma cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA)) and mid-childhood metabolic score (MetSco) ((including fat mass index (zFMI), homeostatic model assessment of insulin resistance (zHOMA-IR) and dyslipidemia (zTG - zHDLc)/2) z-scores)) were investigated in a prospective study of 293 mother-child dyads.nnRESULTS: Highest versus low-mid pregnancy tHcy tertile was associated with higher mid-childhood MetSco, specifically with higher child zFMI. Stratifying by sex, the maternal tHcy-child MetSco association was limited to boys and confirmed for zFMI and zHOMA-IR. The maternal tHcy-child zFMI association was not mediated by birth weight z-score. First trimester plasma cobalamin was not associated with child outcomes, but other indicators of cobalamin status were. Lowest versus mid-high plasma holoTC tertile was associated with MetSco (specifically zFMI and zHOMA-IR) and highest versus low-mid plasma MMA tertile with higher MetSco and dyslipidemia in boys.nnCONCLUSIONS: Moderately elevated pregnancy tHcy and low cobalamin status were associated with mid-childhood metabolic score in boys. The pregnancy tHcy-child zFMI association was not mediated by birth weight.nnIMPACT: Fasting plasma total homocysteine (tHcy) during pregnancy and low cobalamin status during early pregnancy are associated with mid-childhood metabolic score and its components in the offspring. These findings were only significant in male offspring. The study provides new evidence that impaired one carbon metabolism during pregnancy is associated with negative health outcomes in the offspring, in a population with low prevalence of cobalamin deficiency. The maternal-offspring associations were observed in the functional markers of cobalamin status (holotranscobalamin and methylmalonic acid) and tHcy, not with plasma cobalamin concentration. Screening for low pregnancy cobalamin status should be considered.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36894239,

title = {Relationship between Ketones, Ghrelin, and, Appetite on Isocaloric Diets with Varying Carbohydrate Quality and Amount: Results from a Randomized Controlled Trial in People with Obesity (CARBFUNC)},

author = {Cathrine Horn Sommersten and Eirin Semb Gjerde and Johnny Laupsa-Borge and Amanda Io Andersen and Laurence Lawrence-Archer and Adrian McCann and Patrik Hansson and Ghulam S Raza and Karl Heinz Herzig and Gülen Arslan Lied and Catia Martins and Gunnar Mellgren and Jutta Dierkes and Simon N Dankel},

doi = {10.1016/j.tjnut.2022.12.030},

issn = {1541-6100},

year  = {2023},

date = {2023-02-01},

journal = {J Nutr},

volume = {153},

number = {2},

pages = {459--469},

abstract = {BACKGROUND: Low-carbohydrate high-fat (LCHF) diets may suppress the increase in appetite otherwise seen after diet-induced fat loss. However, studies of diets without severe energy restriction are lacking, and the effects of carbohydrate quality relative to quantity have not been directly compared.nnOBJECTIVES: To evaluated short- (3 mo) and long-term (12 mo) changes in fasting plasma concentrations of total ghrelin, β-hydroxybutyrate (βHB), and subjective feelings of appetite on 3 isocaloric eating patterns within a moderate caloric range (2000-2500 kcal/d) and with varying carbohydrate quality or quantity.nnMETHODS: We performed a randomized controlled trial of 193 adults with obesity, comparing eating patterns based on "acellular" carbohydrate sources (e.g., flour-based whole-grain products; comparator arm), "cellular" carbohydrate sources (minimally processed foods with intact cellular structures), or LCHF principles. Outcomes were compared by an intention-to-treat analysis using constrained linear mixed modeling. This trial was registered at clinicaltrials.gov as NCT03401970.nnRESULTS: Of the 193 adults, 118 (61%) and 57 (30%) completed 3 and 12 mo of follow-up. Throughout the intervention, intakes of protein and energy were similar with all 3 eating patterns, with comparable reductions in body weight (5%-7%) and visceral fat volume (12%-17%) after 12 mo. After 3 mo, ghrelin increased significantly with the acellular (mean: 46 pg/mL; 95% CI: 11, 81) and cellular (mean: 54 pg/mL; 95% CI: 21, 88) diets but not with the LCHF diet (mean: 11 pg/mL; 95% CI: -16, 38). Although βHB increased significantly more with the LCHF diet than with the acellular diet after 3 m (mean: 0.16 mmol/L; 95% CI: 0.09, 0.24), this did not correspond to a significant group difference in ghrelin (unless the 2 high-carbohydrate groups were combined [mean: -39.6 pg/mL; 95% CI: -76, -3.3]). No significant between-group differences were seen in feelings of hunger.nnCONCLUSIONS: Modestly energy-restricted isocaloric diets differing in carbohydrate cellularity and amount showed no significant differences in fasting total ghrelin or subjective hunger feelings. An increase in ketones with the LCHF diet to 0.3-0.4 mmol/L was insufficient to substantially curb increases in fasting ghrelin during fat loss.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38187791,

title = {Vitamin B: a scoping review for Nordic Nutrition Recommendations 2023},

author = {Anne-Lise Bjørke-Monsen and Per Magne Ueland},

doi = {10.29219/fnr.v67.10259},

issn = {1654-661X},

year  = {2023},

date = {2023-01-01},

journal = {Food Nutr Res},

volume = {67},

abstract = {Pyridoxal 5´-phosphate (PLP) is the main form of vitamin B in animal tissue and functions as a coenzyme for more than 160 different enzymatic reactions in the metabolism of amino acids, carbohydrates, lipids, and neurotransmitters. Estimated dietary intake of vitamin B and plasma PLP values differ a lot between studies, something which may be due to variable use of supplements, variations in dietary assessment and analytical methods. These factors make it difficult to achieve precise data for setting a correct recommended intake of vitamin B. In addition, a plasma PLP concentration of 30 nmol/L is considered to be sufficient and the current recommendations for vitamin B intake is based on this concept. However, the metabolic marker for vitamin B status, HK ratio (HKr), starts to increase already when plasma PLP falls below 100 nmol/L and increases more steeply below 50 nmol/L, indicating biochemical deficiency. Consequently, a plasma PLP concentration of 30 nmol/L, may be too low as a marker for an adequate vitamin B status.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38187793,

title = {Folate - a scoping review for Nordic Nutrition Recommendations 2023},

author = {Anne-Lise Bjørke-Monsen and Per Magne Ueland},

doi = {10.29219/fnr.v67.10258},

issn = {1654-661X},

year  = {2023},

date = {2023-01-01},

journal = {Food Nutr Res},

volume = {67},

abstract = {Folate is an essential micronutrient for normal development and metabolic function, and folate deficiency is associated with an increased risk of cancer, cardiovascular disease, mental dysfuntion and negative pregnancy outcomes. When estimating folate requirements, one must consider different bioavailability and functionality between synthetic folic acid and dietary folate, together with increased needs of folate in women of fertile age, pregnant and lactating women, preterm and small for gestational age weight infants and individuals who are homozygote for the 5,10-methylenetetrahydrofolate reductase () gene polymorphism. In order to achieve an adequate metabolic status based on the metabolic marker total homocysteine, and not merely the absence of clinical signs of folate deficiency, the recommended intake of folate differs according to age, pregnancy and lactation. According to the World Health Organization, a decision limit for folate deficiency in adults is serum folate level below 10 nmol/L, and in women of fertile age a red blood cell folate level below 906 nmol/L in order to prevent neural tube defects. Qualified systematic reviews along with identified relevant literature have been used for this scoping review prepared for the Nordic Nutrition Recommendations 2023.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36724153,

title = {Cystatin C proteoforms in chronic kidney disease},

author = {Helene Dahl and Klaus Meyer and Kristina Sandnes and Natasha Lervaag Welland and Iselin Arnesen and Hans-Peter Marti and Jutta Dierkes and Vegard Lysne},

doi = {10.1371/journal.pone.0269436},

issn = {1932-6203},

year  = {2023},

date = {2023-01-01},

journal = {PLoS One},

volume = {18},

number = {2},

pages = {e0269436},

abstract = {Cystatin C, a cysteine protease inhibitor, is used as a biomarker of renal function. It offers several advantages compared to creatinine, and formulas for the estimation of the glomerular filtration rate based on cystatin C have been developed. Recently, several proteoforms of cystatin C have been discovered, including an intact protein with a hydroxylated proline at the N-terminus, and N-terminal truncated forms. There is little knowledge about the biological significance of these proteoforms.nnMETHODS: Cross-sectional study of patients with different stages of chronic renal disease (pre-dialysis n = 53; hemodialysis n = 51, renal transplant n = 53). Measurement of cystatin C proteoforms by MALDI-TOF MS, assessment of medicine prescription using the first two levels of the Anatomical Therapeutic chemical system from patients' records.nnRESULTS: Patients receiving hemodialysis had the highest cystatin C concentrations, followed by pre-dialysis patients and patients with a renal transplant. In all groups, the most common proteoforms were native cystatin C and CysC 3Pro-OH while the truncated forms made up 28%. The distribution of the different proteoforms was largely independent of renal function and total cystatin C. However, the use of corticosteroids (ATC-L02) and immunosuppressants (ATC-H04) considerably impacted the distribution of proteoforms.nnCONCLUSION: The different proteoforms of cystatin C increased proportionally with total cystatin C in patients with chronic kidney disease. Prescription of corticosteroids and immunosuppressants had a significant effect on the distribution of proteoforms. The biological significance of these proteoforms remains to be determined.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36631895,

title = {Serum concentrations of amino acids and tryptophan metabolites are affected by consumption of a light breakfast: a clinical intervention study in adults with overweight or obesity},

author = {Ingrid V Hagen and Anita Helland and Marianne Bratlie and Øivind Midttun and Adrian McCann and Arve Ulvik and Gunnar Mellgren and Per M Ueland and Oddrun A Gudbrandsen},

doi = {10.1186/s40795-022-00661-1},

issn = {2055-0928},

year  = {2023},

date = {2023-01-01},

journal = {BMC Nutr},

volume = {9},

number = {1},

pages = {10},

abstract = {BACKGROUND: Epidemiological studies often investigate amino acids and their metabolites as biomarkers, but do not always consistently use fasting or non-fasting blood samples, or may lack information on the prandial status of the study participants. Since little information is available on the effects of the prandial status on many biomarkers, and since blood is typically sampled early in the day with participants in a fasting state or after having consumed a light meal in many trials, the main purpose of this study was to investigate the short-term effects of a light breakfast on serum concentrations of amino acids and related metabolites.nnMETHODS: Blood was collected from sixty-three healthy adults (36 women) in the fasting state and at set times for 120 min after intake of a light breakfast with low protein content (14 g protein, 2218 kJ). Relative changes in serum biomarker concentrations from fasting to postprandial serum concentrations were tested using T test.nnRESULTS: The serum concentrations of 13 of the 20 measured amino acids were significantly changed 60 min following breakfast intake, with the most marked effects seen as increases in alanine (34%) and proline (45%) concentrations. The response did not reflect the amino acid composition of the breakfast. The concentrations of seven kynurenine metabolites were significantly decreased after breakfast.nnCONCLUSION: Consumption of a light breakfast affected serum concentrations of several amino acids and related metabolites, underlining the importance of having information regarding the participants' prandial state at the time of blood sampling in studies including these biomarkers.nnTRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT02350595 (registered January 2015).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36653422,

title = {A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium},

author = {Øivind Midttun and Arve Ulvik and Klaus Meyer and Hana Zahed and Graham G Giles and Jonas Manjer and Malte Sandsveden and Arnulf Langhammer and Elin Pettersen Sørgjerd and Annelie F Behndig and Mikael Johansson and Neal D Freedman and Wen-Yi Huang and Chu Chen and Ross Prentice and Victoria L Stevens and Ying Wang and Loïc Le Marchand and Stephanie J Weinstein and Qiuyin Cai and Alan A Arslan and Yu Chen and Xiao-Ou Shu and Wei Zheng and Jian-Min Yuan and Woon-Puay Koh and Kala Visvanathan and Howard D Sesso and Xuehong Zhang and J Michael Gaziano and Anouar Fanidi and Hilary A Robbins and Paul Brennan and Mattias Johansson and Per M Ueland},

doi = {10.1038/s41598-023-28135-9},

issn = {2045-2322},

year  = {2023},

date = {2023-01-01},

journal = {Sci Rep},

volume = {13},

number = {1},

pages = {1011},

abstract = {Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan-NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36409557,

title = {Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients},

author = {Leiv Otto Watne and Christian Thomas Pollmann and Bjørn Erik Neerland and Else Quist-Paulsen and Nathalie Bodd Halaas and Ane-Victoria Idland and Bjørnar Hassel and Kristi Henjum and Anne-Brita Knapskog and Frede Frihagen and Johan Raeder and Aasmund Godø and Per Magne Ueland and Adrian McCann and Wender Figved and Geir Selbæk and Henrik Zetterberg and Evandro F Fang and Marius Myrstad and Lasse M Giil},

doi = {10.1172/JCI163472},

issn = {1558-8238},

year  = {2023},

date = {2023-01-01},

journal = {J Clin Invest},

volume = {133},

number = {2},

abstract = {BACKGROUNDThe kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.METHODSWe undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and 1-year mortality.RESULTSIn delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA) (OR 2.26 [1.78, 2.87], P < 0.001) to be increased and also found increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL) (β 0.43, P < 0.001) and was a strong predictor of 1-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA ≥ 100 nmol/L, P < 0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons.CONCLUSIONOur data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP.FUNDINGNorwegian Health Association and South-Eastern Norway Regional Health Authorities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35916742,

title = {Circulating trimethylamine N-oxide levels do not predict 10-year survival in patients with or without coronary heart disease},

author = {Espen Ø Bjørnestad and Indu Dhar and Gard F T Svingen and Eva R Pedersen and Stein Ørn and Mads M Svenningsson and Grethe S Tell and Per M Ueland and Gerhard Sulo and Reijo Laaksonen and Ottar Nygård},

doi = {10.1111/joim.13550},

issn = {1365-2796},

year  = {2022},

date = {2022-12-01},

journal = {J Intern Med},

volume = {292},

number = {6},

pages = {915--924},

abstract = {BACKGROUND: Trimethylamine N-oxide (TMAO) is an amine oxide generated by gut microbial metabolism. TMAO may contribute to atherothrombosis and systemic inflammation. However, the prognostic value of circulating TMAO for risk stratification is uncertain.nnMETHODS: We assessed prospective relationships of plasma TMAO with long-term risk of all-cause, cardiovascular (CV), and non-CV mortality in the Western Norway Coronary Angiography Cohort (WECAC; 4132 patients with suspected coronary artery disease) and the Hordaland Health Study (HUSK; 6393 community-based subjects). Risk associations were examined using Cox regression analyses.nnRESULTS: Mean follow-up was 9.8 and 10.5 years in WECAC and HUSK, respectively. Following adjustments for established CV risk factors and indices of renal function in WECAC, the hazard ratios (HRs) (95% confidence intervals [CIs]) per one standard deviation increase in log-transformed plasma TMAO were 1.04 (0.97-1.12), 1.06 (0.95-1.18), and 1.03 (0.93-1.13) for all-cause, CV, and non-CV mortality, respectively. Essentially similar results were obtained in patients with angiographically significant coronary artery disease and patients with reduced left ventricular ejection fraction. Corresponding HRs (95% CIs) in the HUSK cohort were 1.03 (0.96-1.10), 1.01 (0.89-1.13), and 1.03 (0.95-1.12) for all-cause-, CV, and non-CV mortality, respectively.nnCONCLUSIONS: Circulating TMAO did not predict long-term all-cause, CV, or non-CV mortality in patients with coronary heart disease or in community-based adults. This large study does not support a role of TMAO for patient risk stratification in primary or secondary prevention.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}