Dataset Information

Serum B₆ vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

ABSTRACT:

Background

Vitamin B₆ is an important enzymatic cofactor in pathways relevant for the development of pancreatic cancer. In order to evaluate vitamin B₆ as a preventive factor for pancreatic cancer, a biomarker approach is needed to overcome the limitations inherent in self-reported dietary information.

Methods

To determine whether levels of serum B₆ vitamers, including pyridoxal 5'-phosphate (PLP), pyridoxal (PL), 4-pyridoxic acid (PA), and the PA/(PLP + PL) ratio (PAr), were associated with risk of pancreatic cancer, two nested case-control studies of 187 incident pancreatic cancer cases and 258 individually matched controls were conducted within two prospective cohorts of 81,501 participants in Shanghai, China, and Singapore. PLP, PL, and PA were quantified in pre-diagnostic serum samples. Odds ratios and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for potential confounders.

Results

The median (5th-95th percentiles) concentrations of serum PLP among control subjects of the Shanghai and Singapore cohorts were 25.7 (10.0-91.7) nmol/L and 58.1 (20.8-563.0) nmol/L, respectively. In pooled analyses, high serum PLP was associated with a reduced risk of pancreatic cancer (P for trend = 0.048); the adjusted odds ratio for the highest category of PLP (>52.4 nmol/L) was 0.46 (95% CI 0.23, 0.92) compared to vitamin B₆ deficiency (<20 nmol/L). No associations were found for serum PL, PA, or PAr with pancreatic cancer risk.

Conclusions

Higher concentrations of PLP may protect against the development of pancreatic cancer. The protective effect may be more apparent in populations with low concentrations of circulating vitamin B₆.

SUBMITTER: Huang JY

PROVIDER: S-EPMC5161671 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

Serum B<sub>6</sub> vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

Huang Joyce Y JY Butler Lesley M LM Midttun Øivind Ø Koh Woon-Puay WP Ueland Per M PM Wang Renwei R Jin Aizhen A Gao Yu-Tang YT Yuan Jian-Min JM

Cancer causes & control : CCC 20161109 12

<h4>Background</h4>Vitamin B<sub>6</sub> is an important enzymatic cofactor in pathways relevant for the development of pancreatic cancer. In order to evaluate vitamin B<sub>6</sub> as a preventive factor for pancreatic cancer, a biomarker approach is needed to overcome the limitations inherent in self-reported dietary information.<h4>Methods</h4>To determine whether levels of serum B<sub>6</sub> vitamers, including pyridoxal 5'-phosphate (PLP), pyridoxal (PL), 4-pyridoxic acid (PA), and the PA/ ...[more]

PMID: 27830400

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Project description:BackgroundMultivariable linear regression (MLR) models were previously used to predict serum pyridoxal 5'-phosphate (PLP) concentration, the active coenzyme form of vitamin B6, but with low predictability. We developed a deep learning algorithm (DLA) to predict serum PLP based on dietary intake, dietary supplements, and other potential predictors.MethodsThis cross-sectional analysis included 3778 participants aged ≥20 years in the National Health and Nutrition Examination Survey (NHANES) 2007-2010, with completed information on studied variables. Dietary intake and supplement use were assessed with two 24-hour dietary recalls. We included potential predictors for serum PLP concentration in the models, including dietary intake and supplement use, sociodemographic variables (age, sex, race-ethnicity, income, and education), lifestyle variables (smoking status and physical activity level), body mass index, medication use, blood pressure, blood lipids, glucose, and C-reactive protein. We used a 4-hidden-layer deep neural network to predict PLP concentration, with 3401 (90%) participants for training and 377 (10%) participants for test using random sampling. We obtained outputs after sending the features of the training set and conducting forward propagation. We then constructed a loss function based on the distances between outputs and labels and optimized it to find good parameters to fit the training set. We also developed a prediction model using MLR.ResultsAfter training for 105 steps with the Adam optimization method, the highest R2 was 0.47 for the DLA and 0.18 for the MLR model in the test dataset. Similar results were observed in the sensitivity analyses after we excluded supplement-users or included only variables identified by stepwise regression models.ConclusionsDLA achieved superior performance in predicting serum PLP concentration, relative to the traditional MLR model, using a nationally representative sample. As preliminary data analyses, the current study shed light on the use of DLA to understand a modifiable lifestyle factor.

Project description:Antimicrobial resistance is a significant cause of mortality globally due to infections, a trend that is expected to continue to rise. As existing treatments fail and new drug discovery slows, the urgency to develop novel antimicrobial therapeutics grows stronger. One promising strategy involves targeting bacterial systems exclusive to pathogens, such as the transcription regulator protein GabR. Expressed in diverse bacteria including Escherichia coli, Bordetella pertussis, and Klebsiella pneumoniae, GabR has no homolog in eukaryotes, making it an ideal therapeutic target. Bacillus subtilis GabR (bsGabR), the most studied variant, regulates its own transcription and activates genes for GABA aminotransferase (GabT) and succinic semialdehyde dehydrogenase (GabD). This intricate regulatory system presents a compelling antimicrobial target with the potential for agonistic intervention to disrupt bacterial gene expression and induce cellular dysfunction, especially in bacterial stress responses. To explore manipulation of this system and the potential of this protein as an antimicrobial target, an in-depth understanding of the unique PLP-dependent transcription regulation is critical. Herein, we report the successful structural modification of the cofactor PLP and demonstrate the biochemical reactivity of the PLP analog pyridoxal-5'-tetrazole (PLT). Through both spectrophotometric and X-ray crystallographic analyses, we explore the interaction between bsGabR and PLT, together with a synthesized GABA derivative (S)-4-amino-5-phenoxypentanoate (4-phenoxymethyl-GABA or 4PMG). Most notably, we present a crystal structure of the condensed, external aldimine complex within bsGabR. While PLT alone is not a drug candidate, it can act as a probe to study the detailed mechanism of GabR-mediated function. PLT employs a tetrazole moiety as a bioisosteric replacement for phosphate in PLP. In addition, the PLP-4PMG adduct observed in the structure may serve as a novel chemical scaffold for subsequent structure-based antimicrobial design.

Project description:Recently, biallelic variants in PLPBP coding for pyridoxal 5'-phosphate homeostasis protein (PLPHP) were identified as a novel cause of early-onset vitamin B6-dependent epilepsy. The molecular function and precise role of PLPHP in vitamin B6 metabolism are not well understood. To address these questions, we used PLPHP-deficient patient skin fibroblasts and HEK293 cells and YBL036C (PLPHP ortholog)-deficient yeast. We showed that independent of extracellular B6 vitamer type (pyridoxine, pyridoxamine, or pyridoxal), intracellular pyridoxal 5'-phosphate (PLP) was lower in PLPHP-deficient fibroblasts and HEK293 cells than controls. Culturing cells with pyridoxine or pyridoxamine led to the concentration-dependent accumulation of pyridoxine 5'-phosphate and pyridoxamine 5'-phosphate (PMP), respectively, suggesting insufficient pyridox(am)ine 5'-phosphate oxidase activity. Experiments utilizing 13C4-pyridoxine confirmed lower pyridox(am)ine 5'-phosphate oxidase activity and revealed increased fractional turnovers of PLP and pyridoxal, indicating increased PLP hydrolysis to pyridoxal in PLPHP-deficient cells. This effect could be partly counteracted by inactivation of pyridoxal phosphatase. PLPHP deficiency had a distinct effect on mitochondrial PLP and PMP, suggesting impaired activity of mitochondrial transaminases. Moreover, in YBL036C-deficient yeast, PLP was depleted and PMP accumulated only with carbon sources requiring mitochondrial metabolism. Lactate and pyruvate accumulation along with the decrease of tricarboxylic acid cycle intermediates downstream of α-ketoglutarate suggested impaired mitochondrial oxidative metabolism in PLPHP-deficient HEK293 cells. We hypothesize that impaired activity of mitochondrial transaminases may contribute to this depletion. Taken together, our study provides new insights into the pathomechanisms of PLPBP deficiency and reinforces the link between PLPHP function, vitamin B6 metabolism, and mitochondrial oxidative metabolism.

Dataset Information

Serum B₆ vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

Background

Methods

Results

Conclusions

Publications

Serum B<sub>6</sub> vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Serum B6 vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

Background

Methods

Results

Conclusions

Publications

Serum B<sub>6</sub> vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Serum B₆ vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.