Vitamin B6 — why might an ordinary tablet not work?

Aim of the study: Pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency is an ultrarare inherited neurometabolic disease, characterized by primarily neonatal-onset B6-responsive epileptic encephalopathies. Treatment often requires sustainable access to high-quality pyridoxal-5'-phosphate (PLP, i.e., active vitamin B6), although some patients (also) respond to pyridoxine (PN).

Results: The majority of PLP-responsive patients responded exclusively to PLP, with PN being attempted but ineffective in most of them (n = 30/33, 90.9%) Liver toxicity was the most frequently observed adverse event (n = 10, 20.4%) and although the underlying pathophysiological mechanism remains unclear, it may be associated with high-dose PLP. Therefore, regular liver disease screening is recommended during PLP therapy. This means that PLP remains the only effective therapy for achieving and maintaining seizure control in the majority of PNPO deficient patients, but the therapeutic window for optimal management is narrow. Thus, it is essential to ensure patient access to high-quality and appropriate forms of PLP.

Aim of the study: Tumor-infiltrating lymphocytes are usually dysfunctional but demonstrate stem cell-like behavior through unclear mechanisms. Here, we report that administration of vitamin B6 or its active form, pyridoxal phosphate (PLP), endows mouse and human CD8+ T cells with improved persistence, stemness-like phenotypes, and tumor clearance capabilities.

Results: Mechanistically, PLP preserves T cell function by directly binding to and inhibiting p70S6 kinase (p70S6K). Through limiting p70S6K-mediated BTB domain and CNC homolog 2 (BACH2) phosphorylation, PLP increases nuclear retention and functional activation of BACH2, promoting stemness gene expression while dampening exhaustion gene expression. In preclinical tumor models, PLP treatment improves the efficacy of anti-programmed death receptor 1 (PD-1) antibody therapy. Thus, our study reveals a pathway that preserves T cell functional stemness-like phenotypes to drive the acquisition of antitumor immunity, highlighting the clinical potential of vitamin B6/PLP-enhanced T cell function strategies in cancer immunotherapy.

Aim of the study: Vitamin B6 is essential for life and plays a critical role in many biochemical and physiological processes in the human body. The term B6 collectively refers to 6 water-soluble vitamers, and only the pyridoxal 5'-phosphate (PLP) serves as the biologically active form. A plasma PLP concentration above 30 nmol/L (7.4 μg/L) is indicative of an adequate vitamin B6 status for all age and sex groups.

Aim of the study: The active form of vitamin B6, pyridoxal 5'-phosphate (PLP), serves as a co-factor in more than 150 enzymatic reactions. Plasma PLP has consistently been shown to be low in inflammatory conditions; there is a parallel reduction in liver PLP, but minor changes in erythrocyte and muscle PLP and in functional vitamin B6 biomarkers.

Results: Plasma PLP also predicts the risk of chronic diseases like cardiovascular disease and some cancers, and is inversely associated with numerous inflammatory markers in clinical and population-based studies. Vitamin B6 intake and supplementation improve some immune functions in vitamin B6-deficient humans and experimental animals. A possible mechanism involved is mobilization of vitamin B6 to the sites of inflammation where it may serve as a co-factor in pathways producing metabolites with immunomodulating effects. Relevant vitamin B6-dependent inflammatory pathways include vitamin B6 catabolism, the kynurenine pathway, sphingosine 1 phosphate metabolism, the transsulfuration pathway, and serine and glycine metabolism.

Aim of the study: Evidence regarding the associations of pyridoxal 5'-phosphate level in plasma and dietary intake of vitamin B6 with depression risk is scarce. Accordingly, we investigated the aforementioned associations in US adults.

Results: In the multivariable model, the highest quarter of dietary intake of vitamin B6 was associated with a significantly lower risk of depression compared to the lowest quarter (OR = 0.63, 95% CI: 0.50, 0.79, p < 0.001). Similarly, the highest quartile of plasma PLP levels was linked to a reduced risk of depression compared to the lowest quartile (OR = 0.76, 95% CI: 0.62, 0.93, p < 0.01). With increasing quartiles of dietary intake of vitamin B6 and plasma PLP levels, the risk of depression also decreased accordingly (all p for trend < 0.01). Furthermore, the correlation analysis revealed that for every 1-SD increase in the level of plasma lutein + zeaxanthin and dietary intake of vitamin B6, the risk of depression showed a decreasing trend (all p < 0.01). The interaction test results indicated that the dietary consumption of vitamin B6 did not significantly interact with any of the stratification factors (all p for interaction > 0.05).

Aim of the study: Nutrients involved in one-carbon metabolism may play a key role in pancreatic carcinogenesis. The aim of this study was to examine the association between pancreatic cancer risk and intake or blood levels of vitamins B6, B12 and methionine via meta-analysis.

Results: A total of 18 studies were included in this meta-analysis on the association of vitamin B6, B12 and methionine with pancreatic cancer risk. The combined risk estimate (95% CI) of pancreatic cancer for the highest vs lowest category of vitamin B6 intake and blood pyridoxal 5'-phosphate (PLP, active form of vitamin B6) levels was 0.63 (0.48-0.79) and 0.65 (0.52-0.79), respectively. The results indicated a non-linear dose-response relationship between vitamin B6 intake and pancreatic risk. Linear dose-response relationship was found, and the risk of pancreatic cancer decreased by 9% for every 10 nmol/L increment in blood PLP levels. No significant association were found between pancreatic cancer risk and vitamin B12 intake, blood vitamin B12 levels, methionine intake and blood methionine levels. Our study suggests that high intake of vitamin B6 and high concentration of blood PLP levels may be protective against the development of pancreatic cancer.

Aim of the study: Previous epidemiological studies have focused on the association of dietary vitamin B6 or circulating pyridoxal-5′-phosphate (PLP) with colorectal cancer risk. This study aimed to investigate the vitamin B6 in relation to colorectal cancer risk combining the biomarkers of PLP, pyridoxal (PL) plus PLP, and PAr (the ratio of 4-pyridoxic acid over the sum of PLP and PL).

Results: Comparing the highest with the lowest quartile, the adjusted OR (95% CI) was 0.26 (0.20−0.33, Ptrend < 0.001) for serum PLP, 0.51 (0.40−0.66, Ptrend < 0.001) for serum PLP plus PL, and 2.90 (2.25−3.75, Ptrend < 0.001) for PAr. Serum PLP and PAr had significantly stronger associations with colorectal cancer risk in the male group and smoking group. Our results supported the protective role of vitamin B6 in colorectal cancer risk among Chinese people. The positive association of PAr with colorectal cancer risk suggested the potential role of inflammation and oxidative stress in colorectal carcinogenesis.

Aim of the study: ATP acting on P2X3 receptors (P2X3R) within carotid bodies (CBs) underpins chemoreflex-mediated sympathetic overactivity in spontaneously hypertensive rats (SHR). Pyridoxal 5' phosphate (PLP), the active form of vitamin B6, has been reported to act as a non-selective P2X receptor blocker. Hence, we hypothesised that PLP antagonism of P2X3R in the CB would treat hypertension.

Results: Herein, we employed a multipronged approach to investigate PLP's capability to attenuate CB hyperexcitability in hypertension.First, PLP inhibited Ca2+ responses evoked by α, β-methylene ATP in cell lines expressing human (h) P2X3R with an IC50 of 8.7 µM. Next, in-silico data predicted that PLP binds to the same site of Gefapixant, supporting an allosteric antagonism. Using an isolated perfused carotid artery bifurcation-CB preparation, arterial infusion of PLP (50 µM; 15 min) attenuated CBs sensory firing in SHR (P = 0.012). Using the in situ working-heart brainstem preparation, carotid artery injections of PLP (1-5 mM) attenuated the chemoreflex-evoked sympathetic (P = 0.023) but not phrenic (P = 0.62) responses; the CB was stimulated with potassium cyanide (KCN,50 µL; 0.04%).

Aim of the study: Vitamin B6 metabolism is implicated in chronic inflammation and insulin resistance, two important factors influencing stroke and type 2 diabetes, respectively. This study aimed to investigate the prospective associations of multiple plasma biomarkers of vitamin B6 homeostasis, i.e.

Results: Compared with individuals with the lowest quartile of plasma PAr, the odds ratio (OR) and 95% CI was 2.915 (2.072-4.101) for the highest quartile. By contrast, the ORs (95% CIs) of the highest quartile versus the lowest were 0.577 (0.432-0.771) for PL, 0.652 (0.488-0.871) for PLP, and 1.232 (0.897-1.692) for PA, respectively. In addition, adding plasma levels of PAr, PL and PLP offered incremental reclassification ability for incident stroke beyond the conventional risk factors. The greatest reclassification ability improvement was observed for the combination of PAr, PL and PLP (NRI: 0.482, 95% CI: 0.395-0.568). Plasma levels of PAr, PL and PLP were significantly associated with the risk of incident stroke and provided incremental ability for the risk prediction of stroke in individuals with type 2 diabetes.