Vitamin B6 ameliorates acute pancreatitis by suppressing the caspase3 signaling pathway.

BACKGROUND: Acute pancreatitis (AP) is a prevalent exocrine inflammatory disorder of the pancreas characterized by pancreatic inflammation and injury to acinar cells. Vitamin B6 (VB6) is a vital nutrient that plays a significant role in preserving human health and has anti-inflammatory and anti-apoptotic effects. METHODS: This study aimed to explore the potential pancreatic protective effects of VB6 in mitigating pancreatic inflammation and apoptosis induced by taurocholate sodium (TLCS) in an AP model and to assess the underlying mechanism of action. AP was induced in Sprague‒Dawley (SD) rats through TLCS administration and lipopolysaccharide (LPS)-treated AR42J cells, followed by treatment with VB6. RESULTS: Various parameters associated with AP were assessed in both plasma and pancreatic tissues. VB6 has been shown to ameliorate the severity of AP through various mechanisms. It effectively reduces the levels of serum amylase, lipase, and inflammatory factors, thereby mitigating histological injury to the pancreas. Moreover, VB6 inhibited pancreatic apoptosis by downregulating bax expression and up-regulating Bcl2 expression in TLCS-treated rats. Additionally, VB6 suppressed the expression of caspase3. The anti-inflammatory and anti-apoptotic effects of VB6 observed in LPS-treated AR42J cells are consistent with those observed in a rat model of AP. CONCLUSIONS: These results suggest that VB6 exerts anti-inflammatory and anti-apoptotic effects through inhibition of the caspase3 signaling pathway and has a protective effect against AP.

Vitamin B6 alleviates chronic sleep deprivation-induced hippocampal ferroptosis through CBS/GSH/GPX4 pathway.

Several studies have found that sleep deprivation (SD) can lead to neuronal ferroptosis and affect hippocampal function. However, there are currently no effective interventions. Vitamin B6 is a co-factor for key enzymes in the transsulfuration pathway which is critical for maintaining cell growth in the presence of cysteine deprivation. The results showed that SD inhibited cystine-glutamate antiporter light chain subunit xCT protein expression and caused cysteine deficiency, which reduced the synthesis of the glutathione (GSH) to trigger neuronal ferroptosis. Nissl staining further revealed significant neuronal loss and shrinkage in the CA1 and CA3 regions of the hippocampus in SD mice. Typical ferroptotic indicators characterized by lipid peroxidation and iron accumulation were showed in the hippocampus after sleep deprivation. As expected, vitamin B6 could alleviate hippocampal ferroptosis by upregulating the expression of cystathionine beta-synthase (CBS) in the transsulfuration pathway, thereby replenishing the intracellular deficient GSH and restoring the expression of GPX4. Similar anti-ferroptotic effects of vitamin B6 were demonstrated in HT-22 cells treated with ferroptosis activator erastin. Furthermore, vitamin B6 had no inhibitory effect on erastin-induced ferroptosis in CBS-knockout HT22 cells. Our findings suggested chronic sleep deprivation caused hippocampal ferroptosis by disrupting the cyst(e)ine/GSH/GPX4 axis. Vitamin B6 alleviated sleep deprivation-induced ferroptosis by enhancing CBS expression in the transsulfuration pathway.

Discovery and characterization of natural product luteolin as an effective inhibitor of human pyridoxal kinase.

Pyridoxal kinase (PDXK) is an essential enzyme in the synthesis of pyridoxal 5-phosphate (PLP), the active form of vitamin B6, which plays a pivotal role in maintaining the enzyme activity necessary for cell metabolism. Thus, PDXK has garnered attention as a potential target for metabolism regulation and tumor therapy. Despite this interest, existing PDXK inhibitors have faced limitations, including weak suppressive activity, unclear mechanisms of action, and associated toxic side effects. In this study, we present the discovery of a novel PDXK inhibitor, luteolin, through a high-throughput screening approach based on enzyme activity. Luteolin, a natural product, exhibits micromolar-level affinity for PDXK and effectively inhibits the enzyme's activity in vitro. Our crystal structures reveal that luteolin occupies the ATP binding pocket through hydrophobic interactions and a weak hydrogen bonding pattern, displaying reversible characteristics as confirmed by biochemical assays. Moreover, luteolin disrupts vitamin B6 metabolism by targeting PDXK, thereby inhibiting the proliferation of leukemia cells. This research introduces a novel screening method for identifying high-affinity and potent PDXK inhibitors and sheds light on clarification of the structural mechanism of PDXK-luteolin for subsequent structure optimization of inhibitors.

New copper(II) and oxidovanadium(IV) complexes with a vitamin B6 Schiff base: mechanism of action and synergy studies on 2D and 3D human osteosarcoma cell models.

We report the synthesis, characterization and anticancer activity of a new Schiff base (H2L) derived from the condensation of pyridoxamine with pyridoxal and its novel copper(II) and oxidovanadium(IV) complexes: [Cu(HL)Cl] (1), [Cu(LH2)(phen)]Cl2 (2), [Cu(LH2)(amphen)]Cl2 (3), [VIVO(HL)Cl] (4), and [VIVO(LH2)(phen)]Cl2 (5), where phen is 1,10-phenanthroline and amphen is its 5-amino derivative. All compounds were characterized by analytical and spectroscopic techniques, namely FTIR, UV-vis and EPR spectroscopy. Their stability in aqueous media was evaluated, revealing that the presence of the phen co-ligand significantly increases the stability. The ternary Cu(II) complexes (2 and 3) impaired cell viability of osteosarcoma cells (MG-63) (IC50 values of 3.6 ± 0.6 and 7 ± 1.9 µM for 2 and 3), while 1 and the VIVO complexes did not show relevant anticancer activity. Complexes 2 and 3 are also more active than cisplatin (CDDP). Synergistic studies between 2 and sorafenib showed significant synergism on MG-63 cells for the following combinations: 2 (2.0 µM) + sorafenib (10.0 µM) and 2 (2.5 µM) + sorafenib (12.5 µM), whilst the combination of 2 and CDDP did not show synergy. Complex 2 interacts with DNA, inducing significant genotoxic effects on MG-63 cells from 1.0 to 2.5 µM and it increases the ROS levels 880% over basal. Moreover, 2 induces apoptosis at 1.0 and 2.0 µM, while its combination with sorafenib induces apoptosis and necrosis. Finally, compound 2 reduces the cell viability of MG-63 spheroids showing an IC50 value 7-fold lower than that of CDDP (8.5 ± 0.4 µM vs. 65 ± 6 µM). The combination of 2 and sorafenib also showed synergism on spheroids, suggesting that the combination of these drugs improves the anticancer effect against bone cancer cells.

Green Pea (Pisum sativum L.) Hull Polyphenol Extract Alleviates NAFLD through VB6/TLR4/NF-κB and PPAR Pathways.

Green pea hull is a processing byproduct of green pea and rich in polyphenols. Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease characterized by accumulation of lipids in the liver for which there are no effective treatment strategies. Here, a mouse model of NAFLD induced by a DSS+high-fat diet (HFD) was established to investigate the effect of green pea hull polyphenol extract (EGPH). The results show that EGPH relief of NAFLD was a combined effect, including reducing hepatic fat accumulation, improving antioxidant activity and blood lipid metabolism, and maintaining glucose homeostasis. Increased intestinal permeability aggravated NAFLD. Combined metabolomics and transcriptomic analysis showed that vitamin B6 is the key target substance for EGPH to alleviate NAFLD, and it may be the intestinal flora metabolite. After EGPH intervention, the level of vitamin B6 in mice was significantly increased, and more than 60% in the blood enters the liver, which activated or inhibited PPAR and TLR4/NF-κB signaling pathways to relieve NAFLD. Our research could be a win-win for expanding the use of green pea hull and the search for NAFLD prophylactic drugs.

Protective effect of vitamin B6 against doxorubicin-induced cardiotoxicity by modulating NHE1 expression.

Doxorubicin (DOX) has been used to treat various types of cancer, but its application is limited due to its heart toxicity as well as other drawbacks. Chronic inhibition of Na+ /H+ exchanger (NHE1) reduces heart failure and reduces the production of reactive oxygen species (ROS); vitamin B6 (VitB6 ) has been demonstrated to have a crucial role in antioxidant mechanism. So, this study was designed to explore the effect of VitB6 supplement on the DOX-induced cardiotoxicity and to imply whether NHE1 is involved. Ultrasonic cardiogram analysis revealed that VitB6 supplement could alleviate DOX-induced cardiotoxicity; hematoxylin and eosin (HE) and Masson's staining further confirmed this effect. Furthermore, VitB6 supplement exhibited significant antioxidative stress and antiapoptosis effect, which was evidenced by decreased serum malondialdehyde (MDA) content and increased serum superoxide dismutase (SOD) content, and decreased Bcl-2-associated X protein/B-cell lymphoma-2 ratio, respectively. Collectively, VitB6 supplement may exert antioxidative and antiapoptosis effects to improve cardiac function by decreasing NHE1 expression and improve DOX-induced cardiotoxicity.

Susceptibility to Low Vitamin B6 Diet-induced Gestational Diabetes Is Modulated by Strain Differences in Mice.

Gestational diabetes is a common pregnancy complication that adversely influences the health and survival of mother and child. Pancreatic islet serotonin signaling plays an important role in ß-cell proliferation in pregnancy, and environmental and genetic factors that disrupt serotonin signaling are associated with gestational diabetes in mice. Our previous studies show that pregnant C57BL/6J mice fed a diet that is low in vitamin B6, a critical co-factor in serotonin synthesis, develop hyperglycemia and glucose intolerance, phenotypes that are consistent with gestational diabetes in humans. The current study shows that, unlike in the C57BL/6J mice, low vitamin B6 diet does not alter glucose tolerance and insulin secretion in pregnant DBA/2J mice. The hypothesis to be tested in the current study is that pregnant DBA/2J mice are protected against low vitamin B6-induced gestational diabetes due to their higher expression and enzymatic activities of tissue nonspecific alkaline phosphatase (ALPL) relative to C57BL/6J. ALPL is a rate-limiting enzyme that regulates vitamin B6 bioavailability. Interestingly, treating pregnant DBA/2J mice with 7.5 mg/kg/day of the ALPL inhibitor SBI-425 is associated with glucose intolerance in low vitamin B6-fed mice, implying that inhibition of ALPL activity is sufficient to modulate resilience to low vitamin B6-induced metabolic impairment.

A gene-nutrient interaction between vitamin B6 and serine hydroxymethyltransferase (SHMT) affects genome integrity in Drosophila.

Pyridoxal 5'-phosphate (PLP), the catalytically active form of vitamin B6, participates as a cofactor to one carbon (1C) pathway that produces precursors for DNA metabolism. The concerted action of PLP-dependent serine hydroxymethyltransferase (SHMT) and thymidylate synthase (TS) leads to the biosynthesis of thymidylate (dTMP), which plays an essential function in DNA synthesis and repair. PLP deficiency causes chromosome aberrations (CABs) in Drosophila and human cells, rising the hypothesis that an altered 1C metabolism may be involved. To test this hypothesis, we used Drosophila as a model system and found, firstly, that in PLP deficient larvae SHMT activity is reduced by 40%. Second, we found that RNAi-induced SHMT depletion causes chromosome damage rescued by PLP supplementation and strongly exacerbated by PLP depletion. RNAi-induced TS depletion causes severe chromosome damage, but this is only slightly enhanced by PLP depletion. dTMP supplementation rescues CABs in both PLP-deficient and PLP-proficient SHMTRNAi . Altogether these data suggest that a reduction of SHMT activity caused by PLP deficiency contributes to chromosome damage by reducing dTMP biosynthesis. In addition, our work brings to light a gene-nutrient interaction between SHMT decreased activity and PLP deficiency impacting on genome stability that may be translated to humans.

Vitamin B6 regulates IL-33 homeostasis to alleviate type 2 inflammation.

Interleukin-33 (IL-33) is a crucial nuclear cytokine that induces the type 2 immune response and maintains immune homeostasis. The fine-tuned regulation of IL-33 in tissue cells is critical to control of the type 2 immune response in airway inflammation, but the mechanism is still unclear. Here, we found that healthy individuals had higher phosphate-pyridoxal (PLP, an active form of vitamin B6) concentrations in the serum than asthma patients. Lower serum PLP concentrations in asthma patients were strongly associated with worse lung function and inflammation. In a mouse model of lung inflammation, we revealed that PLP alleviated the type 2 immune response and that this inhibitory effect relied on the activity of IL-33. A mechanistic study showed that in vivo, pyridoxal (PL) needed to be converted into PLP, which inhibited the type 2 response by regulating IL-33 stability. In mice heterozygous for pyridoxal kinase (PDXK), the conversion of PL to PLP was limited, and IL-33 levels were increased in the lungs, aggravating type 2 inflammation. Furthermore, we found that the mouse double minute 2 homolog (MDM2) protein, an E3 ubiquitin-protein ligase, could ubiquitinate the N-terminus of IL-33 and sustain IL-33 stability in epithelial cells. PLP reduced MDM2-mediated IL-33 polyubiquitination and decreased the level of IL-33 through the proteasome pathway. In addition, inhalation of PLP alleviated asthma-related effects in mouse models. In summary, our data indicate that vitamin B6 regulates MDM2-mediated IL-33 stability to constrain the type 2 response, which might help develop a potential preventive and therapeutic agent for allergy-related diseases.

Untargeted metabolomics reveals the preventive effect of quercetin on nephrotoxicity induced by four organophosphorus pesticide mixtures.

This research aimed to explore the protective effect of quercetin against nephrotoxicity induced by four organophosphate pesticide mixtures (PM) using untargeted metabolomics technology in rat kidneys. Sixty male Wistar rats were randomly divided into six groups: control, low-dose quercetin treated (10 mg/kg bw), high-dose quercetin treated (50 mg/kg bw), PM-treated, and two dosages of quercetin + PM-treated. Metabolomics results showed that 17 differential metabolites were identified in the PM-treated group, and pathway analysis revealed that renal metabolic disorders include purine metabolism, glycerophospholipid metabolism, and vitamin B6 metabolism. When high-dose quercetin and PM-treated were administered to rats concurrently, the intensities of differential metabolites were substantially restored (p < 0.01), suggesting that quercetin can improve renal metabolic disorders caused by organophosphate pesticides (OPs). Mechanistically, quercetin could regulate the purine metabolism disorder and endoplasmic reticulum stress (ERS)-mediated autophagy induced by OPs by inhibiting XOD activity. Moreover, quercetin inhibits PLA2 activity to regulate glycerophospholipid metabolism and it could also exert antioxidant and anti-inflammatory effects to correct vitamin B6 metabolism in rat kidneys. Taken together, the high dose of quercetin (50 mg/kg. bw) has a certain protective effect on OPs-induced nephrotoxicity in rats, which provides a theoretical basis for quercetin against nephrotoxicity caused by OPs.

Vitamin B6 based Pt(II) complexes: biomolecule derived potential cytotoxic agents for thyroid cancer.

Vitamin B6 is an essential vitamin that serves as a co-enzyme in a number of enzymatic reactions in metabolism of lipids, amino acids, and glucose. In the current study, we synthesized vitamin B6 derived ligand (L) and its complex Pt(L)Cl (C1). The ancillary chloride ligand of C1 was exchanged with pyridine co-ligand and another complex Pt(L)(py).BF4 (C2) was obtained. Both these complexes were obtained in excellent isolated yields and characterized thoroughly by different analytical methods. Thyroid cancer is one of the most common malignancies of the endocrine system, we studied the in vitro anticancer activity and mechanism of these vitamin B6 derived L and Pt(II) complexes in thyroid cancer cell line (FTC). Based on MTT assay, cell proliferation rate was reduced in a dose-dependent manner. According to apoptosis analysis, vitamin B6 based Pt(II) complexes treated cells depicted necrotic effect and TUNEL based apoptosis was observed in cancer cells. Furthermore, qRT-PCR analyses of cancer cells treated with C1 and/or C2 showed regulated expression of anti-apoptotic, pro-apoptosis and autophagy related genes. Western blot results demonstrated that C1 and C2 induced the activation of p53 and the cleavage of Poly (ADP-ribose) polymerase (PARP). These results suggest that these complexes inhibit the growth of FTC cells and induce apoptosis through p53 signaling. Thus, vitamin B6 derived Pt(II) complexes C1 and C2 may be potential cytotoxic agents for the treatment of thyroid cancer.

Vitamin B6 rescues insulin resistance and glucose-induced DNA damage caused by reduced activity of Drosophila PI3K.

The insulin signaling pathway controls cell growth and metabolism, thus its deregulation is associated with both cancer and diabetes. Phosphatidylinositol 3-kinase (PI3K) contributes to the cascade of phosphorylation events occurring in the insulin pathway by activating the protein kinase B (PKB/AKT), which phosphorylates several substrates, including those involved in glucose uptake and storage. PI3K inactivating mutations are associated with insulin resistance while activating mutations are identified in human cancers. Here we show that RNAi-induced depletion of the Drosophila PI3K catalytic subunit (Dp110) results in diabetic phenotypes such as hyperglycemia, body size reduction, and decreased glycogen content. Interestingly, we found that hyperglycemia produces chromosome aberrations (CABs) triggered by the accumulation of advanced glycation end-products and reactive oxygen species. Rearing PI3KRNAi flies in a medium supplemented with pyridoxal 5'-phosphate (PLP; the catalytically active form of vitamin B6) rescues DNA damage while, in contrast, treating PI3KRNAi larvae with the PLP inhibitor 4-deoxypyridoxine strongly enhances CAB frequency. Interestingly, PLP supplementation rescues also diabetic phenotypes. Taken together, our results provide a strong link between impaired PI3K activity and genomic instability, a crucial relationship that needs to be monitored not only in diabetes due to impaired insulin signaling but also in cancer therapies based on PI3K inhibitors. In addition, our findings confirm the notion that vitamin B6 is a good natural remedy to counteract insulin resistance and its complications.

Effects of a New Multicomponent Nutritional Supplement on Muscle Mass and Physical Performance in Adult and Old Patients Recovered from COVID-19: A Pilot Observational Case-Control Study.

OBJECTIVE: The purpose of the present study was to assess the effect of a specific oral nutritional supplement among patients recovered from COVID-19 but suffering symptoms of fatigue. METHODS: This is an observational case-control study involving a sample of 66 COVID-19 survivors divided in two groups, 33 subjects in the intervention group who received the nutritional supplement and 33 subjects in the control group. The nutritional supplement received by subjects in the active group was based on amino acids; vitamin B6 and B1; and malic, succinic and citric acids. After an 8-week follow-up, the main outcomes considered were skeletal muscle index (measured by bioelectrical impedance analysis), physical performance measures (handgrip strength, one-minute chair-stand test, six-minute walking test), and quality of life (using EuroQol visual analogue scale). RESULTS: All the considered areas increased significantly in the subjects receiving the active treatment with oral nutritional supplement in comparison with the baseline values. After adjusting for age, gender, and baseline values, skeletal muscle index, handgrip strength test, the one-minute chair-stand test, and six-minute walking test values were higher among participants in the treatment group compared with subjects in control group. The oral nutritional supplement significantly improved the handgrip strength; similarly, participants in the active group showed a higher improvement in skeletal muscle index, the one-minute chair-stand test, the six-minute walking test, and in quality of life. CONCLUSION: The nutritional supplement containing nine essential amino acids plus cysteine; vitamin B6 and B1; and malic, succinic and citric acids had a positive effect on nutritional status, functional recovery, and quality of life in COVID-19 survivors still suffering from fatigue. Additional controlled clinical trials are required to corroborate these results.

Mechanism of vitamin B6 benzoyl hydrazone platinum(II) complexes overcomes multidrug resistance in lung cancer.

To overcome the resistance of tumour cells to cis-diaminedichloroplatinum(II) (cisplatin, DDP), we designed and synthesised platinum(II) complexes with copper coordination active sites using vitamin B6 and benzohydrazide derivatives as raw materials.The 3D structures of the complexes were confirmed by X-ray single-crystal diffraction. The results of the biological activity assay showed that the Pt(II) complexes (VB6-Pt1 and VB6-Pt2) have higher anti-tumour activity on detected typical lung cancer cells than DDP. Among them, VB6-Pt1 (IC50 = 0.78 µM) efficiently reversed DDP resistance in A549/DDP cell line and increased selectivity index (26) against mortal MRC-5 fibroblasts. The study showed that VB6-Pt1 overcomes tumor drug resistance by significantly increasing the level of reactive oxyge species and inducing lysosomal membrane permeability, which leads to mitochondrial dysfunction and cell apoptosis. Furthermore, the inhibitory effect of VB6-Pt1 on A549 xenograft tumours was 81.5%, which was much higher than that of cisplatin (50.0%), without significantly increasing p-glycoprotein (P-gp) protein expression. The copper-coordinated active site in Pt(II) complexes may be a key factor in their ability to overcome DDP-resistant cancer cells.

Pyridoxal Kinase of Disease-causing Human Parasites: Structural and Functional Insights to Understand its Role in Drug Discovery.

Human parasites cause several diseased conditions with high morbidity and mortality in a large section of the population residing in various geographical areas. Nearly three billion people suffer from either one or many parasitic infections globally, with almost one million deaths annually. In spite of extensive research and advancement in the medical field, no effective vaccine is available against prominent human parasitic diseases that necessitate identification of novel targets for designing specific inhibitors. Vitamin B6 is an important ubiquitous co-enzyme that participates in several biological processes and plays an important role in scavenging ROS (reactive oxygen species) along with providing resistance to oxidative stress. Moreover, the absence of the de novo vitamin B6 biosynthetic pathway in human parasites makes this pathway indispensable for the survival of these pathogens. Pyridoxal kinase (PdxK) is a crucial enzyme for vitamin B6 salvage pathway and participates in the process of vitamers B6 phosphorylation. Since the parasites are dependent on pyridoxal kinase for their survival and infectivity to the respective hosts, it is considered a promising candidate for drug discovery. The detailed structural analysis of PdxK from disease-causing parasites has provided insights into the catalytic mechanism of this enzyme as well as significant differences from their human counterpart. Simultaneously, structure-based studies have identified small lead molecules that can be exploited for drug discovery against protozoan parasites. The present review provides structural and functional highlights of pyridoxal kinase for its implication in developing novel and potent therapeutics to combat fatal parasitic diseases.

PDX1.1-dependent biosynthesis of vitamin B6 protects roots from ammonium-induced oxidative stress.

Despite serving as a major inorganic nitrogen source for plants, ammonium causes toxicity at elevated concentrations, inhibiting root elongation early on. While previous studies have shown that ammonium-inhibited root development relates to ammonium uptake and formation of reactive oxygen species (ROS) in roots, it remains unclear about the mechanisms underlying the repression of root growth and how plants cope with this inhibitory effect of ammonium. In this study, we demonstrate that ammonium-induced apoplastic acidification co-localizes with Fe precipitation and hydrogen peroxide (H2O2) accumulation along the stele of the elongation and differentiation zone in root tips, indicating Fe-dependent ROS formation. By screening ammonium sensitivity in T-DNA insertion lines of ammonium-responsive genes, we identified PDX1.1, which is upregulated by ammonium in the root stele and whose product catalyzes de novo biosynthesis of vitamin B6. Root growth of pdx1.1 mutants is hypersensitive to ammonium, while chemical complementation or overexpression of PDX1.1 restores root elongation. This salvage strategy requires non-phosphorylated forms of vitamin B6 that are able to quench ROS and rescue root growth from ammonium inhibition. Collectively, these results suggest that PDX1.1-mediated synthesis of non-phosphorylated B6 vitamers acts as a primary strategy to protect roots from ammonium-dependent ROS formation.

Satellite Cells Exhibit Decreased Numbers and Impaired Functions on Single Myofibers Isolated from Vitamin B6-Deficient Mice.

Emerging research in human studies suggests an association among vitamin B6, sarcopenia, and muscle strength. However, very little is known regarding its potential role at the cellular level, especially in muscle satellite cells. Therefore, to determine whether vitamin B6 affects the satellite cells, we isolated single myofibers from muscles of vitamin B6-deficient and vitamin B6-supplemented mice. Subsequently, we subjected them to single myofiber culture and observed the number and function of the satellite cells, which remained in their niche on the myofibers. Prior to culture, the vitamin B6-deficient myofibers exhibited a significantly lower number of quiescent satellite cells, as compared to that in the vitamin B6-supplemented myofibers, thereby suggesting that vitamin B6 deficiency induces a decline in the quiescent satellite cell pool in mouse muscles. After 48 and 72 h of culture, the number of proliferating satellite cells per cluster was similar between the vitamin B6-deficient and -supplemented myofibers, but their numbers decreased significantly after culturing the myofibers in vitamin B6-free medium. After 72 h of culture, the number of self-renewing satellite cells per cluster was significantly lower in the vitamin B6-deficient myofibers, and the vitamin B6-free medium further decreased this number. In conclusion, vitamin B6 deficiency appears to reduce the number of quiescent satellite cells and suppress the proliferation and self-renewal of satellite cells during myogenesis.

Vitamin B6 prevents Isocarbophos-induced posterior cerebral artery injury in offspring rats through up-regulating S1P receptor expression.

We have previously reported that the long-term exposure of Isocarbophos, a kind of organophosphorus compounds, induces vascular dementia (VD) in rats. Studies have also shown that organophosphorus compounds have adverse effects on offsprings. Vitamin B6 is a coenzyme mainly involved in the regulation of metabolism and has been demonstrated to ameliorate VD. Sphingosine-1-phosphate (S1P), a biologically active lipid, plays a vital role in the cardiovascular system. However, whether S1P is involved in the therapeutic effects of Vitamin B6 on posterior cerebral artery injury has yet to be further answered. In the present study, we aimed to explore the potential influence of Vitamin B6 on Isocarbophos-induced posterior cerebral artery injury in offspring rats and the role of the S1P receptor in this process. We found that Vitamin B6 significantly improves the vasoconstriction function of the posterior cerebral artery in rats induced by Isocarbophos by the blood gas analysis and endothelium-dependent relaxation function assay. We further demonstrated that Vitamin B6 alleviates the Isocarbophos-induced elevation of ICAM-1, VCAM-1, IL-1, and IL-6 by using the enzyme-linked immunosorbent assay kits. By performing immunofluorescence and the western blot assay, we revealed that Vitamin B6 prevents the down-regulation of S1P in posterior cerebral artery injury. It is worth noting that Fingolimod, the S1P inhibitor, significantly inhibits the Vitamin B6-induced up-regulation of S1P in posterior cerebral artery injury. Collectively, our data indicate that Vitamin B6 may be a novel drug for the treatment of posterior cerebral artery injury and that S1P may be a drug target for its treatment.

Combined Supplementation with Vitamin B-6 and Curcumin is Superior to Either Agent Alone in Suppressing Obesity-Promoted Colorectal Tumorigenesis in Mice.

BACKGROUND: Obesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation. OBJECTIVES: We examined whether the combination of CUR and vitamin B-6 amplifies each supplement's effects and thereby suppress obesity-promoted tumorigenesis. METHODS: Male Friend Virus B (FVB) mice (4-week-old; n = 110) received 6 weekly injections of azoxymethane beginning 1 week after arrival. Thereafter, they were randomized to receive a low-fat diet (10% energy from fat), a high-fat diet (HFD; 60% energy from fat), a HFD containing 0.2% CUR, a HFD containing supplemental vitamin B-6 (24 mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C + B) for 15 weeks. Colonic inflammation, assessed by fecal calprotectin, and tumor metrics were the primary endpoints. The anti-inflammatory efficacy of the combination was also determined in human colonic organoids. RESULTS: HFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P < 0.02), a 1.9-fold increase in fecal calprotectin (P < 0.05), and a 2.2-fold increase in tumor multiplicity (P < 0.05). Compared to the HFD group, the C + B combination, but not the individual agents, decreased fecal calprotectin (66%; P < 0.01) and reduced tumor multiplicity and the total tumor burden by 60%-80% (P < 0.03) in an additive fashion. The combination of C + B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-κB signaling by 31%-47% (P < 0.05), effects largely absent with the single agents. Observations that may explain how the 2 agents work additively include a 2.8-fold increased colonic concentration of 3-hydroxyanthranillic acid (P < 0.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P < 0.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%-93% (P < 0.03), demonstrating relevance to humans. CONCLUSIONS: In this mouse model, C + B is superior to either agent alone in preventing obesity-promoted colorectal carcinogenesis. Augmented suppression of procancerous signaling pathways may be the means by which this augmentation occurs.

Antihyperlipidemic and Hepatoprotective Properties of Vitamin B6 Supplementation in Rats with High-Fat Diet-Induced Hyperlipidemia.

BACKGROUND: The incidence and mortality of hyperlipidemia are increasing year by year, showing a younger trend. At present, the treatment of hyperlipidemia is mainly dependent on western medicine, but its side effects on liver and kidney function are common in clinics. Therefore, it is necessary to study the treatment of hyperlipidemia by augmenting effective dietary nutrition supplements. Vitamin B6 (VitB6), as an essential cofactor for enzymes, participates in lipid metabolism. The effects of VitB6 on hyperlipidemia, however, have not been reported until now. AIM: The present study was to investigate the influence of VitB6 on hepatic lipid metabolism in hyperlipidaemia rats induced by a High-Fat Diet (HFD). METHODS: Male Sprague-Dawley rats were kept on HFD for two weeks to establish the hyperlipidemia model. The rats in low-dosage and high-dosage groups were received 2.00 and 3.00 mg/kg/- day of VitB6 for eight weeks, respectively. RESULTS: The results showed that both doses of VitB6 reduced HFD-induced hepatic Low-Density Lipoprotein Cholesterol (LDL-C); decreased blood cholesterol (TC), triglycerides, LDL-C, atherogenic index (AI), Atherogenic Index of Plasma (AIP), apolipoprotein B (ApoB) and ApoB/apolipoprotein A-1(ApoA1) ratio; increased liver High-Density Lipoprotein Cholesterol (HDL-C) and serum ApoA1; reduced hepatic steatosis and triglyceride accumulation, lowered fat storage, and recovered heart/body and brain/body ratio to a normal level. In addition, VitB6 supplementation markedly decreased HMGR level, increased the mRNA abundance of LDLR and CYP7A1, and protein expression of SIRT1, following the downregulation of SREBP-1 and PPARγ protein expression in the liver of hyperlipidemia rats. CONCLUSION: In summary, oral VitB6 supplementation can ameliorate HFD-induced hepatic lipid accumulation and dyslipidemia in SD rats by inhibiting fatty acid and cholesterol synthesis, promoting fatty acid decomposition and cholesterol transport.