Structure and dynamics of the staphylococcal pyridoxal 5-phosphate synthase complex reveal transient interactions at the enzyme interface.

Infectious diseases are a significant cause of death, and recent studies estimate that common bacterial infectious diseases were responsible for 13.6% of all global deaths in 2019. Among the most significant bacterial pathogens is Staphylococcus aureus, accounting for more than 1.1 million deaths worldwide in 2019. Vitamin biosynthesis has been proposed as a promising target for antibacterial therapy. Here, we investigated the biochemical, structural, and dynamic properties of the enzyme complex responsible for vitamin B6 (pyridoxal 5-phosphate, PLP) biosynthesis in S. aureus, which comprises enzymes SaPdx1 and SaPdx2. The crystal structure of the 24-mer complex of SaPdx1-SaPdx2 enzymes indicated that the S. aureus PLP synthase complex forms a highly dynamic assembly with transient interaction between the enzymes. Solution scattering data indicated that SaPdx2 typically binds to SaPdx1 at a substoichiometric ratio. We propose a structure-based view of the PLP synthesis mechanism initiated with the assembly of SaPLP synthase complex that proceeds in a highly dynamic interaction between Pdx1 and Pdx2. This interface interaction can be further explored as a potentially druggable site for the design of new antibiotics.

Drosophila carrying epilepsy-associated variants in the vitamin B6 metabolism gene PNPO display allele- and diet-dependent phenotypes.

Pyridox(am)ine 5 ' -phosphate oxidase (PNPO) catalyzes the rate-limiting step in the synthesis of pyridoxal 5 ' -phosphate (PLP), the active form of vitamin B6 required for the synthesis of neurotransmitters gamma-aminobutyric acid (GABA) and the monoamines. Pathogenic variants in PNPO have been increasingly identified in patients with neonatal epileptic encephalopathy and early-onset epilepsy. These patients often exhibit different types of seizures and variable comorbidities. Recently, the PNPO gene has also been implicated in epilepsy in adults. It is unclear how these phenotypic variations are linked to specific PNPO alleles and to what degree diet can modify their expression. Using CRISPR-Cas9, we generated four knock-in Drosophila alleles, hWT , hR116Q , hD33V , and hR95H , in which the endogenous Drosophila PNPO was replaced by wild-type human PNPO complementary DNA (cDNA) and three epilepsy-associated variants. We found that these knock-in flies exhibited a wide range of phenotypes, including developmental impairments, abnormal locomotor activities, spontaneous seizures, and shortened life span. These phenotypes are allele dependent, varying with the known biochemical severity of these mutations and our characterized molecular defects. We also showed that diet treatments further diversified the phenotypes among alleles, and PLP supplementation at larval and adult stages prevented developmental impairments and seizures in adult flies, respectively. Furthermore, we found that hR95H had a significant dominant-negative effect, rendering heterozygous flies susceptible to seizures and premature death. Together, these results provide biological bases for the various phenotypes resulting from multifunction of PNPO, specific molecular and/or genetic properties of each PNPO variant, and differential allele-diet interactions.

Maintenance of cellular vitamin B6 levels and mitochondrial oxidative function depend on pyridoxal 5'-phosphate homeostasis protein.

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.

Pyridoxal-5'-phosphate: A cost-effective treatment candidate for hypertensive patients?

OBJECTIVES: Because angiotensin (Ang) II is an essential vasoconstrictive peptide, we analyzed the impact of its post-translational modification to pyruvamide-Ang II (Ang P) by pyridoxal-5'-phosphate (PLP) on blood pressure. PLP is a less expensive vitamin B6 derivative and, therefore, could be a cost-effective drug against hypertension. METHODS: Effect of Ang P on calcium ion entry into vascular smooth muscle cells (VSMCs) was analyzed. Binding affinity of Ang P to angiotensin II type 1 receptor (AT1R) was measured. Vasoconstrictive effect of Ang P was investigated using the bioassay of isolated perfused rat kidneys. Spontaneously hypertensive rats (SHR) were administered PLP. Additionally, Wistar Kyoto rats (WKY) received Ang II and PLP. Blood pressure was measured time-dependently. RESULTS: Ang II, incubated with PLP, was post-translationally modified to Ang P. Calcium ion entry in VSMCs was significantly lower with Ang P compared to Ang II. Binding affinity of Ang P to AT1R was lower compared to Ang II. Perfusion pressure of isolated perfused rat kidneys increased less by Ang P than by Ang II. Blood pressure of SHR treated with PLP decreased significantly. Blood pressure of WKY rats treated with Ang II was increased to hypertensive values, whereas blood pressure of WKY rats cotreated with Ang II and PLP was not. CONCLUSION: PLP induces a post-translational modification of Ang II decreasing blood pressure in rats. Assuming that increased PLP intake in the form of vitamin B6 might reduce blood pressure in hypertensive patients, PLP might be a cost-effective drug against hypertension.

Identification of YigL as a PLP/PNP phosphatase in Escherichia coli.

In various organisms, the coenzyme form of vitamin B6, pyridoxal phosphate (PLP), is synthesized from pyridoxine phosphate (PNP). Control of PNP levels is crucial for metabolic homeostasis because PNP has the potential to inhibit PLP-dependent enzymes and proteins. Although the only known pathway for PNP metabolism in Escherichia coli involves oxidation by PNP oxidase, we detected a strong PNP phosphatase activity in E. coli cell lysate. To identify the unknown PNP phosphatase(s), we performed a multicopy suppressor screening using the E. coli serA pdxH strain, which displays PNP-dependent conditional lethality. The results showed that overexpression of the yigL gene, encoding a putative sugar phosphatase, effectively alleviated the PNP toxicity. Biochemical analysis revealed that YigL has strong phosphatase activity against PNP. A yigL mutant exhibited decreased PNP phosphatase activity, elevated intracellular PNP concentrations, and increased PNP sensitivity, highlighting the important role of YigL in PNP homeostasis. YigL also shows reactivity with PLP. The phosphatase activity of PLP in E. coli cell lysate was significantly reduced by mutation of yigL and nearly abolished by additional mutation of ybhA, which encodes putative PLP phosphatase. These results underscore the important contribution of YigL, in combination with YbhA, as a primary enzyme in the dephosphorylation of both PNP and PLP in E. coli.IMPORTANCEPyridoxine phosphate (PNP) metabolism is critical for both vitamin B6 homeostasis and cellular metabolism. In Escherichia coli, oxidation of PNP was the only known mechanism for controlling PNP levels. This study uncovered a novel phosphatase-mediated mechanism for PNP homeostasis. Multicopy suppressor screening, kinetic analysis of the enzyme, and knockout/overexpression studies identified YigL as a key PNP phosphatase that contributes to PNP homeostasis when facing elevated PNP concentrations in E. coli. This study also revealed a significant contribution of YigL, in combination with YbhA, to PLP metabolism, shedding light on the mechanisms of vitamin B6 regulation in bacteria.

Exploration of Vitamin B6-Based Redox-Active Pyridinium Salts Towards the Application in Aqueous Organic Flow Batteries.

Pyridoxal hydrochloride, a vitamin B6 vitamer, was synthetically converted to a series of diverse redox-active benzoyl pyridinium salts. Cyclic voltammetry studies demonstrated redox reversibility under basic conditions, and two of the most promising salts were subjected to laboratory-scale flow battery tests involving galvanostatic cycling at 10 mM in 0.1 M NaOH. In these tests, the battery was charged completely, corresponding to the transfer of two electrons to the electrolyte, but no discharge was observed. Both CV analysis and electrochemical simulations confirmed that the redox wave observed in the experimental voltammograms corresponds to a two-electron process. To explain the irreversibility in the battery tests, we conducted bulk electrolysis with the benzoyl pyridinium salts, affording the corresponding benzylic secondary alcohols. Computational studies suggest that the reduction proceeds in three consecutive steps: first electron transfer (ET), then proton-coupled electron transfer (PCET) and finally proton transfer (PT) to give the secondary alcohol. 1H NMR deuterium exchange studies indicated that the last PT step is not reversible in 0.1 M NaOH, rendering the entire redox process irreversible. The apparent reversibility observed in CV at the basic media likely arises from the slow rate of the PT step at the timescale of the measurement.

Vitamin B-6 Prevents Heart Failure with Preserved Ejection Fraction Through Downstream of Kinase 3 in a Mouse Model.

BACKGROUND: There is an urgent need to develop an efficient therapeutic strategy for heart failure with preserved ejection fraction (HFpEF), which is mediated by phenotypic changes in cardiac macrophages. We previously reported that vitamin B-6 inhibits macrophage-mediated inflammasome activation. OBJECTIVES: We sought to examine whether the prophylactic use of vitamin B-6 prevents HFpEF. METHODS: HFpEF model was elicited by a combination of high-fat diet and Nω-nitro-l-arginine methyl ester supplement in mice. Cardiac function was assessed using conventional echocardiography and Doppler imaging. Immunohistochemistry and immunoblotting were used to detect changes in the macrophage phenotype and myocardial remodeling-related molecules. RESULTS: Co-administration of vitamin B-6 with HFpEF mice mitigated HFpEF phenotypes, including diastolic dysfunction, cardiac macrophage phenotypic shifts, fibrosis, and hypertrophy. Echocardiographic improvements were observed, with the E/E' ratio decreasing from 42.0 to 21.6 and the E/A ratio improving from 2.13 to 1.17. The exercise capacity also increased from 295.3 to 657.7 min. However, these beneficial effects were negated in downstream of kinase (DOK) 3-deficient mice. Mechanistically, vitamin B-6 increased DOK3 protein concentrations and inhibited macrophage phenotypic changes, which were abrogated by an AMP-activated protein kinase inhibitor. CONCLUSIONS: Vitamin B-6 increases DOK3 signaling to lower risk of HFpEF by inhibiting phenotypic changes in cardiac macrophages.

A critical review of electrochemical and optical Vitamin B6 sensing: evolution of biosensor platforms based on advanced nanosystems.

Vitamin B6 (VB6) is a member of the water-soluble B vitamins which have a vital performance in nervous system operating activities. VB6 is highly demanded to maintain excellent skin and immune systems in the human body. furthermore, VB6 is tremendously substantial in the functions of some enzymes that participate in the metabolism of proteins, amino acids, etc. The deficiency of VB6 will eventuate in anemic situations and may lead to permanent injuries in the brain. moreover, recent studies disclosed that adequate Vitamin B6 in the human body can decrease the intensity of illnesses such as diabetes, stress, etc., in patients with COVID-19 infections. Thus, the detection of VB6 from real samples is crucial to control the amount of this vitamin in biological fluids and to monitor the pharmaceutical dosage quality. Various analytical approaches have been employed for the VB6 detection in biological and pharmaceutical samples. Although biosensing and sensing approaches hold several obvious advantages such as simplicity, capability for miniaturization, quick response time, etc. from other analytical methods. Hence, through the last decades, designing and fabricating biosensors with sufficient sensitivity and selectivity have been investigated by many researchers in order to detect VB6. The purpose of this review is to illustrate the importance of diverse electrochemical and optical approaches for VB6 detection. Additionally, novel VB6 detection techniques based on electrochemical, optical, and conventional methods have been considerably discussed, and compared with each other. Furthermore, a comprehensive summary of the current limitations and future challenges in VB6 analysis are explained and also create a pathway for subsequent expansions and applications.

Vitamin B₆ is an essential compound for proper function of human body.Various nanomaterial-based methods such as conational approach, electrochemical biosensing and apta-sensing analyses for Vitamin B₆ detection has been developed.Different techniques for detecting of Vitamin B₆ have been comprehensively discussed.Various electrochemical sensors fabrication and its application in Vitamin B₆ detection with nanomaterials have been assessed.The article points out the recent progress limitations, and also the upcoming tasks in the successful sensor fabrication with the functionalized nanomaterials.

Enhancement of vitamin B6 production driven by omics analysis combined with fermentation optimization.

BACKGROUND: Microbial engineering aims to enhance the ability of bacteria to produce valuable products, including vitamin B6 for various applications. Numerous microorganisms naturally produce vitamin B6, yet the metabolic pathways involved are rigorously controlled. This regulation by the accumulation of vitamin B6 poses a challenge in constructing an efficient cell factory. RESULTS: In this study, we conducted transcriptome and metabolome analyses to investigate the effects of the accumulation of pyridoxine, which is the major commercial form of vitamin B6, on cellular processes in Escherichia coli. Our omics analysis revealed associations between pyridoxine and amino acids, as well as the tricarboxylic acid (TCA) cycle. Based on these findings, we identified potential targets for fermentation optimization, including succinate, amino acids, and the carbon-to-nitrogen (C/N) ratio. Through targeted modifications, we achieved pyridoxine titers of approximately 514 mg/L in shake flasks and 1.95 g/L in fed-batch fermentation. CONCLUSION: Our results provide insights into pyridoxine biosynthesis within the cellular metabolic network for the first time. Our comprehensive analysis revealed that the fermentation process resulted in a remarkable final yield of 1.95 g/L pyridoxine, the highest reported yield to date. This work lays a foundation for the green industrial production of vitamin B6 in the future.

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 Cofactor Pyridoxal 5'-phosphate Conjugated Papain-Stabilized Fluorescent Gold Nanoclusters for Switch-on Detection of Zinc(II).

In this study, fluorescent gold nanoclusters (AuNCs) conjugated with pyridoxal-5-phosphate (PLP) were synthesized, characterized, and used for Zn2+ fluorescence turn-on sensing. PLP was conjugated over the surface of papain-stabilized fluorescent gold nanoclusters (pap-AuNCs; λex = 380 nm, λem = 670 nm) by forming imine linkage. Due to this modification, the red color emitting pap-AuNCs changed to orange color emitting nanoclusters PLP_pap-AuNCs. The nano-assembly PLP_pap-AuNCs detect Zn2+ selectively by showing a notable fluorescence enhancement at 477 nm. Zn2+ detection with PLP_pap-AuNCs was quick and easy, with an estimated detection limit of 0.14 µM. Further, paper strips and cotton buds coated with PLP_pap-AuNCs were developed for affordable on-site visual detection of Zn2+. Finally, the detection of Zn2+ in actual environmental water samples served as validation of the usefulness of PLP_pap-AuNCs.

Primary hyperoxaluria: Long-term outcomes of isolated kidney versus simultaneous liver/kidney transplant.

OBJECTIVES: To compare long-term transplant outcomes (organ rejection and retransplant) of simultaneous liver/kidney transplant (SLK) versus isolated kidney transplant (IK) for patients with primary hyperoxaluria (PH). METHODS: The Rare Kidney Stone Consortium PH registry was queried to identify patients with PH who underwent SLK or IK from 1999 to 2021. Patient characteristics and long-term transplant outcomes were abstracted and analyzed. Statistical comparisons were performed with Kaplan-Meier plots and Cox proportional hazards models. RESULTS: We identified 250 patients with PH, of whom 35 received care at Mayo Clinic and underwent SLK or IK. Patients who underwent SLK as their index transplant had lower odds of kidney rejection than did those who underwent IK (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.08-0.99; p = .048). The immunoprotective effect of concomitant liver and kidney transplant appeared to enhance outcomes for patients with PH. Additionally, the odds of retransplant were significantly lower for patients who underwent SLK as their index transplant than for those who underwent IK (HR, 0.08; 95% CI, 0.02-0.42; p = .003). Of five patients who underwent IK and had maintained graft function for at least 5 years after transplant, three (60%) had documented vitamin B6 responsiveness. CONCLUSIONS: Patients with PH who underwent SLK had a lower risk of kidney rejection and retransplant than those who underwent IK. Accurate genetic assessment for vitamin B6 responsiveness may optimize IK allocation. Novel therapeutics, such as lumasiran, have been introduced as promising agents for the management of PH.

Folic acid and autism: updated evidences.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that impairs communication, socialization, and behavior. The association of ASD with folic acid has been investigated due to the importance of this vitamin for neurological health. This study is an update of the publication 'Folic acid and autism: What do we know?' and aims to systematically review studies examining the relationship between folic acid and ASD. The search resulted in 2,389 studies on folic acid and ASD, which were selected by two reviewers based on their titles and abstracts. Studies meeting the inclusion criteria were fully read. The 52 included studies involved 10,429 individuals diagnosed with ASD and assessed the intake of vitamin B6, folic acid, and vitamin B12; serum levels of these vitamins, homocysteine, and methionine; therapeutic interventions using folic acid; and the association between maternal exposure to this vitamin and the risk of ASD. The evidence of insufficient folic acid intake in most individuals with ASD remains consistent in this update. No association was found between maternal exposure to folic acid and the risk of ASD in their children. Despite observed improvements in communication, socialization, and behavior in individuals with ASD following folic acid interventions, it is crucial to consider the individuality and complexity of ASD. Given the relevance of the topic, there remains a need for more high-quality research and clinical trials characterized by rigorous methodological designs.

Metal complexes containing vitamin B6-based scaffold as potential DNA/BSA-binding agents inducing apoptosis in hepatocarcinoma (HepG2) cells.

A ligand (HL) was synthesized from the pyridoxal hydrochloride (vitamin B6 form) and 1-(2-Aminoethyl)piperidine in one single step. The metal complexes [Zn(L)(Bpy)]NO3 (1), [Cu(L)(Bpy)]NO3 (2), and [Co(L)(Bpy)]NO3 (3) were prepared by tethering HL and 2,2'-bipyridine. The synthesized HL and metal complexes 1-3 were thoroughly characterized using spectroscopic techniques such as 1H NMR, 13C NMR, FTIR, EI-MS, molar conductance, and magnetic moment, in addition to CHN elemental analysis. The geometry of complexes was square pyramidal around the metal ions {Zn(II), Cu(II), and Co(II)}. The interaction of ligand and metal complexes with DNA and BSA macromolecules was accomplished by UV-Vis absorption and fluorescence spectroscopy in vitro. The hyperchromism in band at 303-325 with no shift supports the groove binding with some partial intercalation in grooves. Similarly, in BSA-binding studies, complex 2 shows greater binding potential in the hydrophobic core probably near the Trp-212 in the subdomain IIA. Furthermore, complex 2 shows excellent cytotoxicity on HepG2 cancer cells with IC50 = 25.0 ± 0.45 µM. The detailed analysis by cell-cycle studies shows cell arrest at the G2/M phase. The type of cell death was authenticated by an annexin V-FTIC dual staining experiment that reveals maximum death by apoptosis together with non-specific necrosis.

Establishing reference intervals for thiamine pyrophosphate and pyridoxal 5'-phosphate in whole blood in a Danish cohort using liquid chromatography tandem-mass spectrometry (LC-ms/ms).

Vitamin B1 (thiamine pyrophosphate (TPP)) and B6 (pyridoxal 5'- phosphate (PLP)) deficiencies pose significant health risks. The current measurement method employs High-Performance Liquid Chromatography (HPLC), though, Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) is considered a more sensitive and selective analytical method. However, there is a lack of LC-MS/MS-based reference intervals. Moreover, none of the existing reference intervals are established in Danish populations. Therefore, the aim of this study was to establish a reference interval for whole blood concentrations of TPP and PLP in Danish blood donors using LC-MS/MS. Blood samples were collected from healthy Danish blood donors and analysed using the reagent kit, MassChrom® Vitamins B1 and B6 in whole blood (Chromsystems Instruments & Chemicals GmbH, Munich, Germany) for quantitative determination of both TPP and PLP concentration in whole blood, using LC-MS/MS. Reference intervals were determined with non-parametric methods as the 2.5th and 97.5th percentile and presented with 90% confidence intervals (CI). In total 120 blood donors were included. The concentrations of TTP or PLP were not statistically different between sexes just as age did not affect the concentrations, hence, combined reference intervals were employed. The resulting reference intervals are: TPP, nmol/L: 101.0 (90% CI: 96.4-108.5) - 189.0 (90% CI: 184.7-192.0) and PLP, nmol/L: 64.0 (90% CI: 60.9-66.7) - 211.8 (90% CI: 168.3-231.0). In conclusion, reference intervals for whole blood TTP and PLP in a healthy Danish population were established based on a LC-MS/MS method. Furthermore, the reference intervals were not affected by age or sex.

Vitamin B6 inhibits activity of Helicobacter pylori adenylosuccinate synthetase and growth of reference and clinical, antibiotic-resistant H. pylori strains.

The current therapies against gastric pathogen Helicobacter pylori are ineffective in over 20% of patients. Enzymes belonging to the purine salvage pathway are considered as novel drug targets in this pathogen. Therefore, the main aim of the current study was to determine the antibacterial activity of pyridoxal 5'-phosphate (PLP), an active form of vitamin B6, against reference and clinical strains of H. pylori. Using a broad set of microbiological, physicochemical (UV absorption, LC-MS, X-ray analysis) and in silico experiments, we were able to prove that PLP inhibits adenylosuccinate synthetase (AdSS) from H. pylori by the competition with GTP (IC50eq ∼30 nM). This behaviour was attributed to formation of a Schiff base with a lysine residue (a covalent bond with Lys322 in the GTP binding site of AdSS) and was potentiated by the presence of vitamin C. This antibacterial activity of PLP gives hope for its future use against H. pylori.

Vitamin B6 alleviates osteoarthritis by suppressing inflammation and apoptosis.

BACKGROUND: Although various anti-inflammatory medicines are widely recommended for osteoarthritis (OA) treatment, no significantly clinical effect has been observed. This study aims to examine the effects of vitamin B6, a component that has been reported to be capable of alleviating inflammation and cell death in various diseases, on cartilage degeneration in OA. METHODS: Collagen-induced arthritis (CIA) mice model were established and the severity of OA in cartilage was determined using the Osteoarthritis Research Society International (OARSI) scoring system. The mRNA and protein levels of indicators associated with extracellular matrix (ECM) metabolism, apoptosis and inflammation were detected. The effect of vitamin B6 (VB6) on the mice were assessed using HE staining and masson staining. The apoptosis rate of cells was assessed using TdT-mediated dUTP nick end labeling. RESULTS: Our results showed a trend of improved OARSI score in mice treated with VB6, which remarkably inhibited the hyaline cartilage thickness, chondrocyte disordering, and knees hypertrophy. Moreover, the VB6 supplementation reduced the protein expression of pro-apoptosis indicators, including Bax and cleaved caspase-3 and raised the expression level of anti-apoptosis marker Bcl-2. Importantly, VB6 improved ECM metabolism in both in vivo and in vitro experiments. CONCLUSIONS: This study demonstrated that VB6 alleviates OA through regulating ECM metabolism, inflammation and apoptosis in chondrocytes and CIA mice. The findings in this study provide a theoretical basis for targeted therapy of OA, and further lay the theoretical foundation for studies of mechanisms of VB6 in treating OA.

A Gadolinium(III) Complex Based on Pyridoxine Molecule with Single-Ion Magnet and Magnetic Resonance Imaging Properties.

Pyridoxine (pyr) is a versatile molecule that forms part of the family of B vitamins. It is used to treat and prevent vitamin B6 deficiency and certain types of metabolic disorders. Moreover, the pyridoxine molecule has been investigated as a suitable ligand toward metal ions. Nevertheless, the study of the magnetic properties of metal complexes containing lanthanide(III) ions and this biomolecule is unexplored. We have synthesized and characterized a novel pyridoxine-based GdIII complex of formula [GdIII(pyr)2(H2O)4]Cl3 · 2 H2O (1) [pyr = pyridoxine]. 1 crystallizes in the triclinic system and space group Pi. In its crystal packing, cationic [Gd(pyr)2(H2O)4]3+ entities are connected through H-bonding interactions involving non-coordinating water molecules and chloride anions. In addition, Hirshfeld surfaces of 1 were calculated to further investigate their intermolecular interactions in the crystal lattice. Our investigation of the magnetic properties of 1, through ac magnetic susceptibility measurements, reveals the occurrence of a slow relaxation in magnetization in this mononuclear GdIII complex, indicating an unusual single-ion magnet (SIM) behavior for this pseudo-isotropic metal ion at very low temperatures. We also studied the relaxometric properties of 1, as a potential contrast agent for high-field magnetic resonance imaging (MRI), from solutions of 1 prepared in physiological serum (0.0-3.2 mM range) and measured at 3 T on a clinical MRI scanner. The values of relaxivity obtained for 1 are larger than those of some commercial MRI contrast agents based on mononuclear GdIII systems.

Does Vitamin B6 Act as an Exercise Mimetic in Skeletal Muscle?

Marginal vitamin B6 (B6) deficiency is common in various segments worldwide. In a super-aged society, sarcopenia is a major concern and has gained significant research attention focused on healthy aging. To date, the primary interventions for sarcopenia have been physical exercise therapy. Recent evidence suggests that inadequate B6 status is associated with an increased risk of sarcopenia and mortality among older adults. Our previous study showed that B6 supplementation to a marginal B6-deficient diet up-regulated the expression of various exercise-induced genes in the skeletal muscle of rodents. Notably, a supplemental B6-to-B6-deficient diet stimulates satellite cell-mediated myogenesis in rodents, mirroring the effects of physical exercise. These findings suggest the potential role of B6 as an exercise-mimetic nutrient in skeletal muscle. To test this hypothesis, we reviewed relevant literature and compared the roles of B6 and exercise in muscles. Here, we provide several pieces of evidence supporting this hypothesis and discuss the potential mechanisms behind the similarities between the effects of B6 and exercise on muscle. This research, for the first time, provides insight into the exercise-mimetic roles of B6 in skeletal muscle.

Dynamics of rhizosphere microbial structure and function associated with the biennial bearing of moso bamboo.

Moso bamboo (Phyllostachys edulis) is a valuable nontimber forestry product with a biennial cycle, producing abundant bamboo shoots within one year (on-year) and few shoots within the following year (off-year). Moso bamboo plants undergo clonal reproduction, resulting in similar genetic backgrounds. However, the number of moso bamboo shoots produced each year varies. Despite this variation, the impact of soil nutrients and the root microbiome on the biennial bearing of moso bamboo is poorly understood. We collected 139 soil samples and determined 14 major physicochemical properties of the rhizosphere, rhizoplane, and bulk soil in different seasons (i.e., the growing and deciduous seasons) and different years (i.e., on- and off-years). Based on 16S rRNA and metagenomic sequencing, major variations were found in the rhizospheric microbial composition during different seasons and years in the moso bamboo forest. Environmental driver analysis revealed that essential nutrients (i.e., SOC, TOC, TN, P, and NH4+) were the main drivers of the soil microbial community composition and were correlated with the on- and off-year cycles. Moreover, 19 MAGs were identified as important biomarkers that could distinguish on- and off-years. We found that both season and year influenced both the microbial community structure and functional pathways through the biosynthesis of nutrients that potentially interact with the moso bamboo growth rhythm, especially the on-year root-associated microbiome, which had a greater abundance of specific nutrients such as gibberellins and vitamin B6. This work provides a dynamic perspective of the differential responses of various on- and off-year microbial communities and enhances our understanding of bamboo soil microbiome biodiversity and stability.