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1.
Adv Nutr ; 12(5): 1911-1929, 2021 10 01.
Article in English | MEDLINE | ID: mdl-33912895

ABSTRACT

Vitamin B-6 in the form of pyridoxine (PN) is commonly used by the general population. The use of PN-containing supplements has gained lots of attention over the past years as they have been related to the development of peripheral neuropathy. In light of this, the number of reported cases of adverse health effects due to the use of vitamin B-6 have increased. Despite a long history of study, the pathogenic mechanisms associated with PN toxicity remain elusive. Therefore, the present review is focused on investigating the mechanistic link between PN supplementation and sensory peripheral neuropathy. Excessive PN intake induces neuropathy through the preferential injury of sensory neurons. Recent reports on hereditary neuropathy due to pyridoxal kinase (PDXK) mutations may provide some insight into the mechanism, as genetic deficiencies in PDXK lead to the development of axonal sensory neuropathy. High circulating concentrations of PN may lead to a similar condition via the inhibition of PDXK. The mechanism behind PDXK-induced neuropathy is unknown; however, there is reason to believe that it may be related to γ-aminobutyric acid (GABA) neurotransmission. Compounds that inhibit PDXK lead to convulsions and reductions in GABA biosynthesis. The absence of central nervous system-related symptoms in PDXK deficiency could be due to differences in the regulation of PDXK, where PDXK activity is preserved in the brain but not in peripheral tissues. As PN is relatively impermeable to the blood-brain barrier, PDXK inhibition would similarly be confined to the peripheries and, as a result, GABA signaling may be perturbed within peripheral tissues, such as sensory neurons. Perturbed GABA signaling within sensory neurons may lead to excitotoxicity, neurodegeneration, and ultimately, the development of peripheral neuropathy. For several reasons, we conclude that PDXK inhibition and consequently disrupted GABA neurotransmission is the most plausible mechanism of toxicity.


Subject(s)
Peripheral Nervous System Diseases , Pyridoxine , Humans , Peripheral Nervous System Diseases/chemically induced , Pyridoxal Kinase , Pyridoxine/toxicity , Vitamin B 6/toxicity , Vitamins
2.
Toxins (Basel) ; 13(2)2021 01 26.
Article in English | MEDLINE | ID: mdl-33530619

ABSTRACT

Ginkgo biloba seeds are wildly used in the food and medicine industry. It has been found that 4'-O-methylpyridoxine (MPN) is responsible for the poisoning caused by G. biloba seeds. The objective of this study was to explore and optimize the extraction method of MPN from G. biloba seeds, and investigate its toxic effect on human gastric epithelial cells (GES-1) and the potential related mechanisms. The results showed that the extraction amount of MPN was 1.933 µg/mg, when extracted at 40 °C for 100 min, with the solid-liquid ratio at 1:10. MPN inhibited the proliferation of GES-1 cells, for which the inhibition rate was 38.27% when the concentration of MPN was 100 µM, and the IC50 value was 127.80 µM; meanwhile, the cell cycle was arrested in G2 phase. High concentration of MPN (100 µM) had significant effects on the nucleus of GES-1 cells, and the proportion of apoptotic cells reached 43.80%. Furthermore, the Western blotting analysis showed that MPN could reduce mitochondrial membrane potential by increasing the expression levels of apoptotic proteins Caspase 8 and Bax in GES-1 cells. In conclusion, MPN may induce apoptosis in GES-1 cells, which leads to toxicity in the human body.


Subject(s)
Apoptosis/drug effects , Epithelial Cells/drug effects , Gastric Mucosa/drug effects , Ginkgo biloba , Plant Extracts/toxicity , Pyridoxine/analogs & derivatives , Seeds , Caspase 8/metabolism , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Epithelial Cells/metabolism , Epithelial Cells/pathology , G2 Phase Cell Cycle Checkpoints/drug effects , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Ginkgo biloba/chemistry , Humans , Membrane Potential, Mitochondrial/drug effects , Plant Extracts/isolation & purification , Pyridoxine/isolation & purification , Pyridoxine/toxicity , Seeds/chemistry , bcl-2-Associated X Protein/metabolism
3.
J Sci Food Agric ; 101(4): 1589-1597, 2021 Mar 15.
Article in English | MEDLINE | ID: mdl-32869870

ABSTRACT

BACKGROUND: Ginkgotoxin including 4'-O-methylpyridoxine (MPN) and MPN-5'-glucoside (MPNG) is responsible for Ginkgo seed food poisoning. The purpose of the work reported was to prepare detoxified Ginkgo seed powder and at the same time to retain the nutritional and functional components of Ginkgo seed powder to the maximum extent. RESULTS: Resin adsorption technology was firstly employed to remove ginkgotoxin from water extract of Ginkgo seed powder. Under optimal conditions, the adsorption efficiency of the optimal resin for MPN could reach 100%, and that for MPNG could only reach 85.4 ± 0.93%. Resin adsorption alone could not effectively remove MPN and MPNG simultaneously. Endogenous enzymatic hydrolysis was next attempted to transform MPNG to MPN. MPNG could be completely hydrolyzed to MPN by endogenous enzyme(s) at 40 °C and pH 5.0 in 180 min. Ginkgotoxin only in the form of MPN in the enzymatic hydrolysate was then adsorbed with resin and the conditions were statistically optimized. The adsorption efficiency of MPN reached 98.89 ± 0.99% under the optimized conditions. CONCLUSIONS: Removal of ginkgotoxin by combining endogenous enzymatic hydrolysis with resin adsorption could preserve the main nutritional and functional components of Ginkgo seed powder to the most extent, and did not change its main characteristics. The ginkgotoxin removal method developed in this work is a relatively simple and efficient approach. © 2020 Society of Chemical Industry.


Subject(s)
Food Handling/methods , Ginkgo biloba/chemistry , Plant Proteins/metabolism , Seeds/toxicity , Adsorption , Food Handling/instrumentation , Ginkgo biloba/enzymology , Ginkgo biloba/toxicity , Hot Temperature , Hydrolysis , Powders/chemistry , Powders/toxicity , Pyridoxine/analogs & derivatives , Pyridoxine/chemistry , Pyridoxine/toxicity , Resins, Synthetic/chemistry , Seeds/chemistry
4.
J Sci Food Agric ; 101(8): 3290-3297, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33222187

ABSTRACT

BACKGROUND: Ginkgo biloba seeds are used as a functional food across Asia. However, the presence of toxic compounds has limited their application. In this study, freeze drying, infrared drying, hot-air drying and pulsed-vacuum drying were used to dry G. biloba seeds. A comprehensive analysis was performed on their product quality, antioxidant activities, bioactive and toxic components. RESULTS: Results showed that the drying methods had a significant influence on product quality with freeze drying being superior due to the minimal microstructural damage, followed by infrared drying and pulsed-vacuum drying. Infrared-dried product possessed the strongest antioxidant activities and higher bioactive compound content than hot-air-dried and pulsed-vacuum-dried product. Toxic compounds in fresh G. biloba seeds (ginkgotoxin, ginkgolic acid and cyanide) were reduced markedly by drying. Ginkgotoxin was reduced fourfold, and the contents of acrylamide, ginkgolic acid and cyanide in dried G. biloba seeds were reduced to the scope of safety. Amongst the four drying methods, infrared drying had the shortest drying time, and its product showed higher quality and bioactive compound content, and stronger antioxidant activities. CONCLUSIONS: These findings will offer salient information for selecting a drying method during the processing of ginkgo seeds. Infrared drying could be considered as a multiple-effect drying method in the processing of ginkgo seeds. © 2020 Society of Chemical Industry.


Subject(s)
Antioxidants/analysis , Desiccation/methods , Food Handling/methods , Ginkgo biloba/chemistry , Seeds/chemistry , Cyanides/analysis , Cyanides/toxicity , Desiccation/instrumentation , Food Handling/instrumentation , Ginkgo biloba/toxicity , Pyridoxine/analogs & derivatives , Pyridoxine/analysis , Pyridoxine/toxicity , Quality Control , Salicylates/analysis , Seeds/toxicity
5.
Biochem Pharmacol ; 182: 114294, 2020 12.
Article in English | MEDLINE | ID: mdl-33080184

ABSTRACT

Epilepsy is a common neurological disorder affecting people of all ages, races and ethnic backgrounds world-wide. Vitamin B6 supplementation has been widely used as an adjuvant for treating epilepsy. However, the adverse effects, including nausea and peripheral sensory neuropathy, caused by long-term and high-dose consumption of vitamin B6 have undermined the usefulness of vitamin B6 supplementation, justifying additional experimental scrutiny of vitamin B6-associated toxicity. In the current study, we found that the presence of pyridoxine, the inactive form of B6 vitamer included in most nutrient supplements, increased the mortality of the larvae displaying chemical-induced epilepsy. The expression of leptin-b, one zebrafish ortholog of human leptin, was significantly increased in the larvae displaying seizures. Increased leptin-b expression alleviated larval seizure-like behavior when exposed to epilepsy inducer, but also increased larval mortality in the presence of pyridoxine. Meanwhile, elevated adam17 and mmp13 mRNA level were found in the larvae simultaneously exposed to epilepsy-inducer and pyridoxine. Adding TNF-α inhibitor and mmp13 inhibitor effectively improved the survival of larvae injected with leptin-b mRNA and exposed to pyridoxine subsequently. We conclude that increased leptin-b and metalloprotease expression contributed, at least partly, to the pyridoxine-associated toxicity observed in larvae displaying seizures.


Subject(s)
Larva/metabolism , Metalloproteases/biosynthesis , Pyridoxine/toxicity , Receptors, Leptin/biosynthesis , Seizures/chemically induced , Seizures/metabolism , Animals , Animals, Genetically Modified , Dose-Response Relationship, Drug , Gene Expression Regulation, Enzymologic , Gene Knockdown Techniques , Larva/drug effects , Larva/genetics , Metalloproteases/genetics , Receptors, Leptin/genetics , Seizures/genetics , Vitamin B Complex/toxicity , Zebrafish
6.
Molecules ; 25(18)2020 Sep 22.
Article in English | MEDLINE | ID: mdl-32971844

ABSTRACT

A series of 108 novel quaternary bis-ammonium pyridoxine derivatives carrying various substituents at the quaternary nitrogen's and acetal carbon was synthesized. Thirteen compounds exhibited antibacterial and antifungal activity (minimum inhibitory concentration (MIC) 0.25-16 µg/mL) comparable or superior than miramistin, benzalkonium chloride, and chlorhexidine. A strong correlation between the lipophilicity and antibacterial activity was found. The most active compounds had logP values in the range of 1-3, while compounds with logP > 6 and logP < 0 were almost inactive. All active compounds demonstrated cytotoxicity comparable with miramistin and chlorhexidine on HEK-293 cells and were three-fold less toxic when compared to benzalkonium chloride. The antibacterial activity of leading compound 5c12 on biofilm-embedded Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli or Pseudomonas aeruginosa was comparable or even higher than that of the benzalkonium chloride. In vivo 5c12was considerably less toxic (LD50 1705 mg/kg) than benzalkonium chloride, miramistine, and chlorhexidine at oral administration on CD-1 mice. An aqueous solution of 5c12 (0.2%) was shown to be comparable to reference drugs efficiency on the rat's skin model. The molecular target of 5c12 seems to be a cellular membrane as other quaternary ammonium salts. The obtained results make the described quaternary bis-ammonium pyridoxine derivatives promising and lead molecules in the development of the new antiseptics with a broad spectrum of antimicrobial activity.


Subject(s)
Ammonium Compounds/chemistry , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Pyridoxine/chemical synthesis , Pyridoxine/pharmacology , Salts/chemistry , Anti-Infective Agents/chemistry , Anti-Infective Agents/toxicity , Biofilms/drug effects , Chemistry Techniques, Synthetic , HEK293 Cells , Humans , Microbial Sensitivity Tests , Pyridoxine/chemistry , Pyridoxine/toxicity , Structure-Activity Relationship
7.
BMC Neurosci ; 21(1): 11, 2020 03 24.
Article in English | MEDLINE | ID: mdl-32204694

ABSTRACT

BACKGROUND: Pyridoxine (PDX; vitamin B6), is an essential vitamin. PDX deficiency induces various symptoms, and when PDX is misused it acts as a neurotoxicant, inducing severe sensory neuropathy. RESULTS: To assess the possibility of creating a reversible sensory neuropathy model using dogs, 150 mg/kg of PDX was injected subcutaneously into dogs for 7 days and body weight measurements, postural reaction assessments, and electrophysiological recordings were obtained. In addition, the morphology of dorsal root ganglia (DRG) and changes in glial fibrillary acidic protein (GFAP) immunoreactive satellite glial cells and ionized calcium-binding adapter molecule 1 (Iba-1) immunoreactive microglia/macrophages were assessed at 1 day, 1 week, and 4 weeks after the last PDX treatment. During the administration period, body weight and proprioceptive losses occurred. One day after the last PDX treatment, electrophysiological recordings showed the absence of the H-reflex in the treated dogs. These phenomena persisted over the four post-treatment weeks, with the exception of body weight which recovered to the pre-treatment level. Staining (CV and HE) results revealed significant losses of large-sized neurons in the DRG at 1 day and 1 week after PDX treatment cessation, but the losses were recovered at 4 weeks post-treatment. The Iba-1 and GFAP immunohistochemistry results showed pronounced increases in reactive microglia/macrophage and satellite glial cell at 1 day and 1 week, respectively, after the last PDX treatment, and thereafter, immunoreactivity decreased with increasing time after PDX treatment. CONCLUSIONS: The results suggest that PDX-induced neuropathy is reversible in dogs; thus, dogs can be considered a good experimental model for research on neuropathy.


Subject(s)
Ganglia, Spinal/drug effects , Ganglia, Spinal/pathology , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/pathology , Pyridoxine/toxicity , Vitamin B Complex/toxicity , Animals , Disease Models, Animal , Dogs , H-Reflex/drug effects , Neuroglia/drug effects , Neuroglia/pathology , Neurons/drug effects , Neurons/pathology , Peripheral Nervous System Diseases/physiopathology
9.
Yakugaku Zasshi ; 139(1): 1-6, 2019.
Article in Japanese | MEDLINE | ID: mdl-30606915

ABSTRACT

Overconsumption of Ginkgo biloba seeds induces food poisoning characterized by tonic-clonic convulsions and vomiting. The primary toxic component, 4'-O-methylpyridoxine (MPN), was purified from the seeds in 1985. This review includes the following aspects of ginkgo seed poisoning: 1) toxicity related to the content of MPN and MPN glucoside in G. biloba seeds; 2) the effect of MPN on vitamin B6 analogs, including an increase in pyridoxal and pyridoxic acid and decrease in pyridoxal-5'-phosphate plasma concentrations; 3) case reports of ginkgo seed poisoning in Asia, North America, and Europe, and their effective treatment via vitamin B6 administration. Considering the increase in the use of G. biloba seeds, it is essential to raise global awareness of their potential toxicity.


Subject(s)
Foodborne Diseases/etiology , Ginkgo biloba/chemistry , Ginkgo biloba/poisoning , Pyridoxine/analogs & derivatives , Vitamin B 6 Deficiency/etiology , Humans , Pyridoxal Phosphate/blood , Pyridoxic Acid/blood , Pyridoxine/isolation & purification , Pyridoxine/toxicity , Vitamin B 6/administration & dosage , Vitamin B 6/metabolism , Vitamin B 6 Deficiency/drug therapy
10.
Bioorg Med Chem ; 27(1): 100-109, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30503413

ABSTRACT

The pyridine-derived biomolecules are of considerable interest in developing medicinal compounds with various specific activities. Novel ammonium salts of pyridoxine, (S)-(-)-nicotine and nicotinamide with O,O-diorganyl dithiophosphoric acids (DTPA) were synthesized and characterized. The complexation of chiral monoterpenyl DTPA, including (S)-(-)-menthyl, (R)-(+)-menthyl, (1R)-endo-(+)-fenchyl, (1S,2S,3S,5R)-(+)-isopinocampheolyl derivatives, with pyridoxine and nicotine provided effective antibacterial compounds 3a,b,e,f, and 5a,b,d,f with MIC values against Gram-positive bacteria as low as 10 µM (6 µg/mL). Two selected pyridoxine and nicotine salts based on menthyl DTPA 3a and 5a were similarly active against antibiotic-resistant bacteria from burn wounds including MRSA. The compounds had enhanced amphiphilic and hemolytic properties and effectively altered surface characteristics and matrix-secreting ability of P. aeroginosa and S. aureus. MBC/MIC ratios of 3a and 5a suggested the bactericidal mode of their action. Furthermore, the compounds exhibited moderate cytotoxicity towards human skin fibroblasts (IC50 = 48.6 and 57.6 µM, respectively, 72 h), encouraging their further investigation as potential antimicrobials against skin and wound infections.


Subject(s)
Anti-Bacterial Agents/pharmacology , Niacinamide/pharmacology , Nicotine/pharmacology , Phosphates/pharmacology , Pyridoxine/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/toxicity , Fibroblasts/drug effects , Gram-Negative Bacteria/drug effects , Hemolysis/drug effects , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Niacinamide/chemical synthesis , Niacinamide/chemistry , Niacinamide/toxicity , Nicotine/chemical synthesis , Nicotine/chemistry , Nicotine/toxicity , Phosphates/chemical synthesis , Phosphates/chemistry , Phosphates/toxicity , Pyridoxine/chemical synthesis , Pyridoxine/chemistry , Pyridoxine/toxicity , Staphylococcus epidermidis/drug effects
11.
Sci Rep ; 8(1): 11432, 2018 07 30.
Article in English | MEDLINE | ID: mdl-30061626

ABSTRACT

Growing evidence shows that improper intake of vitamin B6 increases cancer risk and several studies indicate that diabetic patients have a higher risk of developing tumors. We previously demonstrated that in Drosophila the deficiency of Pyridoxal 5' phosphate (PLP), the active form of vitamin B6, causes chromosome aberrations (CABs), one of cancer prerequisites, and increases hemolymph glucose content. Starting from these data we asked if it was possible to provide a link between the aforementioned studies. Thus, we tested the effect of low PLP levels on DNA integrity in diabetic cells. To this aim we generated two Drosophila models of type 2 diabetes, the first by impairing insulin signaling and the second by rearing flies in high sugar diet. We showed that glucose treatment induced CABs in diabetic individuals but not in controls. More interestingly, PLP deficiency caused high frequencies of CABs in both diabetic models demonstrating that hyperglycemia, combined to reduced PLP level, impairs DNA integrity. PLP-depleted diabetic cells accumulated Advanced Glycation End products (AGEs) that largely contribute to CABs as α-lipoic acid, an AGE inhibitor, rescued not only AGEs but also CABs. These data, extrapolated to humans, indicate that low PLP levels, impacting on DNA integrity, may be considered one of the possible links between diabetes and cancer.


Subject(s)
DNA Damage , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/pathology , Drosophila melanogaster/physiology , Protective Agents/therapeutic use , Vitamin B 6/therapeutic use , Animals , Body Size/drug effects , Brain/pathology , Chromosome Aberrations , DNA/metabolism , Disease Models, Animal , Drosophila melanogaster/anatomy & histology , Drosophila melanogaster/drug effects , Female , Glucose/toxicity , Glycation End Products, Advanced/toxicity , Histones/metabolism , Insulin/metabolism , Larva/drug effects , Male , Protective Agents/pharmacology , Pyridoxine/analogs & derivatives , Pyridoxine/toxicity , Signal Transduction/drug effects , Vitamin B 6/pharmacology
12.
PLoS One ; 12(10): e0186645, 2017.
Article in English | MEDLINE | ID: mdl-29053735

ABSTRACT

Pyridoxine dependent epilepsy (PDE) is caused by likely pathogenic variants in ALDH7A1 (PDE-ALDH7A1) and inherited autosomal recessively. Neurotoxic alpha-amino adipic semialdehyde (alpha-AASA), piperideine 6-carboxylate and pipecolic acid accumulate in body fluids. Neonatal or infantile onset seizures refractory to anti-epileptic medications are clinical features. Treatment with pyridoxine, arginine and lysine-restricted diet does not normalize neurodevelopmental outcome or accumulation of neurotoxic metabolites. There is no animal model for high throughput drug screening. For this reason, we developed and characterized the first knock-out aldh7a1 zebrafish model using CRISPR-Cas9 technology. Zebrafish aldh7a1 mutants were generated by using a vector free method of CRISPR-Cas9 mutagenesis. Genotype analysis of aldh7a1 knock-out zebrafish was performed by high resolution melt analysis, direct sequencing and QIAxcel system. Electroencephalogram was performed. Alpha-AASA, piperideine 6-carboxylate and pipecolic acid, were measured by liquid chromatography-tandem mass spectrometry. Our knock-out aldh7a1 zebrafish has homozygous 5 base pair (bp) mutation in ALDH7A1. Knock-out aldh7a1 embryos have spontaneous rapid increase in locomotion and a rapid circling swim behavior earliest 8-day post fertilization (dpf). Electroencephalogram revealed large amplitude spike discharges compared to wild type. Knock-out aldh7a1 embryos have elevated alpha-AASA, piperideine 6-carboxylate and pipecolic acid compared to wild type embryos at 3 dpf. Knock-out aldh7a1 embryos showed no aldh7a1 protein by western blot compared to wild type. Our knock-out aldh7a1 zebrafish is a well characterized model for large-scale drug screening using behavioral and biochemical features and accurately recapitulates the human PDE-ALDH7A1 disease.


Subject(s)
Aldehyde Dehydrogenase/genetics , Clustered Regularly Interspaced Short Palindromic Repeats , Epilepsy/chemically induced , Pyridoxine/toxicity , Zebrafish/genetics , Action Potentials , Animals , Behavior, Animal , Electroencephalography , Epilepsy/genetics , Epilepsy/physiopathology , Gene Knockdown Techniques , Zebrafish/embryology
13.
Cancer Med ; 6(6): 1437-1452, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28544589

ABSTRACT

Erymet is a new therapy resulting from the encapsulation of a methionine gamma-lyase (MGL; EC number 4.4.1.11) in red blood cells (RBC). The aim of this study was to evaluate erymet potential efficacy in methionine (Met)-dependent cancers. We produced a highly purified MGL using a cGMP process, determined the pharmacokinetics/pharmacodynamics (PK/PD) properties of erymet in mice, and assessed its efficacy on tumor growth prevention. Cytotoxicity of purified MGL was tested in six cancer cell lines. CD1 mice were injected with single erymet product supplemented or not with vitamin B6 vitamer pyridoxine (PN; a precursor of PLP cofactor). NMRI nude mice were xenografted in the flank with U-87 MG-luc2 glioblastoma cells for tumor growth study following five intravenous (IV) injections of erymet with daily PN oral administration. Endpoints included efficacy and event-free survival (EFS). Finally, a repeated dose toxicity study of erymet combined with PN cofactor was conducted in CD1 mice. Recombinant MGL was cytotoxic on 4/6 cell lines tested. MGL half-life was increased from <24 h to 9-12 days when encapsulated in RBC. Conversion of PN into PLP by RBC was demonstrated. Combined erymet + PN treatment led to a sustained Met depletion in plasma for several days with a 85% reduction of tumor volume after 45 days following cells implantation, and a significant EFS prolongation for treated mice. Repeated injections in mice exhibited a very good tolerability with only minor impact on clinical state (piloerection, lean aspect) and a slight decrease in hemoglobin and triglyceride concentrations. This study demonstrated that encapsulation of methioninase inside erythrocyte greatly enhanced pharmacokinetics properties of the enzyme and is efficacy against tumor growth. The perspective on these results is the clinical evaluation of the erymet product in patients with Met starvation-sensitive tumors.


Subject(s)
Antineoplastic Agents/administration & dosage , Carbon-Sulfur Lyases/administration & dosage , Drug Delivery Systems , Erythrocytes , Neoplasms/drug therapy , Pyridoxine/administration & dosage , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Carbon-Sulfur Lyases/pharmacokinetics , Carbon-Sulfur Lyases/therapeutic use , Carbon-Sulfur Lyases/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Male , Methionine/blood , Methionine/metabolism , Mice, Nude , Neoplasms/blood , Neoplasms/metabolism , Neoplasms/pathology , Pyridoxal Phosphate/blood , Pyridoxine/pharmacokinetics , Pyridoxine/therapeutic use , Pyridoxine/toxicity , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Recombinant Proteins/toxicity , Tumor Burden/drug effects
14.
Biomed Res Int ; 2016: 3864193, 2016.
Article in English | MEDLINE | ID: mdl-27800491

ABSTRACT

A series of novel quaternary ammonium 4-deoxypyridoxine derivatives was synthesized. Two compounds demonstrated excellent activity against a panel of Gram-positive methicillin-resistant S. aureus strains with MICs in the range of 0.5-2 µg/mL, exceeding the activity of miramistin. At the same time, both compounds were inactive against the Gram-negative E. coli and P. aeruginosa strains. Cytotoxicity studies on human skin fibroblasts and embryonic kidney cells demonstrated that the active compounds possessed similar toxicity with benzalkonium chloride but were slightly more toxic than miramistin. SOS-chromotest in S. typhimurium showed the lack of DNA-damage activity of both compounds; meanwhile, one compound showed some mutagenic potential in the Ames test. The obtained results make the described chemotype a promising starting point for the development of new antibacterial therapies.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemical synthesis , Bacterial Physiological Phenomena/drug effects , Pyridoxine/analogs & derivatives , Quaternary Ammonium Compounds/administration & dosage , Anti-Bacterial Agents/toxicity , Apoptosis/drug effects , Apoptosis/physiology , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Pyridoxine/administration & dosage , Pyridoxine/chemical synthesis , Pyridoxine/chemistry , Pyridoxine/toxicity , Quaternary Ammonium Compounds/chemical synthesis , Quaternary Ammonium Compounds/toxicity
15.
Med Chem ; 11(7): 656-65, 2015.
Article in English | MEDLINE | ID: mdl-25938426

ABSTRACT

A series of 26 quaternary ammonium pyridoxine derivatives were synthesized and their cytotoxicity and antibacterial activities against clinically relevant bacterial strains were tested in vitro. The antibacterial activity of mono-ammonium salts increased with the rise of the lipophilicity and compound 3,3,5-trimethyl-8,8-dioctyl-1,7,8,9-tetrahydro-[1,3]dioxino[5,4-d]pyrrolo[3,4-b]pyridin-8-ium chloride (2d) reaches a maximum among them. Bis-ammonium salt of pyridoxine 4 with two dimethyloctylamine groups also demonstrated high antibacterial activity despite lower lipophilicity. The results of MTT assay indicated that HEK 293 cells were more sensitive than HSF to quaternary ammonium pyridoxine derivatives. Compounds 2d and 4 did not induce the damage of the DNA and might be of interest in the development of new antimicrobials.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Pyridoxine/chemical synthesis , Pyridoxine/pharmacology , Quaternary Ammonium Compounds/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/toxicity , Bacteria/drug effects , Chemistry Techniques, Synthetic , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Mutagenicity Tests , Pyridoxine/chemistry , Pyridoxine/toxicity
16.
Neuroscience ; 289: 233-41, 2015 Mar 19.
Article in English | MEDLINE | ID: mdl-25592428

ABSTRACT

Our understanding of the role of somatosensory feedback in regulating motility during chicken embryogenesis and fetal development in general has been hampered by the lack of an approach to selectively alter specific sensory modalities. In adult mammals, pyridoxine overdose has been shown to cause a peripheral sensory neuropathy characterized by a loss of both muscle and cutaneous afferents, but predominated by a loss of proprioception. We have begun to explore the sensitivity of the nervous system in chicken embryos to the application of pyridoxine on embryonic days 7 and 8, after sensory neurons in the lumbosacral region become post-mitotic. Upon examination of the spinal cord, dorsal root ganglion and peripheral nerves, we find that pyridoxine causes a loss of neurotrophic tyrosine kinase receptor type 3-positive neurons, a decrease in the diameter of the muscle innervating nerve tibialis, and a reduction in the number of large diameter axons in this nerve. However, we found no change in the number of Substance P or calcitonin gene-related peptide-positive neurons, the number of motor neurons or the diameter or axonal composition of the femoral cutaneous nerve. Therefore, pyridoxine causes a peripheral sensory neuropathy in embryonic chickens largely consistent with its effects in adult mammals. However, the lesion may be more restricted to proprioception in the chicken embryo. Therefore, pyridoxine lesion induced during embryogenesis in the chicken embryo can be used to assess how the loss of sensation, largely proprioception, alters spontaneous embryonic motility and subsequent motor development.


Subject(s)
Ganglia, Spinal/drug effects , Ganglia, Spinal/embryology , Pyridoxine/toxicity , Spinal Cord/drug effects , Spinal Cord/embryology , Teratogens/toxicity , Animals , Avian Proteins/metabolism , Axons/drug effects , Axons/pathology , Axons/physiology , Calcitonin Gene-Related Peptide/metabolism , Cell Count , Chick Embryo , Femoral Nerve/drug effects , Femoral Nerve/embryology , Femoral Nerve/pathology , Ganglia, Spinal/pathology , Immunohistochemistry , Motor Neurons/drug effects , Motor Neurons/pathology , Motor Neurons/physiology , Neurons, Afferent/drug effects , Neurons, Afferent/pathology , Neurons, Afferent/physiology , Receptor, trkC/metabolism , Spinal Cord/pathology , Substance P/metabolism
17.
ILAR J ; 54(3): 315-23, 2014.
Article in English | MEDLINE | ID: mdl-24615445

ABSTRACT

Despite the progress in our understanding of pathogeneses and the identification of etiologies of peripheral neuropathy, idiopathic neuropathy remains common. Typically, attention to peripheral neuropathies resulting from exposure to environmental agents is limited relative to more commonly diagnosed causes of peripheral neuropathy (diabetes and chemotherapeutic agents). Given that there are more than 80,000 chemicals in commerce registered with the Environmental Protection Agency and that at least 1000 chemicals are known to have neurotoxic potential, very few chemicals have been established to affect the peripheral nervous system (mainly after occupational exposures). A wide spectrum of exposures, including pesticides, metals, solvents, nutritional sources, and pharmaceutical agents, has been related, both historically and recently, to environmental toxicant-induced peripheral neuropathy. A review of the literature shows that the toxicity and pathogeneses of chemicals adversely affecting the peripheral nervous system have been studied using animal models. This article includes an overview of five prototypical environmental agents known to cause peripheral neuropathy--namely, organophosphates, carbon disulfide, pyridoxine (Vitamin B6), acrylamide, and hexacarbons (mainly n-hexane, 2,5-hexanedione, methyl n-butyl ketone). Also included is a brief introduction to the structural components of the peripheral nervous system and pointers on common methodologies for histopathologic evaluation of the peripheral nerves.


Subject(s)
Disease Models, Animal , Hazardous Substances/toxicity , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/pathology , Acrylamide/toxicity , Animals , Carbon Disulfide/toxicity , Hexanes/toxicity , Histological Techniques , Organophosphates/toxicity , Pyridoxine/toxicity
18.
Dis Model Mech ; 5(6): 785-95, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22736461

ABSTRACT

The etiology of epilepsy is a very complicated, multifactorial process that is not completely understood. Therefore, the availability of epilepsy animal models induced by different mechanisms is crucial in advancing our knowledge and developing new therapeutic regimens for this disorder. Considering the advantages of zebrafish, we have developed a seizure model in zebrafish larvae using ginkgotoxin, a neurotoxin naturally occurring in Ginkgo biloba and hypothesized to inhibit the formation of the neurotransmitter γ-aminobutyric acid (GABA). We found that a 2-hour exposure to ginkgotoxin induced a seizure-like behavior in zebrafish larvae. This seizure-like swimming pattern was alleviated by the addition of either pyridoxal-5'-phosphate (PLP) or GABA and responded quickly to the anti-convulsing activity of gabapentin and phenytoin, two commonly prescribed anti-epileptic drugs (AEDs). Unexpectedly, the ginkgotoxin-induced PLP depletion in our experimental setting did not affect the homeostasis of folate-mediated one-carbon metabolism, another metabolic pathway playing a crucial role in neural function that also relies on the availability of PLP. This ginkgotoxin-induced seizure behavior was also relieved by primidone, which had been tested on a pentylenetetrazole-induced zebrafish seizure model but failed to rescue the seizure phenotype, highlighting the potential use and complementarity of this ginkgotoxin-induced seizure model for AED development. Structural and morphological characterization showed that a 2-hour ginkgotoxin exposure did not cause appreciable changes in larval morphology and tissues development. In conclusion, our data suggests that this ginkgotoxin-induced seizure in zebrafish larvae could serve as an in vivo model for epileptic seizure research and potential AED screening.


Subject(s)
Anticonvulsants/therapeutic use , Behavior, Animal , Neurotoxins/toxicity , Pyridoxal Phosphate/therapeutic use , Pyridoxine/analogs & derivatives , Seizures/drug therapy , Zebrafish/physiology , gamma-Aminobutyric Acid/therapeutic use , Animals , Anticonvulsants/pharmacology , Behavior, Animal/drug effects , Carbon/metabolism , Folic Acid/metabolism , Larva/anatomy & histology , Larva/drug effects , Models, Neurological , Neurons/drug effects , Neurons/pathology , Pentylenetetrazole , Primidone/pharmacology , Primidone/therapeutic use , Pyridoxal Phosphate/pharmacology , Pyridoxine/toxicity , Seizures/chemically induced , Seizures/pathology , Swimming , Zebrafish/growth & development , gamma-Aminobutyric Acid/pharmacology
19.
Int J Risk Saf Med ; 24(1): 31-5, 2012.
Article in English | MEDLINE | ID: mdl-22436257

ABSTRACT

Until recently epidemiological evidence was not regarded as helpful in determining cause and effect. It generated associations that then had to be explained in terms of bio-mechanisms and applied to individual patients. A series of legal cases surrounding possible birth defects triggered by doxylamine (Bendectin) and connective tissue disorders linked to breast implants made it clear that in some instances epidemiological evidence might have a more important role, but the pendulum swung too far so that epidemiological evidence has in recent decades been given an unwarranted primacy, partly perhaps because it suits the interests of certain stakeholders. Older and more recent epidemiological studies on doxylamine and other antihistamines are reviewed to bring out the ambiguities and pitfalls of an undue reliance on epidemiological studies.


Subject(s)
Causality , Forensic Sciences/legislation & jurisprudence , Pharmacoepidemiology/legislation & jurisprudence , Pharmacovigilance , Abnormalities, Drug-Induced/epidemiology , Antiemetics/adverse effects , Antiemetics/toxicity , Breast Implantation/adverse effects , Breast Implantation/statistics & numerical data , Connective Tissue Diseases/epidemiology , Dicyclomine/adverse effects , Dicyclomine/toxicity , Doxylamine/adverse effects , Doxylamine/toxicity , Drug Combinations , Female , Forensic Sciences/organization & administration , Humans , Pharmacoepidemiology/organization & administration , Pharmacology/legislation & jurisprudence , Pharmacology/methods , Pregnancy , Pyridoxine/adverse effects , Pyridoxine/toxicity
20.
Dev Med Child Neurol ; 53(12): 1150-3, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21707605

ABSTRACT

Pyridoxine-dependent epilepsy (PDE) is a treatable inborn error of metabolism with autosomal recessive inheritance. Antenatal and postnatal prophylactic administration of pyridoxine has been recommended to improve the developmental outcome in possible future pregnancies. We report on a male offspring of a second pregnancy at risk for PDE. While on prophylactic treatment with oral pyridoxine, the newborn developed encephalopathy and status epilepticus at age 14 days. Seizures did not respond to parenteral pyridoxine and additional treatment with folinic acid. After treatment was changed to pyridoxal 5'-phosphate, the infant's condition improved. Antiquitin deficiency was excluded by biochemical and molecular genetic testing, and cofactor treatment was stopped on day 26. He has since remained seizure-free with normal psychomotor development. In healthy newborns, high-dose treatment with pyridoxine may result in increased rather than decreased neuroexcitability. Postnatal prophylactic pyridoxine treatment of fetuses and neonates at risk for PDE should be limited to the shortest possible time, by either prenatal diagnosis or immediate postnatal biochemical and genetic testing.


Subject(s)
Epilepsy/prevention & control , Pyridoxine/toxicity , Status Epilepticus/etiology , Vitamin B Complex/toxicity , Adult , Aldehyde Dehydrogenase/blood , Aldehyde Dehydrogenase/deficiency , Aldehyde Dehydrogenase/genetics , Epilepsy/genetics , Female , Humans , Infant , Infant, Newborn , Infusions, Parenteral , Leucovorin/administration & dosage , Leucovorin/adverse effects , Leucovorin/therapeutic use , Male , Pregnancy , Pyridoxal Phosphate/administration & dosage , Pyridoxal Phosphate/therapeutic use , Pyridoxine/administration & dosage , Pyridoxine/therapeutic use , Secondary Prevention , Status Epilepticus/diagnosis , Status Epilepticus/drug therapy , Vitamin B Complex/administration & dosage , Vitamin B Complex/therapeutic use
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