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Journal of Inherited Metabolic Disease Jun 2024This review summarises progress in the research of homocystinuria (HCU) in the past three decades. HCU due to cystathionine β-synthase (CBS) was discovered in 1962, and...
This review summarises progress in the research of homocystinuria (HCU) in the past three decades. HCU due to cystathionine β-synthase (CBS) was discovered in 1962, and Prof. Jan Peter Kraus summarised developments in the field in the first-ever Komrower lecture in 1993. In the past three decades, significant advancements have been achieved in the biology of CBS, including gene organisation, tissue expression, 3D structures, and regulatory mechanisms. Renewed interest in CBS arose in the late 1990s when this enzyme was implicated in biogenesis of HS. Advancements in genetic and biochemical techniques enabled the identification of several hundreds of pathogenic CBS variants and the misfolding of missense mutations as a common mechanism. Several cellular, invertebrate and murine HCU models allowed us to gain insights into functional and metabolic pathophysiology of the disease. Establishing the E-HOD consortium and patient networks, HCU Network Australia and HCU Network America, offered new possibilities for acquiring clinical data in registries and data on patients´ quality of life. A recent analysis of data from the E-HOD registry showed that the clinical variability of HCU is broad, extending from severe childhood disease to milder (late) adulthood forms, which typically respond to pyridoxine. Pyridoxine responsiveness appears to be the key factor determining the clinical course of HCU. Increased awareness about HCU played a role in developing novel therapies, such as gene therapy, correction of misfolding by chaperones, removal of methionine from the gut and enzyme therapies that decrease homocysteine or methionine in the circulation.
PubMed: 38873792
DOI: 10.1002/jimd.12767 -
BMJ Case Reports Jun 2024Granulomatous amoebic encephalitis due to spp is a rare, near-fatal central nervous system infection. It is often seen in immunocompromised individuals. Here we...
Granulomatous amoebic encephalitis due to spp is a rare, near-fatal central nervous system infection. It is often seen in immunocompromised individuals. Here we describe a survivor of this infection who was co-infected with multidrug-resistant tuberculosis. He presented to us with features of meningitis and a history of chronic cough. The chest X-ray was classical for pulmonary tuberculosis. Neuroimaging was suggestive of encephalitis; herpes simplex virus PCR was negative. Cerebrospinal fluid (CSF) showed lymphocytic pleocytosis. Wet mounts revealed trophozoites of Currently, he is being treated with oral bedaquiline, levofloxacin, linezolid, clofazimine, cycloserine and pyridoxine for tuberculosis. He received intravenous amikacin and oral cotrimoxazole and fluconazole for infection for 1 month. The resolution was confirmed by repeating the CSF wet mount, culture and neuroimaging. He was then discharged with oral rifampicin, cotrimoxazole and fluconazole. He is currently under our close follow-up.
Topics: Humans; Male; Acanthamoeba; Tuberculosis, Meningeal; Amebiasis; Tuberculosis, Multidrug-Resistant; Immunocompetence; Coinfection
PubMed: 38871639
DOI: 10.1136/bcr-2024-260613 -
ELife Jun 2024Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these...
Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal 5'-phosphate phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5'-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small-molecule screening, protein crystallography, and biolayer interferometry, we discover, visualize, and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.
Topics: Animals; Mice; Humans; Enzyme Inhibitors; Phosphoric Monoester Hydrolases; Hippocampus; Neurons; Pyridoxal Phosphate; Flavones; Mice, Inbred C57BL
PubMed: 38856179
DOI: 10.7554/eLife.93094 -
Reproduction in Domestic Animals =... Jun 2024This study evaluated whether the treatment of pseudopregnancy in bitches with vitamin B6 modulates uterine expression of receptors for progesterone (PR), oestrogen...
This study evaluated whether the treatment of pseudopregnancy in bitches with vitamin B6 modulates uterine expression of receptors for progesterone (PR), oestrogen (ERα), androgen (AR), thyroid hormone (TRα) and the kisspeptin/Kiss1r system. Eighteen pseudopregnant bitches were treated for 20 days in groups receiving placebo (n = 6); cabergoline (5 μg/kg/day; n = 6); or vitamin B6 (50 mg/kg/day; n = 6). Blood was collected on the 1st day of drug administration and 120 h later to measure serum prolactin (PRL). After treatment, they were ovariohysterectomized and uterine fragments were collected for histomorphometry and immunohistochemical evaluation of PR, ERα, AR, TRα, Kiss1 and Kiss1r. After 120 h of cabergoline or vitamin B6 treatment, PRL levels were reduced in the bitches, confirming the antiprolactinemic effect of these drugs. Furthermore, regardless of treatment, the animals exhibited uterine histomorphometry consistent with dioestrus. The PR showed strong immunostaining in all regions and an increase in scores was observed for this receptor in animals treated with vitamin B6 in deep glands. In contrast, ERα and Kiss1R receptors showed weak to no immunostaining in all uterine regions and no changes between groups. Regarding AR, most animals treated with vitamin B6 showed increased trends in the deep gland and myometrium marking scores. In contrast, in both vitamin B6 and cabergoline treatments, a reduction in TRα marking scores was observed compared to the control group. In addition, on the endometrial surface, a reduction was observed in the marked area of Kiss1 after administration of cabergoline when compared to the pseudopregnant control group. These findings shed valuable insight into the use of vitamin B6 as a drug with actions similar to cabergoline in reducing PRL and uterine modulation in bitches.
Topics: Animals; Female; Dogs; Kisspeptins; Uterus; Cabergoline; Prolactin; Pseudopregnancy; Receptors, Progesterone; Receptors, Androgen; Ergolines
PubMed: 38847348
DOI: 10.1111/rda.14630 -
Clinical Drug Investigation Jun 2024Musculoskeletal disorders are an important cause of work absence. Clinical practice guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) for grade I-II... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Musculoskeletal disorders are an important cause of work absence. Clinical practice guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) for grade I-II cervical sprains. The combination of thiamine + pyridoxine + cyanocobalamin vitamins has been used, alone and in combination with NSAIDs, for pain and inflammation in musculoskeletal disorders.
OBJECTIVE
The objective of this study was to demonstrate the analgesic synergy of dexketoprofen, and the combination of vitamins thiamine + pyridoxine + cyanocobalamin in a fixed-dose combination (FDC) for the treatment of acute pain caused by grade I-II cervical sprains.
METHODS
We conducted a multicentre, prospective, randomized, double-blind, phase IIIb clinical study comparing two treatment groups: (1) dexketoprofen 25 mg/vitamin B (thiamine 100 mg, pyridoxine 50 mg and cyanocobalamin 0.50 mg) in an FDC (two or more active ingredients combined in a single dosage form) versus (2) dexketoprofen 25 mg monotherapy (single drug to treat a particular disease), one capsule or tablet orally, every 8 h for 7 days. Final mean, average change, and percentage change in pain perception (measured using a visual analogue scale [VAS]) were compared with baseline between groups. A p value < 0.05 was considered statistically significant. Analyses were conducted using SPSS software, v.29.0.
RESULTS
A statistically significant reduction in pain intensity was observed from the third day of treatment with the FDC compared with monotherapy (- 3.1 ± - 1.5 and - 2.6 ± - 1.1 cm, respectively) measured using the VAS (p = 0.011). Regarding the degree of disability, using the Northwick Park Neck Pain Questionnaire (NPQ), statistical difference was observed for the final measurement (7.5%, interquartile range [IQR] 2.5, 10.5; vs. 7.9%, IQR 5.0, 13.8; p = 0.028). A lower proportion of adverse events was reported when using the FDC.
CONCLUSIONS
The FDC of dexketoprofen/thiamine + pyridoxine + cyanocobalamin vitamins demonstrated superior efficacy and a better safety profile compared with dexketoprofen monotherapy for pain treatment in patients with grade I-II cervical sprains.
CLINICAL TRIALS REGISTRATION
NCT05001555, registered 29 July 2021 ( https://clinicaltrials.gov/study/NCT05001555 ).
Topics: Humans; Double-Blind Method; Thiamine; Ketoprofen; Female; Adult; Pyridoxine; Male; Anti-Inflammatory Agents, Non-Steroidal; Vitamin B 12; Middle Aged; Tromethamine; Drug Combinations; Prospective Studies; Vitamin B Complex; Pain Measurement; Young Adult
PubMed: 38842764
DOI: 10.1007/s40261-024-01370-2 -
Wei Sheng Yan Jiu = Journal of Hygiene... May 2024To establish an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of 11 nutritional components(thiamine,...
OBJECTIVE
To establish an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of 11 nutritional components(thiamine, riboflavin, nicotinamide, nicotinic acid, pantothenic acid, pyridoxine, pyridoxal, pyridoxamine, biotin, choline, L-carnitine) in liquid milk.
METHODS
Milk samples were shaken with 20 mmol/L ammonium formate solution and heated in a water bath at 100 ℃ for 30 min, then incubated with papain and acid phosphatase at 45 ℃ for 16 h, the lower liquid was collected after centrifugation for analysis. UPLC separation was performed on an ACQUITY~(TM) HSS T3(3.0 mm×150 mm, 1.8 μm) column, 2 mmol/L ammonium formate(containing 0.1% formic acid) solution and acetonitrile(containing 0.1% formic acid) were used as mobile phase. Quantitative detection was performed by internal standard method.
RESULTS
11 nutritional components can be effectively separated and detected in 12 min, and the linear correlation coefficients(R~2) were all above 0.995. The limits of detection(LODs) were between 0.05 and 0.50 μg/L, and the limits of quantification(LOQs) were between 0.20 and 1.25 μg/L. The recovery rates of three-level addition were 85.6%-119.3%, and the precision RSDs were between 3.68% and 7.82%(n=6). Based on the detection of 60 liquid milk samples from 5 different animals, it was found that the contents of 11 nutrients in liquid milk from different milk sources were significantly different, but pyridoxine could not be detected.
CONCLUSION
The method can quantitatively detect 11 water-soluble nutrients, including free and bound forms, by effective enzymolysis. It is sensitive, reproducible and can meet the needs of quantitative detection.
Topics: Milk; Tandem Mass Spectrometry; Animals; Chromatography, High Pressure Liquid; Niacinamide; Riboflavin; Nutrients; Pantothenic Acid; Cattle; Pyridoxine; Niacin; Carnitine
PubMed: 38839588
DOI: 10.19813/j.cnki.weishengyanjiu.2024.03.017 -
Nature Metabolism Jun 2024Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing...
Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.
Topics: Lysosomes; Macrophages; Animals; Mice; Pyridoxal Phosphate; Hypoxia; Cell Hypoxia; Vitamin B 6; Oxygen; Inflammation
PubMed: 38822028
DOI: 10.1038/s42255-024-01053-4 -
Talanta May 2024Due to their susceptibility to degradation, vitamin levels in food formulations may differ from those found in the finished product. Vitamin levels can be impacted by...
Due to their susceptibility to degradation, vitamin levels in food formulations may differ from those found in the finished product. Vitamin levels can be impacted by processing and storage. In this work, the ingredients of Strong B50 ® film-coated tablets were estimated simultaneously using simple efficient stability indicating HPLC method. Strong B50 ® film-coated tablets contain thiamine (VB1), riboflavin (VB2), calcium pantothenate (VB5), pyridoxine (VB6), vitamin C (VC), folic acid (FA), biotin (BT), inositol (IS), niacin (NC), para-aminobenzoic acid (PB), cyanocobalamine (B12), choline bitartarate, and iron gluconate. Hypersil BDS C18 column was used for achieving reasonable separation. Mobile phases (A) and (B) were utilized, the mobile phase (A) consisted of 0.015 M Hexane sulfonic acid sodium salt + 0.1 % Triethylamine and orthophosphoric acid was used to adjust the pH to (2.9) while (B) system consisted of acetonitrile. Validation of the method was assessed using International Conference of Harmonization (ICH) parameters, where linearity, accuracy, selectivity, and robustness of the method were investigated. Correlations were above 0.99, accuracy results ranged from 97.6 to 102.8 % and limits for detection and quantitation (LOD and LOQ) values were determined for each vitamin in μg/mL except for FA and BT in ng/mL. LOD values were between 0.006 and 15.08 μg/mL while LOQ values ranged from 0.031 to 49.77 μg/mL. Stability studies were conducted under stressed conditions and degradation percentages were computed. Where, VB5, VB6, FA and PB, VC, and NC were the most degradable vitamins. Whiteness evaluation using the modern RGB 12 algorithm compared our method and the old reported one by Sasaki et al., 2020. The comparison favored our newly developed method in terms of analytical performance, practical applicability and greenness. Besides, AGREE and GAPI soft wares were used to assess the greenness of the method. It was clear that the results of colored pictograms confirm low hazardous impact and that the new method is greener with AGREE score of 0.66. Furthermore, the functionality and applicability of the novel HPLC approach were concluded via the Blue Applicability Grade Index (BAGI) tool with a final score of 82.5.
PubMed: 38820824
DOI: 10.1016/j.talanta.2024.126324 -
Neonatal Network : NN May 2024Although a rare cause of neonatal seizures, inborn errors of metabolism (IEMs) remain an essential component of a comprehensive differential diagnosis for poorly... (Review)
Review
Although a rare cause of neonatal seizures, inborn errors of metabolism (IEMs) remain an essential component of a comprehensive differential diagnosis for poorly controlled neonatal epilepsy. Diagnosing neonatal-onset metabolic conditions proves a difficult task for clinicians; however, routine state newborn screening panels now include many IEMs. Three in particular-pyridoxine-dependent epilepsy, maple syrup urine disease, and Zellweger spectrum disorders-are highly associated with neonatal epilepsy and neurocognitive injury yet are often misdiagnosed. As research surrounding biomarkers for these conditions is emerging and gene sequencing technologies are advancing, clinicians are beginning to better establish early identification strategies for these diseases. In this literature review, the authors aim to present clinicians with an innovative clinical guide highlighting IEMs associated with neonatal-onset seizures, with the goal of promoting quality care and safety.
Topics: Humans; Infant, Newborn; Seizures; Neonatal Screening; Metabolism, Inborn Errors; Diagnosis, Differential; Maple Syrup Urine Disease
PubMed: 38816225
DOI: 10.1891/NN-2023-0048 -
Scientific Reports May 2024The effect of high-dose pyridoxine (PN) on activity of 5-fluorouracil (FUra) and folinic acid (FA)-containing regimens was studied in 50 patients including 14 with...
The effect of high-dose pyridoxine (PN) on activity of 5-fluorouracil (FUra) and folinic acid (FA)-containing regimens was studied in 50 patients including 14 with digestive tract, and 36 with breast carcinomas (BC) in advanced stages with poor prognostic characteristics. Patients with colorectal, and pancreas adenocarcinoma received oxaliplatin, irinotecan, FUra, FA (Folfirinox), and patients with squamous cell carcinoma of the esophagus had paclitaxel, carboplatin, FUra, FA (TCbF). Patients with BC received AVCF (doxorubicin, vinorelbine, cyclophosphamide, FUra, FA) followed by TCbF or TCbF only, and patients who overexpressed HER2 received TCbF plus trastuzumab and pertuzumab. PN (1000-3000 mg/day iv) preceded each administration of FUra and FA. 47 patients (94%) responded, including 16 (32%) with CR. Median tumor reduction was 93%. Median event-free survival (EFS) was 37.7 months. The 25 patients with tumor shrinkage ≥ 91% had EFS of 52% from 42 months onwards. Unexpected toxicity did not occur. PN enhances potency of chemotherapy regimens comprising FUra and FA.
Topics: Humans; Fluorouracil; Leucovorin; Pyridoxine; Female; Middle Aged; Aged; Male; Antineoplastic Combined Chemotherapy Protocols; Adult; Breast Neoplasms; Neoplasm Staging; Treatment Outcome
PubMed: 38802419
DOI: 10.1038/s41598-024-62860-z