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Cellular and Molecular Life Sciences :... Jun 2022The SLC25A32 dysfunction is associated with neural tube defects (NTDs) and exercise intolerance, but very little is known about disease-specific mechanisms due to a...
The SLC25A32 dysfunction is associated with neural tube defects (NTDs) and exercise intolerance, but very little is known about disease-specific mechanisms due to a paucity of animal models. Here, we generated homozygous (Slc25a32 and Slc25a32) and compound heterozygous (Slc25a32) knock-in mice by mimicking the missense mutations identified from our patient. A homozygous knock-out (Slc25a32) mouse was also generated. The Slc25a32 and Slc25a32 mice presented with mild motor impairment and recapitulated the biochemical disturbances of the patient. While Slc25a32 mice die in utero with NTDs. None of the Slc25a32 mutations hindered the mitochondrial uptake of folate. Instead, the mitochondrial uptake of flavin adenine dinucleotide (FAD) was specifically blocked by Slc25a32, Slc25a32, and Slc25a32 mutations. A positive correlation between SLC25A32 dysfunction and flavoenzyme deficiency was observed. Besides the flavoenzymes involved in fatty acid β-oxidation and amino acid metabolism being impaired, Slc25a32 embryos also had a subunit of glycine cleavage system-dihydrolipoamide dehydrogenase damaged, resulting in glycine accumulation and glycine derived-formate reduction, which further disturbed folate-mediated one-carbon metabolism, leading to 5-methyltetrahydrofolate shortage and other folate intermediates accumulation. Maternal formate supplementation increased the 5-methyltetrahydrofolate levels and ameliorated the NTDs in Slc25a32 embryos. The Slc25a32 and Slc25a32 mice had no glycine accumulation, but had another formate donor-dimethylglycine accumulated and formate deficiency. Meanwhile, they suffered from the absence of all folate intermediates in mitochondria. Formate supplementation increased the folate amounts, but this effect was not restricted to the Slc25a32 mutant mice only. In summary, we established novel animal models, which enabled us to understand the function of SLC25A32 better and to elucidate the role of SLC25A32 dysfunction in human disease development and progression.
Topics: Animals; Humans; Mice; Carbon; Flavin-Adenine Dinucleotide; Folic Acid; Formates; Glycine; Mitochondria; Neural Tube Defects
PubMed: 35727412
DOI: 10.1007/s00018-022-04404-0 -
Scientific Reports Apr 2017Riboflavin deficiency is widespread in many regions over the world, especially in underdeveloped countries. In this study, we investigated the effects of riboflavin...
Riboflavin deficiency is widespread in many regions over the world, especially in underdeveloped countries. In this study, we investigated the effects of riboflavin deficiency on protein expression profiles in HepG2 cells in order to provide molecular information for the abnormalities induced by riboflavin deficiency. HepG2 cells were cultured in media containing different concentrations of riboflavin. Changes of cell viability and apoptosis were assessed. A comparative proteomic analysis was performed using a label-free shotgun method with LC-MS/MS to investigate the global changes of proteomic profiles in response to riboflavin deficiency. Immunoblotting test was used to validate the results of proteomic approach. The cell viability and apoptosis tests showed that riboflavin was vital in maintaining the cytoactivity of HepG2 cells. The label-free proteomic analysis revealed that a total of 37 proteins showing differential expression (±2 fold, p < 0.05) were identified after riboflavin deficiency. Bioinformatics analysis indicated that the riboflavin deficiency caused an up-regulation of Parkinson's disease pathway, steroid catabolism, endoplasmic reticulum stress and apoptotic process, while the fatty acid metabolism, tricarboxylic citrate cycle, oxidative phosphorylation and iron metabolism were down-regulated. These findings provide a molecular basis for the elucidation of the effects caused by riboflavin deficiency.
Topics: Animals; Apoptosis; Cell Survival; Hep G2 Cells; Humans; Lipid Metabolism; Parkinson Disease; Proteome; Riboflavin; Riboflavin Deficiency; Signal Transduction
PubMed: 28367977
DOI: 10.1038/srep45861 -
Asia Pacific Journal of Clinical... 2022Poor nutritional status is a common finding in pulmonary tuberculosis (TB) patients with and without type 2 diabetes mellitus (T2DM), thiamin (VB-1) and riboflavin...
BACKGROUND AND OBJECTIVES
Poor nutritional status is a common finding in pulmonary tuberculosis (TB) patients with and without type 2 diabetes mellitus (T2DM), thiamin (VB-1) and riboflavin (VB-2) are coenzymes important for the activation of many enzymes involved in improving nutritional status. We aimed to investigate enzymatic activities and the associations between VB-1 and VB-2, and their relations to nutritional status in TB and TB+T2DM patients.
METHODS AND STUDY DESIGN
This was a cross-sectional study that prospectively enrolled TB 40 patients with or without T2DM respectively from the Chest Hospital of Qingdao and 76 healthy controls with similar age and gender distributions were recruited from the medical center of the affiliated hospital of Qingdao Medical College. The erythrocyte transketolase activation coefficient (ETKac, for VB-1 deficiency), the glutathione reductase activation coefficient (EGRac, for VB-2 deficiency), and metabolic enzyme activities were analyzed.
RESULTS
VB-1 and VB-2 deficiency rates were higher, and enzyme activities were lower in TB and TB+T2DM relative to control group. ETKac and EGRac were negatively correlated with enzyme activities, either with body mass index (BMI), while enzyme activities were positively associated with BMI.
CONCLUSIONS
VB-1 and VB-2 concentrations were lower in TB patients with or without T2DM relative to controls, with concomitant reductions in the activity levels of key metabolic enzymes. Significant correlations were observed between VB-1 and VB-2 concentrations and the activity of these metabolic enzymes, they all correlated with nutrition status. VB-1 and VB-2 concentrations may thus impact metabolic enzyme activity and thereby influence nutritional status.
Topics: China; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Riboflavin; Riboflavin Deficiency; Thiamine; Tuberculosis, Pulmonary
PubMed: 35766561
DOI: 10.6133/apjcn.202206_31(2).0011 -
BMC Research Notes May 2021The double burden of malnutrition is an emerging public health concern nowadays which a correlation with obesity. This study aimed to examine the relationship between...
OBJECTIVE
The double burden of malnutrition is an emerging public health concern nowadays which a correlation with obesity. This study aimed to examine the relationship between resting metabolic rate (RMR) and dietary intake of zinc, vitamin C, and riboflavin in overweight and obese women.
RESULTS
The RMR/FFM showed a significant association with riboflavin (β = 1.59; 95% CI 1.04-23.26, P = 0.04) and zinc (β = 0.78; 95% CI 1.04-4.61, P = 0.03) in the crude model. Moreover, differences in vitamin C and RMR/FFM was marginal significant (β = 0.75; 95% CI 0.95-4.77, P = 0.06). After adjusting for confounders the riboflavin association change to marginal significance (β = 1.52; 95% CI 0.91-23.04, P = 0.06). After controlling for potential confounders, the associations change between zinc and RMR/FFM (β = 0.66; 95% CI 0.78-4.86, P = 0.15) and between RMR/FFM and vitamin C (β = 0.48; 95% CI 0.66-3.96, P = 0.28). Our study showed a significant association between dietary intake of zinc, riboflavin, and vitamin C and change in RMR/FFM in overweight and obese women.
Topics: Basal Metabolism; Body Composition; Cross-Sectional Studies; Eating; Female; Humans; Obesity; Overweight
PubMed: 33980283
DOI: 10.1186/s13104-021-05582-z -
The British Journal of Nutrition Apr 2015Micronutrient deficiencies and low dietary intakes among community-dwelling older adults are associated with functional decline, frailty and difficulties with... (Review)
Review
Micronutrient deficiencies and low dietary intakes among community-dwelling older adults are associated with functional decline, frailty and difficulties with independent living. As such, studies that seek to understand the types and magnitude of potential dietary inadequacies might be beneficial for guiding future interventions. We carried out a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Observational cohort and longitudinal studies presenting the habitual dietary intakes of older adults (≥65 years) were included. Sex-specific mean (and standard deviation) habitual micronutrient intakes were extracted from each article to calculate the percentage of older people who were at risk for inadequate micronutrient intakes using the estimated average requirement (EAR) cut-point method. The percentage at risk for inadequate micronutrient intakes from habitual dietary intakes was calculated for twenty micronutrients. A total of thirty-seven articles were included in the pooled systematic analysis. Of the twenty nutrients analysed, six were considered a possible public health concern: vitamin D, thiamin, riboflavin, Ca, Mg and Se. The extent to which these apparent inadequacies are relevant depends on dynamic factors, including absorption and utilisation, vitamin and mineral supplement use, dietary assessment methods and the selection of the reference value. In light of these considerations, the present review provides insight into the type and magnitude of vitamin and mineral inadequacies.
Topics: Aged; Calcium; Diet; Diet Surveys; Dietary Supplements; Female; Humans; Magnesium; Male; Micronutrients; Nutritional Requirements; Nutritional Status; Riboflavin; Selenium; Thiamine; Vitamin D
PubMed: 25822905
DOI: 10.1017/S0007114515000203 -
The Journal of Nutrition Nov 2010A systematic review was conducted to identify all studies that were published between 1988 and 2008 reporting micronutrient intakes of women in resource-poor settings.... (Review)
Review
A systematic review was conducted to identify all studies that were published between 1988 and 2008 reporting micronutrient intakes of women in resource-poor settings. Inclusion criteria were study location (resource-poor), dietary assessment method (24-h recall, estimated/weighed record, or locally validated FFQ), energy and 1 or more micronutrient intakes reported (vitamin A, vitamin B-6, vitamin B-12, vitamin C, thiamin, riboflavin, niacin, folate, iron, or zinc), age range (15-50 y), sample size (≥30), and sex (female). Of the 1560 papers identified, 52 papers were included. Results showed that, except for vitamin A (29%), vitamin C (34%), and niacin (34%), the reported mean/median intakes in over 50% of studies were below the Estimated Average Requirement (EAR). Folate intake was most often below EAR (91% of studies). Regional differences were apparent for intakes of vitamins A, C, and B-6 and riboflavin; mean/median intakes in Latin America exceeded the EAR, whereas in Asia, reported mean/median intakes of vitamin C, vitamin A, and riboflavin were below the EAR in 47, 50, and 77% of the studies, respectively, as was the case for vitamin B-6 in 75% of the studies in Africa. These results suggest that inadequate intakes of multiple micronutrients are common among women living in resource-poor settings and emphasize the need for increased attention to the quality of women's diets. There is a need for more high-quality studies of women's micronutrient intakes.
Topics: Adolescent; Adult; Deficiency Diseases; Developing Countries; Diet; Female; Humans; Micronutrients; Middle Aged; Poverty Areas; Risk Factors; Young Adult
PubMed: 20881075
DOI: 10.3945/jn.110.123463 -
The American Journal of Tropical... Aug 2013
Topics: Anemia, Iron-Deficiency; Female; Hemoglobinopathies; Humans; Male; Micronutrients; Parasitic Diseases; Riboflavin Deficiency
PubMed: 23926144
DOI: 10.4269/ajtmh.13-0168b -
Journal of Experimental Botany Oct 2016Iron (Fe) is an essential mineral that has low solubility in alkaline soils, where its deficiency results in chlorosis. Whether low Fe supply and alkaline pH stress are...
Alkaline stress and iron deficiency regulate iron uptake and riboflavin synthesis gene expression differently in root and leaf tissue: implications for iron deficiency chlorosis.
Iron (Fe) is an essential mineral that has low solubility in alkaline soils, where its deficiency results in chlorosis. Whether low Fe supply and alkaline pH stress are equivalent is unclear, as they have not been treated as separate variables in molecular physiological studies. Additionally, molecular responses to these stresses have not been studied in leaf and root tissues simultaneously. We tested how plants with the Strategy I Fe uptake system respond to Fe deficiency at mildly acidic and alkaline pH by measuring root ferric chelate reductase (FCR) activity and expression of selected Fe uptake genes and riboflavin synthesis genes. Alkaline pH increased cucumber (Cucumis sativus L.) root FCR activity at full Fe supply, but alkaline stress abolished FCR response to low Fe supply. Alkaline pH or low Fe supply resulted in increased expression of Fe uptake genes, but riboflavin synthesis genes responded to Fe deficiency but not alkalinity. Iron deficiency increased expression of some common genes in roots and leaves, but alkaline stress blocked up-regulation of these genes in Fe-deficient leaves. In roots of the melon (Cucumis melo L.) fefe mutant, in which Fe uptake responses are blocked upstream of Fe uptake genes, alkaline stress or Fe deficiency up-regulation of certain Fe uptake and riboflavin synthesis genes was inhibited, indicating a central role for the FeFe protein. These results suggest a model implicating shoot-to-root signaling of Fe status to induce Fe uptake gene expression in roots.
Topics: Chlorophyll; Cucumis sativus; Cucurbitaceae; FMN Reductase; Gene Expression Regulation, Plant; Hydrogen-Ion Concentration; Iron Deficiencies; Plant Leaves; Plant Roots; Riboflavin; Stress, Physiological
PubMed: 27605716
DOI: 10.1093/jxb/erw328 -
The Journal of Nutrition Jun 2018Riboflavin is an essential component of the human diet and its derivative cofactors play an established role in oxidative metabolism. Riboflavin deficiency has been...
BACKGROUND
Riboflavin is an essential component of the human diet and its derivative cofactors play an established role in oxidative metabolism. Riboflavin deficiency has been linked with various human diseases.
OBJECTIVE
The objective of this study was to identify whether riboflavin depletion promotes tumorigenesis.
METHODS
HEK293T and NIH3T3 cells were cultured in riboflavin-deficient or riboflavin-sufficient medium and passaged every 48 h. Cells were collected every 5 generations and plate colony formation assays were performed to observe cell proliferation. Subcutaneous tumorigenicity assays in NU/NU mice were used to observe tumorigenicity of riboflavin-depleted HEK293T cells. Mechanistically, gene expression profiling and gene ontology analysis were used to identify abnormally expressed genes induced by riboflavin depletion. Western blot analyses, cell cycle analyses, and chromatin immunoprecipitation were used to validate the expression of cell cycle-related genes.
RESULTS
Plate colony formation of NIH3T3 and HEK293T cell lines was enhanced >2-fold when cultured in riboflavin-deficient medium for 10-20 generations. Moreover, we observed enhanced subcutaneous tumorigenicity in NU/NU mice following injection of riboflavin-depleted compared with normal HEK293T cells (55.6% compared with 0.0% tumor formation, respectively). Gene expression profiling and gene ontology analysis revealed that riboflavin depletion induced the expression of cell cycle-related genes. Validation experiments also found that riboflavin depletion decreased p21 and p27 protein levels by ∼20%, and increased cell cycle-related and expression-elevated protein in tumor (CREPT) protein expression >2-fold, resulting in cyclin D1 and CDK4 levels being increased ∼1.5-fold, and cell cycle acceleration. We also observed that riboflavin depletion decreased intracellular riboflavin levels by 20% and upregulated expression of riboflavin transporter genes, particularly SLC52A3, and that the changes in CREPT and SLC52A3 correlated with specific epigenetic changes in their promoters in riboflavin-depleted HEK293T cells.
CONCLUSION
Riboflavin depletion contributes to HEK293T and NIH3T3 cell tumorigenesis and may be a risk factor for tumor development.
Topics: Animals; Carcinogenesis; Cell Cycle; Cell Proliferation; Gene Expression Regulation; HEK293 Cells; Humans; Mice; NIH 3T3 Cells; Riboflavin
PubMed: 29741716
DOI: 10.1093/jn/nxy047 -
Anales de Pediatria Jan 2022Inborn errors of metabolism are a highly heterogeneous group of orphan diseases. Diet therapy and enzyme and coenzyme replacement are the most frequently used treatment....
INTRODUCTION
Inborn errors of metabolism are a highly heterogeneous group of orphan diseases. Diet therapy and enzyme and coenzyme replacement are the most frequently used treatment. There are few patients and published studies about inborn errors of metabolism. The main objective of this study was to describe the effectiveness of orphan drugs in inborn errors of metabolism in paediatric patients.
MATERIAL AND METHODS
Retrospective descriptive study of 24 months on patients diagnosed with inborn errors of metabolism during childhood and who attended the pharmacy clinic or Day-Care Unit of a 630-bed general hospital.
RESULTS
The study included 15 patients with a median age of 17.8 years and were treated with nine different drugs: sapropterin, sodium phenylbutyrate, miglustat, velaglucerase, sebelipase, idursulfase, 5-hydroxytryptophan, succinate, and riboflavin. Seven different inborn errors of metabolism were observed: phenylketonuria, defects of the urea cycle, Gaucher, Nieman-Pick, Hunter's disease, along with acid lipase deficiency, and mitochondrial diseases. Orphan drugs used for the treatment of inborn errors of metabolism accounted for 1.3% of hospital drug costs. Some orphan drugs achieved asymptomatic patients, but others just produced a modest symptomatic improvement. Most patients showed good tolerance to the treatment.
CONCLUSIONS
Orphan drugs used in inborn errors of metabolism had an easy to manage toxicity profile, with many disparities in effectiveness. These drugs have a high economic impact. The cost-effectiveness ratio for orphan drugs is a controversial issue due to their high cost and the inconclusive clinical evidence.
Topics: Adolescent; Child; Humans; Metabolic Diseases; Metabolism, Inborn Errors; Orphan Drug Production; Rare Diseases; Retrospective Studies
PubMed: 34992005
DOI: 10.1016/j.anpede.2020.09.014