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Frontiers in Molecular Neuroscience 2021Riboflavin, also known as vitamin B, isfound in foods and is used as a dietary supplement. Its deficiency (also called ariboflavinosis) results in some skin lesions and...
Riboflavin, also known as vitamin B, isfound in foods and is used as a dietary supplement. Its deficiency (also called ariboflavinosis) results in some skin lesions and inflammations, such as stomatitis, cheilosis, oily scaly skin rashes, and itchy, watery eyes. Various therapeutic effects of riboflavin, such as anticancer, antioxidant, anti-inflammatory, and anti-nociceptive effects, are well known. Although some studies have identified the clinical effect of riboflavin on skin problems, including itch and inflammation, its underlying mechanism of action remains unknown. In this study, we investigated the molecular mechanism of the effects of riboflavin on histamine-dependent itch based on behavioral tests and electrophysiological experiments. Riboflavin significantly reduced histamine-induced scratching behaviors in mice and histamine-induced discharges in single-nerve fiber recordings, while it did not alter motor function in the rotarod test. In cultured dorsal root ganglion (DRG) neurons, riboflavin showed a dose-dependent inhibitory effect on the histamine- and capsaicin-induced inward current. Further tests wereconducted to determine whether two endogenous metabolites of riboflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), have similar effects to those of riboflavin. Here, FMN, but not FAD, significantly inhibited capsaicin-induced currents and itching responses caused by histamine. In addition, in transient receptor potential vanilloid 1 (TRPV1)-transfected HEK293 cells, both riboflavin and FMN blocked capsaicin-induced currents, whereas FAD did not. These results revealed that riboflavin inhibits histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how riboflavin exerts antipruritic effects and suggests that it might be a useful drug for the treatment of histamine-dependent itch.
PubMed: 34220447
DOI: 10.3389/fnmol.2021.643483 -
The Journal of Nutrition May 2005Secretory proteins such as apolipoprotein B-100 (apoB) undergo oxidative folding (formation of disulfide bonds) in the endoplasmic reticulum (ER) before secretion....
Secretory proteins such as apolipoprotein B-100 (apoB) undergo oxidative folding (formation of disulfide bonds) in the endoplasmic reticulum (ER) before secretion. Oxidative folding depends on flavoproteins in eukaryotes. Here, human liver (HepG2) cells were used to model effects of riboflavin concentrations in culture media on folding and secretion of apoB. Cells were cultured in media containing 3.1, 12.6, and 300 nmol/L of riboflavin, representing moderately deficient, physiological, and pharmacological plasma concentrations in humans, respectively. When cells were cultured in riboflavin-deficient medium, secretion of apoB decreased by >80% compared with controls cultured in physiological medium. The nuclear translocation of the transcription factor ATF-6 increased by >180% in riboflavin-deficient cells compared with physiological controls; this is consistent with ER stress. Nuclear translocation of ATF-6 was associated with activation of the unfolded protein response. Expression of stress-response genes coding for ubiquitin-activating enzyme 1, growth arrest and DNA damage inducible gene, and glucose regulated protein of 78 kDa was greater in riboflavin-deficient cells compared with other treatment groups. Finally, phosphorylation of the eukaryotic initiation factor (eukaryotic initiation factor 2alpha) increased in riboflavin-deficient cells, consistent with decreased translational activity. We conclude 1) that riboflavin deficiency causes ER stress and activation of unfolded protein response in HepG2 cells, and 2) that riboflavin deficiency decreases protein secretion in HepG2 cells. Decreased secretion of apoB in riboflavin-deficient cells might interfere with lipid homeostasis in vivo.
Topics: Apolipoprotein B-100; Apolipoproteins B; Carcinoma, Hepatocellular; Cell Line, Tumor; Endoplasmic Reticulum; Homeostasis; Humans; Liver Neoplasms; Oxidative Stress; Protein Folding; Riboflavin Deficiency
PubMed: 15867268
DOI: 10.1093/jn/135.5.978 -
Journal of Investigative Medicine High... 2023We are reporting monochorionic, diamniotic twin premature infants born at 25 weeks and 6 days gestation with riboflavin (vitamin B2) and biotin (vitamin B7) deficiency,...
Twin Premature Infants With Riboflavin and Biotin Deficiency Presenting With Refractory Lactic Acidosis, Rash, and Multiorgan Failure During Prolonged Parenteral Nutrition.
We are reporting monochorionic, diamniotic twin premature infants born at 25 weeks and 6 days gestation with riboflavin (vitamin B2) and biotin (vitamin B7) deficiency, while on prolonged total parenteral nutrition (TPN) during vitamin shortage. They presented initially with skin rash, lactic acidosis, and thrombocytopenia. Both twins progressed to severe respiratory failure, severe lactic acidosis, with refractory vasodilatory shock, pancytopenia, ischemic bowel injury, acute kidney injury, liver injury, and capillary leak syndrome leading to death of twin A. The surviving twin B was diagnosed with riboflavin and biotin deficiency that presented with abnormal metabolic work up suggestive of maple syrup urine disease, glutaric acidemia type 2, and X-linked adrenoleukodystrophy. Twin B was started on riboflavin and biotin supplementation at 41 days of life, with rapid improvement in clinical findings and laboratory abnormalities within days of starting biotin and riboflavin supplementation. He was discharged home in stable condition at 49 weeks of postmenstrual age.
Topics: Male; Infant, Newborn; Infant; Humans; Acidosis, Lactic; Biotin; Thiamine Deficiency; Parenteral Nutrition; Infant, Premature; Riboflavin; Vitamins; Exanthema; Multiple Organ Failure
PubMed: 37085971
DOI: 10.1177/23247096231168111 -
Advances in Nutrition (Bethesda, Md.) Mar 2014Flavin-dependent monooxygenases and oxidoreductases are located at critical branch points in the biosynthesis and metabolism of cholesterol and vitamin D. These... (Review)
Review
Flavin-dependent monooxygenases and oxidoreductases are located at critical branch points in the biosynthesis and metabolism of cholesterol and vitamin D. These flavoproteins function as obligatory intermediates that accept 2 electrons from NAD(P)H with subsequent 1-electron transfers to a variety of cytochrome P450 (CYP) heme proteins within the mitochondria matrix (type I) and the (microsomal) endoplasmic reticulum (type II). The mode of electron transfer in these systems differs slightly in the number and form of the flavin prosthetic moiety. In the type I mitochondrial system, FAD-adrenodoxin reductase interfaces with adrenodoxin before electron transfer to CYP heme proteins. In the microsomal type II system, a diflavin (FAD/FMN)-dependent cytochrome P450 oxidoreductase [NAD(P)H-cytochrome P450 reductase (CPR)] donates electrons to a multitude of heme oxygenases. Both flavoenzyme complexes exhibit a commonality of function with all CYP enzymes and are crucial for maintaining a balance of cholesterol and vitamin D metabolites. Deficits in riboflavin availability, imbalances in the intracellular ratio of FAD to FMN, and mutations that affect flavin binding domains and/or interactions with client proteins result in marked structural alterations within the skeletal and central nervous systems similar to those of disorders (inborn errors) in the biosynthetic pathways that lead to cholesterol, steroid hormones, and vitamin D and their metabolites. Studies of riboflavin deficiency during embryonic development demonstrate congenital malformations similar to those associated with genetic alterations of the flavoenzymes in these pathways. Overall, a deeper understanding of the role of riboflavin in these pathways may prove essential to targeted therapeutic designs aimed at cholesterol and vitamin D metabolism.
Topics: Animals; Cholesterol; Cytochrome P-450 Enzyme System; Disease Models, Animal; Flavins; Humans; Lipid Metabolism; Mitochondria; Mixed Function Oxygenases; Oxidoreductases; Riboflavin; Vitamin D
PubMed: 24618756
DOI: 10.3945/an.113.005181 -
Balkan Medical Journal Jul 2022To evaluate the clinical, pathological, and genetic features of patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD).
AIMS
To evaluate the clinical, pathological, and genetic features of patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD).
METHODS
Thirty-one patients with RR-MADD admitted to our hospital from January 2005 to November 2020 were enrolled, and their clinical data were collected. Pathological characteristics of the muscle tissue and possible pathogenic gene mutations were analyzed.
RESULTS
The most common clinical features in all patients were symmetrical proximal muscle weakness. Laboratory examination revealed elevated levels of creatine kinase, homocysteine, and uric acid, acylcarnitines, and organic acid. The muscle biopsy revealed typical pathological changes like lipid deposition. Genetic analysis identified ETFDH mutations in 29 patients, among which one had homozygotes, 19 had compound heterozygotes, 7 had heterozygous mutations, and 2 had heterozygous mutations of both ETFDH and ETFA. Two patients had no pathogenic gene mutations. All patients were treated with riboflavin, and their symptoms improved, which was consistent with the diagnosis of RR-MADD.
CONCLUSION
The clinical manifestations and genetic test results of patients with RR-MADD are heterogeneous. Therefore, a comprehensive analysis of clinical, pathological, and genetic testing is essential for the early diagnosis of RR-MADD.
Topics: Electron-Transferring Flavoproteins; Humans; Iron-Sulfur Proteins; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Oxidoreductases Acting on CH-NH Group Donors; Riboflavin
PubMed: 35734957
DOI: 10.4274/balkanmedj.galenos.2022.2022-1-127 -
JCI Insight Oct 2022Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis...
Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis elegans animal models of DLD deficiency generated by graded feeding of dld-1(RNAi) revealed that full or partial reduction of DLD-1 expression recapitulated increased pyruvate levels typical of pyruvate dehydrogenase complex deficiency and significantly altered animal survival and health, with reductions in brood size, adult length, and neuromuscular function. DLD-1 deficiency dramatically increased mitochondrial unfolded protein stress response induction and adaptive mitochondrial proliferation. While ATP levels were reduced, respiratory chain enzyme activities and in vivo mitochondrial membrane potential were not significantly altered. DLD-1 depletion directly correlated with the induction of mitochondrial stress and impairment of worm growth and neuromuscular function. The safety and efficacy of dichloroacetate, thiamine, riboflavin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), l-carnitine, and lipoic acid supplemental therapies empirically used for human DLD disease were objectively evaluated by life span and mitochondrial stress response studies. Only dichloroacetate and thiamine showed individual and synergistic therapeutic benefits. Collectively, these C. elegans dld-1(RNAi) animal model studies demonstrate the translational relevance of preclinical modeling of disease mechanisms and therapeutic candidates. Results suggest that clinical trials are warranted to evaluate the safety and efficacy of dichloroacetate and thiamine in human DLD disease.
Topics: Adult; Animals; Humans; Thiamine; Caenorhabditis elegans; Dihydrolipoamide Dehydrogenase; Thioctic Acid; Riboflavin; Carnitine; Pyruvates; Adenosine Triphosphate
PubMed: 36278487
DOI: 10.1172/jci.insight.156222 -
Current Developments in Nutrition Sep 2019Vitamin deficiencies remain major etiological factors in the global burden of disease, especially in low- and middle-income countries. The purpose of this... (Review)
Review
Vitamin deficiencies remain major etiological factors in the global burden of disease, especially in low- and middle-income countries. The purpose of this state-of-the-art review was to update current information on deficiencies of vitamins and public health approaches to addressing them. Some stages of life present a higher risk of deficiency than others: risks are higher in pregnant women, children (from conception to young childhood), adolescents, the elderly, and all of the over 800 million people globally who are undernourished. At risk are approximately 125 million preschool children with vitamin A deficiency, as well as sub-populations at risk of deficiencies of folate, thiamin, vitamin B12, niacin, riboflavin, other B vitamins. and vitamin D. Addressing micronutrient deficiencies requires identifying those at risk and then working to prevent and manage that risk. Public health approaches include improved, diversified diets; supplementation; fortification and biofortification; and other supportive public health measures. Historically, as with pellagra and beriberi and, in the last 3 decades, with vitamin A and folic acid, there has been encouraging progress, but much remains to be done.
PubMed: 31598578
DOI: 10.1093/cdn/nzz075 -
International Journal of Molecular... Nov 2023Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion... (Review)
Review
Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits.
Topics: Humans; Diet; Dietary Supplements; Micronutrients; Trace Elements; Metabolic Diseases; Fatty Acids
PubMed: 38069347
DOI: 10.3390/ijms242317024 -
Biological & Pharmaceutical Bulletin 2021Riboflavin (vitamin B2) plays an important role in cellular growth and function. Riboflavin transporter 2 (RFVT2) is widely expressed in several tissues, especially in...
Riboflavin (vitamin B2) plays an important role in cellular growth and function. Riboflavin transporter 2 (RFVT2) is widely expressed in several tissues, especially in the brain and salivary glands, and plays an important role in the tissue disruption of riboflavin. During the last 10 years, mutations in SLC52A2 have been documented in patients with a rare neurological disorder known as Brown-Vialetto-Van Laere syndrome. However, no suitable animal model of this disease has been reported. Here, we aimed to clarify the physiological role of RFVT2 using Slc52a2-mutant mice. The appearance, body weight, and plasma riboflavin concentration of Slc52a2 heterozygous mutant (Slc52a2+/-) mice were similar to those of wild-type (WT) mice. However, intercrossing between Slc52a2+/- mice failed to generate Slc52a2 homozygous mutant (Slc52a2-/-) mice. This suggested that Slc52a2 gene deficiency results in early embryonic lethality. Our findings suggested that RFVT2 is essential for growth and development, and its deletion may influence embryonic survival.
Topics: Animals; Bulbar Palsy, Progressive; Disease Models, Animal; Embryonic Development; Female; Genes, Lethal; Hearing Loss, Sensorineural; Humans; Male; Membrane Transport Proteins; Mice; Mice, Knockout; Mutation; Receptors, G-Protein-Coupled; Riboflavin
PubMed: 33518683
DOI: 10.1248/bpb.b20-00751 -
Animal : An International Journal of... Jan 2022Data from breeder hens and chicks are particularly critical for the development of vitamin B2 recommendations for organic poultry. To test safe thresholds of...
Data from breeder hens and chicks are particularly critical for the development of vitamin B2 recommendations for organic poultry. To test safe thresholds of supplementation, 100 breeder hens (Hubbard JA 57 K) and ten cockerels were allocated to ten housing groups, with each receiving supplementation of either 4.0 (treatment CON) or 2.5 mg (treatment RED) riboflavin per kg feed. After 15 weeks of experimental feeding, 256 eggs were incubated. From the hatched chicks (Hubbard S757), 192 were allocated to four treatments based on their parents' treatment (CON- or RED-) and on their own supplementation of either 4.0 (-CON) or 2.5 mg (-RED) riboflavin per kg feed. Two groups of each combination (CON-CON, CON-RED, RED-CON, RED-RED), each with 24 chicks of both sexes, were fattened for nine weeks and slaughtered. Analysis of total riboflavin (sum of native concentrations and supplements) in the parent's feeds revealed an average, over the 15 weeks, of 7.8 and 5.8 mg per kg feed for CON and RED, respectively. Body weight, plumage integrity, gait appearance, footpad, claw and keel bone integrity, lesion scores, laying performance, and egg mass were found to be of similarly high levels for all hens without any treatment effects. Performance traits of the hens in both treatments reached the specifications of the producer for this genotype. Yolk and albumen riboflavin concentrations were not affected although yolk colour in the RED treatment group became darker. Fertility was not affected, and hatchability was 100 per cent. Total riboflavin concentrations in the broiler diets were on average, over 9 weeks, 8.2 and 6.1 mg/kg for CON and RED, respectively. In chicks, RED treatment of their parents led to significant depressions of feed intake and growth. The RED treatment of the chicks themselves also impaired growth. Growth rates of the CON-CON treatment were in line with the specifications of the producer for this genotype. Plumage scores, footpad integrity and walking appearance of the broilers, and dressing percentage of the carcasses were not affected by treatment. The RED treatment of chicks caused lower spleen and heart weights, while pancreas and liver weights, and liver riboflavin concentrations were not affected. In conclusion, supplementation of 4.0 mg/kg to organic diets did not evoke any health or performance problems for breeder hens or broiler chicks, while a supplementation level of 2.5 mg per kg feed led to reduced weight gains, although without any other riboflavin deficiency symptoms.
Topics: Animal Feed; Animals; Chickens; Diet; Dietary Supplements; Female; Fertility; Male; Riboflavin
PubMed: 34999564
DOI: 10.1016/j.animal.2021.100433