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Plant-based diets are increasingly popular worldwide. A well-planned plant-based diet lowers the risk of cardiovascular disease, type 2 diabetes and certain cancers. In contrast, a poorly planned plant-based diet increases the risk of certain micronutrient deficiencies, chiefly, vitamin B12 (B12). Because B12 is not present in plants or in unfortified plant-based foodstuffs, the safest way to prevent its deficiency in plant-based diets is to take an oral B12 supplement. Studies determining the dose and frequency of B12 to be taken by healthy individuals on a plant-based diet to support an adequate B12 status are scarce. Here, we summarize the natural sources, metabolic requirements, biomarker findings with and without supplementation with B12, and current recommendations to help prevent vitamin B12 deficiency in healthy individuals adhering or transitioning to plant-based diets. This review focuses on the prevention of vitamin B12 deficiency in healthy individuals adhering to plant-based diets. The information covered in this review does not apply to individuals suffering from autoimmune-based malabsorption of vitamin B12 resulting from pernicious anemia due to atrophic gastritis, other acquired causes of B12 malabsorption or to those with genetic disorders that impair vitamin B12 absorption, transport and utilization.
Plain language titleVitamin B12 in Plant-Based DietsPlain language summaryPlant-based diets are increasingly popular worldwide. Because vitamin B12 is not found in plants, individuals must acquire the micronutrient by consuming fortified foods or by taking an oral vitamin B12 supplement. We review B12 sources, required daily intake, and use of B12 supplements among those on plant-based diets. The safest way to prevent B12 deficiency in individuals adhering to plant-based diets is by using an oral B12 supplement.
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Dieta a Base de Plantas , Suplementos Dietéticos , Deficiencia de Vitamina B 12 , Vitamina B 12 , Humanos , Dieta a Base de Plantas/efectos adversos , Estado Nutricional , Vitamina B 12/administración & dosificación , Deficiencia de Vitamina B 12/etiología , Deficiencia de Vitamina B 12/prevención & controlRESUMEN
Choline has important physiological functions as a precursor for essential cell components, signaling molecules, phospholipids, and the neurotransmitter acetylcholine. Choline is a water-soluble charged molecule requiring transport proteins to cross biological membranes. Although transporters continue to be identified, membrane transport of choline is incompletely understood and knowledge about choline transport into intracellular organelles such as mitochondria remains limited. Here we show that SLC25A48 imports choline into human mitochondria. Human loss-of-function mutations in SLC25A48 show impaired choline transport into mitochondria and are associated with elevated urine and plasma choline levels. Thus, our studies may have implications for understanding and treating conditions related to choline metabolism.
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Classical homocystinuria is a rare disease caused by mutations in cystathionine ß-synthase (CBS) gene (OMIM 613381). CBS catalyzes the first step of the transsulfuration pathway that converts homocysteine (Hcy) into cystathionine (Cysta) via a number of co-substrates and mechanisms. Formation of Cysta by condensation of Hcy and cysteine (Cys) produces a molar equivalent of hydrogen sulfide (H2S). H2S plays important roles in cognitive and vascular functions. Clinically, patients with CBS deficiency present with vascular, ocular, neurological and skeletal impairments. Biochemically, CBS deficiency manifests with elevated Hcy and reduced concentration of Cysta in plasma and urine. A number of pathogenic variants of human CBS have been characterized by their residual enzymatic activity, but very few studies have examined H2S production by pathogenic CBS variants, possibly due to technical hurdles in H2S detection and quantification. We describe a method for the real-time, continuous quantification of H2S formed by wild-type and pathogenic variants of human recombinant CBS, as well as by fibroblast extracts from healthy controls and patients diagnosed with CBS deficiency. The method takes advantage of the specificity and high affinity of hemoglobin I of the clam Lucina pectinata toward H2S and is based on UV-visible spectrophotometry. Comparison with the gold-standard, end-point H2S quantification method employing monobromobimane, as well as correlations with CBS enzymatic activity determined by LC-MS/MS showed agreement and correlation, and permitted the direct, time-resolved determination of H2S production rates by purified human recombinant CBS and by CBS present in fibroblast extracts. Rates of H2S production were highest for wild-type CBS, and lower for pathogenic variants. This method enables the examination of structural determinants of CBS that are important for H2S production and its possible relevance to the clinical outcome of patients.
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BACKGROUND: Healthy plant-based diets, such as the lacto-ovo-vegetarian and the vegan diet, offer numerous benefits to human health. Poorly designed plant-based diets, however, bear the risk for vitamin- and micronutrient deficiencies. Vitamin B12 (B12, cobalamin) is a nutrient of particular concern in both diets, and should be readily supplemented on a continuous basis to ensure adequate B12 levels and to prevent deficiencies. CASE REPORT: This case reports describes the history of a healthy man in his mid-30s who adopted a vegan diet approximately 10 y ago. Well informed about the risks of vitamin B12 deficiency on a plant-based diet, he regularly supplemented methylcobalamin for years (single oral dose: 500 µg, 3-4 times a week) in order to maintain an adequate vitamin B12 status. In late 2023, however, he decided to cease B12 supplementation for undisclosed reasons. Subsequent to this decision, we closely monitored his B12 status and longitudinally measured serum B12, homocysteine, and holotranscobalamin (holo-TC). Total serum folate was also determined as it is a modifier of homocysteine concentration. A gradual decrease in holo-TC and vitamin B12 levels was observed after 4 weeks and supplements had to be re-introduced after 16 weeks. Homocysteine increased concomitantly up to 18.2 µmol/L after 20 weeks. CONCLUSIONS: While a short-term B12 supplement intake cessation might be well tolerated by vegans with an adequate B12 status, an interruption of more than 8 weeks could signify B12 loss approaching suboptimal status. This case report reiterates the need for continuous B12 supplementation in persons following an unfortified plant-based diet.
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Dieta Vegana , Suplementos Dietéticos , Homocisteína , Veganos , Deficiencia de Vitamina B 12 , Vitamina B 12 , Humanos , Vitamina B 12/sangre , Vitamina B 12/administración & dosificación , Vitamina B 12/análogos & derivados , Masculino , Deficiencia de Vitamina B 12/sangre , Deficiencia de Vitamina B 12/tratamiento farmacológico , Adulto , Homocisteína/sangre , Transcobalaminas/análisis , Estado Nutricional , Dieta Vegetariana/métodos , Ácido Fólico/sangre , Ácido Fólico/administración & dosificaciónRESUMEN
BACKGROUND: The beneficial effects of a plant-based diet on gut microbiota diversity are well documented, however, its impact on clinical bowel health and defecation patterns are less well understood. Vegetarian diets have been associated with a higher bowel movement (BM) frequency as well as softer stools in cross-sectional studies. The effects of the de-novo adoption of a vegan diet on bowel health, however, have never been investigated in a randomized-controlled trial. MATERIALS AND METHODS: The present study examined bowel health and defecation patterns in relation to diet and nutrient intake in a young and healthy sample of n = 65 physically-active German university students who were randomly assigned to either a vegan or a meat-rich diet for eight weeks. Bowel health assessment included the Bristol Stool Form Scale (BSFS), the Gastrointestinal Quality of Life Index (GIQLI) and the Cleveland Clinic Fecal Incontinence Score (CCFIS). Nutrient intake was assessed using weighed food diaries. The study was prospectively registered at the German Clinical Trial Register (DRKS00031541). RESULTS: Weekly BM frequency slightly increased in vegans, whereas it remained unaltered in participants assigned to a meat-rich diet. Fiber intake increased significantly in vegans (34.89 (18.46) g/d) whereas it decreased in those assigned to the meat-rich group (22.79 (12.5) g/d). No significant intergroup differences in BSFS and CCFIS patterns were observed. Adoption of a vegan diet neither resulted in a transient increase in abdominal discomfort nor in a decreased gastrointestinal quality of life, which was comparable across the diet groups. CONCLUSIONS: The short-term de-novo adoption of a vegan diet did not negatively affect markers of bowel health in this study.
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Defecación , Dieta Vegana , Humanos , Estudios Transversales , Calidad de Vida , Dieta , Ingestión de AlimentosRESUMEN
PURPOSE: Serine (Ser) and glycine (Gly) levels were reported to differ between patients with macular telangiectasia type 2 (MacTel) compared with healthy controls. Because they are closely related to methylation metabolism, this report investigates methylation-associated metabolite levels in patients with MacTel and retinal changes in monogenetic methylation disorders. METHODS: Prospective, monocentric study on patients with MacTel and healthy controls underwent a standardized protocol including a blood draw. Methylation-associated metabolite levels in plasma were determined using targeted quantitative metabolomics. Furthermore, patient records of cystathionine beta-synthase, methylenetetrahydrofolate reductase, and methylmalonic aciduria and homocystinuria type C protein (MMACHC) deficiency were screened for reported retinal changes. RESULTS: In total, 29 patients with MacTel and 27 healthy controls were included. Patients with MacTel showed lower plasma Ser ( P = 0.02 and P = 0.01) and Gly ( P = 0.11 and P = 0.11) levels than controls. Principal component analyses revealed that methylation-associated metabolite, especially homocysteine, contributed to a distinct clustering of patients with MacTel. No retinal changes were seen in cystathionine beta-synthase (n = 1) and methylenetetrahydrofolate reductase (n = 2) deficiency, while two patients with MMACHC (n = 4) deficiency displayed extensive macular dystrophy. CONCLUSION: Patients with MacTel show distinct clustering of methylation-associated metabolite compared with controls. Of the three homocystinurias, only MMACHC resulted in macular dystrophy, possibly due to distinct compensatory pathways.
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Telangiectasia Retiniana , Humanos , Femenino , Masculino , Estudios Prospectivos , Telangiectasia Retiniana/diagnóstico , Telangiectasia Retiniana/metabolismo , Telangiectasia Retiniana/genética , Persona de Mediana Edad , Tomografía de Coherencia Óptica , Adulto , Anciano , Metilación , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Angiografía con Fluoresceína/métodos , Glicina , Homocistinuria/genética , Homocistinuria/complicaciones , Homocistinuria/diagnósticoRESUMEN
Autoimmune-mediated obsessive-compulsive disorder (OCD) can occur in multiple sclerosis (MS). Here, a well-studied case study of a patient with OCD and MS-compatible diagnostic findings is presented. The 42-year-old female patient had displayed OCD symptoms for 6 years. Magnetic resonance imaging (MRI) identified several periventricular and one brainstem lesion suggestive of demyelination. Cerebrospinal fluid (CSF) analyses detected an increased white blood cell count, intrathecal immunoglobulin (Ig) G and IgM synthesis, CSF-specific oligoclonal bands, and a positive MRZ reaction. Neopterin was increased, but sarcoidosis was excluded. In the absence of neurological attacks and clues for MRI-based dissemination in time, a radiologically isolated syndrome, the pre-disease stage of MS, was diagnosed. Neurotransmitter measurements of CSF detected reduced serotonin levels. In the absence of visible strategic demyelinating lesions within the cortico-striato-thalamo-cortical circuits, OCD symptoms may relate to reduced intrathecal serotonin levels and mild neuroinflammatory processes. Serotonin abnormalities in MS should be studied further, as they could potentially explain the association between neuroinflammation and mental illnesses.
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Esclerosis Múltiple , Trastorno Obsesivo Compulsivo , Femenino , Humanos , Adulto , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Serotonina , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , Inmunoglobulina G , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Encéfalo/patologíaRESUMEN
Chronic kidney disease (CKD) affects over 0.5 billion people worldwide across their lifetimes. Despite a growingly ageing world population, an increase in all-age prevalence of kidney disease persists. Adult-onset forms of kidney disease often result from lifestyle-modifiable metabolic illnesses such as type 2 diabetes. Pediatric and adolescent forms of renal disease are primarily caused by morphological abnormalities of the kidney, as well as immunological, infectious and inherited metabolic disorders. Alterations in energy metabolism are observed in CKD of varying causes, albeit the molecular mechanisms underlying pathology are unclear. A systematic indexing of metabolites identified in plasma and urine of patients with kidney disease alongside disease enrichment analysis uncovered inborn errors of metabolism as a framework that links features of adult and pediatric kidney disease. The relationship of genetics and metabolism in kidney disease could be classified into three distinct landscapes: (i) Normal genotypes that develop renal damage because of lifestyle and / or comorbidities; (ii) Heterozygous genetic variants and polymorphisms that result in unique metabotypes that may predispose to the development of kidney disease via synergistic heterozygosity, and (iii) Homozygous genetic variants that cause renal impairment by perturbing metabolism, as found in children with monogenic inborn errors of metabolism. Interest in the identification of early biomarkers of onset and progression of CKD has grown steadily in the last years, though it has not translated into clinical routine yet. This systematic review indexes findings of differential concentration of metabolites and energy pathway dysregulation in kidney disease and appraises their potential use as biomarkers.
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Diabetes Mellitus Tipo 2 , Errores Innatos del Metabolismo , Insuficiencia Renal Crónica , Adulto , Adolescente , Humanos , Niño , Riñón/metabolismo , Insuficiencia Renal Crónica/genética , Metabolómica , Biomarcadores , Errores Innatos del Metabolismo/genéticaRESUMEN
BACKGROUND/OBJECTIVE: Plant-based diets reduce the risk of cardiovascular disease but also increase the risk of certain micronutrient deficiencies, particularly, of vitamin B12 (B12). The extent to which the unsupervised use of oral nutrient supplements is sufficient to prevent these deficiencies is not well established. We analyzed nutrient intake, laboratory biomarkers, supplementation behavior, and B12 status adequacy amongst young, healthy, physically active omnivores, lacto-ovo-vegetarians and vegans from Germany. METHODS: We recruited 115 participants (n = 40 omnivores; n = 37 lacto-ovo-vegetarians, and n = 38 vegans) with comparable age, sex, marital status, physical activity and educational levels through online advertisements and local newspapers in Freiburg, Germany. RESULTS: Energy intake and macronutrient distribution were comparable across diets. Major differences included intake of fiber, cholesterol, and several vitamins. Vegans had the lowest intake of B12 from foods (0.43 (0.58) µg/d), compared to omnivores (2.14 (2.29) µg/d) and lacto-ovo-vegetarians (0.98 (1.34) µg/day). Multivariate analysis of 36 blood biomarkers revealed that three major classes of biomarkers contributed the most to the clustering of individuals by dietary group, namely, biomarkers of B12 status (B12, holoTC, Hcy), iron (iron, ferritin, transferrin) and lipid metabolism (vitamin A, HDL, LDL, total cholesterol, TAG). This suggests that nutrients that modify the metabolic pathways represented by these biomarkers have the most penetrating effect on health status across diets. Analysis of B12 status (including 4cB12) revealed adequacy in omnivores and vegans, and a poorer B12 status amongst lacto-ovo-vegetarians. Fewer lacto-ovo-vegetarians used B12 supplements compared to vegans (51% versus 90%). CONCLUSIONS: Even amongst homogeneously healthy Germans, each diet manifested with measurable differences in dietary intakes and biomarkers of health. Plant-based diets, in particular the vegan diet, exhibited the most favorable patterns of lipid metabolism and glycemic control, but the lowest food intake of B12. Supplementation of healthy vegans with B12 (median 250 µg B12/day, over 2 years) secured an adequate B12 status that was comparable to that of healthy omnivores.Clinical Trial Registry: German Clinical Trial register number: DRKS00027425.
Plant-based diets, in particular the vegan diet, exhibited the most favorable patterns of lipid metabolism and glycemic control, but the lowest food intake of B12.Analysis of B12 status (including 4cB12) revealed adequacy in omnivores and vegans, and a poorer B12 status amongst lacto-ovo-vegetarians.Supplementation with B12 (median 250 µg B12/day, over 1 year) in healthy physically-active vegans secured an adequate B12 status that was comparable to that of healthy omnivores.
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Dieta Vegana , Veganos , Humanos , Estado Nutricional , Vitamina B 12 , Estudios Transversales , Dieta Vegetariana , Vegetarianos , Dieta , Suplementos Dietéticos , Vitaminas , Colesterol , Hierro , BiomarcadoresRESUMEN
OBJECTIVE: Exhausted T cells with limited effector function are enriched in chronic hepatitis B and C virus (HBV and HCV) infection. Metabolic regulation contributes to exhaustion, but it remains unclear how metabolism relates to different exhaustion states, is impacted by antiviral therapy, and if metabolic checkpoints regulate dysfunction. DESIGN: Metabolic state, exhaustion and transcriptome of virus-specific CD8+ T cells from chronic HBV-infected (n=31) and HCV-infected patients (n=52) were determined ex vivo and during direct-acting antiviral (DAA) therapy. Metabolic flux and metabolic checkpoints were tested in vitro. Intrahepatic virus-specific CD8+ T cells were analysed by scRNA-Seq in a HBV-replicating murine in vivo model of acute and chronic infection. RESULTS: HBV-specific (core18-27, polymerase455-463) and HCV-specific (NS31073-1081, NS31406-1415, NS5B2594-2602) CD8+ T cell responses exhibit heterogeneous metabolic profiles connected to their exhaustion states. The metabolic state was connected to the exhaustion profile rather than the aetiology of infection. Mitochondrial impairment despite intact glucose uptake was prominent in severely exhausted T cells linked to elevated liver inflammation in chronic HCV infection and in HBV polymerase455-463 -specific CD8+ T cell responses. In contrast, relative metabolic fitness was observed in HBeAg-negative HBV infection in HBV core18-27-specific responses. DAA therapy partially improved mitochondrial programmes in severely exhausted HCV-specific T cells and enriched metabolically fit precursors. We identified enolase as a metabolic checkpoint in exhausted T cells. Metabolic bypassing improved glycolysis and T cell effector function. Similarly, enolase deficiency was observed in intrahepatic HBV-specific CD8+ T cells in a murine model of chronic infection. CONCLUSION: Metabolism of HBV-specific and HCV-specific T cells is strongly connected to their exhaustion severity. Our results highlight enolase as metabolic regulator of severely exhausted T cells. They connect differential bioenergetic fitness with distinct exhaustion subtypes and varying liver disease, with implications for therapeutic strategies.
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Hepatitis B Crónica , Hepatitis C Crónica , Hepatitis C , Humanos , Animales , Ratones , Linfocitos T CD8-positivos/metabolismo , Antivirales/uso terapéutico , Infección Persistente , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/metabolismo , Hepatitis C/tratamiento farmacológico , Virus de Hepatitis , Virus de la Hepatitis BRESUMEN
Understanding mechanisms of epigenetic regulation in embryonic stem cells (ESCs) is of fundamental importance for stem cell and developmental biology. Here, we identify Spic, a member of the ETS family of transcription factors (TFs), as a marker of ground state pluripotency. We show that Spic is rapidly induced in ground state ESCs and in response to extracellular signal-regulated kinase (ERK) inhibition. We find that SPIC binds to enhancer elements and stabilizes NANOG binding to chromatin, particularly at genes involved in choline/one-carbon (1C) metabolism such as Bhmt, Bhmt2, and Dmgdh. Gain-of-function and loss-of-function experiments revealed that Spic controls 1C metabolism and the flux of S-adenosyl methionine to S-adenosyl-L-homocysteine (SAM-to-SAH), thereby, modulating the levels of H3R17me2 and H3K4me3 histone marks in ESCs. Our findings highlight betaine-dependent 1C metabolism as a hallmark of ground state pluripotency primarily activated by SPIC. These findings underscore the role of uncharacterized auxiliary TFs in linking cellular metabolism to epigenetic regulation in ESCs.
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Epigénesis Genética , Histonas , Carbono , Células Madre Embrionarias , Metilación , S-AdenosilmetioninaRESUMEN
Chronic low-grade metabolic acidosis is now a common phenomenon in the Western world. The high dietary intake of sulfur-containing amino acids in the form of processed meats results in an excessive release of acid in the form of protons and non-metabolizable acidic anions. The kidneys produce increasing amounts of ammonia to excrete this acid. This process requires the breakdown of the nitrogenous amino acid glutamine, which the body provides by breaking down muscle tissue. Hitherto not examined, we hypothesized that a high dietary acid load (DAL) could alter the serum concentrations of selected amino acids. Using secondary data from a 4-week dietary intervention study conducted in 2017, we examined the associations between various amino acids and DAL in n = 42 individuals who either consumed a meat-rich or vegan diet. Results from this secondary data analysis suggested that DAL (as measured by the potential renal acid load and net endogenous acid production) is positively correlated with higher serum concentrations of lysine and 1-methyl-histidine (r = 0.50 and 0.43, respectively) and negatively correlated with glutamine and glycine (r = -0.43 and -0.47, respectively). The inverse association with glycine and glutamine warrants special attention, as both play an important role in many metabolic disorders and the immune system.
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Acidosis , Dieta Vegana , Humanos , Veganos , Análisis de Datos Secundarios , Glutamina , Dieta , Carne , Ácidos/metabolismo , GlicinaRESUMEN
Methylmalonic aciduria (MMA-uria) is caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). MUT deficiency hampers energy generation from specific amino acids, odd-chain fatty acids and cholesterol. Chronic kidney disease (CKD) is a well-known long-term complication. We exposed human renal epithelial cells from healthy controls and MMA-uria patients to different culture conditions (normal treatment (NT), high protein (HP) and isoleucine/valine (I/V)) to test the effect of metabolic stressors on renal mitochondrial energy metabolism. Creatinine levels were increased and antioxidant stress defense was severely comprised in MMA-uria cells. Alterations in mitochondrial homeostasis were observed. Changes in tricarboxylic acid cycle metabolites and impaired energy generation from fatty acid oxidation were detected. Methylcitrate as potentially toxic, disease-specific metabolite was increased by HP and I/V load. Mitophagy was disabled in MMA-uria cells, while autophagy was highly active particularly under HP and I/V conditions. Mitochondrial dynamics were shifted towards fission. Sirtuin1, a stress-resistance protein, was down-regulated by HP and I/V exposure in MMA-uria cells. Taken together, both interventions aggravated metabolic fingerprints observed in MMA-uria cells at baseline. The results point to protein toxicity in MMA-uria and lead to a better understanding, how the accumulating, potentially toxic organic acids might trigger CKD.
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Errores Innatos del Metabolismo de los Aminoácidos , Insuficiencia Renal Crónica , Humanos , Homeostasis , Metilmalonil-CoA Mutasa/metabolismo , Células Epiteliales/metabolismoRESUMEN
In the revised diagnostic classification systems ICD-11 and DSM-5, secondary, organic forms of obsessive-compulsive disorder (OCD) are implemented as specific nosological entities. Therefore, the aim of this study was to clarify whether a comprehensive screening approach, such as the Freiburg-Diagnostic-Protocol for patients with OCD (FDP-OCD), is beneficial for detecting organic OCD forms. The FDP-OCD includes advanced laboratory tests, an expanded magnetic resonance imaging (MRI) protocol, and electroencephalography (EEG) investigations as well as automated MRI and EEG analyses. Cerebrospinal fluid (CSF), [18F]fluorodeoxyglucose positron emission tomography, and genetic analysis were added for patients with suspected organic OCD. The diagnostic findings of the first 61 consecutive OCD inpatients (32 female and 29 male; mean age: 32.7 ± 12.05 years) analyzed using our protocol were investigated. A probable organic cause was assumed in five patients (8%), which included three patients with autoimmune OCD (one patient with neurolupus and two with specific novel neuronal antibodies in CSF) and two patients with newly diagnosed genetic syndromes (both with matching MRI alterations). In another five patients (8%), possible organic OCD was detected (three autoimmune cases and two genetic cases). Immunological serum abnormalities were identified in the entire patient group, particularly with high rates of decreased "neurovitamin" levels (suboptimal vitamin D in 75% and folic acid in 21%) and increased streptococcal (in 46%) and antinuclear antibodies (ANAs; in 36%). In summary, the FDP-OCD screening led to the detection of probable or possible organic OCD forms in 16% of the patients with mostly autoimmune forms of OCD. The frequent presence of systemic autoantibodies such as ANAs further support the possible influence of autoimmune processes in subgroups of patients with OCD. Further research is needed to identify the prevalence of organic OCD forms and its treatment options.
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Autoanticuerpos , Pacientes Internos , Humanos , Femenino , Masculino , Adulto Joven , Adulto , Anastrozol , Manual Diagnóstico y Estadístico de los Trastornos Mentales , ElectroencefalografíaRESUMEN
Phenylketonuria (PKU, MIM #261600) is one of the most common inborn errors of metabolism (IEM) with an incidence of 1:10000 in the European population. PKU is caused by autosomal recessive mutations in phenylalanine hydroxylase (PAH) and manifests with elevation of phenylalanine (Phe) in plasma and urine. Untreated PKU manifests with intellectual disability including seizures, microcephaly and behavioral abnormalities. Early treatment and good compliance result in a normal intellectual outcome in many but not in all patients. This study examined plasma metabolites in patients with PKU (n = 27), hyperphenylalaninemia (HPA, n = 1) and healthy controls (n = 32) by LC- MS/MS. We hypothesized that PKU patients would exhibit a distinct "submetabolome" compared to that of healthy controls. We further hypothesized that the submetabolome of PKU patients with good metabolic control would resemble that of healthy controls. Results from this study show: (i) Distinct clustering of healthy controls and PKU patients based on polar metabolite profiling, (ii) Increased and decreased concentrations of metabolites within and afar from the Phe pathway in treated patients, and (iii) A specific PKU-submetabolome independently of metabolic control assessed by Phe in plasma. We examined the relationship between PKU metabolic control and extended metabolite profiles in plasma. The PKU submetabolome characterized in this study represents the combined effects of dietary adherence, adjustments in metabolic pathways to compensate for defective Phe processing, as well as metabolic derangements that could not be corrected with dietary management even in patients classified as having good metabolic control. New therapeutic targets may be uncovered to approximate the PKU submetabolome to that of healthy controls and prevent long-term organ damage.
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Fenilalanina Hidroxilasa , Fenilcetonurias , Humanos , Punto Alto de Contagio de Enfermedades , Espectrometría de Masas en Tándem , Fenilalanina Hidroxilasa/genética , Fenilalanina Hidroxilasa/metabolismo , Fenilalanina , Análisis por ConglomeradosRESUMEN
Vitamin B12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shifting towards higher consumption of plant-based foods in ever-increasing numbers. Vitamin B12 plays crucial metabolic roles across the life-course and in particular during pregnancy and in early development (first 1000 days of life). Evidence now implicates vitamin B12 deficiency with increased risk to a range of neuro, vascular, immune, and inflammatory disorders. However, the current UK recommended nutrient intake for vitamin B12 does not adequately consider the vitamin B12 deficit for those choosing a plant-based diet, including vegetarianism and in particular veganism, representing a hidden hunger. We provide a cautionary note on the importance of preventing vitamin B12 deficits for those individuals choosing a plant-based diet and the health professionals advising them.
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Dieta , Vitamina B 12 , Humanos , Femenino , Embarazo , Dieta Vegetariana/efectos adversos , Dieta Vegana , VitaminasRESUMEN
Cytochrome c (cyt c) can undergo reversible conformational changes under biologically relevant conditions. Revealing these alternative cyt c conformers at the cell and tissue level is challenging. A monoclonal antibody (mAb) identifying a key conformational change in cyt c was previously reported, but the hybridoma was rendered nonviable. To resurrect the mAb in a recombinant form, the amino-acid sequences of the heavy and light chains were determined by peptide mapping-mass spectrometry-bioinformatic analysis and used to construct plasmids encoding the full-length chains. The recombinant mAb (R1D3) was shown to perform similarly to the original mAb in antigen-binding assays. The mAb bound to a variety of oxidatively modified cyt c species (e.g., nitrated at Tyr74 or oxidized at Met80), which lose the sixth heme ligation (Fe-Met80); it did not bind to several cyt c phospho- and acetyl-mimetics. Peptide competition assays together with molecular dynamic studies support that R1D3 binds a neoepitope within the loop 40-57. R1D3 was employed to identify alternative conformations of cyt c in cells under oxidant- or senescence-induced challenge as confirmed by immunocytochemistry and immunoaffinity studies. Alternative conformers translocated to the nuclei without causing apoptosis, an observation that was further confirmed after pinocytic loading of oxidatively modified cyt c to B16-F1 cells. Thus, alternative cyt c conformers, known to gain peroxidatic function, may represent redox messengers at the cell nuclei. The availability and properties of R1D3 open avenues of interrogation regarding the presence and biological functions of alternative conformations of cyt c in mammalian cells and tissues.
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Citocromos c , Hemo , Animales , Secuencia de Aminoácidos , Anticuerpos Monoclonales , Citocromos c/química , Hemo/química , Hibridomas , Oxidación-Reducción , Melanoma Experimental , RatonesRESUMEN
Contemporary diets in Western countries are largely acid-inducing and deficient in potassium alkali salts, resulting in low-grade metabolic acidosis. The chronic consumption of acidogenic diets abundant in animal-based foods (meats, dairy, cheese and eggs) poses a substantial challenge to the human body's buffering capacities and chronic retention of acid wherein the progressive loss of bicarbonate stores can cause cellular and tissue damage. An elevated dietary acid load (DAL) has been associated with systemic inflammation and other adverse metabolic conditions. In this narrative review, we examine DAL quantification methods and index observational and clinical evidence on the role of plant-based diets, chiefly vegetarian and vegan, in reducing DAL. Quantitation of protein and amino acid composition and of intake of alkalising organic potassium salts and magnesium show that plant-based diets are most effective at reducing DAL. Results from clinical studies and recommendations in the form of expert committee opinions suggest that for a number of common illnesses, wherein metabolic acidosis is a contributing factor, the regular inclusion of plant-based foods offers measurable benefits for disease prevention and management. Based on available evidence, dietary shifts toward plant-based nutrition effectively reduces dietary-induced, low-grade metabolic acidosis.