Editorial

3 pages, 184 KiB

Open AccessEditorial

Folate and Other B Vitamins in Brain Health and Disease

by Edward V. Quadros

Nutrients 2023, 15(11), 2525; https://0-doi-org.brum.beds.ac.uk/10.3390/nu15112525 - 29 May 2023

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B vitamins as a group play essential roles in a multitude of metabolic reactions involved in cellular replication, energy production, the synthesis of intermediary compounds, and neurotransmitters [...] Full article

(This article belongs to the Special Issue Folate and Other B Vitamins in Brain Health and Disease)

Research

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18 pages, 3184 KiB

Open AccessArticle

Brain Uptake of Folate Forms in the Presence of Folate Receptor Alpha Antibodies in Young Rats: Folate and Antibody Distribution

by Natasha Bobrowski-Khoury, Jeffrey M. Sequeira and Edward V. Quadros

Nutrients 2023, 15(5), 1167; https://0-doi-org.brum.beds.ac.uk/10.3390/nu15051167 - 25 Feb 2023

Cited by 3 | Viewed by 2110

Abstract

In a rat model, following exposure to rat folate receptor alpha antibodies (FRαAb) during gestation, FRαAb accumulates in the placenta and the fetus and blocks folate transport to the fetal brain and produces behavioral deficits in the offspring. These deficits could be prevented [...] Read more.

In a rat model, following exposure to rat folate receptor alpha antibodies (FRαAb) during gestation, FRαAb accumulates in the placenta and the fetus and blocks folate transport to the fetal brain and produces behavioral deficits in the offspring. These deficits could be prevented with folinic acid. Therefore, we sought to evaluate folate transport to the brain in young rat pups and determine what effect FRαAb has on this process, to better understand the folate receptor autoimmune disorder associated with cerebral folate deficiency (CFD) in autism spectrum disorders (ASD). When injected intraperitoneally (IP), FRαAb localizes to the choroid plexus and blood vessels including the capillaries throughout the brain parenchyma. Biotin-tagged folic acid shows distribution in the white matter tracts in the cerebrum and cerebellum. Since these antibodies can block folate transport to the brain, we orally administered various folate forms to identify the form that is better-absorbed and transported to the brain and is most effective in restoring cerebral folate status in the presence of FRαAb. The three forms of folate, namely folic acid, D,L-folinic acid and levofolinate, are converted to methylfolate while L-methylfolate is absorbed as such and all are efficiently distributed to the brain. However, significantly higher folate concentration is seen in the cerebrum and cerebellum with levofolinate in the presence or absence of FRαAb. Our results in the rat model support testing levofolinate to treat CFD in children with ASD. Full article

(This article belongs to the Special Issue Folate and Other B Vitamins in Brain Health and Disease)

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11 pages, 793 KiB

Open AccessArticle

Developing a Sensitive Platform to Measure 5-Methyltetrahydrofolate in Subjects with MTHFR and PON1 Gene Polymorphisms

by Mong-Liang Lu, Wei-Chi Ku, Nailis Syifa, Shu-Chin Hu, Chia-Te Chou, Yi-Hsio Wu, Po-Hsiu Kuo, Chun-Hsin Chen, Wei J. Chen and Tzu-Hua Wu

Nutrients 2022, 14(16), 3320; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14163320 - 13 Aug 2022

Cited by 3 | Viewed by 1916

Abstract

Inadequate levels of 5-methyltetrahydrofolate (5-MTHF) and the T variant of MTHFR C677T have been suggested to be associated with an increased risk of developing mental illness, whereas the PON1 SNP variant provides a protective role. However, reports validating the methodology for plasma 5-MTHF [...] Read more.

Inadequate levels of 5-methyltetrahydrofolate (5-MTHF) and the T variant of MTHFR C677T have been suggested to be associated with an increased risk of developing mental illness, whereas the PON1 SNP variant provides a protective role. However, reports validating the methodology for plasma 5-MTHF levels in schizophrenia patients are limited. A sensitive LC–MS/MS system using an amide column and calibration curve was determined by dialyzed human plasma, and applied to schizophrenia patients and healthy controls in Taiwan, and the differences between the subgroups were discussed. This analysis system meets regulation criteria, and the lower limit of quantification for 5-MTHF levels was 4 nM from 200 μL plasma, within 7 min. The mean plasma 5-MTHF levels in schizophrenia patients (n = 34; 11.70 ± 10.37 nM) were lower than those in the healthy controls (n = 42; 22.67 ± 11.12 nM) significantly (p < 0.01). 5-MTHF concentrations were significantly lower in male carriers than in female carriers (18.30 ± 10.37 nM vs. 24.83 ± 11.01 nM, p < 0.05), especially in subjects who were MTHFR CT/PON1 Q allele carriers. In conclusion, this quantitative system, which employed sensitive and simple processing methods, was successfully applied, and identified that schizophrenic patients had significantly lower levels of 5-MTHF. Lower plasma 5-MTHF concentrations were observed in male subjects. Full article

(This article belongs to the Special Issue Folate and Other B Vitamins in Brain Health and Disease)

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16 pages, 9972 KiB

Open AccessArticle

Absorption and Tissue Distribution of Folate Forms in Rats: Indications for Specific Folate Form Supplementation during Pregnancy

by Natasha Bobrowski-Khoury, Jeffrey M. Sequeira, Erland Arning, Teodoro Bottiglieri and Edward V. Quadros

Nutrients 2022, 14(12), 2397; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14122397 - 09 Jun 2022

Cited by 4 | Viewed by 4381

Abstract

Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the emergence of conditions where folate metabolism and transport are disrupted, such as folate receptor alpha autoantibody (FRαAb)-induced folate deficiency, it is [...] Read more.

Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the emergence of conditions where folate metabolism and transport are disrupted, such as folate receptor alpha autoantibody (FRαAb)-induced folate deficiency, it is critical to find a folate form that is effective and safe for pharmacologic dosing for prolonged periods. Therefore, in this study, we explored the absorption and tissue distribution of folic acid (PGA), 5-methyl-tetrahydrofolate (MTHF), l-folinic acid (levofolinate), and d,l-folinic acid (Leucovorin) in adult rats. During absorption, all forms are converted to MTHF while some unconverted folate form is transported into the blood, especially PGA. The study confirms the rapid distribution of absorbed folate to the placenta and fetus. FRαAb administered, also accumulates rapidly in the placenta and blocks folate transport to the fetus and high folate concentrations are needed to circumvent or overcome the blocking of FRα. In the presence of FRαAb, both Leucovorin and levofolinate are absorbed and distributed to tissues better than the other forms. However, only 50% of the leucovorin is metabolically active whereas levofolinate is fully active and generates higher tetrahydrofolate (THF). Because levofolinate can readily incorporate into the folate cycle without needing methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) in the first pass and is relatively stable, it should be the folate form of choice during pregnancy, other disorders where large daily doses of folate are needed, and food fortification. Full article

(This article belongs to the Special Issue Folate and Other B Vitamins in Brain Health and Disease)

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18 pages, 3524 KiB

Open AccessArticle

Vitamin B Complex and Experimental Autoimmune Encephalomyelitis –Attenuation of the Clinical Signs and Gut Microbiota Dysbiosis

by Marija Mandić, Katarina Mitić, Predrag Nedeljković, Mina Perić, Bojan Božić, Tanja Lunić, Ana Bačić, Mirjana Rajilić-Stojanović, Sanja Peković and Biljana Božić Nedeljković

Nutrients 2022, 14(6), 1273; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14061273 - 17 Mar 2022

Cited by 7 | Viewed by 2767

Abstract

The present study aimed to investigate the neuroprotective effects of the vitamin B complex (B1, B2, B3, B5, B6, and B12—VBC), by studying the changes in the femoral nerve, quadriceps muscle, popliteal lymph nodes and gut microbiota in the rat model of multiple [...] Read more.

The present study aimed to investigate the neuroprotective effects of the vitamin B complex (B1, B2, B3, B5, B6, and B12—VBC), by studying the changes in the femoral nerve, quadriceps muscle, popliteal lymph nodes and gut microbiota in the rat model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). VBC treatment attenuated clinical signs of EAE during the disease, and reduced the duration of EAE thereby contributing to a faster recovery. In VBC-treated EAE rats, a significant decrease in nerve and muscle nuclear density was revealed during the onset period of the disease, while a marked increase was detected at the end of the disease, compared with untreated EAE rats. In the lymph nodes of VBC-treated EAE rats, a fewer number of lymphoid follicles in the cortical area and smaller epithelioid granulomas were detected. The changes in microbiota composition were examined using 16S rRNA gene sequencing and bioinformatics analysis, which revealed the potential of VBC treatment in establishing and/or maintaining gut microbiota homeostasis. Finally, the present study demonstrated that VBC treatment ameliorated the cellular changes in the affected peripheral nerve, muscles innervated by this nerve, and the gut microbiota dysbiosis which occurred during the EAE. Full article

(This article belongs to the Special Issue Folate and Other B Vitamins in Brain Health and Disease)

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19 pages, 4743 KiB

Open AccessArticle

Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Sex-Specific Gene Expression in Brain of Young Mice and Embryos

by Yan Luan, Marta Cosín-Tomás, Daniel Leclerc, Olga V. Malysheva, Marie A. Caudill and Rima Rozen

Nutrients 2022, 14(5), 1051; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14051051 - 02 Mar 2022

Cited by 10 | Viewed by 2546

Abstract

Food fortification and increased vitamin intake have led to higher folic acid (FA) consumption by many pregnant women. We showed that FA-supplemented diet in pregnant mice (fivefold higher FA than the recommended level (5xFASD)) led to hyperactivity-like behavior and memory impairment in pups. [...] Read more.

Food fortification and increased vitamin intake have led to higher folic acid (FA) consumption by many pregnant women. We showed that FA-supplemented diet in pregnant mice (fivefold higher FA than the recommended level (5xFASD)) led to hyperactivity-like behavior and memory impairment in pups. Disturbed choline/methyl metabolism and altered placental gene expression were identified. The aim of this study was to examine the impact of 5xFASD on the brain at two developmental stages, postnatal day (P) 30 and embryonic day (E) 17.5. Female C57BL/6 mice were fed a control diet or 5xFASD for 1 month before mating. Diets were maintained throughout the pregnancy and lactation until P30 or during pregnancy until E17.5. The 5xFASD led to sex-specific transcription changes in a P30 cerebral cortex and E17.5 cerebrum, with microarrays showing a total of 1003 and 623 changes, respectively. Enhanced mRNA degradation was observed in E17.5 cerebrum. Expression changes of genes involved in neurotransmission, neuronal growth and development, and angiogenesis were verified by qRT-PCR; 12 and 15 genes were verified at P30 and E17.5, respectively. Hippocampal collagen staining suggested decreased vessel density in FASD male embryos. This study provides insight into the mechanisms of neurobehavioral alterations and highlights potential deleterious consequences of moderate folate oversupplementation during pregnancy. Full article

(This article belongs to the Special Issue Folate and Other B Vitamins in Brain Health and Disease)

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16 pages, 1013 KiB

Open AccessArticle

Optimal Dietary Intake Composition of Choline and Betaine Is Associated with Minimized Visceral Obesity-Related Hepatic Steatosis in a Case-Control Study

by Ting-Yu Chang, Chien-Hsien Wu, Chi-Yang Chang, Fu-Jen Lee, Bei-Wen Wang, Jia-Yau Doong, Yu-Shun Lin, Chang-Sheng Kuo and Rwei-Fen S. Huang

Nutrients 2022, 14(2), 261; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14020261 - 08 Jan 2022

Cited by 9 | Viewed by 4002

Abstract

Few studies on humans have comprehensively evaluated the intake composition of methyl-donor nutrients (MDNs: choline, betaine, and folate) in relation to visceral obesity (VOB)-related hepatic steatosis (HS), the hallmark of non-alcoholic fatty liver diseases. In this case–control study, we recruited 105 patients with [...] Read more.

Few studies on humans have comprehensively evaluated the intake composition of methyl-donor nutrients (MDNs: choline, betaine, and folate) in relation to visceral obesity (VOB)-related hepatic steatosis (HS), the hallmark of non-alcoholic fatty liver diseases. In this case–control study, we recruited 105 patients with HS and 104 without HS (controls). HS was diagnosed through ultrasound examination. VOB was measured using a whole-body analyzer. MDN intake was assessed using a validated quantitative food frequency questionnaire. After adjustment for multiple HS risk factors, total choline intake was the most significant dietary determinant of HS in patients with VOB (Beta: −0.41, p = 0.01). Low intake of choline (<6.9 mg/kg body weight), betaine (<3.1 mg/kg body weight), and folate (<8.8 μg/kg body weight) predicted increased odds ratios (ORs) of VOB-related HS (choline: OR: 22, 95% confidence interval [CI]: 6.5–80; betaine: OR: 14, 95% CI: 4.4–50; and folate: OR: 19, 95% CI: 5.2–74). Combined high intake of choline and betaine, but not folate, was associated with an 81% reduction in VOB-related HS (OR: 0.19, 95% CI: 0.05–0.69). Our data suggest that the optimal intake of choline and betaine can minimize the risk of VOB-related HS in a threshold-dependent manner. Full article

(This article belongs to the Special Issue Folate and Other B Vitamins in Brain Health and Disease)

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Review

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19 pages, 2379 KiB

Open AccessReview

Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies

by Vincent Th. Ramaekers and Edward V. Quadros

Nutrients 2022, 14(15), 3096; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14153096 - 28 Jul 2022

Cited by 15 | Viewed by 3704

Abstract

Cerebral folate deficiency syndrome (CFDS) is defined as any neuropsychiatric or developmental disorder characterized by decreased CSF folate levels in the presence of normal folate status outside the nervous system. The specific clinical profile appears to be largely determined by the presence or [...] Read more.

Cerebral folate deficiency syndrome (CFDS) is defined as any neuropsychiatric or developmental disorder characterized by decreased CSF folate levels in the presence of normal folate status outside the nervous system. The specific clinical profile appears to be largely determined by the presence or absence of intrauterine folate deficiency as well as postnatal age at which cerebral folate deficiency occurs. The primary cause of CFDS is identified as the presence of serum folate receptor-alpha (FRα) autoantibodies impairing folate transport across the choroid plexus to the brain whereas, in a minority of cases, mitochondrial disorders, inborn errors of metabolism and loss of function mutations of the FRα (FOLR1) gene are identified. Early recognition and diagnosis of CFDS and prompt intervention is important to improve prognosis with successful outcomes. In this article we focus on FRα autoimmunity and its different age-dependent clinical syndromes, the diagnostic criteria, and treatments to be considered, including prevention strategies in this at-risk population. Full article

(This article belongs to the Special Issue Folate and Other B Vitamins in Brain Health and Disease)

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