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Effects of folate deficiency on proliferation, migration, and differentiation-associated death of hippocampal cells. A) Temporal changes in cell proliferation reflected by the number of cells. B) Temporal changes in cell migration reflected by the colonization by progenitors of the part of the well where cells were previously removed, as described in Materials and Methods. Average distance of migration was assessed by using Cell Analysis software (Olympus). C) Temporal changes in cell viability by using the CellTiter-Glo luminescent cell viability assay (Promega). Other methods, i.e., MTT and trypan blue, gave similar results (not shown). D) Percentage of apoptotic cells reflected by Apostain immunostaining. E) Changes in the mitochondrial membrane potential depicted by the MitoCapture detection kit (Calbiochem). F) Temporal evolution of the expression of various key proteins assessed by Western blot after induction of differentiation in control and folate-deficient cells. Corresponding quantifications by densitometric analyses are provided in Supplemental Fig. S1. All values were obtained from 3 separate experiments and by using 3 different wells for each protein. Data are reported as means sd. *P 0.05, **P 0.01 vs. control.
Source publication
Despite the key role in neuronal development of a deficit in the methyl donor folate, little is known on the underlying mechanisms. We therefore studied the consequences of folate deficiency on proliferation, differentiation, and plasticity of the rat H19-7 hippocampal cell line. Folate deficit reduced proliferation (17%) and sensitized cells to di...
Contexts in source publication
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... the permissive temperature of 33°C, the rate of proliferation in folate-deficient cells was reduced by 17% starting from the third day of culture ( Fig. 2A). Concomitantly, the capacity of migration was reduced by 50% and then remained lower than controls (Fig. 2B). Following induction of differentiation, cell viability gradually decreased under control conditions (Fig. 2C), and the percentage of Apostain-positive cells, indicative of apoptosis-associated single-strand DNA, increased with ...
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... the permissive temperature of 33°C, the rate of proliferation in folate-deficient cells was reduced by 17% starting from the third day of culture ( Fig. 2A). Concomitantly, the capacity of migration was reduced by 50% and then remained lower than controls (Fig. 2B). Following induction of differentiation, cell viability gradually decreased under control conditions (Fig. 2C), and the percentage of Apostain-positive cells, indicative of apoptosis-associated single-strand DNA, increased with time (Fig. 2D). A progressive disruption of mitochondrial membrane potential was recorded in cells after ...
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... of 33°C, the rate of proliferation in folate-deficient cells was reduced by 17% starting from the third day of culture ( Fig. 2A). Concomitantly, the capacity of migration was reduced by 50% and then remained lower than controls (Fig. 2B). Following induction of differentiation, cell viability gradually decreased under control conditions (Fig. 2C), and the percentage of Apostain-positive cells, indicative of apoptosis-associated single-strand DNA, increased with time (Fig. 2D). A progressive disruption of mitochondrial membrane potential was recorded in cells after induction of differentiation (Fig. 2E). Folate deficiency significantly augmented cell apoptosis. The loss of ...
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... 2A). Concomitantly, the capacity of migration was reduced by 50% and then remained lower than controls (Fig. 2B). Following induction of differentiation, cell viability gradually decreased under control conditions (Fig. 2C), and the percentage of Apostain-positive cells, indicative of apoptosis-associated single-strand DNA, increased with time (Fig. 2D). A progressive disruption of mitochondrial membrane potential was recorded in cells after induction of differentiation (Fig. 2E). Folate deficiency significantly augmented cell apoptosis. The loss of mitochondrial membrane potential was higher in folate-deficient progenitors at 13 and 24 h of differ- entiation, when a significant ...
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... of differentiation, cell viability gradually decreased under control conditions (Fig. 2C), and the percentage of Apostain-positive cells, indicative of apoptosis-associated single-strand DNA, increased with time (Fig. 2D). A progressive disruption of mitochondrial membrane potential was recorded in cells after induction of differentiation (Fig. 2E). Folate deficiency significantly augmented cell apoptosis. The loss of mitochondrial membrane potential was higher in folate-deficient progenitors at 13 and 24 h of differ- entiation, when a significant increase in the number of Apostain-positive cells was observed. Also, the expres- sion of active caspase-9 and caspase-3 was highly ...
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... augmented cell apoptosis. The loss of mitochondrial membrane potential was higher in folate-deficient progenitors at 13 and 24 h of differ- entiation, when a significant increase in the number of Apostain-positive cells was observed. Also, the expres- sion of active caspase-9 and caspase-3 was highly stimu- lated in folate-deficient cells (Fig. ...
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... expression was high when differentiation was induced and then decreased 13 h later (Fig. 2F). PP2Ac was dramatically repressed in deficient cells. Differentia- tion of progenitors in control conditions was associated with a steady expression of cyclin E and a concomitant decreased expression of cdk2 in neurons at 13 h of differentiation. Folate deficiency enhanced cyclin E ex- pression in the first hours of differentiation ...
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... shown by the expression of VGluT2, but the presence of VGluT2 in folate-deficient cells was dramat- ically reduced in neurites (see Fig. 7 for illustration). Whereas NeuroD expression was more elevated in deficient cells at 13 h postdifferentiation, its localiza- tion was strikingly restricted to the perinuclear area (Figs. 3B, C and Supplemental Fig. ...
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... of microtubule proteins -tubulin, -tubulin, and particularly acetylated -tubulin, which are nor- mally ideally suited as tracks to deliver vesicles and organelles to distal cellular regions, as well as amounts of microtubule-associated protein 2 (Map2), were sig- nificantly reduced in vitamin B 9 -deficient cells at 13 h ( Fig. 3D and Supplemental Fig. S2). Interestingly, fo- late deficiency was associated with reduced levels of the mature components Map2A/B, along with higher levels of the immature isoform Map2C. Immunohistochemi- cal analyses showed a disorganization of the cytoskele- ton in vitamin B 9 -deficient cells, with abnormal filopo- dias, a lack of cell polarity that ...
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... 3 independent experiments, with each assay comprising a minimum of 10 visual fields at 60 view. Data are reported as means sd. *P 0.05, ** P 0.01 vs. control. B) Western blot analysis of NeuroD in control and folate-deficient cells at 6 and 13 h after induction of differentiation. Corresponding densitometric analyses are provided in Supplemental Fig. S2. C) Immunostaining of NeuroD at 13 h after induction of differentiation. Cell nuclei were counterstained by DAPI. D) Left panel: expression of proteins assessed by Western blot in control (C) and folate-deficient (D) cells at 6 and 13 h after induction of differentiation. Right panel: effect of treatment by 5-aza (2 M) or SAHA (2.5 M) ...
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... Cell nuclei were counterstained by DAPI. D) Left panel: expression of proteins assessed by Western blot in control (C) and folate-deficient (D) cells at 6 and 13 h after induction of differentiation. Right panel: effect of treatment by 5-aza (2 M) or SAHA (2.5 M) at 13 h. Corresponding densitometric analyses are provided in Supplemental Fig. S2. E-G) Immunohistological analyses of proteins related to microtubules: -tubulin (E), Map2 and -tubulin (F), and acetylated -tubulin (G). Note the lack of polarization in vitamin B 9 -deficient cells (bottom panels). itor of DNA methyltransferase (5-aza) or by the HDAC inhibitor (SAHA) had no effect on the expression of -tubulin, SAHA ...
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... (F), and acetylated -tubulin (G). Note the lack of polarization in vitamin B 9 -deficient cells (bottom panels). itor of DNA methyltransferase (5-aza) or by the HDAC inhibitor (SAHA) had no effect on the expression of -tubulin, SAHA significantly increased -tubulin total levels and particularly acetylated -tubulin levels in deficient cells (Fig. 3D and Supplemental Fig. S2). SAHA had little effect on Map2, while the treatment by 5-aza raised the levels of Map2C both in control and folate-deficient ...
Citations
... Subsequent studies showed that N-homocysteinylation of other proteins conferred on them immunogenic [57,58], atherogenic [59,60], thrombogenic [8,61,62], amyloidogenic [56], neuropathic [63][64][65][66], and oncogenic [23,67] properties [9,22,30,31]. ...
... Additional evidence supporting the mechanism of N-Hcy-protein biogenesis comes from the identification by mass spectrometry of specific N-Hcy-lysine (KHcy) residues in proteins: K525Hcy, K212Hcy, and K137Hcy in human and mouse serum albumin [53][54][55]61]; αK562Hcy, βK344Hcy, and γK385Hcy in human fibrinogen [61,70]; K160Hcy in mouse collagen [71]; five KHcy residues (K14Hcy, K18Hcy, K23Hcy, K27Hcy, and K56Hcy) in histone H3 from HTL-treated HEK293 T cells [72]; five KHcy residues (K32Hcy, K121Hcy, K338Hcy, K1173, and K1812) in ATR from HCT116 cells [67], K1218Hcy in dynein from rat brain [63], 304 KHcy residues in proteins from HTL-treated HeLa cells [73]; 2,525 KHcy residues in 870 different proteins from NE4C cell [66]; H3K79Hcy and other histone KHcy residues in human fetal NTD brain [74]; K411Hcy in MAP1 from rat brain [75]; K80Hcy in α-synuclein from mouse brain [64]; K182Hcy in DJ-1 from HEK293 cells [65]. ...
Elevated levels of homocysteine (Hcy) and related metabolites are associated with Alzheimer’s disease (AD). Severe hyperhomocysteinemia causes neurological deficits and worsens behavioral and biochemical traits associated with AD. Although Hcy is precluded from entering the Genetic Code by proofreading mechanisms of aminoacyl-tRNA synthetases, and thus is a non-protein amino acid, it can be attached to proteins via an N-homocysteinylation reaction mediated by Hcy-thiolactone. Because N-homocysteinylation is detrimental to protein’s function and biological integrity, Hcy-thiolactone detoxifying enzymes – PON1, BLMH, BPHL – have evolved. This review provides an account of the biological function of these enzymes and of consequences of their impairments leading to phenotypes characteristic of AD.
... For instance, studies found an association between maternal iron deficiency and the risk of autism spectrum disorders among offspring due to epigenetic modulation (Insel et al., 2008;. The effects of folic acid on epigenetics through the methionine pathway to generate methyl donors for DNA and histone methylation might support fetal neural tube development (Akchiche et al., 2012;Berry et al., 1999;Guéant et al., 2013; "Use of Folic Acid for Prevention of Spina Bifida and Other Neural Tube Defects-1983Defects- -1991Defects- ," 1991. N-3 polyunsaturated fatty acids (PUFAs) are also known to control DNA methylation state globally and via gene-specific methylation of promoter sequences during development (Heberden and Maximin, 2019). ...
Abstract: Changes in gene expression are involved in many brain functions. Epigenetic processes modulate gene expression by histone modification and DNA methylation or RNA-mediated processes, which is important for brain function. Consequently, epigenetic changes are also a part of brain diseases such as mental illness and addiction. Understanding the role of different factors on the brain epigenome may help us understand the function of the brain. This review discussed the effects of caffeine, lipids, addictive substances, physical activity, and pollutants on the epigenetic changes in the brain and their modulatory effects on brain function.
... These neurological defects include brain atrophy, demyelinated area, and EEG abnormality [4,15]. However, studies on rats showed that methyl donor deficiency that is characterized by a drop in SAM/SAH ratio is often linked to neuronal cell death, pro-apoptotic state, metabolic alteration, development and cell differentiation impairment, and synaptic alterations [29][30][31] which could affect visual cortex processing thus participating to the decrease visual acuity as reported in animals' models with altered visual cortex [32][33][34]. This hypothesis will be investigated in a future study focusing on brain defects related to visual pathway through the deep examination of the epigenetic, metabolic, cellular, and molecular changes related to the visual cortex, providing a better knowledge of the multiple causes leading to ocular symptoms in cblG pathology. ...
Background
MTR gene encodes the cytoplasmic enzyme methionine synthase, which plays a pivotal role in the methionine cycle of one-carbon metabolism. This cycle holds a significant importance in generating S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the respective universal methyl donor and end-product of epigenetic transmethylation reactions. cblG type of inherited disorders of vitamin B12 metabolism due to mutations in MTR gene exhibits a wide spectrum of symptoms, including a retinopathy unresponsive to conventional therapies.
Methods
To unveil the underlying epigenetic pathological mechanisms, we conducted a comprehensive study of epigenomic-wide alterations of DNA methylation by NGS of bisulfited retinal DNA in an original murine model with conditional Mtr deletion in retinal tissue. Our focus was on postnatal day 21, a critical developmental juncture for ocular structure refinement and functional maturation.
Results
We observed delayed eye opening and impaired visual acuity and alterations in the one-carbon metabolomic profile, with a notable dramatic decline in SAM/SAH ratio predicted to impair DNA methylation. This metabolic disruption led to epigenome-wide changes in genes involved in eye development, synaptic plasticity, and retinoid metabolism, including promoter hypermethylation of Rarα, a regulator of Lrat expression. Consistently, we observed a decline in cone photoreceptor cells and reduced expression of Lrat, Rpe65, and Rdh5, three pivotal genes of eye retinoid metabolism.
Conclusion
We introduced an original in vivo model for studying cblG retinopathy, which highlighted the pivotal role of altered DNA methylation in eye development, cone differentiation, and retinoid metabolism. This model can be used for preclinical studies of novel therapeutic targets.
... Moreover, MMP-9 modifies both NMDA and AMPA receptors increasing the efficiency of glutamatergic transmission, contributing to the formation of hyperexcitable neuronal circuits [94]. Disruption of homocysteine remethylation and its subsequent accumulation has been reported to sensitize hippocampal neurons to excitotoxicity and oxidative stress and promote mitochondrial apoptosis [54,95]. ...
Aims
Neonatal seizures are severe pathologies which may result in long-term neurological consequences. High plasma concentrations of homocysteine – hyperhomocysteinemia (hHCy) - are associated with epilepsy. In the present study, we evaluated susceptibility to seizure of neonatal rats with prenatal hHCy.
Main methods
Prenatal hHCy was induced by feeding females with a high-methionine diet. Experiments were performed on pups during the first three postnatal weeks. Flurothyl-induced epileptic behavior was assessed according to Racine's scale. Epileptiform activity in the hippocampus was recorded using electrophysiological methods. The balance of excitation/inhibition, functional GABAergic inhibition and GABA reversal potential in hippocampal neurons were analyzed.
Key findings
Rats with hHCy developed more severe stages of behavioral patterns during flurothyl-induced epilepsy with shorter latency. Electrophysiological recordings demonstrated higher background neuronal activity in rats with hHCy. Seizure-like events triggered by flurothyl (in vivo) or 4-aminopyridine (in vitro) showed shorter latency, higher power and amplitude. An increased glutamate/GABA synaptic ratio was shown in the pyramidal neurons of rats with hHCy and more slices demonstrated excitation by isoguvacine, a selective GABA(A) receptor agonist, during the first and second postnatal weeks. The GABA driving force and the reversal potential of GABA(A) currents were more positive during the second postnatal week for hHCy rats.
Significance
The higher susceptibility to seizures in rats with prenatal hHCy due to a shift in the balance of excitation/inhibition toward excitation may underlie the clinical evidence about the association of hHCy with an increased risk of epilepsy.
Full text: https://www.sciencedirect.com/science/article/pii/S002432052300588X
... Apoptosis is an evolutionarily regulated, conserved programmed cell death that plays a critical role in normal physiological processes such as brain development and tissue homeostasis in animals, but the excessive apoptosis of NSCs has a negative impact on neurodevelopment and global brain growth [14]. Thus, regulating the proliferation and apoptosis of NSCs is crucial for CNS development [15]. In the developing CNS, the proliferation and apoptosis of NSCs are primarily influenced by epigenetic or environmental exposures (i.e., malnutrition) [16]. ...
The effect of maternal folate status on the fetal central nervous system (CNS) is well recognized, while evidence is emerging that such an association also exists between fathers and offspring. The biological functions of telomeres and telomerase are also related to neural cell proliferation and apoptosis. The study aimed to investigate the effect of parental folate deficiency on the proliferation and apoptosis of neural stem cells (NSCs) in neonatal offspring and the role of telomeres in this effect. In this study, rats were divided into four groups: maternal folate-deficient and paternal folate-deficient diet (D-D) group; maternal folate-deficient and paternal folate-normal diet (D-N) group; maternal folate-normal and paternal folate-deficient diet (N-D) group; and the maternal folate-normal and paternal folate-normal diet (N-N) group. The offspring were sacrificed at postnatal day 0 (PND0), and NSCs were cultured from the hippocampus and striatum tissues of offspring for future assay. The results revealed that parental folate deficiency decreased folate levels, increased homocysteine (Hcy) levels of the offspring’s brain tissue, inhibited proliferation, increased apoptosis, shortened telomere length, and aggravated telomere attrition of offspring NSCs in vivo and in vitro. In vitro experiments further showed that offspring NSCs telomerase activity was inhibited due to parental folate deficiency. In conclusion, parental folate deficiency inhibited the proliferation and increased apoptosis of offspring NSCs, maternal folate deficiency had more adverse effects than paternal, and the mechanisms may involve the telomere attrition of NSCs.
... One of the Hcy effects on the mechanisms of neuronal plasticity is modification of neuronal proteins. In cultured hippocampal neuronal cells, folate deficiency, which leads to the increase in the Hcy levels, upregulated the processes of homocysteinylation and aggregation of the motor proteins dynein and kinesin required for the synapse formation and development of neurons [173]. Multiple studies have reported that Hcy induces tau protein hyperphosphorylation and β-amyloid aggregation in hippocampus, which are the cause of cognitive impairments and NDDs associated with a decrease in synaptic plasticity [166][167][168][169]. ...
According to modern view, susceptibility to diseases, specifically to cognitive and neuropsychiatric disorders, can form during embryonic development. Adverse factors affecting mother during the pregnancy increase the risk of developing pathologies. Despite the association between elevated maternal blood homocysteine (Hcy) and fetal brain impairments, as well as cognitive deficits in the offspring, the role of brain plasticity in the development of these pathologies remains poorly studied. Here, we review the data on the negative impact of hyperhomocysteinemia (HHcy) on the neural plasticity, in particular, its possible influence on the offspring brain plasticity through epigenetic mechanisms, such as changes in intracellular methylation potential, activity of DNA methyltransferases, DNA methylation, histone modifications, and microRNA expression in brain cells. Since placenta plays a key role in the transport of nutrients and transmission of signals from mother to fetus, its dysfunction due to aberrant epigenetic regulation can affect the development of fetal CNS. The review also presents the data on the impact of maternal HHcy on the epigenetic regulation in the placenta. The data presented in the review are not only interesting from purely scientific point of view, but can help in understanding the role of HHcy and epigenetic mechanisms in the pathogenesis of diseases, such as pregnancy pathologies resulting in the delayed development of fetal brain, cognitive impairments in the offspring during childhood, and neuropsychiatric and neurodegenerative disorders later in life, as well as in the search for approaches for their prevention using neuroprotectors.
... As a result, women worldwide are recommended to take 400 μg FA/day from preconception until the end of the first trimester to prevent NTD-affected pregnancies. While the first trimester is a significant time for neural tube closure and the formation of brain vesicles, in second and third trimester there occurs massive expansion of the brain accompanied by synaptogenesis and cortex maturation: thus continued maternal supplementation could have benefits beyond the prevention of NTDs [3][4][5][6]. These developmental and histological changes are accompanied by significant changes to the epigenome, in particular DNA methylation, and FA is a major component of the methyl donor cycle (reviewed in [5]). ...
Background
We previously showed that continued folic acid (FA) supplementation beyond the first trimester of pregnancy appears to have beneficial effects on neurocognitive performance in children followed for up to 11 years, but the biological mechanism for this effect has remained unclear. Using samples from our randomized controlled trial of folic acid supplementation in second and third trimester (FASSTT), where significant improvements in cognitive and psychosocial performance were demonstrated in children from mothers supplemented in pregnancy with 400 µg/day FA compared with placebo, we examined methylation patterns from cord blood (CB) using the EPIC array which covers approximately 850,000 cytosine–guanine (CG) sites across the genome. Genes showing significant differences were verified using pyrosequencing and mechanistic approaches used in vitro to determine effects on transcription.
Results
FA supplementation resulted in significant differences in methylation, particularly at brain-related genes. Further analysis showed these genes split into two groups. In one group, which included the CES1 gene, methylation changes at the promoters were important for regulating transcription. We also identified a second group which had a characteristic bimodal profile, with low promoter and high gene body (GB) methylation. In the latter, loss of methylation in the GB is linked to decreases in transcription: this group included the PRKAR1B / HEATR2 genes and the dopamine receptor regulator PDE4C . Overall, methylation in CB also showed good correlation with methylation profiles seen in a published data set of late gestation foetal brain samples.
Conclusion
We show here clear alterations in DNA methylation at specific classes of neurodevelopmental genes in the same cohort of children, born to FA-supplemented mothers, who previously showed improved cognitive and psychosocial performance. Our results show measurable differences at neural genes which are important for transcriptional regulation and add to the supporting evidence for continued FA supplementation throughout later gestation. This trial was registered on 15 May 2013 at www.isrctn.com as ISRCTN19917787.
... O 5-metilenotetrahidrofolato, principal forma ativa do folato, tem um papel fundamental para a metilação da Hyc em metionina. In vitro o acúmulo de Hyc por deficiência de folato reduz a proliferação de células neuronais e induz o processo de apoptose(Akchiche et al., 2012). Além disso, metionina é necessária para a formação da SAMe e é considerada um doador comum do grupo metil em várias reações de metilação no cérebro que são importantes para a síntese de neurotransmissores como dopamina, serotonina e noradrenalina, que desempenham um papel fundamental na etiologia da depressão(Ebara, 2017;Sousa et al., 2020).Silva et al. (2019) apontam que as concentrações de folato e Hyc predizem a gravidade e a resposta ao tratamento da depressão. ...
A depressão caracteriza-se por sintomas de tristeza profunda e alteração no humor. Os níveis deficientes de folato e vitamina B12 têm sido relacionados com o desenvolvimento da depressão, pois desempenham papéis fundamentais para o bom funcionamento do cérebro. O objetivo do estudo foi investigar a associação entre a concentração sérica de Vitamina B12 e folato e os sintomas de depressão em idosos do sul do Brasil. Foram analisados os dados da segunda onda da pesquisa de base populacional e domiciliar (EpiFloripa). O total de 590 idosos (≥60 anos) participaram da coleta de sangue para análises bioquímicas. A presença de sintomas de depressão foi avaliada pela Escala Geriátrica de Depressão (GDS-15) com ponto de corte ≥ 6. As vitaminas B12 e o folato, foram mensuradas através de exames bioquímicos. Foi utilizada a Regressão Logística Binária para as análises de associação entre a variável sintomas de depressão e as vitaminas. 16,4% dos idosos apresentaram sintomas de depressão, sendo mais frequente em mulheres, pessoas com doença crônica e baixa escolaridade. A menor média da vitamina B12 sérica não explica a presença de sintomas de depressão (OR= 1,000; IC: 0,999; 1,001). A menor média de folato sérico associou-se na análise bruta à presença de sintomas de depressão (OR= 0,931; IC: 0,886; 0,978) e foi mantida após o ajuste para as variáveis de controle (OR= 0,937; IC: 0,888; 0,988). A maior média de folato sérico é um fator de proteção para a ocorrência de sintomas depressivos. Embora a vitamina B12 não tenha sido associada com sintomas de depressão, recomenda-se manutenção de médias mais elevadas em idosos.
... This causes aberrant homocystinylation of neural proteins, which hamper neuronal development. 1 Our body is not able to synthesize folate, rather one has to meet up the daily necessities of folate by foods or through chemically synthesized oxidized folate form as vitamin supplements. Therefore, taking folic acid as supplements is the only way to overcome this deficiency and related neuronal disorders. ...
Synthesized organometallic gold-based folate nanoparticles (FAuNPs) were characterized, and its defense against lipopolysaccharide (LPS)-induced brain inflammation in Zebra fish was proven. Vitamin entrapment efficiency of these particles was found to be nearly 70%. The in vitro pH-dependent drug release dialysis study of FAuNPs confirmed a slow, sustained, and gradual release of folate for a period of 24 h. Both AuNPs and FAuNPs did not cause any marked changes in food intake, body weight, color, behavioral pattern, blood parameters, and hepatotoxicity. Histology of liver showed no changes between treated and control groups of fishes. The ex vivo study showed significant uptake of FAuNPs to free folate in folate receptor negative Hek293 cells, confirming a strategy to overcome folate deficiency in the brain. Antioxidant status and activities of few crucial brain enzymes were also measured to assess the brain function and found to be returned to the basal level, following FAuNP treatment. The transcription factor NRF2-Keap 1 expression pattern was also noted, and a prominent modulation was observed in the LPS-treated and FAuNP-administered group. Decisive brain enzymes like AChE and Na+K+ATPase were decreased significantly after LPS treatment, which is restored with FAuNP treatment. Caspases increased sharply after LPS treatment and diminished following FAuNP treatment. We conclude that FAuNP due to its high physical stability and uptake could be utilized against severe brain inflammation, leading to brain injury and neurodegeneration.
... Optimal folate status is essential for normal brain development and function due to the involvement of folate derivatives in key processes, including synthesis of nucleotides and neurotransmitters, methylation reactions, and regulation of plasma homocysteine concentrations [1,2]. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate-dependent methylation reactions. ...
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.
