Serum Folate, Red Blood Cell Folate, and Zinc Serum Levels Are Related with Gestational Weight Gain and Offspring's Birth-Weight of Adolescent Mothers.

BACKGROUND: Gestational weight gain below or above the Institute of Medicine recommendations has been associated with adverse perinatal and neonatal outcomes. Very few studies have evaluated the association between serum and red blood cell folate concentrations and gestational weight gain in adolescents. Additionally, zinc deficiency during pregnancy has been associated with impaired immunity, prolonged labor, preterm and post-term birth, intrauterine growth restriction, low birth weight, and pregnancy-induced hypertension. OBJECTIVE: The purpose of our study is to evaluate the association between serum concentrations of zinc, serum folate, and red blood cell folate, with the increase in gestational weight and the weight and length of the newborn in a group of adolescent mothers from Mexico City. RESULTS: In our study, 406 adolescent-neonate dyads participated. The adolescents' median age was 15.8 years old. The predominant socioeconomic level was middle-low (57.8%), single (57%), 89.9% were engaged in home activities, and 41.3% completed secondary education. Excessive gestational weight gain was observed in 36.7% of cases, while insufficient gestational weight gain was noted in 38.4%. Small for gestational age infants were observed in 20.9% of the sample. Low serum folate (OR 2.1, 95% CI 1.3-3.3), decreased red blood cell folate (OR 1.6, 95% CI 1.0-2.6), and reduced serum zinc concentrations (OR 3.3, 95% CI 2.1-5.2) were associated with insufficient gestational weight gain. Decreased serum zinc levels (OR 1.2, 95% CI 1.2-3.4) were linked to an increased probability of delivering a baby who is small for their gestational age. CONCLUSIONS: Low serum folate, red blood cell folate, and serum zinc concentrations were associated with gestational weight gain and having a small gestational age baby. Both excessive and insufficient gestational weight gain, as well as having a small gestational age baby, are frequent among adolescent mothers.

Association of vitamin B12, folate, and homocysteine with COVID-19 severity and mortality: A systematic review and meta-analysis.

Objective: We aimed to review the available evidence on the association between vitamin B12, folate, and homocysteine levels with worse outcomes among COVID-19 patients. Methods: The search was carried out in ten databases simultaneously run on 10 May 2023, without language restrictions. We included cross-sectional, case-control, and cohort studies. The random-effects meta-analysis was performed using the Sidik-Jonkman method and corrected 95% confidence intervals using the truncated Knapp-Hartung standard errors. Standardized mean difference and 95% CI was used as the measure effect size. Results: Thirteen articles were included in this review (n = 2134). Patients with COVID-19 who did not survive had the highest serum vitamin B12 values (SMD: 1.05; 95% CI: 0.31-1.78; p = 0.01, I2 = 91.22%). In contrast, low serum folate values were associated with patients with severe COVID-19 (SMD: -0.77; 95% CI: -1.35 to -0.19; p = 0.02, I2 = 59.09%). The remaining tested differences did not yield significant results. Conclusion: Elevated serum levels of vitamin B12 were associated with higher mortality in patients with COVID-19. Severe cases of COVID-19 were associated with low serum folate levels. Future studies should incorporate a larger sample size.

Folate induces stemness and increases oxygen consumption under glucose deprivation by notch-1 pathway activation in colorectal cancer cell.

Evidence for folate's protective effects on neural tube defects led the USA and Chile to start mandatory folic acid (FA) fortification programs, decreasing up to 50%. However, ∼30% of the population consuming fortified foods reach supraphysiologic serum levels. Although controversial, several epidemiological and clinical observations suggest that folate increases cancer risk, giving concern about the risks of FA supplementation. The Cancer stem cells (CSCs) model has been used to explain survival to anticancer therapies. The Notch-1 pathway plays a role in several cancers and is associated with the stemness process. Different studies show that modulation of metabolic pathways regulates stemness capacity in cancer. Supraphysiologic concentrations of FA increase the proliferation of HT-29 cells by Notch-1 activation. However, whether folate can induce a stemness-like phenotype in cancer is not known. We hypothesized that FA protects from glucose deprivation-induced cell death through Notch-1 activation. HT-29 cells were challenged with glucose deprivation at basal (20 nM) and supraphysiological (400 nM) FA and 5-MTHF concentrations. We analyzed changes in stemness-like gene expression, cell death and different energetic metabolic functions. Supraphysiological concentrations of FA increased stemness-like genes, and improved survival and oxygen consumption, inducing AMPK phosphorylation and HSP-70 protein expression. We evaluated the Notch-1 pathway using the DAPT and siRNA as inhibitors, decreasing the stemness-like gene expression and preventing the FA protection against glucose deprivation-induced cell death. Moreover, they decreased oxygen consumption and AMPK phosphorylation. These results suggest that FA protects against glucose deprivation. These effects were associated with AMPK activation, a critical metabolic mediator in nutrient consumption and availability that activates the Notch-1 pathway.

Folate deficiency modifies the risk of CIN3+ associated with DNA methylation levels: a nested case-control study from the ASCUS-COL trial.

PURPOSE: To our knowledge, there are very few studies evaluating if the levels of folate modify the risk of cervical intraepithelial neoplasia grade 2 and higher (CIN2+ and CIN3+) associated with the levels of HPV genome methylation, two cofactors related to single carbon metabolism and independently associated with cervical cancer in previous studies. We conducted a case-control study nested in a three-arm randomized clinical pragmatic trial (ASCUS-COL trial) to evaluate the risk of CIN3+ associated with methylation levels according to serum folate concentrations. METHODS: Cases (n = 155) were women with histologically confirmed CIN2+ (113 CIN2, 38 CIN3, and 4 SCC) and controls were age and follow-up time at diagnosis-matched women with histologically confirmed ≤ CIN1 (n = 155), selected from the 1122 hrHPV + women of this trial. The concentrations of serum folate were determined by the radioimmunoassay SimulTRAC-SNB-VitaminB12/Folate-RIAKit and the methylation levels by the S5 classifier. Stepwise logistic regression models were used to estimate the association between folate or methylation levels and CIN2+ or CIN3+. The joint effect of folate levels and methylation on the risk of CIN3+ was estimated using combinations of categorical stratifications. RESULTS: Folate levels were significantly lower in women with CIN3+ than in other diagnostic groups (p = 0.019). The risk of CIN3+ was eight times higher (OR 8.9, 95% CI 3.4-24.9) in women with folate deficiency and high methylation levels than in women with normal folate and high methylation levels (OR 1.4, 95% CI 0.4-4.6). CONCLUSION: High methylation and deficient folate independently increased the risk of CIN3+ while deficient folate combined with high methylation was associated with a substantially elevated risk of CIN3+.

Invivo and invitro evaluation of antitumor effects of iron oxide and folate core shell-iron oxide nanoparticles / Avaliação in vivo e in vitro dos efeitos antitumorais de nanopartículas de óxido de ferro e óxido de ferro com núcleo de folato

Abstract Nanoparticles are considered viable options in the treatment of cancer. This study was conducted to investigate the effect of magnetite nanoparticles (MNPs) and magnetite folate core shell (MFCS) on leukemic and hepatocarcinoma cell cultures as well as their effect on the animal model of acute myelocytic leukemia (AML). Through current study nanoparticles were synthesized, characterized by various techniques, and their properties were studied to confirm their nanostructure. Invivo study, nanoparticles were evaluated to inspect their cytotoxic activity against SNU-182 (human hepatocellular carcinoma), K562 (human leukemia), and THLE2 (human normal epithelial liver) cells via MTT test. Apoptotic signaling proteins Bcl-2 and Caspase-3 expression were inspected through RT-PCR method. A cytotoxic effect of MNPs and MFCS was detected in previous cell cultures. Moreover, the apoptosis was identified through significant up-regulation of caspase-3, with Bcl-2 down-regulation. Invitro study, AML was induced in rats by N-methyl-N-nitrosourea followed by oral treatment with MNPS and MFCS. Biochemical indices such as aspartate and alanine amino transferases, and lactate dehydrogenase activities, uric acid, complete blood count, and Beta -2-microglubulin were assessed in serum. Immunophenotyping for CD34 and CD38 detection was performed. Liver, kidney, and bone marrow were microscopically examined. Bcl-2 promoter methylation, and mRNA levels were examined. Although, both MNPs and MFCS depict amelioration in biochemical parameters, MFCS alleviated them toward normal control. Anticancer activity of MNPs and MFCS was approved especially for AML. Whenever, administration of MFCS was more effective than MNPs. The present work is one of few studies used MFCS as anticancer agent.

Resumo Nanopartículas são consideradas opções viáveis ​​no tratamento do câncer. Este estudo foi conduzido para investigar o efeito de nanopartículas de magnetita (MNPs) e núcleo de folato de magnetita (MFCS) em culturas de células leucêmicas e de hepatocarcinoma, bem como seu efeito no modelo animal de leucemia mielocítica aguda (LMA). Através do atual estudo, nanopartículas foram sintetizadas, caracterizadas por várias técnicas, e suas propriedades foram estudadas para confirmar sua nanoestrutura. No estudo in vivo, as nanopartículas foram avaliadas para inspecionar sua atividade citotóxica contra células SNU-182 (carcinoma hepatocelular humano), K562 (leucemia humana) e THLE2 (fígado epitelial humano normal) por meio do teste MTT. A expressão das proteínas sinalizadoras apoptóticas Bcl-2 e Caspase-3 foram inspecionadas através do método RT-PCR. Um efeito citotóxico de MNPs e MFCS foi detectado em culturas de células anteriores. Além disso, a apoptose foi identificada por meio de regulação positiva significativa da Caspase-3, com regulação negativa de Bcl-2. No estudo in vitro, a AML foi induzida em ratos por N-metil-N-nitrosoureia seguida por tratamento oral com MNPS e MFCS. Índices bioquímicos como aspartato e alanina aminotransferases e atividades de lactato desidrogenase, ácido úrico, hemograma completo e Beta-2-microglubulina foram avaliados no soro. A imunofenotipagem para detecção de CD34 e CD38 foi realizada. Fígado, rim e medula óssea foram examinados microscopicamente. A metilação do promotor Bcl-2 e os níveis de mRNA foram examinados. Embora tanto os MNPs quanto os MFCS representem uma melhora nos parâmetros bioquímicos, o MFCS os aliviou em direção ao controle normal. A atividade anticâncer de MNPs e MFCS foi aprovada especialmente para AML. Sempre, a administração de MFCS foi mais eficaz do que MNPs. O presente trabalho é um dos poucos estudos que utilizou o MFCS como agente anticâncer.

Invivo and invitro evaluation of antitumor effects of iron oxide and folate core shell-iron oxide nanoparticles

Abstract Nanoparticles are considered viable options in the treatment of cancer. This study was conducted to investigate the effect of magnetite nanoparticles (MNPs) and magnetite folate core shell (MFCS) on leukemic and hepatocarcinoma cell cultures as well as their effect on the animal model of acute myelocytic leukemia (AML). Through current study nanoparticles were synthesized, characterized by various techniques, and their properties were studied to confirm their nanostructure. Invivo study, nanoparticles were evaluated to inspect their cytotoxic activity against SNU-182 (human hepatocellular carcinoma), K562 (human leukemia), and THLE2 (human normal epithelial liver) cells via MTT test. Apoptotic signaling proteins Bcl-2 and Caspase-3 expression were inspected through RT-PCR method. A cytotoxic effect of MNPs and MFCS was detected in previous cell cultures. Moreover, the apoptosis was identified through significant up-regulation of caspase-3, with Bcl-2 down-regulation. Invitro study, AML was induced in rats by N-methyl-N-nitrosourea followed by oral treatment with MNPS and MFCS. Biochemical indices such as aspartate and alanine amino transferases, and lactate dehydrogenase activities, uric acid, complete blood count, and Beta -2-microglubulin were assessed in serum. Immunophenotyping for CD34 and CD38 detection was performed. Liver, kidney, and bone marrow were microscopically examined. Bcl-2 promoter methylation, and mRNA levels were examined. Although, both MNPs and MFCS depict amelioration in biochemical parameters, MFCS alleviated them toward normal control. Anticancer activity of MNPs and MFCS was approved especially for AML. Whenever, administration of MFCS was more effective than MNPs. The present work is one of few studies used MFCS as anticancer agent.

Resumo Nanopartículas são consideradas opções viáveis no tratamento do câncer. Este estudo foi conduzido para investigar o efeito de nanopartículas de magnetita (MNPs) e núcleo de folato de magnetita (MFCS) em culturas de células leucêmicas e de hepatocarcinoma, bem como seu efeito no modelo animal de leucemia mielocítica aguda (LMA). Através do atual estudo, nanopartículas foram sintetizadas, caracterizadas por várias técnicas, e suas propriedades foram estudadas para confirmar sua nanoestrutura. No estudo in vivo, as nanopartículas foram avaliadas para inspecionar sua atividade citotóxica contra células SNU-182 (carcinoma hepatocelular humano), K562 (leucemia humana) e THLE2 (fígado epitelial humano normal) por meio do teste MTT. A expressão das proteínas sinalizadoras apoptóticas Bcl-2 e Caspase-3 foram inspecionadas através do método RT-PCR. Um efeito citotóxico de MNPs e MFCS foi detectado em culturas de células anteriores. Além disso, a apoptose foi identificada por meio de regulação positiva significativa da Caspase-3, com regulação negativa de Bcl-2. No estudo in vitro, a AML foi induzida em ratos por N-metil-N-nitrosoureia seguida por tratamento oral com MNPS e MFCS. Índices bioquímicos como aspartato e alanina aminotransferases e atividades de lactato desidrogenase, ácido úrico, hemograma completo e Beta-2-microglubulina foram avaliados no soro. A imunofenotipagem para detecção de CD34 e CD38 foi realizada. Fígado, rim e medula óssea foram examinados microscopicamente. A metilação do promotor Bcl-2 e os níveis de mRNA foram examinados. Embora tanto os MNPs quanto os MFCS representem uma melhora nos parâmetros bioquímicos, o MFCS os aliviou em direção ao controle normal. A atividade anticâncer de MNPs e MFCS foi aprovada especialmente para AML. Sempre, a administração de MFCS foi mais eficaz do que MNPs. O presente trabalho é um dos poucos estudos que utilizou o MFCS como agente anticâncer.

An improved folate stable isotope dilution assay of unexploited food sources from Brazil.

Brazil has a diverse plant community, including underutilized non-conventional food crops (PANCs), which have the potential to be a rich source of food and contribute to food security. For assessing the folate content in a range of Brazilian PANCs, we extended the validation of an existing stable isotope dilution assay (SIDA) for the stably 13C-labelled 10-formyl-Pte[13C5]Glu (10-CHO-Pte[13C5]Glu). The SIDA method with an enzymatic treatment, purification step, and an LC-MS/MS measurement was validated regarding linearity, precision, LoD/LoQ, and recovery for 10-CHO-PteGlu. After successful validation, the study of some underutilized Brazilian non-conventional fruits and leaves from the São Paulo State University campus revealed them as an important source of folates. It provided the first insights into the folate content of unexploited food sources from Brazil. Pequi had the highest folate content among the fruits studied, with mean values of 333 µg/100 g based on fresh weight (FW). The analysis also shows that different cultivars of fruit or fruits from different growing locations have a high variability in folate content or other nutritional factors. In most fruits, the main vitamer was 5-CH3-H4folate, but jenipapo and taioba showed the highest content of 10-CHO-PteGlu with 28.22 µg/100 g (FW) in jenipapo peel and 75.64 µg/100 g (FW) in the taioba leaves. Thus, this study also provides results on the importance of the folate vitamer 10-CHO-PteGlu contributing to the total folate content.

Vitamin B12, folate, and homocysteine in metabolic syndrome: a systematic review and meta-analysis.

Background & aims: Metabolic syndrome (MetS) is associated with life-threatening conditions. Several studies have reported an association of vitamin B12, folic acid, or homocysteine (Hcy) levels with MetS. This systematic review and meta-analysis assessed the association of vitamin B12, folic acid, and Hcy levels with MetS. Methods: PubMed, Scopus, Embase, Ovid/Medline, and Web of Science were searched up to February 13, 2023. Cross-sectional, case-control, or cohort studies were included. A random-effects model was performed using the DerSimonian and Laird method to estimate the between-study variance. Effect measures were expressed as odds ratios (OR) with their corresponding 95% confidence intervals (95% CI). Between-study heterogeneity was evaluated using Cochran's Q test and the I2 statistic. Results: Sixty-six articles (n = 87,988 patients) were included. Higher vitamin B12 levels were inversely associated with MetS (OR = 0.87; 95% CI: 0.81-0.93; p < 0.01; I2 = 90%). Higher Hcy levels were associated with MetS (OR = 1.19; 95% CI: 1.14-1.24; p < 0.01; I2 = 90%). Folate levels were not associated with MetS (OR = 0.83; 95% CI: 0.66-1.03; p = 0.09; I2 = 90%). Conclusion: Higher vitamin B12 levels were inversely associated with MetS, whereas higher Hcy levels were associated with MetS. Studies assessing the pathways underlying this association are required.

Association of C677T and A1298C polymorphisms of the MTHFR gene with maternal risk for Down syndrome: A meta-analysis of case-control studies.

BACKGROUND: Several studies around the world support the hypothesis that genetic polymorphisms involved in folate metabolism could be related to the maternal risk for Down syndrome (DS). Most of them investigated the role of MTHFR C677T and/or A1298C polymorphisms as maternal risk factors for DS, but their results are often conflicting and still inconclusive. METHODS: We conducted a systematic review and meta-analysis to clarify the association of MTHFR C677T and/or A1298C polymorphisms with the maternal risk of DS. Our search strategy selected 42 eligible case control studies for a total of 4131 case mothers and 5452 control mothers. The Newcastle-Ottawa Scale was used to assess the methodological quality of the selected studies. To assess the confidence of statistically significant associations we applied false positive report probability test, and we performed the trial sequential analysis to minimize the type I error and random error. RESULTS: We observed significant associations between the MTHFR C677T polymorphism and maternal risk for DS for each of the genetic models investigated (dominant, recessive, codominant, and allelic contrast). Subgroup analysis by region revelated significant association in the Asian population for all the genetic models investigated. Significant associations were also found for certain genetic models in North American, South American, and Middle Eastern populations, while no association was observed in Europeans. The MTHFR A1298C polymorphism did not show any association with the maternal risk of DS, either alone or in combination with the C677T one. The results of false positive report probability to verify the confidence of a significant association suggest that the association between the MTHFR C677T polymorphism and the maternal risk for DS is noteworthy, with high confidence in Asians. CONCLUSION: The results of this meta-analysis support that the MTHFR C677T polymorphism, but not the A1298C one, is associated with the maternal risk for DS. Further studies are required to better characterize the contribution of gene-gene and gene-nutrient interactions as well as those of other regional or ethnic factors that could explain the observed different effect size in different populations.

De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.

p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in ~50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. Whether other nucleotide metabolic genes and pathways are affected by p16/CDKN2A loss and if these can be specifically targeted in p16/CDKN2A-low tumors has not been previously explored. Using CRISPR KO libraries in multiple isogenic human and mouse melanoma cell lines, we determined that many nucleotide metabolism genes are negatively enriched in p16/CDKN2A knockdown cells compared to controls. Indeed, many of the genes that are required for survival in the context of low p16/CDKN2A expression based on our CRISPR screens are upregulated in p16 knockdown melanoma cells and those with endogenously low CDKN2A expression. We determined that cells with low p16/Cdkn2a expression are sensitive to multiple inhibitors of de novo purine synthesis, including anti-folates. Tumors with p16 knockdown were more sensitive to the anti-folate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2A-low tumors as loss of p16/CDKN2A may provide a therapeutic window for these agents.

Ultra-Processed Foods and Schooling Are Independently Associated with Lower Iron and Folate Consumption by Pregnant Women Followed in Primary Health Care.

Combined deficiencies of nutrients such as iron and folic acid intake during pregnancy are related to nutritional deficiencies risk, such as anemia. The objective of this study was to analyze the association between risk factors (sociodemographic, dietary and lifestyle) and the intake of iron and folate by pregnant women followed up in Primary Health Care (PHC) in the Federal District, Brazil. A cross-sectional observational study was carried out with adult pregnant women of different gestational ages. A semi-structured questionnaire was applied by researchers trained to collect sociodemographic, economic, environmental, and health data. Two nonconsecutive 24-hour recalls (24hr) were carried out to collect data about food consumption. Multivariate linear regression models were used to analyze the association between sociodemographic and dietary risk factors and the consumption of iron and folate. The mean daily energy intake was 1726 kcal (95% CI 1641-1811), with 22.4% (95% CI 20.09-24.66) derived from ultra-processed foods (UPFs). The mean iron and folate intake were 5.28 mg (95% CI 5.09-5.48) and 193.42 µg (95% CI 182.22-204.61), respectively. According to the multivariate model, the highest quintile of ultra-processed foods intake was associated with lower iron (ß = -1.15; IC 95%: -1.74; 0.55; p < 0.001) and folate intake (ß = -63.23; IC 95%: -98.32; -28.15; p < 0.001). Pregnant women with high school degree presented higher iron intake (ß = 0.74; IC 95%: 0.20; 1.28; p = 0.007) and folate intake (ß = 38.95; IC 95%: 6.96; 70.95; p = 0.017) compared to pregnant women with elementary school degree. Folate consumption was also associated with the second gestational period (ß = 39.44; IC 95%: 5.58; 73.30; p = 0.023) and pregnancy planning (ß = 26.88; IC 95%: 3.58; 50.18; p = 0.024). Further research is warranted to enhance evidence on the relationship between the role of processed foods and micronutrients intake to strengthen the nutritional quality of diet of pregnant women attended in Primary Health Care.

A quest for genetic causes underlying signaling pathways associated with neural tube defects.

Neural tube defects (NTDs) are serious congenital deformities of the nervous system that occur owing to the failure of normal neural tube closures. Genetic and non-genetic factors contribute to the etiology of neural tube defects in humans, indicating the role of gene-gene and gene-environment interaction in the occurrence and recurrence risk of neural tube defects. Several lines of genetic studies on humans and animals demonstrated the role of aberrant genes in the developmental risk of neural tube defects and also provided an understanding of the cellular and morphological programs that occur during embryonic development. Other studies observed the effects of folate and supplementation of folic acid on neural tube defects. Hence, here we review what is known to date regarding altered genes associated with specific signaling pathways resulting in NTDs, as well as highlight the role of various genetic, and non-genetic factors and their interactions that contribute to NTDs. Additionally, we also shine a light on the role of folate and cell adhesion molecules (CAMs) in neural tube defects.

Barriers and facilitators to the implementation of mandatory folate fortification as an evidence-based policy to prevent neural tube defects.

BACKGROUND: Neural tube defects continue to be one of the main congenital malformations affecting the development of the nervous system and a significant cause of disability and disease burden to individuals living with these conditions. Mandatory food fortification with folic acid is, by far, one of the most efficacious, safe, and cost-effective interventions to prevent neural tube defects. However, most countries fail to effectively fortify staple foods with folic acid, impacting public health and healthcare systems and generating dismal disparities. AIM: This article discusses the main barriers and facilitators for implementing mandatory food fortification as an evidence-based policy to prevent neural tube defects worldwide. METHODS: A comprehensive review of the scientific literature allowed the identification of the determinant factors acting as barriers or facilitators for the reach, adoption, implementation, and scaling up of mandatory food fortification with folic acid as an evidence-based policy. RESULTS: We identified eight barriers and seven facilitators as determinant factors for food fortification policies. The identified factors were classified as individual, contextual, and external, inspired by the Consolidated Framework for Implementation of Research (CFIR). We discuss mechanisms to overcome obstacles and seize the opportunities to approach this public health intervention safely and effectively. CONCLUSIONS: Several determinant factors acting as barriers or facilitators influence the implementation of mandatory food fortification as an evidence-based policy worldwide. Notoriously, policymakers in many countries may lack knowledge of the benefits of scaling up their policies to prevent folic acid-sensitive neural tube defects, improve the health status of their communities, and promote the protection of many children from these disabling but preventable conditions. Not addressing this problem negatively affects four levels: public health, society, family, and individuals. Science-driven advocacy and partnerships with essential stakeholders can help overcome the barriers and leverage the facilitators for safe and effective food fortification.

High Serum Folate Concentration, Vitamin B12 Deficiency, and Anthropometric Nutritional Status in Brazilian Children Aged 6-59 Months: Data from the Brazilian National Survey of Child Nutrition.

BACKGROUND: Vitamin B12 and folate are key nutrients that help children reach their full potential in growth and development; however, little is known about the status of these vitamins in Brazilian children. OBJECTIVES: To describe the serum concentrations of vitamin B12 and folate, to investigate the association between high folate concentration (HFC) and vitamin B12 deficiency, and to evaluate the association between vitamin B12 and stunting/underweight in Brazilian children aged 6-59 mo. METHODS: Data from 7417 children aged 6-59 mo collected during the Brazilian National Survey on Child Nutrition were used. Serum concentrations of vitamin B12 of <150 pmol/L and folate of <10 nmol/L were classified as deficient, and folate concentrations of >45.3 nmol/L were classified as HFC. Children with length/height-for-age z-score of less than -2 were considered stunted, and those with weight-for-age z-score of less than -2 were underweight. Logistic regression models were performed. RESULTS: In Brazil, 14.2% (95% CI: 12.2, 16.1) of children aged 6-59 mo had vitamin B12 deficiency, 1.1% (95% CI: 0.5, 1.6) had folate deficiency, and 36.9% (95% CI: 33.4, 40.3) had HFC. Vitamin B12 deficiency was higher in children from the northern region of Brazil (28.5%), between 6 and 24 mo (25.3%), whose mothers had lower formal education (0-7 y; 18.7%). Children with HFC had 62% lower odds (OR: 0.38; 95% CI: 0.27, 0.54) of vitamin B12 deficiency than those with normal/deficient folate. Children with vitamin B12 deficiency and normal/deficient folate had higher odds of stunting (OR: 1.58; 95% CI: 1.02, 2.43) than children without vitamin B12 deficiency and normal/deficient folate. CONCLUSIONS: Vitamin B12 deficiency is a public health problem among Brazilian children aged <2 y with vulnerable socioeconomic status. HFC was inversely associated with vitamin B12 deficiency, and lower odds of stunting were observed in children with HFC and vitamin B12 deficiency than in those with vitamin B12 deficiency and normal/deficient folate.

Pafolacianine for intraoperative molecular imaging of cancer in the lung: The ELUCIDATE trial.

OBJECTIVE: The study objective was to determine the clinical utility of pafolacianine, a folate receptor-targeted fluorescent agent, in revealing by intraoperative molecular imaging folate receptor α positive cancers in the lung and narrow surgical margins that may otherwise be undetected with conventional visualization. METHODS: In this Phase 3, 12-center trial, 112 patients with suspected or biopsy-confirmed cancer in the lung scheduled for sublobar pulmonary resection were administered intravenous pafolacianine within 24 hours before surgery. Participants were randomly assigned to surgery with or without intraoperative molecular imaging (10:1 ratio). The primary end point was the proportion of participants with a clinically significant event, reflecting a meaningful change in the surgical operation. RESULTS: No drug-related serious adverse events occurred. One or more clinically significant event occurred in 53% of evaluated participants compared with a prespecified limit of 10% (P < .0001). In 38 participants, at least 1 event was a margin 10 mm or less from the resected primary nodule (38%, 95% confidence interval, 28.5-48.3), 32 being confirmed by histopathology. In 19 subjects (19%, 95% confidence interval, 11.8-28.1), intraoperative molecular imaging located the primary nodule that the surgeon could not locate with white light and palpation. Intraoperative molecular imaging revealed 10 occult synchronous malignant lesions in 8 subjects (8%, 95% confidence interval, 3.5-15.2) undetected using white light. Most (73%) intraoperative molecular imaging-discovered synchronous malignant lesions were outside the planned resection field. A change in the overall scope of surgical procedure occurred for 29 of the subjects (22 increase, 7 decrease). CONCLUSIONS: Intraoperative molecular imaging with pafolacianine improves surgical outcomes by identifying occult tumors and close surgical margins.

Association of development quotient with nutritional status of vitamins B6, B12, and folate in 6-59-month-old children: Results from the Brazilian National Survey on Child Nutrition (ENANI-2019).

BACKGROUND: Vitamins B6, B12, and folate are essential for the formation and maintenance of the human brain, but studies evaluating these vitamins with early childhood development (ECD) in children under 5 y are limited and controversial. OBJECTIVES: To evaluate the association between vitamins B6, B12, and folate concentrations/status and ECD. METHODS: Data regarding 6520 children aged 6-59 mo from the ENANI-2019 (the Brazilian National Survey on Child Nutrition) were analyzed. ECD was assessed using the Survey of Well-being of Young Children's milestones questionnaire. Vitamin B6 concentration (nmol/L) was classified according to the tertile of the distribution and with the cutoff <20 nmol/L. Folate concentrations >45.3 nmol/L were classified as high, and vitamin B12 <150 pmol/L was deficient. The graded response model was used to estimate developmental age, and the developmental quotient (DQ) was calculated as the developmental age divided by chronological age. Multiple linear regression models were adjusted for confounders. RESULTS: The DQ mean (95% confidence interval) for Brazilian children was 0.99 (0.97-1.01). Children aged 6-23 mo [1.13 (1.10-1.16)] had a higher DQ mean than those aged 24-35 [0.99 (0.95-1.03)] and 36-59 mo [0.89 (0.86-0.92)]. Child age was inversely associated with DQ (ß = -0.007; P < 0.001). An interaction between child age and vitamin B12 deficiency in the DQ (ß = -0.005; P < 0.001) indicated that, in children aged 36-59 mo, the DQ was markedly lower in children with vitamin B12 deficiency than in those without vitamin B12 deficiency. Vitamin B6 concentrations were directly associated with the DQ (ß = 0.0004; P = 0.031) among children aged 24-59 mo in the adjusted model. No association was observed between folate status and DQ. CONCLUSIONS: In Brazil, the DQ is lower among older children and those with vitamin B12 deficiency. Vitamin B6 status was directly associated with the DQ in children aged 24-59 mo.

Folate administration ameliorates neurobehavioral effects of prenatal ethanol exposure.

Background: Prenatal ethanol exposure (PEE) induces heightened ethanol intake at adolescence in preclinical studies. Ethanol intake alters the absorption of folate, a methyl-group donor critical for numerous cellular functions. The prenatal administration of folate is, therefore, a promising approach to reduce the effects of PEE.Objectives: Experiment 1 determined if prenatal folate modulated the effects of PEE on ethanol intake, anxiety-like response, and exploratory behaviors (Experiment 1) in Wistar rats. Experiment 2 assessed, in rats not given PEE, if postnatal folate reversed effects of ethanol exposure at postnatal days 28-42. Experiment 3 assessed if folate altered blood ethanol levels (BELs).Methods: Experiment 1 involved 242 (125 male) adolescent Wistar rats derived from dams given folate (20 mg/kg, gestational days - GD- 13-20) + ethanol (2.0 g/kg, GD 17-20), ethanol, or vehicle only at pregnancy. Experiment 2 involved 29 male adolescents administered vehicle or ethanol doses co-administered or not with folate. In Experiment 3 twelve adult females were tested for BELs after folate administration. These tests were applied: intake tests, light dark box (LDB), elevated plus maze, open field and concentric square field.Results: PEE heightened ethanol intake (η2 ps = 0.06-07) and induced hyperactivity and a reduced latency to exit the white area of the LDB (η2 ps = 0.12-17). These effects were partially inhibited by folate (p > .05). Rats exposed to ethanol exposure at adolescence exhibited reduced motor activity (η2 p = .17), regardless of folate treatment. Folate did not affect BELs.Conclusion: Folate administration should be considered as a preventive or acute treatment to attenuate the neurobehavioral effects of PEE.

Folate Metabolism in Hepatocellular Carcinoma. What Do We Know So Far?

Cancer cells are characterized by accelerated proliferation and an outstanding adaptation of their metabolic pathways to meet energy demands. The folate cycle, also known as folate metabolism or one-carbon metabolism, through enzymatic interconversions, provides metabolites necessary for nucleotide synthesis, methylation, and reduction power, helping to maintain the high rate of proliferation; therefore, the study of this metabolic pathway is of great importance in the study of cancer. Moreover, multiple enzymes involved in this cycle have been implicated in different types of cancer, corroborating the cell's adaptations under this pathology. During the last decade, nonalcoholic fatty liver disease has emerged as the leading etiology related to the rise in the incidence and deaths of hepatocellular carcinoma. Specifically, cholesterol accumulation has been a determinant promoter of tumor formation, with solid evidence that an enriched-cholesterol diet plays a crucial role in accelerating the development of an aggressive subtype of hepatocellular carcinoma compared to other models. In this review, we will discuss the most recent findings to understand the contribution of folate metabolism to cancer cells and tumor microenvironment while creating a link between the dynamics given by cholesterol and methylenetetrahydrofolate dehydrogenase 1-like, a key enzyme of the cycle located in the mitochondrial compartment.

Development of Folate-Group Impedimetric Biosensor Based on Polypyrrole Nanotubes Decorated with Gold Nanoparticles.

In this study, polypyrrole nanotubes (PPy-NT) and gold nanoparticles (AuNPs) were electrochemically synthesized to form a hybrid material and used as an electroactive layer for the attachment of proteins for the construction of a high-performance biosensor. Besides the enhancement of intrinsic conductivity of the PPy-NT, the AuNPs act as an anchor group for the formation of self-assembly monolayers (SAMs) from the gold-sulfur covalent interaction between gold and Mercaptopropionic acid (MPA). This material was used to evaluate the viability and performance of the platform developed for biosensing, and three different biological approaches were tested: first, the Avidin-HRP/Biotin couple and characterizations were made by using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), wherein we detected Biotin in a linear range of 100-900 fmol L-1. The studies continued with folate group biomolecules, using the folate receptor α (FR-α) as a bioreceptor. Tests with anti-FR antibody detection were performed, and the results obtained indicate a linear range of detection from 0.001 to 6.70 pmol L-1. The same FR-α receptor was used for Folic Acid detection, and the results showed a limit of detection of 0.030 nmol L-1 and a limit of quantification of 90 pmol L-1. The results indicate that the proposed biosensor is sensitive and capable of operating in a range of clinical interests.