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Preeclampsia (PE) is hypertension with proteinuria that develops during pregnancy and affects at least 5% of pregnancies. The Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: the Folic Acid Clinical Trial (FACT) aims to recruit 3,656 high risk women to evaluate a new prevention strategy for PE: supplementation of folic acid throughout pregnancy. Pregnant women with increased risk of developing PE presenting to a trial participating center between 8(0/7) and 16(6/7) weeks of gestation are randomized in a 1 : 1 ratio to folic acid 4.0 mg or placebo after written consent is obtained. Intent-to-treat population will be analyzed. The FACT study was funded by the Canadian Institutes of Health Research in 2009, and regulatory approval from Health Canada was obtained in 2010. A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time. To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting. Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013. This trial is registered with NCT01355159.
Folic acid supplementation is recommended perinatally, but may increase unmetabolized folic acid (UMFA) in human milk; this is concerning as it is an inactive form which may be less bioavailable for the infant. "Natural" (6S)-5-methyltetrahydrofolic acid [(6S)-5-MTHF] is available as an alternative to folic acid, and may prevent the accumulation of UMFA in human milk. Pregnant women (n = 60) were enrolled at 8-21 weeks of gestation and randomized to 0.6 mg/day folic acid or (6S)-5-MTHF. At ~ 1-week postpartum, participants provided a human milk specimen. Total human milk folate (nmol/L) and concentrations of UMFA (nmol/L) were quantified via LC-MS/MS. Differences between groups were evaluated using multivariable quantile/linear regression, adjusting for dietary folate, weeks supplementing, and milk collection methods. No significant difference in total milk folate was found; however, the median milk UMFA concentration was 11 nmol/L higher in those receiving folic acid versus (6S)-5-MTHF (95% CI = 6.4-17 nmol/L), with UMFA representing 28% and 2% of total milk folate. In conclusion, the form of supplemental folate had markedly differential effects on the human milk folate profile, with folic acid increasing the mean proportion of milk UMFA by ~ 14-fold. Investigation of whether increased UMFA impacts folate-related metabolism and infant health outcomes is required.
The improved drug delivery systems (DDS) are needed for the targeted delivery of their therapeutic cargo (biologically active protein/peptide molecules, nucleic acids, vaccines, etc.) to diseased cells. Thus, we aimed to develop magnetite nanoparticles (Fe3O4), stabilized with polyethylene glycol (PEG) and decorated (surface-functionalized) with folic acid (FA) (Fe3O4@PEG@FA) to ensure targeted internalization in cells expressing the folic acid receptors (FR). The Fe3O4@PEG@FA nanoparticles were synthesized by co-precipitation in a one-pot methodology. Curcumin (Curc), a polyphenol with anti-tumoral activity, was loaded on the nanoparticles, and FA-targeted (Fe3O4@PEG@FA@Curc) and non-targeted (Fe3O4@PEG@Curc) systems were obtained. The internalization of Fe3O4@PEG@FA@Curc and Fe3O4@PEG@Curc nanoparticles was determined in two tumor cell lines, the FR-positive MCF-7 human breast carcinoma cell line and A549 human lung adenocarcinoma cell line, expressing a low level of FR. The results showed that MCF-7 cells internalize FA-functionalized nanoparticles to a greater extent than non-targeted ones and also than A549 cells. The competitive studies performed in the presence of FA in excess suggested that internalization is an FR-dependent process. The increased internalization of Fe3O4@PEG@FA@Curc nanoparticles in MCF-7 cells is correlated with increased cytotoxicity in this cell line compared to A549 cells. In conclusion, the FA-functionalized magnetic systems can ensure a better internalization of the nanoparticles and can be used to deliver various therapeutic agents, both in cancer treatment and also in the treatment of other inflammation-associated diseases such as rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, Crohn's disease or atherosclerosis.
We recently showed that folic acid (FA) could decrease the proliferation rate of colorectal cancer cells in vitro and reduce the volume of COLO-205 tumor in vivo. Since cancer cell proliferation and migration are two major events during cancer development, we further examined whether FA could also affect the migration of colorectal cancer cells. Transwell invasion assays demonstrated that FA reduced the invasion ability of colorectal cancer cell lines, COLO-205, LoVo and HT-29. Using COLO-205 as a cell model, we further delineated the molecular mechanism underlying FA-inhibited colorectal cancer cell invasion. Western blot analyses showed that FA (10 μM) activated cSrc, ERK1/2, NFκB, and p27 at serine 10 (Ser10), and up-regulated p53, p27, and KIS protein. Subcellular fractionation illustrated that FA treatment increased cytosolic translocation of p27, formation of the p27-RhoA complex, and RhoA degradation. The FA-induced migration inhibition in COLO-205 was abolished by blockade of the cSrc or ERK1/2 activity, knockdown of p27 or KIS using the siRNA technique, or over-expression of a constitutive active RhoA cDNA. Our results suggest that FA up-regulated p27 through increasing the cSrc/ERK1/2/NFκB/p53-mediated pathway. In the nucleus, FA up-regulated KIS, which in turn increased p27 phosphorylation at serine 10 (Ser10), subsequently resulting in cytosolic translocation of p27 and forming the p27-RhoA complex, thereby causing RhoA degradation, and eventually inhibited COLO-205 cell migration. Together with our previous findings suggest that FA reduced colorectal cancer development through inhibiting colorectal cancer cell proliferation and migration.
Folic acid (FA) can be protected the neural tube defects (NTDs) causing nitric oxide (NO) induction, but the alleviation mechanism of the detailed FA function against NO has not yet been clarified. This study focused on elucidation of the interaction of FA and NO. FA suppressed nitrite accumulation as the NO indicator in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, then the expression of the iNOS gene due to the LPS treatment was not inhibited by FA, suggesting that FA can modulate against NO or nitrogen radicals. NOR3 (4-Ethyl-2-hydroxyamino-5-nitro-3-hexenamide) as the NO donor was used for evaluation of the NO scavenging activity of FA. FA suppressed the nitrite accumulation in a dose-dependent manner. To confirm the reaction product of FA and NO (FA-NO), liquid chromatography-mass spectrometry (LC/MS) was used to measure a similar system containing NOR3 and FA, and then detected the mass numbers of the FA-NO as m/z 470.9 (M + H)+ and m/z 469.1 (M - H)-. In addition, the adducts of the FA-NO derived from 14NO and 15NO gave individual mass numbers of the isotopic ratio of nitrogen for the following products: FA-14NO, m/z 471.14 (M + H)+; m/z 469.17 (M - H)- and FA-15NO, m/z 472.16 (M + H)+; m/z 470.12 (M - H)-. To clarify the detailed NO scavenging action of FA, an electron spin resonance (ESR) study for radical detecting of the system containing carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) as an NO detection reagent in the presence of NOR3 and FA was performed. The carboxy-PTI (2-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl) radical produced from the reaction with NO reduced in the presence of FA showing that FA can directly scavenge NO. These results indicated that NO scavenging activity of FA reduced the accumulation of nitrite in the LPS-stimulated RAW264.7 cells. The NO modulation due to FA would be responsible for the alleviation from the failure in neural tube formation causing a high level of NO production.
The link between folate deficiency and congenital spina bifida defects was first suggested in the 1960s. Although the prevention of these defects by preconception folic acid supplementation was confirmed in a large multi-centre controlled trial in 1991, its subsequent implementation as health education advice has made very little difference. North America's policy of folic acid fortification of flour and bread has had a beneficial impact. No European country has implemented fortification due to concern over possible adverse effects on older subjects, but a recent review shows these to be largely hypothetical and far outweighed by beneficial effects. Recent research by Menezo et al. has, however, shown that folic acid is ineffective for some women with severe fertility problems including recurrent miscarriage and failed in vitro fertilisation. There is a genetically determined bottleneck (677TT) in their folate metabolism that can be successfully overridden by going straight to the next step in the metabolic pathway and taking 5-methylytetrahydrofolate, as a preconception supplement. Menezo suggests that all women with fertility problems should be tested for 677TT. If fortification of flour and bread is to be implemented in the UK, there should be monitoring for possible adverse effects including the incidence of colorectal cancers and cognitive decline. In conclusion, whilst there are concerns that fortification could have a detrimental effect on these conditions, there is sound evidence that it would have much greater beneficial effects.
Additional folic acid (FA) treatment appears to have a neutral effect on reducing vascular risk in countries that mandate FA fortification of food (e.g., USA and Canada). However, it is uncertain whether FA therapy reduces stroke risk in countries without FA food fortification. The purpose of this study was to comprehensively evaluate the efficacy of FA therapy on stroke prevention in countries without FA food fortification.
The fortification of flour with folic acid for the prevention of neural tube defects (NTD) is currently mandated in over eighty countries worldwide, hence compelling its consumption by the greater part of the world's population. Notwithstanding its beneficial impact on rates of NTD, pervasive folic acid supplementation has invariably led to additive daily intakes reaching well beyond their original target, resulting in the circulation of unmetabolized folic acid. Associated idiopathic side-effects ranging from allergies to cancer have been suggested, albeit inconclusively. Herein, we hypothesize that their inconsistent detection and elusive etiology are linked to the in vivo generation of the immunosuppressive folic acid metabolite 6-formylpterin, which interferes with the still emerging and varied functions of Major Histocompatibility Complex-related molecule 1 (MR1)-restricted T cells. Accordingly, we predict that fortification-related adverse health outcomes can be eliminated by substituting folic acid with the bioequivalent folate vitamer 5-methyltetrahydrofolate, which does not break down into 6-formylpterin.
Using highly specific antisera, the neuroanatomical distribution of folic acid (FA) and retinoic acid (RA) has been studied for the first time in the children brainstem. Neither immunoreactive structures containing RA nor immunoreactive fibers containing FA were found. FA-immunoreactive perikarya (fusiform, small/medium in size, one short dendrite) were only found in the pons in three regions: central gray, reticular formation, and locus coeruleus. The number of cell bodies decreased with age. In the first case studied (2 years), a moderate density of cell bodies was observed in the central gray and reticular formation, whereas a low density was found in the locus coeruleus. In the second case (6 years), a low density of these perikarya was observed in the central gray, reticular formation, and locus coeruleus. In the third case (7 years), a low density of FA-immunoreactive cell bodies was found in the central gray and reticular formation, whereas in the locus coeruleus no immunoreactive cell bodies were observed. The distribution of FA in the central nervous system of humans and monkeys is different and, in addition, in these species the vitamin was located in different parts of the nerve cells. The restricted distribution of FA suggests that the vitamin is involved in specific physiological mechanisms.
Human Amylin, or islet amyloid polypeptide (hIAPP), is a small hormone secreted by pancreatic β-cells that forms aggregates under insulin deficiency metabolic conditions, and it constitutes a pathological hallmark of type II diabetes mellitus. In type II diabetes patients, amylin is abnormally increased, self-assembled into amyloid aggregates, and ultimately contributes to the apoptotic death of β-cells by mechanisms that are not completely understood. We have screened a library of approved drugs in order to identify inhibitors of amylin aggregation that could be used as tools to investigate the role of amylin aggregation in type II diabetes or as therapeutics in order to reduce β-cell damage. Interestingly, three of the compounds analyzed-benzbromarone, quercetin, and folic acid-are able to slow down amylin fiber formation according to Thioflavin T binding, turbidimetry, and Transmission Electron Microscopy assays. In addition to the in vitro assays, we have tested the effect of these compounds in an amyloid toxicity cell culture model and we have found that one of them, quercetin, has the ability to partly protect cultured pancreatic insulinoma cells from the cytotoxic effect of amylin. Our data suggests that quercetin can contribute to reduce oxidative damage in pancreatic insulinoma β cells by modulating the aggregation propensity of amylin.
Therapeutic drug delivery systems using polymeric materials is an emerging field of research. However, the use of certain polymers has gained much-needed attention by the researchers due to their low toxic nature. In recent years, chitosan has gained popularity as a potential biodegradable polymer that can be used as a component in drug delivery systems. In this study, we synthesized a chitosan derivative that is composed of both folic acid and zinc and may serve as a viable component of a drug delivery system. The results of Fourier Transform Infrared Spectroscopy (FTIR), solid-state 13C Nuclear Magnetic Resonance Spectroscopy (NMR) and UV-visible Spectroscopy demonstrated a substantial difference between chitosan and ZnS/Chitosan-Folic acid derivative. The results were also confirmed using Thermogravimetric Analysis (TGA) and Scanning Electron Microscopy/Energy Dispersive X-ray Spectroscopy (SEM-EDS) techniques. The average particle size of the ZnS/Chitosan-Folic acid system was measured to be 463.67 ± 5.76 nm, showing that the product is within the nano-size range.
The results of the British Medical Research Council's randomized controlled trial proved that folic acid can prevent spina bifida and anencephaly. The trial provided critical scientific data upon which to base public health policy for preventing folic acid-preventable spina bifida and anencephaly. Within weeks of publication of the results, the Centers for Disease Control and Prevention in the US developed and issued guidelines for women who had had a pregnancy affected by spina bifida or anencephaly. A year later, the US Public Health Service issued the recommendation that all women of child-bearing age who are capable of becoming pregnant should consume 0.4 mg of folic acid per day. The Public Health Service needed a year to make inferential judgements about dose, target groups, safety, timing of ingestion, and existing and proposed vitamin and drug policies and regulations. Current policy discussions concern whether to permit manufacturers of vitamins or food products to claim that folic acid will prevent folic acid-preventable spina bifida and anencephaly and whether to allow a food staple to be fortified with folic acid.
Folic acid (vitamin B9) is an essential micronutrient for human health. It can be obtained using different biological pathways as a competitive option for chemical synthesis, but the price of its separation is the key obstacle preventing the implementation of biological methods on a broad scale. Published studies have confirmed that ionic liquids can be used to separate organic compounds. In this article, we investigated folic acid separation by analyzing 5 ionic liquids (CYPHOS IL103, CYPHOS IL104, [HMIM][PF6], [BMIM][PF6], [OMIM][PF6]) and 3 organic solvents (heptane, chloroform, and octanol) as the extraction medium. The best obtained results indicated that ionic liquids are potentially valuable for the recovery of vitamin B9 from diluted aqueous solutions as fermentation broths; the efficiency of the process reached 99.56% for 120 g/L CYPHOS IL103 dissolved in heptane and pH 4 of the aqueous folic acid solution. Artificial Neural Networks (ANNs) were combined with Grey Wolf Optimizer (GWO) for modelling the process, considering its characteristics.
The advanced biochemical characterisation of green, red lentil and wheat flours was performed by assessing their folic acid content as well as individual minerals, amino acids, fatty acids and volatile compounds. Moreover, a nutritionally improved wheat-lentil composite flour, with a content of 133.33 μg of folic acid/100 g, was proposed in order to assure the folic acid daily intake (200 μg) for an adult person. The wheat and lentil flours percentages used for the composite were calculated by using the equations for total material balance and folic acid content material balance. Bread was selected as model food for the composite flour due to its high daily intake (~ 250 g day-1) and to its great potential in biofortification. By this algorithm, two composite flours were developed, wheat-green lentil flour (22.21-77.79%) and wheat-red lentil flour (42.62-57.38%), their advanced biochemical characteristics being predicted based on the determined compositions of their constituents. The baking behaviour of the new developed wheat-lentils composite flours with optimised folic acid content was tested. In order to objectively compare the bread samples, texture profile analysis was considered the most relevant test. A good baking behaviour was observed for the wheat-red lentil bread, while for the wheat-green lentil composite flour, encouraging results were obtained.
Folic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism remains poorly explored. The aim of this study is to investigate the protective effect of LA on FA-induced renal damage. Our findings showed that LA could ameliorate renal dysfunction and histopathologic damage induced by FA overdose injection. Moreover, FA injection induced severe inflammation, indicated by increased release of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1β, as well as infiltration of macrophage, which can be alleviated by LA supplementation. In addition, LA not only reduced the cellular iron overload by upregulating the expressions of Ferritin and ferroportin (FPN), but also mitigated reactive oxygen species (ROS) accumulation and lipid peroxidation by increasing the levels of antioxidant glutathione (GSH) and glutathione peroxidase-4 (GPX4). More importantly, we found that LA supplementation could reduce the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive tubular cells caused by FA, indicating that the tubular cell death mediated by ferroptosis may be inhibited. Further study demonstrated that LA supplementation could reverse the decreased expression of cystine/glutamate antiporter xCT (SLC7A11), which mediated GSH synthesis. What is more, mechanistic study indicated that p53 activation was involved in the inhibitory effect of SLC7A11 induced by FA administration, which could be suppressed by LA supplementation. Taken together, our findings indicated that LA played the protective effect on FA-induced renal damage mainly by inhibiting ferroptosis.
The results from epidemiologic studies linking blood folate concentrations, folic acid supplementation, or dietary folate to the risk of preterm birth are inconsistent. In this study, we aimed to summarize the available evidence on these associations. A systematic search of the PubMed/MEDLINE, Google Scholar, Web of Science, and Cochrane Library databases up to October 20, 2018 was performed and reference lists of retrieved articles were screened. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the highest vs. the lowest levels of folate concentrations, folic acid supplementation, and dietary folate were calculated using random-effects models. Subgroup analyses and univariate meta-regression were performed to explore the sources of heterogeneity. Ten studies (six prospective cohort studies and four case-control studies) were included on folate concentrations, 13 cohort studies were included about folic acid supplementation, and 4 cohort studies were included regarding dietary folate intake. Higher maternal folate levels were associated with a 28% reduction in the risk of preterm birth (OR 0.72, 95% CI 0.56-0.93). Higher folic acid supplementation was associated with 10% lower risk of preterm birth (OR 0.90, 95% CI 0.85-0.95). In addition, a significant negative association was observed between dietary folate intake and the risk of preterm birth (OR 0.68, 95% CI 0.55-0.84), but no significant relation was seen between dietary folate and the risk of spontaneous preterm birth (OR 0.89, 95% CI 0.57-1.41). In the subgroup analysis, higher maternal folate levels in the third trimester were associated with a lower risk of preterm birth (OR 0.58, 95% CI 0.36-0.94). To initiate taking folic acid supplementation early before conception was adversely associated with preterm birth risk (OR 0.89, 95% CI 0.83-0.95). In conclusion, higher maternal folate levels and folic acid supplementation were significantly associated with a lower risk of preterm birth. The limited data currently available suggest that dietary folate is associated with a significantly decreased risk of preterm birth.
Cationic polymers have been accepted as effective nonviral vectors for gene delivery with low immunogenicity unlike viral vectors. However, the lack of organ or cell specificity sometimes hampers their application and the modification of polymeric vectors has also shown successful improvements in achieving cell-specific targeting delivery and in promoting intracellular gene transfer efficiency.
Hetero-nanoparticles self-assembled from a conjugate bearing folic acid as the targeting agent, and another bearing paclitaxel as the active agent are reported. Hetero-nanoparticles containing varying percentages of folic acid conjugates are characterised, and their biological activity is determined.
Folate has received international attention regarding its role in the risk-reduction of birth defects, specifically neural tube defects (NTDs). In 1998, health officials in Canada, like the United States, mandated the addition of folic acid to white flour and select grain products to increase the folate intake of reproductive-aged women. Subsequent to this initiative there has been an increase in blood folate concentrations in Canada and a 50% reduction in NTDs. Many countries, including Korea, have not mandated folic acid fortification of their food supply. Reasons vary but often include concern over the masking of vitamin B(12) deficiency, a belief that folate intakes among womenare adequate, low priority relative to other domestic issues, and the philosophy that individuals have the right not to consume supplemental folic acid if they so choose. Prior to folic acid fortification of the food supply in Canada, the folate intakes of women were low, and their blood folate concentrations while not sufficiently low to produce overt signs of folate deficiency (eg. anemia) were inconsistent with a level known to reduce the risk of an NTD-affected pregnancy. The purpose of this article is to describe the role of folate during the periconceptional period, pregnancy, and during lactation. The rationale for, and history of recommending folic acid-containing supplements during the periconceptional period and pregnancy is described as is folic acid fortification of the food supply. The impact of folic acid fortification in Canada is discussed, and unresolved issues associated with this policy described. While the incidence of NTDs in Canada pre-folic acid fortification were seemingly higherthan that of Korea today, blood folate levels of Korean women are strikingly similar. We will briefly explore these parallels in an attempt to understand whether folic acid fortification of the food supply in Korea might be worth consideration.
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