As many studies are exploring the association between ingestion of bioactive compounds and decreased risk of non-communicable diseases, the scientific community continues to show considerable interest in these compounds. In addition, as many non-nutrients with putative health benefits are reducing agents, hydrogen donors, singlet oxygen quenchers or metal chelators, measurement of antioxidant activity using in vitro assays has become very popular over recent decades. Measuring concentrations of total phenolics, flavonoids, and other compound (sub)classes using UV/Vis spectrophotometry offers a rapid chemical index, but chromatographic techniques are necessary to establish structure-activity. For bioactive purposes, in vivo models are required or, at the very least, methods that employ distinct mechanisms of action (i.e., single electron transfer, transition metal chelating ability, and hydrogen atom transfer). In this regard, better understanding and application of in vitro screening methods should help design of future research studies on 'bioactive compounds'.

Following an introduction of the importance of folates and the rationale for seeking to estimate fractional folate absorption from foods (especially for countries not having a mandatory folic acid fortification policy), scientific papers covering the mechanisms of folate absorption and initial biotransformation are discussed. There appears (post-1983) to be a consensus that physiological doses of folic acid undergo biotransformation in the absorptive cells of the upper small intestine to 5-methyltetrahydrofolic acid (as happens for all naturally-occurring reduced 1-carbon-substituted folates). This 'validates' short-term experimental protocols assessing 'relative' folate absorption in human subjects that use folic acid as the 'reference' dose. The underlying scientific premise on which this consensus is based is challenged on three grounds: (i) the apparent absence of a 5-methyltetrahydrofolic acid response in the human hepatic portal vein following absorption of folic acid, (ii) the low dihydrofolate reductase activity peculiar to man and (iii) the implications derived from recent stable-isotope studies of folate absorption. It is concluded that the historically accepted case for folic acid being a suitable 'reference folate' for studies of the 'relative absorption' of reduced folates in human subjects is invalid. It is hypothesised that the liver, and not the absorptive cells of the upper small intestine, is the initial site of folic acid metabolism in man and that this may have important implications for its use as a supplement or fortificant since human liver's low capacity for reduction may eventually give rise to saturation, resulting in significant (and potentially deleterious) unmetabolised folic acid entering the systemic circulation.

AIMSThe objective of this review was to collect available data on the following: (i) adverse effects observed in humans from the intake of plant food supplements or botanical preparations; (ii) the misidentification of poisonous plants; and (iii) interactions between plant food supplements/botanicals and conventional drugs or nutrients. METHODSPubMed/MEDLINE and Embase were searched from database inception to June 2014, using the terms 'adverse effect/s', 'poisoning/s', 'plant food supplement/s', 'misidentification/s' and 'interaction/s' in combination with the relevant plant name. All papers were critically evaluated according to the World Health Organization Guidelines for causality assessment. RESULTSData were obtained for 66 plants that are common ingredients of plant food supplements; of the 492 papers selected, 402 (81.7%) dealt with adverse effects directly associated with the botanical and 89 (18.1%) concerned interactions with conventional drugs. Only one case was associated with misidentification. Adverse effects were reported for 39 of the 66 botanical substances searched. Of the total references, 86.6% were associated with 14 plants, including Glycine max/soybean (19.3%), Glycyrrhiza glabra/liquorice (12.2%), Camellia sinensis/green tea ( 8.7%) and Ginkgo biloba/gingko (8.5%). CONCLUSIONSConsidering the length of time examined and the number of plants included in the review, it is remarkable that: (i) the adverse effects due to botanical ingredients were relatively infrequent, if assessed for causality; and (ii) the number of severe clinical reactions was very limited, but some fatal cases have been described. Data presented in this review were assessed for quality in order to make the results maximally useful for clinicians in identifying or excluding deleterious effects of botanicals.

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Background: Current thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply.Objective: We tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa.Design: We conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope–labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein.Results: Fifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose).Conclusions: The human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid. This trial was registered at clinicaltrials.gov as NCT02135393.

Single (13)C(6)-labeled doses of pteroylmonoglutamic acid (PteGlu: 634 nmol; n = 14), (6S-)5-formyltetrahydrofolic acid (431-569 nmol; n = 16), or [(15)N(1-7)]-intrinsically labeled spinach (mainly 5-methyltetrahydrofolate) (588 nmol; n = 14) were fed to fasting adult volunteers. Plasma-labeled 5-methyltetrahydrofolic acid responses were monitored for 8 h. There was a slower rate of increase in plasma-labeled 5-methyltetrahydrofolic acid and longer time to peak (171 +/- 9 min; mean +/- SEM) following an oral dose of [(13)C(6)]PteGlu than either [(13)C(6)]5-formyltetrahydrofolic acid (54 +/- 10 min) or [(15)N(1-7)]spinach folate (60 +/- 13 min) suggesting saturated metabolic capacity for the biotransformation of PteGlu. Mathematical modeling generated a significantly higher mean "apparent absorption" for 5-formyltetrahydrofolic acid (38%) and spinach folate (44%) than for PteGlu (24%). The high "relative absorption" of reduced folates to PteGlu was unexpected given that PteGlu itself, from (14)C-tracer mass balance experiments, is almost completely absorbed. Although it is ubiquitously accepted that a physiological dose of PteGlu is reduced and methylated in the epithelial cells of the small intestine, and that essentially only 5-methyltetrahydrofolic acid is exported into the hepatic portal vein (HPV), as is the case for absorbed reduced 1-carbon-substituted folates, modeling indicated greater liver sequestration when PteGlu was used as the test dose, suggesting that PteGlu enters the HPV unaltered and that the liver is the primary site of initial metabolism. Because of the observed differential plasma response and the hypothesized difference in the site of initial metabolism, the historical use of PteGlu as a "reference folate" in studies of folate bioavailability is seriously questioned.

BackgroundDietary assessment is complex, and strategies to select the most appropriate dietary assessment tool (DAT) in epidemiological research are needed. The DIETary Assessment Tool NETwork (DIET@NET) aimed to establish expert consensus on Best Practice Guidelines (BPGs) for dietary assessment using self-report.MethodsThe BPGs were developed using the Delphi technique. Two Delphi rounds were conducted. A total of 131 experts were invited, and of these 65 accepted, with 48 completing Delphi round I and 51 completing Delphi round II. In all, a total of 57 experts from North America, Europe, Asia and Australia commented on the 47 suggested guidelines.ResultsForty-three guidelines were generated, grouped into the following four stages: Stage I. Define what is to be measured in terms of dietary intake (what? who? and when?); Stage II. Investigate different types of DATs; Stage III. Evaluate existing tools to select the most appropriate DAT by evaluating published validation studies; Stage IV. Think through the implementation of the chosen DAT and consider sources of potential biases.ConclusionsThe Delphi technique consolidated expert views on best practice in assessing dietary intake. The BPGs provide a valuable guide for health researchers to choose the most appropriate dietary assessment method for their studies. These guidelines will be accessible through the Nutritools website, www.nutritools.org.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0962-x) contains supplementary material, which is available to authorized users.

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