Implementing Hormetic Effects in the Risk Assessment Process: Differentiating Beneficial and Adverse Hormetic Effects in the RfD Derivation Process

Hormetic effects have been purported to be both beneficial and adverse. The decision of whether an effect is adverse or beneficial can have important implications for public health and risk assessment. A functional approach is proposed for determining the types of responses available for the incorporation of hormesis in the RfD process. These response categories include: (1) beneficial; (2) adverse; and (3) either beneficial or adverse depending on specific circumstances. Examples of endpoints in each category are presented and discussed. Other issues affecting the RfD process include: (1) the integration of multiple hormetic responses; (2) the importance of endpoint selection in determining the type of hormetic response; and (3) the assumption of hormesis when responses are unobservable due to low background response in controls.     

Direct Modification of the Proinflammatory Cytokine Macrophage Migration Inhibitory Factor by Dietary Isothiocyanates

Isothiocyanates are a class of phytochemicals with widely reported anti-cancer and anti-inflammatory activity. However, knowledge of their activity at a molecular level is limited. The objective of this study was to identify biological targets of phenethyl isothiocyanate (PEITC) using an affinity purification approach. An analogue of PEITC was synthesized to enable conjugation to a solid-phase resin. The pleiotropic cytokine macrophage migration inhibitory factor (MIF) was the major protein captured from cell lysates. Site-directed mutagenesis and mass spectrometry showed that PEITC covalently modified the N-terminal proline residue of MIF. This resulted in complete loss of catalytic tautomerase activity and disruption of protein conformation, as determined by impaired recognition by a monoclonal antibody directed to the region that receptors and interacting proteins bind to MIF. The conformational change was supported by in silico modeling. Monoclonal antibody binding to plasma MIF was disrupted in humans consuming watercress, a major dietary source of PEITC. The isothiocyanates have significant potential for development as MIF inhibitors, and this activity may contribute to the biological properties of these phytochemicals.     

The Benefits and Risks of n-3 Polyunsaturated Fatty Acids

There is a growing number of animal models and clinical trials of n-3 polyunsaturated fatty acid (PUFAs) supplementation in disease. Epidemiologic and biochemical studies have suggested beneficial effects of n-3 PUFAs. But also, the use of n-3 PUFAs has some potential toxicological risks that can be circumvented by careless processing, storing, and preserving the PUFAs. The use of n-3 PUFAs is safe if appropriate preparations and dosages are selected. Much research is needed to clarify their use under different disease conditions. The newly established clinical and nutritional facts on n-3 PUFAs will induce industry to develop food products based on this knowledge.     

Chemopreventive Effects of Minor Dietary Constituents in Common Foods on Human Cancer Cells

Epidemiological evidence has sugged that vegetables and fruits may have a role in cancer prevention. The aim of the present study was to examine the anti-proliferative activity of ten related pure compounds from common vegetables and fruits. Studies were conducted on a series of carcinoma cells derived from eight human organs. The results show that linalool possessed the strongest activity against nine carcinoma cells, and that baicalein and luteolin also exhibited a broad spectrum of anti-proliferative activities. Among them, linalool showed the strongest activity against carcinoma of the cervix (IC₅₀: 0.37 μg/ml), stomach (IC₅₀: 14.1 μg/ml), skin (IC₅₀: 14.9 μg/ml), lung (IC₅₀: 21.5 μg/ml) and bone (IC₅₀: 21.7 μg/ml). As for the flavonoids, luteolin exhibited the strongest activity against carcinoma of the stomach (IC₅₀: 7.1 μg/ml), cervix (IC₅₀: 7.7 μg/ml), lung (IC₅₀: 11.7 μg/ml) and bladder (IC₅₀: 19.5 μg/ml), whereas baicalein possessed the strongest anti-proliferative activity against carcinoma of the cervix (IC₅₀: 9.8 μg/ml), stomach (IC₅₀: 16.1 μg/ml) and skin (IC₅₀: 19.5 μg/ml). The present study indicates that linalool possessed the strongest activity against a broad spectrum of carcinoma cells, especially cervical carcinoma cells, suggesting that linalool and flavonoids are partially responsible for the cancer prevention of common vegetables and fruits.     

Hormetic/Cytotoxic Effects of Nigella sativa Seed Alcoholic and Aqueous Extracts on MCF-7 Breast Cancer Cells Alone or in Combination with Doxorubicin

In this study, we investigate the possible cytotoxic effects of different Nigella sativa seed extracts on human MCF-7 breast cancer cells and screening the effects of a wide range of extracts concentrations and their application as an adjuvant therapy to doxorubicin. The results obtained showed that the cytotoxic solvent dimethyl sulfoxide can be used for permeation assay in concentration range 697.5–0.341 mmol/ml without affecting the viability of MCF-7 cells. N. sativa lipid extract is cytotoxic to MCF-7 cells with LC₅₀ of 2.72 ± 0.232 mg/ml, while its aqueous extract cytotoxicity exhibited when the applied concentration is high as ≈ 50 mg/ml. The results of this study reveal for the first time that low concentrations of aqueous extract of the seed has a hormetic rather than cytotoxic effect. It is also possible to use cell culture medium or bovine serum to dilute the oil extract for the permeation assay. In conclusion, N. sativa aqueous extract should not be used as antitumor compound by its own. The oil is a promising antitumor compound and its cytotoxicity was greatly enhanced with its nanoemulsion formulation. Antitumor activity of doxorubicin was enhanced, as a function of time, when N. sativa extracts were involved as adjunct therapeutic compounds. Adding doxorubicin to the prepared lipid nanoemulsion has a beneficial impact to their bioactivity. These doxorubicin—N. sativa lipid nanoemulsion are promising and potential therapeutic modality.     

Clinical Experience with U500 Insulin: Risks and Benefits

ObjectiveTo describe our clinical experience with U500 insulin in insulin-resistant patients, including change in glucose control, body weight, insulin dose, and hypoglycemic episodes.MethodsIn September 2010, we undertook a retrospective chart review of patients who had U500 insulin in their medication list in the preceding 2 years who were treated in the endocrinology section at Dartmouth Hitchcock Medical Center. Glycosylated hemoglobin (A1C), body weight, and insulin dosage were documented before U500 insulin introduction, after 6 months of U500 insulin use, and at the last clinic visit when the patient was still taking U500 insulin. Hypoglycemic episodes and number of daily injections were recorded.ResultsRecords of 53 patients were analyzed, one of the largest reports of U500 insulin use published to date. The mean A1C level decreased from 10.1% before U500 insulin was initiated to 9.1% after 6 months of U500 use to 8.6% at the last follow-up visit (mean follow-up was 36.6 ± 24 months). At the last charted visit, body weight increased by a mean of 6.8 kg and insulin dosage increased by a mean of 0.44 units/kg. We observed a significant increase in the number of nonsevere hypoglycemic episodes and a decrease in the number of daily injections.ConclusionPatients with uncontrolled, severely insulin-resistant diabetes can be satisfactorily treated with U500 insulin with the potential to improve glycemic control. An increase in body weight, insulin dosage, and the number of nonsevere hypoglycemic episodes was observed. (Endocr Pract. 2012;18:56-61)     

Antifungal Activity of Isothiocyanates and Related Compounds: II. Mononuclear Aromatic Isothiocyanates

Antifungal activity on Aspergillus niger, Penicillium cyclopium, and Rhizopus oryzae, as well as on additional saprophytic and parasitic fungi, was determined in 57 substituted derivatives of phenylisothiocyanate. Most of the investigated compounds displayed rather equal activity against the three mentioned fungi, in contradistinction to the analogues of natural benzyl- and beta-phenylethylisothiocyanate with their characteristic low activity against R. oryzae. Differences occurred in the type of activity of compounds in which the -NCS group is directly bound on the aromatic moiety, as compared with those compounds in which this group is bound to the aliphatic radical or to the aromatic moiety indirectly by means of the methyl group or by a longer aliphatic chain. The results obtained confirm the negative influence of ionized substituents on the aromatic moiety, i.e., of -COOH, -CH(2)- COOH, and -SO(3)H groups, as well as of substituents which cause an extreme increase in reactivity of the -NCS group resulting in a high instability of the entire isothiocyanate molecule.     

The Effects and Mechanisms of Flavonoids on Cancer Prevention and Therapy: Focus on Gut Microbiota

Flavonoids are a group of polyphenolic compounds which are ubiquitously found in plants and are consumed as part of the human diet in substantial amounts. The verification of flavonoids'' cancer chemopreventive benefits has led to a significant interest in this field. Gut microbiota includes a diverse community of microorganisms and has a close relationship with cancer development. Increasing evidence has indicated that flavonoids exert anticarcinogenic effects by reshaping gut microbiota. Gut microbiota can convert flavonoids into bioactive metabolites that possess anticancer activity. Here, we present a brief introduction to gut microbiota and provide an overview of the interplay between gut microbiota and cancer pathogenesis. We also highlight the crucial roles of flavonoids in preventing cancer based on their regulation of gut microbiota. This review would encourage research on the flavonoid-intestinal microbiota interactions and clinical trials to validate the chemotherapeutic potentials of targeting gut microbiota by dietary bioactive compounds.     

Spiritual Struggles and Interleukin-6: Assessing Potential Benefits and Potential Risks

The purpose of this study is to evaluate the relationship between spiritual struggles and levels of interleukin-6 (IL-6) with a subsample (N = 943) of participants who took part in a nationwide survey. This study, which was completed in 2014, was conducted in the United States. Spiritual struggles refer to difficulties that a person may encounter with his or her faith and include having a troubled relationship with God, encountering difficulties with religious others, and being unable to find a sense of ultimate meaning in life. Based on the notion that spiritual struggles may be associated with personal growth as well physical health problems, it was hypothesized that there is a nonlinear relationship between the two: levels of IL-6 will decline at relatively low levels of spiritual struggles, but levels of IL-6 will increase as spiritual struggles become more severe. The findings support this hypothesis and suggest there is a quadratic relationship between spiritual struggles and IL-6. The clinical implications of these findings are discussed.     

Antifungal Activity of Isothiocyanates and Related Compounds: I. Naturally Occurring Isothiocyanates and Their Analogues

Data are presented concerning the antifungal activity of 11 natural isothiocyanates and 27 synthetized analogues in Aspergillus niger, Penicillium cyclopium, and Rhizopus oryzae, as well as in 13 additional saprophytic and parasitic fungi. A remarkable antifungal activity was observed in some analogues of benzylisothiocyanate and β-phenylethylisothiocyanate. The latter-mentioned compounds have not been described previously. In the group of benzylisothiocyanates, a correlation, which was inversely proportional, was detected between ed₁₀₀ values for A. niger and R. oryzae and the corresponding molar solubilities of compounds in water. In contradistinction, no relationship was observed between antifungal activity and chemical reactivity of investigated derivatives.     

Anticipation of Risks and Benefits of Emerging Technologies: A Prospective Analysis Method

Methods for the identification, evaluation, and control of hazards are well recognized, whereas a method for the anticipation of hazards has eluded the field of industrial hygiene. The Emerging Technologies Team at the National Institute for Occupational Safety and Health has developed a method for anticipating not only occupational hazards but also potential benefits of emerging technologies for occupational safety and health. This method incorporates forecasting tools with a prospective assessment step into the risk assessment model, stresses research results as an iterative driver in the assessment, and depends on inherently safer design to eliminate or reduce hazards. An iterative process that involves the occupational safety and health professional as a team member in the development of emerging technologies is recommended.     

Dietary Benefits of Twilight Foraging by the Insectivorous Bat Hipposideros speoris1

Although bats are nocturnal, many species emerge from roosts to forage during twilight, despite a presumed high risk of predation at this time. Here, we describe twilight foraging by a maternity colony of Schneider's leafnosed bat (Hipposideros speoris) in the dry zone of Sri Lanka and determine the dietary benefits of such behavior. Bats usually began foraging during dusk, sometimes before sunset, and also foraged during twilight in the morning. Mean use of available twilight by four radio‐tagged bats was 75 percent. Twilight foraging made up, on average, 47 percent of the total foraging time of these bats (range = 25–96%), although twilight consisted of only 12 percent of the available time between sunset and sunrise the next morning. Eight species of potential predators (7 birds and 1 mammal) were observed within a 1 km radius of the colony, of which 5 species are predicted to regularly capture bats. Bats took a wide diversity of prey (11 insect orders, including at least 27 families, and spiders) that ranged in wing length from 2.0 to 54.0 mm. Major orders in the diet were Coleoptera, Lepidoptera, and Diptera. Prey of secondary importance included Hemiptera, Hymenoptera, Isoptera, and Neuroptera. Bats captured large numbers of insects that were only available or had marked peaks in abundance during twilight. These groups included small, swarming insects (especially flies) that have peaks in flight activity at dusk and dawn, large diurnal species (especially dragonflies) that have crepuscular activity, and winged termites that emerge in swarms at dusk. Access to these insects was a clear benefit of twilight foraging.