Vitamin D is defined as a nutrient despite its rare occurrence in food. Vitamin D status is determined mainly by solar UV light action in skin. However, the strategy to combat vitamin D deficiency ...has been to increase oral intake of vitamin D in greater amounts than could be obtained from food. Persistent large intakes of vitamin D can cause hypercalcaemic toxicity. Although the amounts recommended to prevent deficiency are far less than those causing such toxicity, the possibility of other toxic actions from increased intake of vitamin D has been ignored. Animal experiments have demonstrated that moderate amounts of oral vitamin D over time result in atherosclerosis. Differences in the fate of vitamin D could explain this angiotoxicity.
Vitamin D is defined as a micronutrient, yet very few foods contain more than a trace of vitamin D.Solar UV light induces vitamin D formation in skin, and surveys have demonstrated that vitamin D status is determined mainly by this method. The amount of vitamin D produced in skin is far greater than could be obtained from natural foods.Potential toxicity of vitamin A, a true micronutrient, is prevented by esterification or by binding to specific proteins, but no protective mechanisms prevent toxicity of oral vitamin D. By contrast, large amounts can be produced in skin without any toxicity.Animals fed vitamin D in greater amounts than required to prevent deficiency disease developed vascular pathology of atherosclerosis.The toxicity of oral vitamin D is postulated to be mediated by 25-hydroxyvitamin D delivered to cells in arterial walls in very-low-density lipoproteins.
Sustainably feeding the next generation is often described as one of the most pressing "grand challenges" facing the 21st century. Generally, scholars propose addressing this problem by increasing ...agricultural production, investing in technology to boost yields, changing diets, or reducing food waste. In this paper, we explore whether global food production is nutritionally balanced by comparing the diet that nutritionists recommend versus global agricultural production statistics. Results show that the global agricultural system currently overproduces grains, fats, and sugars while production of fruits and vegetables and protein is not sufficient to meet the nutritional needs of the current population. Correcting this imbalance could reduce the amount of arable land used by agriculture by 51 million ha globally but would increase total land used for agriculture by 407 million ha and increase greenhouse gas emissions. For a growing population, our calculations suggest that the only way to eat a nutritionally balanced diet, save land and reduce greenhouse gas emissions is to consume and produce more fruits and vegetables as well as transition to diets higher in plant-based protein. Such a move will help protect habitats and help meet the Sustainable Development Goals.
As part of a larger project to determine if there are animal-welfare-related values shared by some commercial food–animal producers and non-producers in Canada, open-ended, semi-structured interviews ...were conducted to elicit opinions about animal welfare among 24 urban and rural residents not involved in commercial animal production. All participants possessed a self-described interest in food animal well-being and were therefore assumed to represent the views of Canadian non-producers most apt to engage in efforts to shape the animal welfare policies of governments and businesses. Participants described animal welfare in moral or ethical terms, expressed virtually unanimous support for animals having access to “natural” living conditions, and (somewhat less often) linked animal welfare to positive affective states. Maintaining reasonable health and biological functioning was seen as important but was not to take precedence over the benefits of natural living. Participants favoured small family farms and unanimously objected to confinement housing. Participants did, however, offer qualified support for intensive practices and were unanimous in not assigning blame to producers, whom they regarded sympathetically. Predictably perhaps, given our sample, most were critical of industries preoccupied with profits and of consumers who unthinkingly seek cheap food. Recommended ways of improving welfare included instilling in consumers a greater appreciation for the intrinsic value of humanely reared animals, and better education of children regarding the connection between animals and food. Disagreements arose over the welfare implications of organic production and approaches to animal advocacy. Differing demographic backgrounds, experiential involvement with food animals and knowledge of food animal production practices may have influenced the nature or specificity of welfare concerns. Many participants admitted a lack of knowledge about contemporary production practices and some expressed an interest in obtaining additional knowledge. These findings contribute to a broader effort to identify shared values among different stakeholder groups as a basis for formulating widely acceptable, farm animal care and handling polices.
Vitamin D deficiency is associated with a range of muscle disorders, including myalgia, muscle weakness, and falls. In humans, polymorphisms of the vitamin D receptor (VDR) gene are associated with ...variations in muscle strength, and in mice, genetic ablation of VDR results in muscle fiber atrophy and motor deficits. However, mechanisms by which VDR regulates muscle function and morphology remain unclear. A crucial question is whether VDR is expressed in skeletal muscle and directly alters muscle physiology. Using PCR, Western blotting, and immunohistochemistry (VDR-D6 antibody), we detected VDR in murine quadriceps muscle. Detection by Western blotting was dependent on the use of hyperosmolar lysis buffer. Levels of VDR in muscle were low compared with duodenum and dropped progressively with age. Two in vitro models, C2C12 and primary myotubes, displayed dose- and time-dependent increases in expression of both VDR and its target gene CYP24A1 after 1,25(OH)2D (1,25 dihydroxyvitamin D) treatment. Primary myotubes also expressed functional CYP27B1 as demonstrated by luciferase reporter studies, supporting an autoregulatory vitamin D-endocrine system in muscle. Myofibers isolated from mice retained tritiated 25-hydroxyvitamin D3, and this increased after 3 hours of pretreatment with 1,25(OH)2D (0.1nM). No such response was seen in myofibers from VDR knockout mice. In summary, VDR is expressed in skeletal muscle, and vitamin D regulates gene expression and modulates ligand-dependent uptake of 25-hydroxyvitamin D3 in primary myofibers.
This is the first study of historical attempts by animal welfare groups to ban the Jewish method of slaughter (shechita). It details cases from Australia, Canada, England, Scotland, and the United ...States, many for the first time, in which anti-animal cruelty groups prosecuted those engaged in shechita as part of their attempts to introduce compulsory stunning of animals before slaughter. Despite claims to the contrary, this study offers clear evidence of underlying, unrelenting antisemitic motivations in the prosecutions, and highlights the ways in which a basic idea of innate Jewish cruelty was always juxtaposed with an overtly Christian ideal of humane treatment of animals across time and borders.
Since the discovery of vitamin D, it has been accepted that its physiological supply is either from food or by endogenous synthesis in skin exposed to solar UV light. Yet vitamin D is a component of ...very few foods and its supply as a natural nutrient is unable to maintain good vitamin D status for human populations. One aspect of vitamin D physiology that has been ignored is that the mechanisms for its transport and processing from these two sources are quite different. Excess intake of vitamin D causes hypercalcaemic toxicity. However, experiments with different animal species have shown that long-term supply of oral vitamin D in apparently non-toxic amounts causes atherosclerosis in large arteries. A mechanism for this toxicity is proposed. Alternative strategies for addressing widespread vitamin D deficiency by food fortification should be considered in light of the angiotoxicity caused by oral vitamin D in animal experiments.
Via pleiotropic targeting of membrane and nuclear fatty acid receptors regulating key metabolic and inflammatory pathways in the liver, long-chain omega-3 fatty acids could offer a unique therapeutic ...approach for the treatment of metabolic-inflammatory diseases such as NASH. However, they lack efficacy for the treatment of NASH, likely due to unfavorable distribution, metabolism, and susceptibility to peroxidation.
Structurally engineered fatty acids (SEFAs), as exemplified by icosabutate, circumvent the inherent limitations of unmodified long-chain fatty acids, and demonstrate markedly enhanced pharmacodynamic effects without sacrificing safety and tolerability. We cover icosabutate's structural modifications, their rationale and the fatty acid receptor and pathway targeting profile. We also provide an overview of the clinical data to date, including interim data from a Phase 2b trial in NASH subjects.
Ideally, candidate drugs for NASH and associated liver fibrosis should be pleiotropic in mechanism and work upstream on multiple drivers of NASH, including lipotoxic lipid species, oxidative stress, and key modulators of inflammation, liver cell injury, and fibrosis. Icosabutate has demonstrated the ability to target these pathways in preclinical NASH models with interim data from the ICONA trial supporting, at least noninvasively, the clinical translation of highly promising pre-clinical data.
Although long-chain omega-3 fatty acids (LCn-3FAs) regulate inflammatory pathways of relevance to non-alcoholic steatohepatitis (NASH), their susceptibility to peroxidation may limit their ...therapeutic potential. We compared the metabolism of eicosapentaenoic acid (EPA) with an engineered EPA derivative (icosabutate) in human hepatocytes in vitro and their effects on hepatic glutathione metabolism, oxidised lipids, inflammation, and fibrosis in a dietary mouse model of NASH, and in patients prone to fatty liver disease.
Oxidation rates and cellular partitioning of EPA and icosabutate were compared in primary human hepatocytes. Comparative effects of delayed treatment with either low- (56 mg/kg) or high-dose (112 mg/kg) icosabutate were compared with EPA (91 mg/kg) or a glucagon-like peptide 1 receptor agonist in a choline-deficient (CD), L-amino acid-defined NASH mouse model. To assess the translational potential of these findings, effects on elevated liver enzymes and fibrosis-4 (FIB-4) score were assessed in overweight, hyperlipidaemic patients at an increased risk of NASH.
In contrast to EPA, icosabutate resisted oxidation and incorporation into hepatocytes. Icosabutate also reduced inflammation and fibrosis in conjunction with a reversal of CD diet-induced changes in the hepatic lipidome. EPA had minimal effect on any parameter and even worsened fibrosis in association with depletion of hepatic glutathione. In dyslipidaemic patients at risk of NASH, icosabutate rapidly normalised elevated plasma ALT, GGT and AST and reduced FIB-4 in patients with elevated ALT and/or AST.
Icosabutate does not accumulate in hepatocytes and confers beneficial effects on hepatic oxidative stress, inflammation and fibrosis in mice. In conjunction with reductions in markers of liver injury in hyperlipidaemic patients, these findings suggest that structural engineering of LCn-3FAs offers a novel approach for the treatment of NASH.
Long-chain omega-3 fatty acids are involved in multiple pathways regulating hepatic inflammation and fibrosis, but their susceptibility to peroxidation and use as an energy source may limit their clinical efficacy. Herein, we show that a structurally modified omega-3 fatty acid, icosabutate, overcame these challenges and had markedly improved antifibrotic efficacy in a mouse model of non-alcoholic steatohepatitis. A hepatoprotective effect of icosabutate was also observed in patients with elevated circulating lipids, in whom it led to rapid reductions in markers of liver injury.
Display omitted
•The susceptibility of PUFAs to peroxidation may limit their efficacy in NASH.•Icosabutate, a modified PUFA derivative, does not accumulate in liver cells.•Icosabutate, but not eicosapentaenoic acid, reduces inflammation and fibrosis in mice.•Markers of liver injury are reduced after icosabutate treatment in humans.•Activation of FFAR4 (GPR120) may underlie the beneficial effects of icosabutate.
PDF
