Anthocyanin actions at the gastrointestinal tract: Relevance to their health benefits

Anthocyanins (AC) are flavonoids abundant in the human diet, which consumption has been associated to several health benefits, including the mitigation of cardiovascular disease, type 2 diabetes, non-alcoholic fatty liver disease, and neurological disorders. It is widely recognized that the gastrointestinal (GI) tract is not only central for food digestion but actively participates in the regulation of whole body physiology. Given that AC, and their metabolites reach high concentrations in the intestinal lumen after food consumption, their biological actions at the GI tract can in part explain their proposed local and systemic health benefits. In terms of mechanisms of action, AC have been found to: i) inhibit GI luminal enzymes that participate in the absorption of lipids and carbohydrates; ii) preserve intestinal barrier integrity and prevent endotoxemia, inflammation and oxidative stress; iii) sustain goblet cell number, immunological functions, and mucus production; iv) promote a healthy microbiota; v) be metabolized by the microbiota to AC metabolites which will be absorbed and have systemic effects; and vi) modulate the metabolism of GI-generated hormones. This review will summarize and discuss the latest information on AC actions at the GI tract and their relationship to overall health benefits.Fil: Oteiza, Patricia I.. University of California at Davis; Estados UnidosFil: Cremonini, Eleonora. University of California at Davis; Estados UnidosFil: Fraga, César Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentin

Dietary Anthocyanins Mitigate High-Fat Diet-Induced Hippocampal Inflammation in Mice

BackgroundObesity and consumption of high-fat diets (HFD) are associated with intestinal permeabilization and increased paracellular transport of endotoxins, which can promote neuroinflammation. Inflammation can affect the hypothalamic pituitary adrenal (HPA) axis, which controls responses to stress and downregulates the brain-derived neurotrophic factor (BDNF), which can promote anxiety and depression, conditions frequently found in obesity. We previously showed that consumption of anthocyanins (AC) mitigate HFD-induced insulin resistance, intestinal permeability, and inflammation.ObjectivesThis study investigated if a dietary supplementation with a cyanidin- and delphinidin-rich extract (CDRE) could counteract HFD/obesity-induced hippocampal inflammation in mice.MethodsC57BL/6J male mice were fed for 14 wk on one of the following diets: 1) a control diet containing 10% total calories from fat (C), 2) a control diet supplemented with 40 mg AC/kg body weight (BW) (CAC), 3) a HFD containing 60% total calories from fat (lard) (HF), or 4) the HFD supplemented with 2, 20, or 40 mg AC/kg BW (HFA2, HFA20, and HFA40, respectively). In plasma and in the hippocampus, parameters of neuroinflammation and the underlying cause (endotoxemia) and consequences (alterations to the HPA and BDNF downregulation) were measured.ResultsConsumption of the HFD caused endotoxemia. Accordingly, hippocampal Tlr4 mRNA levels were 110% higher in the HF group, which were both prevented by CDRE supplementation. Consumption of the HFD also caused: 1) microgliosis and increased expression of genes involved in neuroinflammation, that is, Iba-1, Nox4, Tnfα, and Il-1β, 2) alterations of HPA axis regulation, that is, with low expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors; and 3) decreased Bdnf expression. Supplementation of HFD-fed mice with CDRE mitigated neuroinflammation, microgliosis, and MR and BDNF decreases.ConclusionsCDRE supplementation mitigates the negative effects associated with HFD consumption and obesity in mouse hippocampus, in part by decreasing inflammation, improving glucocorticoid metabolism, and upregulating BDNF

(-)-Epicatechin and NADPH oxidase inhibitors prevent bile acid-induced Caco-2 monolayer permeabilization through ERK1/2 modulation

Secondary bile acids promote gastrointestinal (GI) tract permeabilization both in vivo and in vitro. Consumption of high fat diet s increases bile acid levels in the GI tract which can contribute to intestinal permeabilization and consequent local and systemic inflammation. This work investigated the mechanisms involved in bile acid (deoxycholic acid (DCA))-induced intestinal epithelial cell monolayer permeabilization and the preventive capacity of (-)-epicatechin (EC). While EC prevented high fat diet-induced intestinal permeabilization in mice, it did not mitigate the associated increase in fecal/cecal total and individual bile acids. In vitro, using differentiated Caco-2 cells as a model of epithelial barrier, EC and other NADPH oxidase inhibitors (VAS-2870 and apocynin) mitigated DCA-induced Caco-2 monolayer permeabilization. While EC inhibited DCA-mediated increase in cell oxidants, it did not prevent DCA-induced mitochondrial oxidant production. Prevention of DCA-induced ERK1/2 activation with EC, VAS-2870, apocynin and the MEK inhibitor U0126, also prevented monolayer permeabilization, stressing the key involvement of ERK1/2 in this process and its redox regulation. Downstream, DCA promoted myosin light chain (MLC) phosphorylation which was related to MLC phosphatase (MLCP) inhibition by ERK1/2. DCA also decreased the levels of the tight junction proteins ZO-1 and occludin, which can be related to MMP-2 activation and consequent ZO-1 and occludin degradation. Both events were prevented by EC, NADPH oxidase and ERK1/2 inhibitors. Thus, DCA-induced Caco-2 monolayer permeabilization occurs mainly secondary to a redox-regulated ERK1/2 activation and downstream disruption of TJ structure and dynamic. EC's capacity to mitigate in vivo the gastrointestinal permeabilization caused by consumption of high-fat diets can be in part related to its capacity to inhibit bile-induced NADPH oxidase and ERK1/2 activation

Flavonoid-membrane Interactions: A Protective Role of Flavonoids at the Membrane Surface?

Flavonoids can exert beneficial health effects through multiple mechanisms. In this paper, we address the important, although not fully understood, capacity of flavonoids to interact with cell membranes. The interactions of polyphenols with bilayers include: (a) the partition of the more non-polar compounds in the hydrophobic interior of the membrane, and (b) the formation of hydrogen bonds between the polar head groups of lipids and the more hydrophilic flavonoids at the membrane interface. The consequences of these interactions are discussed. The induction of changes in membrane physical properties can affect the rates of membrane lipid and protein oxidation. The partition of certain flavonoids in the hydrophobic core can result in a chain breaking antioxidant activity. We suggest that interactions of polyphenols at the surface of bilayers through hydrogen bonding, can act to reduce the access of deleterious molecules (i.e. oxidants), thus protecting the structure and function of membranes

Anthocyanins protect the gastrointestinal tract from high fat diet-induced alterations in redox signaling, barrier integrity and dysbiosis.

The gastrointestinal (GI) tract can play a critical role in the development of pathologies associated with overeating, overweight and obesity. We previously observed that supplementation with anthocyanins (AC) (particularly glycosides of cyanidin and delphinidin) mitigated high fat diet (HFD)-induced development of obesity, dyslipidemia, insulin resistance and steatosis in C57BL/6J mice. This paper investigated whether these beneficial effects could be related to AC capacity to sustain intestinal monolayer integrity, prevent endotoxemia, and HFD-associated dysbiosis. The involvement of redox-related mechanisms were further investigated in Caco-2 cell monolayers. Consumption of a HFD for 14 weeks caused intestinal permeabilization and endotoxemia, which were associated with a decreased ileum expression of tight junction (TJ) proteins (occludin, ZO-1 and claudin-1), increased expression of NADPH oxidase (NOX1 and NOX4) and NOS2 and oxidative stress, and activation of redox sensitive signals (NF-κB and ERK1/2) that regulate TJ dynamics. AC supplementation mitigated all these events and increased GLP-2 levels, the intestinal hormone that upregulates TJ protein expression. AC also prevented, in vitro, tumor necrosis factor alpha-induced Caco-2 monolayer permeabilization, NOX1/4 upregulation, oxidative stress, and NF-κB and ERK activation. HFD-induced obesity in mice caused dysbiosis and affected the levels and secretion of MUC2, a mucin that participates in intestinal cell barrier protection and immune response. AC supplementation restored microbiota composition and MUC2 levels and distribution in HFD-fed mice. Thus, AC, particularly delphinidin and cyanidin, can preserve GI physiology in HFD-induced obesity in part through redox-regulated mechanisms. This can in part explain AC capacity to mitigate pathologies, i.e. insulin resistance and steatosis, associated with HFD-associated obesity

Early Developmental Marginal Zinc Deficiency Affects Neurogenesis Decreasing Neuronal Number and Altering Neuronal Specification in the Adult Rat Brain

During pregnancy, a decreased availability of zinc to the fetus can disrupt the development of the central nervous system leading to defects ranging from severe malformations to subtle neurological and cognitive effects. We previously found that marginal zinc deficiency down-regulates the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and affects neural progenitor cell (NPC) proliferation. This study investigated if marginal zinc deficiency during gestation in rats could disrupt fetal neurogenesis and affect the number and specification of neurons in the adult offspring brain cortex. Rats were fed a marginal zinc deficient or adequate diet throughout gestation and until postnatal day (P) 2, and subsequently the zinc adequate diet until P56. Neurogenesis was evaluated in the offspring at embryonic day (E)14, E19, P2, and P56 measuring parameters of NPC proliferation and differentiation by Western blot and/or immunofluorescence. At E14 and E19, major signals (i.e., ERK1/2, Sox2, and Pax6) that stimulate NPC proliferation and self-renewal were markedly downregulated in the marginal zinc deficient fetal brain. These alterations were associated to a lower number of Ki67 positive cells in the ventricular (VZs) and subventricular zones (SVZs). Following the progression of NPCs into intermediate progenitor cells (IPCs) and into neurons, Pax6, Tbr2 and Tbr1 were affected in the corresponding areas of the brain at E19 and P2. The above signaling alterations led to a lower density of neurons and a selective decrease of glutamatergic neurons in the young adult brain cortex exposed to maternal marginal zinc deficiency from E14 to P2. Current results supports the concept that marginal zinc deficiency during fetal development can disrupt neurogenesis and alter cortical structure potentially leading to irreversible neurobehavioral impairments later in life

Supplementation with cyanidin and delphinidin mitigates high fat diet-induced endotoxemia and associated liver inflammation in mice

Consumption of high fat diets (HFD) and the associated metabolic endotoxemia can initiate liver inflammation and lipid deposition that with time can progress to non-alcoholic fatty liver disease (NAFLD). We previously observed that 14 weeks supplementation with the anthocyanidins cyanidin and delphinidin mitigated HFD-induced metabolic endotoxemia and liver insulin resistance, steatosis, inflammation and oxidative stress. This work investigated if a 4-week supplementation of mice with a cyanidin- and delphinidin-rich extract (CDRE) could mitigate or reverse HFD (60% calories from lard fat)-induced liver steatosis and inflammation. After a first 4-weeks period on the HFD, mice showed increased endotoxemia and activation of liver proinflammatory signaling cascades. Supplementation with CDRE between weeks 4 and 8 did not mitigate liver steatosis or the altered lipid and glucose plasma levels. However, CDRE supplementation reverted HFD-induced metabolic endotoxemia, in parallel with the mitigation of the overexpression of hepatic TLR2 and TLR4, and of the activation of: (i) NF-κB, (ii) AP-1 and upstream mitogen-activated kinases p38 and ERK1/2, and (iii) HIF-1. Thus, even a short-term consumption of cyanidin and delphinidin could help mitigate the adverse consequences, i.e. metabolic endotoxemia and associated liver inflammation, triggered by the regular consumption of diets rich in fat.Fil: Cremonini, Eleonora. University of California at Davis; Estados UnidosFil: Iglesias, Dario Ezequiel. University of California at Davis; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Matsukuma, Karen E.. University of California at Davis; Estados UnidosFil: Hester, Shelly N.. No especifíca;Fil: Wood, Steven M.. No especifíca;Fil: Bartlett, Mark. No especifíca;Fil: Fraga, César Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Oteiza, Patricia I.. University of California at Davis; Estados Unido

The Role of Zinc in the Modulation of Neuronal Proliferation and Apoptosis

Although a requirement of zinc (Zn) for normal brain development is well documented, the extent to which Zn can modulate neuronal proliferation and apoptosis is not clear. Thus, we investigated the role of Zn in the regulation of these two critical events. A low Zn availability leads to decreased cell viability in human neuroblastoma IMR-32 cells and primary cultures of rat cortical neurons. This occurs in part as a consequence of decreased cell proliferation and increased apoptotic cell death. In IMR-32 cells, Zn deficiency led to the inhibition of cell proliferation through the arrest of the cell cycle at the G0/G1 phase. Zn deficiency induced apoptosis in both proliferating and quiescent neuronal cells via the intrinsic apoptotic pathway. Reductions in cellular Zn triggered a translocation of the pro-apoptotic protein Bad to the mitochondria, cytochrome c release, and caspase-3 activation. Apoptosis is the resultant of the inhibition of the prosurvival extracellular-signal-regulated kinase, the inhibition of nuclear factor-kappa B, and associated decreased expression of antiapoptotic proteins, and to a direct activation of caspase-3. A deficit of Zn during critical developmental periods can have persistent effects on brain function secondary to a deregulation of neuronal proliferation and apoptosis

A pan-European epidemiological study reveals honey bee colony survival depends on beekeeper education and disease control

Reports of honey bee population decline has spurred many national efforts to understand the extent of the problem and to identify causative or associated factors. However, our collective understanding of the factors has been hampered by a lack of joined up trans-national effort. Moreover, the impacts of beekeeper knowledge and beekeeping management practices have often been overlooked, despite honey bees being a managed pollinator. Here, we established a standardised active monitoring network for 5 798 apiaries over two consecutive years to quantify honey bee colony mortality across 17 European countries. Our data demonstrate that overwinter losses ranged between 2% and 32%, and that high summer losses were likely to follow high winter losses. Multivariate Poisson regression models revealed that hobbyist beekeepers with small apiaries and little experience in beekeeping had double the winter mortality rate when compared to professional beekeepers. Furthermore, honey bees kept by professional beekeepers never showed signs of disease, unlike apiaries from hobbyist beekeepers that had symptoms of bacterial infection and heavy Varroa infestation. Our data highlight beekeeper background and apicultural practices as major drivers of honey bee colony losses. The benefits of conducting trans-national monitoring schemes and improving beekeeper training are discussed