Search

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

Introduction D-Glucosamine (GlcN) is one of the most widely consumed dietary supplements and complementary medicines in the world and has been traditionally used to attenuate osteoarthritis in humans. GlcN extends lifespan in different animal models. In humans, its supplementation has been strongly associated with decreased total mortality and improved vascular endothelial function. GlcN acts as a suppressor of inflammation and by inhibiting glycolysis, it can activate the metabolism of stored fat and mitochondrial respiration. Methods The conventional human GlcN dose is 1,500 mg x day-1 but extensive evidence indicates that much higher doses are well tolerated. GlcN is one of the supplements that has experienced a greater use in the last years in elite athletes mainly due to its potential chondroprotective effects that may promote cartilage health. However, the possibility of it being an ergogenic aid has not been explored. We aimed to study the potential beneficial effects of GlcN on mitochondrial content, on physical performance and oxidative stress in mice that were aerobically trained and supplemented with three different doses of glucosamine (250, 500, and 1,000 mg x Kg-1) for six weeks. We measured exercise performance (grip strength, motor coordination and running capacity) before and after the training period. Proteins involved in mitochondrial biogenesis (AMPK, PGC-1, NRF-1, SIRT-1, cytochrome c, citrate synthase), markers of oxidative stress (GSSG/GSH) or damage (MDA, carbonylated proteins), antioxidant enzymes (NRF-2, SOD1, SOD2, Catalase and PRDX6) and MAPKs (p38 and ERK ½) were also determined in skeletal muscle. Results and conclusions Our results show that GlcN supplementation in aerobically trained mice, at doses equivalent to those conventionally used in humans, increases the protein levels of mitochondrial biogenesis markers, improves motor coordination and may have a synergistic effect with exercise training on running distance.

Consumption of high fat diets (HFD) mimics a modern or "Western style" diet pattern and can impair intestinal barrier integrity, leading to endotoxemia and associated unhealthy conditions. This study investigated if supplementation with an anthocyanin (cyanidin and delphinidin glucosides)-rich extract (CDRE) could revert or mitigate HFD-induced alterations of colonic physiology in part through the regulation of Toll-Like Receptor 4 (TLR-4)- and redox-regulated signaling. C57BL/6J male mice were fed for 4 weeks with a control or an HFD. Then, mice were divided in four groups fed either control or HFD, or these diets supplemented with CDRE for the subsequent 4 weeks. After 8 weeks on the HFD we observed in the colon: i) disruption of tight junction structure and function; ii) increased TLR-4 expression; iii) increased NADPH oxidase NOX1 expression, and iv) activation of redox-sensitive and TLR-4-triggered pathways, i.e. NF-κB, ERK1/2, JNK1/2, PI3K/Akt. All these events were prevented or reverted by CDRE supplementation. Supporting the relevance of CDRE-mediated downregulation of TLR-4 on its colon beneficial effect; in vitro (Caco-2 cell monolayers), cyanidin, delphinidin and their metabolites protocatechuic and gallic acid, mitigated lipopolysaccharide (LPS)-induced monolayer permeabilization by restoring tight junction structure and dynamics and preventing lipid/protein oxidation. The CDRE also mitigated HFD-mediated alterations in parameters of goblet cell differentiation and function, including the downregulation of markers of goblet cell differentiation (Klf4), and intestinal mucosa healing (Tff3). Results show that a short-term supplementation with cyanidin and delphinidin, protect from HFD-induced alterations in colon physiology in part through the modulation of TLR-4- and redox-regulated signaling.

Background Caloric restriction (CR) without micronutrient deficiency has been shown to increase both lifespan and healthspan. In animals, CR has been demonstrated to increase glutathione (GSH), a neuroprotective antioxidant, in the brain and preserve brain mitochondrial function by altering neuroenergetics. In humans it has been associated with improvements in mood states and cognitive function. However, most CR studies have employed a 30–60% reduction in calories which is likely too stringent for most people to adhere to long-term. Thus, there is an unmet need for nutritional supplements which can mimic the biological effects of CR, without the need for calorie limitations. Aim The purpose of the present randomized, placebo-controlled clinical trial was to use Proton (1H) Magnetic Resonance Spectroscopic (MRS) measurements to determine non-invasively whether a blend of micronutrients, a putative CR mimetic, positively modulates metabolites related to neuroprotection and neuroenergetics in the brain. Methods Healthy middle-aged men and women (N = 63 [33 women]; age: 40–60 years) were randomized in a double-blind manner to 6 weeks supplementation with either the putative CR mimetic or placebo. At baseline and 6 weeks, subjects underwent MRS at 3 T to investigate changes in brain chemistry, including the neurometabolites: GSH, Glutamate (Glu), Glutamine (Gln) and N-Acetylaspartate (NAA). Results GSH, a marker of antioxidant and cellular redox status, increased in the brain of participants in the supplement group. The supplement group also showed an increase in the Glu/Gln ratio, a marker of excitatory neurotransmission and bioenergetics. A trend for an increase in NAA/H2O, a marker of neuronal integrity, was observed in females in the supplement group. Conclusions The present study reveals that 6-weeks daily supplementation with a micronutrient blend elicits positive changes in brain neurochemistry. This is the first study to demonstrate that a putative CR mimetic increases brain GSH concentrations and improves neuroprotection and neuroenergetics in the brain of healthy humans. This study was registered at www.clinicaltrials.gov as NCT02439983.

(1) Background: The gastrointestinal tract (GI) tract is one of the main organs exposed to particulate matter (PM) directly through ingestion of contaminated food or indirectly through inhalation. Previous studies have investigated the effects of chronic PM exposure on intestinal epithelia in vitro using Caco&minus, 2 cells and in vivo using mice. In this study, we hypothesized that chronic PM exposure would increase epithelial permeability and decrease barrier function due to altered redox homeostasis, which alters levels and/or localization of barrier-associated proteins in human three-dimensional (3D) intestinal tissues. (2) Methods: Transepithelial electrical resistance (TEER) in tissues exposed to 50, 100, 150, 250, and 500 &micro, g/cm2 of PM for 1 week and 2 weeks was analyzed. Levels and localization of tight junction proteins zonula occludens protein 1 (ZO&minus, 1) and claudin&minus, 1 and desmosome-associated desmocollin were analyzed using immunofluorescence. As a marker of oxidative stress, levels of 4-hydroxy-nonenal (4HNE) adducts were measured. (3) Results: No differences in TEER measurements were observed between exposed and un-exposed tissues. However, increased levels of 4HNE adducts in exposed tissues were observed. Additionally, decreased levels of ZO&minus, 1, claudin&minus, 1, and desmocollin were demonstrated. (4) Conclusion: These data suggest that chronic PM exposure results in an increase of oxidative stress, modified levels of barrier-associated proteins could possibly link to GI tract inflammatory conditions.

Background: We previously described a novel micronutrient blend that behaves like a putative calorie restriction mimetic. The aim of this paper was to analyze the beneficial effects of our micronutrient blend in mice and C. elegans, and compare them with calorie restriction. Methods: Whole transcriptomic analysis was performed in the brain cortex, skeletal muscle and heart in three groups of mice: old controls (30 months), old + calorie restriction and old + novel micronutrient blend. Longevity and vitality were tested in C. elegans. Results: The micronutrient blend elicited transcriptomic changes in a manner similar to those in the calorie-restricted group and different from those in the control group. Subgroup analysis revealed that nuclear hormone receptor, proteasome complex and angiotensinogen genes, all of which are known to be directly related to aging, were the most affected. Furthermore, a functional analysis in C. elegans was used. We found that feeding C. elegans the micronutrient blend increased longevity as well as vitality. Conclusions: We describe a micronutrient supplement that causes similar changes (transcriptomic and promoting longevity and vitality) as a calorie restriction in mice and C. elegans, respectively, but further studies are required to confirm these effects in humans.

OBJECTIVES: Consumption of supplements have been found to improve skin health, but there is only a limited number of studies to support these claims. The main objective of this single center, randomized placebo-controlled study was to determine the effects of a nutritional supplement containing collagen peptides, wheat extract oil containing ceramides, and lutein on skin appearance in healthy adults. METHODS: Sixty healthy, nonsmoking men and women between the ages of 40 and 75 years with Fitzpatrick skin types I and II were recruited to participate in the study. The variables measured were changes in skin attributes including skin color, skin carotenoids levels, skin hydration, and visible results as assessed by a dermatologist and self-assessment between groups given supplement: collagen peptides, ceramides, and lutein (CCL) or placebo. The study also investigated if using a facial cleansing device along with CCL influenced facial skin appearance. RESULTS: Skin carotenoid levels significantly increased from baseline with CCL at 30 and 120d with a mean increase of 10,750 Raman Intensity Units (RIUs) following 120d supplementation. Significant improvements in facial skin radiance, texture, and overall appearance were found for CCL, cleansing device or combination of both. An increase was found in skin facial color (b(*)) at 30 and 120d with CCL supplementation while placebo treatment was unchanged between baseline and 30d, but then increased between 30 and 120d. No changes in lines and skin firmness were noted. CONCLUSIONS: Supplementation for 120d with CCL with and without a cleansing device supported skin health and improved several skin attributes thus confirming evidence of benefit on skin health and identifying potential for added benefit of device along with supplementation. FUNDING SOURCES: NSE Products, Inc., Provo, Utah.

Summary Caloric restriction (CR) without malnutrition has been shown to retard several aspects of the aging process and to extend lifespan in different species. There is strong interest in the identification of CR mimetics (CRMs), compounds that mimic the beneficial effects of CR on lifespan and healthspan without restriction of energy intake. Identification of CRMs in mammals is currently inefficient due to the lack of screening tools. We have performed whole-genome transcriptional profiling of CR in seven mouse strains (C3H/HeJ, CBA/J, DBA/2J, B6C3F1/J, 129S1/SvImJ, C57BL/6J, and BALB/cJ) in white adipose tissue (WAT), gastrocnemius muscle, heart, and brain neocortex. This analysis has identified tissue-specific panels of genes that change in expression in multiple mouse strains with CR. We validated a subset of genes with qPCR and used these to evaluate the potential CRMs bezafibrate, pioglitazone, metformin, resveratrol, quercetin, 2,4-dinitrophenol, and L-carnitine when fed to C57BL/6J 2-month-old mice for 3 months. Compounds were also evaluated for their ability to modulate previously characterized biomarkers of CR, including mitochondrial enzymes citrate synthase and SIRT3, plasma inflammatory cytokines TNF-α and IFN-γ, glycated hemoglobin (HbA1c) levels and adipocyte size. Pioglitazone, a PPAR-γ agonist, and L-carnitine, an amino acid involved in lipid metabolism, displayed the strongest effects on both the novel transcriptional markers of CR and the additional CR biomarkers tested. Our findings provide panels of tissue-specific transcriptional markers of CR that can be used to identify novel CRMs, and also represent the first comparative molecular analysis of several potential CRMs in multiple tissues in mammals.

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., Graphical abstract Image 1, Highlights • Anthocyanidins (AC) mitigate high fat diet (HFD)-induced intestinal permeabilization and endotoxemia. • AC inhibit HFD-induced ileum NADPH oxidase upregulation and oxidative stress. • AC inhibit the activation of redox sensitive signals that cause intestinal permeabilization. • AC mitigate HFD-induced dysbiosis and improve ileum endocrine/immunological responses. • AC's beneficial systemic effects in HFD-mice could begin at the GI tract.

SummaryBackground The human body relies on several aging defense mechanisms (ADMs) to limit damage induced from pro-aging stressors (aging aggressors). However, such protective mechanisms can be compromised, leading to accelerated aging. The skin provides a model to probe the effects of an oral nutritional intervention on ADMs in response to ultraviolet radiation (UVR)-induced damage. Objective To determine whether supplementation with a novel nutritional and phytonutrient blend could protect against UVR-induced skin damage and positively influence facial skin attributes and characteristics by bolstering ADMs. Methods Thirty-six healthy, nonsmoking women (40–75 years) with Fitzpatrick skin types I and II were recruited. UVR-induced erythema and the number of apoptotic cells were determined before (pre-) and after 8-week (post-) supplementation. Other clinical variables included skin carotenoid concentrations, facial skin attributes and characteristics. Results Eight-week supplementation led to protection against UVR-induced skin damage as evidenced by reductions in erythema at all three minimal erythema doses (MEDs) (9.1 to 7.4 [P = 0.10]; 15.8 to 13.6 [P = 0.02]; and 19.6 to 17.3 [P = 0.01] for one, two, and three MEDs and a reduction in the average number of apoptotic cells [11.3 to 5.3, P < 0.0001] pre- and post-supplementation, respectively). Skin carotenoid concentrations increased from 28 111 Raman intensity units to 38 472 (P < 0.0001) along with noticeable improvements in facial skin attributes and characteristics: elasticity, transepidermal water loss, radiance, texture, and overall appearance (all P < 0.05) following supplementation. Conclusion Eight weeks of oral supplementation positively impacted ADMs resulting in protection against UVR-induced skin damage and improvements in facial skin attributes and characteristics.

Consumption of diets high in fat and/or fructose content promotes tissue inflammation, oxidative stress, and insulin resistance, activating signals (e.g. NF-κB/JNK) that downregulate the insulin cascade. Current evidence supports the concept that select flavonoids can mitigate obesity and type 2 diabetes (T2D). This work investigated if supplementation with the anthocyanidins (AC) cyanidin and delphinidin could attenuate the adverse consequences of consuming a high fat diet (HFD) in mice. Consumption of an AC-rich blend mitigated HFD-induced obesity, dyslipidemia and insulin resistance (impaired responses to insulin and glucose). HFD-fed mice were characterized by increased liver lipid deposition and inflammation, which were also attenuated upon AC supplementation. HFD caused liver oxidative stress showing an increased expression of NADPH oxidases, generators of superoxide and H2O2, and high levels of oxidized lipid-protein adducts. This was associated with the activation of the redox sensitive signals IKK/NF-κB and JNK1/2, and increased expression of the NF-κB-regulated PTP1B phosphatase, all known inhibitors of the insulin pathway. In agreement with an improved insulin sensitivity, AC supplementation inhibited oxidative stress, NF-κB and JNK activation, and PTP1B overexpression. Thus, cyanidin and delphinidin consumption either through diet or by supplementation could be a positive strategy to control the adverse effects of Western style diets, including overweight, obesity, and T2D. Modulation of inflammation, oxidative stress, and NF-κB/JNK activation emerge as relevant targets of AC beneficial actions., Graphical abstract fx1, Highlights • Anthocyanidins (AC) mitigate high fat diet (HFD)-induced obesity and insulin resistance in mice. • AC inhibits HFD-induced liver lipid deposition and inflammation. • AC inhibit HFD-induced liver NADPH oxidase upregulation and oxidative stress. • AC inhibit the activation of redox sensitive signals that cause insulin resistance. • AC could be beneficial against the adverse effects of Western style diets.

Background. Anthocyanins and prebiotics impact overall health and wellness, likely through modulation of the microbiota and the intestinal ecosystem. Objectives. An 8-week open-label study in male and female volunteers with uncomplicated obesity was designed to study the efficacy of an anthocyanin and prebiotic blend in modulating intestinal microbiota and intestinal inflammation. Results. After 8 weeks of daily supplementation, participants had a significant decrease in Firmicutes (p<0.001) and Actinobacteria (p<0.001) and a significant increase in Bacteroidetes (p<0.001). Bowel habits were improved as evidenced by reductions in the severity of bloating (p<0.05), gas (p=0.035), and abdominal pain (p=0.015) as well as significant improvements in stool consistency (p<0.05). Finally, a nonsignificant decrease in the inflammatory marker fecal calprotectin was seen (p=0.107). The supplement was safe and well tolerated. Conclusions. The results suggest that regular consumption of the anthocyanin-prebiotic blend positively modulated the intestinal ecosystem and provided insights into the mechanisms of action and its impact on health benefits.

An increased permeability of the intestinal barrier is proposed as a major event in the pathophysiology of conditions characterized by chronic gut inflammation. This study investigated the capacity of pure anthocyanins (AC), and berry and rice extracts containing different types and amounts of AC, to inhibit tumor necrosis alpha (TNFα)-induced permeabilization of Caco-2 cell monolayers. Caco-2 cells differentiated into intestinal epithelial cell monolayers were incubated in the absence/presence of TNFα, with or without the addition of AC or AC-rich plant extracts (ACRE). AC and ACRE inhibited TNFα-induced loss of monolayer permeability as assessed by changes in transepithelial electrical resistance (TEER) and paracellular transport of FITC-dextran. In the range of concentrations tested (0.25–1 μM), O-glucosides of cyanidin, and delphinidin, but not those of malvidin, peonidin and petunidin protected the monolayer from TNFα-induced decrease of TEER and increase of FITC-dextran permeability. Cyanidin and delphinidin acted by mitigating TNFα-triggered activation of transcription factor NF-κB, and downstream phosphorylation of myosin light chain (MLC). The protective actions of the ACRE on TNFα-induced TEER increase was positively correlated with the sum of cyanidins and delphinidins (r2 = 0.83) content in the ACRE. However, no correlation was observed between TEER and ACRE total AC, malvidin, or peonidin content. Results support a particular capacity of cyanidins and delphinidins in the protection of the intestinal barrier against inflammation-induced permeabilization, in part through the inhibition of the NF-κB pathway. Fil: Cremonini, Eleonora. University of California at Davis; Estados Unidos Fil: Mastaloudis, Angela. Nu Skin Enterprises; Estados Unidos Fil: Hester, Shelly N.. Nu Skin Enterprises; Estados Unidos Fil: Verstraeten, Sandra Viviana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina Fil: Anderson, Maureen. University of California at Davis; Estados Unidos Fil: Wood, Steven M.. Nu Skin Enterprises; Estados Unidos Fil: Waterhouse, Andrew L.. University of California at Davis; Estados Unidos Fil: Fraga, César Guillermo. 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 de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Oteiza, Patricia Isabel. University of California at Davis; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Human milk (HM) is rich in oligosaccharides (HMO) that exert prebiotic and anti-infective activities. HM feeding reduces the incidence of rotavirus (RV) infection in infants. Herein, the anti-RV activity of oligosaccharides was tested in an established in vitro system for assessing cellular binding and viral infectivity/replication, and also tested in a newly developed, acute RV infection, in situ piglet model. For the in vitro work, crude HMO isolated from pooled HM, neutral HMO (lacto-N-neotetraose, LNnT; 2′-fucosyllactose) and acidic HMO (aHMO, 3′-sialyllactose, 3′-SL; 6′-sialyllactose, 6′-SL) were tested against the porcine OSU strain and human RV Wa strain. The RV Wa strain was not inhibited by any oligosaccharides. However, the RV OSU strain infectivity was dose-dependently inhibited by sialic acid (SA)-containing HMO. 3′-SL and 6′-SL concordantly inhibited 125I-radiolabelled RV cellular binding and infectivity/replication. For the in situ study, a midline laparotomy was performed on 21-d-old formula-fed piglets and six 10 cm loops of ileum were isolated in situ. Briefly, 2 mg/ml of LNnT, aHMO mixture (40 % 6′-SL/10 % 3′-SL/50 % SA) or media with or without the RV OSU strain (1 × 107 focus-forming units) were injected into the loops and maintained for 6 h. The loops treated with HMO treatments+RV had lower RV replication, as assessed by non-structural protein-4 (NSP4) mRNA expression, than RV-treated loops alone. In conclusion, SA-containing HMO inhibited RV infectivity in vitro; however, both neutral HMO and SA with aHMO decreased NSP4 replication during acute RV infection in situ.

Bronchial-associated immune development is critically important to protect neonates from respiratory infections. Herein, bronchial-associated immune development in formula-fed and sow-reared pigs is described. Colostrum-fed newborn piglets were fed medicated sow milk replacer formula beginning at 48 h of life or remained with the sow. Blood and tissues were sampled at one-week (d7) and three-weeks (d21) of age. Lymphocyte subpopulations, including T helper 2, cytotoxic T, memory T, and NK cells, in peripheral blood, mediastinal lymph nodes, and thoracic lymph nodes were identified using flow cytometry. Additionally, IL-1β, IL-6, IL-12, TNFα, TGF-β1, TGF-β2, IFNα, IFNβ, and dectin gene expression were analyzed by quantitative RT-PCR. Total IgG, IgM, and IgA concentrations in serum were analyzed. Dietary and developmental effects were observed. This set of baseline measurements provides a framework for future respiratory challenge studies where the effects of diet on the neonate's ability to resist and/or recover from infection can be tested.

Nucleotides (NT) and human milk oligosaccharides (HMO) individually affect epithelial cell growth, but their combined effects had not been studied. Herein, the impact of NT and HMO on cell proliferation, apoptosis, necrosis and cell cycle in the fetal epithelial cell line (FHs-74 Int) was determined. Cells were incubated with media containing 2.5% FBS and no epidermal growth factor (Control); fucosyllactose (FL) mix [85% 2’FL/15% 3’FL], sialyllactose (SL) mix [40% 6’SL/10% 3’SL/50% sialic acid (SA)] or LNnT at 125, 250, 500 or 1000 μg/mL with and without 250 μg/mL NT (43% CMP, 18.5% UMP, 16.4% AMP, and 22.0% GMP) for 24 or 72 h. NT alone significantly increased proliferation, but did not affect cell cycle or apoptosis/necrosis. All HMO treatments at 1000 μg/mL significantly decreased proliferation and some were also inhibitory at 250 or 500 μg/mL. When NT and HMO were simultaneously added, NT ameliorated the anti-proliferative effect of HMO. FL significantly increased cells in S phase and SL and LNnT treatments significantly increased cells in G2/M and S phases, which concomitantly decreased cells in G0/G1. HMO with NT significantly decreased the percent of cells in the G2/M phase compared to HMO alone. Higher HMO doses significantly increased the percentage of apoptotic and necrotic cells compared to control. In conclusion, HMO reduced cell proliferation and this effect is partially ameliorated by NT. It appears that HMO initially induced apoptosis/necrosis, which was later evidenced by G2/M cell cycle arrest and decreased proliferation.

Identification of caloric restriction mimetics (CRMs), compounds that mimic the beneficial effects of caloric restriction (CR) without limiting energy intake would be a scientific advancement. This study investigated transcriptomics elicited by a putative CRM nutrient blend compared to CR in diverse tissues following long-term feeding in 4 groups of B6C3F1 mice: Young Controls (YC; 5 months) and 3 groups treated from 14–30 months: Old Controls (OC), Old CR (OCR; 25% CR) and Old Supplemented (OS). Gene expression profiling in cerebral cortex (CC), skeletal muscle (SKL), heart (HRT), white adipose (WAT)and liver (LVR) was performed with Affymetrix Mouse 2.0ST arrays. This was followed by a dose-response study in C. elegans investigating longevity and mobility. Principal component analysis revealed that gene expression profiles of YC and OC were distinct from one another in all tissues except WAT at 30 months. The OS mimicked OCR transcriptomics most dramatically in tissues most relevant to aging and age-associated diseases, CCT, HRT and SKL. In C. elegans, the blend mimicked the known benefits of CR, increasing lifespan and vitality in a dose-dependent manner. These CRM effects may have positive implications for healthy human aging or ‘youthspan’ and warrant further investigation.

Identification of caloric restriction mimetics (CRMs), compounds that mimic the beneficial effects of caloric restriction (CR) without restriction of dietary energy would be an advancement in anti-aging science. The present study investigated whether the transcriptional profiles of a putative CRM nutrient blend could mimic that of CR in diverse tissues following long-term feeding in B6C3F1 male mice. Study design: Young Controls (YC; 5 mo.) and 3 groups treated from 14-30 mo.: Old Controls (OC), Old CR (OCR; 25% CR) and Old Supplemented (OS); n=7/group. Gene expression profiling in cerebral cortex (CCT), skeletal muscle (gastrocnemius)(SKL), heart (HRT), white adipose tissue (WAT) and liver (LVR) was performed using Affymetrix Mouse 2.0ST arrays. Principal component analysis revealed that gene expression profiles of YC and OC were distinct from one another in all tissues at 30 months. Using differential analysis, genes commonly expressed in OCR and OS groups compared to the OC group were identified in CCT (3,468), SKL (2,386), HRT (3,523), LVR (1,276) and WAT (683). The OS group mimicked OCR transcriptional profiles most dramatically in CCT, HRT and SKL, tissues highly relevant to aging and age-associated diseases. These CRM effects, elicited by a mid-life intervention, may have positive implications for healthy human aging or ‘youthspan’ and warrant further investigation.

An increased permeability of the intestinal barrier is proposed as one underlying factor of obesity-associated pathologies. Consumption of high fat diet (HFD) is associated with intestinal permeabilization and increased paracellular transport of endotoxins, which can promote steatosis and insulin resistance. We investigated the capacity of dietary anthocyanidins (AC) to mitigate steatosis and improve insulin sensitivity in HFD-fed mice. Male C57BL/6 J mice were fed for 14 w control (C) or high fat (HF) diet, with or without supplementation with 2, 20, or 40 mg/kg BW of a blend of AC-rich plant extracts (ACE). The consumption of HFD caused overweight and insulin resistance, which were mitigated by ACE consumption. Concurrently, ACE prevented HFD-induced intestinal permeabilization, altered expression of ileum tight junction proteins (decreased ZO-1 and occludin) and endotoxemia. AC protection of barrier permeability is in part due to the inhibition of HFD-induced ileum ERK1/2 and AMPK activation, increased GLP-2 levels, and mitigation of dysbiosis. Consistently, the highest AC dose prevented steatosis and improved blood and liver inflammation and oxidative stress. Findings suggest that ACE supplementation could be an important strategy to mitigate obesity and Western style diets-associated insulin resistance in part through the preservation of intestinal barrier integrity.

Infant formulas lack the complex mixture of oligosaccharides found in human milk. These human milk oligosaccharides (HMO) may be pivotal to the development of the neonatal immune system. Few comprehensive analyses of the effects of HMO on immune cells from neonates have been undertaken. Herein, the direct effects of HMO on immune cells were analysedex vivo. Peripheral blood mononuclear cells (PBMC) isolated from 10-d-old sow-reared (SR) or colostrum-deprived formula-fed (FF) pigs were stimulated for 72 h with single HMO, mixtures of single HMO or a complex mixture of HMO isolated from human milk (iHMO). T-cell phenotype, cytokine production and proliferation were measured by flow cytometry, immunoassay and [3H]thymidine incorporation, respectively. Stimulation with HMO had direct effects on PBMC. For instance, cells stimulated with iHMO produced more IL-10 than unstimulated cells, and cells stimulated with fucosylated HMO tended to proliferate less than unstimulated cells. Additionally, co-stimulation with HMO mixtures or single HMO altered PBMC responses to phytohaemagglutinin (PHA) or lipopolysaccharide (LPS) stimulation. Compared with PBMC stimulated with PHA alone, cells co-stimulated with iHMO and PHA proliferated more and had fewer detectable CD4+CD8+T cells. Compared with PBMC stimulated by LPS alone, cells co-stimulated with a mixture of sialylated HMO and LPS proliferated more and tended to have fewer detectable CD4+T cells. Differences in the baseline responses of PBMC isolated from the SR or FF pigs were observed. In summary, HMO directly affected PBMC populations and functions. Additionally,ex vivomeasurements of PBMC phenotype, cytokine production and proliferation were influenced by the neonate's diet.

Identification and characterization of compounds that enhance the growth, development, and health of infants who are not breastfed continues to be a goal for nutritional science. This study explored the effects of one dietary component, (1,3/1,6)-β-D-glucan (Wellmune WGP), on lung immune development in the neonatal piglet. The hypothesis was that supplementation with WGP, a pathogen-associated molecular pattern, would enhance pathogen-responsive elements of the immune system, for instance, by increasing the size of the cytotoxic T-cell population or the expression of inflammatory cytokines. Piglets were fed a control formula or formula plus WGP at 1.8, 18, or 90 mg/kg body weight per day. Serum, thoracic lymph nodes (TLNs), mediastinal lymph nodes, and lung were collected at days 7 or 21. Immune parameters including tissue messenger RNA (mRNA) expression and T-cell phenotypes were analyzed. Normal developmental changes were observed, with a decrease in T-helper cells and an increase in cytotoxic T cells in both TLN and mediastinal lymph node, but there was no effect of WGP. Dietary WGP reduced the mRNA expression of transforming growth factor (TGF) β2 and tended to reduce the mRNA expression of TGF-β1 in lung tissue. With the exception of reducing TGF-β mRNA in the lung and tending to decrease the ratio of T helper to cytotoxic T cell in the TLN, dietary WGP did not affect lung-associated adaptive immunity in piglets.

Faster weight gain early in infancy may contribute to a greater risk of later obesity in formula-fed compared to breast-fed infants. One potential explanation for the difference in weight gain is higher macronutrient intake in formula-fed infants during the first weeks of life. A systematic review was conducted using Medline to assess the macronutrient and energy content plus volume of intake in breast-fed and formula-fed infants in early infancy. All studies from healthy, term, singleton infants reporting values for the composition of breast milk during the first month of life were included. The energy content of colostrum (mean, SEM:53.6±2.5 kcal/100 mL), transitional milk (57.7±4.2 kcal/100 mL), and mature milk (65.2±1.1 kcal/100 mL) was lower than conventional infant formula (67 kcal/100 mL) on all days analyzed. The protein concentration of colostrum (2.5±0.2 g/100 mL) and transitional milk (1.7±0.1 g/100 mL) was higher than formula (1.4 g/100 mL), while the protein content of mature milk (1.3±0.1 g/100 mL) was slightly lower. Formula-fed infants consume a higher volume and more energy dense milk in early life leading to faster growth which could potentially program a greater risk of long-term obesity.

Influenza virus is a serious health concern. β-glucans derived from plants, bacteria, and fungi have been shown to potentiate immune system responses including those elicited by vaccination. However, in these studies β-glucan was administered as an adjuvant in the vaccine preparation. We hypothesized that addition of a commercially available whole glucan particle supplement to the diet would improve immune response to primary and secondary influenza vaccination in mice. β-glucan was added to pelleted diet and fed to mice at concentrations designed to deliver 0 (control), 1.8 or 90 mg·kg(-1)·day(-1) to each mouse. Influenza vaccine was given intramuscularly in the left hindlimb and primary and secondary responses were assessed. Supplementation with β-glucan was not effective in boosting immune responses to the vaccine, either in the primary or secondary vaccination experiments. Surprisingly, addition of particulate β-glucan to the vaccine itself also failed to elicit a greater antibody response. These observations suggest that this particular form of β-glucan is ineffective in boosting immune response to intramuscular influenza vaccination. Further study is warranted to determine if the use of different mouse models, different vaccine delivery systems, or β-glucans purified from different strains of bacteria, fungi, or plants could improve outcomes using this or similar protocols.

Infant formulas lack the complex mixture of oligosaccharides (HMO) found in human milk, which may be pivotal to the development of the neonatal microbiota and immune system. Few comprehensive analy...