The Human Milk Oligosaccharides 3-FL, Lacto-N-Neotetraose, and LDFT Attenuate Tumor Necrosis Factor-alpha Induced Inflammation in Fetal Intestinal Epithelial Cells In Vitro through Shedding or Interacting with Tumor Necrosis Factor Receptor 1

Scope Human milk oligosaccharides (hMOs) can attenuate inflammation by modulating intestinal epithelial cells, but the mechanisms of action are not well-understood. Here, the effects of hMOs on tumor necrosis factor-alpha (TNF-alpha) induced inflammatory events in gut epithelial cells are studied. Methods and results The modulatory effects of 2'-fucosyllactose, 3-fucosyllactose (3-FL), 6'-sialyllactose, lacto-N-tetraose, lacto-N-neotetraose (LNnT), lactodifucotetraose (LDFT), and lacto-N-triaose (LNT2) on immature (FHs 74 Int) and adult (T84) intestinal epithelial cells with or without TNF-alpha are determined. Interleukin-8 (IL-8) secretion in FHs 74 Int and T84 are quantified to determine hMO induced attenuation of inflammatory events by ELISA. 3-FL, LNnT, and LDFT significantly attenuate TNF-alpha induced inflammation in FHs 74 Int, while LNT2 induces IL-8 secretion in T84. In addition, microscale thermophoresis assays and ELISA are used to study the possible mechanisms of interaction between effective hMOs and tumor necrosis factor receptor 1 (TNFR1). 3-FL, LNnT, and LDFT exert TNFR1 ectodomain shedding while LNnT also shows binding affinity to TNFR1 with a Kd of 900 +/- 660 nM. Conclusion The findings indicate that specific hMO types attenuate TNF-alpha induced inflammation in fetal gut epithelial cells through TNFR1 in a hMO structure-dependent fashion suggest possibilities to apply hMOs in management of TNF-alpha dependent diseases

Effects of Different Human Milk Oligosaccharides on Growth of Bifidobacteria in Monoculture and Co-culture With Faecalibacterium prausnitzii

Human milk oligosaccharides (hMOs) are important bioactive components in mother’s milk contributing to infant health by supporting colonization and growth of gut microbes. In particular, Bifidobacterium genus is considered to be supported by hMOs. Approximately 200 different hMOs have been discovered and characterized, but only a few abundant hMOs can be produced in sufficient amounts to be applied in infant formula. These hMOs are usually supplied in infant formula as single molecule, and it is unknown which and how individual hMOs support growth of individual gut bacteria. To investigate how individual hMOs influence growth of several relevant intestinal bacteria species, we studied the effects of three hMOs (2′-fucosyllactose, 3-fucosyllactose, and 6′-sialyllactose) and an hMO acid hydrolysate (lacto-N-triose) on three Bifidobacteria and one Faecalibacterium and introduced a co-culture system of two bacterial strains to study possible cross-feeding in presence and absence of hMOs. We observed that in monoculture, Bifidobacterium longum subsp. infantis could grow well on all hMOs but in a structure-dependent way. Faecalibacterium prausnitzii reached a lower cell density on the hMOs in stationary phase compared to glucose, while B. longum subsp. longum and Bifidobacterium adolescentis were not able to grow on the tested hMOs. In a co-culture of B. longum subsp. infantis with F. prausnitzii, different effects were observed with the different hMOs; 6′-sialyllactose, rather than 2′-fucosyllactose, 3-fucosyllactose, and lacto-N-triose, was able to promote the growth of B. longum subsp. infantis. Our observations demonstrate that effects of hMOs on the tested gut microbiota are hMO-specific and provide new means to support growth of these specific beneficial microorganisms in the intestine.</p

Toll-like receptor mediated activation is possibly involved in immunoregulating properties of cow's milk hydrolysates

Immunomodulating proteins and peptides are formed during the hydrolysis of cow's milk proteins. These proteins are potential ingredients in functional foods used for the management of a range of immune related problems, both in infants and adults. However, the mechanism behind these effects is unknown. We hypothesize that the interaction of peptides with Toll-like receptors (TLRs) can induce immune effects, since these receptors are known to sample many dietary molecules in the intestine in order to regulate immune effects. To investigate this, we compared the immune effects and TLR activation and inhibition by whey and casein hydrolysates with different hydrolysis levels. We first measured cytokine production in primary peripheral blood mononuclear cells stimulated with either whey, casein, or their hydrolysates. IL-10 and TNF alpha were induced by whey hydrolysates (decreasing with increasing hydrolysis level), but not by casein hydrolysates. Next, the activation of TLR 2, 3, 5 and 9 receptors were observed by intact and mildly hydrolysed whey proteins only and not by casein hydrolysates in TLR reporter cell lines. Many casein hydrolysates inhibited TLR signaling (mainly TLR 5 and 9). These results demonstrate that the effects of cow's milk proteins on the immune system are protein type and hydrolysis dependent. TLR signaling is suggested as a possible mechanism for differences in effect. This knowledge contributes to a better understanding of the immune effects of hydrolysates and the design of infant formula, and nutrition in general, with specific immunoregulatory effects

CanScreen5, a global repository for breast, cervical and colorectal cancer screening programs

The CanScreen5 project is a global cancer screening data repository that aims to report the status and performance of breast, cervical and colorectal cancer screening programs using a harmonized set of criteria and indicators. Data collected mainly from the Ministry of Health in each country underwent quality validation and ultimately became publicly available through a Web-based portal. Until September 2022, 84 participating countries reported data for breast (n = 57), cervical (n = 75) or colorectal (n = 51) cancer screening programs in the repository. Substantial heterogeneity was observed regarding program organization and performance. Reported screening coverage ranged from 1.7% (Bangladesh) to 85.5% (England, United Kingdom) for breast cancer, from 2.1% (Côte d’Ivoire) to 86.3% (Sweden) for cervical cancer, and from 0.6% (Hungary) to 64.5% (the Netherlands) for colorectal cancer screening programs. Large variability was observed regarding compliance to further assessment of screening programs and detection rates reported for precancers and cancers. A concern is lack of data to estimate performance indicators across the screening continuum. This underscores the need for programs to incorporate quality assurance protocols supported by robust information systems. Program organization requires improvement in resource-limited settings, where screening is likely to be resource-stratified and tailored to country-specific situations.</p

Dynamic Energy Landscapes of Riboswitches Help Interpret Conformational Rearrangements and Function

Riboswitches are RNAs that modulate gene expression by ligand-induced conformational changes. However, the way in which sequence dictates alternative folding pathways of gene regulation remains unclear. In this study, we compute energy landscapes, which describe the accessible secondary structures for a range of sequence lengths, to analyze the transcriptional process as a given sequence elongates to full length. In line with experimental evidence, we find that most riboswitch landscapes can be characterized by three broad classes as a function of sequence length in terms of the distribution and barrier type of the conformational clusters: low-barrier landscape with an ensemble of different conformations in equilibrium before encountering a substrate; barrier-free landscape in which a direct, dominant “downhill” pathway to the minimum free energy structure is apparent; and a barrier-dominated landscape with two isolated conformational states, each associated with a different biological function. Sharing concepts with the “new view” of protein folding energy landscapes, we term the three sequence ranges above as the sensing, downhill folding, and functional windows, respectively. We find that these energy landscape patterns are conserved in various riboswitch classes, though the order of the windows may vary. In fact, the order of the three windows suggests either kinetic or thermodynamic control of ligand binding. These findings help understand riboswitch structure/function relationships and open new avenues to riboswitch design

A Systematic Review of Psychobiotic Interventions in Children and Adolescents to Enhance Cognitive Functioning and Emotional Behavior

This systematic review brings together human psychobiotic interventions in children and adolescents (aged 6–25 years) to evaluate the efficacy of pre- and probiotic supplements on stress, anxiety, and cognitive outcomes. Psychobiotic interventions in animal studies highlighted sensitivity to effects during development and maturation in multiple domains from emotion to cognitive processing. Several translational psychobiotic interventions in humans have been carried out to assess effects on emotion and cognition during childhood and into adulthood. The findings illustrate that there are limited consistent psychobiotic effects in developing human populations, and this is proposed to be due to heterogeneity in the trials conducted. Consequentially, it is recommended that three specific factors are considered in future psychobiotic trials: (1) Specificity of population studied (e.g., patients, developmental age), (2) specificity of intervention, and (3) homogeneity in outcome measures

Reef-building Pacific oysters record seasonal variations in water mass-properties of tidal basins from the Central Wadden Sea (North Sea)

High-resolution proxy records are needed to evaluate models simulating past, present and future climatic conditions. Before such records can be reliably employed, calibration studies have to be conducted to assess the confidence intervals of the proxies. Here, we use shells of the fast growing Pacific oyster Magallana gigas from the Central Wadden Sea, North Sea, a temperate barrier island-backbarrier tidal flat-salt marsh system with large seasonal changes of water mass-properties, for the calibration of geochemical proxies. M. gigas represents a non-native invasive species that rapidly develops oyster reefs. Calcite shells of two specimens from the intertidal and subtidal zones were sampled in high resolution yielding sub-monthly data sets. The time period represented in the shell, based on delta O-18 age modeling, was estimated at 8-10 years and the growth of the shells was restricted from (late) spring to (early) autumn of each year. Mg/Ca, Mn/Ca and Sr/Ca ratios of the intertidal and subtidal specimens show similar seasonal patterns. Mg/Ca and Sr/Ca ratios are investigated as high-resolution sea surface temperature (SST) proxies. Important ontogenetic effects (i.e., increasing time-averaging with increasing age) as well as inter-specimen variability are discussed as limiting factors for the proxy development. Intertidal Mg/Ca ratios show only a significant correlation to the high-resolution SST record of the Central Wadden Sea when the early ontogenetic stage is considered. Sr/Ca ratios were comparable in terms of absolute values and amplitudes to those of M. gigas in the Northern Wadden Sea, but amplitudes were decreasing with increasing age. These findings seriously hamper the application of Mg/Ca and Sr/Ca for reliable palaeotemperature reconstructions regardless of ontogenetic stage. The Mn/Ca ratios were investigated as proxy for Mn cycling in tidal basins, where it is interrelated with seasonal changes in primary production. In addition to the generally observed seasonal variability of the Mn/Ca oyster records, the subtidal Mn/Ca is significantly elevated compared to intertidal Mn/Ca. The subtidal Mn/Ca offset likely reflects differences in Mn cycling in tidal settings and could, therefore, serve in the palaeorecord as indicator to differentiate inter- and subtidal habitats in the same embedding sedimentary facies. This habitat effect has to be considered as an important factor besides environmental change when interpreting the high-resolution proxy record of fossil oysters

Human milk oligosaccharides and its acid hydrolysate LNT2 show immunomodulatory effects via TLRs in a dose and structure-dependent way

Human milk oligosaccharides (HMOs) have beneficial immune effects but the mechanisms of action are not well understood. Here we study Toll-like receptor (TLR) signaling of the HMOs 2'-FL, 3-FL, 6'-SL, LNT2, and LNnT and their effect on cytokine production in human macrophages. 3-FL activated TLR2 and LNT2 activated all TLRs in a dose-dependent way. In an inhibition assay, 2'-FL, 6'-SL, and LNnT inhibited TLR5 and 7, while 3-FL inhibited TLR5, 7, and 8. 6'-SL showed a synergistic effect on ssRNA40-induced TLR8 activation. In addition, we measured HMO-induced cytokine production in THP1 macrophages. IL-10 and TNF alpha were induced by LNT2, and the effects were NF-kappa B dependent, while the other HMOs had minor effects. The potent effects of LNT2 might be explained by the unique N-acetylglucosamine end that binds to leucine-rich repeats on TLRs. Our data suggest that the effects of HMOs on TLR signaling and immunomodulation of macrophages are HMO-structure dependent

Immunomodulating protein aggregates in soy and whey hydrolysates and their resistance to digestion in an in vitro infant gastrointestinal model:New insights in the mechanism of immunomodulatory hydrolysates

Hydrolysates, which are used in hypoallergenic infant formulas, have been found to possess immune modulating effects. For an optimal utilization of hydrolysates, the working mechanisms and responsible proteins underlying the effects should be elucidated. In this study, the immunomodulating activity of whey and soy hydrolysates was studied by quantifying TLR activation and assessing cytokine production in hydrolysate stimulated dendritic cells. The responsible protein fraction was identified and characterized by gel electrophoresis. The immune effects under gastrointestinal conditions were studied by digesting the hydrolysates in an in vitro infant digestion model, after which the digests were analyzed. In both soy and whey hydrolysates, TLR activation and cytokine production in dendritic cells were induced by a fraction containing protein aggregates larger than 1000 kDa, which were formed by electrostatic interactions and disulfide bonds. Only soy aggregates remained intact during duodenal digestion, and maintained the TLR activating capacity. Soy and whey protein aggregates larger than 1000 kDa possess immunomodulatory properties, but only soy aggregates remain under intestinal digestion conditions. This knowledge is important for a better understanding of the effects of hydrolysates

Modular synthesis and immunological evaluation of suspected allergenic galactooligosaccharides

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