Activation of Liver X Receptors and Peroxisome Proliferator-Activated Receptors by Lipid Extracts of Brown Seaweeds:A Potential Application in Alzheimer’s Disease?

The nuclear liver X receptors (LXRα/β) and peroxisome proliferator-activated receptors (PPARα/γ) are involved in the regulation of multiple biological processes, including lipid metabolism and inflammation. The activation of these receptors has been found to have neuroprotective effects, making them interesting therapeutic targets for neurodegenerative disorders such as Alzheimer's Disease (AD). The Asian brown seaweed Sargassum fusiforme contains both LXR-activating (oxy)phytosterols and PPAR-activating fatty acids. We have previously shown that dietary supplementation with lipid extracts of Sargassum fusiforme prevents disease progression in a mouse model of AD, without inducing adverse effects associated with synthetic pan-LXR agonists. We now determined the LXRα/β- and PPARα/γ-activating capacity of lipid extracts of six European brown seaweed species ( Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, Himanthalia elongata, Saccharina latissima, and Sargassum muticum) and the Asian seaweed Sargassum fusiforme using a dual luciferase reporter assay. We analyzed the sterol and fatty acid profiles of the extracts by GC-MS and UPLC MS/MS, respectively, and determined their effects on the expression of LXR and PPAR target genes in several cell lines using quantitative PCR. All extracts were found to activate LXRs, with the Himanthalia elongata extract showing the most pronounced efficacy, comparable to Sargassum fusiforme, for LXR activation and transcriptional regulation of LXR-target genes. Extracts of Alaria esculenta, Fucus vesiculosus, and Saccharina latissima showed the highest capacity to activate PPARα, while extracts of Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, and Sargassum muticum showed the highest capacity to activate PPARγ, comparable to Sargassum fusiforme extract. In CCF-STTG1 astrocytoma cells, all extracts induced expression of cholesterol efflux genes ( ABCG1, ABCA1, and APOE) and suppressed expression of cholesterol and fatty acid synthesis genes ( DHCR7, DHCR24, HMGCR and SREBF2, and SREBF1, ACACA, SCD1 and FASN, respectively). Our data show that lipophilic fractions of European brown seaweeds activate LXRs and PPARs and thereby modulate lipid metabolism. These results support the potential of brown seaweeds in the prevention and/or treatment of neurodegenerative diseases and possibly cardiometabolic and inflammatory diseases via concurrent activation of LXRs and PPARs. </p

24(S)-Saringosterol Prevents Cognitive Decline in a Mouse Model for Alzheimer's Disease

We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXR beta-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-beta (A beta) deposition in an Alzheimer's disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1 Delta E9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1 Delta E9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1 Delta E9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, A beta and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1 Delta E9 mice without affecting the A beta plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1 Delta E9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1 Delta E9 mice independent of effects on A beta load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline

Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Edible seaweed-derived constituents: an undisclosed source of neuroprotective compounds

Edible marine algae, or seaweeds, are a rich source of several bioactive compounds including phytosterols, carotenoids, and polysaccharides. Over the last decades, seaweed-derived constituents turned out to not only reside in the systemic circulation, but are able to cross the blood-brain barrier to exert neuro-active functions both in homeostatic and pathological conditions. Therefore, seaweed-derived constituents have gained increasing interest for their neuro-immunomodulatory and neuroprotective properties, rendering them interesting candidates for the management of several neurodegenerative disorders. In particular seaweed-derived phytosterols gained interest for the treatment of neurodegenerative disorders as they potentiate neuroplasticity, enhance phagocytic clearance of neurotoxic peptides and have anti-inflammatory properties. Though, the anti-inflammatory and anti-oxidative properties of other constituents including carotenoids, phenols and polysaccharides have recently gained more interest. In this review, we provide an overview of a selection of the described neuro-active properties of seaweed-derived constituents with a focus on phytosterols

Edible seaweed-derived constituents: an undisclosed source of neuroprotective compounds

Edible marine algae, or seaweeds, are a rich source of several bioactive compounds including phytosterols, carotenoids, and polysaccharides. Over the last decades, seaweed-derived constituents turned out to not only reside in the systemic circulation, but are able to cross the blood-brain barrier to exert neuro-active functions both in homeostatic and pathological conditions. Therefore, seaweed-derived constituents have gained increasing interest for their neuro-immunomodulatory and neuroprotective properties, rendering them interesting candidates for the management of several neurodegenerative disorders. In particular seaweed-derived phytosterols gained interest for the treatment of neurodegenerative disorders as they potentiate neuroplasticity, enhance phagocytic clearance of neurotoxic peptides and have anti-inflammatory properties. Though, the anti-inflammatory and anti-oxidative properties of other constituents including carotenoids, phenols and polysaccharides have recently gained more interest. In this review, we provide an overview of a selection of the described neuro-active properties of seaweed-derived constituents with a focus on phytosterols

Sub-7 fs radially-polarized pulses by post-compression in thin fused silica plates

We experimentally demonstrate the post-compression of radially polarized 25 fs pulses at 800 nm central wavelength in a multiple thin plate arrangement for the first time, to the best of our knowledge. Sub-7 fs pulses with 90 µJ energy were obtained after dispersion compensation, corresponding to a compression factor of more than 3.5. Preservation of radial polarization state was confirmed by polarized intensity distribution measurements. Linear projections of the radially polarized pulses were also fully characterized in the temporal domain

Plastic deformation of LiNi0.5Mn1.5O4 single crystals due to domain orientation dynamics

The core principles and nanoscale mechanisms of ion deintercalation in battery cathode materials remain poorly understood, in particular, the relationship between crystallographic defects (dislocations, small angle grain boundaries, vacancies, etc.) and microscopic features of Li deintercalation. Here, we used operando scanning X-ray diffraction microscopy (SXDM) to investigate the local strain and lattice tilt inhomogeneities inside Li1−xMn1.5Ni0.5O4 cathode crystals (diameter from 1 to 2 µm) during electrochemical delithiation and lithiation. The technique has been combined to operando multi crystal X-ray diffraction (MCXD) to differentiate between inter- and intra-particle heterogeneity in the sample. Operando SXDM revealed three distinct domains within the crystal that displayed metastable angular rotations of the lattice during both of the phase transitions. These rotations, reaching up to 0.4°, likely arise due to a dynamic lattice mismatch between phases with different unit cell parameters coexisting within the particle. The persistent location of tilt boundaries implies the presence of inherent structural defects locally facilitating the defect formation. Residual misorientations were observed in the particle even after the full discharge suggesting an irreversible change of the lattice structure. Tilt boundaries, affecting ionic conductivity, may impede the rate capability and lead to localized strain, stress, and potential capacity fade due to cracking. However, the observed self-healing angular lattice reorganization could enable the coexistence of two phases in a single crystal. Understanding this phenomenon can optimize cathode material microstructure