Association between sleep apnoea and risk of cognitive impairment and Alzheimer's disease: a meta-analysis of cohort-based studies.

PURPOSE: To provide updated evidence on the association of obstructive sleep apnoea (OSA)/sleep-disordered breathing (SDB) with risk of all-cause cognitive impairment/dementia and Alzheimer's disease (AD). METHODS: A systematic literature search was done in PubMed, EMBASE and Scopus databases for cohort studies (retrospective or prospective) that documented the association of SDB/OSA with the risk of cognitive impairment or all-cause dementia or AD. Only studies that were published in the year 2000 and onwards were included. The random-effects model was used for all the analyses and effect sizes were reported as hazards ratio (HR) with 95% confidence intervals. RESULTS: Of 15 studies were included in the meta-analysis, SDB/OSA was diagnosed with at-home polysomnography in six studies, while five studies relied on self-report or questionnaires. In the remaining studies, International Classification of Diseases (ICD) codes determined the diagnosis of SDB. The overall pooled analysis showed that patients with SDB/OSA had higher risk of cognitive impairment and/or all-cause dementia (HR 1.52, 95% CI: 1.32, 1.74), when compared to patients without SDB/OSA. However, when studies with diagnosis of SDB based on polysomnography were pooled together, the strength of association for all-cause cognitive impairment was weaker (HR 1.32, 95% CI: 1.00, 1.74). CONCLUSION: Findings suggest a possible association of SDB/OSA with risk of all-cause cognitive impairment and/or dementia. However, careful interpretation is warranted as the majority of the studies did not rely on objective assessment based on polysomnography.

YAP regulates porcine skin-derived stem cells self-renewal partly by repressing Wnt/ß-catenin signaling pathway.

Skin-derived stem cells (SDSCs) are a class of adult stem cells (ASCs) that have the ability to self-renew and differentiate. The regulation mechanisms involved in the differentiation of SDSCs are a hot topic. In this paper, we explore the link between the transcriptional regulator yes-associated protein (YAP) and the fate of porcine SDSCs (pSDSCs). We found that lysophosphatidylcholine (LPC) activates YAP, promotes pSDSCs pluripotency, and counteracts transdifferentiation of pSDSCs into porcine primordial germ cell-like cells (pPGCLCs). YAP promotes the pluripotent state of pSDSCs by maintaining the high expression of the pluripotency genes Oct4 and Sox2. The overexpression of YAP prevented the differentiation of pSDSCs, and the depletion of YAP by small interfering RNA (siRNAs) suppressed the self-renewal of pSDSCs. In addition, we found that YAP regulates the fate of pSDSCs through a mechanism related to the Wnt/ß-catenin signaling pathway. When an activator of the Wnt/ß-catenin signaling pathway, CHIR99021, was added to pSDSCs overexpressing YAP, the ability of pSDSCs to differentiate was partially restored. Conversely, when XAV939, an inhibitor of the Wnt/ß-catenin signaling pathway, was added to YAP knockdown pSDSCs a higher self-renewal ability resulted. Taken together, our results suggested that YAP and the Wnt/ß-catenin signaling pathway interact to regulate the fate of pSDSCs.

Cryopreservation of porcine skin-derived stem cells using melatonin or trehalose maintains their ability to self-renew and differentiate.

Porcine skin-derived stem cells (pSDSCs) are a type of adult stem cells (ASCs) that retain the ability to self-renew and differentiate. Currently, pSDSCs research has entered an intense period of development; however there has been no research regarding methods of cryopreservation. In this paper, we explored an efficient cryopreservation method for pSDSCs. Our results demonstrated that cryopreserving 50 µm diameter pSDSCs aggregates resulted in a lower apoptosis rate and a greater ability to proliferate to form larger spherical cell aggregates than during single-cell cryopreservation. To further optimize the cryopreservation method, we added different concentrations of melatonin (N-acetyl-5-methoxytryptamine, MLT) and trehalose (d-trehalose anhydrous, TRE) to act as cryoprotectants (CPAs) for the pSDSCs. After comparative experiments, we found that the cryopreservation efficiency of 50 mM TRE was superior. Further experiments demonstrated that the reason why 50 mM TRE improved cryopreservation efficiency was that it reduced the intracellular oxidative stress and mitochondrial damage caused by cryopreservation. Taken together, our results suggest that cryopreserving 50 µm diameter pSDSCs aggregates in F12 medium with 10% dimethyl sulfoxide (DMSO) and 50 mM TRE promotes the long-term storage of pSDSCs.

Structural Basis for a Dual Function ATP Grasp Ligase That Installs Single and Bicyclic ω-Ester Macrocycles in a New Multicore RiPP Natural Product.

Among the ribosomally synthesized and post-translationally modified peptide (RiPP) natural products, "graspetides" (formerly known as microviridins) contain macrocyclic esters and amides that are formed by ATP-grasp ligase tailoring enzymes using the side chains of Asp/Glu as acceptors and Thr/Ser/Lys as donors. Graspetides exhibit diverse patterns of macrocylization and connectivities exemplified by microviridins, that have a caged tricyclic core, and thuringin and plesiocin that feature a "hairpin topology" with cross-strand ω-ester bonds. Here, we characterize chryseoviridin, a new type of multicore RiPP encoded by Chryseobacterium gregarium DS19109 (Phylum Bacteroidetes) and solve a 2.44 Å resolution crystal structure of a quaternary complex consisting of the ATP-grasp ligase CdnC bound to ADP, a conserved leader peptide and a peptide substrate. HRMS/MS analyses show that chryseoviridin contains four consecutive five- or six-residue macrocycles ending with a microviridin-like core. The crystal structure captures respective subunits of the CdnC homodimer in the apo or substrate-bound state revealing a large conformational change in the B-domain upon substrate binding. A docked model of ATP places the γ-phosphate group within 2.8 Å of the Asp acceptor residue. The orientation of the bound substrate is consistent with a model in which macrocyclization occurs in the N- to C-terminal direction for core peptides containing multiple Thr/Ser-to-Asp macrocycles. Using systematically varied sequences, we validate this model and identify two- or three-amino acid templating elements that flank the macrolactone and are required for enzyme activity in vitro. This work reveals the structural basis for ω-ester bond formation in RiPP biosynthesis.

Structural characteristics and anti-complement activities of polysaccharides from Sargassum hemiphyllum.

Three polysaccharides (SH-1, SH-2 and SH-3) were purified from a brown macroalgea, Sargassum hemiphyllum. The autohydrolysis products from each polysaccharide were separated to three fractions (S fractions as oligomers, L fractions as low molecular weight polysaccharides and H fractions as high molecular weight polysaccharides). Mass spectroscopy of S fractions (SH-1-S, SH-2-S and SH-3-S) showed that these three polymers all contained short stretches of sulfated fucose. The structures of L fractions (SH-1-L, SH-2-L and SH-3-L) were determined by nuclear magnetic resonance (NMR). SH-1-L was composed of two units, unit A (sulfated galactofucan) and unit B (sulfated xylo-glucuronomannan). Unit A contained a backbone of (1, 6-linked ß-D-Gal) n1, (1, 3-linked 4-sulfated α-L-Fuc) n2, (1, 3-linked 2, 4-di-sulfated α-L-Fuc) n3, (1, 4-linked α-L-Fuc) n4 and (1, 3-linked ß-D-Gal) n5, accompanied by some branches, such as sulfated fuco-oligomers, sulfated galacto-oligomers or sulfated galacto-fuco-oligomers. And unit B consisted of alternating 1, 4-linked ß-D-glucuronic acid (GlcA) and 1, 2-linked α-D-mannose (Man) with the Man residues randomly sulfated at C6 or branched with xylose (Xyl) at C3. Both SH-2-L and SH-3-L were composed of unit A and their difference was attributed to the ratio of n1: n2: n3: n4: n5. Based on monosaccharide analysis, we hypothesize that both SH-1-H and SH-2-H contained unit A and unit B while SH-3-H had a structure similar to SH-3-L. An assessment of anti-complement activities showed that the sulfated galactofucan had higher activities than sulfated galacto-fuco-xylo-glucuronomannan. These results suggest that the sulfated galactofucans might be a good candidate for anti-complement drugs.

Evaluation of Turning-Sized Gold Nanoparticles on Cellular Adhesion by Golgi Disruption in Vitro and in Vivo.

In contrast to the booming production and application of nanomaterials, research on the toxicological impacts and possible hazards of nanoparticles to tissues and organs is still in its infancy. Golgi apparatus is one of the most important organelles in cells and plays a key role in intracellular protein processing. The structural integrity of Golgi is vital for its normal function, and Golgi disturbance could result in a wide range of diseases and disorders. In this study, for the first time we found gold nanoparticles (Au NPs) induced size-dependent cytoplasmic calcium increase and Golgi fragmentation, which hampers normal Golgi functions, leads to abnormal protein processing, and causes cellular adhesion decrease, while cell viability was not significantly compromised. Additionally, early renal pathological changes were induced in vivo. This work is significant to nanoparticle research because it illustrates the important role of size on Au NP-induced changes in Golgi morphology and their consequences in vitro and in vivo, which has important implications for the biological applications of nanomaterials.

HDAC10 upregulation contributes to interleukin 1ß-mediated inflammatory activation of synovium-derived mesenchymal stem cells in temporomandibular joint.

Histone deacetylases (HDACs) are important in chronic inflammation, and inflammatory responses affect synovium-derived mesenchymal stem cell (SMSC) function in temporomandibular joint repair. However, the effect of HDACs on SMSC inflammatory activation remains unclear. In this study, temporomandibular joint fibroblast-like synoviocytes obtained from osteoarthritis patients met the minimal mesenchymal stem cell criteria. Interleukin 1ß (IL-1ß) upregulated IL-6 and IL-8 expression in SMSCs through nuclear factor-κB (NF-κB) pathway activation. IL-6 and IL-8 upregulation were blocked by broad-acting HDAC inhibitors SAHA and LBH589. MC1568 alleviated IL-1ß activation of SMSCs, whereas CI994 and FK228 produced a minimal or opposite effect in vitro. We also found HDAC10 was highly associated with localized IL-1ß expression in vivo and in vitro. HDAC10 knockdown alleviated IL-1ß-mediated SMSC activation and blocked NF-κB pathway activation. Conversely, HDAC10 overexpression promoted IL-6 and IL-8 expression and IL-1ß-mediated NF-κB pathway activation. In conclusion, HDAC10 upregulation contributed to IL-1ß-mediated inflammatory activation of SMSCs, indicating that HDAC10 may be a novel therapeutic target.

Temporomandibular joint disorders contribute to anxiety in BalB/C mice.

Despite a high comorbidity between these two disorders, the physiological association between temporomandibular joint disorders (TMDs) and anxiety remains unknown. This study aimed to investigate whether TMDs contribute to anxiety through the induction of oligodendrogenesis in the hippocampus using a mouse model of TMD. Forty 8-week-old male BalB/C mice were used in the experiments. The mice were randomly divided into 4 groups: (1) control group (N group); (2) elevated occlusion group (E group); (3) restriction group (R group); and (4) elevated occlusion and restriction group (ER group). The mice were subjected to behavior tests of open field tests and elevated plus maze analysis. The serum corticosterone levels and expression of mature oligodendrocyte marker MBP and the oligodendrocyte marker RIP were analyzed. All data were statistically analyzed using by one-way analysis of variance. The TMD group showed condylar degeneration compared with the control group. Additionally, exposure to chronic restraint stress for 3 weeks after TMD significantly exacerbated anxiety-like behavior and resulted in a significant increase in serum corticosterone levels and in the expression of MBP and RIP in the dentate gyrus (DG) and CA3 in the hippocampus. Taken together, these data suggest that TMD lead to increased oligodendrogenesis in the hippocampus, which contributes to the development of anxiety-like behavior. TMD could contribute to anxiety by inducing oligodendrogenesis in the hippocampus.

Uncommon Polyoxygenated Sesquiterpenoids from South China Sea Soft Coral Lemnalia flava.

A detailed chemical investigation of the Chinese soft coral Lemnalia flava yielded four new nardosinane-type sesquiterpenoids (1-4), one new neolemnane-type sesquiterpenoid (5), and one new sesquiterpenoid with an uncommon 6/9 fused bicyclic skeleton (6), together with two known related compounds (7 and 8). The structures and absolute configurations of 1-8 were determined on the basis of extensive spectroscopic data analyses, X-ray diffraction analysis, chemical reactions, and computer-assisted structural elucidation including 13C NMR data calculation, residual dipolar coupling based NMR analysis, and time-dependent density functional theoryelectronic circular dichroism calculation. Plausible biogenetic pathways of two uncommon sesquiterpenoids (4 and 6) were proposed.

Chemistry and Biology of Siderophores from Marine Microbes.

Microbial siderophores are multidentate Fe(III) chelators used by microbes during siderophore-mediated assimilation. They possess high affinity and selectivity for Fe(III). Among them, marine siderophore-mediated microbial iron uptake allows marine microbes to proliferate and survive in the iron-deficient marine environments. Due to their unique iron(III)-chelating properties, delivery system, structural diversity, and therapeutic potential, marine microbial siderophores have great potential for further development of various drug conjugates for antibiotic-resistant bacteria therapy or as a target for inhibiting siderophore virulence factors to develop novel broad-spectrum antibiotics. This review covers siderophores derived from marine microbes.

Quorum Sensing Inhibitors from Marine Microorganisms and Their Synthetic Derivatives.

Quorum sensing inhibitors (QSIs) present a promising alternative or potent adjuvants of conventional antibiotics for the treatment of antibiotic-resistant bacterial strains, since they could disrupt bacterial pathogenicity without imposing selective pressure involved in antibacterial treatments. This review covers a series of molecules showing quorum sensing (QS) inhibitory activity that are isolated from marine microorganisms, including bacteria, actinomycetes and fungi, and chemically synthesized based on QSIs derived from marine microorganisms. This is the first comprehensive overview of QSIs derived from marine microorganisms and their synthetic analogues with QS inhibitory activity.

Structure Analysis and Anti-Tumor and Anti-Angiogenic Activities of Sulfated Galactofucan Extracted from Sargassum thunbergii.

Sulfated galactofucan (ST-2) was obtained from Sargassum thunbergii. It was then desulfated to obtain ST-2-DS, and autohydrolyzed and precipitated by ethanol to obtain the supernatant (ST-2-S) and precipitate (ST-2-C). ST-2-C was further fractionated by gel chromatography into two fractions, ST-2-H (high molecular weight) and ST-2-L (low molecular weight). Mass spectrometry (MS) of ST-2-DS was performed to elucidate the backbone of ST-2. It was shown that ST-2-DS contained a backbone of alternating galactopyranose residues (Gal)n (n ≤ 3) and fucopyranose residues (Fuc)n. In addition, ST-2-S was also determined by MS to elucidate the branches of ST-2. It was suggested that sulfated fuco-oligomers might be the branches of ST-2. Compared to the NMR spectra of ST-2-H, the spectra of ST-2-L was more recognizable. It was shown that ST-2-L contain a backbone of (Gal)n and (Fuc)n, sulfated mainly at C4 of Fuc, and interspersed with galactose (the linkages were likely to be 1→2 and 1→6). Therefore, ST-2 might contain a backbone of (Gal)n (n ≤ 3) and (Fuc)n. The sulfation pattern was mainly at C4 of fucopyranose and partially at C4 of galactopyranose, and the branches were mainly sulfated fuco-oligomers. Finally, the anti-tumor and anti-angiogenic activities of ST-2 and its derivates were determined. It was shown that the low molecular-weight sulfated galactofucan, with higher fucose content, had better anti-angiogenic and anti-tumor activities.

Terpenoids from Marine Soft Coral of the Genus Lemnalia: Chemistry and Biological Activities.

Lemnalia is one of the most widely-distributed marine soft coral in tropical oceans and is known to produce novel terpenoids with a broad spectrum of biological activities. This review provides the first comprehensive overview of terpenoids produced by soft coral Lemnalia since their first discovery in 1974.

Albisporachelin, a New Hydroxamate Type Siderophore from the Deep Ocean Sediment-Derived Actinomycete Amycolatopsisalbispora WP1T.

Marine actinobacteria continue to be a rich source for the discovery of structurally diverse secondary metabolites. Here we present a new hydroxymate siderophore produced by Amycolatopsis albispora, a recently described species of this less explored actinomycete genus. Strain WP1T was isolated from sediments collected at -2945 m in the Indian Ocean. The new siderophore, designated albisporachelin, was isolated from iron depleted culture broths and the structure was established by 1D and 2D NMR and MS/MS experiments, and application of a modified Marfey's method. Albisporachelin is composed of one N-methylated-formylated/hydroxylated l-ornithine (N-Me-fh-l-Orn), one l-serine (l-Ser), one formylated/hydroxylated l-ornithine (fh-l-Orn) and a cyclo-N-methylated-hydroxylated l-ornithine (cyclo-N-Me-h-l-Orn).

The LncRNA ZBED3-AS1 induces chondrogenesis of human synovial fluid mesenchymal stem cells.

Human synovial fluid-derived mesenchymal stem cells (SFMSCs) have great potential for cartilage induction and are promising for cell-based strategies for articular cartilage repair. Many long non-coding RNAs (lncRNAs) regulate chondrogenesis of MSCs. We hypothesized that the divergent lncRNA ZBED3-AS1, which binds locally to chromatin, could promote the expression of zbed3, a novel Axin-interacting protein that activates Wnt/ß-catenin signaling, involved in chondrogenesis. However, the function of ZBED3-AS1 in SFMSCs is unclear. In this study, the expression, biological function, and roles of ZBED3-AS1 in SFMSC chondrogenesis were examined by multilineage differentiation, flow cytometry, and gain-of-function studies. We found that ZBED3-AS1 promotes chondrogenesis. Furthermore, ZBED3-AS1 could directly increase zbed3 expression. Finally, the wnt-inhibitor DKK1 could reverse the stimulatory effect of ZBED3-AS1 on chondrogenesis. These findings demonstrate the role of a new lncRNA, ZBED3-AS1, in SFMSC chondrogenesis and may improve osteoarthritis treatment.

A Human Gut Commensal Ferments Cranberry Carbohydrates To Produce Formate.

Commensal bifidobacteria colonize the human gastrointestinal tract and catabolize glycans that are impervious to host digestion. Accordingly, Bifidobacterium longum typically secretes acetate and lactate as fermentative end products. This study tested the hypothesis that B. longum utilizes cranberry-derived xyloglucans in a strain-dependent manner. Interestingly, the B. longum strain that efficiently utilizes cranberry xyloglucans secretes 2.0 to 2.5 mol of acetate-lactate. The 1.5 acetate:lactate ratio theoretical yield obtained in hexose fermentations shifts during xyloglucan metabolism. Accordingly, this metabolic shift is characterized by increased acetate and formate production at the expense of lactate. α-l-Arabinofuranosidase, an arabinan endo-1,5-α-l-arabinosidase, and a ß-xylosidase with a carbohydrate substrate-binding protein and carbohydrate ABC transporter membrane proteins are upregulated (>2-fold change), which suggests carbon flux through this catabolic pathway. Finally, syntrophic interactions occurred with strains that utilize carbohydrate products derived from initial degradation from heterologous bacteria.IMPORTANCE This was a study of bacterial metabolism of complex cranberry carbohydrates termed xyloglucans that are likely not digested prior to reaching the colon. This is significant, as bifidobacteria interact with this dietary compound to potentially impact human host health through energy and metabolite production by utilizing these substrates. Specific bacterial strains utilize cranberry xyloglucans as a nutritive source, indicating unknown mechanisms that are not universal in bifidobacteria. In addition, xyloglucan metabolism proceeds by using an alternative pathway that could lead to further research to investigate mechanisms underlying this interaction. Finally, we observed cross-feeding between bacteria in which one strain degrades the cranberry xyloglucan to make it available to a second strain. Similar nutritive strategies are known to occur within the gut. In aggregate, this study may lead to novel foods or supplements used to impact human health through rational manipulation of the human microbiome.

Tricholides A and B and Unnarmicin D: New Hybrid PKS-NRPS Macrocycles Isolated from an Environmental Collection of Trichodesmium thiebautii.

Bioassay-guided isolation of the lipophilic extract of Trichodesmium thiebautii bloom material led to the purification and structure characterization of two new hybrid polyketide-non-ribosomal peptide (PKS-NRPS) macrocyclic compounds, tricholides A and B (1 and 2). A third macrocyclic compound, unnarmicin D (3), was identified as a new depsipeptide in the unnarmicin family, given its structural similarity to the existing compounds in this group. The planar structures of 1-3 were determined using 1D and 2D NMR spectra and complementary spectroscopic and spectrometric procedures. The absolute configurations of the amino acid components of 1-3 were determined via acid hydrolysis, derivitization with Marfey's reagent and HPLC-UV comparison to authentic amino acid standards. The absolute configuration of the 3-hydroxydodecanoic acid moiety in 3 was determined using a modified Mosher's esterification procedure on a linear derivative of tricharmicin (4) and additionally by a comparison of 13C NMR shifts of 3 to known depsipeptides with ß-hydroxy acid subunits. Tricholide B (2) showed moderate cytotoxicity to Neuro-2A murine neuroblastoma cells (EC50: 14.5 ± 6.2 µM).

PDGF-D/PDGFRß promotes tongue squamous carcinoma cell (TSCC) progression via activating p38/AKT/ERK/EMT signal pathway.

Platelet-derived growth factor D (PDGF-D) signaling plays significant roles during the development and progression of human malignancies via interacting with the receptor of PDGF-D (PDGFR). Meanwhile, the majority of human tumor metastasis is closely associated with epithelial-mesenchymal transition (EMT). However, the underlying mechanism between PDGF-D/PDGFR signaling and EMT which involved in tumor metastasis remain dismal. This study aimed to investigate the role of PDGF-D signaling during EMT process of tongue squamous cell carcinoma (TSCC). In our study, the expression of PDGF-D and PDGFR were examined in primary TSCC samples and the expression of PDGF-D was also determined in TSCC cell lines. In addition, the correlation between PDGF-D expression and TSCC aggressive histopathological features was analyzed. Our results implied that upregulation of PDGFRß in UM1 cells induced with exogenous PDGF-D can remarkably promote tumor cells invasiveness; conversely, when using small interfering RNA (siRNA), the invasiveness can be severely prohibited. Furthermore, PDGF-D downstream signal molecules p38, AKT, ERK and EMT biomarkers (E-cadherin, N-cadherin, Vimentin and snail) were measured using Western blot. Our results showed that PDGF-D can induce p38, AKT and ERK phosphorylation; downregulate epithelial markers and upregulate mesenchymal markers. On the contrary, PDGFRß siRNA significantly prohibited p38, AKT and ERK phosphorylation; inhibited EMT process. Function analysis revealed that PDGFRß siRNA obviously interfered with UM1 cell migration and invasion, according to transwell and wound healing assay. In conclusion, this study suggested that EMT process can be triggered by the PDGF-D/PDGFRß axis in TSCC, and then involved in the tumor cell invasion via activation of p38/AKT/ERK/EMT pathway.

N-Acyl Dehydrotyrosines, Tyrosinase Inhibitors from the Marine Bacterium Thalassotalea sp. PP2-459.

Thalassotalic acids A-C and thalassotalamides A and B are new N-acyl dehydrotyrosine derivatives produced by Thalassotalea sp. PP2-459, a Gram-negative bacterium isolated from a marine bivalve aquaculture facility. The structures were elucidated via a combination of spectroscopic analyses emphasizing two-dimensional NMR and high-resolution mass spectrometric data. Thalassotalic acid A (1) displays in vitro inhibition of the enzyme tyrosinase with an IC50 value (130 µM) that compares favorably to the commercially used control compounds kojic acid (46 µM) and arbutin (100 µM). These are the first natural products reported from a bacterium belonging to the genus Thalassotalea.