L-fucose and fucoidan alleviate high-salt diet-promoted acute inflammation.

Excessive salt intake is a widespread health issue observed in almost every country around the world. A high salt diet (HSD) has a strong correlation with numerous diseases, including hypertension, chronic kidney disease, and autoimmune disorders. However, the mechanisms underlying HSD-promotion of inflammation and exacerbation of these diseases are not fully understood. In this study, we observed that HSD consumption reduced the abundance of the gut microbial metabolite L-fucose, leading to a more substantial inflammatory response in mice. A HSD led to increased peritonitis incidence in mice, as evidenced by the increased accumulation of inflammatory cells and elevated levels of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemotactic protein-1 (MCP-1, also known as C-C motif chemokine ligand 2 or CCL2), in peritoneal lavage fluid. Following the administration of broad-spectrum antibiotics, HSD-induced inflammation was abolished, indicating that the proinflammatory effects of HSD were not due to the direct effect of sodium, but rather to HSD-induced alterations in the composition of the gut microbiota. By using untargeted metabolomics techniques, we determined that the levels of the gut microbial metabolite L-fucose were reduced by a HSD. Moreover, the administration of L-fucose or fucoidan, a compound derived from brown that is rich in L-fucose, normalized the level of inflammation in mice following HSD induction. In addition, both L-fucose and fucoidan inhibited LPS-induced macrophage activation in vitro. In summary, our research showed that reduced L-fucose levels in the gut contributed to HSD-exacerbated acute inflammation in mice; these results indicate that L-fucose and fucoidan could interfere with HSD-promotion of the inflammatory response.

Exogenous l-fucose attenuates neuroinflammation induced by lipopolysaccharide.

α1,6-Fucosyltransferase (Fut8) catalyzes the transfer of fucose to the innermost GlcNAc residue of N-glycan to form core fucosylation. Our previous studies showed that lipopolysaccharide (LPS) treatment highly induced neuroinflammation in Fut8 homozygous KO (Fut8-/-) or heterozygous KO (Fut8+/-) mice, compared with the WT (Fut8+/+) mice. To understand the underlying mechanism, we utilized a sensitive inflammation-monitoring mouse system that contains the human interleukin-6 (hIL6) bacterial artificial chromosome transgene modified with luciferase (Luc) reporter cassette. We successfully detected LPS-induced neuroinflammation in the central nervous system by exploiting this bacterial artificial chromosome transgenic monitoring system. Then we examined the effects of l-fucose on neuroinflammation in the Fut8+/- mice. The lectin blot and mass spectrometry analysis showed that l-fucose preadministration increased the core fucosylation levels in the Fut8+/- mice. Notably, exogenous l-fucose attenuated the LPS-induced IL-6 mRNA and Luc mRNA expression in the cerebral tissues, confirmed using the hIL6-Luc bioluminescence imaging system. The activation of microglial cells, which provoke neuroinflammatory responses upon LPS stimulation, was inhibited by l-fucose preadministration. l-Fucose also suppressed the downstream intracellular signaling of IL-6, such as the phosphorylation levels of JAK2 (Janus kinase 2), Akt (protein kinase B), and STAT3 (signal transducer and activator of transcription 3). l-Fucose administration increased gp130 core fucosylation levels and decreased the association of gp130 with the IL-6 receptor in Fut8+/- mice, which was further confirmed in BV-2 cells. These results indicate that l-fucose administration ameliorates the LPS-induced neuroinflammation in the Fut8+/- mice, suggesting that core fucosylation plays a vital role in anti-inflammation and that l-fucose is a potential prophylactic compound against neuroinflammation.

L-Fucose promotes enteric nervous system regeneration in type 1 diabetic mice by inhibiting SMAD2 signaling pathway in enteric neural precursor cells.

BACKGROUND: Diabetes can lead to extensive damage to the enteric nervous system (ENS), causing gastrointestinal motility disorders. However, there is currently a lack of effective treatments for diabetes-induced ENS damage. Enteric neural precursor cells (ENPCs) closely regulate the structural and functional integrity of the ENS. L-Fucose, is a dietary sugar that has been showed to effectively ameliorate central nervous system injuries, but its potential for ameliorating ENS damage and the involvement of ENPCs in this process remains uncertain. METHODS: Genetically engineered mice were generated for lineage tracing of ENPCs in vivo. Using diabetic mice in vivo and high glucose-treated primary ENPCs in vitro, the effects of L-Fucose on the injured ENS and ENPCs was evaluated by assessing gastrointestinal motility, ENS structure, and the differentiation of ENPCs. The key signaling pathways in regulating neurogenesis and neural precursor cells properties, transforming growth factor-ß (TGF-ß) and its downstream signaling pathways were further examined to clarify the potential mechanism of L-Fucose on the injured ENS and ENPCs. RESULTS: L-Fucose improved gastrointestinal motility in diabetic mice, including increased defecation frequency (p < 0.05), reduced total gastrointestinal transmission time (p < 0.001) and bead expulsion time (p < 0.05), as well as enhanced spontaneous contractility and electric field stimulation-induced contraction response in isolated colonic muscle strips (p < 0.001). The decrease in the number of neurons and glial cells in the ENS of diabetic mice were reversed by L-Fucose treatment. More importantly, L-Fucose treatment significantly promoted the proportion of ENPCs differentiated into neurons and glial cells both in vitro and in vivo, accompanied by inhibiting SMAD2 phosphorylation. CONCLUSIONS: L-Fucose could promote neurogenesis and gliogenesis derived from ENPCs by inhibiting the SMAD2 signaling, thus facilitating ENS regeneration and gastrointestinal motility recovery in type 1 diabetic mice. Video Abstract.

Fucose promotes intestinal stem cell-mediated intestinal epithelial development through promoting Akkermansia-related propanoate metabolism.

Intestinal stem cells (ISCs) are critical for the development and rapid turnover of intestinal epithelium. The regulatory effects of gut microbiota and their metabolites on ISCs stemness remain elusive. Fucose has been demonstrated to mediate host-microbe interactions in the intestine. However, the association between fucose, gut bacteria, and ISCs stemness remains unclear. To investigate the effects of fucose on ISCs-mediated intestinal epithelial cells (IECs) development, we administered fucose to 4-week-old mice for 4 weeks. ISCs stemness, IECs proliferation, and differentiation were examined. Variations in gut microbes and metabolism were detected using 16S rDNA sequencing and metabolomic analysis. Fucose was added to the bacterial culture medium to further study its effects on metabolism. Crypts were isolated from the mouse ileum for organoids culture in vitro to evaluate the effects of metabolites and the underlying mechanism. The results showed that fucose accelerated ISCs proliferation and secretory lineage differentiation in mice, whereas antibiotics eliminated these effects. The composition and functions of gut bacteria were altered by fucose treatment, while significant increases in Akkermansia and propanoate metabolism were noted. Propionic acid and propionate have been shown to promote organoid development. Fucose fermentation increases the production of propionic acid in Akkermansia muciniphila and enhances its ability to increase the stemness of ISCs. Moreover, ileal contents from fucose-treated mice promoted organoid development in a Gpr41/Gpr43-dependent manner. Fucose administration activates the Wnt signaling pathway in ISCs, and Wnt inhibitors suppress the effects of fucose. We conclude that fucose accelerates ISC-mediated intestinal epithelial development by promoting Akkermansia-related propanoate metabolism. These findings provide new insights into the promotion of gut homeostasis and the application potential of fucose as a prebiotic.

Promoting Effect of L-Fucose on the Regeneration of Intestinal Stem Cells through AHR/IL-22 Pathway of Intestinal Lamina Propria Monocytes.

The recovery of the intestinal epithelial barrier is the goal for curing various intestinal injurious diseases, especially IBD. However, there are limited therapeutics for restoring intestinal epithelial barrier function in IBD. The stemness of intestinal stem cells (ISCs) can differentiate into various mature intestinal epithelial cells, thus playing a key role in the rapid regeneration of the intestinal epithelium. IL-22 secreted by CD4+ T cells and ILC3 cells was reported to maintain the stemness of ISCs. Our previous study found that L-fucose significantly ameliorated DSS-induced colonic inflammation and intestinal epithelial injury. In this study, we discovered enhanced ISC regeneration and increased intestinal IL-22 secretion and its related transcription factor AHR in colitis mice after L-fucose treatment. Further studies showed that L-fucose promoted IL-22 release from CD4+ T cells and intestinal lamina propria monocytes (LPMCs) via activation of nuclear AHR. The coculture system of LPMCs and intestinal organoids demonstrated that L-fucose stimulated the proliferation of ISCs through an indirect manner of IL-22 from LPMCs via the IL-22R-p-STAT3 pathway, and restored TNF-α-induced organoid damage via IL-22-IL-22R signaling. These results revealed that L-fucose helped to heal the epithelial barrier by accelerating ISC proliferation, probably through the AHR/IL-22 pathway of LPMCs, which provides a novel therapy for IBD in the clinic.

Oudemansiella raphanipies Polysaccharides Improve Lipid Metabolism Disorders in Murine High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease.

Oudemansiella raphanipies, also called "Edible Queen," is a mushroom that possesses antioxidant, anti-inflammatory, anti-bacterial, anti-tumor and immunity-enhancing properties. The present study aimed to assess the effect of O. raphanipies-derived polysaccharide (ORPS) on the progression of nonalcoholic fatty liver disease (NAFLD) in mice. We studied the structure of ORPS-1 by high-performance gel permeation chromatography (HPGPC), ion chromatography-mass spectrometry (GC-MS), and Fourier transform-infrared spectroscopy (FT-IR). ORPS-1 mainly comprised galactose, fucose, glucose, mannose, and xylose, following an 18:6:6:4:1 molar ratio. In addition, the therapeutic effect as well as a potential mechanism of ORPS-1 in the treatment of high-fat diet (HFD)-induced NAFLD were investigated. The results showed that ORPS-1 improved liver function, ameliorated liver steatosis, and reduced lipid droplet accumulation in HFD mice. A metabolomics approach with GC-MS was utilized to evaluate liver improvement by ORPS-1 treatment. Principal component analysis showed that liver metabolic profiling was significantly altered by HFD feeding or treatment with an intermediate dose of ORPS-1 in mice compared with that of control mice. By investigating the metabolic pathways with identified biomarkers, various pathways such as steroid biosynthesis, valine, leucine, and isoleucine biosynthesis, glycerol phospholipid metabolism, glyceride metabolism, and arginine and proline metabolism in HFD mice were observed to be significantly influenced by ORPS-1 treatment. The results indicate ORPS-1 metabolic effects on liver tissues, provide methods for assessing the molecular impact of ORPS-1 on NAFLD, and suggest the potential mechanism underlying its health benefits.

Sargassum fusiforme fucoidan ameliorates diet-induced obesity through enhancing thermogenesis of adipose tissues and modulating gut microbiota.

Obesity has become a global epidemic. Sargassum fusiforme fucoidan (Fuc) is a group of water-soluble heteropolysaccharides that exhibits a wide range of medicinal functions. It consists of l-fucose and sulfate groups, with l-fucose as the main monosaccharide. This study investigated the therapeutic effects of Fuc on diet-induced obesity (DIO) in C57BL/6J female mice. Fuc significantly alleviated obesity in mice induced by high-fat high-fructose (HFHF) feeding, inhibiting body weight gain, reducing fat accumulation, and improving hepatic steatosis. In addition, Fuc significantly improved glucose tolerance and insulin sensitivity by enhancing the phosphorylation level of AKT (at Ser473) in the adipose tissues. Mechanistically, although Fuc did not decrease the energy intake in DIO mice, it significantly increased the energy expenditure by up-regulating the expression of uncoupling protein 1 (UCP1) in the adipose tissues. Notably, Fuc also improved the obesity-driven dysbiosis of gut microbiota and decreased the relative abundance of the obesity-related intestinal bacteria. However, Fuc was unable to alleviate DIO-induced metabolic disorders in pseudo-sterile mice. Our findings suggested that Fuc might remodel gut microbiota and exert its weight loss and hypolipidemic effects by increasing the energy expenditure, thus providing a novel perspective for treating obesity and related complications.

Structure of a unique fucose-containing exopolysaccharide from Sayram ketteki yoghurt and its anti-MRSA biofilm effect.

In this work, we reported an in situ exopolysaccharide (in situ-EPS1) containing rare fucose produced by Lactobacillus helveticus MB2-1 in Sayram ketteki yoghurt, which made it unique. Its fine structure was characterized by GPC, HPLC, FT-IR, GC-MS,1HNMR and 13CNMR together with two-dimensional (2D) NMR spectra. The results revealed that in situ-EPS1 was a new heteropolysaccharide with molecular weight of 1.06 × 105 Da, and was composed of mannose, rhamnose, glucose, galactose and fucose with the following repeating units. Furthermore, the in situ-EPS1 exhibited significant antibiofilm effect against Methicillin-resistant Staphylococcus aureus (MRSA). Notably, the in situ-EPS1 did not interfere with the planktonic growth of MRSA strain, whereas inhibited its cell metabolic activity and the transcription of genes related to biofilm formation. This unique antibiofilm but non-antibacterial mechanism supposedly prevented the development of bacterial drug resistance, which may open a new door to fight against these drug-resistant microorganisms.

Gastroprotective effect of vitamin U in D-galactosamine-induced hepatotoxicity.

Galactosamine (GalN) is a well-known agent for inducing viral hepatitis models in rodents, but it can cause toxicity on different organs. Vitamin U (Vit U) has been proved as a powerful antioxidant on many toxicity models. The present study was designed to investigate the protective effects of Vit U on GalN-induced stomach injury. Rats were divided into four groups as follows: control (group I), Vit U given animals (50 mg/kg per day; group II), GalN administered animals (500 mg/kg at a single dose; group III), GalN + Vit U given animals (at the same dose and time, group IV). At the end of the 3rd day, animals were killed, and stomach tissues were taken. They were homogenized and centrifuged. In comparison to the control group, glutathione, total antioxidant capacity levels, catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and Na+ /K+ -ATPase activities of GalN group were found to be decreased. On the contrary, lipid peroxidation, advanced oxidized protein products, hexose-hexosamine, fucose, sialic acid, reactive oxygen species levels, as well as the activities of myeloperoxidase, xanthine oxidase, and lactate dehydrogenase were elevated. Administration of Vit U reversed these abnormalities in the GalN group. It can be concluded that Vit U exerts its unique antioxidant effect and prevents GalN-induced gastric damage.

Lens culinaris agglutinin inhibits human hepatoma cell migration via mannose and fucose-mediated ERK1/2 and JNK1/2/3 signalling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is the main types of primary liver cancer, which shows some abnormal glycosylation, such as the increase of fucose. Lens culinaris agglutinin (LCA), a natural plant lectin that can bind to mannose and fucose, has been reported to be antiproliferative to may tumors. However, the effect of LCA on the vitality and migration ability of human hepatoma cells is not demonstrated. Therefore, the aim of this study is to investigate the effects of LCA on vitality and migration in human hepatoma cells and its potential mechanisms. METHODS AND RESULTS: LCA had no significant effect on viability of human hepatoma cells (HCCLM3, MHCC97L and HepG2) and hepatocytes (L02) by CCK-8 kit, but it could inhibit human hepatoma cells migration significantly without affecting hepatocytes by Transwell method. Sugar inhibition assay was used to verify the possible binding site between LCA and human hepatoma cells. The result showed that Mannose- and fucose- related sites were associated with LCA inhibiting human hepatoma cells migration. Moreover, LCA could affect HCCLM3 migration by activating ERK1/2 and JNK1/2/3 signalling pathways. LCA did not affect MMP-2 and MMP-9 of HCCLM3 through gelatinase zymography. However, the results of immunofluorescence standing showed that LCA could reduce the F-actin formation in HCCLM3 via ERK1/2 and JNK1/2/3 signalling pathways. CONCLUSIONS: LCA might inhibit human hepatoma cell migration by reducing the F-actin formation via the mannose and fucose-mediated ERK1/2 and JNK1/2/3 signalling pathway. This result will deepen people's understanding on plant lectin as a drug in tumor glycobiology.

L-Fucose inhibits the progression of cholangiocarcinoma by causing microRNA-200b overexpression.

BACKGROUND: Cholangiocarcinoma (CCA) is a malignant biliary tract tumor with an extremely poor prognosis. There is an urgent demand to explore novel therapeutic strategies. L-fucose has been confirmed to participate in anti-inflammation and antitumor activities. However, the effect of L-fucose on the progression of CCA has not been well investigated. This study aimed to determine whether L-fucose induced the inhibition of CCA and its possible mechanism. METHODS: The anti-growth activity was determined using Cell Counting Kit-8 assay, colony formation assays, Annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) assay, and cell cycle analysis. The anti-metastasis activity was determined by wound healing, transwell, and invasion assays. The anti-angiogenesis activity was determined by tube formation and transwell assays. MicroRNAs that may be involved in the L-fucose-induced CCA inhibition was analyzed using bioinformatics methods. The preclinical therapeutic efficacy was mainly estimated by ultrasound in xenograft nude mouse models. Differences were analyzed via Student's t test or one-way analysis of variance. RESULTS: L-Fucose induced apoptosis and G0/G1 cell cycle arrest, inhibited cell epithelial-mesenchymal transition of CCA cells, and additionally inhibited tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, leading to a decrease in cell proliferation, metastasis, and angiogenesis. Mechanistically, L-fucose induced microRNA-200b (miR-200b) upregulation, and mitogen-activated protein kinase 7 (MAPK7) downregulation was found to be targeted by miR-200b, with decreased cell proliferation and metastasis. Additionally, phosphorylated signal transducer and activator of transcription 3 was found to be downregulated after L-fucose treatment. Finally, in vivo experiments in CCA xenograft models also confirmed the antitumor properties of L-fucose. CONCLUSION: L-Fucose inhibited the progression of CCA via the miR-200b/MAPK7 and signal transducer and activator of transcription 3 signaling pathways.

Comparative study on the mechanisms of anti-lung cancer activities of three sulfated galactofucans.

Sulfated galactofucans, as the active compositions of fucoidan, were reported to exhibit antitumor activity. In the current study, a sulfated galactofucan (SGF) from Sargassum thunbergii and its three derivatives (SGF-H, SGF-L, and SGF-S) were prepared for structural analysis. Structural analysis showed that SGF-H was a high molecular weight sulfated galactofucan (51.5/17.8 kDa) with a high molar ratio of galactose (Gal) to fucose (Fuc) (0.66 : 1), SGF-L was a low molecular weight sulfated galactofucan (17.7 kDa) with a low molar ratio of Gal to Fuc (0.20 : 1), and SGF-S was a mixture (1.7 kDa) of sulfated galacto-fuco-oligomers or fuco-oligomers. It was noteworthy that the linkage of Gal residues in SGF-H was a ß-linkage while SGF-L was an α-linkage. A comparative study on the anti-lung cancer activity in vitro and in vivo, antimetastatic effects, the metastasis-associated protein expression, and binding abilities to fibroblast growth factors (FGFs) of SGF, SGF-H, and SGF-L was performed to understand the structure-activity relationship. To some extent, SGF-L showed the strongest activity in the inhibition of human lung cancer cells A549 cell proliferation, while SGF-H exhibited the strongest activity in the inhibition of human bronchial epithelial cells BEAS-2B cell proliferation. SGF-L showed the strongest antimetastatic activity, followed by SGF-H and SGF. The expression of metastasis-associated proteins showed only a small difference. The in vivo tumor inhibition of SGF, SGF-H, and SGF-L was 45%, 41%, and 31%, respectively. SPR analysis showed SGF-H binds preferentially to FGF1 and FGF2, while SGF-L preferentially binds to FGF7 and FGF10, suggesting that the anti-lung cancer activity from sulfated galactofucan could involve the FGF-FAK/mTOR pathway.

N-Glycomic Analysis of the Cell Shows Specific Effects of Glycosyl Transferase Inhibitors.

Glycomic profiling methods were used to determine the effect of metabolic inhibitors on glycan production. These inhibitors are commonly used to alter the cell surface glycosylation. However, structural analysis of the released glycans has been limited. In this research, the cell membranes were enriched and the glycans were released to obtain the N-glycans of the glycocalyx. Glycomic analysis using liquid chromatography-mass spectrometry (LC-MS) with a PGC chip column was used to profile the structures in the cell membrane. Glycans of untreated cells were compared to glycans of cells treated with inhibitors, including kifunensine, which inhibits the formation of complex- and hybrid-type structures, 2,4,7,8,9-Penta-O-acetyl-N-acetyl-3-fluoro-b-d-neuraminic acid methyl ester for sialylated glycans, 2-deoxy-2-fluorofucose, and 6-alkynyl fucose for fucosylated glycans. Kifunensine was the most effective, converting nearly 95% of glycans to high mannose types. The compound 6-alkynyl fucose inhibited some fucosylation but also incorporated into the glycan structure. Proteomic analysis of the enriched membrane for the four inhibitors showed only small changes in the proteome accompanied by large changes in the N-glycome for Caco-2. Future works may use these inhibitors to study the cellular behavior associated with the alteration of glycosylation in various biological systems, e.g., viral and bacterial infection, drug binding, and cell-cell interactions.

Polygalacto-fucopyranose biopolymer structured nanoparticle conjugate attenuates glucocorticoid-induced osteoporosis: An in vivo study.

Naturally occurring polysaccharide-structured nanoparticles have developed as promising materials for treatment of bone health disorders. Silver nanoparticle (ST-AgNP) structured from sulfated polygalacto-fucopyranose comprising of recurring structural entities of 2-SO3-α-(1 â†’ 3)-fucopyranose and 6-O-acetyl-ß-(1 â†’ 4)-galactopyranose isolated from marine macroalga Sargassum tenerrimum demonstrated potential activities associated with osteogenesis. Subsequent treatment with ST-AgNP, activity of alkaline phosphatase (63 mU/mg) was raised in osteoblast stem cells (human mesenchymal, hMSC) than that in control (30 mU/mg). Intense growth of mineralized nodule on the surface of hMSC was apparent following treatment with ST-AgNP. Increased population of bone morphogenic protein-2 (23%) and osteocalcin+ cells (50%) on M2 macrophages were apparent following treatment with ST-AgNP (0.25 mg/mL). Glucocorticoid-induced in vivo animal model studies of ST-AgNP exhibited significant recovery of serum biochemical parameters along with serum estradiol and parathyroid hormone compared to disease control. Disease-induced groups treated with ST-AgNP showed the disappearance of osteoporotic cavities in the trabecular bone. Following treatment with ST-AgNP, serum calcium and phosphorus contents were significantly recovered.

Molecular Mechanism of Anti-Inflammatory Activities of a Novel Sulfated Galactofucan from Saccharina japonica.

Seaweed of Saccharina japonica is the most abundantly cultured brown seaweed in the world, and has been consumed in the food industry due to its nutrition and the unique properties of its polysaccharides. In this study, fucoidan (LJNF3), purified from S. japonica, was found to be a novel sulfated galactofucan, with the monosaccharide of only fucose and galactose in a ratio of 79.22:20.78, and with an 11.36% content of sulfate groups. NMR spectroscopy showed that LJNF3 consists of (1→3)-α-l-fucopyranosyl-4-SO3 residues and (1→6)-ß-d-galactopyranose units. The molecular mechanism of the anti-inflammatory effect in RAW264.7 demonstrated that LJNF3 reduced the production of nitric oxide (NO), and down-regulated the expression of MAPK (including p38, ENK and JNK) and NF-κB (including p65 and IKKα/IKKß) signaling pathways. In a zebrafish experiment assay, LJNF3 showed a significantly protective effect, by reducing the cell death rate, inhibiting NO to 59.43%, and decreasing about 40% of reactive oxygen species. This study indicated that LJNF3, which only consisted of fucose and galactose, had the potential to be developed in the biomedical, food and cosmetic industries.

Role of NMDA Receptors and Protein Synthesis in the Conditioned Aversion Learning in Young Chicks.

The brain mechanisms underlying conditioned aversion learning in birds were studied using experimental model in young chicks. The learning consisted of a conditioning stimulus presentation followed by a delayed sickness-inducing treatment reinforcement. Intraventricular administration of an NMDA receptor antagonist MK-801, a protein synthesis inhibitor anisomycin, or an inhibitor of glycoprotein fucosylation 2-deoxygalactose just before presentation of the conditioning stimulus prevented aversion learning. Injections of the same chemicals before reinforcement did not affect learning. The obtained results show that the investigated mechanisms underlying aversion learning were critical at the early stage of memory formation. Later processes of association of the conditioning stimulus with the reinforcement appear to be independent of the NMDA receptors and protein synthesis/glycosylation, or alternatively to be located in other brain areas.

Exogenous l-fucose protects the intestinal mucosal barrier depending on upregulation of FUT2-mediated fucosylation of intestinal epithelial cells.

FUT2, a protein that uses l-fucose to mediate fucosylation of intestinal epithelial cells, is one of the detected gene variants in IBD patients. We aimed to investigate whether exogenous l-fucose could be an enteral nutritional supplement to protect intestinal barrier function. The effect of l-fucose on the restoration of epithelial barrier function in both the DSS-induced colitis mouse model and LPS-stimulated Caco-2 cells was investigated, and the impact on fucosylation of epithelial cells was examined. The severity of DSS-induced colitis was significantly reduced by l-fucose. Restoration of epithelial barrier function by l-fucose was detected. Direct l-fucose-mediated protection of tight junctions was observed in Caco-2 cells. Moreover, exogenous l-fucose promoted the exogenous metabolic pathway of l-fucose, and fucosylation of epithelial cells both in vivo and in vitro. Moreover, knockout of the FUT2 gene restrained fucosylation and the protective effect of l-fucose on barrier function. The severity of colitis was not improved by l-fucose in Fut2 knockout mice. Therefore we conclude that exogenous l-fucose protects intestinal barrier function and relieves intestinal inflammation via upregulation of FUT2-mediated fucosylation of intestinal epithelial cells.

Polygalacto-fucopyranose from marine alga as a prospective antihypertensive lead.

Consumption of marine alga-based polysaccharides as additional functional foods can endow with health benefits by diminishing the risk of chronic diseases. A polygalacto-fucopyranose characterized as [→1)-2, 4-SO3-α-Fucp-(3 → 1)-{2-SO3-α-Fucp-(3→}] with [(4 → 1)-6-OAc-ß-Galp-(4→] side chain isolated from marine alga Sargassum wightii exhibited potential antihypertensive activity. Upon treatment with studied polygalactofucan (50 mg/kg BW), serum hypertension biomarkers troponin-T (1.3 pg/mL), troponin-I (1.2 µg/dL) and angiotensin-II converting enzyme (0.18 pg/mL) were significantly recovered in hypertensive rats compared to disease control. Serum cardiovascular risk indices of diseased rats were significantly decreased (< 10%, p < 0.05) after administration of the studied galactofucan (50 mg/kg BW) related to hypertension group (> 17%), and were comparable with standard antihypertensive agent telmisartan (8.3-10.2% at 2 mg/kg BW). The studied compound was safe for consumption as obvious from the high LD50 value (>5 g/kg), and could be developed as a prospective functional food ingredient attenuating the pathophysiological attributes causing hypertension-related conditions.

Structural Characterization and Heparanase Inhibitory Activity of Fucosylated Glycosaminoglycan from Holothuria floridana.

Unique fucosylated glycosaminoglycans (FG) have attracted increasing attention for various bioactivities. However, the precise structures of FGs usually vary in a species-specific manner. In this study, HfFG was isolated from Holothuria floridana and purified by anion exchange chromatography with the yield of ~0.9%. HfFG was composed of GlcA, GalNAc and Fuc, its molecular weight was 47.3 kDa, and the -OSO3-/-COO- molar ratio was 3.756. HfFG was depolymerized by a partial deacetylation-deaminative cleavage method to obtain the low-molecular-weight HfFG (dHfFG). Three oligosaccharide fragments (Fr-1, Fr-2, Fr-3) with different molecular weights were isolated from the dHfFG, and their structures were revealed by 1D and 2D NMR spectroscopy. HfFG should be composed of repeating trisaccharide units -{(L-FucS-α1,3-)d-GlcA-ß1,3-d-GalNAc4S6S-ß1,4-}-, in which sulfated fucose (FucS) includes Fuc2S4S, Fuc3S4S and Fuc4S residues linked to O-3 of GlcA in a ratio of 45:35:20. Furthermore, the heparanase inhibitory activities of native HfFG and oligosaccharide fragments (Fr-1, Fr-2, Fr-3) were evaluated. The native HfFG and its oligosaccharides exhibited heparanase inhibitory activities, and the activities increased with the increase of molecular weight. Additionally, structural characteristics such as sulfation patterns, the terminal structure of oligosaccharides and the presence of fucosyl branches may be important factors affecting heparanase inhibiting activity.

Hexavalent thiofucosides to probe the role of the Aspergillus fumigatus lectin FleA in fungal pathogenicity.

Aspergillus fumigatus is a pathogenic fungus infecting the respiratory system and responsible for a variety of life-threatening lung diseases. A fucose-binding lectin named FleA which has a controversial role in A. fumigatus pathogenesis was recently identified. New chemical probes with high affinity and enzymatic stability are needed to explore the role of FleA in the infection process. In this study, we developed potent FleA antagonists based on optimized and non-hydrolysable thiofucoside ligands. We first synthesized a set of monovalent sugars showing micromolar affinity for FleA by isothermal titration calorimetry. The most potent derivative was co-crystallized with FleA to gain insights into the binding mode in operation. Its chemical multimerization on a cyclodextrin scaffold led to an hexavalent compound with a significantly enhanced binding affinity (Kd = 223 ± 21 nM) thanks to a chelate binding mode. The compound could probe the role of bronchial epithelial cells in a FleA-mediated response to tissue invasion.