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Polyguluronate (PG) consists entirely of α-L-guluronic acid derived from alginate, which is an acidic polysaccharide extracted from brown algae. PG has a short half-life and is easily degraded by microorganisms, resulting in decreased activity and thus its application in the medical field. In this study, polyguluronate liposomes (PGLs) were prepared to improve the macrophage-stimulating activity of PG. The morphology, encapsulation efficiency, particle size distribution, zeta potential and stability of the PGLs were characterized. Results showed that PGLs were uniformly round with an encapsulation efficiency of 77.76 ± 0.89%, a particle size of 63.96 ± 3.98 nm and a zeta potential of -53.4 ± 1.75 mV. The stability studies showed that PGLs should be stored in a neutral environment at 4 °C. The macrophage-stimulating activity of PGLs was better than that of PG. This study provides a promising carrier for the further application of PG in food or medicine.

Polyguluronic acid (PG) is a type of polysaccharide found in edible brown seaweeds. This study synthesized a new sulfated saccharide (SOGA) by sulfating PG-derived unsaturated oligoguluronic acid (OGA). The molecular weight and degree of sulfate-group substitution of SOGA were 1.6 kDa and 1.03, respectively. The structures of PG, OGA, and SOGA were elucidated using FT-IR and NMR spectroscopy. Furthermore, the immunomodulatory effects of PG, OGA, and SOGA on LPS-triggered RAW264.7 and BV2 cells were evaluated. SOGA, but not PG or OGA, significantly reduced the LPS-stimulated overproduction of proinflammatory mediators and suppressed the activation of corresponding signalling pathways. Also, SOGA could actively regulate immune balance by inhibiting apoptosis and pyroapoptosis. These results suggested that SOGA is a potential therapeutic agent for the prevention of diseases associated with immune disorders owing to its remarkable immunomodulatory effects, and that sulfate groups in the carbohydrate chain play a crucial role for its bioactivities.

Alzheimer's disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules is considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.

Alginate, a linear polymer consisting of β-D-mannuronic acid (M) and α-L-guluronic acid (G) with 1,4-glycosidic linkages and comprising 40% of the dry weight of algae, possesses various applications in the food and nutraceutical industries. However, the potential applications of alginate are restricted in some fields because of its low water solubility and high solution viscosity. Alginate oligosaccharides (AOS) on the other hand, have low molecular weight which result in better water solubility. Hence, it becomes a more popular target to be researched in recent years for its use in foods and nutraceuticals. AOS can be obtained by multiple degradation methods, including enzymatic degradation, from alginate or alginate-derived poly G and poly M. AOS have unique bioactivity and can bring human health benefits, which render them potentials to be developed/incorporated into functional food. This review comprehensively covers methods of the preparation and analysis of AOS, and discussed the potential applications of AOS in foods and nutraceuticals.

European eel (Anguilla anguilla) is considered to be a vital commercial fish species. In this study, the effect and molecular mechanism of bioactive peptides from European eel on macrophage-stimulating activity in RAW264.7 cells were investigated. Eel peptide (EP) markedly induced NO and iNOS production and promoted TNF-α and IL-6 secretion in a concentration-dependent manner. Moreover, EP dose-dependently activated NF-κB and MAPK signaling pathways in RAW264.7 cells. In addition, EP was purified using a Sephadex A-25 column and a Bio-Gel P-6 column, and the fraction (Fr-1-1) showing the strongest NO-inducing activity was obtained. Then, the molecular weights of the components in Fr-1-1 were analyzed by LC-MS/MS and found to range from 700 to 1900 Da for the majority of components, which suggested that Fr-1-1 mainly consisted of peptides containing 8-20 amino acid residues. Overall, our results indicated that EP from Anguilla anguilla activated macrophages and could be used as a potential nutraceutical or pharmaceutical.

Alginate is a dietary polysaccharide that exerts antioxidative, immunomodulatory and anti-allergic effects. In this study, the effects of alginate on the secondary structure of ovalbumin (OVA) in vitro and on the regulation of OVA-induced gut microbiota disorders in vivo were investigated. First, the interactions between OVA and alginate were studied by multiple spectroscopic methods, which showed that alginate could change the secondary structure of OVA. Then, the regulation of allergic diarrhoea by alginate was evaluated in OVA-sensitized mice, which demonstrated that alginate could attenuate allergic diarrhoea and duodenal morphological damage. Additionally, when diarrhoea symptoms were ameliorated by alginate, the richness and diversity of the gut microbiota could be partially restored, and the relative abundances of Alloprevotella, Bacteroides, Parabacteroides and Rikenellaceae_RC9_gut_group showed recovery trends. Therefore, alginate could improve OVA-induced gut microbiota disorder, and alginate could be used as a potential agent for intestinal protection in the food or pharmaceutical industry.

Alginate is an unbranched polymer composed of polymannuronate (PM) and polyguluronate and widely used as a colloid in food industries. Seleno-polymannuronate (Se-PM), a kind of seleno-polysaccharide, was synthesized through selenylation replacement reaction of PM. And its neuroimmunoregulatory activity in LPS-induced BV2 cells and in vivo septic shock model was conducted. Se-PM could significantly attenuate the NO and PGE2 secretion, as well as the iNOS and COX-2 expression, and the release of TNF-α and IL-1β, 6 and 12 in LPS-activated microglia. Meanwhile, the changes in cellular morphology and migration were recovered by pretreating the LPS-activated microglia with Se-PM. Moreover, the overactivation of the NF-κB and MAPK signaling pathways stimulated by LPS in BV2 microglia was prominently alleviated by Se-PM. In the septic shock mouse model, Se-PM could remarkably decrease the TNF-α and IL-6 production in the serum and brain. These results indicate that alginate-derived Se-PM is a good candidate to be used in alternative/supplementary medication or functional foods for treating/managing neurodegenerative disorder.

Unsaturated mannuronate oligosaccharide (MOS) is an enzymatic depolymerization product from alginate-derived polymannuronate (PM). In this study, we investigated for the first time the potential therapeutic effect of MOS on Alzheimer's disease (AD) and its molecular mechanism in N2a-sw cells and 3×Tg-AD primary cortex neurons. Our results showed that MOS ranges from mannuronate dimer to mannuronate undecamer (M2-M11) with an unsaturated nonreducing terminal structure and with a double bond and 1,4-glycosidic linkages. It significantly inhibited the aggregation of amyloid-β (Aβ)1-42 oligomer, decreased expression of Aβ1-42 and reduced levels of amyloid precursor protein (APP) and BACE1. It promoted the autophagy, which involves the inactivation of mTOR signaling pathway and the facilitation of the fusion of autophagosomes and lysosomes. Finally, autophagy inhibitors blocked MOS' anti-AD actions, confirming the involvement of autophagy. In conclusion, MOS from seaweed alginate might be a promising nutraceutical or natural medicine for AD therapy.

Background Euglena is a new super health food resource that is rich in the natural polysaccharide paramylon, a linear β-1,3-glucan with various biological activities including activity on the immune system in different cell lines and animals. Despite these reports, the immune regulation mechanism of paramylon is still unclear. Results We investigate the signaling pathways paramylon impacts in immune macrophages. In RAW264.7 macrophages, sonicated and alkalized paramylon oligomers up-regulated inducible nitric oxide synthase (iNOS) and increased secretion of nitric oxide (NO), interleukin (IL)-6 and tumor necrosis factor (TNF)-α, in a concentration-dependent manner. In addition, paramylon activated the nuclear factor-κB(NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways and inhibiting these pathways attenuated the paramylon-induced secretion of the above immune-mediators. Conclusions These results demonstrate that Euglena gracilis paramylon modulates the immune system via activation of the NF-κB and MAPK signaling pathways and thus has potential therapeutic benefits.

Seleno-polymannuronate (Se-PM) was prepared from alginate-derived polymannuronate (PM) through a sulfation followed by a selenylation replacement reaction. The organic selenium content of Se-PM was 437.25 μg/g and its average molecular weight was 2.36 kDa. The neuroprotection effect of Se-PM and corresponding molecular mechanisms were investigated. Our results showed that, comparing to both sulfated PM (S-PM) and PM, Se-PM remarkably inhibited the aggregation of Aβ1–42 oligomer in vitro and significantly reduced the APP and BACE1 protein expression in N2a-sw cells, highlighting the critical function of the selenium presented in Se-PM. Moreover, Se-PM decreased the expression of cytochrome c and the ratio of Bax to Bcl-2, and enhanced the mitochondrial membrane potential in N2a-sw cells. These results suggested that Se-PM treatment can markedly inhibit N2a-sw cell apoptosis and promote N2a-sw cell survival and that Se-PM might be a potential therapeutic agent for the prevention of neurodegeneration owing to its remarkable neuroprotection effect.

Alzheimer's disease (AD) is a common neurodegenerative disease which is partly characterized by the aggregation of hyperphosphorylated Tau proteins forming neurofibrillary tangles that promote AD pathogenesis. In this study, we investigated the effects of tanshinone IIA (Tan IIA) isolated from Salvia miltiorrhiza on Tau degradation in the treatment of AD. The results showed that Tan IIA reduced the Tau expression and attenuated Tau phosphorylation in N2a cells, Tau-overexpressing cells, and 3×Tg-AD mouse primary neuron cells. Moreover, Tan IIA increased polyubiquitinated Tau accumulation and induced proteasomal degradation of the Tau protein. Additionally, Tan IIA became bound to the Tau protein and inhibited the formation of heparin-induced Tau fibrils. In summary, Tan IIA can increase polyubiquitinated Tau accumulation and induce the proteasomal degradation of the Tau protein and the binding of Tan IIA to the Tau protein, inhibiting the formation of Tau fibrils. Tan IIA may be further explored as a potential candidate for AD treatment.

Polymannuronate (PM) is an acidic polymer separated from alginate. PM is a linear block polysaccharide in edible brown algae that has been widely used in the food industry. Seleno-polymannuronate (Se-PM) is a seleno-derivative of PM synthesized from PM and Na2SO3 in our laboratory. We investigated the anti-neuroinflammatory activity of Se-PM in lipopolysaccharide (LPS)-activated primary microglia and astrocytes and a mouse model of acute inflammation. Our results show that Se-PM could markedly reduce NO and PGE2 production, iNOS and COX-2 expression, and TNF-α, IL-1β and IL-6 secretion in LPS-treated primary microglia and astrocytes. Moreover, the LPS-triggered overactivation of NF-κB and MAPK signalling was attenuated by Se-PM. In addition, in vivo, LPS-induced microglial and astrocytic activation was remarkably suppressed by Se-PM. These results suggest that Se-PM merits exploration as an alternative medicinal or functional food for alleviating neuroinflammation.

Unsaturated guluronate oligosaccharide (GOS) was prepared from alginate-derived homopolymeric blocks of guluronic acid by alginate lyase-mediated depolymerization. In this study, a GOS-based water-in-oil-in-water (W1/O/W2) nanoemulsion was prepared, and different influencing factors were investigated. First, linseed oil was selected as the optimal carrier oil. Then, other optimal conditions of the GOS nanoemulsion were determined based on response surface methodology (RSM). Under the optimal conditions, the obtained GOS nanoemulsion showed a spherical structure with an average particle size of 273.93 ± 8.91 nm, and its centrifugal stability was 91.37 ± 0.45 %. Moreover, the GOS nanoemulsion could achieve the aim of sustained release in vitro and be stably stored at 4°C for at least 5 days. This work prepared a novel GOS-based W1/O/W2 nanoemulsion that may effectively address the storage difficulties of unsaturated GOS and provides a valuable contribution to the application of GOS in the food and medicine fields.

Alginate is a naturally acidic polysaccharide consisting alternately of β-d-mannuronic acid and α-l-guluronic acid with 1, 4-glycosidic linkages and is derived from brown seaweeds. Herein, the effect of alginate on the promotion of macrophage phagocytosis and the corresponding molecular mechanisms were investigated in murine RAW264.7 cells. Alginate could enhance the intracellular phagocytosis of gold nanoparticles (AuNPs), fluorescent microspheres and immunoglobulin G (IgG)-opsonized Staphylococcus aureus (S. aureus). Moreover, alginate increased Toll-like receptor 4 (TLR4) expression and activated the Akt/nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signalling pathways. Alginate-promoted phagocytosis was suppressed by the addition of inhibitors of TLR4, NF-κB and p38 MAPK and by TLR4 gene knockdown, indicating the involvement of these key components. This work is the first to propose that alginate promotes phagocytosis via upregulating TLR4 expression and stimulating the Akt/NF-κB and p38 MAPK signalling pathways, which may contribute to the capacity of alginate to activate macrophages.

Alginate-derived polymannuronate (PM) is a type of polysaccharide found in edible brown seaweeds. Seleno-polymannuronate (Se-PM) was prepared from PM via synthesis using sulfation- and selenation-replacement reactions. The anti-inflammatory activity of Se-PM and its corresponding molecular mechanisms were investigated. In lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cells, Se-PM significantly attenuated the production of nitric oxide (NO), prostaglandin E2 (PGE2), and reactive oxygen species (ROS); the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); and the secretion of proinflammatory cytokines. Moreover, Se-PM remarkably suppressed the LPS-induced activation of the nuclear-factor (NF)-κB and mitogen-activated-protein-kinase (MAPK) signaling pathways in RAW264.7 cells. Furthermore, Se-PM also decreased the production of proinflammatory mediators in LPS-triggered primary murine macrophages. Additionally, Se-PM inhibited the inflammatory response in the a...

Alginate is a natural polysaccharide extracted from various species of marine brown algae. Alginate-derived guluronate oligosaccharide (GOS) obtained by enzymatic depolymerization has various pharmacological functions. Previous studies have demonstrated that GOS can trigger the production of inducible nitric oxide synthase (iNOS)/nitric oxide (NO), reactive oxygen species (ROS) and tumor necrosis factor (TNF)-α by macrophages and that it is involved in the nuclear factor (NF)-κB and mitogen-activated protein (MAP) kinase signaling pathways. To expand upon the current knowledge regarding the molecular mechanisms associated with the GOS-induced immune response in macrophages, comparative proteomic analysis was employed together with two-dimensional electrophoresis (2-DE), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS) and Western blot verification. Proteins showing significant differences in expression in GOS-treated cells were categorized into multiple functional pathways, including the NF-κB signaling pathway and pathways involved in inflammation, antioxidant activity, glycolysis, cytoskeletal processes and translational elongation. Moreover, GOS-stimulated changes in the morphologies and actin cytoskeleton organization of RAW264.7 cells were also investigated as possible adaptations to GOS. This study is the first to reveal GOS as a promising agent that can modulate the proper balance between the pro- and anti-inflammatory immune responses, and it provides new insights into pharmaceutical applications of polysaccharides.

Alginate, a natural acidic polysaccharide extracted from marine brown seaweeds, is composed of different blocks of β-(1, 4)-D-mannuronate (M) and its C-5 epimer α-(1, 4)-L-guluronate (G). Alginate-derived guluronate oligosaccharide (GOS) readily activates macrophages. However, to understand its role in immune responses, further studies are needed to characterize GOS transport and signalling. Our results show that GOS is recognized by and upregulates Toll-like receptor 4 (TLR4) on RAW264.7 macrophages, followed by its endocytosis via TLR4. Increased expression of TLR4 and myeloid differentiation protein 2 (MD2) results in Akt phosphorylation and subsequent activation of both nuclear factor-κB (NF-κB) and mechanistic target of rapamycin (mTOR). Moreover, GOS stimulates mitogen-activated protein kinases (MAPKs); notably, c-Jun N-terminal kinase (JNK) phosphorylation depends on TLR4 initiation. All these events contribute to the production of inflammatory mediators, either together or separately. Our findings also reveal that GOS induces cytoskeleton remodelling in RAW264.7 cells and promotes macrophage proliferation in mice ascites, both of which improve innate immunity. Conclusively, our investigation demonstrates that GOS, which is dependent on TLR4, is taken up by macrophages and stimulates TLR4/Akt/NF-κB, TLR4/Akt/mTOR and MAPK signalling pathways and exerts impressive immuno-stimulatory activity.

Alginate from marine seaweeds is receiving continuous attention owing to its wide physiological activities. Herein, we sought to elucidate possible effects of alginate-derived polyguluronate (PG) and unsaturated guluronate oligosaccharide (GOS) on antibacterial activities of macrophages. Our results showed that, in contrast to PG, GOS markedly increased the phagocytosis of IgG-opsonized Escherichia coli and Staphylococcus aureus and further inhibited the survival of intracellular bacteria in macrophages. In line with this, GOS treatment resulted in the enhanced expression of Fcγ receptors on macrophages. In addition, GOS activated NF-κB pathway, induced TNF-α secretion, and elevated the expression of inducible nitric oxide synthase and the production of nitric oxide. Meanwhile, GOS stimulated the production of reactive oxygen species in macrophages. Moreover, guluronate trimer to hexamer (G3-G6) in GOS exhibited significant activity that increased the bacterial phagocytosis of macrophages, with the pentamer (G5), displaying the highest activity. Finally, our in vivo results further confirmed that GOS but not PG significantly improved bacterial clearance in murine acute peritonitis. In conclusion, GOS enhances antibacterial activities of macrophages via modulating signaling pathways related to innate immunity, suggesting that GOS might be a promising therapeutic candidate to improve the host defense against bacterial infection.

Alginate from marine brown algae has been widely applied in biotechnology. In this work, the effects of alginate-derived oligosaccharide (AdO) on lipopolysaccharide (LPS)/β-amyloid (Aβ)-induced neuroinflammation and microglial phagocytosis of Aβ were studied. We found that pretreatment of BV2 microglia with AdO prior to LPS/Aβ stimulation led to a significant inhibition of production of nitric oxide (NO) and prostaglandin E2 (PGE2), expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and secretion of proinflammatory cytokines. We further demonstrated that AdO remarkably attenuated the LPS-activated overexpression of toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB in BV2 cells. In addition to the impressive inhibitory effect on neuroinflammation, we also found that AdO promoted the phagocytosis of Aβ through its interaction with TLR4 in microglia. Our results suggested that AdO exerted the inhibitory effect on neuroinflammation and the promotion effect on microglial phagocytosis, indicating its potential as a nutraceutical or therapeutic agent for neurodegenerative diseases, particularly Alzheimer’s disease (AD).