Rapid Discovery of Aß42 Fibril Disintegrators from Ganoderma lucidum via Ligand Fishing and Their Neuroprotective Effects on Alzheimer's Disease.

An amyloid-ß (Aß) fibril is a vital pathogenic factor of Alzheimer's disease (AD). Aß fibril disintegrators possess great potential to be developed into novel anti-AD agents. Here, a ligand fishing method was employed to rapidly discover Aß42 fibril disintegrators from Ganoderma lucidum using Aß42 fibril-immobilized magnetic beads, which led to the isolation of six Aß42 fibril disintegrators including ganodermanontriol, ganoderic acid DM, ganoderiol F, ganoderol B, ganodermenonol, and ergosterol. Neuroprotective evaluation in vitro exhibited that these Aß42 fibril disintegrators could significantly mitigate Aß42-induced neurotoxicity. Among these six disintegrators, ergosterol and ganoderic acid DM with stronger protecting activity were further selected to evaluate their neuroprotective effect on AD in vivo. Results showed that ergosterol and ganoderic acid DM could significantly alleviate Aß42-induced cognitive dysfunction and hippocampus neuron loss in vivo. Moreover, ergosterol and ganoderic acid DM could significantly inhibit Aß42-induced neuron apoptosis and Nrf2-mediated neuron oxidative stress in vitro and in vivo.

Codonopsis lanceolata polysaccharide ameliorates high-fat diet induced-postpartum hypogalactia via stimulating prolactin receptor-mediated Jak2/Stat5 signaling.

This study aims to investigate the ameliorative effect of Codonopsis lanceolata polysaccharide (PCL) on mice with hypogalatia induced by a high-fat diet (HFD) and the potential underlying mechanism. We found that oral administration of PCL demonstrated significant benefits in countering the negative effects of HFD, including weight gain, hepatic steatosis, mesenteric adipocyte hypertrophy, and abnormal glucose/lipid metabolism. In addition, PCL improved mammary gland development and enhanced lactogenesis performance. Histologically, PCL ameliorated the retardation of ductal growth, reduced mammary fat pad thickness, improved the incomplete linear encapsulation of luminal epithelium and myoepithelium, and increased the proliferation of mammary epithelial cells. Flow cytometry analysis showed that PCL mitigated the detrimental effects of HFD on mammary gland development by promoting the proliferation and differentiation of mammary epithelial cells. Mechanistic studies revealed that PCL upregulated the levels of prolactin (PRL) and its receptor (PRLR) in the mammary gland, activated JAK2/STAT5 signaling pathway, and increased the expression of p63, ERBB4, and NRG1. Overall, PCL can ameliorate HFD-induced hypogalactia by activating PRLR-mediated JAK2/STAT5 signaling. Our findings offer a methodological and theoretical foundation for investigating the functional constituents of traditional Chinese medicine in the treatment of hypogalactia.

Purification, structural characteristics and anti-atherosclerosis activity of a novel green tea polysaccharide.

A new homogeneous polysaccharide (TPS3A) was isolated and purified from Tianzhu Xianyue fried green tea by DEAE-52 cellulose and Sephacryl S-500 column chromatography. Structural characterization indicated that TPS3A mainly consisted of arabinose, galactose, galacturonic acid and rhamnose in a molar ratio of 5.84: 4.15: 2.06: 1, with an average molecular weight of 1.596 × 104 kDa. The structure of TPS3A was characterized as a repeating unit consisting of 1,3-Galp, 1,4-Galp, 1,3,6-Galp, 1,3-Araf, 1,5-Araf, 1,2,4-Rhap and 1-GalpA, with two branches on the C6 of 1,3,6-Galp and C2 of 1,2,4-Rhap, respectively. To investigate the preventive effects of TPS3A on atherosclerosis, TPS3A was administered orally to ApoE-deficient (ApoE-/-) mice. Results revealed that TPS3A intervention could effectively delay the atherosclerotic plaque progression, modulate dyslipidemia, and reduce the transformation of vascular smooth muscle cells (VSMCs) from contractile phenotype to synthetic phenotype by activating the expression of contractile marker alpha-smooth muscle actin (α-SMA) and inhibiting the expression of synthetic marker osteopontin (OPN) in high-fat diet-induced ApoE-/- mice. Our findings suggested that TPS3A markedly alleviated atherosclerosis by regulating dyslipidemia and phenotypic transition of VSMCs, and might be used as a novel functional ingredient to promote cardiovascular health.

Laminaria japonica polysaccharide attenuates podocyte epithelial-mesenchymal transformation via TGF-ß1-mediated Smad3 and p38MAPK pathways.

In the present work, we explored the interventional effect and potential mechanism of a purified Laminaria japonica polysaccharide (LJP61A) on podocyte epithelial-mesenchymal transition (EMT) in TGF-ß1-induced podocytes and adriamycin-treated mice. Results showed that compared to the model groups, LJP61A significantly up-regulated the levels of epithelial markers (Nephrin, WT-1, podocin) and down-regulated the levels of mesenchymal markers (α-SMA, FN1) in vitro and in vivo, thus preventing EMT-like morphological changes of podocytes, proteinuria and kidney injury. Smad3 and p38MAPK are two central pathways mediating podocyte EMT activated by TGF-ß1. We found that LJP61A suppressed TGF-ß1-induced activation of Smad3, Smad4 and p38MAPK in vitro and in vivo. Moreover, the inhibitory actions of LJP61A on podocyte EMT were synergistically strengthened by Smad3 inhibitor SIS3 and p38MAPK inhibitor SB203580. Taken together, these findings revealed that LJP61A could prevent podocyte EMT, which might be related to the inhibition of TGF-ß1-mediated Smad3 and p38MAPK pathways.

Polygonatum cyrtonema Hua Polysaccharide Alleviates Fatigue by Modulating Osteocalcin-Mediated Crosstalk between Bones and Muscles.

Osteocalcin was reported to regulate muscle energy metabolism, thus fighting fatigue during exercise. The current work aimed to investigate the anti-fatigue effect and the underlying mechanism of a homogeneous polysaccharide (PCPY-1) from Polgonatum cyrtonema after structure characterization. In the exhaustive swimming mouse model and the co-culture system of BMSCs/C2C12 cells, PCPY-1 significantly stimulated BMSC differentiation into osteoblasts as determined by ALP activity, matrix mineralization, and the protein expressions of osteogenic markers BMP-2, phosphor-Smad1, RUNX2, and osteocalcin. Meanwhile, PCPY-1 remarkably enhanced myoblast energy metabolism by upregulating osteocalcin release and GPRC6A protein expression; the phosphorylation levels of CREB and HSL; the mRNA levels of GLUT4, CD36, FATP1, and CPT1B; and ATP production in vitro and in vivo. Accordingly, PCPY-1 exhibited good anti-fatigue capacity in mice as confirmed by fatigue-related indicators. Our findings indicated PCPY-1 could enhance osteocalcin-mediated communication between bones and muscles, which was conducive to muscle energy metabolism and ATP generation, thus alleviating fatigue in exhausted swimming mice.

Inhibition of Ca2+-calpain signaling is a new mechanism using Laminaria japonica polysaccharide to prevent macrophage foam cell formation and atherosclerosis.

The Ca2+-calpain signaling plays a pivotal role in regulating the upstream signaling pathway of cellular autophagy. The aim of the current work was to investigate the role of Ca2+-calpain signaling in the regulation of macrophage autophagy by a Laminaria japonica polysaccharide (LJP61A) in Ox-LDL induced macrophages and high fat diet fed atherosclerotic mice. Results revealed that the LJP61A markedly decreased the levels of intracellular Ca2+, calpain1, calpain2 and their downstream effectors (Gsα, cAMP and IP3), and simultaneously enhanced autophagy activity and lipid metabolism, thereby reducing lipid accumulation in the Ox-LDL stimulated macrophages and lipid-laden plaques in atherosclerotic mice. Moreover, BAPTA-AM (a Ca2+ chelator) and calpeptin (a calpain inhibitor) synergistically strengthened the beneficial effects of LJP61A on autophagy and lipid metabolism by decreasing the levels of intracellular Ca2+, calpain1, calpain2, and their downstream effectors (Gsα, cAMP and IP3) induced by Ox-LDL. These findings suggested that the LJP61A suppressed macrophage derived foam cell formation and atherosclerosis by modulating the Ca2+-calpain-mediated autophagy.

Dendrobium huoshanense stem polysaccharide ameliorates alcohol-induced gastric ulcer in rats through Nrf2-mediated strengthening of gastric mucosal barrier.

This study aimed to explore whether Dendrobium huoshanense stem polysaccharide (cDHPS) ameliorates alcohol-induced gastric ulcer (GU) through the strengthening effect of the gastric mucosal barrier in rats and its potential mechanism. In normal rats, the pretreatment of cDHPS effectively strengthened gastric mucosal barrier by increasing mucus secretion and tight junction protein expression. In GU rats, cDHPS supplementation effectively alleviated alcohol-induced gastric mucosal injury and nuclear factor κB (NF-κB)-driven inflammation by strengthening gastric mucosal barrier. Moreover, cDHPS significantly activated nuclear factor E2-related factor 2 (Nrf2) signaling and promoted antioxidant enzymes activities in both normal and GU rats. These results suggested that the pretreatment of cDHPS could strengthen gastric mucosal barrier to inhibit oxidative stress and NF-κB-driven inflammation induced gastric mucosal injury, which was likely related to the activation of Nrf2 signaling.

Dendrobium fimbriatum polysaccharide ameliorates DSS-induced intestinal mucosal injury by IL-22-regulated intestinal stem cell regeneration.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with unknown etiology and difficult treatment. In this study, the intervention effect of Dendrobium fimbriatum Hook polysaccharide (cDFPW1) on UC was verified by constructing a dextran sulfate sodium (DSS)-induced colitis mouse model, and the protective effect of cDFPW1 on intestinal mucosal integrity in UC was explored by the co-culture system consisting of intestinal organoids and lamina propria lymphocytes (LPLs) combined with the experiment of microbial depletion mice. Results showed that cDFPW1 significantly alleviated UC symptoms in mice and promoted the proliferation of intestinal epithelial cells. Importantly, cDFPW1 could directly improve DSS-induced morphological damage of intestinal organoids and increase the number of epithelial cells, which was validated in mice. During repair, an increase in the number of Lgr5+ cells in intestinal organoids and mouse intestines was promoted by cDFPW1. Meanwhile, cDFPW1 promoted intestinal stem cells (ISCs)-mediated intestinal epithelial regeneration by significantly upregulating IL-22 expression. We further confirmed that the secretion of IL-22 was mediated by LPLs. Together, these findings suggest that cDFPW1 promotes ISCs regeneration by LPLs-mediated up-regulation of IL-22 to protect the intestinal mucosal integrity, thereby playing an important role in improving UC.

Hydrolytic Quinoa Protein and Cationic Lotus Root Starch-Based Micelles for Co-Delivery of Quercetin and Epigallo-catechin 3-Gallate in Ulcerative Colitis Treatment.

The accumulation and sustained release of drugs in the colonic inflammatory region are the favorable strategy for treating ulcerative colitis (UC). In this study, we developed a synergistic anti-inflammatory drug (quercetin/EGCG)-loaded micelle using hydrolytic quinoa protein (HQP) and cationic lotus root starch (CLRS) by a layer-by-layer assembly method. The encapsulation efficiency of quercetin and EGCG in the Que-HQP-EGCG-CLRS micelles reached 91.5 and 89.4%, respectively. This composite micelle exhibited a core-shell structure, where Que-HQP-EGCG was the core and CLRS was the coating shell. Moreover, the in vitro experiments indicated that these micelles can make Que/EGCG pass through gastric environments stably and delay their release in the intestine. Animal experiments further confirmed that the Que-HQP-EGCG-CLRS micelles can efficiently accumulate in the colonic inflammatory region and enable sustained release of drugs (more than 24 h), thus notably alleviating the symptoms of UC. These results suggested that Que-HQP-EGCG-CLRS micelles have good gastric stability, colonic inflammatory-accumulated effect, and sustained drug release ability, which are a promising co-delivery system for UC treatment.

Bioactive polysaccharides and their potential health benefits in reducing the risks of atherosclerosis: A review.

Atherosclerosis is a kind of lipid-driven chronic inflammatory disease of arteries and is the principal pathological basis of life-threatening cardiovascular disease events, such as strokes and heart attacks. Clinically, statins are the most commonly prescribed drugs for the treatment of atherosclerosis, but prolonged use of these drugs exhibit many adverse reactions and have limited efficacy. Polysaccharides are important natural biomacromolecules widely existing in plants, animals, microorganisms and algae. They have drawn considerable attention worldwide due to their multiple healthy functions, along with their non-toxic property. Importantly, a growing number of studies have demonstrated that bioactive polysaccharides exhibit prominent efficiency in controlling atherosclerotic risk factors like hyperlipemia, hypertension, oxidative stress, and inflammation. In recent decades, various bioactive polysaccharides with different structural features and anti-atherosclerotic potential from natural sources have been isolated, purified, and characterized. The aim of this review is to focus on the research progress of natural polysaccharides in reducing the risks of atherosclerosis based on evidence of in vitro and in vivo studies from 1966 to 2022. PRACTICAL APPLICATIONS: In the future, it is still necessary to strengthen the research on the development and mechanism of polysaccharides with anti-atherosclerotic potential. These anti-atherosclerotic polysaccharides with different structural characteristics and physiochemical properties from different sources will constitute a huge source of materials for future applications, especially in functional foods and drugs. The information summarized here may serve as useful reference materials for further investigation, production, and application of these polysaccharides in functional foods and therapeutic agents.

Protective Effects of Three Flavonoids from Dendrobium huoshanense Flowers on Alcohol-Induced Hepatocyte Injury via Activating Nrf2 and Inhibiting NF-κB Pathways.

Dendrobium huoshanense flowers have been widely used for liver protection in China. This work was aimed to discover the natural products with activity of mitigating alcoholic hepatocyte injury from Dendrobium huoshanense flowers via bioactivity-guided isolation, and to clarify the underlying mechanisms of these natural products. As a result, three flavonoids, 3'-O-methylquercetin-3-O-ß-D-galactopyranoside (1), 3'-O-methylquercetin-3-O-ß-D-glucopyranoside (2) and quercetin-3-O-ß-D-glucopyranoside (3), were firstly isolated from D. huoshanense flowers. Results exhibited that flavonoids 1-3 could enhance the cell viability, decrease the expression of ALT and AST, inhibit the cell apoptosis, alleviate the oxidative stress, and mitigate the inflammatory response of alcohol-induced L02 cells. Mechanism study exhibited that flavonoids 1-3 could increase the expression of Nrf2 as well as its downstream antioxidation genes of alcohol-induced L02 cells, while ML-385 (Nrf2 inhibitor) could abolish the inhibitory effects of 1-3 on alcohol-induced hepatocyte injury. Flavonoids 1-3 could also reduce the phosphorylation levels of IκBα and NF-κB p65 of alcohol-induced L02 cells, while SC75741 (NF-κB inhibitor) could not enhance the inhibitory effects of 1-3 on alcohol-induced L02 cells injury. The data above indicated that flavonoids 1-3 could inhibit alcohol-induced hepatocyte injury, which might be attributed to alleviating oxidative stress and mitigating inflammatory response by activating Nrf2 and inhibiting NF-κB pathways.

Microencapsulation of blueberry anthocyanins by spray drying with soy protein isolates/high methyl pectin combination: Physicochemical properties, release behavior in vitro and storage stability.

Eleven anthocyanins in the blueberry anthocyanins powders (BAP) were identified and quantified by HPLC-DAD-ESI-MS. BAP microcapsules (MBAP) were produced by spray drying using high methyl pectin (HMP) combined with whey protein isolates (WPI) or soy protein isolates (SPI) in different proportions as wall materials. Generally, SPI/HMP combination was more efficient in increasing the encapsulation efficiency and Tg, and in decreasing the particle size and hygroscopicity of the microcapsules than WPI or HMP or WPI/HMP combination. Microcapsules created with 4% SPI + 2% HMP combination (MBAPc), possessed superior anthocyanin release behavior and antioxidant stability to those produced with 4% SPI alone (MBAPs). Both MBAPc and MBAPs had continuous release of anthocyanins throughout the simulated gastrointestinal digestion, and exhibited two first-order kinetics, but MBAPc exhibited higher stability than MBAPs and BAP, because it showed the longest half-life and the lowest anthocyanin degradation rate at 25 °C and 35 °C during 6-months' storage.

Dendrobium officinale polysaccharide promotes M1 polarization of TAMs to inhibit tumor growth by targeting TLR2.

Promoting M1 polarization of tumor-associated macrophages (TAMs) is an effective pathway for malignant tumor therapy. In this study, we aimed to demonstrate whether homogeneous Dendrobium officinale polysaccharide (DOP) could promote M1 polarization of TAMs to inhibit tumor growth, and how it promoted. Results exhibited that DOP could inhibit the tumor growth and promote the M1 polarization of TAMs in tumor-bearing mice. Macrophage depletion and replenishment experiment clearly proved that the inhibitory effect of DOP on tumor growth is dependent on promoting M1 polarization of TAMs. Moreover, we found that DOP could reach tumor microenvironment (TME) and directly bind to TAMs to promote its M1 polarization via targeting toll-like receptor 2 (TLR2) after oral administration. These results clarified that DOP could remarkably inhibit the tumor growth of tumor-bearing mice via directly targeting the TLR2 of TAMs to promote its M1 polarization.

Intervention and potential mechanism of non-starch polysaccharides from natural resources on ulcerative colitis: A review.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology that affects the colon and rectum. It has evolved into a global burden due to the high incidence in developed countries and the highly-increased incidence in developing countries. Non-starch polysaccharides (NSPs) from natural resources, as a type of functional carbohydrates, have a significant therapeutic effect on UC because of their good anti-inflammatory and immunomodulatory activities. Based on the etiology and pathogenesis of UC, this review summarizes the intervention effects and mechanisms of NSPs in the prevention and treatment of UC. The results showed that NSPs can improve UC by protecting the intestinal mucosal barrier, regulating the immune response of the intestinal mucosa, and remodeling the intestinal flora and metabolites. These contents provide theoretical basis for the application of polysaccharides in the prevention and treatment of UC.

Dendrobine inhibits dopaminergic neuron apoptosis via MANF-mediated ER stress suppression in MPTP/MPP+-induced Parkinson's disease models.

BACKGROUND: Parkinson's disease (PD) is an age-related neurodegenerative disorder without effective treatments. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been suggested to be capable of protecting against PD by inhibiting endoplasmic reticulum (ER) stress-mediated neuronal apoptosis. PURPOSE: This study was aimed to evaluate the antiparkinsonian effect of dendrobine and reveal its underlying mechanisms from the perspective of MANF-mediated ER stress suppression. METHODS: Behavioral assessments of PD mice as well as LDH/CCK-8 assay in SH-SY5Y cells and primary midbrain neurons were carried out to detect the antiparkinsonian effect of dendrobine. Immunofluorescence, western blot, flow cytometry and shRNA-mediated MANF knockdown were used to determine the apoptosis of dopaminergic neurons and the expressions of ER stress-related proteins for investigating the underlying mechanism of dendrobine. RESULTS: Dendrobine significantly ameliorated the motor performance of PD mice and attenuated the injuries of dopaminergic neurons. Dendrobine could also relieve neuronal apoptosis, up-regulate MANF expression and inhibit ER stress, which were largely abolished by shRNA-mediated MANF knockdown in PD model. CONCLUSION: Dendrobine might protect against PD by inhibiting dopaminergic neuron apoptosis, which was achieved by facilitating MANF-mediated ER stress suppression. Our study suggested that dendrobine could act as a MANF up-regulator to protect against PD, and provided a potential candidate for exploring etiological agents of PD.

Co-encapsulation systems for delivery of bioactive ingredients.

To improve the solubility, stability and bioavailability of bioactive compounds, a series of delivery systems have been designed and developed in recent years. However, most delivery systems are limited to loading a single nutrient. Co-delivery systems that encapsulate two or more nutrients have great sense to enhance the nutritional values and health benefits of food products. In this paper, the recent advancements of co-encapsulation systems including emulsions, nanoparticles, microcapsules, liposomes, hydrogels, and related products have been reviewed. The co-encapsulation mechanisms of bioactive ingredients in various delivery systems were illustrated. Furthermore, the release, digestion and absorption mechanisms of bioactive ingredients in the human digestive system were also discussed. Co-encapsulation systems have the ability to mask astringency of different bioactive ingredients and enhance their stability and bioavailability, as well as to maximize the biological function of bioactive ingredients with synergistic effect. The present review provides examples for the application of co-encapsulation systems in food industries.

The nanomicelles consisting of lotus root amylopectin and quinoa protein: Construction and encapsulation for quercetin.

To improve the water solubility, stability and bioavailability of quercetin, the quercetin (Que)-quinoa protein (QP)-lotus root amylopectin (LRA) nanomicelles (Que-QP-LRA) were constructed via self-assembly in the present study. Results showed that a uniform and stable Que-QP-LRA nanomicelles was formed when the mass ratio of Que/QP/LRA was 2.5:6:24. Under this condition, the particle size, polydispersity index and zeta potential of the nanomicelles were 157.3 nm, 0.289 and -16.7 mV, respectively. Transmission electron microscopy exhibited that the Que-QP-LRA nanomicelles have a core-shell structure. The analysis of molecular interaction indicated that hydrogen bonding and hydrophobic interaction were the main driving forces to maintain stable structure of Que-QP-LRA nanomicelles. Additionally, the in vitro simulated digestion experiments suggested that Que-QP-LRA nanomicelles can enhance the stability of quercetin in the stomach and enable it to be sustained release in the intestine. These results suggested that Que-QP-LRA nanomicelles were beneficial for improving the bioavailability of quercetin.

Laminaria japonica Polysaccharide Suppresses Atherosclerosis via Regulating Autophagy-Mediated Macrophage Polarization.

The present work aimed to explore the effect and underlying mechanism of a homogeneous Laminaria japonica polysaccharide (LJP61A) on macrophage polarization in high-fat-diet-fed LDLr-/- mice and Ox-LDL-induced macrophages. Results showed that LJP61A remarkably reduced the lesion burden in atherosclerotic mice, alleviated lipid deposition in Ox-LDL-stimulated macrophages, decreased the expression of M1 macrophage markers, and increased the expression of M2 macrophage markers, thus reducing the M1/M2 macrophage phenotype ratio. Meanwhile, the autophagic flux of macrophages was enhanced by LJP61A treatment in vitro and in vivo. 3-Methyladenine is an autophagic inhibitor. As expected, this inhibitor blocked the effects of LJP61A on macrophage polarization. SIRT1 and FoxO1 are two key upstream genes that control the autophagy behavior. We also found that LJP61A significantly up-regulated the expression of SIRT1 and FoxO1. However, these effects of LJP61A were abolished by the SIRT1 siRNA and FoxO1 inhibitor AS1842856. These results suggested that LJP61A reduced atherosclerosis in HFD-induced LDLr-/- mice via regulating autophagy-mediated macrophage polarization.

Dendrobium fimbriatum Hook polysaccharide ameliorates dextran-sodium-sulfate-induced colitis in mice via improving intestinal barrier function, modulating intestinal microbiota, and reducing oxidative stress and inflammatory responses.

The ameliorative effect of Dendrobium fimbriatum polysaccharide (cDFPW1) on ulcerative colitis (UC) was investigated using a dextran-sodium-sulfate-induced (DSS-induced) mouse model in the present study. The results showed that cDFPW1 effectively improved colitis in mice by ameliorating weight loss, disease activity index (DAI) and colonic pathological damage, and by protecting the intestinal barrier function integrity. Moreover, cDFPW1 modulated the composition and metabolism of intestinal microbiota through enhancing Romboutsia, Lactobacillus and Odoribacter, and reducing Parasutterella, Burkholderia-Caballeronia-Paraburkholderia and Acinetobacter in colitis mice. Notably, cDFPW1 significantly restored the homeostasis of Th17/regulatory T (Treg) cells and the expression of specific cytokines. Western blotting of colon tissues showed that cDFPW1 markedly up-regulated the expression of Nrf2 and inhibited the phosphorylation of NF-κB signaling. These results indicated that cDFPW1 possesses the potential of improving UC and its effect on palliating colitis may be connected with the regulation of Nrf2/NF-κB signaling.