Prevotella copri exhausts intrinsic indole-3-pyruvic acid in the host to promote breast cancer progression: inactivation of AMPK via UHRF1-mediated negative regulation.

Emerging evidence has revealed the novel role of gut microbiota in the development of cancer. The characteristics of function and composition in the gut microbiota of patients with breast cancer patients has been reported, however the detailed causation between gut microbiota and breast cancer remains uncertain. In the present study, 16S rRNA sequencing revealed that Prevotella, particularly the dominant species Prevotella copri, is significantly enriched and prevalent in gut microbiota of breast cancer patients. Prior-oral administration of P. copri could promote breast cancer growth in specific pathogen-free mice and germ-free mice, accompanied with sharp reduction of indole-3-pyruvic acid (IPyA). Mechanistically, the present of excessive P. copri consumed a large amount of tryptophan (Trp), thus hampering the physiological accumulation of IPyA in the host. Our results revealed that IPyA is an intrinsic anti-cancer reagent in the host at physiological level. Briefly, IPyA directly suppressed the transcription of UHRF1, following by the declined UHRF1 and PP2A C in nucleus, thus inhibiting the phosphorylation of AMPK, which is just opposite to the cancer promoting effect of P. copri. Therefore, the exhaustion of IPyA by excessive P. copri strengthens the UHRF1-mediated negative control to inactivated the energy-controlling AMPK signaling pathway to promote tumor growth, which was indicated by the alternation in pattern of protein expression and DNA methylation. Our findings, for the first time, highlighted P. copri as a risk factor for the progression of breast cancer.

Exome-Based Amino Acid Optimization: A Dietary Strategy to Satisfy Human Nutritional Demands and Enhance Muscle Strength in Breast Tumor Mice Undergoing Chemotherapy.

Breast cancer patients undergoing chemotherapy often experience muscle wasting and weakness, which impact their quality of life. A potential solution lies in customizing amino acid compositions based on exome-derived formulations (ExAAs). The study hypothesized that tailoring dietary amino acids using ExAAs could enhance muscle health. Theoretical amino acid requirements were calculated from the genome's exome region, and a breast cancer mouse model undergoing paclitaxel treatment was established. The mice were supplemented with a cancer-specific nutritional formula (QJS), and the effects of QJS and amino acid-adjusted QJS (adjQJS) were compared. Both formulations improved the nutritional status without compromising tumor growth. Notably, adjQJS significantly enhanced muscle strength compared to QJS (1.51 ± 0.25 vs. 1.30 ± 0.08 fold change, p < 0.05). Transcriptome analysis revealed alterations in complement and coagulation cascades, with an observed upregulation of C3 gene expression in adjQJS. Immune regulation also changed, showing a decrease in B cells and an increase in monocytes in skeletal muscle with adjQJS. Importantly, adjQJS resulted in a notable increase in Alistipes abundance compared to QJS (10.19 ± 0.04% vs. 5.03 ± 1.75%). This study highlights the potential of ExAAs as valuable guide for optimizing amino acid composition in diets for breast cancer patients undergoing chemotherapy.

Polysaccharide isolated from Grifola frondosa eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T cells responses.

Myeloid derived suppressor cells (MDSCs) are known to accumulate in cancer patients and tumor-bearing mice, playing a significant role in promoting tumor growth. Depleting MDSCs has emerged as a potential therapeutic strategy for cancer. Here, we demonstrated that a fungal polysaccharide, extracted from Grifola frondosa, can effectively suppress breast tumorigenesis in mice by reducing the accumulation of MDSCs. Treatment with Grifola frondosa polysaccharide (GFI) leads to a substantial decrease in MDSCs in the blood and tumor tissue, and a potent inhibition of tumor growth. GFI treatment significantly reduces the number and proportion of MDSCs in the spleen, although this effect is not observed in the bone marrow. Further analysis reveals that GFI treatment primarily targets PMN-MDSCs, sparing M-MDSCs. Our research also highlights that GFI treatment has the dual effect of restoring and activating CD8+T cells, achieved through the downregulation of TIGIT expression and the upregulation of Granzyme B. Taken together, our findings suggest that GFI treatment effectively eliminates PMN-MDSCs in the spleen, leading to a reduction in MDSC numbers in circulation and tumor tissues, ultimately enhancing the antitumor immune response of CD8+T cells and inhibiting tumor growth. This study introduces a promising therapeutic agent for breast cancer.

Comparison of Neuroprotection and Regulating Properties on Gut Microbiota between Selenopeptide Val-Pro-Arg-Lys-Leu-SeMet and Its Native Peptide Val-Pro-Arg-Lys-Leu-Met In Vitro and In Vivo.

Selenopeptides are promising candidates for intervening in neuroinflammation; however, the key role of selenium (Se) in selenopeptides remains poorly understood. To address this gap, we compared the neuroprotective effects of selenopeptide Val-Pro-Arg-Lys-Leu-SeMet (namely, Se-P1) and its native peptide Val-Pro-Arg-Lys-Leu-Met (namely, P1). Our results demonstrate that Se-P1 treatment exhibits superior antioxidant and antineuroinflammatory effects in PC12 cells and lipopolysaccharide (LPS)-injured mice compared to P1. Moreover, the administration of Se-P1 and P1 resulted in a shift in the gut microbiota composition. Notably, during LPS-induced injury, Se-P1 treatment demonstrated greater stability in maintaining gut microbiota composition compared to P1 treatment. Specifically, Se-P1 may have a positive impact on gut microbiota dysbiosis by modulating inflammatory-related bacteria such as enhancing Lactobacillus abundance while reducing that of Lachnospiraceae_NK4A136_group. Furthermore, the alteration of metabolites induced by Se-P1 treatment exhibited a significant correlation with gut microbiota, subsequently modulating the inflammatory-related metabolic pathways including histidine metabolism, lysine degradation, and purine metabolism. These findings suggest that organic Se contributes to the bioactivities of Se-P1 in mitigating neuroinflammation in LPS-injured mice compared to P1. These findings hold significant value for the development of potential preventive or therapeutic strategies against neurodegenerative diseases and introduce novel concepts in selenopeptide nutrition and supplementation recommendations.

A Ganoderma lucidum polysaccharide F31 alleviates hyperglycemia through kidney protection and adipocyte apoptosis.

In this paper, we reported an excellent hypoglycemic effect of a Ganoderma lucidium polysaccharide F31 with efficacies between 45 and 54 %, approaching to that of liraglutide (52 %). Significantly, F31 reduced the body weight gains and food intakes. F31 decreased 4 key compounds, consisting of adenosine, adenosine, galactitol and glycerophosphocholine and elevated 8 key compounds, including arginine, proline, arachidonic acid, creatine, aspartic acid, leucine, phenylalanine and ornithine, which protected kidney function. Also, apoptosis was promoted by F31 in epididymal fat through increasing Caspase-3, Caspase-6 and Bax and decreasing Bcl-2. On 3 T3-L1 preadipocyte cells, F31 induced early apoptosis through reducing mitochondrial membrane potential. Finally, a molecular docking was performed to reveal a plausible cross-talk between kidney and epididymal fat through glycerophosphorylcholine-Bax axis. Overall, F31 alleviated hyperglycemia through kidney protection and adipocyte apoptosis in db/db mice. This work may provide novel insights into the hypoglycemic activity of polysaccharides.

Hypouricemic effect of 2,4-dihydroxybenzoic acid methyl ester in hyperuricemic mice through inhibiting XOD and down-regulating URAT1.

In this paper, we reported the hypouricemic effect of 2,4-dihydroxybenzoic acid methyl ester (DAE), a component of Ganoderma applanatum, in hyperuricemic mice through inhibiting XOD and down-regulating URAT1. Computationally, DAE showed a high similarity to allopurinol and depicted a high affinity in docking to XOD. In vitro, DAE exhibited an inhibitory effect against XOD. Importantly, DAE demonstrated a remarkable hypouricemic effect, decreasing serum uric acids (SUAs) of hyperuricemic mice (407 ± 31 µmol/L) to 195 ± 23, 145 ± 33 and 134 ± 16 µmol/L (P < 0.01) at the doses of 20, 40, and 80 mg/kg with a dose-dependent manner and showing efficacies at 54-68 %, which were close to the efficacies of allopurinol (61 %) and benzbromarone (57 %). DAE depicted higher and negatively dose-independent urinary uric acids in comparison with that of the hyperuricemic control, implying DAE exerted an uricosuric effect and also a reduction effect on uric acid production. Unlike toxic allopurinol and benzbromarone, no general toxicity on body weights and no negative influence on liver, kidney, spleen and thymus were observed for DAE. Mechanistically, DAE inhibited XOD activities in vivo. Moreover, DAE up-regulated OAT1 and down-regulated GLUT9, URAT1 and CNT2. Overall, DAE may present a hypouricemic effect through inhibiting XOD and up-regulating OAT1 and down-regulating GLUT9, URAT1 and CNT2. This work provided novel insights into the hypouricemic effect of DAE and G. applanatum.

Caffeic acid phenethyl ester alleviated hypouricemia in hyperuricemic mice through inhibiting XOD and up-regulating OAT3.

BACKGROUND: Hyperuricemia is characterized with high serum uric acids (SUAs) and directly causes suffering gout. Caffeic acid phenethyl ester (CAPE) is widely included in dietary plants and especially propolis of honey hives. HYPOTHESIS/PURPOSE: Since CAPE exerts a property resembling a redox shuttle, the hypothesis is that it may suppress xanthine oxidase (XOD) and alleviate hyperuricemia. The aim is to unveil the hypouricemic effect of CAPE and the underlying mechanisms. METHODS: By establishing a hyperuricemic model with potassium oxonate (PO) and hypoxanthine (HX) together, we investigated the hypouricecmic effect of CAPE. On this model, the expressions of key mRNAs and proteins, including glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), and the activity of XOD were assayed in vivo. Also, the inhibitory effect of CAPE against XOD was assayed in vitro through enzymatic activity tests and by molecular docking. RESULTS: CAPE demonstrated a remarkable hypouricemic effect, which reduced the SUAs of hyperuricemic mice (401 ± 111 µmol/l) to 209 ± 56, 204 ± 65 and 154 ± 40 µmol/l (p < 0.01) at the doses of 15, 30 and 60 mg/kg respectively, depicting efficacies between 48 and 62% and approaching allopurinol's efficacy (52%). Serum parameters, body weights, inner organ coefficients, and H&E staining suggested that CAPE displayed no general toxicity and it alleviated the liver and kidney injuries caused by hyperuricemia. Mechanistically, CAPE decreased XOD activities significantly in vivo, presented an IC50 at 214.57 µM in vitro and depicted a favorable binding to XOD in molecular simulation, indicating that inhibiting XOD may be an underlying mechanism of CAPE against hyperuricemia. CAPE did decreased GLUT9 protein and down-regulated URAT1 mRNA and protein. In addition, CAPE up-regulated ATP binding cassette subfamily G member 2 (ABCG2) and organic anion transporter 3 (OAT3) mRNA and proteins in comparison with that of the hyperuricemic control. All above, CAPE may alleviate hyperuricmia through inhibiting XOD, decreasing GLUT9 and URAT1 and increasing ABCG2 and OAT3. CONCLUSION: CAPE presented potent hypouricemic effect in hyperuricemic mice through inhibiting XOD activity and up-regulating OAT3. CAPE may be a promising treatment against hyperuricemia.

Immunoregulatory activity of a low-molecular-weight heteropolysaccharide from Ganoderma leucocontextum fruiting bodies in vitro and in vivo.

The chemical structure of GLP-1, a novel water-soluble heteropolysaccharide purified Ganoderma leucocontextum fruiting bodies, has been characterized in our previous study. This study aimed to investigate the immunostimulatory activity of GLP-1 in vitro and in vivo by using RAW264.7 macrophages and cyclophosphamide-induced immunosuppressed mice model. Results showed that GLP-1 was able to enhance phagocytic activity and promote the production of reactive oxygen species, nitric oxide, tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 in RAW264.7 macrophages. Moreover, GLP-1 could activate mitogen-activated protein kinase, phosphatidylinositol-3-kinase/protein kinase B, and nuclear factor-kappa B signaling pathways through toll-like receptor 2 and dectin-1 receptors. Furthermore, GLP-1 increased the thymus index, serum immunoglobulin levels, and percentage of CD3+ T lymphocytes in cyclophosphamide-induced immunosuppressed mice. These results demonstrated that GLP-1 possessed significant immunostimulatory effects in vivo and in vitro and could be developed as an effective immunomodulator for application in functional foods.

Preparation, chemical structure, and immunostimulatory activity of a water-soluble heteropolysaccharide from Suillus granulatus fruiting bodies.

A water-soluble heteropolysaccharide (SGP2-1) was purified from Suillus granulatus fruiting bodies by anion-exchange chromatography and gel permeation chromatography. The structural characteristics were analyzed by high-performance gel permeation chromatography, high-performance liquid chromatography, Fourier transform infrared spectroscopy, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy. The immunostimulatory activity was investigated using RAW 264.7 macrophages. Results showed that SGP2-1 with weight average molecular weight of 150.75 kDa was composed of mannose, glucose, and xylose. The backbone of SGP2-1 was mainly composed of â†’ 4)-α-Glcp-(1→, and the terminal group α-d-Glcp â†’ was linked to the main chain by O-6 position. SGP2-1 could significantly enhance pinocytic capacity, reactive oxygen species production, and cytokines secretion. SGP2-1 exerted immunomodulatory effects through interacting with toll-like receptor 2, and activating mitogen-activated protein kinase, phosphatidylinositol-3-kinase/protein kinase B, and nuclear factor-kappa B signaling pathways. These findings indicated that SGP2-1 could be explored as a potential immunomodulatory agent for application in functional foods.

Polysaccharide from Agrocybe cylindracea prevents diet-induced obesity through inhibiting inflammation mediated by gut microbiota and associated metabolites.

Polysaccharide from Agrocybe cylindracea (ACP) has been demonstrated with various health benefits, but its anti-obesity effect and underlying mechanisms remain poorly understood. This study aimed to investigate the beneficial effects of ACP in high-fat diet (HFD)-induced obese mice by targeting gut microbiota and metabolites. 9-week ACP supplementation in HFD-fed mice reduced body weight, adipose accumulation, impaired insulin resistance, lipid levels, and liver injuries, which were negatively correlated to the pro-inflammatory factors, particularly tumor necrosis factor-alpha (TNF-α) and interleukin- 6 (IL-6). Moreover, ACP not only restored HFD-induced gut disorder, as indicated by the depletion of Desulfovibrio and Oscillibacter and the enrichment of the Bacteroides, Parabacteroides, Butyricimonas, and Dubosiella, but also positively regulated gut metabolites such as solavetivone and N-acetylneuraminic acid. Spearman's correlation analysis revealed that the ACP-altered microbes and metabolites were highly correlated with inflammation-related indexes. Notably, ACP greatly lowered the obesity-related TNF-α- and IL-6-levels partially by reducing Desulfovibrio and increasing Parabacteroides abundances, together with the associated decrease of solavetivone level. These findings suggest that ACP may be used as a prebiotic agent to prevent diet-induced obesity, and target-specific microbiota and metabolites may have unique therapeutic promise for inflammation-related diseases.

The circular RNA circNlgnmediates doxorubicin-inducedcardiac remodeling and fibrosis.

Doxorubicin is a chemotherapeutic medication commonly used to treat many types of cancers, but it has side effects including vomiting, rash, hair loss, and bone marrow suppression. The most dangerous side effects are cardiomyopathy, cardiofibrosis, and heart failure, as doxorubicin generates cytotoxicity and stops DNA replication. There is no treatment to block these side effects. We have developed a transgenic mouse line overexpressing the circular RNA circNlgn and shown that circNlgn is a mediator of doxorubicin-induced cardiofibrosis. Increased expression of circNlgn decreased cardiac function and induced cardiofibrosis by upregulating Gadd45b, Sema4C, and RAD50 and activating p38 and pJNK in circNlgn transgenic heart. Silencing circNlgn decreased the effects of doxorubicin on cardiac cell activities and prevented doxorubicin-induced expression of fibrosis-associated molecules. The protein (Nlgn173) translated by circNlgn could bind and activate H2AX, producing γH2AX, resulting in upregulation of IL-1b, IL-2Rb, IL-6, EGR1, and EGR3. We showed that silencing these molecules in the signaling pathway prevented doxorubicin-induced cardiomyocyte apoptosis, increased cardiomyocyte viability, decreased cardiac fibroblast proliferation, and inhibited collagen production. This mechanism may hold therapeutic implications for mitigating the side effects of doxorubicin therapy in cancer patients.

Novel Selenium Peptides Obtained from Selenium-Enriched Cordyceps militaris Alleviate Neuroinflammation and Gut Microbiota Dysbacteriosis in LPS-Injured Mice.

Increasing attention focuses on the relationship between neuroinflammation and Alzheimer's disease (AD). The reports on the microbiota-gut-brain axis reveal that the regulation by gut microbiota is an effective way to intervene in neuroinflammation-related AD. In this study, two novel selenium peptides (Se-Ps), VPRKL(Se)M (Se-P1) and RYNA(Se)MNDYT (Se-P2), with neuroprotection effects were obtained from Se-enriched Cordyceps militaris. Se-P1 and Se-P2 pre-protection led to a 30 and 33% increase in the PC-12 cell viability compared to the damage group, respectively. Moreover, Se-Ps exhibited a significant pre-protection against LPS-induced inflammatory and oxidative stress in the colon and brain by inhibiting the production of pro-inflammatory mediators (p < 0.05) and malondialdehyde, as well as promoting anti-inflammatory cytokine level and antioxidant enzyme activity (p < 0.05), which may alleviate the cognitive impairment in LPS-injured mice (p < 0.05). Se-Ps not only repaired the intestinal mucosa damage of LPS-injured mice but also had a positive effect on gut microbiota dysbacteriosis by increasing the abundance of Lactobacillus and Alistipes and decreasing the abundance of Akkermansia and Bacteroides. Collectively, the antioxidant, anti-inflammatory, and regulating properties on gut microflora of Se-Ps contribute to their neuroprotection, supporting that Se-Ps could be a promising dietary supplement in the prevention and/or treatment of AD.

Protein hydrolysates from Pleurotus geesteranus obtained by simulated gastrointestinal digestion exhibit neuroprotective effects in H2 O2 -injured PC12 cells.

Neurodegenerative diseases are considered to be among the diseases most threatening to human beings. Increasing evidence shows that antioxidant hydrolysates/peptides with neuroprotective effects may relieve neurodegenerative diseases. However, related research in mushrooms, one of the richest sources of antioxidant hydrolysates/peptides, is in its infancy. Therefore, the in vitro neuroprotective effects of protein hydrolysates from Pleurotus geesteranus were researched in this study. Proteins were extracted from P. geesteranus and then hydrolyzed by simulated gastrointestinal digestion. The neuroprotective effects of the protein hydrolysates were evaluated by H2 O2 -injured PC12 cells. The hydrolysates showed a superior antioxidative ability and had a higher abundance of hydrophobic amino acids (e.g., leucine, alanine, and phenylalanine). Neither cytotoxicity nor the increase of ROS in PC12 cells was observed under treatment with the hydrolysates. However, pre-treatment with the hydrolysates in PC12 cells, which were then injured by H2 O2 , markedly attenuated ROS generation and enhanced the activities and mRNA expression of the endogenous antioxidant enzymes (catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)), leading to a 26.68% increase in cell viability. The hydrolysates exhibited strong neuroprotective activity in H2 O2 -injured PC12 cells, possibly by reducing ROS generation and enhancing the activity of the antioxidant enzymatic system. PRACTICAL APPLICATIONS: Antioxidant hydrolysates with neuroprotection were obtained from Pleurotus geesteranus proteins by simulating gastrointestinal digestion, which exhibited an excellent pre-protective effect in oxidatively damaged PC12 cells. Further study showed that hydrolysates pre-protection may exert antioxidant activities not only as an exogenous antioxidant to scavenge ROS but also as a gene regulator to modulate the endogenous antioxidant enzymes gene expression. These results indicated that the potential of antioxidant peptides, derived from P. geesteranus through gastrointestinal digestion, could serve as a source of bioactive molecules in the prevention, relief or even treatment of neurodegenerative disorders.

Bruceae Fructus Oil Inhibits Triple-Negative Breast Cancer by Restraining Autophagy: Dependence on the Gut Microbiota-Mediated Amino Acid Regulation.

Triple-negative breast cancer (TNBC) has been acknowledged as an aggressive disease with worst prognosis, which requires endeavor to develop novel therapeutic agents. Bruceae fructus oil (BO), a vegetable oil derived from the fruit of Brucea javanica (L.) Merr., is an approved marketable drug for the treatment of cancer in China for several decades. Despite that the anti-breast cancer activity of several quassinoids derived from B. javanica has been found, it was the first time that the potential of BO against TNBC was revealed. Although BO had no cytotoxicity on TNBC cell lines in vitro, the oral administration of BO exhibited a gut microbiota-dependent tumor suppression without toxicity on the non-targeted organs in vivo. By metagenomics and untargeted metabolomics, it was found that BO not only altered the composition and amino acid metabolism function of gut microbiota but also regulated the host's amino acid profile, which was in accordance with the metabolism alternation in gut microbiota. Moreover, the activity of mTOR in tumor was promoted by BO treatment as indicated by the phosphorylation of 4E-binding protein 1 (4E-BP1) and ribosomal protein S6, and hyper-autophagy was consequently restrained. By contrast, the failure of tumor suppression by BO under pseudo germ-free (PGF) condition came with indistinctive changes in autophagy and mTOR activity, implying the critical role of the gut microbiota in BO's anticancer activity. The present study highlighted a promising application of BO against breast cancer with novel efficacy and safety.

Polysaccharides of Sporoderm-Broken Spore of Ganoderma lucidum Modulate Adaptive Immune Function via Gut Microbiota Regulation.

Ganoderma lucidum (Leyss.Fr.) Karst is one of the well-known medicinal macrofungi all over the world, and mounting researches have focused on the polysaccharides derived from the spores of G. lucidum. In the present study, BALB/c mice (n = 8-10) were administered with crude polysaccharides of G. lucidum spores (CPGS) and the refined polysaccharides of G. lucidum spores (RPGS) for 30 days to investigate their effect on the adaptive immune system. Results showed that CPGS and RPGS displayed diverse effects on the lymphocyte activity in the spleen. The splenocyte proliferation activity upon mitogen was suppressed by CPGS and RPGS, while the NK cell's tumor-killing ability was promoted by CPGS. Both CPGS and RPGS could increase the proportion of naïve T cells in thymus, but only RPGS significantly uplifted the percentage of T cells, as well as the T cell subsets, in peripheral blood, and promoted the activation by upregulating the expression of costimulatory factor CD28. Moreover, 16S sequencing results showed that the effects of CPGS and RPGS were closely related to the regulation of gut microbiota. ß-diversity of the microbiome was evidently changed by CPGS and RPGS. The phytoestrogen/polysaccharide-metabolizing bacteria (Adlercreutzia, Parabacteroides, and Prevotella), and an unclassified Desulfovibrionaceae, were remarkably enriched by CPGS or RPGS, and functions involving carbohydrate metabolism, membrane transport, and lipid metabolism were regulated. Moreover, the enrichments of Adlercreutzia, Prevotella, and Desulfovibrionaceae were positively related to the immune regulation by CPGS and RPGS, while that of Parabacteroides displayed a negative correlation. These findings suggested a promising effect of the polysaccharide from sporoderm-broken spore of G. lucidum in immune regulation to promote health control.

A Mycochemical Investigation of the Black Lingzhi Mushroom, Amauroderma rugosum (Agaricomycetes), Reveals Several Lipidic Compounds with Anti-Inflammatory and Antiproliferative Activities.

A mycochemical investigation on the medicinal mushroom Amauroderma rugosum led to the isolation of 30 compounds, including 14 sterols, 6 phenolic constituents, 5 unsaturated fatty acids, and 5 other compounds. The structures of these compounds were elucidated by comparison of their nuclear magnetic resonance spectroscopic and mass spectrometry data with literature data. Among them, compound 27 was obtained as a new natural compound, and compounds 2-4, 7-13, and 15-30 were isolated from the genus Amauroderma for the first time. Sterols and unsaturated fatty acids showed anti-inflammatory and antiproliferative activities in vitro. Compounds 5 and 6 showed the highest inhibitory effect on nitric oxide production in lipopolysaccharide-induced murine macrophage RAW264.7 cells, with half maximal inhibitory concentration (IC50) values of 27.6 ± 2.1 µM and 15.3 ± 2.0 µM respectively. Compound 17 exhibited the strongest inhibition against HepG2 and MDA-MB-231 cell lines, with IC50 values < 25 µM. This study not only enriches the understanding of the diversity of chemical constituents in A. rugosum, but it also provides a basis for further development and utilization of A. rugosum as a source of new potential antitumor or anti-inflammatory chemotherapy agents.

Hypouricaemic and nephroprotective effects of Poria cocos in hyperuricemic mice by up-regulating ATP-binding cassette super-family G member 2.

CONTEXT: Poria coco F.A.Wolf (Polyporaceae) dispels dampness and promotes diuresis implying hypouricaemic action. OBJECTIVE: To examine hypouricaemic action of Poria coco. MATERIALS AND METHODS: Ethanol extract (PCE) was prepared by extracting the sclerotium of P. cocos with ethanol, and the water extract (PCW) was produced by bathing the remains with water. PCE and PCW (50, 100 and 200 mg/kg, respectively) were orally administered to hyperuricemic Kunming mice (n = 8) to examine its hypouricaemic effect. Also, molecular docking was performed. RESULTS: P. cocos showed excellent hypouricaemic action, decreasing the serum uric acid of hyperuricaemia (HUA) control (526 ± 112 µmol/L) to 178 ± 53, 153 ± 57 and 151 ± 62 µmol/L (p < 0.01) by PCE and 69 ± 23, 63 ± 15 and 62 ± 20 µmol/L (p < 0.01) by PCW, respectively. According to SCrs, BUNs and H&E staining, PCE and PCW partially attenuated renal dysfunction caused by HUA. They presented no negative effects on ALT, AST and ALP activities. They elevated ABCG2 (ATP-binding cassette super-family G member 2) mRNA and protein expression in comparison to HUA control. In molecular docking, compound 267, 277, 13824, 15730 and 5759 were predicted as the top bioactives of P. cocos against HUA, which even presented better scores than the positive compound, oestrone 3-sulfate. DISCUSSION AND CONCLUSIONS: This paper demonstrated the hypouricaemic and nephroprotective effects of P. cocos in hyperuricemic mice by up-regulating ABCG2. These results may be useful for the development of a hypouricaemic agent.

NEAT1 regulates microtubule stabilization via FZD3/GSK3ß/P-tau pathway in SH-SY5Y cells and APP/PS1 mice.

Nuclear paraspeckles assembly transcript 1 (NEAT1) is a well-known long noncoding RNA (lncRNA) with various functions in different physiological and pathological processes. Notably, aberrant NEAT1 expression is implicated in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanism of NEAT1 in AD remains poorly understood. In this study, we investigated that NEAT1 regulated microtubules (MTs) polymerization via FZD3/GSK3ß/p-tau pathway. Downregulation of NEAT1 inhibited Frizzled Class Receptor 3 (FZD3) transcription activity by suppressing H3K27 acetylation (H3K27Ac) at the FZD3 promoter. Our data also demonstrated that P300, an important histone acetyltransferases (HAT), recruited by NEAT1 to bind to FZD3 promoter and mediated its transcription via regulating histone acetylation. In addition, according to immunofluorescence staining of MTs, metformin, a medicine for the treatment of diabetes mellitus, rescued the reduced length of neurites detected in NEAT1 silencing cells. We suspected that metformin may play a neuroprotective role in early AD by increasing NEAT1 expression and through FZD3/GSK3ß/p-tau pathway. Collectively, NEAT1 regulates microtubule stabilization via FZD3/GSK3ß/P-tau pathway and influences FZD3 transcription activity in the epigenetic way.

Structural characterization and immunomodulatory activity of a water-soluble polysaccharide from Ganoderma leucocontextum fruiting bodies.

Ganoderma leucocontextum is a new species of Ganoderma discovered in 2014. Up to now, the structural characteristics and immunoregulatory activity of its polysaccharides remain virtually unknown. In this study, a water-soluble polysaccharide termed, GLP-3, was purified from G. leucocontextum by ultrafiltration and column chromatography. The results revealed that GLP-3 mainly consisted of glucose (92.7 %) and its weight average molecular weight was 159.7 kDa. The structural analysis indicated that the backbone of GLP-3 was →4)-α-D-Glcp-(1→4,6)-ß-D-Glcp-(1→ with a ß-Glcp-(1→ branch. Atomic force microscopy and Congo red experiments revealed that GLP-3 might possess a globular structure with triple-helix conformation in water. Moreover, GLP-3 was recognized by toll-like receptor 2 (TLR2) and exerted immunomodulatory effects via activating mitogen-activated protein kinases (MAPKs), phosphatidylinositol-3-kinase (PI3K)/Akt and nuclear factor-κB (NF-κB) signaling pathways in RAW 264.7 macrophages. Collectively, these results suggested that GLP-3 could be developed as a potential functional food ingredient for immunomodulation.

Polysaccharide from spore of Ganoderma lucidum ameliorates paclitaxel-induced intestinal barrier injury: Apoptosis inhibition by reversing microtubule polymerization.

Side effects of chemotherapy are burning questions for physicians and patients involved in cancers. Ganoderma lucidum is a widely consumed traditional Chinese medicine and edible mushroom with multiple functional properties. The present study aims to investigate the potential of polysaccharides from spore of G. lucidum (SGP) on small intestinal barrier function recovery against paclitaxel (PTX) challenge in a breast cancer mice model and IEC-6 cell line. The 4T1 tumor-bearing mice were treated with PTX together with four-week daily oral administration of SGP. Results indicated that combination of PTX and SGP reversed body weight lost and remolded the histology of small intestine, accompanied with promoted proliferation but suppressed apoptosis in intestinal cells. Intestinal barrier function was enhanced by the combination as indicated by reduced endotoxemia and the up-regulation of tight junction proteins, including Zonula occludens-1 (ZO-1), E-cadherin, ß-catenin and Occludin. The protection of SGP was further confirmed in IEC-6 cells affected by PTX in vitro. The combination treatment prevented PTX-induced apoptosis in IEC-6 by inhibiting microtubule polymerization, and the aforementioned tight junction proteins were also upregulated. These findings suggest a promising protective effect of SGP against small intestinal barrier injury caused by PTX, highlighting its clinical implication against the chemotherapy side effects.