Alginate oligosaccharide assimilation by gut microorganisms and the potential role in gut inflammation alleviation.

Dietary fiber metabolism by gut microorganisms plays important roles in host physiology and health. Alginate, the major dietary fiber of daily diet seaweeds, is drawing more attention because of multiple biological activities. To advance the understanding of alginate assimilation mechanism in the gut, we show the presence of unsaturated alginate oligosaccharides (uAOS)-specific alginate utilization loci (AUL) in human gut microbiome. As a representative example, a working model of the AUL from the gut microorganism Bacteroides clarus was reconstructed from biochemistry and transcriptome data. The fermentation of resulting monosaccharides through Entner-Doudoroff pathway tunes the metabolism of short-chain fatty acids and amino acids. Furthermore, we show that uAOS feeding protects the mice against dextran sulfate sodium-induced acute colitis probably by remodeling gut microbiota and metabolome. IMPORTANCE: Alginate has been included in traditional Chinese medicine and daily diet for centuries. Recently discovered biological activities suggested that alginate-derived alginate oligosaccharides (AOS) might be an active ingredient in traditional Chinese medicine, but how these AOS are metabolized in the gut and how it affects health need more information. The study on the working mechanism of alginate utilization loci (AUL) by the gut microorganism uncovers the role of unsaturated alginate oligosaccharides (uAOS) assimilation in tuning short-chain fatty acids and amino acids metabolism and demonstrates that uAOS metabolism by gut microorganisms results in a variation of cell metabolites, which potentially contributes to the physiology and health of gut.

Performance Limit of Ultrathin GaAs Transistors.

High-electron-mobility group III-V compounds have been regarded as a promising successor to silicon in next-generation field-effect transistors (FETs). Gallium arsenide (GaAs) is an outstanding member of the III-V family due to its advantage of both good n- and p-type device performance. Monolayer (ML) GaAs is the limit form of ultrathin GaAs. Here, a hydrogenated ML GaAs (GaAsH2) FET is simulated by ab initio quantum-transport methods. The n- and p-type ML GaAsH2 metal-oxide-semiconductor FETs (MOSFETs) can well satisfy the on-state current, delay time, power dissipation, and energy-delay product requirements of the International Technology Roadmap for Semiconductors until the gate length is scaled down to 3/4 and 3/5 nm for the high-performance/low-power applications, respectively. Therefore, ultrathin GaAs is a prominent channel candidate for devices in the post-Moore era. The p-type ML GaAsH2 MOSFETs with a 2% uniaxially compressive strain and the unstrained n-type counterparts have symmetrical performance for the high-performance application, making ultrathin GaAs applicable for complementary MOS integrated circuits.

Inhibitory Effect of Gualou Guizhi Decoction on Microglial Inflammation and Neuron Injury by Promoting Anti-Inflammation via Targeting mmu-miR-155.

Gualou Guizhi decoction (GLGZD) treatment exerts neuroprotective effects and promotes spasticity following ischemic stroke. However, the molecular mechanism of GLGZD treatment on ischemic stroke remains unclear. Our previous study indicated that GLGZD ameliorates neuronal damage caused by secondary inflammatory injury induced by microglia. In the present study, we investigate the potential mechanism of GLGZD treatment on neuron damage induced by neuroinflammation via mmu-miR-155 in vitro. The HT22 cell line and the BV2 cell line were exposed to oxygen/glucose-deprive (OGD) conditions; the conditioned medium was prepared using the supernatants from OGD-stimulated BV2 cells after pretreating with GLGZD. Cell viability was determined by MTT assays; levels of released inflammatory cytokines were assessed using the BioPlex system. mmu-miR-155 and its targeting genes were detected using real-time reverse transcription polymerase chain reaction (RT-PCR). The expression of anti-inflammatory proteins was evaluated by Western blotting. DAPI staining was used to test the apoptotic cells. Our results showed that GLGZD pretreatment significantly induced IL10 release and decreased the production of TNF-α, IL6, and IFN-γ. In addition, GLGZD markedly attenuated mmu-miR-155 expression and its downstream SOCS1, SMAD2, SHIP1, and TAB2 expression levels. The DAPI-stained apoptotic cell death and caspase-3 activation in HT22 cells exposed to the conditioned medium were reversed by GLGZD treatment. Our findings suggested that GLGZD pretreatment downregulates the mmu-miR-155 signaling, which inhibits microglial inflammation, thereby resulting in the suppression of neuron apoptosis after OGD stress. The underlying mechanisms may provide the support for GLGZD treatment of cerebral ischemic injury.

Natural Triterpenoids Isolated from Akebia trifoliata Stem Explants Exert a Hypoglycemic Effect via α-Glucosidase Inhibition and Glucose Uptake Stimulation in Insulin-Resistant HepG2 Cells.

The inhibition of α-glucosidase activity is a prospective approach to attenuate postprandial hyperglycemia in the treatment of type 2 diabetes mellitus (T2DM). Herein, the inhibition of α-glucosidase by three compounds T1 -T3 of Akebia trifoliata stem, namely hederagenin (T1 ), 3-epiakebonoic acid (T2 ), and arjunolic acid (T3 ) were investigated using enzyme kinetics and molecular docking analysis. The three triterpenoids exhibited excellent inhibitory activities against α-glucosidase. T1 -T3 showed the strongest inhibition with IC50 values of 42.1±5.4, 19.6±3.2, and 11.2±2.3 µM, respectively, compared to the acarbose positive control (IC50 =106.3±8.2). Enzyme inhibition kinetics showed that triterpenoids T1 -T3 demonstrated competitive, mixed, and noncompetitive-type inhibition against α-glucosidase, respectively. The inhibition constant (Ki ) values were 21.21, 7.70, and 3.18 µM, respectively. Docking analysis determined that the interaction of ligands T1 -T3 and α-glucosidase was mainly forced by hydrogen bonds and hydrophobic interactions, which could result in improved binding to the active site of the target enzyme. The insulin resistant (IR)-HepG2 cell model used in this study (HepG2 cells exposed to 10-7  M insulin for 24 h) and glucose uptake assays showed that compounds T1 -T3 had no cytotoxicity with concentrations ranging from 6.25 to 25 µM and displayed significant stimulation of glucose uptake in IR-HepG2 cells. Thus, triterpenoids T1 -T3 showed dual therapeutic effects of α-glucosidase inhibition and glucose uptake stimulation and could be used as potential medicinal resources to investigate new antidiabetic agents for the prevention or treatment of diabetes.

The inhibitory effect of Gualou Guizhi Decoction on post-ischemic neuroinflammation via miR-155 in MCAO rats.

BACKGROUND: Gualou Guizhi Decoction (GLGZD) is commonly used to treat stroke. The present study investigated the potential roles of GLGZD on inflammation involving microRNA-155 (miR-155) in a model of ischemic stroke using middle cerebral artery occlusion (MCAO) rats. METHODS: Sprague-Dawley rats were randomly divided into three groups: Sham operated group, MCAO model group, and GLGZD treatment group. The ischemic model was established by 2 h left MCAO followed by reperfusion. Neurological deficits were evaluated with a modified Ashworth scale in each group. The changes in individual paw parameters were assessed by Catwalk gait analysis. Inflammatory cytokines were measured by enzyme linked immunosorbent assay (ELISA) and protein levels and gene expression related to inflammation were detected by Western blot and quantitative reverse transcription-PCR (qRTPCR) assays, respectively. The expression of inflammatory signaling proteins was additionally detected by immunohistochemistry. RESULTS: Treatment of MCAO rats with GLGZD improved neuronal defects and limb motivity. Additionally, GLGZD was able to inhibit miR-155 upregulation, resulting in down-regulation of miR155-targeted molecules in MCAO rats, including suppressor of cytokine signaling 1 (SOCS1), inhibitor of nuclear factor kappa-B kinase (IKK), mothers against decapentaplegic homolog 2 (SMAD2) and CCAAT/ enhancer binding protein beta (CEBPß). Meanwhile, the production of anti-inflammatory cytokines was dramatically enhanced by GLGZD treatment when comparing with the MCAO model group. CONCLUSIONS: In conclusion, GLGZD down-regulates miR-155, mediating subsequent neuroinflammation and resulting in neuroprotection which contributes to reduced spasticity after ischemic stroke.

Chrysin Alleviates Chronic Hypoxia-Induced Pulmonary Hypertension by Reducing Intracellular Calcium Concentration in Pulmonary Arterial Smooth Muscle Cells.

Chrysin (CH), the main ingredient of many medicinal plants, has been reported to be a very potent flavonoid possessing a large number of pharmacological activities. Recent studies have shown that CH significantly improves hemodynamic parameters such as right ventricular pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in a rat model of chronic hypoxia-induced pulmonary hypertension (CHPH). These improvements are through the inhibition of NOX4 expression, reactive oxygen species and malondialdehyde production, pulmonary arterial smooth muscle cell (PASMC) proliferation, and collagen accumulation. In this study, we investigated another mechanism by which CH alleviates CHPH by regulating intracellular calcium concentrations ([Ca]i) in PASMCs, as well as the underlying signaling pathway. The results show that (1) in CHPH model rats, CH substantially attenuated elevated right ventricular pressure, right ventricular hypertrophy, and pulmonary vascular remodeling; (2) in cultured rat distal PASMCs, CH inhibited the hypoxia-triggered promotion of cell proliferation, store-operated Ca entry and [Ca]i; and (3) CH significantly suppressed the hypoxia-upregulated HIF-1α, BMP4, TRPC1, and TRPC6 expression in distal pulmonary arteries (PAs) and cultured rat distal PASMCs. These results indicate that CH likely exerts its CHPH protective activity by regulating [Ca]i, which may result from the downregulation of HIF-1α, BMP4, TRPC1, and TRPC in PASMCs.

Virtual Screening Based on Ensemble Docking Targeting Wild-Type p53 for Anticancer Drug Discovery.

The tumor-suppressor function of p53 makes it an attractive drug target. Efforts were mostly put on stabilization of the functional p53 or reactivation of mutated p53. Previous studies have shown that small molecules targeting Loop1/Sheet3 (L1/S3) can reactivate the R175H-p53 and stabilize p53 in vitro. Since the L1/S3 pocket is shared by the mutate and the wild type (WT) p53, virtual screening is introduced to identify natural products targeting the L1/S3 of WT p53. Considering the high flexibility of Loop1, ensemble docking method is utilized for different clusters of the L1/S3. Seven conformations were chosen for docking. As one of the 181 selected candidates, torilin not only improved p53 activity, but also increased p21 protein expression level, which lies downstream of p53, therefore suppressing HCT116 cancer cell growth. Torilin may covalently bind to Cys124 of p53 by 2-methyl-2-butenal (2M2B) group, as torilin derivatives, which do not contain the 2M2B group, were not able to increase the p53 transcription activity. In conclusion, this study demonstrated that L1/S3 of WT-p53 is a druggable pocket, and torilin has a potential cytotoxicity through activating the p53 pathway.

The Inhibitory Effect of Propylene Glycol Alginate Sodium Sulfate on Fibroblast Growth Factor 2-Mediated Angiogenesis and Invasion in Murine Melanoma B16-F10 Cells In Vitro.

Melanoma is one of the most malignant and aggressive types of cancer worldwide. Fibroblast growth factor 2 (FGF2) is one of the critical regulators of melanoma angiogenesis and metastasis; thus, it might be an effective anti-cancer strategy to explore FGF2-targeting drug candidates from existing drugs. In this study, we evaluate the effect of the marine drug propylene glycol alginate sodium sulfate (PSS) on FGF2-mediated angiogenesis and invasion. The data shows that FGF2 selectively bound to PSS with high affinity. PSS inhibited FGF2-mediated angiogenesis in a rat aortic ring model and suppressed FGF2-mediated invasion, but not the migration of murine melanoma B16-F10 cells. The further mechanism study indicates that PSS decreased the expression of activated matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9), and also suppressed their activity. In addition, PSS was found to decrease the level of Vimentin in B16-F10 cells, which is known to participate in the epithelial-mesenchymal transition. Notably, PSS did not elicit any changes in cancer cell viability. Based on the results above, we conclude that PSS might be a potential drug to regulate the tumor microenvironment in order to facilitate the recovery of melanoma patients.

Brevilin A, a novel natural product, inhibits janus kinase activity and blocks STAT3 signaling in cancer cells.

Signal abnormalities in human cells usually cause unexpected consequences for individual health. We focus on these kinds of events involved in JAK-STAT signal pathways, especially the ones triggered by aberrant activated STAT3, an oncoprotein which participates in essential processes of cell survival, growth and proliferation in many types of tumors, as well as immune diseases. By establishing a STAT3 signal based high-throughput drug screening system in human lung cancer A549 cells, we have screened a library from natural products which contained purified compounds from medicinal herbs. One compound, named Brevilin A, exhibited both strong STAT3 signal inhibition and STAT3 signal dependent cell growth inhibition. Further investigations revealed that Brevilin A not only inhibits STAT3 signaling but also STAT1 signaling for cytokines induced phosphorylation of STAT3 and STAT1 as well as the expression of their target genes. In addition, we found Brevilin A could attenuate the JAKs activity by blocking the JAKs tyrosine kinase domain JH1. The levels of cytokine induced phosphorylation of STATs and other substrates were dramatically reduced by treatment of Brevilin A. The roles of Brevilin A targeting on JAKs activity indicate that Brevilin A may not only be used as a STAT3 inhibitor but also a compound blocking other JAK-STAT hyperactivation. Thus, these findings provided a strong impetus for the development of selective JAK-STAT inhibitors and therapeutic drugs in order to improve survival of patients with hyperactivated JAKs and STATs.

A comparative field study on dust measurements by different sampling methods with emphasis on estimating factors for recalculation from chinese 'total dust' measurements to respirable dust concentrations.

In China, dust samplers were originally designed to collect 'total dust' for a short term during production, which is different from the widely adopted sampling strategy for dust. With the aim to provide the conversion factor from Chinese total dust to US and German respirable dust and to look at the influences on conversion factors from environment, production, and instruments, a comparative field study on the dust concentration measurements by different sampling methods was carried out in the same Chinese industries as in the 1989-1990 study and in some other factories. A supplemental experiment was also conducted in a wind tunnel. Dust concentration was measured with a parallel sampling strategy by using the following samplers: 10-mm nylon cyclone for US respirable dust (AR), FSP-Berufsgenossenschaftliches Institut für Arbeitssicherheit (BIA) cyclone for German respirable dust (GR), and samplers for Chinese total dust (CT). Totally, 1434 samples were collected (269 AR, 198 GR, and 967 CT), from which 429 matched sample pairs (249 pairs of AR/CT, 180 GR/CT) were available to calculate conversion ratios. Industry- and job-based conversion factors are presented in this study. The conversion factor of AR/CT was 0.38 for tungsten mines, 0.19 for copper/iron mines, 0.65 for tin mines, and 0.20 for pottery industry, while the factor of GR/CT was 0.69 for tungsten, 0.37 for copper/iron, and 0.52 for pottery. In the job category, AR/CT factors varied from 0.16 to 0.96 and GR/CT from 0.12 to 0.72. For the industries studied in 1988-1989, the AR/CT and GR/CT factors were 0.29 and 0.45, respectively. Both factors were definitely influenced by production, CT dust concentration, sample gain, and variation of dust concentration. Moreover, the respirable dust concentration by FSP-BIA was significantly higher than that by 10-mm cyclones, 63.27-73.10% more as showed also by the wind tunnel experiment. Meanwhile, the GR/CT ratio was significantly larger than the AR/CT in every industry or job with only few exceptions. The GR/CT estimates should be considered as independent ones. Following these results, there is a need to use 'ideal samplers' (consistent with the internationally accepted respirable fraction) in practice and to assess the existent samplers in order to homogenize the exposure data situation.

PMS-1077, a PAF antagonist, induced differentiation of HL-60 cells with its novel activity.

The cell differentiation-inducing effect of 2-N,N-diethylaminocarbonyloxymethyl-1-diphenylmethyl-4-(3,4,5-trimethoxybenzoyl) piperazine, hydrochloride (PMS-1077) was determined in human leukaemic HL-60 cells with profiling of cell proliferation, analysis of cell cycling, characterization of expression of various CD molecules and determination of phagocytotic activity of differentiated HL-60 cells. After treatment with PMS-1077, HL-60 cells exhibited a decreased cell viability during which cell cycle was arrested in G0-/G1-phase. Flow cytometric analysis showed CD11b and CD14 were up-regulated, whereas CD15 was unaffected. Together with the finding that PMS-1077-treated HL-60 cells exhibited activities of differentiation by examining their ability of phagocytosing latex beads, an antiproliferative effect and a differentiation-inducing role were determined for PMS-1077 in HL-60 cells.