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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 05 March 2013, Vol.110(10), pp.3841-6
    Description: The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn(2+) and Zn(2+) with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn(2+) sequestration. The asymmetry of the CP heterodimer creates a single Mn(2+)-binding site from six histidine residues, which distinguishes CP from all other Mn(2+)-binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn(2+) and Zn(2+) being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn(2+) sequestration. These data establish the importance of Mn(2+) sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.
    Keywords: Immunity, Innate ; Leukocyte L1 Antigen Complex -- Chemistry ; Manganese -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Biochemical and Biophysical Research Communications, 14 June 2013, Vol.435(4), pp.546-550
    Description: Methylmercury (MeHg) is a potent neurotoxin that enters mammalian cells as a conjugate with -cysteine through L-type large neutral amino acid transporter, LAT1, by a molecular mimicry mechanism by structurally resembling -methionine. ( ) has been increasingly used to study the neurotoxic effects of MeHg, but little is known about uptake and transport of MeHg in the worm. This study examined whether MeHg uptake through LAT1 is evolutionarily conserved in nematodes. MeHg toxicity in was blocked by pre-treatment of worms with -methionine, suggesting a role for amino acid transporters in MeHg transport. Knockdown of , , and , worm homologues to LAT1, increased the survival of following MeHg treatment and significantly attenuated MeHg content following exposure. These results indicate that MeHg is transported in the worm by a conserved mechanism dependent on functioning amino acid transporters.
    Keywords: Methylmercury ; L-Type Large Neutral Amino Acid Transporter ; Molecular Mimicry ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 3
    In: American Journal of Botany, November 2011, Vol.98(11), pp.e330-e332
    Description: • Microsatellite markers were developed in an economically important plant, , to evaluate its genetic diversity. • Using the combined biotin capture method, 15 microsatellite primer sets were isolated and characterized. All of these markers showed polymorphism, and the number of alleles per locus ranged from two to 12 across 98 individuals from cultivars and a wild population. The observed and expected heterozygosities ranged from 0.000 to 0.905 and from 0.000 to 0.845, respectively. • These markers will facilitate the breeding and further study of the genetic diversity of .
    Keywords: Microsatellite Marker ; Siraitia Grosvenorrii ; Ssr
    ISSN: 0002-9122
    E-ISSN: 1537-2197
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(3), p.e0119122
    Description: Cystic fibrosis transmembrane conductance regulator (CFTR) is the principal apical route for transepithelial fluid transport induced by enterotoxin. Inhibition of CFTR has been confirmed as a pharmaceutical approach for the treatment of secretory diarrhea. Many traditional Chinese herbal medicines, like Rhodiola kirilowii (Regel) Maxim, have long been used for the treatment of secretory diarrhea. However, the active ingredients responsible for their therapeutic effectiveness remain unknown. The purpose of this study is to identify CFTR inhibitors from Rhodiola kirilowii (Regel) Maxim via bioactivity-directed isolation strategy. We first identified fractions of Rhodiola kirilowii (Regel) Maxim that inhibited CFTR Cl- channel activity. Further bioactivity-directed fractionation led to the identification of (-)-epigallocatechin-3-gallate (EGCG) as CFTR Cl- channel inhibitor. Analysis of 5 commercially available EGCG analogs including (+)-catechins (C), (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG) and EGCG revealed that ECG also had CFTR inhibitory activity. EGCG dose-dependently and reversibly inhibited CFTR Cl- channel activity in transfected FRT cells with an IC50 value around 100 μM. In ex vivo studies, EGCG and ECG inhibited CFTR-mediated short-circuit currents in isolated rat colonic mucosa in a dose-dependent manner. In an intestinal closed-loop model in mice, intraluminal application of EGCG (10 μg) and ECG (10 μg) significantly reduced cholera toxin-induced intestinal fluid secretion. CFTR Cl- channel is a molecular target of natural compounds EGCG and ECG. CFTR inhibition may account, at least in part, for the antidiarrheal activity of Rhodiola kirilowii (Regel) Maxim. EGCG and ECG could be new lead compounds for development of CFTR-related diseases such as secretory diarrhea.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Journal of bacteriology, April 2014, Vol.196(7), pp.1335-42
    Description: The reactive nature of heme enables its use as an enzymatic cofactor while rendering excess heme toxic. The importance of heme detoxification machinery is highlighted by the presence of various types of these homeostatic systems in Gram-positive and Gram-negative microorganisms. A number of pathogens possess orthologs of the HssRS/HrtAB heme detoxification system, underscoring a potential role this system plays in the survival of bacteria in heme-rich environments such as the vertebrate host. In this work, we sought to determine the role of this system in protection against metalloporphyrin heme analogues identified by previous studies as antimicrobial agents. Our findings demonstrate that only toxic metalloporphyrins maximally activate expression of the Staphylococcus aureus heme detoxification system, suggesting that the sensing mechanism of HssRS might require a component of the associated toxicity rather than or in addition to the metalloporphyrin itself. We further establish that only a subset of toxic metalloporphyrins elicit the oxidative damage previously shown to be a significant component of heme toxicity whereas all toxic noniron metalloporphyrins inhibit bacterial respiration. Finally, we demonstrate that, despite the fact that toxic metalloporphyrin treatment induces expression of S. aureus heme detoxification machinery, the HrtAB heme export pump is unable to detoxify most of these molecules. The ineffectiveness of HrtAB against toxic heme analogues provides an explanation for their increased antimicrobial activity relative to heme. Additionally, these studies define the specificity of HssRS/HrtAB, which may provide future insight into the biochemical mechanisms of these systems.
    Keywords: Gene Expression Regulation, Bacterial ; Bacterial Proteins -- Metabolism ; Heme -- Metabolism ; Staphylococcal Infections -- Microbiology ; Staphylococcus Aureus -- Metabolism
    ISSN: 00219193
    E-ISSN: 1098-5530
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  • 6
    Language: English
    In: Diabetes, February 2014, Vol.63(2), pp.421-32
    Description: Adipose tissue (AT) expansion is accompanied by the infiltration and accumulation of AT macrophages (ATMs), as well as a shift in ATM polarization. Several studies have implicated recruited M1 ATMs in the metabolic consequences of obesity; however, little is known regarding the role of alternatively activated resident M2 ATMs in AT homeostasis or how their function is altered in obesity. Herein, we report the discovery of a population of alternatively activated ATMs with elevated cellular iron content and an iron-recycling gene expression profile. These iron-rich ATMs are referred to as MFe(hi), and the remaining ATMs are referred to as MFe(lo). In lean mice, ~25% of the ATMs are MFe(hi); this percentage decreases in obesity owing to the recruitment of MFe(lo) macrophages. Similar to MFe(lo) cells, MFe(hi) ATMs undergo an inflammatory shift in obesity. In vivo, obesity reduces the iron content of MFe(hi) ATMs and the gene expression of iron importers as well as the iron exporter, ferroportin, suggesting an impaired ability to handle iron. In vitro, exposure of primary peritoneal macrophages to saturated fatty acids also alters iron metabolism gene expression. Finally, the impaired MFe(hi) iron handling coincides with adipocyte iron overload in obese mice. In conclusion, in obesity, iron distribution is altered both at the cellular and tissue levels, with AT playing a predominant role in this change. An increased availability of fatty acids during obesity may contribute to the observed changes in MFe(hi) ATM phenotype and their reduced capacity to handle iron.
    Keywords: Adipose Tissue -- Cytology ; Dietary Fats -- Adverse Effects ; Iron -- Metabolism ; Macrophages -- Metabolism ; Obesity -- Chemically Induced
    ISSN: 00121797
    E-ISSN: 1939-327X
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  • 7
    In: PLoS ONE, 2014, Vol.9(4)
    Description: Inhibitors of cystic fibrosis transmembrane conductance regulator (CFTR) have been widely used for characterizing CFTR function in epithelial fluid transport and in diseases such as secretory diarrhea, polycystic kidney disease and cystic fibrosis. Few small molecule CFTR inhibitors have been discovered so far from combinatorial compound library. In the present study, we used a high throughput screening (HTS)-based natural product discovery strategy to identify new CFTR inhibitors from Chinese medicinal herbs. By screening 40,000 small molecule fractions from 500 herbal plants, we identified 42 positive fractions from 5 herbs and isolated two compounds that inhibited CFTR conductance from Chinese wild grapevine ( Vitis amurensis Rupr ). Mass spectrometry (MS) and nuclear magnetic resonance (NMR) studies determined the two active compounds as trans - ε -viniferin (TV) and r -2-viniferin (RV), respectively. Both compounds dose-dependently blocked CFTR-mediated iodide influx with IC 50 around 20 μM. Further analysis by excised inside-out patch-clamp indicated strong inhibition of protein kinase A (PKA)-activated CFTR chloride currents by TV and RV. In ex vivo studies, TV and RV inhibited CFTR-mediated short-circuit Cl − currents in isolated rat colonic mucosa in a dose-dependent manner. In a closed-loop mouse model, intraluminal applications of TV (2.5 μg) and RV (4.5 μg) significantly reduced cholera toxin–induced intestinal fluid secretion. The present study identified two resveratrol oligomers as new CFTR inhibitors and validates our high-throughput screening method for discovery of bioactive compounds from natural products with complex chemical ingredients such as herbal plants.
    Keywords: Research Article ; Biology And Life Sciences ; Medicine And Health Sciences
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 28 November 2017, Vol.114(48), pp.12669-12674
    Description: Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release d-aminoluciferin for selective reactivity-based detection of Fe with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.
    Keywords: Infectious Disease ; Labile Iron ; Luciferin ; Metal Homeostasis ; Molecular Imaging ; Acinetobacter Infections -- Metabolism ; Anemia, Iron-Deficiency -- Metabolism ; Firefly Luciferin -- Analysis ; Fluorescent Dyes -- Analysis ; Iron -- Metabolism ; Iron Overload -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    Language: English
    In: International Journal of Peptide Research and Therapeutics, 2012, Vol.18(4), pp.327-333
    Description: Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) have a similar but complementary role in regulating blood glucose level. This study was aimed to develop a functional-complementary dual insulinotropic peptide which releases both GLP-1 and GIP in vivo, and to investigate its therapeutic effect on type 2 diabetes in mice. We firstly constructed a vector pET-22b(+)- rolGG to express a recombinant oral long-acting GLP-1–GIP fusion peptide (rolGG) in E. coli . The rolGG peptide was then purified and confirmed its capacity of releasing recombinant oral long-acting GLP-1 (rolGLP-1) and recombinant GIP (rGIP) upon trypsin digestion in vitro, which were designed to resist in vivo enzymatic degradation. The therapeutic effect of rolGG was assessed in comparison with rolGLP-1 alone by daily oral-gavage administration up to 10 days in streptozotocin-induced type 2 diabetic mice. Saline and rosiglitazone administrations were served as negative and positive controls, respectively. The results showed that rolGG treatment decreased plasma glucose level by 26.7 and 46.3 % ( p  〈 0.01), respectively, at 5 and 10 days after the initial oral-gavage. The rolGG treatment also led to a trend of body weight increase, drink level and food intake decrease ( p  〈 0.05). In comparison, the oral administration of rolGLP-1 alone exhibited similar effects to rolGG with regard to plasma glucose level, drink level and food intake. In conclusion, we expressed and purified a dual insulinotropic peptide rolGG. Oral-gavage administration of rolGG showed a therapeutic effect on reduction of plasma glucose and alleviation of emaciation, polydipsia, and polyphagia symptoms in streptozotocin-induced diabetic mice.
    Keywords: Diabetes ; Glucagon-like peptide-1 ; Gastric inhibitory polypeptide ; Fusion peptide
    ISSN: 1573-3149
    E-ISSN: 1573-3904
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  • 10
    Language: English
    In: Journal of agricultural and food chemistry, 08 September 2010, Vol.58(17), pp.9731-8
    Description: Selenium (Se) distribution in Se-enriched rice and optimization of extraction for Se-containing protein were studied. Se availability in Se-containing protein product was simulated using an in vitro gastrointestinal digestion. The results showed that Se was predominately found as organic Se, whereas inorganic Se comprised only 2.85% of the total Se. The glutelin fraction contained the largest amount of Se, approximately 31.3% of the total Se in the rice gain. Utilizing orthogonal analysis, the optimum extraction conditions were selected at a volume to weight of 20:1, 0.08 M NaOH, an extraction time of 3 h, and at a temperature of 35 degrees C. A Se-containing rice protein product with 83.5% protein and 9.09 microg g(-1) Se was sequestered using the optimal extraction method. This rice protein product with high molecular weight Se-containing protein can readily be digested to low molecular weight peptides and selenomethionine (52.3% of total Se in protein extract).
    Keywords: Oryza -- Metabolism ; Selenium -- Pharmacokinetics
    ISSN: 00218561
    E-ISSN: 1520-5118
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