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1.
Pharmacol Ther ; : 107496, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32001311

RESUMO

Berberine (BBR) is a multi-target drug (MTD) that has proven effective in the treatment of metabolism-related chronic diseases (CDs). However, the mode of action (MOA) of BBR remains to be clarified. At a cellular level, the inhibitory effect of BBR on mitochondrial enzymes is probably responsible for many of its biological activities, including the activation of low-density lipoprotein receptor (LDLR), AMP-activated protein kinase (AMPK) and insulin receptor (InsR); these biological activities contribute to ameliorate peripheral blood metabolic profiles, e.g. by reducing plasma lipids and glucose levels, thus improving signs and symptoms of metabolic disorders. In this perspective, BBR acts as a targeted therapy. However, it also exerts pleiotropic systemic activities on some root causes of CDs that include antioxidant / anti-inflammatory effects and modifications of gut microbiota composition and metabolism, which may also contribute to its disease-modifying effects. After reviewing the different MOA of BBR, here we propose that BBR acts through a drug-cloud (dCloud) mechanism, as different to a drug-target effect. The dCloud here is defined as a group of terminal molecular events induced by the drug (or/and related metabolites), as well as the network connections among them. In this scenario, the therapeutic efficacy of BBR is the result of its dCloud effect acting on symptoms/signs as well as on root causes of the diseases. The dCloud concept is applicable to other established MTDs, such as aspirin, metformin, statins as well as to nutrient starvation, thus providing a novel instrument for the design of effective therapies against multifactorial metabolism-related CDs.

2.
Curr Microbiol ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31982965

RESUMO

A Gram-stain-negative, facultative aerobic, non-spore-forming, non-motile, non-flagellated, rod-shaped bacterium, designated strain NAU-18T was isolated from an oil-contaminated soil in China. Strain NAU-18T could grow at 10-42 °C (optimum, 30 °C), at pH 5.0-8.0 (optimum, 7.0) and in the presence of 0-2.0% (w/v) NaCl (optimum, 0.5% NaCl in R2A). The predominant fatty acids were C18:1ω7c (71.2%) and Summed feature 2 (5.1%), representing 76.3% of the total fatty acids. The major respiratory quinones were Q9 and Q10. The DNA G + C content of strain NAU-18T was 61.4 mol% based on its draft genome sequence. Genome annotation of strain NAU-18T predicted the presence of 6668 genes, of which 6588 are coding proteins and 80 are RNA genes. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain NAU-18T was a member of the genus Rhizobium and showed 96.93% (with 93.2% coverage) and 96.81% (with 100% coverage) identities with those of Neorhizobium alkalisoli CCBAU 01393T and Rhizobium oryzicola ZYY136T, respectively. In the phylogenetic analysis, strain NAU-18T and R. oryzicola ZYY136T are consistently placed in the same branch. Strain NAU-18T represents a novel species within the genus Rhizobium, for which the name Rhizobium terrae sp. nov. is proposed, with the type strain NAU-18T (=KCTC 62418T = CCTCC AB 2018075T).

3.
Microb Cell Fact ; 19(1): 4, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910844

RESUMO

BACKGROUND: Swep is an excellent carbamate herbicide that kills weeds by interfering with metabolic processes and inhibiting cell division at the growth point. Due to the large amount of use, swep residues in soil and water not only cause environmental pollution but also accumulate through the food chain, ultimately pose a threat to human health. This herbicide is degraded in soil mainly by microbial activity, but no studies on the biotransformation of swep have been reported. RESULTS: In this study, a consortium consisting of two bacterial strains, Comamonas sp. SWP-3 and Alicycliphilus sp. PH-34, was enriched from a contaminated soil sample and shown to be capable of mineralizing swep. Swep was first transformed by Comamonas sp. SWP-3 to the intermediate 3,4-dichloroaniline (3,4-DCA), after which 3,4-DCA was mineralized by Alicycliphilus sp. PH-34. An amidase gene, designated as ppa, responsible for the transformation of swep into 3,4-DCA was cloned from strain SWP-3. The expressed Ppa protein efficiently hydrolyzed swep and a number of other structural analogues, such as propanil, chlorpropham and propham. Ppa shared less than 50% identity with previously reported arylamidases and displayed maximal activity at 30 °C and pH 8.6. Gly449 and Val266 were confirmed by sequential error prone PCR to be the key catalytic sites for Ppa in the conversion of swep. CONCLUSIONS: These results provide additional microbial resources for the potential remediation of swep-contaminated sites and add new insights into the catalytic mechanism of amidase in the hydrolysis of swep.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31924619

RESUMO

Acetamiprid, a chloronicotinyl neonicotinoid insecticide, is among the most commonly used insecticides worldwide, and its environmental fate has caused considerable concern. The compound 1-(6-chloropyridin-3-yl)-N-methylmethanamine (IM 1-4) has been reported as the main intermediate during acetamiprid catabolism in microorganisms, honeybees and spinach. However, the molecular mechanism underlying the hydrolysis of acetamiprid to IM 1-4 has not yet been elucidated. In this study, a novel amidase (AceAB) that initially hydrolyzes the C-N bond of acetamiprid to generate IM 1-4 was purified and characterized from the acetamiprid-degrading strain Pigmentiphaga sp. D-2. Based on peptide profiling of the purified AceAB and the draft genome sequence of strain D-2, aceA (372 bp) and aceB (2,295 bp) encoding the α and ß subunits of AceAB, respectively, were cloned and found to be necessary for acetamiprid hydrolysis in strain D-2. The characteristics of AceAB were also systematically investigated. Though AceA and AceB showed 35%-56% identities to the α and ß subunits of the N,N-dimethylformamidase from Paracoccus aminophilus, AceAB was specific for the hydrolysis of acetamiprid and showed no activities to N,N-dimethylformamide or its structural analogs.IMPORTANCE Acetamiprid, belonging to the top world-widely used neonicotinoid insecticides, is one of the most important commercial insecticides. Due to its extensive use, the environmental fate of acetamiprid, especially the microbial degradation of acetamiprid, has caused considerable concern. Although the catabolic pathways of acetamiprid in microorganisms have been extensively studied, the molecular mechanisms underlying acetamiprid biodegradation (except for a nitrile hydratase) remain largely unknown, and the enzyme responsible for the biotransformation of acetamiprid to its main intermediate IM 1-4 has not yet been elucidated. The amidase AceAB and its encoding genes aceA and aceB, characterized in this study, was found to be necessary and specific for the initial hydrolysis of C-N bond of acetamiprid to generate IM 1-4 in Pigmentiphaga sp. strain D-2. The finding of the novel amidase AceAB will greatly enhance our understanding of the microbial catabolism of the widely used insecticide acetamiprid on the molecular level.

5.
Autophagy ; : 1-15, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31986961

RESUMO

Although macroautophagy/autophagy is involved in hepatocellular carcinoma (HCC) initiation and development and has been identified as a mechanism of HCC therapy resistance, the role of ULK1 (unc-51 like autophagy activating kinase 1) in HCC remains unclear. Here, we report that both knockdown and knockout of ULK1 inhibited human HCC cell proliferation and invasion, and Ulk1 deletion abrogated tumor growth in a xenograft mouse model. Furthermore, ULK1 ablation in combination with sorafenib significantly inhibited HCC progression compared with sorafenib treatment alone or vehicle control. To identify candidate ULK1 inhibitors, we used a structure-based virtual docking approach to screen 3428 compounds. Among these compounds, XST-14 showed the highest affinity for the ULK1 protein and specifically blocked ULK1 kinase activity. Moreover, the Lys46, Tyr94 and Asp165 amino acid residues of ULK1 were required for its binding to XST-14 according to molecular docking and mutagenesis experiments. Functional assays revealed that XST-14 blocked autophagy and subsequently induced apoptosis and inhibited growth in HCC cells. More importantly, XST-14 acted synergistically with sorafenib to attenuate HCC progression by inhibiting sorafenib-induced autophagy activation both in vitro and in vivo. In addition, XST-14 was well tolerated and exhibited favorable drug metabolism and pharmacokinetic properties and low toxicity in mice. In summary, our study determined that ULK1 may represent a new therapeutic target for HCC and that targeting ULK1 in combination with sorafenib treatment may serve as a promising interventional strategy for treating HCC.Abbreviations: 3MA: 3-methyladenine; ADV: AutoDock Vina; ATP: adenosine triphosphate; EdU: 5-ethynyl-2'-deoxyuridine; ESI: electrospray ionization; HCC: hepatocellular carcinoma; IC50: half maximal inhibitory concentration; KD: kinase domain; q.o.d., every other day; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SPR, surface plasmon resonance.

7.
Environ Microbiol ; 22(1): 286-296, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31667998

RESUMO

The (R)- and (S)-enantiomers of the chiral herbicide napropamide (NAP) show different biological activities and ecotoxicities. These two enantiomers behave differently in the environment due to enantioselective catabolism by microorganisms. However, the molecular mechanisms underlying this enantioselective catabolism remain largely unknown. In this study, the genes (snaH and snpd) involved in the catabolism of NAP were cloned from Sphingobium sp. B2, which was capable of catabolizing both NAP enantiomers. Compared with (R)-NAP, (S)-NAP was much more rapidly transformed by the amidase SnaH, which initially cleaved the amide bonds of (S)/(R)-NAP to form (S)/(R)-2-(1-naphthalenyloxy)-propanoic acid [(S)/(R)-NP] and diethylamine. The α-ketoglutarate-dependent dioxygenase Snpd, showing strict stereoselectivity for (S)-NP, further transformed (S)-NP to 1-naphthol and pyruvate. Molecular docking and site-directed mutagenesis analyses revealed that when the (S)-enantiomers of NAP and NP occupied the active sites, the distance between the ligand molecule and the coordination atom was shorter than that when the (R)-enantiomers occupied the active sites, which facilitated formation of the transition state complex. This study enhances our understanding of the preferential catabolism of the (S)-enantiomer of NAP on the molecular level.

8.
Ecotoxicol Environ Saf ; 187: 109848, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31670182

RESUMO

Dimethyl terephthalate (DMT) is a primary ingredient widely used in the manufacture of polyesters and industrial plastics; its environmental fate is of concern due to its global use. Microorganisms play key roles in the dissipation of DMT from the environment; however, the enzymes responsible for the initial transformation of DMT and the possible altered toxicity due to this biotransformation have not been extensively studied. To reduce DMT toxicity, we identified the esterase gene dmtH involved in the initial transformation of DMT from the AOPP herbicide-transforming strain Sphingobium sp. C3. DmtH shows 24-41% identity with α/ß-hydrolases and belongs to subfamily V of bacterial esterases. The purified recombinant DmtH was capable of transforming DMT to mono-methyl terephthalate (MMT) and potentially transforming other p-phthalic acid esters, including diallyl terephthalate (DAT) and diethyl terephthalate (DET). Using C. elegans as an assay model, we observed the severe toxicity of DMT in inducing reactive oxygen species (ROS) production, decreasing locomotion behavior, reducing lifespan, altering molecular basis for oxidative stress, and inducing mitochondrial stress. In contrast, exposure to MMT did not cause obvious toxicity, induce oxidative stress, and activate mitochondrial stress in nematodes. Our study highlights the usefulness of Sphingobium sp. C3 and its esterase DmtH in transforming p-phthalic acid esters and reducing the toxicity of DMT to organisms.


Assuntos
Poluentes Ambientais/toxicidade , Esterases/genética , Genes Bacterianos , Ácidos Ftálicos/toxicidade , Sphingomonadaceae/metabolismo , Animais , Biodegradação Ambiental , Biotransformação , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Poluentes Ambientais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácidos Ftálicos/metabolismo , Plásticos/química , Sphingomonadaceae/enzimologia , Sphingomonadaceae/genética
9.
Biomed Pharmacother ; 121: 109602, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31707349

RESUMO

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in China, accompanied by an extremely high mortality rate. Chlorogenic acid (CGA) is a small-molecule compound, that has been shown to have a wide range of biological activities, including antitumor. However, the efficacy and molecular mechanism of CGA on ESCC remains unknown. In this study, we confirmed the inhibition of proliferation by CGA in ESCC cells, as well as the reduction of ESCC xenograft volume by CGA in vivo. In addition, CGA also suppressed both the migration and invasion of ESCC cells in vitro. In a carcinogen-induced murine model of ESCC, hyperplasia of the esophagus was slowed by CGA, while mice suffering from ESCC that were treated with CGA had longer survival times than mice in the control group. The measurement of pluripotency factors (BMI1, SOX2, OCT4 and Nanog) that are related to poor prognosis revealed reduced expression of both BMI1 and SOX2, but not of OCT4 or Nanog, in ESCC cells, in both a dose- and time-dependent manner. Together, our initial findings demonstrate that CGA suppresses ESCC progression, downregulates the expression of BMI1 and SOX2, and provide an anti-tumor candidate for ESCC therapy.

10.
Data Brief ; 27: 104633, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31667325

RESUMO

This paper contains data that can be used in interpretation of the pharmacological effects of sinomenine combined with gabapentin or ligustrazine hydrochloride on chronic pain. The data can be divided into two parts. The first part is regarding if there were noticeable side effects accompanying drug applications of sinomenine plus gabapentin or ligustrazine hydrochloride. These side effects include sedation and change of core body temperature as well as tissue edema and sustained itch. The data were acquired from the open field test in mice, and provided insights for the effects of drug combination therapy on locomotive activities, rearing behaviors and body temperature. The second part is regarding whether sinomenine could be accumulated in the central nervous system (CNS) tissue following repeated drug administration. The data were acquired using microdialysis, which illustrated the pharmacokinetic properties of sinomenine, by showing relative concentrations of sinomenine in blood and CNS tissue, following single or repeated drug application. Data presented here is related to and supportive of the research article by Gao et al., "Sinomenine facilitates the efficacy of gabapentin or ligustrazine hydrochloride in animal models of neuropathic pain"[1], where interpretation of the research data presented here is available.

11.
Theranostics ; 9(23): 6745-6763, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31660066

RESUMO

RATIONALE: Inducing cancer differentiation is a promising approach to treat cancer. Here, we identified chlorogenic acid (CA), a potential differentiation inducer, for cancer therapy, and elucidated the molecular mechanisms underlying its differentiation-inducing effects on cancer cells. METHODS: Cancer cell differentiation was investigated by measuring malignant behavior, including growth rate, invasion/migration, morphological change, maturation, and ATP production. Gene expression was analyzed by microarray analysis, qRT-PCR, and protein measurement, and molecular biology techniques were employed for mechanistic studies. LC/MS analysis was the method of choice for chemical detection. Finally, the anticancer effect of CA was evaluated both in vitro and in vivo. Results: Cancer cells treated with CA showed reduced proliferation rate, migration/invasion ability, and mitochondrial ATP production. Treating cancer cells with CA resulted in elevated SUMO1 expression through acting on its 3'UTR and stabilizing the mRNA. The increased SUMO1 caused c-Myc sumoylation, miR-17 family downregulation, and p21 upregulation leading to G0/G1 arrest and maturation phenotype. CA altered the expression of differentiation-related genes in cancer cells but not in normal cells. It inhibited hepatoma and lung cancer growth in tumor-bearing mice and prevented new tumor development in naïve mice. In glioma cells, CA increased expression of specific differentiation biomarkers Tuj1 and GFAP inducing differentiation and reducing sphere formation. The therapeutic efficacy of CA in glioma cells was comparable to that of temozolomide. CA was detectable both in the blood and brain when administered intraperitoneally in animals. Most importantly, CA was safe even at very high doses. CONCLUSION: CA might be a safe and effective differentiation-inducer for cancer therapy. "Educating" cancer cells to differentiate, rather than killing them, could be a novel therapeutic strategy for cancer.

12.
Sci Rep ; 9(1): 13415, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527742

RESUMO

This study is designed to investigate the effects of berberine (BBR) on galectin-3 (Gal-3) and the relationships to its suppressive activities on adipocyte differentiation, proliferation and adiposity. Our results showed that BBR greatly suppressed the differentiation and proliferation of mouse primary preadipocytes isolated from epididymal white adipose tissue (eWAT), during which the expression level of Gal-3 was down-regulated significantly. Overexpression of Gal-3 totally abolished the suppressive activities of BBR on Gal-3 expression, preadipocyte differentiation and proliferation. BBR reduced Gal-3 promoter activity, destabilized its mRNA and inhibited firefly luciferase activity of a recombinant plasmid containing the Gal-3 3' untranslated region (UTR). Furthermore, BBR up-regulated microRNA (miRNA) let-7d expression and the suppressive activity on Gal-3 3'UTR was abolished by point mutation on the let-7d binding site. In mice fed a high-fat diet (HFD), BBR up-regulated let-7d and down-regulated Gal-3 expression in eWAT; it also suppressed adipocyte differentiation and proliferation and reduced adiposity greatly. In summary, our study proves that BBR inhibits the differentiation and proliferation of adipocytes through down-regulating Gal-3, which is closely associated with its anti-obesity effect. Our results may support the future clinical application of BBR for the treatment of obesity or related diseases.

13.
Acta Pharm Sin B ; 9(4): 769-781, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31384537

RESUMO

Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus (HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein (GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A (VAP-A) in competition with the HCV NS5A, causing an interruption of the complex formation between VAP-A and HCV NS5A. As the formation of VAP-A/NS5A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents (DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.

14.
Int J Syst Evol Microbiol ; 69(11): 3443-3447, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31436521

RESUMO

A Gram-stain-negative bacterial strain, designated JW-3T, was isolated from a soil sample collected from farmland in Yantai, Shandong Province, PR China. Cells of strain JW-3T are motile rods and strictly aerobic, showing catalase- and oxidase-positive reactions. Strain JW-3T could grow at 16-37 °C (optimum, 30 °C), at pH 6.0-9.0 (pH 7.0) and in the presence of 0-1 % (w/v) NaCl (0.5 %, in Luria-Bertani broth). The major fatty acids were summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c; 35.5 %), iso-C16 : 0 (16.7 %) and C12 : 0 (10.8 %). The major respiratory quinone was ubiquinone-8 (Q8). The polar lipids of strain JW-3T consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, four unidentified phospholipids, two unidentified lipids, two unidentified glycolipids and a partial unidentified aminophospholipid. Strain JW-3T was most closely related to Steroidobacter agariperforans KA5-BT with 97.67 % 16S rRNA gene sequence similarity. Results of phylogenetic analyses, based on 16S rRNA gene sequencing, showed that strain JW-3T forms a distinct phylogenic lineage within the genus Steroidobacter of the family Sinobacteraceae. The DNA G+C content of strain JW-3T was 62.57 mol%, based on its draft genome sequence. Average nucleotide identity values and digital DNA-DNA hybridization values for draft genomes, between strain JW-3T and strain KA5-BT, were 84.54 and 30.80 %, respectively. Based on its phenotypic, chemotaxonomic and molecular features, and DNA-DNA hybridization results, strain JW-3T represents a novel species of the genus Steroidobacter, for which the name Steroidobactersoli sp. nov. is proposed. The type strain is JW-3T (=CCTCC AB 2018184T=KCTC 62820T).


Assuntos
Fazendas , Gammaproteobacteria/classificação , Filogenia , Microbiologia do Solo , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Gammaproteobacteria/isolamento & purificação , Glicolipídeos/química , Hibridização de Ácido Nucleico , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Ubiquinona/química
15.
Environ Int ; 132: 105081, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31404844

RESUMO

This is a primary investigation on the mitigation of polycyclic aromatic hydrocarbon (phenanthrene as a model PAH) contamination in vegetables including water spinach (Ipomoea aquatica Forsk), pakchoi (Brassica campestris) and Chinese cabbage (Brassica chinensis) using a gfp-labeled PAH-degrading bacterium (RS1-gfp). Effective root colonization led to dense RS1-gfp populations inhabiting the rhizosphere and endosphere of the vegetables, which subsequently led to a reduction in phenanthrene accumulation and risk in vegetables. When compared with the controls without RS1-gfp, the amount of phenanthrene accumulation due to strain RS1-gfp colonization reduced by up to ~93.7% in roots and ~75.2% in shoots of vegetables, respectively. The estimated incremental lifetime cancer risk (ILCR) for adults due to phenanthrene in vegetables was reduced by 24.6%-48% through RS1-gfp inoculation. The proposed method was developed to circumvent the risk of phenanthrene contamination in vegetables by inoculating PAH-degrading bacteria. The findings provide an in-depth understanding of PAH detoxification in agricultural plants grown on contaminated sites by exploiting bacteria like RS1-gfp, which portray both rhizo- and endophytic lifestyles.

16.
Int J Syst Evol Microbiol ; 69(12): 3806-3811, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31464658

RESUMO

A strictly aerobic, Gram-stain-negative, rod-shaped, yellow, non-spore-forming bacterial strain, designated P-25T, was isolated from soil collected in Yantai, Shandong Province, PR China. The temperature, pH and NaCl concentration ranges for the growth of strain P-25T were 10-37 °C (optimum, 28-30 °C), pH 6.0-9.0 (optimum, pH 7.5-8.0) and 0-4 % (w/v) (optimum, 1 % w/v), respectively. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain P-25T was most closely related to Pedobacter xixiisoli S27T (98.1 % 16S rRNA gene sequence similarity), followed by Pedobacter chitinilyticus CM134L-2T (97.2 %) and Pedobacter ureilyticus THG-T11T (97.1 %). The genomic DNA G+C content of strain P-25T based on its draft genome sequence was 38.1 %. MK-7 was the major respiratory quinone, and iso-C15 : 0, C16 : 1ω7c and/or C16 : 1ω6c (summed feature 3) and iso-C17 : 0 3-OH were the major fatty acids. The major polar lipids were phosphatidylethanolamine, one unidentified aminophospholipid, one unidentified phospholipid, two unidentified lipids, five unidentified aminolipids and two unidentified glycolipids. Average nucleotide identity values for the draft genomes between strain P-25T and strains S27T, CM134L-2T and THG-T11T were 81.8, 77.6 and 81.2 %, respectively, and the digital DNA-DNA hybridization (dDDH) values were 30.0, 19.2 and 27.6 %, respectively. Based on their phylogenetic and phenotypic characteristics, chemotaxonomic data, and dDDH results, strain P-25T is considered to represent a novel species of the genus Pedobacter, for which the name Pedobacter helvus sp. nov. is proposed; the type strain is strain P-25T (KCTC 62821T=CCTCC AB 2018185T).


Assuntos
Fazendas , Pedobacter/classificação , Filogenia , Microbiologia do Solo , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Glicolipídeos/química , Hibridização de Ácido Nucleico , Pedobacter/isolamento & purificação , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/química
17.
Int J Syst Evol Microbiol ; 69(9): 2936-2941, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31310195

RESUMO

A novel Gram-stain-negative, strictly aerobic, non-spore-forming, motile with one polar flagellum and short rod-shaped bacterium, designated strain ZLT-5T, was isolated from procymidone-contaminated soil sampled in Nanjing, Jiangsu, PR China. Growth occurred at 26-37 °C (optimum, 37 °C), at pH 6.0-9.0 (pH 7.0) and in the presence of 0-1.5 % NaCl (0.5 %). Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain ZLT-5T belonged to the genus Sphingomonas, with the highest sequence similarity to Sphingomonas kyeonggiensis THG-DT81T (96.6 %), followed by Sphingomonas dokdonensis DSM 21029T (96.5 %) and Sphingomonas silvisoli RP18T (96.3 %). The G+C content of strain ZLT-5T was 68.0 mol% (draft genome sequence). The average nucleotide identity value of the draft genomes between strain ZLT-5T and S. kyeonggiensis THG-DT81T was 75.4 %. Strain ZLT-5T contained ubiquinone-10 as the predominant isoprenoid quinone and sym-homospermidine as the major polyamine. The major polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, phosphoaminolipid and sphingoglycolipid. The main cellular fatty acids (>10 % of the total fatty acids) of strain ZLT-5T were C17 : 1ω6c, summed feature 3 (C16 : 1ω7c and/or C15 : 0 ISO 2-OH) and summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c). Based on phylogenetic analysis and physiological and biochemical characterization, strain ZLT-5T is described as a novel species of the genus Sphingomonas, for which the name Sphingomonas flavalba sp. nov. is proposed. The type strain is ZLT-5T (=CCTCC AB 2018188T=KCTC 62840T).


Assuntos
Compostos Bicíclicos com Pontes , Filogenia , Microbiologia do Solo , Poluentes do Solo , Sphingomonas/classificação , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Espermidina/análogos & derivados , Espermidina/química , Sphingomonas/isolamento & purificação , Ubiquinona/química
18.
Int J Antimicrob Agents ; 54(4): 502-506, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31310806

RESUMO

The current outbreak of Zika virus (ZIKV) is the impetus for novel, safe and efficacious anti-ZIKV agents. ZIKV non-structural protein 5 RNA-dependent RNA polymerase (RdRp) is essential for viral replication and is logically regarded as an attractive drug target. This study used a fluorescence-based polymerase assay to find an anti-infective drug 10-undecenoic acid zinc salt (UA) which could inhibit RdRp activity with a half maximal inhibitory concentration (IC50) of 1.13-1.25 µM. Molecular docking and site-directed mutagenesis analyses identified D535 as the key amino acid in the interaction between RdRp and UA. Importantly, the surface plasmon resonance assay showed that UA had strong direct binding with ZIKV wild-type RdRp and a relatively weak interaction with D535A-RdRp. As a control, the nucleoside inhibitor sofosbuvir triphosphate (PSI-7409) conferred insensitivity to the fluorescence-based RdRp assay and cannot bind directly with RdRp. Moreover, UA showed anti-ZIKV activity comparable to sofosbuvir. All these results indicate that UA is likely to be a promising lead compound against ZIKV, exhibiting a different mechanism than sofosbuvir.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , RNA Replicase/antagonistas & inibidores , Ácidos Undecilênicos/isolamento & purificação , Ácidos Undecilênicos/farmacologia , Zika virus/enzimologia , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , RNA Replicase/genética , Ressonância de Plasmônio de Superfície
19.
Expert Opin Drug Discov ; 14(10): 1037-1052, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31315489

RESUMO

Introduction: Over the past decade, numerous research efforts have identified the gut microbiota as a novel regulator of human metabolic syndrome and cardiovascular disease (CVD). With the elucidation of underlying molecular mechanisms of the gut microbiota and its metabolites, the drug-discovery process of CVD therapeutics might be expedited. Areas covered: The authors describe the evidence concerning the impact of gut microbiota on metabolic disorders and CVD and summarize the current knowledge of the gut microbial mechanisms that underlie CVD with a focus on microbial metabolites. In addition, they discuss the potential impact of the gut microbiota on the drug efficacy of available cardiometabolic therapeutic agents. Most importantly, the authors review the role of the gut microbiome as a promising source of potential drug targets and novel therapeutics for the development of new treatment modalities for CVD. This review also presents the various effective strategies to investigate the gut microbiome for CVD drug-discovery approaches. Expert opinion: With the elucidation of its causative role in cardiometabolic disease and atherosclerosis, the human gut microbiome holds promises as a reservoir of novel potential therapeutic targets as well as novel therapeutic agents, paving a new and exciting avenue in cardiovascular drug discovery.

20.
Acta Pharm Sin B ; 9(3): 496-504, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31193801

RESUMO

As d-amino acids play important roles in the physiological metabolism of bacteria, combination of d-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in vitro and in vivo activity of d-serine alone and in combination with ß-lactams against methicillin-resistant Staphylococcus aureus (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, ß-lactams alone and in combinations was evaluated both in vitro by standard MICs, time-kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of d-serine and ß-lactams against MRSA standard and clinical strains. Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared to ß-lactam alone groups. Initial mechanism study suggested possible revision of d-alanine-d-alanine residue to d-alanine-d-serine in peptidoglycan by adding of d-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, d-serine had synergistic activity in combination with ß-lactams against MRSA strains both in vitro and in vivo. Considering the relatively good safety of d-serine alone or in combination with ß-lactams, d-serine is worth following up as new anti-MRSA infection strategies.

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