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1.
FASEB J ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944405

RESUMO

Mangrove-derived actinobacteria strains are well-known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome-based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose-6-phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.

2.
Appl Microbiol Biotechnol ; 104(2): 701-711, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31820069

RESUMO

Polycyclic tetramate macrolactams (PTMs) are a widely distributed class of structurally complex natural products, and most of them exhibit multiple biological activities. However, the transcriptional regulators (TRs) involved in the regulation of PTM production have seldom been reported. Here, we identified three TRs, i.e., Sxim_22880, CvnABCSx, and WblASx, and revealed their positive roles in the regulation of PTM biosynthesis in mangrove-derived Streptomyces xiamenensis 318. This strain produces a considerable amount of PTMs at 30 °C, but the production of PTMs is mostly blocked at 37 °C. Quantitative real-time PCR analysis confirmed that the transcriptions of PTM biosynthetic genes were downregulated. We determined that the transcriptions of several putative TRs, i.e., WblASx, Sxim_22880, and CvnCSx, were significantly downregulated under such heat-shock conditions. We showed that the transcription of PTM biosynthetic genes and the production of PTMs could be restored at 37 °C if the impaired transcriptions of wblASx, sxim_22880, and cvnABCSx were restored. Electrophoretic mobility shift assays showed that none of these TRs could bind to the promoter region of the PTM gene cluster, suggesting their indirect but positive involvement in the regulation on PTM production. Moreover, concurrent overexpression of the three TRs in S. xiamenensis 318 resulted in a 242.5% increase in PTM production when the strain was cultured at 30 °C. Furthermore, overexpression of these three TRs in Streptomyces sp. FR-008 and S. albus J1074 stimulated the production of new secondary metabolites, indicating that these conserved TRs could be used to activate cryptic secondary metabolite gene clusters in Streptomyces.

3.
J Asian Nat Prod Res ; 22(2): 121-130, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30614270

RESUMO

Three new alkylated benzoquinones, 2-hydroxy-5-ethoxy-3-nonyl-1,4-benzoquinone (1), 5-O-butyl-embelin (2), and 2,5-dihydroxy-6-methyl-3-pentadecyl-1,4-benzoquinone (3), together with seven known analogues (4-10), were isolated from the stems and twigs of mangrove plant, Aegiceras corniculatum. Their structural elucidation was achieved by spectroscopic methods, chemical exchanging experiments, and semisynthesis method. The cytotoxic activities of all the isolated compounds were evaluated by MTT assay. Compounds 1, 2, 8, 9, and 10 possess varying degrees of selective cytotoxicity against HL-60, HepG2, BGC-823, and A2780 cell lines.[Formula: see text].

4.
Chem Commun (Camb) ; 55(98): 14840-14843, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31768510

RESUMO

XimA is a unique amide synthetase that belongs to the ANL superfamily of adenylating enzymes, but with a special structural fold. In order to improve the enzyme promiscuity, we engineered XimA by site-directed mutagenesis at a specific position based on our theoretical model of XimA. Thus, we were able to produce diverse benzopyran derivatives with up to 15 different l-form and d-form amino acid substitutions, catalyzed by several XimA variants. Molecular docking and molecular dynamics simulations conducted for various XimA systems provide further structural insights into the substitution effects of the phenylalanine-201 as an active site residue on protein dynamics and enzyme catalysis.


Assuntos
Amida Sintases/metabolismo , Treonina/análogos & derivados , Amida Sintases/genética , Benzopiranos/química , Benzopiranos/metabolismo , Cinética , Mutagênese Sítio-Dirigida , Peptídeo Sintases/metabolismo , Engenharia de Proteínas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Streptomyces/química , Streptomyces/metabolismo , Especificidade por Substrato , Treonina/biossíntese , Treonina/química
5.
Org Lett ; 21(21): 8577-8581, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613107

RESUMO

The known benzonaphthyridine alkaloid, albogrisin A (1), and six new compounds, including two pyrazinone stereoisomers, albogrisin B (2)/B' (2'), together with four 4H-pyrroloquinolinones, two diastereoisomers, albogrisin C (3)/C' (3'), and their methyl esters, albogrisin D (4)/D' (4'), were isolated from mangrove-derived Streptomyces albogriseolus MGR072. 2 and 2' are converted into 1 in acidic aqueous solution but into 3/3' and 4/4' in 0.05% trifluoroacetic acid acetonitrile. 4 and 4' are new indoleamine 2,3-dioxygenase 1 inhibitors.

7.
R Soc Open Sci ; 6(4): 190418, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31183155

RESUMO

The production of secondary metabolites, while important for bioengineering purposes, presents a paradox in itself. Though widely existing in plants and bacteria, they have no definite physiological roles. Yet in both native habitats and laboratories, their production appears robust and follows apparent metabolic switches. We show in this work that the enzyme-catalysed process may improve the metabolic stability of the cells. The latter can be responsible for the overall metabolic behaviours such as dynamic metabolic landscape, metabolic switches and robustness, which can in turn affect the genetic formation of the organism in question. Mangrove-derived Streptomyces xiamenensis 318, with a relatively compact genome for secondary metabolism, is used as a model organism in our investigation. Integrated studies via kinetic metabolic modelling, transcriptase measurements and metabolic profiling were performed on this strain. Our results demonstrate that the secondary metabolites increase the metabolic fitness of the organism via stabilizing the underlying metabolic network. And the fluxes directing to NADH, NADPH, acetyl-CoA and glutamate provide the key switches for the overall and secondary metabolism. The information may be helpful for improving the xiamenmycin production on the strain.

8.
Appl Environ Microbiol ; 85(7)2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30683747

RESUMO

The pleiotropic transcriptional regulator AdpA positively controls morphological differentiation and regulates secondary metabolism in most Streptomyces species. Streptomyces xiamenensis 318 has a linear chromosome 5.96 Mb in size. How AdpA affects secondary metabolism and morphological differentiation in such a naturally minimized genomic background is unknown. Here, we demonstrated that AdpA Sx , an AdpA orthologue in S. xiamenensis, negatively regulates cell growth and sporulation and bidirectionally regulates the biosynthesis of xiamenmycin and polycyclic tetramate macrolactams (PTMs) in S. xiamenensis 318. Overexpression of the adpASx gene in S. xiamenensis 318 had negative effects on morphological differentiation and resulted in reduced transcription of putative ssgA, ftsZ, ftsH, amfC, whiB, wblA1, wblA2, wblE, and a gene encoding sporulation-associated protein (sxim_29740), whereas the transcription of putative bldD and bldA genes was upregulated. Overexpression of adpASx led to significantly enhanced production of xiamenmycin but had detrimental effects on the production of PTMs. As expected, the transcriptional level of the xim gene cluster was upregulated, whereas the PTM gene cluster was downregulated. Moreover, AdpA Sx negatively regulated the transcription of its own gene. Electrophoretic mobility shift assays revealed that AdpA Sx can bind the promoter regions of structural genes of both the xim and PTM gene clusters as well as to the promoter regions of genes potentially involved in the cell growth and differentiation of S. xiamenensis 318. We report that an AdpA homologue has negative effects on morphological differentiation in S. xiamenensis 318, a finding confirmed when AdpA Sx was introduced into the heterologous host Streptomyces lividans TK24.IMPORTANCE AdpA is a key regulator of secondary metabolism and morphological differentiation in Streptomyces species. However, AdpA had not been reported to negatively regulate morphological differentiation. Here, we characterized the regulatory role of AdpA Sx in Streptomyces xiamenensis 318, which has a naturally streamlined genome. In this strain, AdpA Sx negatively regulated cell growth and morphological differentiation by directly controlling genes associated with these functions. AdpA Sx also bidirectionally controlled the biosynthesis of xiamenmycin and PTMs by directly regulating their gene clusters rather than through other regulators. Our findings provide additional evidence for the versatility of AdpA in regulating morphological differentiation and secondary metabolism in Streptomyces.

9.
ACS Synth Biol ; 7(9): 2094-2104, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30103600

RESUMO

Prenylated aromatic compounds are important intermediates in the biosynthesis of bioactive molecules such as 3-chromanols from plants, ubiquinones from prokaryotes and meroterpenoids from sponges. Biosynthesis of prenylated aromatic compounds using prokaryotic microorganisms has attracted increasing attention in the field of synthetic biology. In this study, we demonstrated that the production of 3-geranyl-4-hydroxybenzoic acid (GBA) and a variety of GBA analogues was feasible in a metabolically engineered E. coli by using XimB, a special prenyltransferase involved in the biosynthesis of xiamenmycin A in Streptomyces xiamenensis 318. XimB exhibits broad substrate specificity and can catalyze the transfer reaction of prenyl moieties with different carbon chain lengths to both the natural substrate 4-hydroxybenzoate (4-HBA) and to different substituted 4-HBA derivatives at C-2 and C-3. Feeding 4-HBA to an engineered E. coli equipped with a hybrid mevalonate pathway increased the production of GBA up to 94.30 mg/L. Considerable amounts of other GBA derivatives, compounds 4, 5, 6, 7, and 9, can be achieved by feeding precursors. The plug-and-play design for inserting C5, C15, and C20 prenyl diphosphate synthetases under the control of the T7 promoter resulted in targeted production of 3-dimethylallyl, 3-farnesyl-, and 3-geranylgeranyl-4-hydroxybenzoic acid, respectively. Furthermore, the valuable benzopyran xiamenmycin B was successfully produced in E. coli R7-MVA by coexpression of a complete biosynthetic gene cluster, which contains ximBDE.


Assuntos
Proteínas de Bactérias/genética , Benzoatos/metabolismo , Dimetilaliltranstransferase/genética , Escherichia coli/metabolismo , Engenharia Metabólica/métodos , Parabenos/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/classificação , Proteínas de Bactérias/metabolismo , Benzoatos/análise , Benzoatos/química , Biocatálise , Cromatografia Líquida de Alta Pressão , Dimetilaliltranstransferase/classificação , Dimetilaliltranstransferase/metabolismo , Escherichia coli/genética , Cinética , Espectrometria de Massas , Parabenos/análise , Parabenos/química , Filogenia , Plasmídeos/genética , Plasmídeos/metabolismo , Alinhamento de Sequência , Streptomyces/genética , Especificidade por Substrato
10.
Sci Rep ; 7: 40689, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28098172

RESUMO

Polycyclic tetramate macrolactams (PTMs) were identified as distinct secondary metabolites of the mangrove-derived Streptomyces xiamenensis 318. Together with three known compounds-ikarugamycin (1), capsimycin (2) and capsimycin B (3)-two new compounds, capsimycin C (4) with trans-diols and capsimycin D (5) with trans-configurations at C-13/C-14, have been identified. The absolute configurations of the tert/tert-diols moiety was determined in 4 by NMR spectroscopic analysis, CD spectral comparisons and semi-synthetic method. The post-modification mechanism of the carbocyclic ring at C-14/C-13 of compound 1 in the biosynthesis of an important intermediate 3 was investigated. A putative cytochrome P450 superfamily gene, SXIM_40690 (ikaD), which was proximally localized to the ikarugamycin biosynthetic pathway, was characterized. In vivo gene inactivation and complementation experiment confirmed that IkaD catalysed the epoxide-ring formation reaction and further hydroxylation of ethyl side chain to form capsimycin G (3'). Binding affinities and kinetic parameters for the interactions between ikarugamycin (1) and capsimycin B (3) with IkaD were measured with Surface Plasmon Resonance. The intermediate compound 3' was isolated and identified as 30-hydroxyl-capsimycin B. The caspimycins 2 and 3, were transferred to methoxyl derivatives, 6 and 7, under acidic and heating conditions. Compounds 1-3 exhibited anti-proliferative activities against pancreatic carcinoma with IC50 values of 1.30-3.37 µM.


Assuntos
Sistema Enzimático do Citocromo P-450/química , Streptomyces/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Humanos , Hidroxilação , Estrutura Molecular , Compostos Orgânicos/química , Compostos Orgânicos/metabolismo , Compostos Orgânicos/farmacologia , Oxirredução , Filogenia , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Streptomyces/classificação , Streptomyces/genética , Relação Estrutura-Atividade
11.
Phys Rev E ; 93(6): 062409, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27415300

RESUMO

While the biochemistry of metabolism in many organisms is well studied, details of the metabolic dynamics are not fully explored yet. Acquiring adequate in vivo kinetic parameters experimentally has always been an obstacle. Unless the parameters of a vast number of enzyme-catalyzed reactions happened to fall into very special ranges, a kinetic model for a large metabolic network would fail to reach a steady state. In this work we show that a stable metabolic network can be systematically established via a biologically motivated regulatory process. The regulation is constructed in terms of a potential landscape description of stochastic and nongradient systems. The constructed process draws enzymatic parameters towards stable metabolism by reducing the change in the Lyapunov function tied to the stochastic fluctuations. Biologically it can be viewed as interplay between the flux balance and the spread of workloads on the network. Our approach allows further constraints such as thermodynamics and optimal efficiency. We choose the central metabolism of Methylobacterium extorquens AM1 as a case study to demonstrate the effectiveness of the approach. Growth efficiency on carbon conversion rate versus cell viability and futile cycles is investigated in depth.


Assuntos
Redes e Vias Metabólicas/fisiologia , Modelos Biológicos , Cinética , Methylobacterium extorquens/metabolismo
12.
Sci Rep ; 6: 18977, 2016 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-26744183

RESUMO

Streptomyces xiamenensis 318, a moderate halophile isolated from a mangrove sediment, produces the anti-fibrotic compound xiamenmycin. The whole genome sequence of strain 318 was obtained through long-read single-molecule real-time (SMRT) sequencing, high-throughput Illumina HiSeq and 454 pyrosequencing technologies. The assembled genome comprises a linear chromosome as a single contig of 5,961,401-bp, which is considerably smaller than other reported complete genomes of the genus Streptomyces. Based on the antiSMASH pipeline, a total of 21 gene clusters were predicted to be involved in secondary metabolism. The gene cluster responsible for the biosynthesis of xiamenmycin resides in a strain-specific 61,387-bp genomic island belonging to the left-arm region. A core metabolic network consisting of 104 reactions that supports xiamenmycin biosynthesis was constructed to illustrate the necessary precursors derived from the central metabolic pathway. In accordance with the finding of a putative ikarugamycin gene cluster in the genome, the targeted chemical profiling of polycyclic tetramate macrolactams (PTMs) resulted in the identification of ikarugamycin. A successful genome mining for bioactive molecules with different skeletons suggests that the naturally minimized genome of S. xiamenensis 318 could be used as a blueprint for constructing a chassis cell with versatile biosynthetic capabilities for the production of secondary metabolites.


Assuntos
Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Genoma Bacteriano , Streptomyces/genética , Treonina/análogos & derivados , Proteínas de Bactérias/metabolismo , Benzopiranos/isolamento & purificação , Mapeamento Cromossômico , Ilhas Genômicas , Sequenciamento de Nucleotídeos em Larga Escala , Lactamas/isolamento & purificação , Lactamas/metabolismo , Redes e Vias Metabólicas/genética , Família Multigênica , Streptomyces/enzimologia , Treonina/biossíntese , Treonina/isolamento & purificação
13.
IET Syst Biol ; 10(1): 17-22, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26816395

RESUMO

Xiamenmycins, a series of prenylated benzopyran compounds with anti-fibrotic bioactivities, were isolated from a mangrove-derived Streptomyces xiamenensis. To fulfil the requirements of pharmaceutical investigations, a high production of xiamenmycin is needed. In this study, the authors present a kinetic metabolic model to evaluate fluxes in an engineered Streptomyces lividans with xiamenmycin-oriented genetic modification based on generic enzymatic rate equations and stability constraints. Lyapunov function was used for a viability optimisation. From their kinetic model, the flux distributions for the engineered S. lividans fed on glucose and glycerol as carbon sources were calculated. They found that if the bacterium can utilise glucose simultaneously with glycerol, xiamenmycin production can be enhanced by 40% theoretically, while maintaining the same growth rate. Glycerol may increase the flux for phosphoenolpyruvate synthesis without interfering citric acid cycle. They therefore believe this study demonstrates a possible new direction for bioengineering of S. lividans.


Assuntos
Redes e Vias Metabólicas , Modelos Biológicos , Treonina/análogos & derivados , Benzopiranos , Cinética , Streptomyces/metabolismo , Biologia de Sistemas , Treonina/biossíntese
15.
Mar Drugs ; 13(2): 727-40, 2015 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-25636156

RESUMO

Xiamenmycin A is an antifibrotic leading compound with a benzopyran skeleton that is isolated from mangrove-derived Streptomyces xiamenensis. As a promising small molecule for fibrotic diseases, less information is known about its metabolic characteristics in vivo. In this study, the time-course of xiamenmycin A in mouse plasma was investigated by relative quantification. After two types of administration of xiamenmycin A at a single dose of 10 mg/kg, the plasma concentrations were measured quantitatively by LC-MS/MS. The dynamic changes in the xiamenmycin A concentration showed rapid absorption and quick elimination in plasma post-administration. Four metabolites (M1-M4) were identified in blood by UPLC-QTOF-MS, and xiamenmycin B (M3) is the principal metabolite in vivo, as verified by comparison of the authentic standard sample. The structures of other metabolites were identified based on the characteristics of their MS and MS/MS data. The newly identified metabolites are useful for understanding the metabolism of xiamenmycin A in vivo, aiming at the development of an anti-fibrotic drug candidate for the therapeutic treatment of excessive fibrotic diseases.


Assuntos
Benzopiranos/sangue , Fibrinolíticos/sangue , Treonina/análogos & derivados , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Feminino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Espectrometria de Massas em Tandem , Treonina/sangue
16.
Mar Drugs ; 11(10): 4035-49, 2013 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-24152563

RESUMO

The benzopyran compound obtained by cultivating a mangrove-derived strain, Streptomyces xiamenensis strain 318, shows multiple biological effects, including anti-fibrotic and anti-hypertrophic scar properties. To increase the diversity in the structures of the available benzopyrans, by means of biosynthesis, the strain was screened for spontaneous rifampicin resistance (Rif), and a mutated rpsL gene to confer streptomycin resistance (Str), was introduced into the S. xiamenensis strain M1-94P that originated from deep-sea sediments. Two new benzopyran derivatives, named xiamenmycin C (1) and D (2), were isolated from the crude extracts of a selected Str-Rif double mutant (M6) of M1-94P. The structures of 1 and 2 were identified by analyzing extensive spectroscopic data. Compounds 1 and 2 both inhibit the proliferation of human lung fibroblasts (WI26), and 1 exhibits better anti-fibrotic activity than xiamenmycin. Our study presents the novel bioactive compounds isolated from S. xiamenensis mutant strain M6 constructed by ribosome engineering, which could be a useful approach in the discovery of new anti-fibrotic compounds.


Assuntos
Benzopiranos/química , Sedimentos Geológicos/química , Sedimentos Geológicos/microbiologia , Streptomyces/química , Streptomyces/genética , Benzopiranos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibrose/tratamento farmacológico , Humanos , Pulmão/efeitos dos fármacos , Mutação/genética , Ribossomos/genética , Treonina/análogos & derivados , Treonina/química , Treonina/farmacologia
17.
Mar Drugs ; 11(10): 3875-90, 2013 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-24129229

RESUMO

Mangrove-derived actinomycetes are promising sources of bioactive natural products. In this study, using homologous screening of the biosynthetic genes and anti-microorganism/tumor assaying, 163 strains of actinomycetes isolated from mangrove sediments were investigated for their potential to produce halogenated metabolites. The FADH2-dependent halogenase genes, identified in PCR-screening, were clustered in distinct clades in the phylogenetic analysis. The coexistence of either polyketide synthase (PKS) or nonribosomal peptide synthetase (NRPS) as the backbone synthetases in the strains harboring the halogenase indicated that these strains had the potential to produce structurally diversified antibiotics. As a validation, a new enduracidin producer, Streptomyces atrovirens MGR140, was identified and confirmed by gene disruption and HPLC analysis. Moreover, a putative ansamycin biosynthesis gene cluster was detected in Streptomyces albogriseolus MGR072. Our results highlight that combined genome mining is an efficient technique to tap promising sources of halogenated natural products synthesized by mangrove-derived actinomycetes.


Assuntos
Actinobacteria/genética , Actinobacteria/metabolismo , Produtos Biológicos/metabolismo , Halogenação/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Genes Bacterianos/genética , Peptídeo Sintases/genética , Peptídeo Sintases/metabolismo , Filogenia , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Streptomyces/genética , Streptomyces/metabolismo
18.
J Invest Dermatol ; 133(5): 1351-60, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23303451

RESUMO

Hypertrophic scarring is a common disease affecting millions of people around the world, but there are currently no satisfactory drugs to treat the disease. Exaggerated inflammation and mechanical stress have been shown to be two main mechanisms of excessive fibrotic diseases. Here we found that a benzopyran natural product, xiamenmycin, could significantly attenuate hypertrophic scar formation in a mechanical stretch-induced mouse model. The compound suppressed local inflammation by reducing CD4+ lymphocyte and monocyte/macrophage retention in fibrotic foci and blocked fibroblast adhesion with monocytes. Both in vivo and in vitro studies found that the compound inhibited the mechanical stress-induced profibrotic effects by suppressing proliferation, activation, fibroblast contraction, and inactivating FAK, p38, and Rho guanosine triphosphatase signaling. Taken together, the compound could simultaneously suppress both the inflammatory and mechanical stress responses, which are the two pivotal pathological processes in hypertrophic scar formation, thus suggesting that xiamenmycin can serve as a potential agent for treating hypertrophic scar formation and other excessive fibrotic diseases.


Assuntos
Benzopiranos/uso terapêutico , Cicatriz Hipertrófica/patologia , Cicatriz Hipertrófica/prevenção & controle , Inflamação/patologia , Inflamação/prevenção & controle , Estresse Mecânico , Animais , Benzopiranos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cicatriz Hipertrófica/metabolismo , Modelos Animais de Doenças , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Quinase 1 de Adesão Focal/metabolismo , Humanos , Técnicas In Vitro , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Treonina/análogos & derivados , Treonina/farmacologia , Treonina/uso terapêutico , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Mar Drugs ; 10(3): 639-54, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22611360

RESUMO

An anti-fibrotic compound produced by Streptomycesn xiamenensis, found in mangrove sediments, was investigated for possible therapeutic effects against fibrosis. The compound, N-[[3,4-dihydro-3S-hydroxy-2S-methyl-2-(4'R-methyl-3'S-pentenyl)-2H-1-benzopyran-6-yl]carbonyl]-threonine (1), was isolated from crude extracts and its structure, including the absolute configuration was determined by extensive spectroscopic data analyses, Mosher's method, Marfey's reagent and quantum mechanical calculations. In terms of biological effects, this compound inhibits the proliferation of human lung fibroblasts (WI26), blocks adhesion of human acute monocytic leukemia cells (THP-1) to a monolayer of WI26 cells, and reduces the contractile capacity of WI26 cells in three-dimensional free-floating collagen gels. Altogether, these data indicate that we have identified a bioactive alkaloid (1) with multiple inhibitory biological effects on lung excessive fibrotic characteristics, that are likely involved in fibrosis, suggesting that this molecule might indeed have therapeutic potential against fibrosis.


Assuntos
Benzopiranos/isolamento & purificação , Benzopiranos/farmacologia , Fibrose/tratamento farmacológico , Sedimentos Geológicos/microbiologia , Streptomyces/metabolismo , Árvores/microbiologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Colágeno/química , Fibroblastos/efeitos dos fármacos , Humanos , Hidrólise , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Conformação Molecular , Streptomyces/crescimento & desenvolvimento
20.
Molecules ; 15(12): 9298-307, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21160454

RESUMO

Mangrove Streptomyces represent a rich source of novel bioactive compounds in medicinal research. A novel alkaloid, named 1-N-methyl-3-methylamino-[N-butanoic acid-3'-(9'-methyl-8'-propen-7'-one)-amide]-benzo[f][1,7]naphthyridine-2-one (1) was isolated from Streptomyces albogriseolus originating from mangrove sediments. The structure of compound 1 was elucidated by extensive spectroscopic data analyses and verified by the ¹³C-NMR calculation at the B3LYP/6-311+G(2d,p) level of theory.


Assuntos
Naftiridinas/química , Naftiridinas/isolamento & purificação , Microbiologia do Solo , Streptomyces/química , Estrutura Molecular
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