RESUMO
Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation, or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon, which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in the accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner. Mechanistically, the inulin fiber diet elevated microbiota-derived bile acids, including cholic acid (CA) that induced expression of ILC2-activating IL-33. In IBD patients, bile acids, their receptor farnesoid X receptor (FXR), IL-33, and eosinophils were all upregulated compared with controls, implicating this diet-microbiota-ILC2 axis in human IBD pathogenesis. Together, these data reveal that dietary fiber-induced changes in microbial metabolites operate as a rheostat that governs protective versus pathologic ILC2 responses with relevance to precision nutrition for inflammatory diseases.
Assuntos
Imunidade Inata , Doenças Inflamatórias Intestinais , Humanos , Animais , Camundongos , Interleucina-33 , Inulina , Linfócitos , Fibras na Dieta , Ácidos e Sais Biliares , InflamaçãoRESUMO
Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites<sup>1,2</sup>, although the immunoregulatory roles of most fibre diets and their microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.
Assuntos
Ácidos e Sais Biliares , Fibras na Dieta , Microbioma Gastrointestinal , Inflamação , Inulina , Animais , Humanos , Camundongos , Ácidos e Sais Biliares/metabolismo , Ácido Cólico/farmacologia , Fibras na Dieta/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Imunidade Inata , Inflamação/induzido quimicamente , Inflamação/classificação , Inflamação/patologia , Inulina/farmacologia , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Metabolômica , Pulmão/efeitos dos fármacos , Pulmão/patologia , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/patologia , Interleucina-33/metabolismo , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologiaRESUMO
The genomes of many filamentous fungi, such as Aspergillus spp., include diverse biosynthetic gene clusters of unknown function. We previously showed that low copper levels upregulate a gene cluster that includes crmA, encoding a putative isocyanide synthase. Here we show, using untargeted comparative metabolomics, that CrmA generates a valine-derived isocyanide that contributes to two distinct biosynthetic pathways under copper-limiting conditions. Reaction of the isocyanide with an ergot alkaloid precursor results in carbon-carbon bond formation analogous to Strecker amino-acid synthesis, producing a group of alkaloids we term fumivalines. In addition, valine isocyanide contributes to biosynthesis of a family of acylated sugar alcohols, the fumicicolins, which are related to brassicicolin A, a known isocyanide from Alternaria brassicicola. CrmA homologs are found in a wide range of pathogenic and non-pathogenic fungi, some of which produce fumicicolin and fumivaline. Extracts from A. fumigatus wild type (but not crmA-deleted strains), grown under copper starvation, inhibit growth of diverse bacteria and fungi, and synthetic valine isocyanide shows antibacterial activity. CrmA thus contributes to two biosynthetic pathways downstream of trace-metal sensing.
Assuntos
Anti-Infecciosos , Vias Biossintéticas , Antibacterianos/metabolismo , Anti-Infecciosos/metabolismo , Aspergillus fumigatus/metabolismo , Carbono/metabolismo , Cobre/metabolismo , Cianetos , Fungos/genética , Família Multigênica , Valina/genéticaRESUMO
Psammocindoles A-C (1-3), a new class of indole alkaloids, were isolated from a Psammocinia vermis sponge. By combined spectroscopic analyses, the structures of these compounds were determined to be the indole-γ-lactams derived from three amino acid residues. In addition, an enantiomer psammocindole D (4), and the N-lactam isomers isopsammocindoles A-D (5-8) were also synthesized. These natural products and synthetic analogues were found to significantly stimulate adiponectin secretion in human bone marrow mesenchymal stem cells.
Assuntos
Alcaloides Indólicos/química , Lactamas/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Poríferos/química , Animais , Produtos Biológicos , Humanos , Alcaloides Indólicos/isolamento & purificação , Lactamas/isolamento & purificação , Células-Tronco Mesenquimais/química , Estrutura Molecular , EstereoisomerismoRESUMO
The maintenance of sufficient but nontoxic pools of metal micronutrients is accomplished through diverse homeostasis mechanisms in fungi. Siderophores play a well established role for iron homeostasis; however, no copper-binding analogs have been found in fungi. Here we demonstrate that, in Aspergillus fumigatus, xanthocillin and other isocyanides derived from the xan biosynthetic gene cluster (BGC) bind copper, impact cellular copper content, and have significant metal-dependent antimicrobial properties. xan BGC-derived isocyanides are secreted and bind copper as visualized by a chrome azurol S (CAS) assay, and inductively coupled plasma mass spectrometry analysis of A. fumigatus intracellular copper pools demonstrated a role for xan cluster metabolites in the accumulation of copper. A. fumigatus coculture with a variety of human pathogenic fungi and bacteria established copper-dependent antimicrobial properties of xan BGC metabolites, including inhibition of laccase activity. Remediation of xanthocillin-treated Pseudomonas aeruginosa growth by copper supported the copper-chelating properties of xan BGC isocyanide products. The existence of the xan BGC in several filamentous fungi suggests a heretofore unknown role of eukaryotic natural products in copper homeostasis and mediation of interactions with competing microbes.
Assuntos
Anti-Infecciosos/farmacologia , Aspergillus fumigatus/metabolismo , Cobre/metabolismo , Cianetos/metabolismo , Anti-Infecciosos/química , Aspergillus fumigatus/química , Aspergillus fumigatus/genética , Aspergillus nidulans/efeitos dos fármacos , Butadienos/síntese química , Butadienos/metabolismo , Butadienos/farmacologia , Cianetos/farmacologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Deleção de Genes , Regulação Fúngica da Expressão Gênica , Lacase/metabolismo , Testes de Sensibilidade Microbiana , Família Multigênica , Mutação , Fenóis/síntese química , Fenóis/metabolismo , Fenóis/farmacologia , Pigmentação , Esporos Fúngicos/fisiologiaRESUMO
Isocadiolides A-H (1-8) and cadiolide N (9), new polybrominated aromatic compounds, were isolated from a Korean Synoicum sp. ascidian. On the basis of the results of extensive spectroscopic analyses, these compounds possessed tris-bromohydroxyphenyl moieties as a common structural motif, while their cores varied [cyclopentenedione (1-5), dihydrofuran (6 and 7), pyranone (8), and furanone (9)], reflecting different extents of rearrangement and oxidation. Several of these compounds exhibited weak antibacterial activities and moderate abilities to inhibit the microbial enzymes sortase A and isocitrate lyase.
Assuntos
Aminoaciltransferases/química , Antibacterianos/química , Proteínas de Bactérias/química , Cisteína Endopeptidases/química , Isocitrato Liase/química , Bifenil Polibromatos/química , Bifenil Polibromatos/farmacologia , Urocordados/química , Animais , Antibacterianos/farmacologia , Isocitrato Liase/metabolismo , Estrutura Molecular , Bifenil Polibromatos/isolamento & purificaçãoRESUMO
Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.
Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Metabolômica , Microbiota/fisiologia , Neurônios/fisiologia , Animais , Antibacterianos/farmacologia , Transtorno Autístico/metabolismo , Sangue/metabolismo , Cálcio/metabolismo , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/metabolismo , Sinais (Psicologia) , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Fezes/química , Vida Livre de Germes , Indicã/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Inibição Neural , Neuroglia/patologia , Neuroglia/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Fenilpropionatos/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/fisiologia , Esquizofrenia/metabolismo , Transcriptoma , Nervo Vago/fisiologiaRESUMO
The selective targeting of cytotoxic agents to a tumor has shown limited success by difficulties in identifying the appropriate target molecules, and more importantly, by the phenotypically dynamic nature of the tumor cells and intratumoral heterogeneity. In an attempt to overcome these issues and efficiently deliver cytotoxic drugs to the tumor, we previously reported a strategy termed radiation-induced apoptosis-targeted chemotherapy (RIATC), which utilizes the radiotherapy for intentionally triggering the caspase-3 and in situ amplification of tumor apoptosis by caspase-3 activated prodrug. Herein, we propose an advanced form of RIATC prodrug, AP1-DEVD-S-DOX, that could more actively target to the ligands of radiation-induced tumor cells, which could accumulate more prodrugs, thereby allowing more effective in situ activation and amplification of tumor apoptosis, comparing to RIATC. Indeed, AP1-DEVD-S-DOX was able to exert improved doxorubicin (DOX) delivery to the tumor and anticancer effect than the RIATC prodrug that lacks apoptotic cell-binding property but having a similar degree of off-target distribution in the other organs. Accordingly, AP1-DEVD-S-DOX could be an efficient prodrug for concurrent chemoradiotherapy by selectively delivering doxorubicin to the tumor with less systemic cytotoxicity.
Assuntos
Antineoplásicos/administração & dosagem , Caspase 3/metabolismo , Quimiorradioterapia , Doxorrubicina/administração & dosagem , Neoplasias/terapia , Oligopeptídeos/administração & dosagem , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Miocárdio/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Oligopeptídeos/farmacocinética , Pró-Fármacos/farmacocinética , Carga Tumoral/efeitos dos fármacosRESUMO
Despite the emergence of advanced therapeutics such as targeted therapy and immunotherapy in the modern oncology, cytotoxic chemotherapy still remains as the first-line treatment option in a wide range of cancers attributing to its potency. Many endeavors have been made to overcome the toxicity issues of cytotoxic chemotherapy by improving the specific delivery to the tumor, with active tumor targeting being one of the most popular approaches. However, such an approach has been challenged by the intratumor heterogeneity and the lack of valid molecular target in many types of cancer. Here, we introduce a novel albumin-binding prodrug MPD02 that could specifically deliver highly potent cytotoxin monomethyl auristatin E (MMAE) to the tumor as an important component of chemoradiotherapy for the treatment of triple-negative breast cancer (TNBC). MPD02 was synthesized by conjugating MMAE to the C-terminus of the KGDEVD peptide via self-eliminating linker and introducing a maleimide group to the Lys side chain of the peptide. MPD02 was able to bind albumin after administration via maleimide group for an extended circulation time and metabolized into MMAE in tumor-specific manner by reacting with the caspase-3 upregulated in tumor by radiotherapy, exerting a highly potent anticancer effect with good safety profile in two different TNBC xenograft models.
Assuntos
Caspase 3/metabolismo , Oligopeptídeos/uso terapêutico , Pró-Fármacos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/radioterapia , Animais , Linhagem Celular Tumoral , Quimiorradioterapia , Feminino , Humanos , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
Tumor heterogeneity is associated with the therapeutic failures of targeted therapies. To overcome such heterogeneity, a novel targeted therapy is proposed that could kill tumor populations with diverse phenotypes by delivering nonselective cytotoxins to target-positive cells as well as to the surrounding tumor cells via a recurrent bystander killing effect. A representative prodrug is prepared that targets integrin αvß3 and releases cytotoxins upon entering cells or by caspase-3. This allows the prodrug to kill integrin αvß3-positive cells and upregulate caspase-3, which in turn, activates the prodrug to release a cytotoxin that could subsequently diffuse into and kill the neighboring tumor cells. Apoptotic cells further upregulate and release caspase-3, which activate more prodrugs leading to another round of adjacent cell death and caspase-3 release. Thus, the bystander killing effect could occur repeatedly, leading to augmented and widespread anticancer activity. This strategy provides an avenue that could advance the current targeted therapy.
RESUMO
Microbial secondary metabolites, including isocyanide moieties, have been extensively mined for their repertoire of bioactive properties. Although the first naturally occurring isocyanide (xanthocillin) was isolated from the fungus Penicillium notatum over half a century ago, the biosynthetic origins of fungal isocyanides remain unknown. Here we report the identification of a family of isocyanide synthases (ICSs) from the opportunistic human pathogen Aspergillus fumigatus Comparative metabolomics of overexpression or knockout mutants of ICS candidate genes led to the discovery of a fungal biosynthetic gene cluster (BGC) that produces xanthocillin (xan). Detailed analysis of xanthocillin biosynthesis in A. fumigatus revealed several previously undescribed compounds produced by the xan BGC, including two novel members of the melanocin family of compounds. We found both the xan BGC and a second ICS-containing cluster, named the copper-responsive metabolite (crm) BGC, to be transcriptionally responsive to external copper levels and further demonstrated that production of metabolites from the xan BGC is increased during copper starvation. The crm BGC includes a novel type of fungus-specific ICS-nonribosomal peptide synthase (NRPS) hybrid enzyme, CrmA. This family of ICS-NRPS hybrid enzymes is highly enriched in fungal pathogens of humans, insects, and plants. Phylogenetic assessment of all ICSs spanning the tree of life shows not only high prevalence throughout the fungal kingdom but also distribution in species not previously known to harbor BGCs, indicating an untapped resource of fungal secondary metabolism.IMPORTANCE Fungal ICSs are an untapped resource in fungal natural product research. Their isocyanide products have been implicated in plant and insect pathogenesis due to their ability to coordinate transition metals and disable host metalloenzymes. The discovery of a novel isocyanide-producing family of hybrid ICS-NRPS enzymes enriched in medically and agriculturally important fungal pathogens may reveal mechanisms underlying pathogenicity and afford opportunities to discover additional families of isocyanides. Furthermore, the identification of noncanonical ICS BGCs will enable refinement of BGC prediction algorithms to expand on the secondary metabolic potential of fungal and bacterial species. The identification of genes related to ICS BGCs in fungal species not previously known for secondary metabolite-producing capabilities (e.g., Saccharomyces spp.) contributes to our understanding of the evolution of BGC in fungi.
Assuntos
Aspergillus fumigatus/enzimologia , Butadienos/metabolismo , Proteínas Fúngicas/metabolismo , Peptídeo Sintases/metabolismo , Fenóis/metabolismo , Aspergillus fumigatus/classificação , Aspergillus fumigatus/genética , Aspergillus fumigatus/metabolismo , Vias Biossintéticas , Butadienos/química , Cianetos/metabolismo , Proteínas Fúngicas/genética , Família Multigênica , Peptídeo Sintases/genética , Fenóis/química , FilogeniaRESUMO
Asperphenins A (1) and B (2), novel diastereomeric lipopeptidyl benzophenone metabolites, were isolated from a marine-derived Aspergillus sp. fungus. On the basis of the results of combined spectroscopic analyses, the structures of these compounds were determined to be linear assemblies of three motifs: a hydroxy fatty acid, a tripeptide, and a trihydroxybenzophenone. The absolute configurations were assigned using chemical modifications and electronic circular dichroism (ECD) calculations. The novel compounds exhibited significant cytotoxicity on diverse cancer cells.
Assuntos
Aspergillus/química , Benzofenonas/metabolismo , Lipopeptídeos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Lipopeptídeos/química , Lipopeptídeos/farmacologia , Conformação Molecular , Metabolismo SecundárioRESUMO
Five new manzamine alkaloids (1-5) and new salt forms of two known manzamines (6 and 7), along with seven known compounds (8-14) of the same structural class, were isolated from an Indonesian Acanthostrongylophora sp. sponge. On the basis of the results of combined spectroscopic analyses, the structure of kepulauamine A (1) was determined to possess an unprecedented pyrrolizine moiety, while others were functional group variants of known manzamines. These compounds exhibited weak cytotoxicity, moderate antibacterial activity, and mild inhibition against the enzyme isocitrate lyase.
Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Carbazóis/isolamento & purificação , Carbazóis/farmacologia , Isocitrato Liase/efeitos dos fármacos , Pirrolnitrina/isolamento & purificação , Pirrolnitrina/farmacologia , Alcaloides/química , Animais , Antibacterianos/química , Carbazóis/química , Indonésia , Isocitrato Liase/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Poríferos , Pirrolnitrina/químicaRESUMO
Panax ginseng C.A. MEYER is one of the most popular medicinal herbs in Asia and the chemical constituents are changed by processing methods such as steaming or sun drying. Metabolomic analysis was performed to distinguish age discrimination of four- and six-year-old red ginseng using ultra-performance liquid chromatography quadruple time of flight mass spectrometry (UPLC-QToF-MS) with multivariate statistical analysis. Principal component analysis (PCA) showed clear discrimination between extracts of red ginseng of different ages and suggest totally six discrimination markers (two for four-year-old and four for six-year-old red ginseng). Among these, one marker was isolated and the structure determined by NMR spectroscopic analysis was 13-cis-docosenamide (marker 6-1) from six-year-old red ginseng. This is the first report of a metabolomic study regarding the age differentiation of red ginseng using UPLC-QToF-MS and determination of the structure of the marker. These results will contribute to the quality control and standardization as well as provide a scientific basis for pharmacological research on red ginseng.
Assuntos
Metabolômica , Panax/química , Panax/metabolismo , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , República da Coreia , Fatores de TempoRESUMO
A liquid chromatography-tandem mass (LC-MS/MS) method was developed for the determination of psammaplin A (PsA) and its newly synthesized derivatives (PsA 107, PsA 109, and PsA 123) in rat plasma using bupropion as an internal standard (IS). The plasma samples were deproteinized with acetonitrile. Chromatographic separation was performed on hydro-RP column (75×2.0mm, 80Å, 4µm) with isocratic elution using 5mM ammonium formate buffer/acetonitrile (30:70, v/v) at a flow rate of 0.4mL/min and the total run time was 5min. Mass spectrometric detection was performed with positive electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The ion transitions monitored were m/z 663.2â331.0, 687.2â343.1, 587.3â293.1, 563.3â281.0, and 240.0â184.0 for PsA, PsA 107, PsA 109, PsA 123, and IS, respectively. All analytes showed good linearity over the concentration range of 5.00-5000ng/mL (r(2)≥0.994). The lower limit of quantification was 5ng/mL for PsA and its three PsA derivatives. Within- and between-run precisions (relative standard deviation, RSD) were less than 9.66% and accuracy (relative error, RE) ranged from -9.34% to 7.25%. Established method was successfully applied to the investigation of pharmacokinetic properties of PsA and its derivatives in rats after intravenous administration at a dose of 2mg/kg.
Assuntos
Cromatografia Líquida/métodos , Dissulfetos/sangue , Espectrometria de Massas em Tandem/métodos , Tirosina/análogos & derivados , Animais , Dissulfetos/química , Dissulfetos/farmacocinética , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tirosina/sangue , Tirosina/química , Tirosina/farmacocinéticaRESUMO
Four new iodobenzene-containing dipeptides (1-4), a related bromotryptophan-containing dipeptide (5), and an iodophenethylamine (6) were isolated from the ascidian Aplidium sp. collected off the coast of Chuja-do, Korea. The structures of these novel compounds, designated as apliamides A-E (1-5) and apliamine A (6) were determined via combined spectroscopic analyses. The absolute configuration of the amino acid residue in 1 was determined by advanced Marfey's analysis. Several of these compounds exhibited moderate cytotoxicity and significant inhibition against Na+/K+-ATPase (4).
Assuntos
Aminoácidos/química , Dipeptídeos/farmacologia , Iodobenzenos/farmacologia , Urocordados/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dipeptídeos/química , Dipeptídeos/isolamento & purificação , Humanos , Iodobenzenos/química , Iodobenzenos/isolamento & purificação , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Análise EspectralRESUMO
A new maltol derivative (2) along with three known maltol derivative (1) and flavonol glycosides (3 and 4) were isolated from the dried flowers of Sophora japonica. Based upon the results of combined spectroscopic methods, the structure of new compound (2) was determined to be maltol-3-O-(4'-O-cis-p-coumaroyl-6'-O-(3-hydroxy-3-methylglutaroyl))-ß-glucopyranoside, an isomer of 1. These compounds strongly inhibited the action of sortase A (SrtA) from Streptococcus mutans, a primary etiologic agent of human dental caries. The onset and magnitude of inhibition of the saliva-induced aggregation in S. mutans treated with compound 2 (4×IC50) were comparable to the behavior of untreated srtA-deletion mutant.
Assuntos
Aminoaciltransferases/antagonistas & inibidores , Proteínas de Bactérias/antagonistas & inibidores , Flores/química , Pironas/farmacologia , Sophora/química , Streptococcus mutans/efeitos dos fármacos , Aminoaciltransferases/genética , Aminoaciltransferases/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Conformação Molecular , Pironas/química , Pironas/isolamento & purificação , Streptococcus mutans/crescimento & desenvolvimento , Streptococcus mutans/metabolismo , Relação Estrutura-AtividadeRESUMO
Twenty-four metabolites, including seven new compounds (1-7), were isolated from the dried fruits of Psoralea corylifolia. On the basis of combined spectroscopic and chemical analysis, the new compounds were determined to be six flavonoids (1-6) and a meroterpenoid (7). The absolute configurations of the natural products obtained, including the previously undetermined 16 and 17, were assigned by several methods, such as NOE spectroscopy, optical rotation, and CD spectroscopy. Several of these compounds exhibited moderate inhibitory activity toward Staphylococcus mutans-derived SrtA (2, 6, and 16) and significant stimulation of SIRT1 activity (2, 3, and 15).
Assuntos
Flavonoides/isolamento & purificação , Frutas/química , Psoralea/química , Terpenos/isolamento & purificação , Aminoaciltransferases/efeitos dos fármacos , Proteínas de Bactérias/efeitos dos fármacos , Cisteína Endopeptidases/efeitos dos fármacos , Flavonoides/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , República da Coreia , Staphylococcus/efeitos dos fármacos , Terpenos/químicaRESUMO
The glyoxylate cycle is a sequence of anaplerotic reactions catalyzed by the key enzymes isocitrate lyase (ICL) and malate synthase (MLS). Mutants of Candida albicans lacking ICL are markedly less virulent in mice than the wild-type. Suvanine sesterterpenes (1-9) isolated from a tropical sponge Coscinoderma sp. were evaluated for their inhibitory activities toward recombinant ICL from C. albicans. These studies led to the identification of a potent ICL inhibitor, suvanine salt (2), which possesses a sodium counterion and displays an inhibitory concentration value (IC50) of 6.35 µM. The growth phenotype of ICL deletion mutants and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses indicated that compound 2 inhibits the ICL mRNA expression in C. albicans under C2-carbon-utilizing conditions. The present data highlight the potential for suvanine sesterterpenes treatment of C. albicans infections via inhibition of ICL activity.
Assuntos
Glioxilatos/metabolismo , Isocitrato Liase/antagonistas & inibidores , Poríferos/química , Sesterterpenos/farmacologia , Terpenos/farmacologia , Animais , Candida albicans/efeitos dos fármacos , Candida albicans/metabolismo , Fenótipo , Sesterterpenos/química , Terpenos/químicaRESUMO
Seven new amino alcohol compounds, pseudoaminols A-G (1-7), were isolated from the ascidian Pseudodistoma sp. collected off the coast of Chuja-do, Korea. Structures of these new compounds were determined by analysis of the spectroscopic data and from chemical conversion. The presence of an N-carboxymethyl group in two of the new compounds (6 and 7) is unprecedented among amino alcohols. Several of these compounds exhibited moderate antimicrobial activity and cytotoxicity, as well as weak inhibitory activity toward Na+/K+-ATPase.