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1.
Chem Biodivers ; 16(8): e1900318, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31364803

RESUMO

Sponges from freshwater environments, unlike marine's, are poorly known producers of natural compounds with medicinal purposes. Amazonian sponges produce massive large specimens and are widely spread, taxonomically diverse and their metabolites could represent a new frontier on unusual natural products to treat diseases such as Alzheimer's and Malaria. Species of Metania and Drulia (Metaniidae) genera are major contributors to the fauna of Amazonian freshwater sponges. Methanolic extracts from several species from these genera had their inhibitory activities evaluated in vitro, for parasite Plasmodium falciparum and acetyl and butyrylcholinesterase enzymes (AChE and BChE). All extracts were able to inhibit AChE, although no activity was observed towards BChE. Drulia uruguayensis extract was the most potent, inhibiting AChE with IC50 =1.04 mg/mL. For antiplasmodial activity, all species showed inhibition to P. falciparum, but Metania reticulata being the most efficient with IC50 =2.7 µg/mL. Mass spectrometry analyses evidenced the presence of fatty acids and sterols in active extracts.


Assuntos
Antiprotozoários/química , Inibidores da Colinesterase/química , Poríferos/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Ácidos Graxos/análise , Ácidos Graxos/química , Plasmodium falciparum/efeitos dos fármacos , Poríferos/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Esteróis/química
2.
Phys Chem Chem Phys ; 21(28): 15487-15503, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31259332

RESUMO

In this paper we show a theoretical rational design approach on a series of intrinsically fluorescent analogues of cholesterol (FLACs), called polyene-sterols (P-sterols), followed by a step-by-step selection of potential candidates, employing, sequentially, state-of-the-art quantum mechanical (QM) computations of the optical properties (single- and multiphoton absorption electronic spectroscopies and emission), molecular dynamics (MD) simulations in model membranes, and multiscale approaches (polarizable embedding). This selection converged to a promising candidate that shows simultaneously interesting single- and multiphoton absorption properties as well as emitting properties and good abilities to mimic cholesterol order effects in model membranes.


Assuntos
Colesterol/análogos & derivados , Simulação de Dinâmica Molecular , Esteróis/química , Fluorescência , Membranas Artificiais , Teoria Quântica
3.
Nature ; 571(7764): 284-288, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31263273

RESUMO

Hedgehog signalling is fundamental to embryonic development and postnatal tissue regeneration1. Aberrant postnatal Hedgehog signalling leads to several malignancies, including basal cell carcinoma and paediatric medulloblastoma2. Hedgehog proteins bind to and inhibit the transmembrane cholesterol transporter Patched-1 (PTCH1), which permits activation of the seven-transmembrane transducer Smoothened (SMO) via a mechanism that is poorly understood. Here we report the crystal structure of active mouse SMO bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of SMO is associated with subtle motions in the extracellular domain, and larger intracellular changes. In contrast to recent models3-5, a cholesterol molecule that is critical for SMO activation is bound deep within the seven-transmembrane pocket. We propose that the inactivation of PTCH1 by Hedgehog allows a transmembrane sterol to access this seven-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO. These results-combined with signalling studies and molecular dynamics simulations-delineate the structural basis for PTCH1-SMO regulation, and suggest a strategy for overcoming clinical resistance to SMO inhibitors.


Assuntos
Membrana Celular/química , Proteínas Hedgehog/agonistas , Transdução de Sinais/efeitos dos fármacos , Receptor Smoothened/agonistas , Receptor Smoothened/metabolismo , Esteróis/farmacologia , Animais , Sítios de Ligação , Técnicas Biossensoriais , Domínio Catalítico/efeitos dos fármacos , Membrana Celular/metabolismo , Colesterol/química , Colesterol/metabolismo , Colesterol/farmacologia , Proteínas Hedgehog/metabolismo , Ligantes , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Receptor Patched-1/antagonistas & inibidores , Receptor Patched-1/metabolismo , Conformação Proteica , Estabilidade Proteica , Anticorpos de Cadeia Única/imunologia , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/química , Esteróis/química , Esteróis/metabolismo , Proteínas de Xenopus/química
4.
Plant Physiol Biochem ; 141: 215-224, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31181509

RESUMO

Plants are usually exposed to several types of abiotic stress in regular field conditions. The lipid profile of barley homozygous lines exposed to drought, heat, salinity, and their combinations, was investigated in the present study. Free fatty acids, free sterols, and diacylglycerols were the most abundant classes (∼8.0% of plant material). The genetic background significantly impacted the lipid composition rather than the treatments, and diacylglycerols were the only lipid class affected by salinity (1.84 mg/100 mg plant tissue; ∼33% reduction). However, the genotype × treatment interaction analysis revealed that the lipid and sterol compositions depended on both genotype and environment. Our results suggest that inborn stress tolerance in barley is manifested by enhanced accumulation of most lipids, mainly sterols, especially in heat/drought-stressed plants. In addition, expression of the LTP2 gene may be indirectly involved in the abiotic stress reaction of barley by mediating intracellular transport of some lipid classes.


Assuntos
Hordeum/química , Lipídeos/química , Folhas de Planta/química , Esteróis/química , Estresse Fisiológico , Adaptação Fisiológica , Diglicerídeos/química , Secas , Ácidos Graxos não Esterificados/química , Cromatografia Gasosa-Espectrometria de Massas , Perfilação da Expressão Gênica , Genótipo , Hordeum/genética , Temperatura Alta , Fenótipo , Fitosteróis/química , Folhas de Planta/genética , Reprodutibilidade dos Testes , Salinidade
5.
Food Chem ; 286: 260-267, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30827604

RESUMO

Coriandrum sativum L. is well known around the world because of its food and medicine uses. The main bioactive constituents in C. sativum are essential oil, fatty acids, tocol, sterol and carotenoids, their yields and chemical compositions being influenced by genotype, variety, planting season, ecotype, planting condition, growth stage, plant part, harvesting time, extracting process and other factors. Coriander and its different extracts possess varying degrees of antioxidative and antimicrobial activities on account of different active constituents. The general usages, chemical compositions and bioactivities of coriander are summarized in this review, along with safety considerations.


Assuntos
Coriandrum/química , Óleos Voláteis/química , Compostos Fitoquímicos/química , Anti-Infecciosos/química , Antioxidantes/química , Carotenoides/química , Coriandrum/metabolismo , Ácidos Graxos/química , Frutas/química , Frutas/metabolismo , Esteróis/química
6.
Chin J Nat Med ; 17(3): 209-217, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30910057

RESUMO

Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a subpopulation of antibiotic-susceptible organisms may evolve into resistant ones during antibiotic treatment and eventually dominate the whole population. In this study, we established a co-culture assay in which an azole-resistant Candida albicans strain was mixed with a susceptible strain labeled with green fluorescent protein to mimic in vivo conditions and screen for antifungal drugs. Fluconazole was used as a positive control to verify the validity of this co-culture assay. Five natural molecules exhibited antifungal activity against both susceptible and resistant C. albicans. Two of these compounds, retigeric acid B (RAB) and riccardin D (RD), preferentially inhibited C. albicans strains in which the efflux pump MDR1 was activated. This selectivity was attributed to greater intracellular accumulation of the drugs in the resistant strains. Changes in sterol and lipid compositions were observed in the resistant strains compared to the susceptible strain, and might increase cell permeability to RAB and RD. In addition, RAB and RD interfered with the sterol pathway, further aggregating the decrease in ergosterol in the sterol synthesis pathway in the MDR1-activated strains. Our findings here provide an alternative for combating resistant pathogenic fungi.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Antifúngicos/farmacologia , Azóis/farmacologia , Candida albicans/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Proteínas Fúngicas/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Antifúngicos/química , Antifúngicos/metabolismo , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Candida albicans/química , Candida albicans/metabolismo , Membrana Celular/química , Membrana Celular/metabolismo , Técnicas de Cocultura , Ergosterol/metabolismo , Proteínas Fúngicas/genética , Lipídeos/química , Estrutura Molecular , Permeabilidade , Éteres Fenílicos/química , Éteres Fenílicos/metabolismo , Éteres Fenílicos/farmacologia , Esteróis/química , Esteróis/metabolismo , Estilbenos/química , Estilbenos/metabolismo , Estilbenos/farmacologia , Triterpenos/química , Triterpenos/metabolismo , Triterpenos/farmacologia
7.
Molecules ; 24(3)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30736477

RESUMO

Enzyme-assisted derivatization for sterol analysis (EADSA) is a technology designed to enhance sensitivity and specificity for sterol analysis using electrospray ionization⁻mass spectrometry. To date it has only been exploited on sterols with a 3ß-hydroxy-5-ene or 3ß-hydroxy-5α-hydrogen structure, using bacterial cholesterol oxidase enzyme to convert the 3ß-hydroxy group to a 3-oxo group for subsequent derivatization with the positively charged Girard hydrazine reagents, or on substrates with a native oxo group. Here we describe an extension of the technology by substituting 3α-hydroxysteroid dehydrogenase (3α-HSD) for cholesterol oxidase, making the method applicable to sterols with a 3α-hydroxy-5ß-hydrogen structure. The 3α-HSD enzyme works efficiently on bile alcohols and bile acids with this stereochemistry. However, as found by others, derivatization of the resultant 3-oxo group with a hydrazine reagent does not go to completion in the absence of a conjugating double bond in the sterol structure. Nevertheless, Girard P derivatives of bile alcohols and C27 acids give an intense molecular ion ([M]⁺) upon electrospray ionization and informative fragmentation spectra. The method shows promise for analysis of bile alcohols and 3α-hydroxy-5ß-C27-acids, enhancing the range of sterols that can be analyzed at high sensitivity in sterolomic studies.


Assuntos
Ácidos e Sais Biliares/análise , Colestanóis/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Betaína/análogos & derivados , Ácidos e Sais Biliares/química , Colestanóis/química , Cromatografia Líquida , Hidroxiesteroide Desidrogenases/química , Espectrometria de Massas , Oxirredução , Esteróis/análise , Esteróis/química , Especificidade por Substrato
8.
J Ind Microbiol Biotechnol ; 46(5): 635-647, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30790119

RESUMO

Cholesterol oxidase, steroid C27 monooxygenase and 3-ketosteroid-Δ1-dehydrogenase are key enzymes involved in microbial catabolism of sterols. Here, three isoenzymes of steroid C27 monooxygenase were firstly characterized from Mycobacterium neoaurum as the key enzyme in sterol C27-hydroxylation. Among these three isoenzymes, steroid C27 monooxygenase 2 exhibits the strongest function in sterol catabolism. To improve androst-1,4-diene-3,17-dione production, cholesterol oxidase, steroid C27 monooxygenase 2 and 3-ketosteroid-Δ1-dehydrogenase were coexpressed to strengthen the metabolic flux to androst-1,4-diene-3,17-dione, and 3-ketosteroid 9α-hydroxylase, which catalyzes the androst-1,4-diene-3,17-dione catabolism, was disrupted to block the androst-1,4-diene-3,17-dione degradation pathway in M. neoaurum JC-12. Finally, the recombinant strain JC-12S2-choM-ksdd/ΔkshA produced 20.1 g/L androst-1,4-diene-3,17-dione, which is the highest reported production with sterols as substrate. Therefore, this work is hopes to pave the way for efficient androst-1,4-diene-3,17-dione production through metabolic engineering.


Assuntos
Androstadienos/química , Isoenzimas/metabolismo , Micobactérias não Tuberculosas/metabolismo , Fitosteróis/metabolismo , Esteróis/química , Hidrocarboneto de Aril Hidroxilases/química , Microbiologia Industrial , Engenharia Metabólica , Metabolismo , Oxigenases de Função Mista/metabolismo , Oxirredutases/química , Plasmídeos/metabolismo , Polienos/metabolismo , Esteroide Hidroxilases/química
9.
Chem Commun (Camb) ; 55(12): 1829-1832, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30672911

RESUMO

Cholesterolysis of Hedgehog family proteins couples endoproteolysis to protein C-terminal sterylation. The transformation is self-catalyzed by HhC, a partially characterized enzymatic domain found in precursor forms of Hedgehog. Here we explore spatial ambiguity in sterol recognition by HhC, using a trio of derivatives where the sterol A-ring is contracted, fused, or distorted. Sterylation assays indicate that these geometric variants react as substrates with relative activity: cholesterol, 1.000 > A-ring contracted, 0.100 > A-ring fused, 0.020 > A-ring distorted, 0.005. Experimental results and computational sterol docking into the first HhC homology model suggest a partially unstructured binding site with substrate recognition governed in large part by hydrophobic interactions.


Assuntos
Proteínas Hedgehog/metabolismo , Esteróis/química , Sítios de Ligação , Colesterol/química , Colesterol/metabolismo , Transferência Ressonante de Energia de Fluorescência , Proteínas Hedgehog/química , Humanos , Cinética , Estrutura Terciária de Proteína , Especificidade por Substrato
10.
Molecules ; 24(3)2019 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-30691248

RESUMO

4,4-Dimethylsterols and 4-methylsterols are sterol biosynthetic intermediates (C4-SBIs) acting as precursors of cholesterol, ergosterol, and phytosterols. Their accumulation caused by genetic lesions or biochemical inhibition causes severe cellular and developmental phenotypes in all organisms. Functional evidence supports their role as meiosis activators or as signaling molecules in mammals or plants. Oxygenated C4-SBIs like 4-carboxysterols act in major biological processes like auxin signaling in plants and immune system development in mammals. It is the purpose of this article to point out important milestones and significant advances in the understanding of the biogenesis and biological activities of C4-SBIs.


Assuntos
Metabolismo dos Lipídeos , Esteróis/metabolismo , Esteróis/farmacologia , Animais , Regulação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Mamíferos , Metilação , Plantas/genética , Plantas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Especificidade da Espécie , Esteróis/química , Relação Estrutura-Atividade
11.
Biochim Biophys Acta Biomembr ; 1861(1): 228-235, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30055131

RESUMO

Theonellamides (TNMs) are antifungal and cytotoxic bicyclic dodecapeptides isolated from the marine sponge Theonella sp. The inclusion of cholesterol (Chol) or ergosterol in the phosphatidylcholine membrane is known to significantly enhance the membrane affinity for theonellamide A (TNM-A). We have previously revealed that TNM-A stays in a monomeric form in dimethylsulfoxide (DMSO) solvent systems, whereas the peptide forms oligomers in aqueous media. In this study, we utilized 1H NMR chemical shift changes (Δδ1H) in aqueous DMSO solution to evaluate the TNM-A/sterol interaction. Because Chol does not dissolve well in this solvent, we used 25-hydroxycholesterol (25-HC) instead, which turned out to interact with membrane-bound TNM-A in a very similar way to that of Chol. We determined the dissociation constant, KD, by NMR titration experiments and measured the chemical shift changes of TNM-A induced by 25-HC binding in the DMSO solution. Significant changes were observed for several amino acid residues in a certain area of the molecule. The results from the solution NMR experiments, together with previous findings, suggest that the TNM-Chol complex, where the hydrophobic cavity of TNM probably incorporates Chol, becomes less polar by Chol interaction, resulting in a greater accumulation of the peptide in membrane. The deeper penetration of TNM-A into the membrane interior enhances membrane disruption. We also demonstrated that hydroxylated sterols, such as 25-HC that has higher solubility in most NMR solvents than Chol, act as a versatile substitute for sterol and could be used in 1H NMR-based studies of sterol-binding peptides.


Assuntos
Colesterol/química , Bicamadas Lipídicas/química , Peptídeos Cíclicos/química , Esteróis/química , Animais , Anisotropia , Antifúngicos/química , Dimetil Sulfóxido/química , Cinética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Fosfatidilcolinas/química , Poríferos/química , Ligação Proteica , Conformação Proteica , Solventes/química , Temperatura Ambiente
12.
Mar Drugs ; 16(12)2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30563009

RESUMO

Microalgae are well known as primary producers in the hydrosphere. As sources of natural products, microalgae are attracting major attention due to the potential of their practical applications as valuable food constituents, raw material for biofuels, drug candidates, and components of drug delivery systems. This paper presents a short review of a low-molecular-weight steroid and sphingolipid glycoconjugates, with an analysis of the literature on their structures, functions, and bioactivities. The discussed data on sterols and the corresponding glycoconjugates not only demonstrate their structural diversity and properties, but also allow for a better understanding of steroid biogenesis in some echinoderms, mollusks, and other invertebrates which receive these substances from food and possibly from their microalgal symbionts. In another part of this review, the structures and biological functions of sphingolipid glycoconjugates are discussed. Their role in limiting microalgal blooms as a result of viral infections is emphasized.


Assuntos
Fatores Biológicos/metabolismo , Glicoconjugados/metabolismo , Microalgas/metabolismo , Phycodnaviridae/metabolismo , Biodiversidade , Fatores Biológicos/química , Vias Biossintéticas/fisiologia , Eutrofização/fisiologia , Glicoconjugados/química , Interações Hospedeiro-Patógeno/fisiologia , Microalgas/química , Microalgas/virologia , Estrutura Molecular , Phycodnaviridae/patogenicidade , Serina C-Palmitoiltransferase/metabolismo , Esfingolipídeos/química , Esfingolipídeos/metabolismo , Esteróis/química , Esteróis/metabolismo , Proteínas Virais/metabolismo
13.
Mar Drugs ; 17(1)2018 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-30586934

RESUMO

Diatoms are unicellular eukaryotic organisms that play a key ecological and biogeochemical role in oceans as major primary producers. Recently, these microalgae have also attracted interest as a promising source of functional products with widespread relevance. Progress in the knowledge of cell and molecular biology of diatoms is envisaged as a key step to understanding regulation of their life cycle in marine environments as well as facilitating their full and profitable exploitation by biotechnological platforms. Recently, we identified sterol sulfates (StS) as regulatory molecules of cell death in the diatom Skeletonema marinoi. As these compounds may have a general role in diatom physiology and chemical signals in aquatic systems, we investigated a suitable tool for their analysis in laboratory and field samples. Herein, we describe a sensitive, fast, and efficient ultra performance liquid chromatography⁻mass spectrometry (UPLC⁻MS) method for qualitative and quantitative analysis of StS from crude extract of diatoms and other microalgae. The method was applied to 13 different strains of our collection of marine protists. This first study suggested a species-specific distribution of StS and identified the sulfated derivatives of 24-methylene cholesterol and 24-methyl cholesterol as the most common members in diatoms.


Assuntos
Fracionamento Químico/métodos , Diatomáceas/química , Microalgas/química , Esteróis/análise , Sulfatos/análise , Fracionamento Químico/instrumentação , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/instrumentação , Cromatografia de Fase Reversa/métodos , Limite de Detecção , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Especificidade da Espécie , Esteróis/química , Esteróis/isolamento & purificação , Sulfatos/química , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
14.
Oxid Med Cell Longev ; 2018: 3939714, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30402205

RESUMO

Diabetes-associated cardiac fibrosis is a severe cardiovascular complication. Momordicine I, a bioactive triterpenoid isolated from bitter melon, has been demonstrated to have antidiabetic properties. This study investigated the effects of momordicine I on high-glucose-induced cardiac fibroblast activation. Rat cardiac fibroblasts were cultured in a high-glucose (25 mM) medium in the absence or presence of momordicine I, and the changes in collagen synthesis, transforming growth factor-ß1 (TGF-ß1) production, and related signaling molecules were assessed. Increased oxidative stress plays a critical role in the development of high-glucose-induced cardiac fibrosis; we further explored momordicine I's antioxidant activity and its effect on fibroblasts. Our data revealed that a high-glucose condition promoted fibroblast proliferation and collagen synthesis and these effects were abolished by momordicine I (0.3 and 1 µM) pretreatment. Furthermore, the inhibitory effect of momordicine I on high-glucose-induced fibroblast activation may be associated with its activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of reactive oxygen species formation, TGF-ß1 production, and Smad2/3 phosphorylation. The addition of brusatol (a selective inhibitor of Nrf2) or Nrf2 siRNA significantly abolished the inhibitory effect of momordicine I on fibroblast activation. Our findings revealed that the antifibrotic effect of momordicine I was mediated, at least partially, by the inhibition of the TGF-ß1/Smad pathway, fibroblast proliferation, and collagen synthesis through Nrf2 activation. Thus, this work provides crucial insights into the molecular pathways for the clinical application of momordicine I for treating diabetes-associated cardiac fibrosis.


Assuntos
Colágeno/biossíntese , Fibroblastos/metabolismo , Fibroblastos/patologia , Glucose/toxicidade , Miocárdio/patologia , Esteróis/farmacologia , Animais , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Modelos Biológicos , Fator 2 Relacionado a NF-E2/metabolismo , Fosforilação/efeitos dos fármacos , Quassinas/farmacologia , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Esteróis/química , Fator de Crescimento Transformador beta1/metabolismo
15.
J Agric Food Chem ; 66(45): 12141-12150, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30362748

RESUMO

To understand the adaptation of Mycobacterium neoaurum ATCC25795 ( Mn) in sterol catabolism and steroid production, we used integrated transcriptome and proteome analysis to identify the biochemical pathways utilized in this process. Metabolic alterations during sterol catabolism center on propionyl-CoA pools. Generally, enhanced pathways for metabolizing propionyl-CoA were found in Mn, which were tightly coordinated with cell-envelope biosynthesis. The cells responded to sterol substrates and toxic steroid products by changing the composition of the cell envelope. This adaptive mechanism allowed Mn to use minimally water-soluble sterol as a carbon source. Several putative efflux proteins were found to be induced in Mn. They probably transported products to the extracellular environment, protecting the cells against high intracellular levels of toxic intermediates, inhibition of which also influenced sterol uptake. The work provided various targets for rational engineering of robust Mn with powerful sterol-uptake capacity and strong tolerance to toxic products for the steroid industry.


Assuntos
Mycobacterium/metabolismo , Esteroides/metabolismo , Esteróis/metabolismo , Acil Coenzima A/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Mycobacterium/química , Mycobacterium/genética , Esteroides/química , Esteróis/química
16.
J Agric Food Chem ; 66(34): 9147-9157, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30075077

RESUMO

Integrated transcriptome and proteome studies were performed to investigate sterol biotransformation in wild-type Mycobacterium neoaurum ATCC 25795 ( Mn) and the mutant strains producing steroid intermediates. Transcriptome and proteome studies indicated that several metabolic activities were noticeably dynamic, including cholesterol degradation, central carbon metabolism, cell envelope biosynthesis, glycerol metabolism, and transport. Interestingly, a poor overall correlation between mRNA and translation profiles was found, which might contribute to the metabolic adaptation in cholesterol catabolism. A gene cluster covering 111 genes was discovered to encode for cholesterol catabolism in Mn. Generally, transcription and/or translation of the genes in KstR1 regulon was upregulated, and the induction of genes in KstR2 regulon was not as significant as that of KstR1 regulon. Several induced genes showing potential roles for cholesterol catabolism were found. Further identification of these genes and investigation of the correlation among key metabolic activities could help for the development of efficient steroid-producing strains.


Assuntos
Proteínas de Bactérias/genética , Mycobacterium/metabolismo , Proteoma/genética , Esteroides/biossíntese , Esteróis/metabolismo , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Família Multigênica , Mycobacterium/química , Mycobacterium/genética , Proteoma/metabolismo , Regulon , Esteroides/química , Esteróis/química , Transcriptoma
17.
Molecules ; 23(8)2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30081608

RESUMO

The sterols ß-sitostenone (1), stigmast-4,6,8(14),22-tetraen-3-one (2), ß-sitosterol (3) and stigmasterol (4), the aromatic derivatives antiarol (5) and gentisic acid (6), the phenylpropanes coniferyl alcohol (7), epoxyconiferyl alcohol (8) and ferulic acid (9), the apocarotenoid vomifoliol (10), the flavonoids naringenin (11), 7,4'-dimethoxytaxifolin (7,4'-dimethoxydihydroquercetin, 12), aromadendrin (13), kaempferol (14), taxifolin (dihydroquercetin, 15), prunin (naringenin-7-O-ß-d-glucoside, 16), populnin (kaempferol-7-O-ß-d-glucoside, 17) and senecin (aromadendrin-7-O-ß-d-glucoside, 18) and the lignans kobusin (19) and pinoresinol (20), were isolated from the dried bark of Cochlospermum vitifolium Spreng (Cochlospermaceae), a Mexican medicinal plant used to treat jaundice, liver ailments and hepatitis C. Fourteen of these compounds were isolated for the first time from this plant and from the Cochlospermum genus. Compounds 3⁻4, 6⁻7, 9⁻11, 13⁻17 and 20 have previously exhibited diverse beneficial liver activities. The presence of these compounds in C. vitifolium correlates with the use of this Mexican medicinal plant.


Assuntos
Bixaceae/química , Flavonoides/química , Flavonoides/farmacologia , Lignanas/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Esteróis/química , Esteróis/farmacologia , Animais , Flavonoides/uso terapêutico , Humanos , Lignanas/farmacologia , Lignanas/uso terapêutico , Casca de Planta/química , Extratos Vegetais/uso terapêutico , Esteróis/uso terapêutico
18.
Chin J Nat Med ; 16(7): 499-504, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30080648

RESUMO

Two previously undescribed steroidal compounds, 16, 23-epoxy-22, 26-epimino-cholest-22(N), 23, 25(26)-trien-3ß-ol-3-O-ß-D-glucopyranosyl-(1→2)-ß-D-glucopyranosyl-(1→4)-ß-D-galactopyranoside (1) and 26-O-ß-D-glucopyranosyl-(25R)-5α-furost-20(22)-en-3ß, 26-diol (2), together with 7 known ones including 26-O-ß-D-glucopyranosyl-(25R)-5, 20(22)-dien-furost-3ß, 26-diol (3), (25R)-5-en-spirost-3ß-ol-O-ß-D-glucopyranosyl-(1→4)-[α-L-rhmanopyranosyl-(1→2)]-ß-D-galactopyranoside (4), funkioside D (5), aspidistrin (6), tigogenin-3-O-ß-D-lucotrioside (7), desglucolanatigonin II (8), and degalactotigonin (9), were isolated from Solanum lyratum Thunb. Their cytotoxic activities were tested in two cancer cell lines by MTT method. One of the steroidal glycosides (6) showed significant cytotoxic activity against gastric cancer SGC7901 and liver cancer BEL-7402 cells.


Assuntos
Alcaloides/toxicidade , Antineoplásicos/isolamento & purificação , Antineoplásicos/toxicidade , Glicosídeos/toxicidade , Extratos Vegetais/toxicidade , Solanum/química , Esteróis/toxicidade , Alcaloides/química , Alcaloides/isolamento & purificação , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glicosídeos/química , Glicosídeos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Fitosteróis/química , Fitosteróis/isolamento & purificação , Fitosteróis/toxicidade , Extratos Vegetais/química , Plantas Medicinais/química , Esteróis/química , Esteróis/farmacologia
19.
Mar Drugs ; 16(7)2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30011911

RESUMO

Hypertension and obesity are two significant factors that contribute to the onset and exacerbation of a cascade of mechanisms including activation of the sympathetic and renin-angiotensin systems, oxidative stress, release of inflammatory mediators, increase of adipogenesis and thus promotion of systemic dysfunction that leads to clinical manifestations of cardiovascular diseases. Seaweeds, in addition to their use as food, are now unanimously acknowledged as an invaluable source of new natural products that may hold noteworthy leads for future drug discovery and development, including in the prevention and/or treatment of the cardiovascular risk factors. Several compounds including peptides, phlorotannins, polysaccharides, carotenoids, and sterols, isolated from brown, red and green macroalgae exhibit significant anti-hypertensive and anti-obesity properties. This review will provide a comprehensive overview of the recent advances on bioactive pure compounds isolated from different seaweed sources focusing on their potential use as drugs to treat or prevent hypertension and obesity. On the other hand, although it is obvious that macroalgae represent promising sources of antihypertensive and anti-obesity compounds, it is also clear that further efforts are required to fully understand their cellular mechanisms of action, to establish structure-inhibition relationships and mainly to evaluate them in pre-clinical and clinical trials.


Assuntos
Fármacos Antiobesidade/farmacologia , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Obesidade/tratamento farmacológico , Alga Marinha/metabolismo , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Fármacos Antiobesidade/uso terapêutico , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/uso terapêutico , Carotenoides/química , Carotenoides/isolamento & purificação , Carotenoides/farmacologia , Carotenoides/uso terapêutico , Descoberta de Drogas , Humanos , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/química , Peptídeos/isolamento & purificação , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Esteróis/química , Esteróis/isolamento & purificação , Esteróis/farmacologia , Esteróis/uso terapêutico , Relação Estrutura-Atividade
20.
J Agric Food Chem ; 66(25): 6373-6381, 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29856218

RESUMO

This study validates a gas chromatography (GC) method for determining the sterol profile of human milk (HM) and compares it with an enzymatic-spectrophotometric (E-S) method. Good linearity ( r > 0.97) and low limits of detection and quantification were obtained with the GC method (<1.8 and <6 µg/100 g of HM, respectively). Suitable intra- and interassay precisions (all <18%) and satisfactory recovery percentages (80-109%) were obtained for both methods. In addition, both methodologies were used to assess cholesterol evolution in HM during lactation, showing a 50% decrease at 6 months versus colostrum. The E-S method overestimated cholesterol content by <20% versus the GC method. The results indicate that both methods may be used by the industry and in research to better understand the differences between the sterol profiles of infant formulas and HM.


Assuntos
Colesterol/química , Cromatografia Gasosa/métodos , Leite Humano/química , Adolescente , Adulto , Catalase/química , Colesterol/metabolismo , Colostro/química , Colostro/metabolismo , Feminino , Humanos , Lactação , Leite Humano/metabolismo , Esteróis/química , Esteróis/metabolismo , Adulto Jovem
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