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1.
Molecules ; 24(13)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288489

RESUMO

Black mulberry is a widely acknowledged ancient traditional medicine. Its extract and constituents have been reported to exert various bioactivities including antimicrobial, hypotensive, analgesic etc. effects. While black mulberry preparations are also used as antispasmodic agents in folk medicine, no related studies are available on its isolated constituents. Through an extensive chromatographic purification, seven phenolic compounds were isolated from the methanol extract of Morus nigra root bark, including morusin (1), kuwanon U (2), kuwanon E (3), moracin P (4), moracin O (5), albanol A (6), and albanol B (7). A complete NMR signal assignment of moracin P and O was achieved, and related literature errors confusing the identity of moracin derivatives are hereby clarified. Compounds 2, 5 and 7 were identified as strong antispasmodic agents on isolated rat ileum and tracheal smooth muscles, while compound 3, a methoxy derivative of 2, was inactive. Moracin O (5) inhibited the ileal and tracheal smooth muscle contractions with Emax values of 85% and 302 mg, respectively. Those actions were superior as compared with papaverine. Our findings demonstrate that prenylated arylbenzofurans, geranylated flavonoids and Diels-Alder adducts from Morus nigra are valuable antispasmodic agents. Compounds 2, 5 and 7 are suggested as marker compounds for quality control of antispasmodic mulberry preparations. Moracin O (5) is a new lead compound for related drug development initiatives.


Assuntos
Morus/química , Parassimpatolíticos/química , Fenóis/química , Casca de Planta/química , Extratos Vegetais/química , Raízes de Plantas/química , Benzofuranos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Flavanonas/metabolismo , Metanol/química , Parassimpatolíticos/farmacologia , Prenilação , Resorcinóis/metabolismo , Solventes/química , Relação Estrutura-Atividade
2.
Chem Commun (Camb) ; 55(61): 8975-8978, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290492
3.
Eur J Med Chem ; 178: 243-258, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185414

RESUMO

To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aß1-42 oligomers, was a potent and selective CB2 ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB2 inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB2 receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.


Assuntos
Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Células CHO , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cricetulus , Desenho de Drogas , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Ligação Proteica , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
4.
J Photochem Photobiol B ; 196: 111509, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31128431

RESUMO

Cnidium officinale Makino is an important medicinal plant of oriental clinics and is considered as the main source of phthalides, polyphenols, and flavonoids. However, there is no available report regarding the effect of different light colors on the secondary metabolites composition of C. officinale. In this study different light (dark, white, blue, red and red: blue) conditions were arranged to raise callus on MS medium containing 0.5 mg·L-1 of each 2,4-D and BAP. Callus grown in dark condition showed maximum (2.0 g) fresh weight with lower total phenolic and flavonoids contents. Also, in dark condition callus faced higher catalase (CAT) and guaiacol peroxidase (GPX) activities to avoid free radicals. Mix (red: blue) light condition favored the synthesis of phenolics and flavonoids in callus at the cost of higher ascorbate peroxidase (APX) and superoxide dismutase (SOD) enzymes expression. However, DPPH free radical scavenging activity was less variable among the samples from the different light conditions. Interestingly, the HPLC profile showed higher (28.3 µg·g-1 DW) phthalide accumulation in dark grown-cultures. Compared to other light conditions, 3-butyledinephthalide accumulation was higher (0.43 µg·g-1 DW) in white light-grown callus. These findings suggest that light conditions play an important role in the regulation of in vitro callus growth and synthesis of important medicinal compounds of C. officinale.


Assuntos
Antioxidantes/metabolismo , Cnidium/química , Flavonoides/metabolismo , Luz , Fenóis/metabolismo , Antioxidantes/química , Ascorbato Peroxidases/metabolismo , Benzofuranos/análise , Benzofuranos/metabolismo , Cromatografia Líquida de Alta Pressão , Cnidium/crescimento & desenvolvimento , Cnidium/metabolismo , Flavonoides/química , Fenóis/química , Células Vegetais/metabolismo , Células Vegetais/efeitos da radiação , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Superóxido Dismutase/metabolismo
5.
Plant Cell Physiol ; 60(8): 1871-1879, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31135027

RESUMO

Wild-type plants of the Japanese morning glory (Ipomoea nil) produce blue flowers that accumulate anthocyanin pigments, whereas its mutant cultivars show wide range flower color such as red, magenta and white. However, I. nil lacks yellow color varieties even though yellow flowers were curiously described in words and woodblocks printed in the 19th century. Such yellow flowers have been regarded as 'phantom morning glories', and their production has not been achieved despite efforts by breeders of I. nil. The chalcone isomerase (CHI) mutants (including line 54Y) bloom very pale yellow or cream-colored flowers conferred by the accumulation of 2', 4', 6', 4-tetrahydoroxychalcone (THC) 2'-O-glucoside. To produce yellow phantom morning glories, we introduced two snapdragon (Antirrhinum majus) genes to the 54Y line by encoding aureusidin synthase (AmAS1) and chalcone 4'-O-glucosyltransferase (Am4'CGT), which are necessary for the accumulation of aureusidin 6-O-glucoside and yellow coloration in A. majus. The transgenic plants expressing both genes exhibit yellow flowers, a character sought for many years. The flower petals of the transgenic plants contained aureusidin 6-O-glucoside, as well as a reduced amount of THC 2'-O-glucoside. In addition, we identified a novel aurone compound, aureusidin 6-O-(6″-O-malonyl)-glucoside, in the yellow petals. A combination of the coexpression of AmAS1 and Am4'CGT and suppression of CHI is an effective strategy for generating yellow varieties in horticultural plants.


Assuntos
Benzofuranos/metabolismo , Flavonoides/metabolismo , Flores/metabolismo , Ipomoea nil/metabolismo , Engenharia Metabólica/métodos , Regulação da Expressão Gênica de Plantas , Transdução de Sinais/fisiologia
6.
Phytochemistry ; 164: 86-93, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102999

RESUMO

Specialised metabolites in lichens are generally considered repellent compounds by consumers. Nevertheless, if the only food available is lichens rich in specialised metabolites, lichenophages must implement strategies to overcome the toxicity of these metabolites. Thus, the balance between phagostimulant nutrients and deterrent metabolites could play a key role in feeding preferences. To further understand lichen-gastropod interactions, we studied the feeding behaviour and consumption in Notodiscus hookeri, the land snail native to sub-Antarctic islands. The lichen Usnea taylorii was used because of its simple chemistry, its richness in usnic acid (specialised metabolite) and arabitol (primary metabolite) and its presence in snail habitats. Choice tests in arenas with intact lichens versus acetone-rinsed lichens were carried out to study the influence of specialised metabolites on snail behaviour and feeding preference. Simultaneously, usnic acid and arabitol were quantified and located within the lichen thallus using HPLC-DAD-MS and in situ imaging by mass spectrometry to assess whether their spatial distribution explained preferential snail grazing. No-choice feeding experiments, with the pure metabolites embedded in an artificial diet, defined a gradual gustatory response, from strong repellence (usnic acid) to high appetence (D-arabitol). This case study demonstrates that the nutritional activity of N. hookeri is governed by the chemical quality of the food and primarily by nutrient availability (arabitol), despite the presence of deterrent metabolite (usnic acid).


Assuntos
Benzofuranos/metabolismo , Caramujos/metabolismo , Álcoois Açúcares/metabolismo , Usnea/metabolismo , Animais , Benzofuranos/química , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Caramujos/química , Álcoois Açúcares/química , Usnea/química
7.
Environ Pollut ; 250: 262-273, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30999203

RESUMO

Dibenzofuran (DBF) derivatives have caused serious environmental problems, especially those produced by paper pulp bleaching and incineration processes. Prominent for its resilient mutagenicity and toxicity, DBF poses a major challenge to human health. In the present study, a new strain of Pseudomonas aeruginosa, FA-HZ1, with high DBF-degrading activity was isolated and identified. The determined optimum conditions for cell growth of strain FA-HZ1 were a temperature of 30 °C, pH 5.0, rotation rate of 200 rpm and 0.1 mM DBF as a carbon source. The biochemical and physiological features as well as usage of different carbon sources by FA-HZ1 were studied. The new strain was positive for arginine double hydrolase, gelatinase and citric acid, while it was negative for urease and lysine decarboxylase. It could utilize citric acid as its sole carbon source, but was negative for indole and H2S production. Intermediates of DBF 1,2-dihydroxy-1,2-dihydrodibenzofuran, 1,2-dihydroxydibenzofuran, 2-hydroxy-4-(3'-oxo-3'H-benzofuran-2'-yliden)but-2-enoic acid, 2,3-dihydroxybenzofuran, 2-oxo-2-(2'-hydrophenyl)lactic acid, and 2-hydroxy-2-(2'-hydroxyphenyl)acetic acid were detected and identified through liquid chromatography-mass analyses. FA-HZ1 metabolizes DBF by both the angular and lateral dioxygenation pathways. The genomic study identified 158 genes that were involved in the catabolism of aromatic compounds. To identify the key genes responsible for DBF degradation, a proteomic study was performed. A total of 1459 proteins were identified in strain FA-HZ1, of which 100 were up-regulated and 104 were down-regulated. A novel enzyme "HZ6359 dioxygenase", was amplified and expressed in pET-28a in E. coli BL21(DE3). The recombinant plasmid was successfully constructed, and was used for further experiments to verify its function. In addition, the strain FA-HZ1 can also degrade halogenated analogues such as 2, 8-dibromo dibenzofuran and 4-(4-bromophenyl) dibenzofuran. Undoubtedly, the isolation and characterization of new strain and the designed pathways is significant, as it could lead to the development of cost-effective and alternative remediation strategies. The degradation pathway of DBF by P. aeruginosa FA-HZ1 is a promising tool of biotechnological and environmental significance.


Assuntos
Benzofuranos/metabolismo , Poluentes Ambientais/metabolismo , Pseudomonas aeruginosa/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biodegradação Ambiental , Dioxigenases/genética , Dioxigenases/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Resíduos Industriais , Redes e Vias Metabólicas/genética , Proteômica , Pseudomonas aeruginosa/química , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/crescimento & desenvolvimento
8.
Molecules ; 24(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939842

RESUMO

A preparation process of salvianolic acid B (SAB) disodium salt from Salvia miltiorrhiza Bunge (Danshen) is provided in this work. A water extract quality standard was also developed to estimate the influences of Danshen quality on SAB disodium salt quality at an early stage of the preparation process. Crude SAB solution was obtained after water extraction, concentration, acidification, 1-butanol extraction, water washing, basification, and water back extraction. Extraction temperature, extraction pH, and back-extraction pH were identified to be key parameters for the preparation of crude SAB solution. These parameters were optimized with Box⁻Behnken designed experiments. Crude SAB solution was further purified with a chromatography process. AMBERCHROW CG161M resin was selected as the best adsorbent. SAB disodium salt could be obtained by drying the eluate. Considering the quality of Danshen may affect the purity and yield of SAB disodium salt, different batches of Danshen were used to prepare SAB disodium salt with the optimized parameters. Water extract indices of phenolic compound purity and phenolic compound yield were measured. By developing models between SAB disodium salt purity and yield with water extract indices, the quality standard of Danshen water extract was obtained. The application of water extract quality standards can improve the quality consistency of SAB disodium salt. The effects of different batches of Danshen raw materials on the final product could be evaluated at the beginning of production stages. The present method could prepare about five grams of high-purity SAB disodium salt (>95%) in one preparation cycle. The method reported in this work can also be used to develop process intermediate quality standards for other natural products.


Assuntos
Benzofuranos/isolamento & purificação , Benzofuranos/metabolismo , Extratos Vegetais/química , Salvia miltiorrhiza/química , Cloreto de Sódio/química , Água/química , Benzofuranos/química
9.
J Appl Microbiol ; 126(5): 1383-1390, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30811736

RESUMO

AIM: To investigate the bioactive metabolite of endophytic fungus from Kalimeris indica. METHODS AND RESULTS: A strain ZJLQ336 was separated from the leaves of K. indica. It was identified as Cadophora orchidicola based on the phylogenetic analysis of ITS-rDNA sequences. From the fermentation broth a metabolite cercosporamide (compound 1) was isolated, and its structure was determined by spectroscopic analysis. Additionally, this compound was subjected to bioactivity assays, including antifungal activity against seven plant pathogenic fungi, as well as its potential immunoregulatory effects on HEK-BLUE™-hTLR4 cells, splenocytes and macrophages. The results showed that cercosporamide had strong growth inhibition against five common plant pathogenic fungi, including Pestalotia diospyri, Botrytis cinerea, Fusarium oxysporum, Sclerotium rolfsii and Penicillum digitatum with EC50 values of 5·29 × 10-3 , 0·61, 0·93, 2·89 and 6·7 µg ml-1 respectively. Among which S. rolfsii was one of the main pathogens in K. indica. Moreover, cercosporamide not only significantly stimulated TLR4 activation, splenocyte proliferation and production of cytokines, IFN-γ and TNF-α, but also up-regulated the production of TNF-α and NO in RAW264.7 macrophages clearly. CONCLUSIONS: This is the first report of endophytic C. orchidicola from K. indica and its metabolite cercosporamide. The results of pharmacological tests highlight the potential fungicide and TLR4 agonist of cercosporamide. SIGNIFICANCE AND IMPACT OF THE STUDY: This study indicates endophytic fungi are good resources for natural bioactive metabolites. It also suggests that cercosporamide is a potential fungicide and TLR4 agonist.


Assuntos
Antifúngicos/farmacologia , Ascomicetos/metabolismo , Aster/microbiologia , Benzofuranos/farmacologia , Receptor 4 Toll-Like/agonistas , Animais , Antifúngicos/metabolismo , Ascomicetos/classificação , Ascomicetos/genética , Ascomicetos/isolamento & purificação , Benzofuranos/metabolismo , Citocinas/metabolismo , Feminino , Células HEK293 , Humanos , Camundongos , Filogenia , Células RAW 264.7
10.
Int J Biol Macromol ; 128: 893-901, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30708006

RESUMO

Thymol and usnic acid as the important secondary metabolites of respectively Artemisia haussknechtii and Protoparmeliopsis muralis were used for reduction and stabilizing of AgNO3 and CuSO4 in metal nanoparticles (MNPs) biosynthesis process. Antibacterial effects of prepared Ag-thymol (ATNPs), Ag-usnic acid (AUNPs), Cu-thymol (CTNPs), and Cu-usnic acid (CUNPs) on multi drug resistant (MDR) bacteria including methicillin-resistant Staphylococcus aureus (MRSA) (gram positive), Acinetobacter baumannii (A52), and Klebsiella pneumonia (K38) (gram negative) were compared with thymol, usnic acid, AgNO3, CuSO4, and tetracycline. Results of this study showed higher antibacterial activities of usnic acid, CUNPs, and CTNPs with MIC/MBC values (20, 40, and 40 µg/mL, respectively) than ATNPs and AUNPs against MRSA bacteria. Leakage of macromolecules involving nucleic acids and proteins from bacteria under stress of MNPs, thymol, and usnic acid proved significant antibacterial activities of usnic acid, and Cu NPs. In addition, SEM images illustrated different patterns of aggregation in biofilms resulted from interactions of these antibacterial agents with bacterial macromolecules. Totally, this investigation illustrated new green method of Ag and Cu NPs biosynthesis with suitable antibacterial properties.


Assuntos
Antibacterianos/farmacologia , Benzofuranos/metabolismo , Cobre/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Nanopartículas Metálicas/química , Prata/química , Timol/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Benzofuranos/química , Biofilmes/efeitos dos fármacos , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Timol/química
11.
Plant Physiol ; 179(4): 1822-1833, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30700538

RESUMO

Jasmonic acid (JA) plays an important role in the induction of herbivore resistance in many plants. However, JA-independent herbivore resistance has been suggested. An herbivore-resistance-inducing substance was isolated from Tobacco mosaic virus-infected tobacco (Nicotiana tabacum) leaves in which a hypersensitive response (HR) was induced and identified as loliolide, which has been identified as a ß-carotene metabolite. When applied to tomato (Solanum lycopersicum) leaves, loliolide decreased the survival rate of the two-spotted spider mite, Tetranychus urticae, egg deposition by the same pest, and the survival rate of larvae of the common cutworm Spodoptera litura without exhibiting toxicity against these herbivores. Endogenous loliolide levels increased not only with an infestation by S litura larvae, but also with the exogenous application of their oral secretions in tomato. A microarray analysis identified cell-wall-associated defense genes as loliolide-responsive tomato genes, and exogenous JA application did not induce the expression of these genes. Suppressor of zeaxanthin-less (szl), an Arabidopsis (Arabidopsis thaliana) mutant with a point mutation in a key gene of the ß-carotene metabolic pathway, exhibited the decreased accumulation of endogenous loliolide and increased susceptibility to infestation by the western flower thrip (Frankliniella occidentalis). A pretreatment with loliolide decreased susceptibility to thrips in the JA-insensitive Arabidopsis mutant coronatine-insensitive1 Exogenous loliolide did not restore reduced electrolyte leakage in szl in response to a HR-inducing bacterial strain. These results suggest that loliolide functions as an endogenous signal that mediates defense responses to herbivores, possibly independently of JA, at least in tomato and Arabidopsis plants.


Assuntos
Benzofuranos/metabolismo , Herbivoria , Tabaco/química , Animais , Arabidopsis/efeitos dos fármacos , Benzofuranos/química , Benzofuranos/isolamento & purificação , Carotenoides/metabolismo , Morte Celular , Lycopersicon esculentum/efeitos dos fármacos , Lycopersicon esculentum/parasitologia , Spodoptera/fisiologia , Tetranychidae/fisiologia , Tabaco/virologia , Vírus do Mosaico do Tabaco
12.
Sci Total Environ ; 660: 595-602, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30641388

RESUMO

This study investigated bacterial communities during aerobic food waste co-composting degradation of highly PCDD/F-contaminated field soil. The total initial toxic equivalent quantity (TEQ) of the soil was 16,004 ng-TEQ kg-1 dry weight. After 42-day composting and bioactivity-enhanced monitored natural attenuation (MNA), the final compost product's TEQ reduced to 1916 ng-TEQ kg-1 dry weight (approximately 75% degradation) with a degradation rate of 136.33 ng-TEQ kg-1 day-1. Variations in bacterial communities and PCDD/F degraders were identified by next-generation sequencing (NGS). Thermophilic conditions of the co-composting process resulted in fewer observed bacteria and PCDD/F concentrations. Numerous organic compound degraders were identified by NGS, supporting the conclusion that PCDD/Fs were degraded during food waste co-composting. Bacterial communities of the composting process were defined by four phyla (Proteobacteria, Actinobacteria, Bacteroidetes and Firmicutes). At the genus level, Bacillus (Firmicutes) emerged as the most dominant phylotype. Further studies on specific roles of these bacterial strains are needed, especially for the thermophiles which contributed to the high degradation rate of the co-co-composting treatment's first 14 days.


Assuntos
Bactérias/metabolismo , Benzofuranos/metabolismo , Compostagem , Recuperação e Remediação Ambiental/métodos , Dibenzodioxinas Policloradas/metabolismo , Poluentes do Solo/metabolismo , Aerobiose , Biodegradação Ambiental , Microbiota , Microbiologia do Solo , Taiwan
13.
Mol Cell ; 73(4): 738-748.e9, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30595437

RESUMO

A class of translation inhibitors, exemplified by the natural product rocaglamide A (RocA), isolated from Aglaia genus plants, exhibits antitumor activity by clamping eukaryotic translation initiation factor 4A (eIF4A) onto polypurine sequences in mRNAs. This unusual inhibitory mechanism raises the question of how the drug imposes sequence selectivity onto a general translation factor. Here, we determined the crystal structure of the human eIF4A1⋅ATP analog⋅RocA⋅polypurine RNA complex. RocA targets the "bi-molecular cavity" formed characteristically by eIF4A1 and a sharply bent pair of consecutive purines in the RNA. Natural amino acid substitutions found in Aglaia eIF4As changed the cavity shape, leading to RocA resistance. This study provides an example of an RNA-sequence-selective interfacial inhibitor fitting into the space shaped cooperatively by protein and RNA with specific sequences.


Assuntos
Benzofuranos/metabolismo , Fator de Iniciação 4A em Eucariotos/metabolismo , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/metabolismo , RNA/metabolismo , Ribossomos/metabolismo , Adenilil Imidodifosfato/química , Adenilil Imidodifosfato/metabolismo , Aglaia/química , Aglaia/genética , Aglaia/metabolismo , Substituição de Aminoácidos , Benzofuranos/química , Benzofuranos/isolamento & purificação , Benzofuranos/farmacologia , Sítios de Ligação , Resistência a Medicamentos/genética , Fator de Iniciação 4A em Eucariotos/química , Fator de Iniciação 4A em Eucariotos/genética , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ligação Proteica , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , Domínios e Motivos de Interação entre Proteínas , Inibidores da Síntese de Proteínas/química , Inibidores da Síntese de Proteínas/isolamento & purificação , Inibidores da Síntese de Proteínas/farmacologia , RNA/química , Ribossomos/química , Ribossomos/efeitos dos fármacos , Ribossomos/genética , Relação Estrutura-Atividade
14.
Int J Biol Macromol ; 121: 77-88, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30261256

RESUMO

Four 4-nitrophenyl-functionalized benzofuran (BF1, BF2) and benzodifuran (BDF1, BDF2) compounds were synthesized by a convenient route based on the Craven reaction. All the compounds underwent a detailed chemical-physical characterization to evaluate their structural, thermal and optical properties. An investigation on the therapeutic potential of the reported compounds was performed by analyzing their antiproliferative activity on prostatic tumour cells (PC-3). In both classes of compounds, anticancer potential is in direct correlation with the lipophilicity. From our study it emerged that antiproliferative activity was higher for benzofuran derivatives as compared to benzodifuran systems. Moreover, we report a mechanistic study relative to the most promising molecule, i.e. the apolar benzofuran BF1, that relates the antiproliferative properties found in our investigation to its ability to bind telomeric DNA (proven by CD and fluorescence techniques on tel22 G4 DNA), and highlights its unexpected impact on cell cycle progression.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , DNA/metabolismo , Nitrofenóis/química , Telômero/genética , Antineoplásicos/metabolismo , Benzofuranos/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células PC-3 , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade
15.
Sci Total Environ ; 647: 20-28, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30077159

RESUMO

Fish samples of different species (i.e. rainbow trout (Onchorhynchus mykiss), barbel (Barbus barbus) and European chub (Squalius cephalus)) were collected from the Sava River Basin for a preliminary investigation of the levels of PCDD/Fs, PCBs, PBDEs and PFAS as a whole. Concentrations of PCDD/Fs, in terms of pg WHO-TEQ/g ww, were below the maximum limit established at the Commission Regulation (EU) No 1259/2011. On the contrary, when DL-PCBs were also included, levels increase up to 11.7 pg WHO-TEQPCDD/Fs+DL-PCBs/g ww in a particular case, with two samples out of a total of ten exceeding the maximum set at this EU Regulation and the EQS established at the European Directive regarding priority substances in the field of water policy (0.0065 ng WHO-TEQPCDD/Fs+DL-PCBs/g ww). A similar trend was also observed for NDL-PCBs, whit the same two samples, from the lower stretch of the river basin, exceeding the maximum limit allowed at the EU Regulation (125 ng/g ww). For PBDEs, levels found in all the samples exceeded the EQS (0.0085 ng/g ww) up to more than a thousand times and 40% of the samples presented PFOS values above the EQS. Data from this study were compared to values reported at the literature for fish from other geographical areas.


Assuntos
Monitoramento Ambiental , Peixes/metabolismo , Poluentes Químicos da Água/metabolismo , Poluição Química da Água/estatística & dados numéricos , Animais , Benzofuranos/metabolismo , Croácia , Dibenzofuranos Policlorados/metabolismo , Política Ambiental , Éteres Difenil Halogenados/metabolismo , Bifenilos Policlorados/metabolismo , Dibenzodioxinas Policloradas/metabolismo , Rios , Poluentes Químicos da Água/normas , Poluição Química da Água/legislação & jurisprudência
16.
Cell Physiol Biochem ; 50(2): 654-667, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30308499

RESUMO

BACKGROUND/AIMS: Nephropathy related with renin can be alleviated with ACE-inhibitors or AT1R blockers, whereas they might be ineffective after long-term administration because of a feedback production of enhanced renin. Therefore, it is urgent to develop a new category of anti-nephropathy medicine directly targeting renin. Riligustilide (C20), originally isolated from the Chinese herb Ligusticumporteri, a rhizome, was confirmed effective against many diseases. METHODS: The therapeutic effect of C20 on renal injury and its underlying mechanism were investigated in three different nephrotic models, which were spontaneously hypertension rats (SHR) model, diabetic nephropathy in BTBR ob/ob mice model and 5/6-nephrectomized (5/6NX) rats model. RESULTS: The intensity of kidney fibrosis was extensively decreased in the C20-treated rats compared to the vehicle animals. C20 significantly alleviated renal injury much more in 5/6 NX rats than in vehicle group. The rats in 5/6 NX without administrated C20 developed albuminuria earlier with more severe symptoms. Additionally, our findings showed that C20 down-regulated the renin expression and relocation of CREB-CBP complex in vivo and in vitro. CONCLUSION: C20 plays importantly reno-protective roles most likely through the relocation of CREB-CBP complex.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzofuranos/farmacologia , Nefropatias Diabéticas/patologia , Regulação para Baixo/efeitos dos fármacos , Renina/metabolismo , Animais , Benzofuranos/metabolismo , Benzofuranos/uso terapêutico , Proteína de Ligação a CREB/metabolismo , Linhagem Celular , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Modelos Animais de Doenças , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Medicina Tradicional Chinesa , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Obesos , Simulação de Acoplamento Molecular , Nefrectomia , Fosfoproteínas/metabolismo , Ratos , Ratos Endogâmicos SHR , Renina/antagonistas & inibidores
17.
Food Chem Toxicol ; 120: 112-118, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29981369

RESUMO

Usnic acid is a lichen compound which is extensively studied due to its cytotoxic, antiproliferative, antimicrobial, antiviral, antiprotozoal, and anti-inflammatory activities. Despite a broad spectrum of biological properties, usnic acid is a hepatotoxic agent, thus its potential use as a drug is limited. Certain hepatotoxic drugs may act by generating reactive metabolites that damage the liver. The aim of the study was to predict the biotransformation of usnic acid enantiomers to reactive products using a trapping assay with glutathione in human, rat, and mice liver microsomes. Our results indicate that each enantiomer forms two reactive metabolites; in turn, these metabolites form adducts with glutathione, which may partially explain the toxicity of usnic acid. In silico analysis indicated structural alerts for the generation of reactive metabolites in usnic acid formula. This study proposes a novel mode of the hepatic toxicity of usnic acid enantiomers; it also provides some useful suggestions for designing safer usnic acid derivatives.


Assuntos
Benzofuranos/metabolismo , Benzofuranos/toxicidade , Fígado/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Animais , Benzofuranos/química , Benzofuranos/isolamento & purificação , Biotransformação , Cromatografia Líquida , Glutationa/metabolismo , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Estereoisomerismo , Espectrometria de Massas em Tandem
18.
Comput Biol Chem ; 76: 61-66, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29957363

RESUMO

Neolignans are a large group of polyphenols found in plants and exhibit a wide range of bioactivities including cytotoxicity, apoptosis inducer, antimalarial and antifungal effects, acetylcholinesterase, tyrosinase, and α-glucosidase inhibition. In this study we tested acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), tyrosinase, and α-glucosidase inhibitory effects of a rare neolignan, (-)-4-O-methyldehydrodiconiferyl alcohol 9'-O-ß-glucopyranoside (1) in search for its new pharmaceutical effects. This compound exhibited good tyrosinase inhibition with an IC50 value of 44.62 ±â€¯3.99 µg/mL. Enzyme kinetics and molecular modelling studies were performed to provide insights into its tyrosinase inhibition mechanism.


Assuntos
Benzofuranos/química , Inibidores da Colinesterase/química , Inibidores de Glicosídeo Hidrolases/química , Lignanas/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Acarbose/química , Agaricales/enzimologia , Benzofuranos/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/metabolismo , Galantamina/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Cinética , Lignanas/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Pironas/química
19.
J Photochem Photobiol B ; 183: 164-171, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29709801

RESUMO

The effect of light-emitting diodes (LEDs) on the production of secondary metabolites in medicinal plants and hairy roots is receiving much attention. The roots and rhizomes of the traditional Chinese medicinal plant Salvia miltiorrhiza Bunge are widely used for treating cardiovascular and cerebrovascular diseases. The main components are liposoluble tanshinones and hydrophilic phenolic acids. Moreover, hairy root culture of S. miltiorrhiza has been used in research of valuable plant-derived secondary metabolites. In this study, we examined the effect of LEDs with different combinations of wavelengths on the content of the main components in hairy roots of S. miltiorrhiza. Tanshinone IIA (TSIIA) content in hairy roots was significantly decreased with all light treatments containing blue light by >60% and was 9 times lower with LED treatment duration changed from 1 week to 3 weeks. HMGR, DXS2, DXR, GGPPS, CPS and CYP76AH1 genes involved in the tanshinone biosynthesis pathway were downregulated by blue light. Furthermore, light quality treatments have different effect on the accumulation of phenolic acids in hairy roots of S. miltiorrhiza. The light treatments 6R3B, 6B3IR, 7RGB and 2R6BUV for 3 weeks could increase rosmarinic acid (RA) content slightly but not salvianolic acid B (SAB) content. Different secondary metabolite contents could be regulated by different wavelength combinations of LEDs. Blue light could reduce TSIIA content in hairy roots of S. miltiorrhiza via gene regulation.


Assuntos
Diterpenos de Abietano/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Luz , Salvia miltiorrhiza/metabolismo , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Benzofuranos/análise , Benzofuranos/metabolismo , Biomassa , Cromatografia Líquida de Alta Pressão , Diterpenos de Abietano/análise , Farnesiltranstransferase/genética , Farnesiltranstransferase/metabolismo , Hidroximetilglutaril-CoA-Redutases NADP-Dependentes/genética , Hidroximetilglutaril-CoA-Redutases NADP-Dependentes/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , Raízes de Plantas/efeitos da radiação , Salvia miltiorrhiza/crescimento & desenvolvimento , Salvia miltiorrhiza/efeitos da radiação
20.
Rapid Commun Mass Spectrom ; 32(16): 1387-1395, 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-29790616

RESUMO

RATIONALE: Fasiglifam is an orally available and selective partial agonist of hGPR40 receptor, which was unexpectedly terminated at phase III clinical trials due to its severe hepatotoxicity. To fully understand the mechanism of action of fasiglifam, it is necessary to investigate its in vitro and in vivo metabolic profiles. METHODS: For in vitro metabolism, fasiglifam was incubated with rat or human liver microsomes in the presence of ß-nicotinamide adenine dinucleotide phosphate tetrasodium salt, glutathione (GSH) and uridine diphosphate glucuronic acid trisodium salt for 60 min. For in vivo metabolism, fasiglifam was orally administered to rats at a single dose of 20 mg/kg and the bile was collected. In vitro and in vivo samples were analyzed by the developed ultrahigh-performance liquid chromatography combined with Q-Exactive Orbitrap tandem mass spectrometry. The structures of metabolites were proposed according to their accurate masses and fragment ions. RESULTS: A total of eight metabolites, including an acyl-GSH adduct, were detected and identified. M1 (acylglucuronide) and M5 (carboxylic acid derivative) were the major metabolites of fasiglifam. Metabolic pathways of fasiglifam involved oxygenation, oxidative dealkylation, dehydrogenation, glucuronidation and GSH conjugation. Fasiglifam may undergo metabolic bioactivation via acylglucuronide. CONCLUSIONS: Oxidative dealkylation and glucuronidation were the predominant metabolic pathways of fasiglifam in vitro and in vivo. Metabolic bioactivation via acylglucuronide may be the perpetrator of its hepatotoxicity. Our findings would be helpful in understanding the disposition of fasiglifam as well as its hepatotoxicity.


Assuntos
Benzofuranos , Cromatografia Líquida de Alta Pressão/métodos , Sulfonas , Espectrometria de Massas em Tandem/métodos , Animais , Benzofuranos/análise , Benzofuranos/química , Benzofuranos/metabolismo , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfonas/análise , Sulfonas/química , Sulfonas/metabolismo
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