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1.
Foods ; 13(9)2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38731738

RESUMO

The study aims to improve the quality of wooden breast meat (WBM) via the use of newly developed marinades based on selected strains of lactic acid bacteria (LAB) in combination with the by-products of the dairy and fruit/berry industries. Six distinct marinades were produced based on milk permeate (MP) fermented with Lacticaseibacillus casei (Lc) and Liquorilactobacillus uvarum (Lu) with the addition of apple (ApBp) and blackcurrant (BcBp) processing by-products. The microbiological and acidity parameters of the fermented marinades were evaluated. The effects of marinades on the microbiological, technical, and physicochemical properties of meat were assessed following 24 and 48 h of WBM treatment. It was established that LAB viable counts in marinades were higher than 7.00 log10 colony-forming units (CFU)/mL and, after 48 h of marination, enterobacteria and molds/yeasts in WBM were absent. Marinated (24 and 48 h) WBM showed lower dry-matter and protein content, as well as water holding capacity, and exhibited higher drip loss (by 8.76%) and cooking loss (by 12.3%) in comparison with controls. After WBM treatment, biogenic amines decreased; besides, the absence of spermidine and phenylethylamine was observed in meat marinated for 48 h with a marinade prepared with Lu. Overall, this study highlights the potential advantages of the developed sustainable marinades in enhancing the safety and quality attributes of WBM.

2.
Front Microbiol ; 15: 1310395, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38601940

RESUMO

Microbial endophytes are microorganisms that live inside plants, and some of them play important yet understudied roles in plant health, growth, and adaptation to environmental conditions. Their diversity within plants has traditionally been underestimated due to the limitations of culture-dependent techniques. Metagenomic profiling provides a culture-independent approach to characterize entire microbial communities. The argan tree (Argania spinosa) is ecologically and economically important in Morocco, yet its seed endophyte microbiome remains unexplored. This study aimed to compare the bacterial and fungal endophyte communities associated with argan seeds collected from six sites across Morocco using Illumina MiSeq sequencing of the 16S rRNA gene and ITS regions, respectively. Bacterial DNA was extracted from surface-sterilized seeds and amplified using universal primers, while fungal DNA was isolated directly from seeds. Bioinformatics analysis of sequencing data identified taxonomic profiles at the phylum to genus levels. The results indicated that bacterial communities were dominated by the genus Rhodoligotrophos, while fungal communities exhibited varying degrees of dominance between Ascomycota and Basidiomycota depending on site, with Penicillium being the most abundant overall. Distinct site-specific profiles were observed, with Pseudomonas, Bacillus, and Aspergillus present across multiple locations. Alpha diversity indices revealed variation in endophyte richness between seed sources. In conclusion, this first exploration of the argan seed endophyte microbiome demonstrated environmental influence on community structure. While facing limitations due to small sample sizes and lack of ecological metadata, it provides a foundation for future mechanistic investigations into how specific endophyte-host interactions shape argan adaptation across Morocco's diverse landscapes.

3.
Plants (Basel) ; 12(6)2023 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-36986932

RESUMO

For more than a century, Cannabis was considered a narcotic and has been banned by lawmakers all over the world. In recent years, interest in this plant has increased due to its therapeutic potential, in addition to a very interesting chemical composition, characterized by the presence of an atypical family of molecules known as phytocannabinoids. With this emerging interest, it is very important to take stock of what research has been conducted so far on the chemistry and biology of Cannabis sativa. The aim of this review is to describe the traditional uses, chemical composition and biological activities of different parts of this plant, as well as the molecular docking studies. Information was collected from electronic databases, namely SciFinder, ScienceDirect, PubMed and Web of Science. Cannabis is mainly popular for its recreational use, but it is also traditionally used as remedy for the treatment of several diseases, including diabetes, digestive, circulatory, genital, nervous, urinary, skin and respiratory diseases. These biological proprieties are mainly due to the presence of bioactive metabolites represented by more than 550 different molecules. Molecular docking simulations proved the presence of affinities between Cannabis compounds and several enzymes responsible for anti-inflammatory, antidiabetic, antiepileptic and anticancer activities. Several biological activities have been evaluated on the metabolites of Cannabis sativa, and these works have shown the presence of antioxidant, antibacterial, anticoagulant, antifungal, anti-aflatoxigenic, insecticidal, anti-inflammatory, anticancer, neuroprotective and dermocosmetic activities. This paper presents the up-to-date reported investigations and opens many reflections and further research perspectives.

4.
Mar Drugs ; 20(8)2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-36005527

RESUMO

For more than 40 years, marine microorganisms have raised great interest because of their major ecological function and their numerous applications for biotechnology and pharmacology. Particularly, Archaea represent a resource of great potential for the identification of new metabolites because of their adaptation to extreme environmental conditions and their original metabolic pathways, allowing the synthesis of unique biomolecules. Studies on archaeal carotenoids are still relatively scarce and only a few works have focused on their industrial scale production and their biotechnological and pharmacological properties, while the societal demand for these bioactive pigments is growing. This article aims to provide a comprehensive review of the current knowledge on carotenoid metabolism in Archaea and the potential applications of these pigments in biotechnology and medicine. After reviewing the ecology and classification of these microorganisms, as well as their unique cellular and biochemical characteristics, this paper highlights the most recent data concerning carotenoid metabolism in Archaea, the biological properties of these pigments, and biotechnological considerations for their production at industrial scale.


Assuntos
Archaea , Carotenoides , Archaea/metabolismo , Biotecnologia , Carotenoides/metabolismo , Pigmentação
5.
Chem Biol Interact ; 355: 109849, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35150652

RESUMO

A phytochemical investigation of cytotoxic extract and fractions of Cnidoscolus quercifolius Pohl led to isolation of five terpenoids, including three lupane-type triterpenes (1-3) and two bis-nor-diterpenes (4-5). Compounds 4 (phyllacanthone) and 5 (favelanone) are commonly found in this species and have unique chemical structure. Although their cytotoxic activity against cancer cells has been previously reported, the anticancer potential of these molecules remains poorly explored. In this paper, the antimelanoma potential of phyllacanthone (PHY) was described for the first time. Cell viability assay showed a promising cytotoxic activity (IC50 = 40.9 µM) against chemoresistant human melanoma cells expressing the BRAF oncogenic mutation (A2058 cell line). After 72 h of treatment, PHY inhibited cell migration and induced apoptosis and cell cycle arrest (p < 0.05). Immunofluorescence assay showed that the pro-apoptotic effect of PHY is probably associated with tubulin depolymerization, resulting in cytoskeleton disruption of melanoma cells. Molecular docking investigation confirmed this hypothesis given that satisfactory interaction between PHY and tubulin was observed, particularly at the colchicine binding site. These results suggest PHY from C. quercifolius could be potential leader for the design of new antimelanoma drugs.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos/química , Euphorbiaceae/química , Proteínas Proto-Oncogênicas B-raf/genética , Tubulina (Proteína)/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular , Colchicina/química , Colchicina/metabolismo , Diterpenos/metabolismo , Diterpenos/farmacologia , Euphorbiaceae/metabolismo , Humanos , Melanoma/metabolismo , Melanoma/patologia , Simulação de Acoplamento Molecular , Mutação , Casca de Planta/química , Casca de Planta/metabolismo , Extratos Vegetais/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Tubulina (Proteína)/química
6.
Chem Biodivers ; 18(12): e2100653, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34786843

RESUMO

The chemical composition and in vitro biological activities of the essential oil (EO) of Micromeria macrosiphon Coss. and M. arganietorum (J. Emb.) R. Morales, two Lamiaceae endemic to south Morocco, were investigated. GC/MS analysis resulted in the identification of 36 metabolites from the EO of M. macrosiphon, 45 from M. arganietorum. Borneol was the major metabolite in both oils and together with related derivatives such as camphor, accounted for 2/3 of the EO of M. macrosiphon, 1/3 of those of M. arganietorum. Pinene and terpinene derivatives were also present in high proportions. From a chemotaxonomic point of view, the composition of the examined samples may be related to those of other species endemic to Macaronesia. Both EOs showed significant toxicity towards liver HepG2 and melanoma B16 4A5 tumor cell lines at 100 µg/mL; however, they were also cytotoxic towards S17 normal cell lines, with a selectivity index <1. No antibacterial activity was noticed against 52 strains at 100 µg/mL.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Lamiaceae/química , Óleos Voláteis/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação
7.
J Ethnopharmacol ; 281: 114528, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34418509

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The argan [Argania spinosa (L.) Skeels] is one of the most important floristic resource in Morocco, it is the only representative of the Sapotaceae family and Argania genus found in Morocco. This tree is fully exploited by the native populations for nutrition, medication and cosmetics. The argan oil extracted from seed is the main tree product for his large use. AIM OF THE REVIEW: This review describes the traditional uses, chemical composition and biological activities of different the argan tree parts. MATERIALS AND METHODS: This review covers the literature available from 1972 to 2021. The informations were collected from electronic databases Scopus, PubMed, Web of Science, SciFinder and Google Scholar. RESULTS: Argan oil have been used for nutrition, and to treat several diseases, namely rheumatisms, hypercholesterolemia, atherosclerosis, lung infections, newborn gastrointestinal disorders, diabetes, skin and hair hydration. The other parts of Argan tree have been used to treat intestinal disorders, dermatosis, and hair caring, with additional uses such as livestock nutrition, carpentry and heating. The argan oil is primarily composed of unsaturated fatty acids mainly oleic and linoleic acids furthermore the chemical composition, of the others part, are very diversified (flavonoids, terpenoids, triacylglycerols, saponins. …). Diverse biological activities have been reported for argan oil, such as antioxidant, skin water retention, hair protection, cholesterol stabilization, antidiabetic, anticancer and antibacterial. Antimicrobial activities have been reported for argan leaves essential oils, when the fruit pulp organic extract presented very interesting antioxidant activity due to the presence of polyphenols. The argan cake is the seed waste produced during the extraction process, it is traditionally used for skin care and for livestock nutrition. Different biological activities of argan cake have been cited essentially antioxidant, haemoprotective, anti-inflammatory and antimicrobial.


Assuntos
Etnobotânica , Compostos Fitoquímicos/farmacologia , Fitoterapia , Plantas Medicinais/química , Sapotaceae/química , Humanos
8.
J Ethnopharmacol ; 278: 114205, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34000364

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Thymus is among the most important genera in the Lamiaceae family with 215 species and is widely distributed globally, mainly in the Mediterranean region. The genus contains many medicinal plants used in traditional Moroccan medicine for a long time in treating diverse diseases. AIM OF THE REVIEW: This review describes the traditional uses, biological activities and chemical composition of essential oils (EOs) obtained from Thymus species growing in Morocco. MATERIALS AND METHODS: Information related to the traditional uses, essential oils chemical composition and biological activities on Moroccan Thymus species were obtained using the electronic databases Web of science, Scopus, SciFinder, Pubmed and Google Scholar. RESULTS: Moroccan Thymus species have been used in treatment of several diseases, namely diabetes, digestive, circulatory, genital, nervous, urinary, skin and respiratory diseases. Diverse biological activities of Moroccan Thymus species EOs have been reported, such as antibacterial, antifungal, antioxidant, anti-proliferative, anti-tumoral, insecticidal, larvicidal, nematicide, anti-inflammatory, anti-cyanobacterial and anti-acetylcholinesterase. The chemical compositions of Thymus EOs is primarily composed of monoterpenes.


Assuntos
Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Thymus (Planta)/química , Animais , Etnofarmacologia , Humanos , Medicina Tradicional/métodos , Marrocos , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Extratos Vegetais/química
9.
Chem Biodivers ; 18(6): e2100115, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33915026

RESUMO

The chemical composition and in vitro antibacterial and cytotoxic activities of the essential oil (EO) of Chiliadenus antiatlanticus (Emb. & Maire) Gómiz, an asteraceous species endemic to the southwest of Morocco, were investigated. The EO yield was 1.07±0.28 %, twenty-seven metabolites were identified representing more than 96.4 % of the total composition. Camphor (35.7 %) and derivatives, borneol (4.9 %) and camphene (4.2 %) together with intermedeol (19.9 %), α-pinene (15.5 %) and (E)-pinocarveol (4.1 %) were the major constituents. An antibacterial activity was noticed against 24 strains (all Gram-positive) out of 71 at MICs values=100 µg/mL. The EO also showed significant toxicity towards liver HepG2 (55.8 % of cell viability) and melanoma B16 4A5 (41.6 % of cell viability) tumor cell lines at 100 µg/mL.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Bactérias Gram-Positivas/efeitos dos fármacos , Óleos Voláteis/farmacologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação
10.
Bioorg Med Chem ; 27(24): 115162, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31703893

RESUMO

We describe the synthesis of 26 compounds, small polycerasoidol analogs, that are Lipinski's rule-of-five compliant. In order to confirm key structural features to activate PPARα and/or PPARγ, we have adopted structural modifications in the following parts: (i) the benzopyran core (hydrophobic nucleus) by benzopyran-4-one, dihydrobenzopyran or benzopyran-4-ol; (ii) the side chain at 2-position by shortening to C3, C4 and C5-carbons versus C-9-carbons of polycerasoidol; (iii) the carboxylic group (polar head) by oxygenated groups (hydroxyl, acetoxy, epoxide, ester, aldehyde) or non-oxygenated motifs (allyl and alkyl). Benzopyran-4-ones 6, 12, 13 and 17 as well as dihydrobenzopyrans 22, 24 and 25 were able to activate hPPARα, whereas benzopyran-4-one (7) with C5-carbons in the side chain exhibited hPPARγ agonism. According to our previous docking studies, SAR confirm that the hydrophobic nucleus (benzopyran-4-one or dihydrobenzopyran) is essential to activate PPARα and/or PPARγ, and the flexible linker (side alkyl chain) should containg at least C5-carbon atoms to activate PPARγ. By contrast, the polar head ("carboxylic group") tolerated several oxygenated groups but also non-oxygenated motifs. Taking into account these key structural features, small polycerasoidol analogs might provide potential active molecules useful in the treatment of dyslipidemia and/or type 2 diabetes.


Assuntos
Benzopiranos/síntese química , Benzopiranos/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Benzopiranos/química , Descoberta de Drogas , Estrutura Molecular , Relação Estrutura-Atividade
11.
J Nat Prod ; 82(7): 1802-1812, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31268307

RESUMO

Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol (1) and polycerasoidin (2) and their derivatives for novel drug development. Nine semisynthetic derivatives were prepared from the natural polycerasoidol (1) and polycerasoidin (2), which were evaluated for PPARα, -γ, -δ and retinoid X receptor-α activity in transactivation assays. Polycerasoidol (1) exhibited potent dual PPARα/γ agonism and low cytotoxicity. Structure-activity relationship studies revealed that a free phenol group at C-6 and a carboxylic acid at C-9' were key features for dual PPARα/γ agonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPARα and PPARγ domains. In addition, polycerasoidol (1) exhibited a potent anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium in a concentration-dependent manner via RXRα/PPARγ interactions. Therefore, polycerasoidol (1) can be considered a hit-to-lead molecule for the further development of novel dual PPARα/γ agonists capable of preventing cardiovascular events associated with metabolic disorders.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Benzopiranos/química , PPAR alfa/agonistas , PPAR gama/agonistas , Prenilação , Benzopiranos/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
12.
Front Microbiol ; 8: 343, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28321210

RESUMO

Ramoplanin is a glycolipodepsipeptide antibiotic obtained from fermentation of Actinoplanes sp. ATCC 33076 that exhibits activity against clinically important multi-drug-resistant, Gram-positive pathogens including vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-intermediate resistant Clostridium difficile. It disrupts bacterial cell wall through a unique mechanism of action by sequestering the peptidoglycan intermediate Lipid II and therefore does not show cross-resistance with other antibiotics. However, while demonstrating excellent antimicrobial activity in systemic use in animal models of infection, ramoplanin presents low local tolerability when injected intravenously. As a consequence of this limitation, new derivatives are desirable to overcome this issue. During a natural product screening program developed to discover compounds that disrupt bacterial cell wall synthesis by inhibiting peptidoglycan transglycosylation through binding to the intermediate Lipid II, 49 actinomycete strains were identified by HR-LCMS as producers of ramoplanin-related compounds. The producing strains were isolated from environmental samples collected worldwide comprising both tropical and temperate areas. To assess the diversity of this microbial population, the 49 isolates were initially identified to the genus level on the basis of their micromorphology, and 16S sequencing confirmed the initial identification of the strains. These analyses resulted in the identification of members of genus Streptomyces, as well as representatives of the families Micromonosporaceae, Nocardiaceae, Thermomonosporaceae, and Pseudonocardiaceae, suggesting that the production of ramoplanins is relatively widespread among Actinomycetes. In addition, all of these isolates were tested against a panel of Gram-positive and Gram-negative bacteria, filamentous fungi, and yeast in order to further characterize their antimicrobial properties. This work describes the diversity of actinomycete strains that produced ramoplanin-related compounds, and the analysis of the antimicrobial activity exhibited by these isolates. Our results strongly suggest the presence of new ramoplanin-analogs among these actinomycete producers.

13.
Eur J Med Chem ; 122: 27-42, 2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-27343851

RESUMO

Dopamine receptors (DR) ligands are potential drug candidates for treating neurological disorders including schizophrenia or Parkinson's disease. Three series of isoquinolines: (E)-1-styryl-1,2,3,4-tetrahydroisoquinolines (series 1), 7-phenyl-1,2,3,7,8,8a-hexahydrocyclopenta[ij]-IQs (HCPIQs) (series 2) and (E)-1-(prop-1-en-1-yl)-1,2,3,4- tetrahydroisoquinolines (series 3), were prepared to determine their affinity for both D1 and D2-like DR. The effect of different substituents on the nitrogen atom (methyl or allyl), the dioxygenated function (methoxyl or catechol), the substituent at the ß-position of the THIQ skeleton, and the presence or absence of the cyclopentane motif, were studied. We observed that the most active compounds in the three series (2c, 2e, 3a, 3c, 3e, 5c and 5e) possessed a high affinity for D2-like DR and these remarkable features: a catechol group in the IQ-ring and the N-substitution (methyl or allyl). The series showed the following trend to D2-RD affinity: HCPIQs > 1-styryl > 1-propenyl. Therefore, the substituent at the ß-position of the THIQ and the cyclopentane ring also modulated this affinity. Among these dopaminergic isoquinolines, HCPIQs stood out for unexpected selectivity to D2-DR since the Ki D1/D2 ratio reached values of 2465, 1010 and 382 for compounds 3a, 3c and 3e, respectively. None of the most active THIQs in D2 DR displayed relevant cytotoxicity in human neutrophils and HUVEC. Finally, and in agreement with the experimental data, molecular modeling studies on DRs of the most characteristic ligands of the three series revealed stronger molecular interactions with D2 DR than with D1 DR, which further supports to the encountered enhanced selectivity to D2 DR.


Assuntos
Ciclopentanos/química , Dopaminérgicos/química , Dopaminérgicos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Receptores de Dopamina D2/metabolismo , Dopaminérgicos/metabolismo , Dopaminérgicos/toxicidade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Isoquinolinas/metabolismo , Isoquinolinas/toxicidade , Ligantes , Modelos Moleculares , Oxigênio/química , Conformação Proteica , Receptores de Dopamina D2/química , Relação Estrutura-Atividade , Especificidade por Substrato
14.
PLoS One ; 11(1): e0145812, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26735308

RESUMO

Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products.


Assuntos
Antimaláricos/farmacologia , Produtos Biológicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/química , Antimaláricos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Bases de Dados Factuais , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/metabolismo , Espectrometria de Massas , Pepstatinas/química , Pepstatinas/farmacologia , Plasmodium falciparum/enzimologia
15.
Antimicrob Agents Chemother ; 59(9): 5145-53, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26055366

RESUMO

Fungal infections have increased dramatically in the last 2 decades, and fighting infectious diseases requires innovative approaches such as the combination of two drugs acting on different targets or even targeting a salvage pathway of one of the drugs. The fungal cell wall biosynthesis is inhibited by the clinically used antifungal drug caspofungin. This antifungal activity has been found to be potentiated by humidimycin, a new natural product identified from the screening of a collection of 20,000 microbial extracts, which has no major effect when used alone. An analysis of transcriptomes and selected Aspergillus fumigatus mutants indicated that humidimycin affects the high osmolarity glycerol response pathway. By combining humidimycin and caspofungin, a strong increase in caspofungin efficacy was achieved, demonstrating that targeting different signaling pathways provides an excellent basis to develop novel anti-infective strategies.


Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/metabolismo , Equinocandinas/farmacologia , Peptídeos/farmacologia , Caspofungina , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Humanos , Lipopeptídeos , Transdução de Sinais/efeitos dos fármacos
16.
Eur J Med Chem ; 86: 700-9, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25232966

RESUMO

Hexahydroindenopyridine (HHIP) is an interesting tricyclic piperidine nucleus that is structurally related to melatonin, a serotonin-derived neurohormone. Melatonin receptor ligands have applications in several cellular, neuroendocrine and neurophysiological disorders, including depression and/or insomnia. We report herein an efficient two-step method to prepare new HHIP via enamine C-alkylation-cyclization. The influence of substituents on the benzene ring and the nitrogen atom on melatoninergic receptors has been studied. Among the 25 synthesized HHIPs, some of them containing methylenedioxy (series 2) and 8-chloro-7-methoxy substituents (series 4) on the benzene ring revealed affinity for the MT1 and/or the MT2 receptors within the nanomolar range or low micromolar. Similar activities were also encountered for those presenting urea (4g), N-aryl (2e) and N-alkyl (2f) acetamide functions. Therefore, new synthesized compounds with a HHIP nucleus have emerged as new promising leads towards the discovery of melatoninergic ligands which could provide new therapeutic agents.


Assuntos
Piridinas/síntese química , Piridinas/metabolismo , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , Sítios de Ligação , Células Cultivadas , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Ligantes , Estrutura Molecular , Piridinas/química , Receptor MT1 de Melatonina/agonistas , Receptor MT1 de Melatonina/química , Receptor MT2 de Melatonina/agonistas , Receptor MT2 de Melatonina/química , Relação Estrutura-Atividade
18.
J Biomol Screen ; 19(1): 57-65, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24045581

RESUMO

Natural products are considered an extremely valuable source for the discovery of new drugs against diverse pathologies. As yet, we have only explored a fraction of the diversity of bioactive compounds, and opportunities for discovering new natural products leading to new drugs are huge. In the present study, U2nesRELOC, a previously established cell-based imaging assay, was employed to screen a collection of extracts of microbial origin for nuclear export inhibition activity. The fluorescent signal of untreated U2nesRELOC cells localizes predominantly to the cytoplasm. Upon treatment with the nuclear export inhibitor leptomycin B, the fluorescent-tagged reporter proteins appear as speckles in the nucleus. A proprietary collection of extracts from fungi, actinomycetes, and unicellular bacteria that covers an uncommonly broad chemical space was used to interrogate this nuclear export assay system. A two-step image-based analysis allowed us to identify 12 extracts with biological activities that are not associated with previously known active metabolites. The fractionation and structural elucidation of active compounds revealed several chemical structures with nuclear export inhibition activity. Here we show that substrates of the nuclear export receptor CRM1, such as Rev, FOXO3a and NF-κB, accumulate in the nucleus in the presence of the fungal metabolite MDN-0105 with an IC50 value of 3.4 µM. Many important processes in tumor formation and progression, as well as in many viral infections, critically depend on the nucleocytoplasmic trafficking of proteins and RNA molecules. Therefore, the disruption of nuclear export is emerging as a novel therapeutic approach with enormous clinical potential. Our work highlights the potential of applying high-throughput phenotypic imaging on natural product extracts to identify novel nuclear export inhibitors.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Produtos Biológicos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala , Animais , Produtos Biológicos/isolamento & purificação , Linhagem Celular , Núcleo Celular/metabolismo , Fracionamento Químico/métodos , Relação Dose-Resposta a Droga , Descoberta de Drogas/métodos , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Concentração Inibidora 50 , NF-kappa B/metabolismo
19.
Curr Microbiol ; 65(5): 622-32, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22886401

RESUMO

Endophytic fungi are considered a rich source of active compounds resulting from their secondary metabolism. Fungi from marine environment grow in a habitat with unique conditions that can contribute to the activation of metabolic pathways of synthesis of different unknown molecules. The production of these compounds may support the adaptation and survival of the fungi in the marine ecosystem. Mangroves are ecosystems situated between land and sea. They are frequently found in tropical and subtropical areas and enclose approximately 18.1 million hectares of the planet. The great biodiversity found in these ecosystems shows the importance of researching them, including studies regarding new compounds derived from the endophytic fungi that inhabit these ecosystems. 3-hydroxypropionic acid (3-HPA) has been isolated from the mangrove endophytic fungus Diaporthe phaseolorum, which was obtained from branches of Laguncularia racemosa. The structure of this compound was elucidated by spectroscopic methods, mainly 1D and 2D NMR. In bioassays, 3-HPA showed antimicrobial activities against both Staphylococcus aureus and Salmonella typhi. The structure of this antibiotic was modified by the chemical reaction of Fischer-Speier esterification to evaluate the biologic activity of its chemical analog. The esterified product, 3-hydroxypropanoic ethyl ester, did not exhibit antibiotic activity, suggesting that the free carboxylic acid group is important to the pharmacological activity. The antibiotic-producing strain was identified with internal transcribed spacer sequence data. To the best of our knowledge, this is the first report of antibacterial activity by 3-HPA against the growth of medically important pathogens.


Assuntos
Antibacterianos/metabolismo , Ascomicetos/metabolismo , Endófitos/metabolismo , Ácido Láctico/análogos & derivados , Antibacterianos/química , Antibacterianos/farmacologia , Ascomicetos/genética , Ascomicetos/isolamento & purificação , Endófitos/genética , Endófitos/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Ácido Láctico/química , Ácido Láctico/metabolismo , Ácido Láctico/farmacologia , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Filogenia , Plantas/microbiologia , Staphylococcus aureus/efeitos dos fármacos
20.
Chem Biodivers ; 9(6): 1095-113, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22700228

RESUMO

The addition of epigenetic modifying agents and ion-exchange resins to culture media and solid-state fermentations have been promoted as ways to stimulate expression of latent biosynthetic gene clusters and to modulate secondary metabolite biosynthesis. We asked how combination of these treatments would affect a population of screening isolates and their patterns of antibiosis relative to fermentation controls. A set of 43 Emericella strains, representing 25 species and varieties, were grown on a nutrient-rich medium comprising glucose, casein hydrolysate, urea, and mineral salts. Each strain was grown in untreated agitated liquid medium, a medium treated with suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, 5-azacytidine, a DNA methylation inhibitor, an Amberlite non-ionic polyacrylate resin, and the same medium incorporated into an inert static vermiculite matrix. Species-inherent metabolic differences more strongly influenced patterns of antibiosis than medium treatments. The antibacterial siderophore, desferritriacetylfusigen, was detected in most species in liquid media, but not in the vermiculite medium. The predominant antifungal component detected was echinocandin B. Some species produced this antifungal regardless of treatment, although higher quantities were often produced in vermiculite. Several species are reported for the first time to produce echinocandin B. A new echinocandin analog, echinocandin E, was identified from E. quadrilineata.


Assuntos
Antibacterianos/química , Emericella/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Equinocandinas/química , Equinocandinas/isolamento & purificação , Equinocandinas/farmacologia , Proteínas Fúngicas/química , Proteínas Fúngicas/isolamento & purificação , Proteínas Fúngicas/farmacologia , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ornitina/análogos & derivados , Ornitina/química , Ornitina/isolamento & purificação , Ornitina/farmacologia , Staphylococcus aureus/efeitos dos fármacos
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