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1.
Trends Plant Sci ; 29(4): 391-393, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38135604

RESUMO

Stressed plants emit a variety of chemicals into the environment, leading to increased pest resistance in neighbouring plants but the genetic and molecular mechanisms of the emissions remain obscure. Recently, Gong et al. identified novel methyl salicylate (MeSA)-mediated airborne defence that confers resistance to neighbouring plants against aphids and viruses.


Assuntos
Afídeos , Salicilatos , Animais , Salicilatos/química , Plantas
2.
PLoS Genet ; 19(5): e1010751, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37141297

RESUMO

Methyl salicylate is an important inter- and intra-plant signaling molecule, but is deemed undesirable by humans when it accumulates to high levels in ripe fruits. Balancing the tradeoff between consumer satisfaction and overall plant health is challenging as the mechanisms regulating volatile levels have not yet been fully elucidated. In this study, we investigated the accumulation of methyl salicylate in ripe fruits of tomatoes that belong to the red-fruited clade. We determine the genetic diversity and the interaction of four known loci controlling methyl salicylate levels in ripe fruits. In addition to Non-Smoky Glucosyl Transferase 1 (NSGT1), we uncovered extensive genome structural variation (SV) at the Methylesterase (MES) locus. This locus contains four tandemly duplicated Methylesterase genes and genome sequence investigations at the locus identified nine distinct haplotypes. Based on gene expression and results from biparental crosses, functional and non-functional haplotypes for MES were identified. The combination of the non-functional MES haplotype 2 and the non-functional NSGT1 haplotype IV or V in a GWAS panel showed high methyl salicylate levels in ripe fruits, particularly in accessions from Ecuador, demonstrating a strong interaction between these two loci and suggesting an ecological advantage. The genetic variation at the other two known loci, Salicylic Acid Methyl Transferase 1 (SAMT1) and tomato UDP Glycosyl Transferase 5 (SlUGT5), did not explain volatile variation in the red-fruited tomato germplasm, suggesting a minor role in methyl salicylate production in red-fruited tomato. Lastly, we found that most heirloom and modern tomato accessions carried a functional MES and a non-functional NSGT1 haplotype, ensuring acceptable levels of methyl salicylate in fruits. Yet, future selection of the functional NSGT1 allele could potentially improve flavor in the modern germplasm.


Assuntos
Solanum lycopersicum , Humanos , Solanum lycopersicum/genética , Salicilatos/análise , Salicilatos/química , Salicilatos/metabolismo , Glicosiltransferases , Equador , Frutas/genética
3.
Methods Mol Biol ; 2657: 15-25, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37149520

RESUMO

Use of the 3,5-dinitrosalicylic acid reagent allows the simple, rapid quantification of reducing sugars. The method can be used for analysis of biological samples or in characterization of enzyme reactions, as new reducing ends are generated when a polysaccharide substrate undergoes hydrolytic cleavage. Presented here is an application of the method in measuring the kinetics of a glycoside hydrolase reaction, including the optimization of the DNSA reagent, and the production of a standard curve of absorbance versus sugar concentration.


Assuntos
Glicosídeo Hidrolases , Salicilatos , Glicosídeo Hidrolases/metabolismo , Cinética , Salicilatos/química , Carboidratos , Especificidade por Substrato
4.
Int J Biol Macromol ; 237: 124230, 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-36990411

RESUMO

The salicylate 1,2-dioxygenase from the bacterium Pseudaminobacter salicylatoxidans DSM 6986T (PsSDO) is a versatile metalloenzyme that participates in the aerobic biodegradation of aromatic compounds, such as gentisates and salicylates. Surprisingly, and unrelated to this metabolic role, it has been reported that PsSDO may transform the mycotoxin ochratoxin A (OTA), a molecule that appears in numerous food products that results in serious biotechnological concern. In this work, we show that PsSDO, together with its dioxygenase activity, behaves as an amidohydrolase with a marked specificity for substrates containing a C-terminal phenylalanine residue, similar to OTA, although its presence is not an absolute requirement. This side chain would establish aromatic stacking interactions with the indole ring of Trp104. PsSDO hydrolysed the amide bond of OTA rendering the much less toxic ochratoxin α and L-ß-phenylalanine. The binding mode of OTA and of a diverse set of synthetic carboxypeptidase substrates these substrates have been characterized by molecular docking simulations, which has permitted us to propose a catalytic mechanism of hydrolysis by PsSDO that, similarly to metallocarboxypeptidases, assumes a water-induced pathway following a general acid/base mechanism in which the side chain of Glu82 would provide the solvent nucleophilicity required for the enzymatic reaction. Since the PsSDO chromosomal region, absent in other Pseudaminobacter strains, contained a set of genes present in conjugative plasmids, it could have been acquired by horizontal gene transfer, probably from a Celeribacter strain.


Assuntos
Dioxigenases , Micotoxinas , Salicilatos/química , Dioxigenases/genética , Simulação de Acoplamento Molecular , Fenilalanina
5.
Environ Toxicol ; 38(6): 1384-1394, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36891644

RESUMO

In the present study, we investigated the antitumor effect and associated molecular mechanisms of the copper (II) complex of salicylate phenanthroline [Cu(sal)(phen)] against hepatocellular carcinoma (HCC). Cu(sal)(phen) inhibited the proliferation of HCC cells (HepG2 and HCC-LM9) and induced apoptosis of HCC cells in a dose-dependent manner by upregulating mitochondrial reactive oxygen species (ROS) production. The expression of the antiapoptotic proteins survivin and Bcl-2 was decreased, while the expression of the DNA damage marker γ-H2 AX and the apoptotic marker cleaved PARP was upregulated with Cu(sal)(phen) treatment. In vivo, the growth of HepG2 subcutaneous xenograft tumors was greatly attenuated by Cu(sal)(phen) treatment. Immunohistochemistry staining showed that the expression of survivin, Bcl-2, and Ki67 in the tumor was downregulated by Cu(sal)(phen). Toxicity experiments with BALB/c mice revealed that Cu(sal)(phen) is a relatively safe drug. Our results indicate that Cu(sal)(phen) possesses great potential as a therapeutic drug for HCC.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Humanos , Carcinoma Hepatocelular/patologia , Survivina/farmacologia , Survivina/uso terapêutico , Cobre/toxicidade , Cobre/química , Fenantrolinas/farmacologia , Fenantrolinas/química , Fenantrolinas/uso terapêutico , Neoplasias Hepáticas/patologia , Salicilatos/farmacologia , Salicilatos/química , Salicilatos/uso terapêutico , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2 , Proliferação de Células , Linhagem Celular Tumoral , Antineoplásicos/uso terapêutico , Células Hep G2
6.
J Ethnopharmacol ; 301: 115828, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36240979

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal properties of Gaultheria have been used in traditional medicine to treat pain and inflammation. AIM OF THE STUDY: Hence, the purpose of this study was to evaluate the analgesic, antipyretic, and anti-inflammatory properties of Gaultheria trichophylla Royle extract and salicylate-rich fraction in vivo, in vitro, and in silico. MATERIALS AND METHODS: In vivo analgesic, antipyretic, and anti-inflammatory of extract and a salicylate-rich fraction (at doses of 100, 200, 300, and 150 mg/kg) were assessed using healthy albino mice employing acetic acid-induced writhing, tail immersion test, carrageenan-induced inflammation, and croton oil-induced edema. For in vitro testing of extracts COX and LOX enzyme inhibition assays were used. Molecular docking studies were conducted for in silico testing of the inhibitory activity of the dominant compound Gaultherin against COX and LOX. RESULTS: G-EXT 200 and 300 and G-SAL 150 mg/kg reduced pyrexia significantly (P < 0.05 and P < 0.01). G-EXT-200, 300, and G-SAL 150 reduce the writing to a significant level (p > 0.05, p < 0.01). G-EXT 200 and 300 and G-SAL 150 mg/kg doses the analgesic effect was significant (p > 0.05, p > 0.01) and was comparable to tramadol. G-EXT 100 200, 300 mg/kg showed 43.8%, 47.94% and 56% respectively. G-SAL 150 mg, rich in salicylates, showed maximum inhibition of 65.75% next to standard drug diclofenac with 76.7% inhibition. G-EXT 100 and 200 mg/kg dose showed significant (p < 0.05) reduction in ear edema. With 300 mg/kg dose the effect was more (61.89%, p < 0.01). The salicylate-rich fraction G-SAL and Celecoxib showed an almost similar effect (p < 0.01). Significance inhibition was shown in the COX-2 test (G-EXT 39.70 and G-SAL 77.20 IC50 µg/ml) and in the 5-LOX test (G-EXT 28.3 and G-SAL 39.70 IC50 µg/ml). The preliminary in silico results suggest that the investigated compound showed excellent inhibitory activity against COX and LOX enzymes as evident from the free binding energy. Molecular docking revealed that Gaultherin binds well in the COX and LOX enzyme catalytic region. CONCLUSION: The extract and salicylate-rich fraction obtained from G. trichophylla showed significant analgesic, anti-inflammatory, and antipyretic effects in vivo, in vitro, and in silico assays that support its use in traditional medicine.


Assuntos
Antipiréticos , Ericaceae , Gaultheria , Animais , Camundongos , Gaultheria/química , Antipiréticos/farmacologia , Simulação de Acoplamento Molecular , Anti-Inflamatórios/efeitos adversos , Analgésicos/efeitos adversos , Salicilatos/química , Salicilatos/farmacologia , Salicilatos/uso terapêutico , Febre/tratamento farmacológico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Carragenina , Inflamação/tratamento farmacológico
7.
Molecules ; 27(22)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36431878

RESUMO

Ginkgols are active constituents from Ginkgo biloba L. (GB) and have pharmacological activities, such as antibacterial and antioxidant activities. In our previous report, only five ginkgols were separated. However, ginkgol C17:1 had two isomers, for which their separation, identification, and bioactivities have not yet been investigated. Hence, this research reports the successful isolation of six ginkgol homologs with alkyl substituents-C17:1-Δ12, C15:1-Δ8, C13:0, C17:2, C17:1-Δ10, and C15:0-for the first time using HPLC. This was followed by the identification of their chemical structures using Fourier transform infrared (FTIR), ultraviolet (UV), gas chromatography and mass spectrometry (GC-MS), carbon-13 nuclear magnetic resonance (13C-NMR), and proton nuclear magnetic resonance (1H-NMR) analysis. The results showed that two ginkgol isomers, C17:1-Δ12 and C17:1-Δ10, were obtained simultaneously from the ginkgol C17:1 mixture and identified entirely for the first time. That aside, the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay showed that the six ginkgol homologs possessed significant antiproliferation effects against HGC and HepG2 cells. Furthermore, the ginkgols with unsaturated side chains (C17:2, C15:1-Δ8, C17:1-Δ12, and C17:1-Δ10) exhibited more potent inhibitory effects than ginkgols with saturated side chains (C13:0, C15:0). In addition, unsaturated ginkgol C15:1-Δ8 showed the most potent cytotoxicity on HepG2 and HGC cells, of which the half-maximal inhibition concentrations (IC50) were 18.84 ± 2.58 and 13.15 ± 2.91 µM, respectively. The IC50 for HepG2 and HGC cells for the three unsaturated ginkgols (C17:1-Δ10, C17:2 and C17:1-Δ12) were ~59.97, ~60.82, and ~68.97 µM for HepG2 and ~30.97, ~33.81, and ~34.55 µM for HGC cells, respectively. Comparing the ginkgols' structure-activity relations, the findings revealed that the position and number of the double bonds of the ginkgols with 17 side chain carbons in length had no significant difference in anticancer activity.


Assuntos
Ginkgo biloba , Salicilatos , Ginkgo biloba/química , Salicilatos/química , Cromatografia Gasosa-Espectrometria de Massas , Cromatografia Líquida de Alta Pressão , Fenômenos Químicos
8.
Int J Mol Sci ; 23(3)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35163434

RESUMO

Pigeon Pea (Cajanus cajan (L.) Millsp.) is a common food crop used in many parts of the world for nutritional purposes. One of its chemical constituents is cajanin stilbene acid (CSA), which exerts anticancer activity in vitro and in vivo. In an effort to identify molecular targets of CSA, we performed a kinome-wide approach based on the measurement of the enzymatic activities of 252 human kinases. The serine-threonine kinase WNK3 (also known as protein kinase lysine-deficient 3) was identified as the most promising target of CSA with the strongest enzymatic activity inhibition in vitro and the highest binding affinity in molecular docking in silico. The lowest binding affinity and the predicted binding constant pKi of CSA (-9.65 kcal/mol and 0.084 µM) were comparable or even better than those of the known WNK3 inhibitor PP-121 (-9.42 kcal/mol and 0.123 µM). The statistically significant association between WNK3 mRNA expression and cellular responsiveness to several clinically established anticancer drugs in a panel of 60 tumor cell lines and the prognostic value of WNK3 mRNA expression in sarcoma biopsies for the survival time of 230 patients can be taken as clues that CSA-based inhibition of WNK3 may improve treatment outcomes of cancer patients and that CSA may serve as a valuable supplement to the currently used combination therapy protocols in oncology.


Assuntos
Cajanus/química , Neoplasias/mortalidade , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Salicilatos/farmacologia , Estilbenos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Modelos Moleculares , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ligação Proteica , Conformação Proteica , Proteínas Quinases/análise , Proteínas Serina-Treonina Quinases/química , Salicilatos/química , Estilbenos/química , Análise de Sobrevida
9.
Photochem Photobiol Sci ; 21(6): 923-934, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35088368

RESUMO

Zn-salophen complexes are a promising class of fluorescent chemosensors for nucleotides and nucleic acids. We have investigated, by means of steady state UV-Vis, ultrafast transient absorption, fluorescence emission and time dependent density functional theory (TD-DFT) the behavior of the excited states of a salicylidene tetradentate Schiff base (Sal), its Zn(II) coordination compound (Zn-Sal) and the effect of the interaction between Zn-Sal and adenosine diphosphate (ADP). TD-DFT shows that the deactivation of the excited state of Sal occurs through torsional motion, due to its rotatable bonds and twistable angles. Complexation with Zn(II) causes rigidity so that the geometry changes in the excited states with respect to the ground state structure are minimal. By addition of ADP to a freshly prepared Zn-Sal ethanol solution, a longer relaxation constant, in comparison to Zn-Sal, was measured, indicative of the interaction between Zn-Sal and ADP. After a few days, the Zn-Sal-ADP solution displayed the same static and dynamic behavior of a solution containing only the Sal ligand, demonstrating that the coordination of the ADP anion to Zn(II)leads to the demetallation of the Sal ligand. Fluorescence measurements also revealed an enhanced fluorescence at 375 nm following the addition of ADP to the solution, caused by the presence of 2,3-diamino naphthalene that is formed by demetallation and partial decomposition of the Sal ligand. The efficient fluorescence of this species at 375 nm could be selectively detected and used as a probe for the detection of ADP in solution.


Assuntos
Salicilatos , Zinco , Difosfato de Adenosina , Ligantes , Salicilatos/química , Zinco/química
11.
ChemMedChem ; 17(3): e202100577, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-34783161

RESUMO

A series of new 5-aryl-2,2'-bipyridines and their (polyfluoro)salicylate complexes of Cu(II), Co(II) and Mn(II) were synthesized. Their antimicrobial activity was evaluated in vitro against six strains of Trichophytons, E. floccosum, M. canis, C. ablicans and Gram-negative bacteria N. gonorrhoeae. Among azo-ligands, Ph-bipy and Tol-bipy showed promising antifungal activity (minimum inhibitory concentration (MIC)<0.8-27 µM). Their antifungal action was found can be realized via binding Fe(III) ions. Tol-bipy suppressed growth of Gram-positive bacteria S. aureus, S. aureus MRSA and their monospecies biofilms (MIC 6-16 µM). Using molecular docking, the anti-staphylococcal action mechanism based on the inhibition of S. aureus DNA gyrase GyrB was proposed for the lead compounds. Among metal complexes, Cu(II) and Mn(II) complexes based on tetrafluorosalicylic acid and Tol-bipy or Ph-bipy had the high antifungal activity (MIC<0.24-32 µM). Mn(SalF4 -2H)2 (Tol-bipy)2 ] suppressed the growth of seven Candida strains at MIC 12-24 µM. [Cu(Sal-2H)(Ph-bipy)] and [Cu(SalF3 -2H)(Ph-bipy)2 ] showed the promising anti-gonorrhoeae activity (MIC 4.2-5.2 µM). (Cu(SalFn -2H)(Tol-bipy)2 ], [Cu(SalF4 -2H)(Ph-bipy)2 ] and [Cu(SalF3 -2H)(Ph-bipy)2 ]) were found active against the bacteria of S. aureus, S. aureus MRSA and their biofilms (MIC 2.4-41.4 µM). The most active compounds were tested for toxicity in vitro against human embryonic kidney (HEK-293) cells and in vivo experiments with CD-1 mice.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Complexos de Coordenação/farmacologia , Metais Pesados/farmacologia , Simulação de Acoplamento Molecular , Salicilatos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Células HEK293 , Humanos , Metais Pesados/química , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neisseria gonorrhoeae/efeitos dos fármacos , Salicilatos/química , Relação Estrutura-Atividade
12.
Molecules ; 26(21)2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34770993

RESUMO

Ginkgo biloba L. has been used in traditional Chinese medicine (TCM) for thousands of years. However, the anti-cancer properties of ginkgolic acids (GAS) isolated from G. biloba have not been investigated in human nasopharyngeal carcinoma cells. In this study, GAS exhibited an inhibitory effect on the ATPase activity of heat shock protein 90 (Hsp90) and anti-proliferative activities against four human cancer cell lines, with IC50 values ranging from 14.91 to 23.81 µg·mL-1. In vivo experiments confirmed that GAS inhibited tumor growth in CNE-2Z cell-xenografted nude mice with low hepatotoxicity. We further demonstrated that GAS suppressed migration and invasion and induced the apoptosis of CNE-2Z cells by inducing the degradation of Hsp90 client proteins (MMP-2, MMP-9, Her-2, c-Raf, Akt, and Bcl-2). Together, GAS are new Hsp90 inhibitors by binding to Hsp90 (hydrogen bond and hydrophobic interaction). Thus, GAS from G. biloba might represent promising Hsp90 inhibitors for the development of anti-nasopharyngeal carcinoma agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ginkgo biloba/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Salicilatos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Salicilatos/química , Salicilatos/isolamento & purificação , Células Tumorais Cultivadas
13.
Eur Rev Med Pharmacol Sci ; 25(19): 6025-6033, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34661262

RESUMO

OBJECTIVE: Spray formulations are currently under development in the field of topical photoprotection. Such forms are characterized by their high fluidity, a property that is obtained by the presence of alcohol in the formula. The purpose of this work was to study the influence of ethanol in sunscreens on the photoprotective efficacy as well as the photostability of UV filters. MATERIALS AND METHODS: The filters tested were octyl methoxycinnamate (OMC), PEG-25 PABA, octyl salicylate and butyl methoxydibenzoylmethane (BMDBM) at their maximum concentration authorized by European regulations and in the presence of increasing amounts of alcohol, up to 15% (w/w). RESULTS: The effect of the presence of alcohol on the efficacy of the filters and their photostability varies depending on the molecule considered. Alcohol has no effect on octyl salicylate, either on its efficacy or its photostability. However, filter stabilization is seen for BMDBM and PEG-25 PABA. CONCLUSIONS: Although these differences are significant, they are not great enough to justify large-scale use of ethanol in sunscreen products due to some of its properties, such as flammability.


Assuntos
Etanol/química , Fotólise , Protetores Solares/química , Ácido 4-Aminobenzoico/química , Cinamatos/química , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Polietilenoglicóis/química , Propiofenonas/química , Salicilatos/química
14.
Drug Des Devel Ther ; 15: 3593-3604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34429588

RESUMO

INTRODUCTION: Endoplasmic reticulum (ER) stress condition is characterized as the accumulation of misfolded or unfolded proteins in lumen of ER. This condition has been implicated in various diseases and pathologies including ß-cell apoptosis, Alzheimer's disease and atherosclerosis. We have reported that hydroxynaphthoic acids (HNA), naphthalene analogues of salicylic acid (SA), reduced ER stress. In this study, we explored structural modification to bi-aryl analogues of SA. METHODS: Palladium-catalyzed cross-coupling was applied to synthesize bi-aryl analogues of SA. Anti-ER stress activity was monitored by using our cell-based assay system where ER stress is induced by tunicamycin. To monitor ER stress markers, ER stress was induced physiologically relevant palmitate system. RESULTS: Many analogues decreased ER stress signal induced by tunicamycin. Compounds creating dihedral angle between Ar group and SA moiety generally increased the activity but gave some cytotoxicity to indicate the crucial role of flat conformation of aromatic region. The best compound (16e) showed up to almost 6-fold and 90-fold better activity than 3-HNA and tauro-ursodeoxycholic acid, positive controls, respectively. ER stress markers such as p-PERK and p-JNK were accordingly decreased in Western blotting upon treatment of 16e under palmitate-induced condition. CONCLUSION: Anti-ER stress activity and toxicity profile of bi-aryl analogues of SA could provide a novel platform for potential therapy for protein misfolding diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Salicilatos/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Células HEK293 , Células Hep G2 , Humanos , Deficiências na Proteostase/tratamento farmacológico , Deficiências na Proteostase/patologia , Salicilatos/síntese química , Salicilatos/química , Relação Estrutura-Atividade , Tunicamicina
15.
ACS Synth Biol ; 10(9): 2159-2166, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34415146

RESUMO

The microbial synthesis of cannabinoids and related molecules requires access to the intermediate olivetolic acid (OA). Whereas plant enzymes have been explored for E. coli and yeast biosynthesis, moderate yields and shunt product formation are major hurdles. Here, based on the chemical logic to form 2,4-dihydroxybenzoate-containing natural products, we discovered a set of fungal tandem polyketide synthases that can produce OA and the related octanoyl-primed derivative sphaerophorolcarboxylic acid in high titers using the model organism Aspergillus nidulans. This new set of enzymes will enable new synthetic biology strategies to access microbial cannabinoids.


Assuntos
Aspergillus nidulans/metabolismo , Vias Biossintéticas/genética , Salicilatos/metabolismo , Aspergillus nidulans/química , Aspergillus nidulans/genética , Canabinoides/química , Canabinoides/metabolismo , Engenharia Metabólica/métodos , Família Multigênica , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Salicilatos/química
16.
Eur J Med Chem ; 224: 113691, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34274830

RESUMO

The Staphylococcus aureus can switch to a transient genotype-invariant dormancy, known as a persister, to survive treatment with high doses of antibiotics. This transient persister is an important reason underlying its resistance. There is an urgent need to find new antibacterial agents capable of eradicating methicillin-resistant S. aureus (MRSA) persisters. In this study, 37 new derivatives of cajaninstilbene acid (CSA) were designed and synthesized, and their biological activity against MRSA persisters was evaluated. Most of the newly synthesized derivatives exhibit more potent antimicrobial properties against S. aureus and MRSA than CSA itself, and 23 of the 37 derivatives show a tendency to eradicate MRSA persisters. A representative compound (A6) was demonstrated to target bacterial cell membranes. It eradicated the adherent biofilm of MRSA in a concentration dependent manner, and showed a synergistic antibacterial effect with piperacilin. In a model mouse abscess caused by MRSA persisters, A6 effectively reduced the bacterial load in vivo. These results indicate that A6 is a potential candidate for treatment of MRSA persister infections.


Assuntos
Antibacterianos/síntese química , Biofilmes/efeitos dos fármacos , Salicilatos/química , Estilbenos/química , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Modelos Animais de Doenças , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Camundongos , Testes de Sensibilidade Microbiana , Células RAW 264.7 , Salicilatos/farmacologia , Salicilatos/uso terapêutico , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/patologia , Staphylococcus aureus/fisiologia , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Relação Estrutura-Atividade
17.
Sci Rep ; 11(1): 12038, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103581

RESUMO

We investigated the larvicidal potential of 10 plant essential oils (EOs) against the Asian tiger mosquito Aedes albopictus. Among the EOs, larvicidal activity against Ae. albopictus was strongest in those derived from massoia (Massoia aromatica) and nutmeg (Myristica fragrans). Larvicidal activities of massoia and nutmeg EOs against Ae. albopictus were 95.0% and 85.0% at 50 µg/mL, respectively. A total of 4 and 14 compounds were identified from massoia and nutmeg, respectively, and two massoia lactones, C10 and C12, were isolated from massoia EO. Among the identified compounds, benzyl salicylate, terpinolene, C12 massoia lactone, sabinene, benzyl benzoate, methyl eugenol, and C10 massoia lactone exhibited the strong larvicidal activity. Cellulose nanocrystal (CNC)-stabilized Pickering emulsions of massoia and nutmeg EOs were developed to overcome the insolubility of EOs in water. CNC/massoia and CNC/nutmeg emulsions were stable for at least 10 days, and larvicidal activities of CNC/massoia PE and CNC/nutmeg were higher than those of crude massoia and nutmeg EOs. This study presents a CNC-stabilized PE, a suitable formulation for EOs, as a potential larvicide against Ae. albopictus.


Assuntos
Aedes/efeitos dos fármacos , Aedes/metabolismo , Celulose/química , Inseticidas/química , Nanopartículas/química , Óleos Voláteis/química , Animais , Benzoatos/química , Cromatografia Gasosa , Monoterpenos Cicloexânicos/química , Emulsões , Eugenol/análogos & derivados , Eugenol/química , Lactonas/química , Larva , Myristica , Óleos de Plantas/química , Salicilatos/química , Solubilidade
18.
Acta Crystallogr C Struct Chem ; 77(Pt 6): 262-270, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089249

RESUMO

The X-ray structures of three new 1:1 pharmaceutical cocrystals of 11-azaartemisinin (11-Aza; systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.04,13.08,13]hexadecan-10-one, C15H23NO4) with bromo-substituted salicylic acids [namely, 5-bromo- (5-BrSalA, C7H5BrO3), 4-bromo- (4-BrSalA, C7H5BrO3) and 3,5-dibromosalicylic acid (3,5-Br2SalA, C7H4Br2O3)] are reported. All the structures are related to the parent 11-Aza:SalA cocrystal (monoclinic P21) reported previously. The 5-BrSalA analogue is isostructural with the parent, with lattice expansion along the c axis. The 4-BrSalA and 3,5-Br2SalA cocrystals retain the highly preserved 21 stacks of the molecular pairs, but these pack with a varying degree of slippage with respect to neighbouring stacks, altering the close contacts between them, and represent two potential alternative homostructural arrangements for the parent compound. Structure redeterminations of the bromosalicylic acids 5-BrSalA, 4-BrSalA and 3,5-Br2SalA at 100 K show that the packing efficiency of the cocrystals need not be higher than the parent coformers, based on specific-volume calculations, attributable to the strong O-H...O=C hydrogen bonds of 2.54 Šin the cocrystals.


Assuntos
Antimaláricos/química , Salicilatos/química , Antimaláricos/farmacologia , Cristalografia por Raios X , Ligação de Hidrogênio , Salicilatos/farmacologia , Solubilidade
19.
Biomed Mater ; 16(4)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34038883

RESUMO

Periodontitis is a chronic, multifactorial, inflammatory disease characterized by the progressive destruction of the periodontal tissues. Guided tissue regeneration (GTR), involving the use of barrier membranes, is one of the most successful clinical procedures for periodontal therapy. Nevertheless, rapid degradation of the membranes and membrane-related infections are considered two of the major reasons for GTR clinical failure. Recently, integration of non-antibiotic, antimicrobial materials to the membranes has emerged as a novel strategy to face the bacterial infection challenge, without increasing bacterial resistance. In this sense, bismuth subsalicylate (BSS) is a non-antibiotic, metal-based antimicrobial agent effective against different bacterial strains, that has been long safely used in medical treatments. Thus, the aim of the present work was to fabricate fibrillar, non-rapidly bioresorbable, antibacterial GTR membranes composed of polycaprolactone (PCL), gelatin (Gel), and BSS as the antibacterial agent. PCL-G-BSS membranes with three different BSS concentrations (2 wt./v%, 4 wt./v%, and 6 wt./v%) were developed by electrospinning and their morphology, composition, water wettability, mechanical properties, Bi release and degradation rate were characterized. The Cytotoxicity of the membranes was studiedin vitrousing human osteoblasts (hFOB) and gingival fibroblasts (HGF-1), and their antibacterial activity was tested againstAggregatibacter actinomycetemcomitans, Escherichia coli, Porphyromonas gingivalisandStaphylococcus aureus.The membranes obtained exhibited adequate mechanical properties for clinical application, and appropriate degradation rates for allowing periodontal defects regeneration. The hFOB and HGF-1 cells displayed adequate viability when in contact with the lixiviated products from the membranes, and, in general, displayed antibacterial activity against the four bacteria strains tested. Thus, the PCL-G-BSS membranes showed to be appropriate as potential barrier membranes for periodontal GTR treatments.


Assuntos
Antibacterianos , Bismuto , Gelatina/química , Membranas Artificiais , Compostos Organometálicos , Poliésteres/química , Salicilatos , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/toxicidade , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/toxicidade , Bismuto/química , Bismuto/farmacologia , Bismuto/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas Eletroquímicas , Fibroblastos/efeitos dos fármacos , Gengiva/citologia , Regeneração Tecidual Guiada Periodontal , Humanos , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Compostos Organometálicos/toxicidade , Salicilatos/química , Salicilatos/farmacologia , Salicilatos/toxicidade
20.
Molecules ; 26(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803102

RESUMO

In this short review, we attempt to unfold various aspects of excited-state intramolecular proton transfer (ESIPT) from the studies that are available up to date. Since Weller's discovery of ESIPT in salicylic acid (SA) and its derivative methyl salicylate (MS), numerous studies have emerged on the topic and it has become an attractive field of research because of its manifold applications. Here, we discuss some critical aspects of ESIPT and tautomerization from the mechanistic viewpoint. We address excitation wavelength dependence, anti-Kasha ESIPT, fast and slow ESIPT, reversibility and irreversibility of ESIPT, hydrogen bonding and geometrical factors, excited-state double proton transfer (ESDPT), concerted and stepwise ESDPT.


Assuntos
Hidrogênio/química , Íons/química , Prótons , Elétrons , Ligação de Hidrogênio , Modelos Moleculares , Teoria Quântica , Salicilatos/química , Ácido Salicílico/química , Termodinâmica
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