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1.
Phytochemistry ; 191: 112905, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34392008

RESUMO

(+)-(2S,3S)- and (-)-(2R,3R)-Oxybaphuslactam A glucosides are two undescribed benzofuran ε-caprolactams featuring a unique 7/6/5 fused tricyclic framework with p-glucosyl-O-phenyl unit. They were isolated from the root of Tibetan medicinal plant Oxybaphus himalaicus along with an undescribed sucrose ester, 3-O-feruloyl sucrose, an undescribed lignan glucoside, (7'R,8R,8'S)-3,3',5,5'-tetramethoxy-7',9-epoxylignan-9'-ol-7-one 4,4'-di-O-ß-D-glucopyranoside and ten known amides and phenylpropanoid derivatives. Based on the spectral analyses, X-ray crystallography and comparison of experimental and TD-DFT calculated ECD spectra, the structures of these compounds were determined. The anti-inflammatory assay showed the undescribed compounds had significant inhibitory effects on the formation of NO, TNF-α and IL-6, which were evaluated by LPS induced RAW 264.7 cell model.


Assuntos
Benzofuranos , Caprolactama , Lignanas , Amidas , Anti-Inflamatórios/farmacologia , Benzofuranos/farmacologia , Glucosídeos/farmacologia , Lignanas/farmacologia , Estrutura Molecular
2.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360821

RESUMO

Dexamethasone (Dexa), frequently used as an anti-inflammatory agent, paradoxically leads to muscle inflammation and muscle atrophy. Receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) lead to nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome formation through nuclear factor-κB (NF-κB) upregulation. NLRP3 inflammasome results in pyroptosis and is associated with the Murf-1 and atrogin-1 upregulation involved in protein degradation and muscle atrophy. The effects of Ecklonia cava extract (ECE) and dieckol (DK) on attenuating Dexa-induced muscle atrophy were evaluated by decreasing NLRP3 inflammasome formation in the muscles of Dexa-treated animals. The binding of AGE or high mobility group protein 1 to RAGE or TLR4 was increased by Dexa but significantly decreased by ECE or DK. The downstream signaling pathways of RAGE (c-Jun N-terminal kinase or p38) were increased by Dexa but decreased by ECE or DK. NF-κB, downstream of RAGE or TLR4, was increased by Dexa but decreased by ECE or DK. The NLRP3 inflammasome component (NLRP3 and apoptosis-associated speck-like), cleaved caspase -1, and cleaved gasdermin D, markers of pyroptosis, were increased by Dexa but decreased by ECE and DK. Interleukin-1ß/Murf-1/atrogin-1 expression was increased by Dexa but restored by ECE or DK. The mean muscle fiber cross-sectional area and grip strength were decreased by Dexa but restored by ECE or DK. In conclusion, ECE or DK attenuated Dexa-induced muscle atrophy by decreasing NLRP3 inflammasome formation and pyroptosis.


Assuntos
Benzofuranos/farmacologia , Dexametasona/efeitos adversos , Glucocorticoides/efeitos adversos , Inflamassomos/efeitos dos fármacos , Atrofia Muscular , Piroptose/efeitos dos fármacos , Animais , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Extratos Vegetais/farmacologia
3.
Biomolecules ; 11(7)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34356597

RESUMO

Usnic acid (UA) is a secondary metabolite of lichens that exhibits a wide range of biological activities. Previously, we found that UA derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1 (TDP1). It can remove covalent complex DNA-topoisomerase 1 (TOP1) stabilized by the TOP1 inhibitor topotecan, neutralizing the effect of the drugs. TDP1 removes damage at the 3' end of DNA caused by other anticancer agents. Thus, TDP1 is a promising therapeutic target for the development of drug combinations with topotecan, as well as other drugs for cancer treatment. Ten new UA enamino derivatives with variation in the terpene fragment and substituent of the UA backbone were synthesized and tested as TDP1 inhibitors. Four compounds, 11a-d, had IC50 values in the 0.23-0.40 µM range. Molecular modelling showed that 11a-d, with relatively short aliphatic chains, fit to the important binding domains. The intrinsic cytotoxicity of 11a-d was tested on two human cell lines. The compounds had low cytotoxicity with CC50 ≥ 60 µM for both cell lines. 11a and 11c had high inhibition efficacy and low cytotoxicity, and they enhanced topotecan's cytotoxicity in cancerous HeLa cells but reduced it in the non-cancerous HEK293A cells. This "protective" effect from topotecan on non-cancerous cells requires further investigation.


Assuntos
Benzofuranos/química , Monoterpenos/química , Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases/metabolismo , Benzofuranos/farmacologia , Células HEK293 , Humanos , Monoterpenos/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia
4.
Molecules ; 26(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34361605

RESUMO

A large number of secondary metabolites have been isolated from the filamentous fungus Stachybotrys chartarum and have been described before. Fourteen of these natural compounds were evaluated in vitro in the present study for their inhibitory activity towards the cancer target CK2. Among these compounds, stachybotrychromene C, stachybotrydial acetate and acetoxystachybotrydial acetate turned out to be potent inhibitors with IC50 values of 0.32 µM, 0.69 µM and 1.86 µM, respectively. The effects of these three compounds on cell proliferation, growth and viability of MCF7 cells, representing human breast adenocarcinoma as well as A427 (human lung carcinoma) and A431 (human epidermoid carcinoma) cells, were tested using EdU assay, IncuCyte® live-cell imaging and MTT assay. The most active compound in inhibiting MCF7 cell proliferation was acetoxystachybotrydial acetate with an EC50 value of 0.39 µM. In addition, acetoxystachybotrydial acetate turned out to inhibit the growth of all three cell lines completely at a concentration of 1 µM. In contrast, cell viability was impaired only moderately, to 37%, 14% and 23% in MCF7, A427 and A431 cells, respectively.


Assuntos
Benzofuranos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Compostos de Espiro/farmacologia , Stachybotrys/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
5.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361791

RESUMO

As a key enzyme regulating postprandial blood glucose, α-Glucosidase is considered to be an effective target for the treatment of diabetes mellitus. In this study, a simple, rapid, and effective method for enzyme inhibitors screening assay was established based on α-glucosidase catalyzes reactions in a personal glucose meter (PGM). α-glucosidase catalyzes the hydrolysis of maltose to produce glucose, which triggers the reduction of ferricyanide (K3[Fe(CN)6]) to ferrocyanide (K4[Fe(CN)6]) and generates the PGM detectable signals. When the α-glucosidase inhibitor (such as acarbose) is added, the yield of glucose and the readout of PGM decreased accordingly. This method can achieve the direct determination of α-glucosidase activity by the PGM as simple as the blood glucose tests. Under the optimal experimental conditions, the developed method was applied to evaluate the inhibitory activity of thirty-four small-molecule compounds and eighteen medicinal plants extracts on α-glucosidase. The results exhibit that lithospermic acid (52.5 ± 3.0%) and protocatechualdehyde (36.8 ± 2.8%) have higher inhibitory activity than that of positive control acarbose (31.5 ± 2.5%) at the same final concentration of 5.0 mM. Besides, the lemon extract has a good inhibitory effect on α-glucosidase with a percentage of inhibition of 43.3 ± 3.5%. Finally, the binding sites and modes of four active small-molecule compounds to α-glucosidase were investigated by molecular docking analysis. These results indicate that the PGM method is feasible to screening inhibitors from natural products with simple and rapid operations.


Assuntos
Benzaldeídos/farmacologia , Benzofuranos/farmacologia , Glicemia/análise , Catecóis/farmacologia , Depsídeos/farmacologia , Diabetes Mellitus Tipo 2/diagnóstico , Inibidores de Glicosídeo Hidrolases/farmacologia , Monitorização Ambulatorial/métodos , alfa-Glucosidases/sangue , Acarbose/química , Acarbose/farmacologia , Benzaldeídos/química , Benzaldeídos/isolamento & purificação , Benzofuranos/química , Benzofuranos/isolamento & purificação , Sítios de Ligação , Técnicas Biossensoriais/instrumentação , Catecóis/química , Catecóis/isolamento & purificação , Depsídeos/química , Depsídeos/isolamento & purificação , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/química , Humanos , Hidrólise , Cinética , Maltose/metabolismo , Simulação de Acoplamento Molecular , Monitorização Ambulatorial/instrumentação , Extratos Vegetais/química , Plantas Medicinais , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Termodinâmica , Dispositivos Eletrônicos Vestíveis , alfa-Glucosidases/química
6.
Molecules ; 26(16)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34443666

RESUMO

The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p < 0.05); when aromaticity increased, the antifungal activity decreased for series I and increased for series II. To verify the validity of the obtained equations, a new set of 44 benzofuran-4-ones was designed by replacing the nitrogen atom of the five-membered ring with oxygen in indol-4-ones. The NICS(0) and NICS(1) of benzofuran-4-ones were calculated and used to predict their biological activities using the previous equations. A set of 10 benzofuran-4-ones was synthesized and tested in eight human pathogenic fungi, showing the validity of the equations. The minimum inhibitory concentration (MIC) in yeasts was 31.25 µg·mL-1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 µg·mL-1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.


Assuntos
Antifúngicos/farmacologia , Benzofuranos/farmacologia , Fungos/efeitos dos fármacos , Antifúngicos/química , Aspergillus niger/efeitos dos fármacos , Aspergillus niger/patogenicidade , Benzofuranos/química , Candida/efeitos dos fármacos , Candida/patogenicidade , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pichia/efeitos dos fármacos , Pichia/patogenicidade , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/farmacologia
7.
Phytomedicine ; 91: 153655, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34388563

RESUMO

BACKGROUND: Potassium usnate (KU), a water-soluble form of usnic acid, shows anticancer activity. However, the underlying mechanisms have not been fully elucidated. PURPOSE: We aimed to identify the pathways involved in anticancer effects of KU in human gastric cancer (GC) and colorectal cancer (CRC) cells using RNA-sequencing (RNA-seq) based transcriptome analysis. STUDY DESIGN: We analyzed the cytotoxic effects of KU to identify the common molecular events in GC and CRC cells upon KU exposure using unbiased approaches. METHODS: Cell viability assays and western blot experiments were used to examine apoptotic changes, cell cycle arrest, and endoplasmic reticulum (ER) stress-induced cellular responses in KU-treated cells. Total RNA from KU-treated human GC and CRC cells was prepared for RNA-seq analysis. Gene ontology term and gene set enrichment analyses were used to identify the key mediators of the cytotoxic effects of KU. The expression of ER stress-induced apoptotic markers was evaluated using quantitative reverse-transcription PCR and western blot analysis. Chromatin immunoprecipitation assays for ATF3 and H3K27ac, and ATF3 knockdown were employed to verify the underlying molecular mechanisms. The inhibitory effect of KU on tumor growth in vivo was validated with metastatic tumor nodule formations in a mouse liver model. RESULTS: KU exerted cytotoxicity in human GC and CRC cells through the activation of the ER stress-induced apoptotic pathway. KU stimulated ATF3 expression, an important mediator of molecular events of apoptosis. ATF3 binds to the promoter region of ATF3, CHOP, GADD34, GADD45A, DR5, and PUMA genes and subsequently promoted apoptotic events. Knockdown of ATF3 significantly reduced the expression of ATF3 target genes and the cytotoxic effects of KU. The intraperitoneal injection of KU induced ATF3 and the apoptosis of implanted colon cancer cells, resulting in reduced metastatic tumor growth in the mouse livers. CONCLUSION: KU exerts cytotoxic effects in human GC and CRC cells by triggering ER stress-induced apoptosis via an ATF3 dependent pathway.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Benzofuranos/farmacologia , Neoplasias do Colo , Estresse do Retículo Endoplasmático , Neoplasias Gástricas , Fator 3 Ativador da Transcrição/genética , Animais , Apoptose , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Perfilação da Expressão Gênica , Humanos , Camundongos , Potássio , Neoplasias Gástricas/tratamento farmacológico
8.
Cell Mol Life Sci ; 78(17-18): 6337-6349, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34398253

RESUMO

Signaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1/2 and AKT phosphorylation). Analysis of normal naïve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of MYC mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of MYC mRNA in anti-IgM treated cells. This was mediated by MYC mRNA stabilization and was not observed for MCL1 mRNA. Following drug wash-out, MYC mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized MYC mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and/or MCL1.


Assuntos
Fator de Iniciação 4A em Eucariotos/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Anticorpos Anti-Idiotípicos/farmacologia , Benzofuranos/farmacologia , Células Cultivadas , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia
9.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299351

RESUMO

Despite a wide range of bactericides and antiseptics, the treatment of chronic or complicated wounds is still a major challenge for modern medicine. Topical medications are the most sought-after new agents for use as treatment. The therapeutic concentration of their active substances is easy to achieve with the lowest possible burden on the patient's body. This study assesses the effect of salvianolic acid B (Sal B) on the proliferation, migration, and production of collagen type III by fibroblasts, which are the most important processes in wound healing. The study was conducted on human gingival fibroblasts obtained from primary cell culture. The results showed that Sal B at a dose of 75 µg/mL increases the cell viability with significant stimulation of the cell migration as demonstrated in the wound healing assay, as well as an increase in the expression of collagen type III, which has great importance in the initial stages of wound scarring. The results obtained in the conducted studies and previous scientific reports on the antibacterial properties and low toxicity of Sal B indicate its high potential in wound healing.


Assuntos
Benzofuranos/farmacologia , Cicatrização/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Gengiva/efeitos dos fármacos , Humanos , Modelos Teóricos
10.
J Enzyme Inhib Med Chem ; 36(1): 1488-1499, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34227457

RESUMO

New cyanobenzofurans derivatives 2-12 were synthesised, and their antiproliferative activity was examined compared to doxorubicin and Afatinib (IC50 = 4.17-8.87 and 5.5-11.2 µM, respectively). Compounds 2 and 8 exhibited broad-spectrum activity against HePG2 (IC50 = 16.08-23.67 µM), HCT-116 (IC50 = 8.81-13.85 µM), and MCF-7 (IC50 = 8.36-17.28 µM) cell lines. Compounds 2, 3, 8, 10, and 11 were tested as EGFR-TK inhibitors to demonstrate their possible anti-tumour mechanism compared to gefitinib (IC50 = 0.90 µM). Compounds 2, 3, 10, and 11 displayed significant EGFR TK inhibitory activity with IC50 of 0.81-1.12 µM. Compounds 3 and 11 induced apoptosis at the Pre-G phase and cell cycle arrest at the G2/M phase. They also increased the level of caspase-3 by 5.7- and 7.3-fold, respectively. The molecular docking analysis of compounds 2, 3, 10, and 11 indicated that they could bind to the active site of EGFR TK.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Desenho de Fármacos , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/síntese química , Benzofuranos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
11.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199160

RESUMO

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Benzofuranos/uso terapêutico , Desenvolvimento de Medicamentos , Ativadores de Enzimas/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Colo/efeitos dos fármacos , Colo/patologia , Dinitrofluorbenzeno/análogos & derivados , Eletroforese em Gel Bidimensional , Ontologia Genética , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
12.
Acta Trop ; 222: 106067, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34303689

RESUMO

Schistosomiasis is a public health problem in many developing countries. The mollusc Biomphalaria glabrata is the most important vector of Schistosoma mansoni in South America. The population control of this vector to prevent the spread of schistosomiasis is currently done with the application of highly toxic molluscicide to the environment. The screening of substances in sublethal concentrations that have deleterious effects on physiological parameters is very relevant for the control of schistosomiasis, since the effectiveness of disease prevention increases if it acts on population control of the vector and on reproduction and elimination in S. mansoni cercariae. The objective of this study was to evaluate the reproductive parameters (fecundity and fertility), intra-mollusk effect (sporocysts I (72 h) and II (14 days after)) on the development of cercariae of S. mansoni and the immune cell profile of B. glabrata exposed to sublethal concentrations (LC25 - 0.5 µg/mL and LC50 - 0.92 µg/mL) of the usnic acid potassium salt (potassium usnate). LC 25 and LC 50 significantly reduced (p < 0.05) the fecundity of B. glabrata when treated infected and/or not exposed to infection, while unviable embryos were not observed in sporocyst stage I, being only significant (p < 0.05) for mollusks infected and treated with LC50 on sporocyst II. LC25 and LC50 of the potassium usnate caused significant reductions (p < 0.05) in the production and cercarial shedding when evaluated on sporocysts I and II. In addition, the mortality of infected and treated B. glabrata in the sporocyst II phase was quite marked after the 9th week of infection. Regarding the immunological cell profile of uninfected B. glabrata, both concentrations led to immunomodulatory responses, with significant morphological changes predominant of hemocytes that entered programmed cell death (apoptosis). It was concluded that the application of LC25 and LC50 from the potassium usnate could be useful in the population control of B. glabrata, since it interferes both in their biology and physiology and in the reproduction of the infectious agent of schistosomiasis mansoni.


Assuntos
Benzofuranos/farmacologia , Biomphalaria , Animais , Biomphalaria/efeitos dos fármacos , Biomphalaria/parasitologia , Potássio , Schistosoma mansoni
13.
Biomed Pharmacother ; 139: 111687, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243611

RESUMO

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.


Assuntos
Benzofuranos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/fisiologia , Obesidade/metabolismo , Substâncias Protetoras/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Células Cultivadas , Fígado Gorduroso/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Termogênese/efeitos dos fármacos
14.
Chem Biol Interact ; 345: 109490, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34144024

RESUMO

The uncontrol respiratory burst in neutrophils can lead to inflammation and tissue damage. This study investigates the effect and the underlying mechanism of ε-viniferin, a lignan from the root of Vitis thunbergii var. thunbergii, inhibits N-formyl-L-methionyl-L-leucyl-l-phenylalanine (fMLP) induced respiratory burst by antagonizing formyl peptide receptor 1 in human neutrophils. Briefly, ε-viniferin specifically inhibited fMLP (0.1 µM: formyl peptide receptor 1 agonist or 1 µM: formyl peptide receptor 1, 2 agonist)-induced superoxide anion production in a concentration-dependent manner (IC50 = 2.30 ± 0.96 or 9.80 ± 0.21 µM, respectively) without affecting this induced by formyl peptide receptor 2 agonist (WKYMVM). ε-viniferin inhibited fMLP (0.1 µM)-induced phosphorylation of ERK, Akt, Src or intracellular calcium mobilization without affecting these caused by WKYMVM. The synergistic suppression of fMLP (1 µM)-induced superoxide anion production was observed only in the combination of ε-viniferin and formyl peptide receptor 2 antagonist (WRW4) but not in combination of ε-viniferin and formyl peptide receptor 1 antagonist (cyclosporine H). ε-viniferin inhibited FITC-fMLP binding to formyl peptide receptors. Moreover, the synergistic suppression of FITC-fMLP binding was observation only in the combination of ε-viniferin and WRW4 but not in other combinations. ATPγS induced superoxide anion production through formyl peptide receptor 1 in fMLP desensitized neutrophils and this effect was inhibited by ε-viniferin. The concentration-response curve of fMLP-induced superoxide anion was not parallel shifted by ε-viniferin. Furthermore, the inhibiting effect of ε-viniferin on fMLP-induced superoxide anion production was reversible. These results suggest that ε-viniferin is an antagonist of formyl peptide receptor 1 in a reversible and non-competitive manner.


Assuntos
Anti-Inflamatórios/farmacologia , Benzofuranos/farmacologia , Terapia de Alvo Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptores de Formil Peptídeo/antagonistas & inibidores , Estilbenos/farmacologia , Sequência de Aminoácidos , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Superóxidos/metabolismo
15.
Chem Biol Interact ; 345: 109552, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34147487

RESUMO

Ethofumesate is a chiral herbicide that may display enantioselective behavior in humans. For this reason, the enantioselective potential of ethofumesate and its main metabolite ethofumesate-2-hydroxy to cause pesticide-drug interactions on cytochrome P450 forms (CYPs) has been evaluated by using human liver microsomes. Among the evaluated CYPs, CYP2C19 had its activity decreased by the ethofumesate racemic mixture (rac-ETO), (+)-ethofumesate ((+)-ETO), and (-)-ethofumesate ((-)-ETO). CYP2C19 inhibition was not time-dependent, but a strong inhibition potential was observed for rac-ETO (IC50 = 5 ± 1 µmol L-1), (+)-ETO (IC50 = 1.6 ± 0.4 µmol L-1), and (-)-ETO (IC50 = 1.8 ± 0.4 µmol L-1). The reversible inhibition mechanism was competitive, and the inhibition constant (Ki) values for rac-ETO (2.6 ± 0.4 µmol L-1), (+)-ETO (1.5 ± 0.2 µmol L-1), and (-)-ETO (0.7 ± 0.1 µmol L-1) were comparable to the Ki values of strong CYP2C19 inhibitors. Inhibition of CYP2C19 by ethofumesate was enantioselective, being almost twice higher for (-)-ETO than for (+)-ETO, which indicates that this enantiomer may be a more potent inhibitor of this CYP form. For an in vitro-in vivo correlation, the Food and Drug Administration's (FDA) guideline on the assessment of drug-drug interactions used in the early stages of drug development was used. The FDA's R1 values were estimated on the basis of the obtained ethofumesate Ki and distribution volume, metabolism, unbound plasma fraction, gastrointestinal and dermal absorption data available in the literature. The correlation revealed that ethofumesate probably inhibits CYP2C19 in vivo for both chronic (oral) and occupational (dermal) exposure scenarios.


Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Inibidores do Citocromo P-450 CYP2C19/química , Inibidores do Citocromo P-450 CYP2C19/farmacologia , Citocromo P-450 CYP2C19/metabolismo , Mesilatos/química , Mesilatos/farmacologia , Praguicidas/química , Praguicidas/farmacologia , Citocromo P-450 CYP2C19/química , Inibidores do Citocromo P-450 CYP2C19/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Estereoisomerismo
16.
Toxicology ; 458: 152831, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34097992

RESUMO

Aryl hydrocarbon receptor (AHR) activation via 2,3,7,8-tetrachlorodibenzofuran (TCDF) induces the accumulation of hepatic lipids. Here we report that AHR activation by TCDF (24  µg/kg body weight given orally for five days) induced significant elevation of hepatic lipids including ceramides in mice, was associated with increased expression of key ceramide biosynthetic genes, and increased activity of their respective enzymes. Results from chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA) and cell-based reporter luciferase assays indicated that AHR directly activated the serine palmitoyltransferase long chain base subunit 2 (Sptlc2, encodes serine palmitoyltransferase 2 (SPT2)) gene whose product catalyzes the initial rate-limiting step in de novo sphingolipid biosynthesis. Hepatic ceramide accumulation was further confirmed by mass spectrometry-based lipidomics. Taken together, our results revealed that AHR activation results in the up-regulation of Sptlc2, leading to ceramide accumulation, thus promoting lipogenesis, which can induce hepatic lipid accumulation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Ceramidas/biossíntese , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Ativação Metabólica/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Benzofuranos/farmacologia , Ceramidas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipidômica , Fígado/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Hidrocarboneto Arílico/genética , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Triglicerídeos/metabolismo
17.
Eur J Med Chem ; 222: 113541, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34116326

RESUMO

A series of benzofuran piperidine derivatives were designed, synthesized and evaluated as multifunctional Aß antiaggregant to treat Alzheimer's disease (AD). In vitro results revealed that all of them are very good Aß antiaggregants and some of the compounds are potent acetylcholinesterase (AChE) inhibitors with moderate antioxidant property. Selected compounds were also tested for neuroprotection activity, LDH release, ATP production and inhibitory activity to prevent Aß peptides binding to the cell membrane. The different modifications introduced in the structure of our lead compound 3 (hAChE IC50 = 61 µM and self induced Aß 25-35 aggregation 45.45%), to increase its activity toward AD related targets. The most interesting multifunctional Aß antiaggregants were compounds 3a, 3h and 3i, highlighting 3h as potent Aß antiaggregant and good antiacetylholinesterase inhibitor (self induced Aß 25-35 aggregation 57.71% and hAChE IC50 = 21 µM), with good neuroprotective and antioxidant activity. In addition, these three most promising compounds prevent intracellular reactive oxygen species (ROS) formation and cell apoptosis induced by Aß25-35 peptides in SH-SY5Y cells. Molecular docking studies were also accomplished to understand the binding interaction of these compounds on Aß monomer, Aß fibril and AChE. Based on all data, compounds 3a, 3h and 3i were concluded as potent multifunctional Aß antiaggregant, useful candidate for the treatment of AD.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Benzofuranos/síntese química , Benzofuranos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piperidinas/síntese química , Piperidinas/química , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismo , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 222: 113540, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34118720

RESUMO

Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I2-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile. Moreover, LSL60101 induced hypothermia in mice while decreased pro-apoptotic FADD protein in the hippocampus. In vivo studies in the familial Alzheimer's disease 5xFAD murine model with the representative compound, revealed significant decreases in the protein expression levels of antioxidant enzymes superoxide dismutase and glutathione peroxidase in hippocampus. Overall, LSL60101 plays a neuroprotective role by reducing apoptosis and modulating oxidative stress.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacologia , Imidazóis/farmacologia , Receptores de Imidazolinas/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzofuranos/síntese química , Benzofuranos/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Receptores de Imidazolinas/metabolismo , Ligantes , Masculino , Camundongos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade
19.
Psychopharmacology (Berl) ; 238(8): 2133-2146, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34173034

RESUMO

RATIONALE: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. G protein-coupled receptor 40 (GPR40) is expressed in brain in addition to periphery and is associated with cognitive function such as space orientation, memory, and learning. However, the effects and mechanisms of GPR40 agonist in improving the AD progression remain largely unknown. OBJECTIVES: The present study aimed to investigate the therapeutic effects and mechanisms of a potent and selective GPR40 agonist TAK-875 on the APPswe/PS1dE9 mice. RESULTS: The results showed that intracerebroventricular administration of TAK-875 significantly rescued cognitive deficits in APPswe/PS1dE9 mice, and these effects may be mediated by the regulation of phospholipase C/protein kinase C signaling pathway, which enhanced α-secretase ADAM10 activity, promoted amyloid precursor protein non-amyloidogenic processing pathway, and reduced ß-amyloid production. CONCLUSIONS: These results suggest that GPR40 may be a potential therapeutic target for AD, and GPR40 agonists may become promising AD drugs in the future.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Benzofuranos/uso terapêutico , Encéfalo/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Receptores Acoplados a Proteínas G/agonistas , Sulfonas/uso terapêutico , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Benzofuranos/farmacologia , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Humanos , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/genética , Receptores Acoplados a Proteínas G/metabolismo , Sulfonas/farmacologia
20.
Exp Parasitol ; 226-227: 108125, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34129877

RESUMO

Chagas disease, caused by Trypanosoma cruzi, is a major public health problem and is described as one of the most neglected diseases worldwide. It affects about 6-7 million people. Currently, only two drugs are available for the treatment of this disease: nifurtimox and benznidazole. However, both drugs are highly toxic and have several side effects, which lead many patients to discontinue treatment. Moreover, these compounds show a significant curative efficacy only in the acute phase of the disease. Therefore, searching for new drugs is necessary. The objective of this study was to evaluate the in vitro and in vivo activity of a benzofuroxan derivative (EA2) against T. cruzi, and to evaluate the hematological and biochemical changes induced by its treatment in animals infected with T. cruzi. The results were then compared with those of healthy controls. In vitro testing was first performed with T. cruzi epimastigote forms. In this experiment, EA2 was diluted at three different concentrations (0.25, 0.50, and 1%). In vitro evaluation of the trypanocidal activity was performed 24, 48, and 72 h after incubation. In vivo assays were performed using three different doses (10, 5, and 2,5 mg/kg). Mice were divided into 10 groups (five animals/group), wherein four groups comprised non-infected animals (A, G, H, I) and six groups comprised infected animals (B, C, D E, F, J). Groups B and J represented the negative and positive controls, respectively. Groups G, H, and I were used to confirm that EA2 was not toxic to non-infected animals. Parasitemia was measured in infected animals and the hematological and biochemical profiles (urea, creatinine, albumin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) were evaluated in all animals. EA2 demonstrated in vitro trypanocidal activity at all concentrations tested. Although it did not demonstrate a curative effect in vivo, EA2 was able to retard the onset of parasitemia, and significantly reduced the parasite count in groups D and E (treated with 5 and 2.5 mg/kg, respectively). EA2 did not induce changes in hematological and biochemical parameters in non-infected animals, demonstrating that it is not toxic. However, further assessments should aim to confirm the safety of EA2 since this was the first in vitro and in vivo study conducted with this molecule.


Assuntos
Benzofuranos/uso terapêutico , Doença de Chagas/tratamento farmacológico , Parasitemia/tratamento farmacológico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Animais , Benzofuranos/farmacologia , Análise Química do Sangue , Doença de Chagas/sangue , Contagem de Eritrócitos , Feminino , Hemoglobinas/análise , Camundongos , Parasitemia/sangue , Contagem de Plaquetas , Distribuição Aleatória , Tripanossomicidas/farmacologia , Trypanosoma cruzi/crescimento & desenvolvimento
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