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1.
Front Immunol ; 12: 585595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093515

RESUMO

Introduction: Asthma is a chronic and recurring airway disease, which related to mast cell activation. Many compounds derived from Chinese herbal medicine has promising effects on stabilizing mast cells and decreasing inflammatory mediator production. Safranal, one of the active compounds from Crocus sativus, shows many anti-inflammatory properties. In this study, we evaluated the effect of safranal in ovalbumin (OVA)-induced asthma model. Furthermore, we investigate the effectiveness of safranal on stabilizing mast cell and inhibiting the production of inflammatory mediators in passive systemic anaphylaxis (PSA) model. Methods: OVA-induced asthma and PSA model were used to evaluate the effect of safranal in vivo. Lung tissues were collected for H&E, TB, IHC, and PAS staining. ELISA were used to determine level of IgE and chemokines (IL-4, IL-5, TNF-α, and IFN-γ). RNA sequencing was used to uncovers genes that safranal regulate. Bone marrow-derived mast cells (BMMCs) were used to investigate the inhibitory effect and mechanism of safranal. Cytokine production (IL-6, TNF-α, and LTC4) and NF-κB and MAPKs signaling pathway were assessed. Results: Safranal reduced the level of serum IgE, the number of mast cells in lung tissue were decreased and Th1/Th2 cytokine levels were normalized in OVA-induced asthma model. Furthermore, safranal inhibited BMMCs degranulation and inhibited the production of LTC4, IL-6, and TNF-α. Safranal inhibits NF-κB and MAPKs pathway protein phosphorylation and decreases NF-κB p65, AP-1 nuclear translocation. In the PSA model, safranal reduced the levels of histamine and LTC4 in serum. Conclusions: Safranal alleviates OVA-induced asthma, inhibits mast cell activation and PSA reaction. The possible mechanism occurs through the inhibition of the MAPKs and NF-κB pathways.


Assuntos
Alérgenos/imunologia , Asma/etiologia , Cicloexenos/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Ovalbumina/efeitos adversos , Terpenos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Asma/metabolismo , Asma/patologia , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Cicloexenos/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Imunoglobulina E/imunologia , Mediadores da Inflamação/metabolismo , Mastócitos/metabolismo , Camundongos , NF-kappa B/metabolismo , Ovalbumina/imunologia , Transdução de Sinais/efeitos dos fármacos , Terpenos/administração & dosagem
2.
Sci Rep ; 11(1): 13413, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183716

RESUMO

Glycoside hydrolases (GH) are a large family of hydrolytic enzymes found in all domains of life. As such, they control a plethora of normal and pathogenic biological functions. Thus, understanding selective inhibition of GH enzymes at the atomic level can lead to the identification of new classes of therapeutics. In these studies, we identified a 4-⍺-glucoside of valienamine (8) as an inhibitor of Streptomyces coelicolor (Sco) GlgE1-V279S which belongs to the GH13 Carbohydrate Active EnZyme family. The results obtained from the dose-response experiments show that 8 at a concentration of 1000 µM reduced the enzyme activity of Sco GlgE1-V279S by 65%. The synthetic route to 8 and a closely related 4-⍺-glucoside of validamine (7) was achieved starting from readily available D-maltose. A key step in the synthesis was a chelation-controlled addition of vinylmagnesium bromide to a maltose-derived enone intermediate. X-ray structures of both 7 and 8 in complex with Sco GlgE1-V279S were solved to resolutions of 1.75 and 1.83 Å, respectively. Structural analysis revealed the valienamine derivative 8 binds the enzyme in an E2 conformation for the cyclohexene fragment. Also, the cyclohexene fragment shows a new hydrogen-bonding contact from the pseudo-diaxial C(3)-OH to the catalytic nucleophile Asp 394 at the enzyme active site. Asp 394, in fact, forms a bidentate interaction with both the C(3)-OH and C(7)-OH of the inhibitor. In contrast, compound 7 disrupts the catalytic sidechain interaction network of Sco GlgE1-V279S via steric interactions resulting in a conformation change in Asp 394. These findings will have implications for the design other aminocarbasugar-based GH13-inhibitors and will be useful for identifying more potent and selective inhibitors.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Cicloexenos/síntese química , Glucosídeos/síntese química , Inibidores de Glicosídeo Hidrolases/síntese química , Glicosídeo Hidrolases/química , Hexosaminas/síntese química , Streptomyces coelicolor/enzimologia , Substituição de Aminoácidos , Aminoácidos/química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Configuração de Carboidratos , Domínio Catalítico , Cristalografia por Raios X , Cicloexenos/farmacologia , Glucosídeos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/genética , Hexosaminas/farmacologia , Maltose/química , Modelos Moleculares , Mutação de Sentido Incorreto , Ressonância Magnética Nuclear Biomolecular , Mutação Puntual , Estereoisomerismo , Streptomyces coelicolor/genética
3.
Toxicol Appl Pharmacol ; 423: 115582, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34019860

RESUMO

NLRP3 inflammasome is involved in several chronic inflammatory diseases. The inflammatory effect of the NLRP3 inflammasome is executed through IL-1ß and IL-18. Therefore, IL-1ß is one of the primary targets in chronic inflammatory conditions. However, current treatment regimens are dependent on anti- IL-1ß biologicals. The therapies targeting IL-1ß through inhibition of NLRP3 inflammasome are thus being actively explored. We identified safranal, a small molecule responsible for the essence of saffron as a potential inhibitor of the NLRP3 inflammasome. Safranal significantly suppressed the release of IL-1ß from ATP stimulated J774A.1 and bone marrow-derived macrophages (BMDMs) by regulating CASP1 and CASP8 dependent cleavage of pro-IL-1ß. Safranal markedly suppressed the expression of NLRP3 and its ATPase activity. Safranal treatment enhanced the expression of NRF2, whereas, si-RNA mediated silencing of Nrf2 abrogated the anti-NLRP3 effect of safranal. Furthermore, safranal inhibited ASC oligomerization and formation of ASC specks. Safranal also displayed anti-NLRP3 activity in multiple mice models. Treatment of animals with safranal reduced the production of IL-1ß in ATP elicited peritoneal inflammation, MSU induced air pouch inflammation, and MSU injected foot paw edema in mice. Thus, our data projects safranal as a potential preclinical drug candidate against NLRP3 inflammasome triggered chronic inflammation.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/antagonistas & inibidores , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Cicloexenos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Terpenos/farmacologia , Animais , Linhagem Celular , Células Cultivadas , Cicloexenos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Terpenos/uso terapêutico
4.
J Org Chem ; 86(16): 11177-11188, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34043349

RESUMO

A secondary metabolites investigation on Biscogniauxia sp. 71-10-1-1 was carried out, which led to the obtention of nine new diisoprenyl-cyclohexene/ane-type meroterpenoids (1-9) and two new isoprenylbenzoic acid-type meroterpeniods (10-11). The structures of these isolates were established on the basis of multispectroscopic analyses, ECD, and 13C chemical shifts calculations, and single-crystal X-ray diffraction. Among them, biscognin A (1) is the first diisoprenyl-cyclohexene-type meroterpenoid with a unique 2-isopropyl-6'-methyloctahydro-1'H-spiro[cyclopropane-1,2'-naphthalene] skeleton. Biscognienyne F (5) is the first diisoprenyl-cyclohexene-type meroterpenoid with a cyclic carbonate. The anti-inflammatory assays of the majority of compounds were evaluated, which exhibited that compounds 3 and 5 can obviously inhibit pro-inflammatory cytokines TNF-α and IL-6 productions. This is the first report for diisoprenyl-cyclohexene-type meroterpenoids with anti-inflammatory activity. Moreover, the possible biogenetic pathways of the majority of compounds (1-5) are proposed.


Assuntos
Cicloexenos , Terpenos , Anti-Inflamatórios/farmacologia , Vias Biossintéticas , Cristalografia por Raios X , Cicloexenos/farmacologia , Terpenos/farmacologia
5.
Eur J Pharmacol ; 902: 174091, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33865830

RESUMO

The synthesis of a novel cyclohexanone derivative (CHD; Ethyl 6-(4-metohxyphenyl)-2-oxo-4-phenylcyclohexe-3-enecarboxylate) was described and the subsequent aim was to perform an in vitro, in vivo and in silico pharmacological evaluation as a putative anti-nociceptive and anti-inflammatory agent in mice. Initial in vitro studies revealed that CHD inhibited both cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes and it also reduced mRNA expression of COX-2 and the pro-inflammatory cytokines TNF-α and IL-1ß. It was then shown that CHD dose dependently inhibited chemically induced tonic nociception in the abdominal constriction assay and also phasic thermal nociception (i.e. anti-nociception) in the hot plate and tail immersion tests in comparison with aspirin and tramadol respectively. The thermal test outcomes indicated a possible moderate centrally mediated anti-nociception which, in the case of the hot plate test, was pentylenetetrazole (PTZ) and naloxone reversible, implicating GABAergic and opioidergic mechanisms. CHD was also effective against both the neurogenic and inflammatory mediator phases induced in the formalin test and it also disclosed anti-inflammatory activity against the phlogistic agents, carrageenan, serotonin, histamine and xylene compared with standard drugs in edema volume tests. In silico studies indicated that CHD possessed preferential affinity for GABAA, opioid and COX-2 target sites and this was supported by molecular dynamic simulations where computation of free energy of binding also favored the formation of stable complexes with these sites. These findings suggest that CHD has prospective anti-nociceptive and anti-inflammatory properties, probably mediated through GABAergic and opioidergic interactions supplemented by COX-2 and 5-LOX enzyme inhibition in addition to reducing pro-inflammatory cytokine expression. CHD may therefore possess potentially beneficial therapeutic effectiveness in the management of inflammation and pain.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Cicloexanonas/farmacologia , Cicloexenos/farmacologia , Inflamação/tratamento farmacológico , Dor Nociceptiva/tratamento farmacológico , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Araquidonato 5-Lipoxigenase/metabolismo , Comportamento Animal/efeitos dos fármacos , Simulação por Computador , Cicloexanonas/química , Cicloexanonas/uso terapêutico , Cicloexanonas/toxicidade , Cicloexenos/química , Cicloexenos/uso terapêutico , Cicloexenos/toxicidade , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/toxicidade , Citocinas/genética , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Inflamação/induzido quimicamente , Inibidores de Lipoxigenase/farmacologia , Inibidores de Lipoxigenase/uso terapêutico , Inibidores de Lipoxigenase/toxicidade , Masculino , Camundongos Endogâmicos BALB C , Dor Nociceptiva/induzido quimicamente , Receptores de GABA/química , Receptores de GABA/efeitos dos fármacos , Receptores Opioides/química , Receptores Opioides/efeitos dos fármacos
6.
Fitoterapia ; 149: 104823, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33387642

RESUMO

Four new cyclohexene derivatives cladoscyclitols A-D (1-4) and one new ribofuranose phenol derivative 4-O-α-D-ribofuranose-2-pentyl-3-phemethylol (5) were obtained from the EtOAC extract of the mangrove-derived endophytic fungus Cladosporium sp. JJM22. The structures were elucidated by extensive NMR and MS analysis, while the absolute configurations of the stereogenic carbons were established based on quantum-chemical electronic circular dichroism calculations or comparison of the optical rotations with those of related compounds. Compounds 2 and 5 displayed potent inhibitory activity against α-glucosidase with the IC50 values of 2.95 and 2.05 µM, respectively.


Assuntos
Cladosporium/química , Cicloexenos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Rhizophoraceae/microbiologia , China , Cicloexenos/isolamento & purificação , Endófitos/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura Molecular
7.
Biochem Biophys Res Commun ; 543: 8-14, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33493986

RESUMO

Paulomycins (PAUs) refer to a group of glycosylated antibiotics with attractive antibacterial activities against Gram-positive bacteria. They contain a special ring A moiety that is prone to dehydrate between C-4 and C-5 to a quinone-type form at acidic condition, which will reduce the antibacterial activities of PAUs significantly. Elucidation of the biosynthetic mechanism of the ring A moiety may facilitate its structure modifications by combinatorial biosynthesis to generate PAU analogues with enhanced bioactivity or stability. Previous studies showed that the ring A moiety is derived from chorismate, which is converted to 3-hydroxyanthranilic acid (3-HAA) by a 2-amino-2-deoxyisochorismate (ADIC) synthase, a 2,3-dihydro-3-hydroxyanthranilic acid (DHHA) synthase, and a DHHA dehydrogenase. Unfortunately, little is known about the conversion process from 3-HAA to the highly decorated ring A moiety of PAUs. In this work, we characterized Pau17 as an unprecedented 3-HAA 6-hydroxylase responsible for the conversion of 3-HAA to 3,6-DHAA by in vivo and in vitro studies, pushing one step forward toward elucidating the biosynthetic mechanism of the ring A moiety of PAUs.


Assuntos
Ácido 3-Hidroxiantranílico/metabolismo , Antibacterianos/biossíntese , Cicloexenos/metabolismo , Dissacarídeos/biossíntese , Oxigenases de Função Mista/metabolismo , Streptomyces/enzimologia , Ácido 3-Hidroxiantranílico/química , Antibacterianos/química , Antibacterianos/farmacologia , Cicloexenos/química , Cicloexenos/farmacologia , Dissacarídeos/química , Dissacarídeos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Oxigenases de Função Mista/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Streptomyces/química , Streptomyces/genética
8.
Naunyn Schmiedebergs Arch Pharmacol ; 394(4): 707-716, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33128592

RESUMO

Safranal, isolated from saffron (Crocus sativus L.), is known to possesses neuroprotective effects. In this study, the neuroprotective potential of safranal against PC12 cell injury triggered by ischemia/reperfusion was investigated. PC12 cells were pretreated with safranal at concentration ranges of 10-160 µM for 2 h and then deprived from oxygen-glucose-serum for 6 h, followed by reoxygenation for 24 h (OGD condition). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 2,7-dichlorofluorescin diacetate (DCF-DA), and comet assays were used to measure the extent of cellular viability, reactive oxygen substances (ROS), and DNA damage, respectively. Also, propidium iodide (PI) flow cytometry assay and western blotting of bax, bcl-2, and cleaved caspase-3 were performed for assessment of apoptosis. OGD exposure reduced the cell viability and increased intracellular ROS production, oxidative DNA damage, and apoptosis, in comparison with untreated control cells. Pretreatment with safranal (40 and 160 µM) significantly attenuated OGD-induced PC12 cell death, oxidative damage, and apoptosis. Furthermore, safranal markedly reduced the overexpression of bax/bcl-2 ratio and active caspase-3 following OGD (p < 0.05). The present findings indicated that safranal protects against OGD-induced neurotoxicity via modulating of oxidative and apoptotic responses.Graphical abstract The schematic representation of the mode of action of safranal against PC12 cells death induced by oxygen-glucose-serum deprivation and reoxygenation (OGD-R).


Assuntos
Cicloexenos/farmacologia , Fármacos Neuroprotetores/farmacologia , Terpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Glucose , Estresse Oxidativo/efeitos dos fármacos , Oxigênio , Células PC12 , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
9.
Psychopharmacology (Berl) ; 238(1): 193-200, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33030593

RESUMO

BACKGROUND AND PURPOSE: Aß1-42-induced neurotoxicity has been considered as a possible mechanism to aggravate the onset and progression of Alzheimer's disease (AD). In this study, we aim to determine the protective effect of DMDD on the apoptosis of SH-SY5Y cells induced by Aß1-42 and elucidate potential mechanism of DMDD's protective function in apoptosis. EXPERIMENTAL APPROACH: CCK-8, AnnexinV-FITC/PI flow cytometry, and transmission electron microscopy analysis were used to determine the protection of DMDD on Aß1-42-evoked apoptosis of SH-SY5Y cells. Cytochrome c release, JC-1 staining, and measuring the protein of Bcl-2 family by Western blot were applied to elucidate the mechanism of DMDD's protective function in apoptosis. KEY RESULTS: Three concentration of DMDD (5 µmol/L, 10 µmol/L, and 20 µmol/L) rescues the cell viability loss and apoptosis of SH-SY5Y cells cultivated in Aß1-42. The expressions of cleaved Caspase-3, -8, -9, the cytochrome c release, and mitochondrial membrane potential loss were inhibited by DMDD in Aß1-42-insulted SH-SY5Y cells. The Western blot analysis showed that DMDD pretreatment clearly downregulated the protein of Bax and upregulated Bcl-2. Moreover, the Bcl-2/Bax ratio was obviously decreased in cells only exposed to Aß1-42, but, which was suppressed by treated with DMDD. CONCLUSION AND IMPLICATIONS: DMDD attenuated the apoptosis of SH-SY5Y cells induced by Aß1-42 through reversing the Bcl-2/Bax ratio.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Apoptose/efeitos dos fármacos , Averrhoa/química , Cicloexenos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fragmentos de Peptídeos/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Doença de Alzheimer/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cicloexenos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos
10.
Bioorg Chem ; 105: 104360, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33074118

RESUMO

A series of mono- and di-methylenecyclohexenone derivatives, 3a-f and 4a-f, respectively, were designed and synthesized from piperlongumine (PL) and their in vitro and in vivo pharmacological properties were evaluated. A majority of the compounds exhibited a potent antiproliferative effect on five human cancer cell lines, especially those causing breast cancer. Compound 4f showed the highest antiproliferative potency among all of the compounds, almost a 10-fold higher inhibitory potency against thioredoxin reductase (TrxR) compared with PL in cells causing breast cancer. In addition, 4f was found to increase the levels of reactive oxygen species (ROS), thus leading to more potent antiproliferative effects. More importantly, the suppression assays of migration and invasion revealed that compound 4f could reverse the epithelial-mesenchymal transition induced by the transforming growth factor ß1, and exhibit prominent anti-metastasis effects. Compound 4f also showed strong inhibition potency toward solid tumors of breast cancer in vivo. Our findings show that compound 4f is a promising therapeutic candidate in the treatment of breast cancer, which, however, needs further research to be proved.


Assuntos
Antineoplásicos/farmacologia , Cicloexenos/farmacologia , Inibidores Enzimáticos/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cicloexenos/síntese química , Cicloexenos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Masculino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/metabolismo , Células Tumorais Cultivadas
11.
Int J Mol Sci ; 21(20)2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33065997

RESUMO

Terpenes constitute one of the largest groups of natural products. They exhibit a wide range of biological activities including antioxidant, anticancer, and drug resistance modulating properties. Saffron extract and its terpene constituents have been demonstrated to be cytotoxic against various types of cancer cells, including breast, liver, lung, pancreatic, and colorectal cancer. In the present work, we have studied anticancer properties of TMPE, a newly synthesized monoterpene derivative of ß-cyclocitral-the main volatile produced by the stigmas of unripe crocuses. TMPE presented selective cytotoxic activity to doxorubicin-resistant colon cancer cells and was identified to be an effective MDR modulator in doxorubicin-resistant cancer cells. Synergy between this derivative and doxorubicin was observed. Most probably, TMPE inhibited transport activity of ABCB1 protein without affecting its expression level. Analysis of TMPE physicochemical parameters suggested it was not likely to be transported by ABCB1. Molecular modeling showed TMPE being more reactive molecule than the parental compound-ß-cyclocitral. Analysis of electrostatic potential maps of both compounds prompted us to hypothesize that reduced reactivity as well as susceptibility to electrophilic attack were related to the lower general toxicity of ß-cyclocitral. All of the above pointed to TMPE as an interesting candidate molecule for MDR reversal in cancer cells.


Assuntos
Antineoplásicos , Neoplasias do Colo/metabolismo , Crocus/química , Cicloexenos/química , Resistencia a Medicamentos Antineoplásicos , Compostos Orgânicos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Aldeídos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Cicloexenos/farmacologia , Diterpenos/química , Células HT29 , Humanos , Compostos Orgânicos/síntese química , Compostos Orgânicos/farmacologia , Ligação Proteica
12.
Drug Des Devel Ther ; 14: 2667-2684, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764871

RESUMO

Background: 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) has been reported to inhibit a variety of cancer cell lines. The purpose of this study was to investigate the effects of DMDD on 4T1 breast cancer cells and the effects of DMDD on 4T1 breast cancer in mice and its molecular mechanisms. Methods: 4T1 breast cancer cells were treated with different concentrations of DMDD, and their proliferation, apoptosis, cell-cycle distribution, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT, Acridine orange and ethidium bromide dual staining analysis (AO/EB) dual staining, flow cytometry, scratch test, and the Transwell assay. Relative quantitative real-time qPCR analysis and Western blot were applied to examine the expression levels of related genes and proteins. In animal experiments, we established a xenograft model to assess the anti-breast cancer effects of DMDD by evaluating the inhibition rate. The apoptotic activity of DMDD was evaluated by hematoxylin-eosin (HE) staining, transmission electron microscope (TEM) analysis and TdT-mediated dUTP nick end labeling (TUNEL) assays. The mRNA expression levels of MAPK pathway components were detected by relative quantitative real-time qPCR. In addition, the protein expression levels of MAPK pathway components were assessed through immunohistochemical assays and Western blotting. Results: Experiments showed that DMDD could inhibit the proliferation, migration, invasion of 4T1 cells and induce cellular apoptosis and G1 cell cycle arrest. Moreover, DMDD down-regulated the mRNA expressions of raf1, mek1, mek2, erk1, erk2, bcl2, and up-regulated the mRNA expression of bax. DMDD reduced the protein expressions of p-raf1, p-mek, p-erk, p-p38, Bcl2, MMP2, MMP9 and increased the protein expressions of Bax and p-JNK. The results showed that DMDD can effectively reduce the tumor volume and weight of breast cancer in vivo, up-regulate the expression of IL-2, down-regulate the expression of IL-4 and IL-10, induce the apoptosis of breast cancer cells in mice, and regulate the expression of genes and proteins of the MAPK pathway. Conclusion: Our study indicates that DMDD can inhibit proliferation, migration, and invasion and induces apoptosis and cell-cycle arrest of 4T1 breast cancer cells. Also, our findings indicate that DMDD induces the apoptosis of breast cancer cells and inhibits the growth in mice. Its mechanism may be related to the MAPK pathway.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cicloexenos/química , Cicloexenos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Averrhoa/química , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cicloexenos/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Raízes de Plantas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
13.
Molecules ; 25(14)2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679643

RESUMO

Anxiety and depression have high prevalence in the general population, affecting millions of people worldwide, but there is still a need for effective and safe treatments. Nutritional supplements have recently received a lot of attention, particularly saffron. Thus, several pre-clinical studies support a beneficial role for bioactive compounds, such as saffron, in anxiety and depression. Here we used an animal model of depression based on social isolation to assess the effects of affron®, a standardized saffron extract containing ≥3.5% of total bioactive compounds safranal and crocin isomers. Affron® was administered both through the oral and the intraperitoneal routes, and several tasks related to anxiety and depression, such as the elevated plus maze, the forced swimming test or the sucrose preference test, were assessed. These tasks model key features of depressive states and anxious states relating to fear, behavioral despair or anhedonia, the lack of motivation and/or pleasure from everyday activities, respectively. Animals receiving oral affron® displayed behaviors congruent with improvements in their anxious/depressive state, showing the enhanced consumption of a sweet solution, as well as an increase in certain escape responses in the forced swimming test. Our data support a beneficial role for oral saffron in anxious/depressive states.


Assuntos
Antidepressivos/farmacologia , Crocus/química , Cicloexenos/farmacologia , Extratos Vegetais/farmacologia , Terpenos/farmacologia , Análise de Variância , Animais , Antidepressivos/química , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Cicloexenos/química , Depressão/tratamento farmacológico , Humanos , Aprendizagem em Labirinto , Extratos Vegetais/química , Ratos , Terpenos/química
14.
Pharmacol Res ; 160: 105076, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32659428

RESUMO

Epigenetic modifiers provide a new target for the development of anti-cancer drugs. The eraser histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase that targets various non-histone proteins such as transcription factors, nuclear receptors, cytoskeletal proteins, DNA repair proteins, and molecular chaperones. Therefore, it became an attractive target for cancer treatment. In this study, virtual screening was applied to the MicroCombiChem database with 1162 drug-like compounds to identify new HDAC6 inhibitors. Five compounds were tested in silico and in vitro as HDAC6 inhibitors. Both analyses revealed 1-cyclohexene-1-carboxamide, 2-hydroxy-4,4-dimethyl-N-1-naphthalenyl-6-oxo- (MCC2344) as the best HDAC6 inhibitor among the five ligands. The binding affinity of MCC2344 to HDAC6 was further confirmed by microscale thermophoresis. Additionally, the anti-cancer activity of MCC2344 was tested in several tumor cell lines. Leukemia cells were the most sensitive cells towards MCC2344, particularly the P-glycoprotein-overexpressing multidrug-resistant cell line CEM/ADR5000 exhibited remarkable collateral sensitivity towards MCC2344. Transcriptome analysis using microarray hybridization was performed for investigating downstream mechanisms of action of MCC2344 in leukemia cells. MCC2344 affected microtubule dynamics and suppressed cell migration in the wound healing assay as well as in a spheroid model by hyper-acetylation of tubulin and HSP-90. MCC2344 induced cell death in CEM/ADR5000 cells by activation of PARP, caspase-3, and p21 in addition to the downregulation of p62. MCC2344 significantly inhibited tumor growth in vivo in zebrafish larvae without mortality until 20 pM. We propose MCC2344 as a novel HDAC6 inhibitor for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Cicloexenos/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Neoplasias/tratamento farmacológico , Acetilação , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Epigênese Genética/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Desacetilase 6 de Histona/metabolismo , Humanos , Células MCF-7 , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Microtúbulos/patologia , Invasividade Neoplásica , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Tubulina (Proteína)/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
15.
J Pharmacol Sci ; 143(3): 156-164, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32278466

RESUMO

Safranal (SFR) is the major constituent of saffron. The purpose of this study was to observe the effect of SFR on myocardial ischemia induced by isoprenaline (ISO) and to explore its possible mechanism. The myocardial ischemia rat model was established by subcutaneous injection of ISO (85 mg/kg/d) on the 8th and 9th day of the experiment. Serum creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured, as were changes in calcium concentration, reactive oxygen species (ROS) and cardiac morphology of the myocardial tissue. The effects of SFR on cell contraction, Ca2+ transient and L-type Ca2+ current (ICa-L) in isolated rat myocardial cells were measured using the Ion Optix detection system and the whole-cell patch-clamp technique. SFR can decrease the activity of serum CK, LDH and MDA, and increase the activity of serum SOD, reduce intracellular calcium concentration and the manufacture of ROS. In addition, SFR can improve changes in heart morphology. SFR can significantly inhibit contraction, Ca2+ transients and ICa-L in isolated ventricular myocytes. SFR has a cardioprotective role in ISO-induced MI rats, and the underling mechanism is related to the inhibition of oxidative stress, myocardial contractility, ICa-L and the regulation of Ca2+ homeostasis.


Assuntos
Cálcio/metabolismo , Crocus/química , Cicloexenos/farmacologia , Cicloexenos/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Terpenos/farmacologia , Terpenos/uso terapêutico , Animais , Cardiotônicos , Células Cultivadas , Cicloexenos/isolamento & purificação , Modelos Animais de Doenças , Isoproterenol/efeitos adversos , Masculino , Malondialdeído/metabolismo , Contração Miocárdica/efeitos dos fármacos , Isquemia Miocárdica/induzido quimicamente , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Terpenos/isolamento & purificação
16.
Mater Sci Eng C Mater Biol Appl ; 109: 110566, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32228987

RESUMO

Marine demosponges of the Verongiida order are considered a gold-mine for bioinspired materials science and marine pharmacology. The aim of this work was to simultaneously isolate selected bromotyrosines and unique chitinous structures from A. aerophoba and to propose these molecules and biomaterials for possible application as antibacterial and antitumor compounds and as ready-to-use scaffolds for cultivation of cardiomyocytes, respectively. Among the extracted bromotyrosines, the attention has been focused on aeroplysinin-1 that showed interesting unexpected growth inhibition properties for some Gram-negative clinical multi-resistant bacterial strains, such as A. baumannii and K. pneumoniae, and on aeroplysinin-1 and on isofistularin-3 for their anti-tumorigenic activity. For both compounds, the effects are cell line dependent, with significant growth inhibition activity on the neuroblastoma cell line SH-SY5Y by aeroplysinin-1 and on breast cancer cell line MCF-7 by isofistularin-3. In this study, we also compared the cultivation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) on the A. aerophoba chitinous scaffolds, in comparison to chitin structures that were pre-coated with Geltrex™, an extracellular matrix mimetic which is used to enhance iPSC-CM adhesion. The iPSC-CMs on uncoated and pure chitin structures started contracting 24 h after seeding, with comparable behaviour observed on Geltrex-coated cell culture plates, confirming the biocompatibility of the sponge biomaterial with this cell type. The advantage of A. aerophoba is that this source organism does not need to be collected in large quantities to supply the necessary amount for further pre-clinical studies before chemical synthesis of the active compounds will be available. A preliminary analysis of marine sponge bioeconomy as a perspective direction for application of biomaterials and secondary bioactive metabolites has been finally performed for the first time.


Assuntos
Acetonitrilas , Alcaloides , Organismos Aquáticos/química , Materiais Biomiméticos , Cicloexenos , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Poríferos/química , Acetonitrilas/química , Acetonitrilas/farmacocinética , Acetonitrilas/farmacologia , Alcaloides/química , Alcaloides/farmacocinética , Alcaloides/farmacologia , Animais , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Materiais Biomiméticos/farmacologia , Linhagem Celular Tumoral , Cicloexenos/química , Cicloexenos/farmacocinética , Cicloexenos/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células MCF-7 , Miócitos Cardíacos/citologia
17.
Biochimie ; 171-172: 158-169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32145350

RESUMO

Many natural phyto-products as perezone (Per) exhibit anti-cancer activities. Using experimental and computational studies, it was described that Poly ADP-ribose polymerase 1(PARP-1) inhibition and the induction of oxidative stress state explain the pro-apoptotic activity of Per. The aim of this study was to evaluate two phyto-products related to Per as anti-cancer agents: hydroxyperezone (OHPer) and its monoangelate (OHPer-MAng). These molecules were structurally characterized employing thermal analysis, IR spectrophotometry and X-ray diffraction techniques. The phyto-compounds evaluated in vitro in six cancer cell lines (K562, MCF-7, MDA-MB-231, HeLa, U373, A549) and non-malignant cells determinate their cytotoxicity, type of induced cell death, ability to avoid cell migration and changes at the redox status of the cell. Using, in vitro and computational studies provided the inhibition of PARP-1 and its potential binding mode. Cell proliferation assays demonstrated that OHPer-MAng treatment significantly induces apoptosis in triple negative breast cancer (TNBC) cell line (MDA-MB-231 IC50 = 3.53 µM), being particularly less cytotoxic to Vero cells (IC50 = 313.92 µM), human lymphocytes (IC50 = 221.46 µM) and rat endothelial cells (IC50=> 400 µM). The treatment of MDA-MB-231 cells with OHPer-MAng showed inhibition of migration by cancer cells. The induction of an oxidative stress state, similar to other quinones and PARP-1 inhibition explains the pro-apoptotic activity of OHPer-MAng. Docking studies showed that OHPer-MAng establishes great non-bonding interactions with the lateral chains of Tyr235, Hys201, Tyr246, Ser203, Asn207, and Gly233 located at the catalytic site of PARP-1, also demonstrating the anti-cancer activity of OHPer-MAng in TNBC cell line.


Assuntos
Antineoplásicos/farmacologia , Asteraceae/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cicloexenos/farmacologia , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Chlorocebus aethiops , Cicloexenos/química , Células Endoteliais , Humanos , Ratos , Sesquiterpenos/química , Células Vero
18.
Fitoterapia ; 143: 104544, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32151638

RESUMO

Two new polyoxygenated cyclohexenes (1-2), one new benzoate derivative (3), and one new dineolignan (4) together with one known neolignan (5) were isolated from whole plants of Piper pleiocarpum. The structures of these compounds were determined by extensive spectroscopic methods including 1D, 2D NMR, HR-ESI-MS, and by comparison with the literature. The 13C NMR spectra of the known compound 5 were completely assigned for the first time. All isolated compounds (1-5) were evaluated for their cytotoxic activities against five human cancer cell lines (including A-549, SMMC-7721, HL-60, MCF-7, and SW-480), Only compound 4 showed inhibitory activity against MCF-7 cell line with IC50 value of 18.24 ± 0.69 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cicloexenos/farmacologia , Lignanas/farmacologia , Piper/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , China , Cicloexenos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Lignanas/isolamento & purificação , Células MCF-7 , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/química
19.
Mar Drugs ; 18(2)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075136

RESUMO

The chemical analysis of the sponge Dysidea avara afforded the known sesquiterpene quinone avarone, along with its reduced form avarol. To further explore the role of the thiazinoquinone scaffold as an antiplasmodial, antileishmanial and antischistosomal agent, we converted the quinone avarone into the thiazinoquinone derivative thiazoavarone. The semisynthetic compound, as well as the natural metabolites avarone and avarol, were pharmacologically investigated in order to assess their antiparasitic properties against sexual and asexual stages of Plasmodium falciparum, larval and adult developmental stages of Schistosoma mansoni (eggs included), and also against promastigotes and amastigotes of Leishmania infantum and Leishmania tropica. Furthermore, in depth computational studies including density functional theory (DFT) calculations were performed. A toxic semiquinone radical species which can be produced starting both from quinone- and hydroquinone-based compounds could mediate the anti-parasitic effects of the tested compounds.


Assuntos
Cicloexenos/farmacologia , Leishmania/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quinonas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Sesquiterpenos/farmacologia , Tiazinas/farmacologia , Animais , Antiparasitários/farmacologia , Dysidea/química , Leishmania infantum/efeitos dos fármacos , Leishmania tropica/efeitos dos fármacos
20.
Eur J Pharmacol ; 873: 172962, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32001220

RESUMO

Hops (Humulus lupulus L.), a major component of beer, contain potentially neuroactive compounds that made it useful in traditional medicine as a sleeping aid. The present study aims to investigate the individual components in hops acting as allosteric modulators in GABAA receptors and bring further insight into the mode of action behind the sedative properties of hops. GABA-potentiating effects were measured using [3H]ethynylbicycloorthobenzoate (EBOB) radioligand binding assay in native GABAA receptors. Flumazenil sensitivity of GABA-potentiating effects, [3H]Ro 15-4513, and [3H]flunitrazepam binding assays were used to examine the binding to the classical benzodiazepines site. Humulone (alpha acid) and 6-prenylnaringenin (prenylflavonoid) were the most potent compounds displaying a modulatory activity at low micromolar concentrations. Humulone and 6-prenylnaringenin potentiated GABA-induced displacement of [3H]EBOB binding in a concentration-dependent manner where the IC50 values for this potentiation in native GABAA receptors were 3.2 µM and 3.7 µM, respectively. Flumazenil had no significant effects on humulone- or 6-prenylnaringenin-induced displacement of [3H]EBOB binding. [3H]Ro 15-4513 and [3H]flunitrazepam displacements were only minor with humulone but surprisingly prominent with 6-prenylnaringenin despite its flumazenil-insensitive modulatory activity. Thus, we applied molecular docking methods to investigate putative binding sites and poses of 6-prenylnaringenin at the GABAA receptor α1ß2γ2 isoform. Radioligand binding and docking results suggest a dual mode of action by 6-prenylnaringenin on GABAA receptors where it may act as a positive allosteric modulator at α+ß- binding interface as well as a null modulator at the flumazenil-sensitive α+γ2- binding interface.


Assuntos
Flavonoides/farmacologia , Moduladores GABAérgicos/farmacologia , Humulus/química , Receptores de GABA-A/efeitos dos fármacos , Animais , Azidas/metabolismo , Benzodiazepinas/metabolismo , Ligação Competitiva/efeitos dos fármacos , Cicloexenos/farmacologia , Relação Dose-Resposta a Droga , Flumazenil/farmacologia , Flunitrazepam/metabolismo , Moduladores GABAérgicos/metabolismo , Masculino , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Terpenos/farmacologia
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