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1.
Phytochemistry ; 180: 112531, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33010535

RESUMO

Five undescribed sesquiterpene coumarins, one undescribed coumarin derivative, and twenty-five known analogues, were isolated from the resin of Ferula sinkiangensis K.M.Shen. The planar structures and relative configurations of the undescribed compounds were determined by NMR experiment and HRESIMS data. The absolute configurations were established by Electrostatic Circular Dichroism method. Among these analogues, Sinkiangenol E showed the best cytotoxic activity against HeLa cervical cancer cells. Annexin V-FITC/PI staining indicated that Sinkiangenol E induced apoptosis in HeLa cells. Cell cycle analysis showed Sinkiangenol E arrested cell cycle at G0/G1 phase. Western blot results proved that Sinkiangenol E affected apoptosis-related and cell cycle regulation-related protein expression by activating the MAPK pathway.


Assuntos
Ferula , Sesquiterpenos , Cumarínicos/farmacologia , Células HeLa , Humanos , Estrutura Molecular , Sesquiterpenos/farmacologia
2.
J Infect Public Health ; 13(11): 1671-1677, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008777

RESUMO

BACKGROUND: The unique anthropological coronavirus which has been titled as SARS-CoV-2 was originally arisen in late 2019 in Wuhan, China affecting respiratory infection named as COVID-19. Coronavirus is disturbing human life in an exceptional method and has converted a public health global crisis. Natural products are ahead consideration due to the huge beneficial window and effective anti-inflammatory, immunomodulatory, antioxidant and antiviral possessions. Consequently, the present study was intended to display inhibition ability of natural products coumarins and their analogues against SARS coronavirus. METHODS: The present study, aims to forecast theoretical assembly for the protease of COVID-19 and to discover advance whether this protein may assist as a target for protease inhibitors such as psoralen, bergapten, imperatorin, heraclenin, heraclenol, saxalin, oxepeucedanin, angelicin, toddacoumaquinone, and aesculetin. The docking score of these natural coumarin analogues compared with standard Hydroxychloroquine. Whereas the 3D assembly of main protease of SARS coronavirus was forecast with SWISS MODEL web server, and molecular interaction studies amongst target protein and ligands were done with AutoDock Vina software. RESULTS: The study more exposed that all the inhibitors acquired with negative dock energy against the target protein. Molecular docking investigation displayed that natural coumarin analogue toddacoumaquinone displayed a remarkable inhibition ability with the binding energy of -7.8 kcal/mol than other compounds against main protease of SARS coronavirus in intricate with α-ketoamide (PDB ID: 5N5O). The synthetic coumarin analogue (1 m) also displayed the comparable inhibition ability with a binding energy of -7.1 kcal/mol against main protease of SARS coronavirus in intricate with α-ketoamide. Keeping the overhead results of ADME and toxicity, all tested compounds were recognized as drug-like nature, passing Lipinski's "Rule of 5" with 0 violation except α-ketoamide passes Lipinski's "Rule of 5" with 1 violation MW > 500. The projected constraints are within the assortment of recognized values. CONCLUSIONS: Based upon the results of the manifold sequence alliance, natural and synthetic coumarin binding sites were preserved. The present in silico examination thus, delivers structural awareness about the protease of COVID-19 and molecular relations with some of the recognised protease inhibitors.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Cumarínicos/farmacologia , Simulação de Acoplamento Molecular , Sítios de Ligação , China , Infecções por Coronavirus/tratamento farmacológico , Humanos , Modelos Moleculares , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia
3.
Pest Manag Sci ; 76(11): 3560-3567, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32815273

RESUMO

BACKGROUND: In order to discover natural-product-based pesticidal candidates, a series of coumarin-like derivatives containing oxime ester fragments at the C-8 position were prepared by structural modification of osthole, a natural plant product isolated from Cnidium monnieri. Their pesticidal activities were evaluated against two typically fruit trees/crop-threatening agricultural pests, Mythimna separata Walker and Tetranychus cinnabarinus Boisduval. RESULTS: Osthole was regioselectively oxidized by selenium dioxide to give the E-isomer, (2'E)-3'-formaldehydylosthole (2). Four key steric structures of 2, (2'E, 4'E)-(o-chloropyrid-3-ylcarbonyl)oximinylosthole (4o), (2'E, 4'E)-(styrylcarbonyl)oximinylosthole (4t), and (2'E, 4'E)-(acetyl)oximinylosthole (4w) were undoubtedly confirmed by X-ray crystallography. Against T. cinnabarinus, it is noteworthy that (2'E, 4'E)-(p-chlorophenylcarbonyl)oximinylosthole (4c) exhibited over three-fold more potent acaricidal activity of the precursor osthole, with especially good control efficiency observed in the glasshouse. Against M. separata, compounds 4c and (2'E, 4'E)-(p-nitrophenylcarbonyl)oximinylosthole (4f) showed the most pronounced growth inhibitory activity. The relationships between their structures and agricultural activities also were studied. CONCLUSION: These results demonstrate that compound 4c could be further structurally modified as pesticidal agents. It will lay the foundation for future application of osthole derivatives as pesticides. © 2020 Society of Chemical Industry.


Assuntos
Cnidium , Animais , Cumarínicos/farmacologia , Estrutura Molecular , Oximas/farmacologia
4.
Molecules ; 25(17)2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32842606

RESUMO

Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Catepsina L/química , Compostos Fitoquímicos/química , Inibidores de Proteases/química , Receptores Virais/química , Serina Endopeptidases/química , Sequência de Aminoácidos , Antivirais/isolamento & purificação , Antivirais/farmacologia , Betacoronavirus/patogenicidade , Sítios de Ligação , Catepsina L/antagonistas & inibidores , Catepsina L/genética , Catepsina L/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Cumarínicos/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Expressão Gênica , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Índia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Monossacarídeos/química , Monossacarídeos/isolamento & purificação , Monossacarídeos/farmacologia , Pandemias , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Inibidores de Proteases/isolamento & purificação , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Quinazolinas/química , Quinazolinas/isolamento & purificação , Quinazolinas/farmacologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/genética , Receptores Virais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Termodinâmica , Internalização do Vírus/efeitos dos fármacos
5.
Nihon Yakurigaku Zasshi ; 155(4): 214-219, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32612031

RESUMO

The peel of Citrus kawachiensis (Kawachi Bankan), a citrus species grown in Ehime, Japan, is abundant in auraptene. Auraptene, a coumarin compound, have been shown to exert anti-inflammatory effects in peripheral tissues, but it was still unclear of the effect in the brain. Hyperglycemia and brain ischemia induce inflammation and oxidative stress and cause massive damage in the brain; therefore, we examined the anti-inflammatory and other effects of the dried peel powder of C. kawachiensis and auraptene in a hyperglycemia and global cerebral ischemia models. The C. kawachiensis treatment inhibited astroglial activation in the hippocampus and the hyperphosphorylation of tau protein in hippocampal neurons, and also relieved the suppression of neurogenesis in the dentate gyrus of the hippocampus in the type 2 diabetic db/db mice. The C. kawachiensis treatment inhibited microglial and astroglial activation, and neuronal cell death in the hippocampus of transient global cerebral ischemia mice. It was suggested that the dried peel powder of C. kawachiensis exerts anti-inflammatory and neuroprotective effects in the brain. We attempted to demonstrate the effect of auraptene in the brains in streptozotocin-induced hyperglycemic mice and transient global cerebral ischemia mice. Auraptene administration showed the similar effects as the peel of C. kawachiensis in the hippocampus of these mice models. These results suggested that auraptene have potential effects as a neuroprotective agent in the peel of C. kawachiensis.


Assuntos
Isquemia Encefálica , Citrus , Hiperglicemia , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/tratamento farmacológico , Cumarínicos/farmacologia , Hipocampo , Hiperglicemia/tratamento farmacológico , Japão , Camundongos , Camundongos Obesos , Fármacos Neuroprotetores/farmacologia
6.
Exp Parasitol ; 217: 107955, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32649953

RESUMO

Nicotiana tabacum, Stemona japonica, and Cnidium monnieri are common plants that are widely used for their anti-parasitic properties. The purpose of this study was to evaluate the acaricidal activity of extracts from these plants against the brown dog tick, Rhipicephalus sanguineus. A composition analysis of crude extracts by GC-MS was conducted to discover compounds with acaricidal effects. The toxicity of extraction against the engorged nymphs of R. sanguineus was evaluated by an immersion test. The results showed that the crude extracts of S. japonica and C. monnieri in varying ratios, concentrations, and from different extraction methods, had a killing effect on R. sanguineus. Lethality reached 76.67% ± 0.04410 when using a 1:1 extract of S. japonica:C. monnieri in 75% ethanol with ultrasonic extraction; the crude extract was determined at a concentration of 0.5 g/mL. GC-MS results showed that osthole and 5-hydroxymethylfurfural (5-HMF) are the main components of the extract. These results suggested that ultrasound-assisted extraction (UAE) extracts contained acaricidal components acting against R. sanguineus, which may result in the development of effective extracts of S. japonica and C. monnieri as a source of low-toxicity, plant-based, natural acaricidal drugs.


Assuntos
Cnidium/química , Extratos Vegetais/farmacologia , Rhipicephalus sanguineus/efeitos dos fármacos , Stemonaceae/química , Controle de Ácaros e Carrapatos/métodos , Animais , Bioensaio , Cumarínicos/análise , Cumarínicos/farmacologia , Furaldeído/análogos & derivados , Furaldeído/análise , Furaldeído/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Muda/efeitos dos fármacos , Ninfa/efeitos dos fármacos , Extratos Vegetais/química , Coelhos , Tabaco/química
7.
Biochim Biophys Acta Proteins Proteom ; 1868(9): 140445, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32405284

RESUMO

Coumarins represent well-established structures to introduce fluorescence into tool compounds for biochemical investigations. They are valued for their small size, chemical stability and accessibility as well as their tunable photochemical properties. As components of fluorophore/quencher pairs or FRET donor/acceptor pairs, coumarins have frequently been applied in substrate mapping approaches for serine and cysteine proteases. This review also focuses on the incorporation of coumarins into the side chain of amino acids and the exploitation of the resulting fluorescent amino acids for the positional profiling of protease substrates. The protease-inhibiting properties of certain coumarin derivatives and the utilization of coumarin moieties to assemble activity-based probes for serine and cysteine proteases are discussed as well.


Assuntos
Cumarínicos/química , Cumarínicos/metabolismo , Cisteína Proteases/metabolismo , Serina Proteases/metabolismo , Domínio Catalítico , Cumarínicos/farmacologia , Cisteína Proteases/efeitos dos fármacos , Fluorescência , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes/química , Serina/metabolismo , Serina Proteases/efeitos dos fármacos , Especificidade por Substrato
8.
J Biomed Sci ; 27(1): 60, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375785

RESUMO

BACKGROUND: Columbianadin (CBN) is one of the main coumarin constituents isolated from Angelica pubescens. The pharmacological value of CBN is well demonstrated, especially in the prevention of several cancers and analgesic activity. A striking therapeutic target for arterial thrombosis is inhibition of platelet activation because platelet activation significantly contributes to these diseases. The current study examined the influence of CBN on human platelet activation in vitro and vascular thrombotic formation in vivo. METHODS: Aggregometry, immunoblotting, immunoprecipitation, confocal microscopic analysis, fibrin clot retraction, and thrombogenic animals were used in this study. RESULTS: CBN markedly inhibited platelet aggregation in washed human platelets stimulated only by collagen, but was not effective in platelets stimulated by other agonists such as thrombin, arachidonic acid, and U46619. CBN evidently inhibited ATP release, intracellular ([Ca2+]i) mobilization, and P-selectin expression. It also inhibited the phosphorylation of phospholipase C (PLC)γ2, protein kinase C (PKC), Akt (protein kinase B), and mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase [ERK] 1/2 and c-Jun N-terminal kinase [JNK] 1/2, but not p38 MAPK) in collagen-activated platelets. Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, reversed the CBN-mediated inhibition of platelet aggregation. CBN had no significant effect in triggering vasodilator-stimulated phosphoprotein phosphorylation. Moreover, it markedly hindered integrin αIIbß3 activation by interfering with the binding of PAC-1; nevertheless, it had no influences on integrin αIIbß3-mediated outside-in signaling such as adhesion number and spreading area of platelets on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Additionally, CBN did not attenuate FITC-triflavin binding or phosphorylation of proteins, such as integrin ß3, Src, and focal adhesion kinase, in platelets spreading on immobilized fibrinogen. In experimental mice, CBN increased the occlusion time of thrombotic platelet plug formation. CONCLUSION: This study demonstrated that CBN exhibits an exceptional activity against platelet activation through inhibition of the PLCγ2-PKC cascade, subsequently suppressing the activation of Akt and ERKs/JNKs and influencing platelet aggregation. Consequently, this work provides solid evidence and considers that CBN has the potential to serve as a therapeutic agent for the treatment of thromboembolic disorders.


Assuntos
Cumarínicos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Trombose/tratamento farmacológico , Animais , Humanos , Camundongos
9.
Int J Nanomedicine ; 15: 2841-2858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425521

RESUMO

Introduction: Osthole (Ost) is a coumarin compound that strengthens hippocampal neurons and neural stem cells against Aß oligomer-induced neurotoxicity in mice, and is a potential drug for the treatment of Alzheimer's disease (AD). However, the effectiveness of the drug is limited by its solubility and bioavailability, as well as by the low permeability of the blood-brain barrier (BBB). In this study, a kind of transferrin-modified Ost liposomes (Tf-Ost-Lip) was constructed, which could improve the bioavailability and enhance brain targeting. Methods: Tf-Ost-Lip was prepared by thin-film hydration method. The ability of liposomal formulations to translocate across BBB was investigated using in vitro BBB model. And the protective effect of Tf-Ost-Lip was evaluated in APP-SH-SY5Y cells. In addition, we performed pharmacokinetics study and brain tissue distribution analysis of liposomal formulations in vivo. We also observed the neuroprotective effect of the varying formulations in APP/PS-1 mice. Results: In vitro studies reveal that Tf-Ost-Lip could increase the intracellular uptake of hCMEC/D3 cells and APP-SH-SY5Y cells, and increase the drug concentration across the BBB. Additionally, Tf-Ost-Lip was found to exert a protective effect on APP-SH-SY5Y cells. In vivo studies of pharmacokinetics and the Ost distribution in brain tissue indicate that Tf-Ost-Lip prolonged the cycle time in mice and increased the accumulation of Ost in the brain. Furthermore, Tf-Ost-Lip was also found to enhance the effect of Ost on the alleviation of Alzheimer's disease-related pathology. Conclusion: Transferrin-modified liposomes for delivery of Ost has great potential for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Cumarínicos/farmacologia , Lipossomos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/patologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular , Cumarínicos/química , Cumarínicos/farmacocinética , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Polietilenoglicóis/química , Presenilina-1/genética , Ratos Sprague-Dawley , Distribuição Tecidual , Transferrina/química
10.
Zhongguo Zhong Yao Za Zhi ; 45(5): 1076-1081, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32237449

RESUMO

To prepare the herpetolide A nanosuspension lyophilized powder(HPA-NS-LP), in order to investigate its anti-hepatitis B virus(HBV) activity and the dissolution in vitro. Herpetolide A nanosuspension(HPA-NS) was prepared by ultrasonic precipitation method. The formulation and process of HPA-NS were optimized by the single factor experiment. Lyophilized powder(HPA-NS-LP) was prepared by freeze-drying method. Scanning electron microscopy was used to observe morphology of HPA-NS-LP. Paddle method was used to determinate the dissolution of HPT-NS-LP in vitro. The anti-HBV activity of herpetolide A coarse suspension lyophilized powder(HPA-CS-LP) and HPA-NS-LP was evaluated by HepG2.2.15 cell model. The mean particle size of optimized HPA-NS was(173.46±4.36) nm, with a polydispersity index of 0.110±0.012. After redispersion, the mean particle size and the polydispersity index of HPA-NS-LP increased, with changes within a rational range. Scanning electron microscopy showed that HPA-NS-LP was spherical in shape. Cumulative dissolution rate of HPA-NS-LP was more than 90% in 2 hours, which was higher than that of HPA-CS-LP. Both HPA-CS-LP and HPA-NS-LP could effectively inhibit the secretion of HepG2.2.15 cell antigens(HBsAg and HBeAg), and the inhibitory effect of HPA-NS-LP was significantly higher than that of HPA CS-LP(P<0.05). HBV-DNA test showed that high, medium and low-dose HPA-NS-LP(50, 25, 12.5 mg·kg~(-1)) significantly decreased the level of HBV-DNA(P<0.05), and the effect was better than that of the same dose of HPA-CS-LP(P<0.05). The results revealed that HPA-NS-LP exhibited anti-HBV activity in vitro, and its effect was superior to that of HPA-CS-LP.


Assuntos
Cumarínicos/farmacologia , Cucurbitaceae/química , Vírus da Hepatite B/efeitos dos fármacos , Nanopartículas , Compostos Fitoquímicos/farmacologia , Cumarínicos/isolamento & purificação , Células Hep G2 , Humanos , Tamanho da Partícula , Compostos Fitoquímicos/isolamento & purificação , Solubilidade , Suspensões
11.
Cancer Sci ; 111(6): 2052-2061, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32291856

RESUMO

KRAS mutation is frequently seen in a subtype of ovarian cancer categorized as type 1. The KRAS-MAPK pathway, which is closely involved in type 1 cancer progression, is under the regulation of receptor tyrosine kinases (RTKs). AXL, one of the RTKs, has been reported to be overexpressed in ovarian cancer and contributes to the poor prognosis. However, there is no useful target-based agent against such gene profiles. We examined the combined effect of the dual RAF/MEK inhibitor CH5126766 and AXL inhibitor R428 on the growth of ovarian cancer HEY-T30 and OVCAR-5 cell lines, both of which bear KRAS mutation and express AXL at a high level, using the WST-8 assay and the colony formation assay. The synergistic effect of the combination was evaluated by the combination index. The apoptotic cells were analyzed by flow cytometry. The expression of apoptotic proteins and the phosphorylation of MAPK and AKT pathway proteins were investigated by western blotting. We found that CH5126766 and R428 suppressed the phosphorylation of ERK and AKT, respectively, and their combination synergistically inhibited the growth of both cell lines with enhancement of apoptosis accompanied by the Bim upregulation. Combined treatment with CH5126766 and R428 is expected as the novel therapeutic option for KRAS-mutated ovarian cancer with high expression of AXL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzocicloeptenos/farmacologia , Carcinoma Epitelial do Ovário/patologia , Cumarínicos/farmacologia , Triazóis/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores Proteína Tirosina Quinases/metabolismo
12.
Xenobiotica ; 50(8): 939-946, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32238050

RESUMO

Osthol, a pharmacologically active ingredient in various traditional Chinese medicines, is predominantly metabolized by CYP2C9. It may be co-administered with other drugs which are metabolized by CYP2C9 in clinical medicine. However, CYP2C9*1/*2/*3 genotype on the pharmacokinetics of osthole and its metabolic diversity between rat and human are unclear.In this study, we investigated the effects of osthole on enzyme activity of CYP2C11/CYP2C9 in rat liver microsomes (RLMs) and human liver microsomes (HLMs), to distinguish metabolic manner of osthole in different species. Interestingly, we found that osthole inhibits the activity of CYP2C11 in a non-competitive manner in RLMs, while inhibits CYP2C9 activity in a competitive manner in pooled HLMs. Then, the effects of CYP2C9*1/*2/*3 allele on the pharmacokinetics of osthole were identified. In human CYP2C9 isoform, the Ki value of 21.93 µM (CYP2C9*1), 18.10 µM (CYP2C9*2), 13.12 µM (CYP2C9*3) indicate that there are individual differences in the inhibition of osthole on CYP2C9 activity.We investigated how the indomethacin pharmacokinetics was affected by osthole in SD rat. To estimate the area under the curve (AUC), maximum plasma concentration (Cmax) and apparent clearance (CL/F), indomethacin (10 mg/kg) was given orally combined with osthole (20 mg/kg) in adult SD rat. We found the value of PK on indomethacin, such as the AUC0-∞, was from 176.40 ± 17.29 to 173.74 ± 27.69 µg/ml h-1, Cmax from 9.02 ± 1.24 to 9.89 ± 0.82 µg/ml and CL/F from 0.11 ± 0.01 to 0.12 ± 0.04 mg/kg/h which were unsignificantly changed compared with the control groups. However, the Tmax was prolonged from 2.00 ± 0.00 h to 7.33 ± 1.15 h, and T1/2 increased from 8.38 ± 2.30 h to 11.37 ± 2.11 h. These results indicate that osthole could potentially affect the metabolism of indomethacin in vivo.


Assuntos
Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Indometacina/farmacocinética , Animais , Citocromo P-450 CYP2C9/metabolismo , Humanos , Indometacina/metabolismo , Medicina Tradicional Chinesa , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Sci Rep ; 10(1): 4495, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161276

RESUMO

Pythiosis is a harmful disease caused by Pythium insidiosum, an aquatic oomycete. Therapeutic protocols based on antifungal drugs are often ineffective because the cytoplasmic membrane of P. insidiosum does not contain ergosterol. Therefore, the treatment of pythiosis is still challenging, particularly making use of natural products and secondary metabolites from bacteria. In this study, xanthyletin and substances obtained from Pseudomonas stutzeri ST1302 and Klebsiella pneumoniae ST2501 exhibited anti-P. insidiosum activity and, moreover, xanthyletin was non-toxic against human cell lines. The hyphae of P. insidiosum treated with these three substances exhibited lysis holes on a rough surface and release of anamorphic material. Therefore, xanthyletin could be considered a promising alternative agent for treating cutaneous pythiosis in the near future.


Assuntos
Antifúngicos/farmacologia , Antiparasitários/farmacologia , Cumarínicos/farmacologia , Pythium/efeitos dos fármacos , Bactérias/química , Bactérias/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Misturas Complexas , Fibroblastos/efeitos dos fármacos , Humanos , Hifas/efeitos dos fármacos , Hifas/ultraestrutura , Testes de Sensibilidade Microbiana
14.
J Med Chem ; 63(6): 3359-3369, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32142286

RESUMO

Cytotoxic T-lymphocytes (CTLs) and natural killer cells (NKs) kill compromised cells to defend against tumor and viral infections. Both effector cell types use multiple strategies to induce target cell death including Fas/CD95 activation and the release of perforin and a group of lymphocyte granule serine proteases called granzymes. Granzymes have relatively broad and overlapping substrate specificities and may hydrolyze a wide range of peptidic epitopes; it is therefore challenging to identify their natural and synthetic substrates and to distinguish their localization and functions. Here, we present a specific and potent substrate, an inhibitor, and an activity-based probe of Granzyme A (GrA) that can be used to follow functional GrA in cells.


Assuntos
Cumarínicos/farmacologia , Corantes Fluorescentes/farmacologia , Granzimas/análise , Oligopeptídeos/farmacologia , Inibidores de Serino Proteinase/farmacologia , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/toxicidade , Desenho de Fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Granzimas/química , Humanos , Oligopeptídeos/síntese química , Oligopeptídeos/toxicidade , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/toxicidade , Especificidade por Substrato
15.
Molecules ; 25(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046013

RESUMO

Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds 6 and 7 displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36-2.91 M and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, 13a and 13c arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound 13c.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Neoplasias/tratamento farmacológico , Células A549 , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Fase G2/efeitos dos fármacos , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular/métodos , Neoplasias/metabolismo , Relação Estrutura-Atividade
16.
Sci Rep ; 10(1): 1606, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005894

RESUMO

The aim of this study is to devise, prepare and characterize nano encapsulated auraptene (AUR) and evaluate cytotoxic and apoptotic effects on HT-29 colon cancer cells. Herein, AUR nano formulations were prepared by triblock (PCL-PEG-PCL) and pentablock (PLA-PCL-PEG-PCL-PLA) biodegradable copolymers in order to increase AUR bioavailability as an anticancer agent. The preparation of nano particles (NPs) was done with rotor stator homogenization (RSH) and Ultrasonic homogenization (USH) methods. The physicochemical characteristics of prepared nanoparticles (NPs) were studied using HNMR, FTIR, GPC, DLS and SEM techniques. The smaller hydrodynamic size (110 nm) and polydispersity index (PDI: 0.288) as well as higher cellular uptake (89%) were observed in PB NPs rather than TB NPs. The highest cytotoxic and apoptotic effects were observed in AUR loaded PB NPs compared to AUR loaded TB NPs and free AUR obtained by MTT assay, cell cycle arrest, Annexin V-FITC, DAPI staining and RT-PCR techniques. Real time PCR results indicated that Bax /Bcl2 expression ratio as an apoptosis predicting criterion, in free AUR, AUR loaded TB and AUR loaded PB have increased 6, 9 and 13 times, respectively (p value < 0.05). In conclusion, using biodegradable nano-vehicles for sustained delivery of natural anti-cancer compounds may open new perspectives for treatment of cancer patients.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Neoplasias do Colo/tratamento farmacológico , Cumarínicos/química , Cumarínicos/farmacologia , Nanopartículas/química , Linhagem Celular Tumoral , Colo/efeitos dos fármacos , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Excipientes/química , Células HT29 , Humanos , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química
17.
Sci Rep ; 10(1): 2893, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076009

RESUMO

The incidence of obesity-related diseases like diabetes, cardiovascular diseases, and different types of cancers shed light on the importance of dietary control as preventive and treatment measures. However, long-term dietary control is challenging to achieve in most individuals. The use of energy restriction mimetic agents (ERMAs) as an alternative approach to affect the energy machinery of cancer cells has emerged as a promising approach for cancer therapy. ERMAs limit the high need for energy in rapidly growing tumor cells, with their survival rate strongly dependent on the robust availability of energy. In this context, initial phenotypic screening of an in-house pilot compound library identified a new class of aminothiazole anchored on coumarin scaffold as potent anticancer lead drug candidates with potential activity as ERMA. The identified chemotypes were able to inhibit glucose uptake and increase ROS content in cancer cells. Compounds 9b, 9c, 9i, 11b, and 11c were highly active against colorectal cancer cell lines, HCT116 and HT-29, with half-maximal inhibitory concertation (IC50) range from 0.25 to 0.38 µM. Further biological evaluations of 9b and 9f using Western blotting, caspase activity, glucose uptake, ROS production, and NADPH/NADP levels revealed the ability of these lead drug candidates to induce cancer cell death via, at least in part, energy restriction. Moreover, the assessment of 9b and 9f synergistic activity with cisplatin showed promising outcomes. The current work highlights the significant potential of the lead compounds, 9b, and 9f as potential anticancer agents via targeting the cellular energy machinery in cancer cells.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Desenho de Fármacos , Metabolismo Energético/efeitos dos fármacos , Tiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Neoplasias Colorretais/patologia , Cumarínicos/síntese química , Cumarínicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Fase G1/efeitos dos fármacos , Glucose/metabolismo , Células HCT116 , Células HT29 , Humanos , Concentração Inibidora 50 , Espécies Reativas de Oxigênio/metabolismo , Tiazóis/síntese química , Tiazóis/química
18.
Sci Rep ; 10(1): 986, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969640

RESUMO

Geranylated 4-phenylcoumarins DMDP-1 and DMDP-2 isolated from Mesua elegans were elucidated for their role in inducing caspase-independent programmed cell death (CI-PCD) in prostate cancer cell lines, PC-3 and DU 145, respectively. Cell homeostasis disruption was demonstrated upon treatment, as shown by the increase in calcium ion through colourimetric assay and endoplasmic reticulum (ER) stress markers GRP 78 and p-eIF2α through western blot. Subsequently, cytoplasmic death protease calpain-2 also showed increased activity during DMDP-1 & -2 treatments, while lysosomic death protease cathepsin B activity was significantly increased in PC-3 treated with DMDP-1. Flow cytometry showed a reduction in mitochondrial membrane potential in both cell lines, while western blotting showed translocation of mitochondrial death protease AIF into the cytoplasm in its truncated form. Furthermore, DMDP-1 & -2 treatments caused significant increase in superoxide level and oxidative DNA damage. Concurrent inhibition of calpain-2 and cathepsin B during the treatment showed an attenuation of cell death in both cell lines. Hence, DMDP-1 & -2 induce CI-PCD in prostate cancer cell lines through calpain-2 and cathepsin B.


Assuntos
Calpaína/metabolismo , Catepsina B/metabolismo , Morte Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Magnoliopsida , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
19.
J Recept Signal Transduct Res ; 40(1): 89-96, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31971049

RESUMO

Objective: Endometrial carcinoma (EC) was the fourth female malignancies in developed countries. Given that the prognosis of EC is extremely poor, it is vital to investigate its pathogenesis and effective therapeutic targets. However, the mechanism of osthole in EC remains unknown.Materials and methods: Firstly, the different doses of osthole (0, 50, 100, and 200 µM) were used to treat the Ishikawa and KLE cells. The cell proliferation, apoptosis, and cell cycle were measured by cell counting kit-8 (CCK-8), Annexin V-FITC/PI, and cell cycle assays. The apoptosis-related protein levels were examined by western blot. The miR-424 levels in Ishikawa and KLE cells were assessed by quantitative RT-PCR (qRT-PCR). Also, the binding of miR-424 and cytoplasmic polyadenylation element binding protein 2 (CEPB2) was detected by the luciferase reporter assay.Results: In this study, the increasing dose of osthole inhibited proliferation and induced apoptosis of Ishikawa and KLE cells. Moreover, the increasing dose of osthole up-regulated miR-424 and down-regulated the expression of CPEB2. CPEB2 was proved to be the target gene of miR-424. Interestingly, the over-expression of CPEB2 could reverse the changes of osthole-induced proliferation and apoptosis of Ishikawa and KLE cells.Conclusions: In summary, we provided first evidences that osthole inhibited proliferation and induced apoptosis through up-regulating miR-424 to inhibit expression of CPEB2 in EC. Our findings indicated that osthole might act as a novel and potential therapeutic agent for the treatment of EC.


Assuntos
Apoptose/efeitos dos fármacos , Cumarínicos/farmacologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Proteínas de Ligação a RNA/metabolismo , Regulação para Cima/genética , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Feminino , Humanos , Proteínas de Ligação a RNA/genética , Regulação para Cima/efeitos dos fármacos
20.
J Ethnopharmacol ; 252: 112606, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31988013

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Porana sinensis Hemsl. has been widely used to treat joint pain and rheumatoid arthritis in traditional Chinese medicine (TCM). Although evidence exists to support a pharmacological action of P. sinensis for the treatment of gout arthritis (GA), the underlying mechanism of action remains unknown due to it being a multi-component and multi-target agent. AIM OF THE STUDY: To clarify the active compounds and mechanism of P. sinensis against GA. MATERIALS AND METHODS: The present study combined network pharmacology with experiments to clarify the mechanism of P. sinensis against GA. A protein-protein interaction network for gout was constructed to identify the potential drug targets, and molecular docking was subsequently performed to determine whether the protein was a target for the compounds of P. sinensis. KEGG pathway analysis was then conducted to elucidate the pathway involved in the P. sinensis-mediated treatment of gout. A rat model of GA was used to further investigate the mechanism of P. sinensis against GA. RESULTS: The network pharmacology study indicates that coumarins and chlorogenic acids of P. sinensis may serve as additives to GA treatment. P. sinensis played a role in the treatment of GA by regulating the PI3K-Akt, MAPK, NF-kappa B and toll-like receptor pathways and so on. Moreover, experimental validation suggests that P. sinensis extract significantly suppressed the expression of TLR2 and MyD88 mRNA, regulating the release of cytokines (IL-1ß, IL-4 and TGF-ß), lowering lipid peroxidation (MDA) and increasing antioxidant status (SOD). CONCLUSION: The present study clarifies the mechanism of P. sinensis against GA, and provides evidence to support its clinical use.


Assuntos
Artrite Gotosa/metabolismo , Convolvulaceae , Extratos Vegetais/farmacologia , Animais , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/patologia , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/genética , Artrite Gotosa/patologia , Ácido Clorogênico/farmacologia , Ácido Clorogênico/uso terapêutico , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Citocinas/sangue , Masculino , Simulação de Acoplamento Molecular , Fator 88 de Diferenciação Mieloide/genética , Farmacologia/métodos , Extratos Vegetais/uso terapêutico , Mapas de Interação de Proteínas , Ratos Sprague-Dawley , Receptor 2 Toll-Like/genética
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