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2.
Fitoterapia ; 139: 104410, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31707127

RESUMO

Phytochemical studies of the air-dried pericarp of Citrus grandis led to the isolation of four new compounds including three prenylated benzenepropanoic acids (2, 3 and 5) and one alkamidic glycoside (6), together with ten known compounds (1, 4 and 7-14). The structures of these compounds were determined by the NMR spectroscopy, optical rotation data and modified Mosher's method. Meanwhile, the anti-neuroinflammatory activities of all isolated compounds were evaluated by detecting the production of nitric oxide (NO) in LPS-stimulated BV2 cells. The results showed that compounds 1, 2, 5 and 13 exhibited strong inhibition effects on NO production in LPS-stimulated BV2 cells. Mechanistically, compounds 1, 2 and 5 could suppress the expressions of iNOS. In addition, compounds 1, 2 and 5 also showed obvious inhibition effects on COX-2 expression, another vital enzyme in the inflammation process, in LPS-treated BV2 cells. These findings shed light on the potent anti-neuroinflammatory effects of Citrus grandis.


Assuntos
Anti-Inflamatórios/farmacologia , Citrus/química , Glicosídeos/farmacologia , Propionatos/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular Tumoral , China , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/farmacologia , Frutas/química , Glicosídeos/isolamento & purificação , Macrófagos , Camundongos , Estrutura Molecular , Neuroblastoma , Óxido Nítrico Sintase Tipo II/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Prenilação , Propionatos/isolamento & purificação
3.
Fitoterapia ; 139: 104372, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31669720

RESUMO

Four new sesquiterpene lactones, named artemargyinolides A-D (1-4), and seven known sesquiterpenoids (5-11) were isolated from Artemisia argyi. Their structures were elucidated based on the extensive analysis of spectroscopic data. The absolute configuration of 1 was assigned by X-ray crystallographic analysis. Compound 1 is an unprecedented sesquiterpene dimer-monoterpene lactone. The cyclooxygenases (COX-1 and COX-2) inhibitory activities of all isolated compounds were evaluated. Compounds 1, 2, 4, and 6-11 showed inhibitory activity against COX-2 with IC50 values ranging from 35.78 ±â€¯0.39 to 256.07 ±â€¯0.38 µM. However, compounds 7, 9, and 10 exhibited weak inhibitory activity against COX-1 with IC50 values of 465.70 ±â€¯1.53, 281.43 ±â€¯3.56, and 490.45 ±â€¯6.07 µM, respectively. Other compounds are inactive against COX-1. Therefore, compounds 1, 2, 4, 6, 8, and 11 displayed selective COX-2 inhibitory activity.


Assuntos
Artemisia/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Lactonas/farmacologia , Sesquiterpenos/farmacologia , China , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Lactonas/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Sesquiterpenos/isolamento & purificação
4.
Int J Nanomedicine ; 14: 7561-7581, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571864

RESUMO

Introduction: This study was conducted to elucidate the chemopreventive potential, cytotoxic, and suppression of cellular metastatic activity of etodolac (ETD)-loaded nanocarriers. Methods: To esteem the effect of charge and composition of the nanovectors on their performance, four types of vectors namely, negative lipid nanovesicles; phosalosomes (N-Phsoms), positive phosalosomes (P-Phsoms), nanostructured lipid carriers (NLCs) and polymeric alginate polymer (AlgNPs) were prepared and compared. ETD was used as a model cyclo-oxygenase-2 (COX-2) inhibitor to evaluate the potency of these nanovectors to increase ETD permeation and retention through human skin and cytotoxicity against squamous cell carcinoma cell line (SCC). Moreover, the chemopreventive activity of ETD nanovector on mice skin cancer model was evaluated. Results: Among the utilized nanovectors, ETD-loaded N-Phsoms depicted spherical vesicles with the smallest particle size (202.96±2.37 nm) and a high zeta potential of -24.8±4.16 mV. N-Phsoms exhibited 1.5, and 3.6 folds increase in the ETD amount deposited in stratum corneum, epidermis and dermis. Moreover, cytotoxicity studies revealed a significant cytotoxic potential of such nanovector with IC50=181.76 compared to free ETD (IC50=982.75), correlated to enhanced cellular internalization. Its efficacy extended to a reduction in the relative tumor weight with 1.70 and 1.51-fold compared to positive control and free ETD, that manifested by a 1.72-fold reduction in both COX-2 and proliferating cell nuclear antigen mRNA (PCNA-mRNA) levels and 2.63-fold elevation in caspase-3 level in skin tumors relative to the positive control group with no hepato-and nephrotoxicity. Conclusion: Encapsulation of ETD in nanovector enhances its in-vitro and in-vivo anti-tumor activity and opens the door for encapsulation of more relevant drugs.


Assuntos
Quimioprevenção , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Nanoestruturas/química , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/toxicidade , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Etodolac/farmacologia , Etodolac/uso terapêutico , Feminino , Humanos , Concentração Inibidora 50 , Lipídeos/química , Camundongos , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Estudos Prospectivos , Absorção Cutânea/efeitos dos fármacos , Neoplasias Cutâneas/patologia , Eletricidade Estática , Resultado do Tratamento
5.
Eur J Med Chem ; 183: 111693, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539778

RESUMO

Novel heterocyclic oxadiazoles viz. 2-subsituted-5-(4-pyridyl)-1,3,4-oxadiazoles, 2-subsituted-5-(3-pyridyl)-1,3,4-oxadiazoles and 2-subsituted-5-(phenyl or 4-chlorophenyl-1,3,4-oxadiazoles) were designed and synthesized as potential anticancer agents. In this investigation, all compounds were evaluated for their COX-1 and COX-2 inhibitory activity in vitro as new therapeutic approaches assumed cytotoxic effect associated with selective COX-2 inhibition. Results showed that most of the derivatives demonstrated inhibition towards both isoforms of COX comparable to the standard reference drugs indomethacin, diclofenac sodium and celecoxib. Then, nine selected compounds (IIId, VIb, VIIc, IX, XI, XIIa, XIVa, XVIb and XVIIIb) were subjected to cytotoxic screening against UO-31 renal cancer cell line using MTT assay. Compounds IIId, IX and XIIa displayed promising behavior by showing good anticancer activity. Moreover, kinase inhibitory assay against the tyrosine kinase EGFR was performed for the three compounds showing the highest cytotoxic activity. The tested compounds were potent against EGFR with the highest activity being observed for compound IX showing nearly double the potency of the reference drug Erlotinib. Moreover, molecular docking and molecular dynamics were performed for IIId, IX and XIIa against EGFR, in an attempt to elucidate a model for their binding at the molecular level, simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids. Finally, in silico pharmacokinetic profile predication was investigated for IIId, IX and XIIIa using SWISS/ADME to identify the most promising small-molecule cytotoxic agent on the basis of displaying the best drug-like properties. Results indicated that compound IX has a potential to serve as a lead compound for developing novel anticancer therapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Desenho de Drogas , Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
Int J Mol Sci ; 20(19)2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547612

RESUMO

The aim of this study was to analyze the analgesic potential of Arrabidaea chica extract (EHA) as an alternative to osteoarthritis (OA) treatment. Thus, the extract was initially evaluated by the cyclooxygenase inhibition test. The analgesic effect of the extract, in vivo, was also verified in a model of OA induced by sodium monoiodoacetate (2 mg). EHA was administered to rats at doses of 50, 150, and 450 mg/kg between 3 and 25 days after OA induction. The animals were clinically evaluated every 7 days, euthanized at 29 days, and the liver, spleen, kidney and knee collected for histopathological analysis. The chemical composition of EHA was identified by HPLC-MS and the identified compounds submitted to molecular docking study. The results showed that the extract promoted cyclooxygenase inhibition and produced significant improvements in disability, motor activity, hyperalgesia, and OA-induced allodynia parameters, in addition to improvements in the radiological condition of the knees (but not observed in the histopathological study). Chemically the extract is rich in flavonoids. Among them, we evidence that amentoflavone showed very favorable interactions with the enzyme COX-2 in the in silico analysis. Thus, it is concluded that A. chica has important analgesic properties for the treatment of OA.


Assuntos
Bignoniaceae/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Flavonoides/farmacologia , Hiperalgesia/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Modelos Animais de Doenças , Flavonoides/química , Hiperalgesia/induzido quimicamente , Hiperalgesia/diagnóstico por imagem , Ácido Iodoacético/toxicidade , Atividade Motora/efeitos dos fármacos , Especificidade de Órgãos/efeitos dos fármacos , Osteoartrite/induzido quimicamente , Osteoartrite/diagnóstico por imagem , Extratos Vegetais/química , Ratos , Ratos Wistar
7.
Eur J Pharmacol ; 860: 172586, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31377156

RESUMO

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), has been reported to exert a variety of important pharmacological effects including anti-inflammatory, anticancer, and direct inhibition of tyrosinase. This study aimed to examine the expression of melanogenic molecules following down-regulation of cyclooxygenase (COX)-2 expression by resveratrol and the related signal transduction pathways in mouse B16F10 melanoma cells and zebrafish larvae. We report that resveratrol suppressed COX-2 in melanocytes and decreased the expressions of tyrosinase and microphthalmia-associated transcription factor (MITF). Furthermore, inhibition of COX-2 with NS398 enhanced resveratrol-reduced tyrosinase and MITF expression. Resveratrol also induced phosphorylation of extracellular signal-regulated 1/2 (ERK1/2) and phosphoinositide-3 (PI-3)-kinase/Akt. Inhibition of ERK1/2 or PI-3K/Akt by PD98059 and LY294002 restored the decreased tyrosinase activity and MITF expression via resveratrol-mediated down-regulation of COX-2. Additionally, resveratrol inhibited body pigmentation in zebrafish. These results indicated that resveratrol inhibited melanogenesis by down-regulating COX-2 via ERK1/2 and PI-3K/Akt pathways in B16F10 cells.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Melaninas/biossíntese , Melanócitos/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/farmacologia , Melanócitos/citologia , Melanócitos/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
8.
J Orthop Res ; 37(12): 2609-2620, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31410880

RESUMO

Arthrofibrosis is a common complication following total knee arthroplasty caused by pathologic fibroblast activation and excessive collagen deposition around a synovial joint leading to debilitating loss of motion. Treatment options are limited because the pathologic mechanisms remain to be characterized. Dysregulation of the inflammatory cascade may lead to communication between myofibroblasts and immune cells triggering tissue metaplasia, and excessive collagen deposition described clinically as arthrofibrosis. We explored the novel use of celecoxib (selective cyclooxygenase-2 [COX-2] inhibitor) to disrupt the downstream effects of the post-traumatic inflammatory cascade and inhibit scar tissue formation in a validated rabbit model of arthrofibrosis combined with new parameters for quantifying the stiffness of the posterior capsule. Biomechanical and molecular analyses, of contracted rabbit knee posterior capsule tissue after COX-2 inhibition revealed increased maximal passive extension and down-regulation of collagen messenger RNA compared with controls. Histopathologic examination suggested a trend of decreased quantities of dense fibrous connective tissue with COX-2 inhibition. These data may suggest that inhibiting the inflammatory cascade could potentially reduce pathologic myofibroblast activation, thereby reducing scar tissue formation and increasing the range of motion in arthrofibrotic joints. Implementing a multi-modal pharmacologic approach may simultaneously target numerous cellular components contributing to the complex process of arthrofibrogenesis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2609-2620, 2019.


Assuntos
Contratura/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/farmacologia , Articulações/patologia , Animais , Artroplastia do Joelho/efeitos adversos , Fenômenos Biomecânicos , Celecoxib/farmacologia , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose , Miofibroblastos/fisiologia , Coelhos
9.
Eur J Med Chem ; 182: 111601, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445233

RESUMO

The cyclic enaminone moiety has been identified as a new scaffold for selective inhibition of cyclooxygenase-2 with anti-inflammatory and analgesic activities. The designed cyclic enaminones have been synthesized conveniently through the development of a new catalyst-free methodology and evaluated for cyclooxygenase (COX-1 and COX-2) inhibitory activities. Three compounds 7d, 8, and 9 predominantly inhibited COX-2 with selectivity index of 74.09, 19.45 and 108.68, respectively, and were assessed for in vivo anti-inflammatory activity in carrageenan induced rat paw edema assay. The anti-inflammatory activity of 7d was comparable to that of celecoxib at a dose of 12.5 mg/kg. However, the compounds 8 and 9 were more/equally effective as anti-inflammatory agent compared to celecoxib at the doses of 12.5 mg/kg and 25 mg/kg and also exhibited anti-inflammatory activity comparable to that of diclofenac. The therapeutic potential of the most active compound 9 was further assessed by performing in vivo thermal and mechanical hyperalgesia tests using various models that revealed its analgesic activity. The in vivo non-ulcerogenicity of 9 revealed the gastrointestinal safety as compared to the non-selective COX inhibitor indomethacin. The in vitro antioxidant activity and in vivo experiments on heart rate and blood pressure provided the cardiovascular safety profile of 9. The molecular docking studies rationalize the COX-2 selectivity of the newly found anti-inflammatory compounds 7d, 8, and 9.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Compostos Heterocíclicos/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Carragenina , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
10.
J Vet Med Sci ; 81(9): 1379-1384, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31366852

RESUMO

In healthy dogs, amino acid infusion significantly attenuates the decrease in body temperature during anesthesia by facilitating insulin secretion, suggesting that such an increase in insulin secretion is related to increased heat production. In dogs, selective cyclooxygenase-2 (COX-2) inhibitors, which are used for pain relief in veterinary medicine, possess anti-pyretic action. And, in mice and humans, selective COX-2 inhibitors increase insulin secretion and sensitivity. Therefore, treatment with COX-2 inhibitors may negate or accelerate the attenuating effect on decreased body temperature during anesthesia by amino acid infusion. In the present study, influences on insulin secretion and body temperature by treatment with meloxicam or robenacoxib at therapeutic dose were evaluated in healthy dogs. Treatment with meloxicam or robenacoxib did not affect insulin secretion in the unanesthetized and anesthetized dogs, and did not affect body temperature and heart rate under the anesthetized condition with amino acid infusion. In conclusion, COX-2 inhibitors at therapeutic doses did not affect body temperature during anesthesia in dogs administered amino acids.


Assuntos
Anestesia/veterinária , Inibidores de Ciclo-Oxigenase 2/farmacologia , Difenilamina/análogos & derivados , Meloxicam/farmacologia , Fenilacetatos/farmacologia , Aminoácidos/administração & dosagem , Anestesia/efeitos adversos , Animais , Temperatura Corporal/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Difenilamina/administração & dosagem , Difenilamina/farmacologia , Cães , Feminino , Teste de Tolerância a Glucose/veterinária , Frequência Cardíaca/efeitos dos fármacos , Infusões Intravenosas/veterinária , Secreção de Insulina/efeitos dos fármacos , Masculino , Meloxicam/administração & dosagem , Fenilacetatos/administração & dosagem
11.
Biol Pharm Bull ; 42(7): 1120-1127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257288

RESUMO

Hydroxytyrosol (HT) is a simple phenol compound present in olive oil. In a previous in vitro study, we showed that HT downregulated lipopolysaccharide-mediated expression of inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor alpha, and interleukin-1ß, resulting in reduced nitric oxide and prostaglandin E2 production. In the present study, we aimed to determine whether HT suppresses COX-2-induced inflammation in a carrageenan-induced rat paw edema model. Additionally, we compared its activity with those of the selective COX-2 inhibitor, celecoxib for a comparative control, and a representative nonsteroidal anti-inflammatory drug (NSAID), indomethacin for a positive control. HT, celecoxib, and indomethacin significantly suppressed swelling in carrageenan-injected rat paws. Although HT was less effective than celecoxib and indomethacin, it had a delayed onset of action. Moreover, we evaluated whether HT aggravates gastric damage, which is a typical adverse effect associated with NSAIDs and COX-2 inhibitors under low dose aspirin (LDA) treatment, in an aspirin-induced gastric damage rat model. Unlike celecoxib and indomethacin, HT did not cause gastric damage when co-administered with aspirin. Our results indicate that HT exerts a delayed but sustained anti-inflammatory effect against COX-2-mediated inflammation. Finally, the combination of short-acting conventional anti-inflammatory drugs and long-acting HT can be considered a new, safe, and effective anti-inflammatory treatment modality even when continuously administered for a long period under LDA treatment.


Assuntos
Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Edema/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Úlcera Gástrica/tratamento farmacológico , Estômago/efeitos dos fármacos , Animais , Aspirina , Carragenina , Celecoxib , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Edema/induzido quimicamente , Edema/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Indometacina , Masculino , Olea , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Ratos Sprague-Dawley , Estômago/patologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo
12.
Chem Pharm Bull (Tokyo) ; 67(9): 966-976, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257308

RESUMO

Honokiol, a biphenolic neolignan isolated from Magnolia officinalis, was reported to have a promising anti-inflammatory activity for the treatment of various diseases. There are many efforts on the synthesis and structure-activity relationship of honokiol derivatives. However, regioselective O-alkylation of honokiol remains a challenge and serves as a tool to provide not only some derivatives but also chemical probes for target identification and mode of action. In this study, we examined the reaction condition for regioselective O-alkylation, in which C2 and C4'-alkylated analogs of honokiol were synthesized and evaluated for inhibitory activity on nitric oxide production and cyclooxygenase-2 expression. Furthermore, we successfully synthesized a potential photoaffinity probe consisting of biotin and benzophenone based on a C4'-alkylated derivative.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Bifenilo/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/tratamento farmacológico , Lignanas/farmacologia , Alquilação , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Humanos , Inflamação/metabolismo , Lignanas/síntese química , Lignanas/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Estereoisomerismo
13.
Fitoterapia ; 137: 104259, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31319108

RESUMO

The cyclooxygenase-2 (COX-2) is a key enzyme in the synthesis of prostaglandins, its inhibitors are effective for the treatment of inflammation. In this study, an analytical method based on bio-affinity ultrafiltration coupled with ultra performance liquid chromatography and quadrupole-time-of-flight mass spectrometry (BAUF-UPLC-Q-TOF-MS) was established for rapidly screening and identifying COX-2 ligands. Meanwhile, the specificity of the method was verified by denatured COX-2 and inactive compound. Next, the biological activity of ligands screened was proved by enzyme inhibition assay. The preferred binding modes for these COX-2 inhibitors were then determined by molecular docking. Finally, network pharmacology was used to explore the pathways involved anti-inflammatory effects. As a result, five COX-2 inhibitors were selected in the extract of Andrographis Herba (AH), including andrographolide (1), 14-deoxy-11,12-didehydroandrographiside (2), andrographidine E (3), andrographidine D (4), and deoxyandrographolide (5). Among them, compounds 2, 3, 4 and 5 were reported to have COX-2 inhibitory activity for the first time. The result of COX-2 inhibition assay showed that compound 3 had an IC50 of 19 µM, compounds 2 and 5 had an IC50 of >200 µM. And each ligand could bind to multiple amino acid residues of COX-2 based on molecular docking. At last, combined with network pharmacology, these ligands could exert anti-inflammatory effects through three pathways related to COX-2, arachidonic acid metabolism, synthesis of prostaglandins, and prostanoid ligand receptors. The method established in the study could be used to rapidly screen other enzyme inhibitors in complex mixtures, and help to understand the mechanism of action.


Assuntos
Andrographis/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Diterpenos/farmacologia , Cromatografia Líquida de Alta Pressão , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Diterpenos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Humanos , Inflamação , Espectrometria de Massas , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Ultrafiltração
14.
Eur J Med Chem ; 180: 86-98, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301566

RESUMO

The aim of this study was to design and synthesize COX-1/COX-2 balanced inhibitors incorporating the structural motifs of anti-inflammatory ascidian metabolites. We designed a series of substituted indole analogs that incorporate the key structures of the ascidian metabolites, herdmanines C and D. The synthesized analogs were tested for their inhibitory activity against COX-1 and COX-2, and compound 5m, which displayed balanced inhibition, was further evaluated for in vitro anti-inflammatory activity. Compound 5m suppressed the expression of pro-inflammatory factors, including iNOS, COX-2, TNF-α, and IL-6 in LPS-stimulated murine RAW264.7 macrophages. The reduction of PGE2, NO, and ROS was also observed, together with the suppression of NF-κB, IKK, and IκBα phosphorylation. Our results characterized 5m as a COX-1/COX-2 balanced inhibitor that subsequently caused ROS inhibition and NF-κB suppression, and culminated in the suppression of iNOS, COX-2, TNF-α, and IL-6 expression.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Desenho de Drogas , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Células RAW 264.7 , Ovinos , Relação Estrutura-Atividade , Urocordados
15.
Cancer Sci ; 110(8): 2520-2528, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215118

RESUMO

Iodothyronine deiodinase 2 (DIO2) converts the prohormone thyroxine (T4) to bioactive T3 in peripheral tissues and thereby regulates local thyroid hormone (TH) levels. Although epidemiologic studies suggest the contribution of TH to the progression of colorectal cancer (CRC), the role of DIO2 in CRC remains elusive. Here we show that Dio2 is highly expressed in intestinal polyps of ApcΔ716 mice, a mouse model of familial adenomatous polyposis and early stage sporadic CRC. Laser capture microdissection and in situ hybridization analysis show almost exclusive expression of Dio2 in the stroma of ApcΔ716 polyps in the proximity of the COX-2-positive areas. Treatment with iopanoic acid, a deiodinase inhibitor, or chemical thyroidectomy suppresses tumor formation in ApcΔ716 mice, accompanied by reduced tumor cell proliferation and angiogenesis. Dio2 expression in ApcΔ716 polyps is strongly suppressed by treatment with the COX-2 inhibitor meloxicam. Analysis of The Cancer Genome Atlas data shows upregulation of DIO2 in CRC clinical samples and a close association of its expression pattern with the stromal component, consistently with almost exclusive expression of DIO2 in the stroma of human CRC as revealed by in situ hybridization. These results indicate essential roles of stromal DIO2 and thyroid hormone signaling in promoting the growth of intestinal tumors.


Assuntos
Proliferação de Células/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Iodeto Peroxidase/metabolismo , Polipose Adenomatosa do Colo/tratamento farmacológico , Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Humanos , Pólipos Intestinais/tratamento farmacológico , Pólipos Intestinais/metabolismo , Pólipos Intestinais/patologia , Camundongos , Camundongos Knockout , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Hormônios Tireóideos/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
16.
Curr Top Med Chem ; 19(13): 1121-1128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210111

RESUMO

BACKGROUND: The discovery of novel potent molecules for both cancer prevention and treatment has been continuing over the past decade. In recent years, identification of new, potent, and safe anticancer agents through drug repurposing has been regarded as an expeditious alternative to traditional drug development. The cyclooxygenase-2 is known to be over-expressed in several types of human cancer. For this reason cyclooxygenase-2 inhibition may be useful tool for cancer chemotherapy. OBJECTIVE: The first aim of the study was to develop a validated linear model to predict antitumor activity. Subsequently, applicability of the model for repurposing these cyclooxygenase-2 inhibitors as antitumor compounds to abridge drug development process. METHODS: We performed a quantitative structure-toxicity relationship (QSTR) study on a set of coumarin derivatives using a large set of molecular descriptors. A linear model predicting growth inhibition on leukemia CCRF cell lines was developed and consequently validated internally and externally. Accordingly, the model was applied on a set of 143 cyclooxygenase-2 inhibitor coumarin derivatives to explore their antitumor activity. RESULTS: The results indicated that the developed QSAR model would be useful for estimating inhibitory activity of coumarin derivatives on leukemia cell lines. Electronegativity was found to be a prominent property of the molecules in describing antitumor activity. The applicability domain of the developed model highlighted the potential antitumor compounds. CONCLUSION: The promising results revealed that applied integrated in silico approach for repurposing by combining both the biological activity similarity and the molecular similarity via the computational method could be efficiently used to screen potential antitumor compounds among cyclooxygenase-2 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Reposicionamento de Medicamentos , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Reprodutibilidade dos Testes
17.
Int J Mol Med ; 44(2): 683-693, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31198976

RESUMO

Celecoxib, a selective cyclooxygenase­2 inhibitor, has chemo­preventive activity against different cancer types, including bladder cancer (BC). However, the mechanisms by which celecoxib exerts its cancer preventative effects have yet to be completely understood. In the present study, the effect of celecoxib on the epithelial­to­mesenchymal transition (EMT) of BC cells and its potential molecular mechanisms were investigated. The results of the present study demonstrated that celecoxib inhibited the proliferation, migration, invasion and EMT of BC cells. Further investigation of the underlying mechanism revealed that celecoxib inhibited EMT by upregulating microRNA (miR)­145 and downregulating the expression of transforming growth factor ß receptor 2 and SMAD family member 3. Furthermore, the combination of celecoxib with miR­145 mimics demonstrated an additive migration and invasion­inhibitory effect in BC cell lines.


Assuntos
Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MicroRNAs/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/prevenção & controle , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Proteína Smad3/genética , Neoplasias da Bexiga Urinária/genética
18.
Int J Mol Sci ; 20(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174295

RESUMO

Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein's ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer generation software for acquiring the best NIB screening results using cyclooxygenase-2 (COX-2) as the example system. Secondly, the entire NIB workflow from the protein structure preparation, model build-up, and ligand conformer generation to the similarity comparison is performed for COX-2. Accordingly, hands-on instructions are provided on how to employ the NIB methodology from start to finish, both with the rigid docking and docking rescoring using noncommercial software. The practical aspects of the NIB methodology, especially the effect of ligand conformers, are discussed thoroughly, thus, making the methodology accessible for new users.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular/métodos , Sítios de Ligação , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Ligação Proteica
19.
Molecules ; 24(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216654

RESUMO

Quinones and nitrogen heterocyclic moieties have been recognized as important pharmacophores in the development of antitumor agents. This study aimed to establish whether there was any correlation between the in silico predicted parameters and the in vitro antiproliferative activity of a family of benzoindazolequinones (BIZQs), and to evaluate overexpressed proteins in human cancer cells as potential biomolecular targets of these compounds. For this purpose, this study was carried out using KATO-III and MCF-7 cell lines as in vitro models. Docking results showed that these BIZQs present better binding energies (ΔGbin) values for cyclooxygenase-2 (COX-2) than for other cancer-related proteins. The predicted ∆Gbin values of these BIZQs, classified in three series, positively correlated with IC50 measured in both cell lines (KATO-III: 0.72, 0.41, and 0.90; MCF-7: 0.79, 0.55, and 0.87 for Series I, II, and III, respectively). The results also indicated that compounds 2a, 2c, 6g, and 6k are the most prominent BIZQs, because they showed better IC50 and ∆Gbin values than the other derivatives. In silico drug absorption, distribution, metabolism, and excretion (ADME) properties of the three series were also analyzed and showed that several BIZQs could be selected as potential candidates for cancer pre-clinical assays.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Quinonas/química , Quinonas/farmacologia , Sítios de Ligação , Fenômenos Químicos , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
20.
J Exp Clin Cancer Res ; 38(1): 208, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113465

RESUMO

BACKGROUND: Thyroid carcinoma includes several variants characterized by different biological and clinical features: from indolent microcarcinoma to undifferentiated and aggressive anaplastic carcinoma. Inflammation plays a critical role in thyroid tumors. Conditions predisposing to cancer, as well as oncogene activity, contribute to the construction of an inflammatory microenvironment that facilitates thyroid tumor progression. Moreover, oncogene-induced senescence, a mechanism tightly connected with inflammation, and able to restrain or promote cancer progression, is involved in thyroid cancer. The interactions between thyroid tumor cells and the microenvironment are not completely clarified. METHODS: We characterize in vitro the interplay between macrophages and senescent thyrocytes and tumor-derived cell lines, modeling early and late thyroid tumor stages, respectively. Purified peripheral blood-derived human monocytes were exposed to thyroid cell-derived conditioned medium (CM) and assessed for phenotype by flow cytometry. The factors secreted by thyroid cells and macrophages were identified by gene expression analysis and ELISA. The protumoral effect of macrophages was assessed by wound healing assay on K1 thyroid tumor cells. The expression of PTGS2 and M2 markers in thyroid tumors was investigated in publicly available datasets. RESULTS: Human monocytes exposed to CM from senescent thyrocytes and thyroid tumor cell lines undergo M2-like polarization, showing high CD206 and low MHC II markers, and upregulation of CCL17 secretion. The obtained M2-like macrophages displayed tumor-promoting activity. Among genes overexpressed in polarizing cells, we identified the prostaglandin-endoperoxide synthase enzyme (PTGS2/COX-2), which is involved in the production of prostaglandin E2 (PGE2). By using COX-2 inhibitors we demonstrated that the M2-like polarization ability of thyroid cells is related to the production of PGE2. Co-expression of PTGS2 and M2 markers is observed a significant fraction of human thyroid tumors. CONCLUSIONS: Our results demonstrate that both senescent thyrocytes and thyroid tumor cell lines trigger M2-like macrophage polarization that is related to PGE2 secretion. This suggests that the interaction with the microenvironment occurs at both early and late thyroid tumor stages, and favors tumor progression. The co-expression of PTGS2 gene and M2 markers in human thyroid carcinoma highlights the possibility to counteract tumor growth through COX-2 inhibition.


Assuntos
Senescência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Inflamação/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Polaridade Celular/efeitos dos fármacos , Senescência Celular/genética , Quimiocina CCL17/genética , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Monócitos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Epiteliais da Tireoide/efeitos dos fármacos , Células Epiteliais da Tireoide/patologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
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