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1.
Nutrients ; 13(10)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34684313

RESUMO

Peptic ulcer episodes cause damage to the stomach and intestine, with inflammatory cell infiltration and oxidative stress as the main players. In this study, we investigated the potential of anthocyanidin malvidin for preventive and curative peptic ulcer treatment. The anthocyanidin effects were examined in gastric ulcer mouse models induced by ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion (IR), acetic acid and duodenal ulcer induced by polypharmacy. Expression levels of oxidative and inflammatory genes were measured to investigate the mechanism of anthocyanin activity. At a dose of 5 mg·kg-1, Malvidin prevented gastric ulcer induction by ethanol, NSAID and repaired the tissue after 6 days of IR. Moreover, the anthocyanidin accelerated the healing of acetic acid-induced ulcer, increased the gene expression of EGF and COX-1, and downregulated MMP-9. Anthocyanin treatment mitigated the effect of polypharmacy on inflammation and oxidative stress observed in the intestine. Additionally, the compound downregulated cytokine expression and TLR4 and upregulated HMOX-1 and IL-10, exhibiting protective activity in the mouse gut. Malvidin thus prevented gastric and duodenal ulcers due to prominent anti-inflammatory and antioxidative effects on the gastrointestinal tract that were related to gene expression modulation and an increase in endogenous defense mechanisms.


Assuntos
Antocianinas/uso terapêutico , Inflamação/complicações , Inflamação/tratamento farmacológico , Estresse Oxidativo , Úlcera Péptica/complicações , Úlcera Péptica/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Ácido Acético , Animais , Antocianinas/farmacologia , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Modelos Animais de Doenças , Duodeno/efeitos dos fármacos , Duodeno/patologia , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Etanol , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Indometacina , Inflamação/genética , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Úlcera Péptica/genética , Úlcera Péptica/imunologia , Polimedicação , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/genética , Úlcera Gástrica/imunologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Cicatrização/efeitos dos fármacos
2.
Molecules ; 26(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34641516

RESUMO

The inflammatory reaction accompanies in part or in full any disease process in the vascularized metazoan. This complicated reaction is controlled by regulatory mechanisms, some of which produce unpleasant symptomatic manifestations of inflammation. Therefore, there has been an effort to develop selective drugs aimed at removing pain, fever, or swelling. Gradually, however, serious adverse side effects of such inhibitors became apparent. Scientific research has therefore continued to explore new possibilities, including naturally available substances. Amygdalin is a cyanogenic glycoside present, e.g., in bitter almonds. This glycoside has already sparked many discussions among scientists, especially about its anticancer potential and related toxic cyanides. However, toxicity at different doses made it generally unacceptable. Although amygdalin given at the correct oral dose may not lead to poisoning, it has not yet been accurately quantified, as its action is often affected by different intestinal microbial consortia. Its pharmacological activities have been studied, but its effects on the body's inflammatory response are lacking. This review discusses the chemical structure, toxicity, and current knowledge of the molecular mechanism of amygdalin activity on immune functions, including the anti-inflammatory effect, but also discusses inflammation as such, its mediators with diverse functions, which are usually targeted by drugs.


Assuntos
Amigdalina/efeitos adversos , Amigdalina/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Amigdalina/química , Amigdalina/toxicidade , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo
3.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502040

RESUMO

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, we decided to modify the structure of already reported 1,3,4-oxadiazole based derivatives of pyrrolo[3,4-d]pyridazinone in order to obtain effective COX inhibitors. Herein we present the synthesis, biological evaluation and molecular docking studies of 12 novel compounds with disubstituted arylpiperazine pharmacophore linked in a different way with 1,3,4-oxadiazole ring. None of the obtained molecules show cytotoxicity on NHDF and THP-1 cell lines and, therefore, all were qualified for further investigation. In vitro cyclooxygenase inhibition assay revealed almost equal activity of new derivatives towards both COX-1 and COX-2 isoenzymes. Moreover, all compounds inhibit COX-2 isoform better than Meloxicam which was used as reference. Anti-inflammatory activity was confirmed in biological assays according to which title molecules are able to reduce induced inflammation within cells. Molecular docking studies were performed to describe the binding mode of new structures to cyclooxygenase. Investigated derivatives take place in the active site of COX, very similar to Meloxicam. For some compounds, promising druglikeness was calculated using in silico predictions.


Assuntos
Inibidores de Ciclo-Oxigenase/síntese química , Oxidiazóis/síntese química , Piridazinas/química , Pirróis/química , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/toxicidade , Humanos , Simulação de Acoplamento Molecular , Oxidiazóis/farmacologia , Oxidiazóis/toxicidade , Ligação Proteica , Células THP-1
4.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299499

RESUMO

The present study aims at the isolation and identification of diverse phenolic polyketides from Aloe vera (L.) Burm.f. and Aloe plicatilis (L.) Miller and includes their 5-LOX/COX-1 inhibiting potency. After initial Sephadex-LH20 gel filtration and combined silica gel 60- and RP18-CC, three dihydroisocoumarins (nonaketides), four 5-methyl-8-C-glucosylchromones (heptaketides) from A. vera, and two hexaketide-naphthalenes from A. plicatilis have been isolated by means of HSCCC. The structures of all polyketides were elucidated by ESI-MS and 2D 1H/13C-NMR (HMQC, HMBC) techniques. The analytical/preparative separation of 3R-feralolide, 3'-O-ß-d-glucopyranosyl- and the new 6-O-ß-d-glucopyranosyl-3R-feralolide into their respective positional isomers are described here for the first time, including the assignment of the 3R-configuration in all feralolides by comparative CD spectroscopy. The chromones 7-O-methyl-aloesin and 7-O-methyl-aloeresin A were isolated for the first time from A. vera, together with the previously described aloesin (syn. aloeresin B) and aloeresin D. Furthermore, the new 5,6,7,8-tetrahydro-1-O-ß-d-glucopyranosyl- 3,6R-dihydroxy-8R-methylnaphtalene was isolated from A. plicatilis, together with the known plicataloside. Subsequently, biological-pharmacological screening was performed to identify Aloe polyketides with anti-inflammatory potential in vitro. In addition to the above constituents, the anthranoids (octaketides) aloe emodin, aloin, 6'-(E)-p-coumaroyl-aloin A and B, and 6'-(E)-p-coumaroyl-7-hydroxy-8-O-methyl-aloin A and B were tested. In the COX-1 examination, only feralolide (10 µM) inhibited the formation of MDA by 24%, whereas the other polyketides did not display any inhibition at all. In the 5-LOX-test, all aloin-type anthranoids (10 µM) inhibited the formation of LTB4 by about 25-41%. Aloesin also displayed 10% inhibition at 10 µM in this in vitro setup, while the other chromones and naphthalenes did not display any activity. The present study, therefore, demonstrates the importance of low molecular phenolic polyketides for the known overall anti-inflammatory activity of Aloe vera preparations.


Assuntos
Aloe/química , Cumarínicos/química , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase/química , Inibidores de Lipoxigenase/química , Naftalenos/química , Policetídeos/química , Antraquinonas/química , Antraquinonas/farmacologia , Anti-Inflamatórios , Araquidonato 5-Lipoxigenase/metabolismo , Cromonas/química , Cromonas/farmacologia , Cumarínicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Glucosídeos/química , Glucosídeos/farmacologia , Inibidores de Lipoxigenase/farmacologia , Naftalenos/farmacologia , Fenóis/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Policetídeos/farmacologia
5.
Eur J Med Chem ; 224: 113682, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34245948

RESUMO

Addressing the global need for the development of safe and potent NSAIDs, new series of oxadiazolo and thiadiazolo fused pyrmidinones were synthesized and initially tested for their analgesic activity. All tested compounds showed promising analgesic activity compared with the reference standard indomethacin. Moreover, anti-inflammatory activity evaluation, ulcerogenic liability, and in vitro COX-1, COX-2 enzyme inhibition assays were also performed for the most active derivatives. The methoxyphenyl piperazinyl derivative 3d showed analgesic activity surpassing indomethacin with protection of 100%, and 83%; respectively. Also 3d showed good anti-inflammatory activity with relatively lower ulcer index compared with other tested compounds, and potent COX-1 and COX-2 inhibitory activity with IC50 = 0.140, 0.007 µm, respectively, and with a selectivity index of 20.00 which was better than the reference standards and the other tested congeners. Additionally, compounds 3b, 3g and 3h revealed moderate selectivity (SI = 3.53, 3.70 and 5.87, respectively). Moreover, in silico physicochemical parameters revealed that the new fused pyrimidinones demonstrated promising pharmacokinetic properties. Furthermore, computational studies in form of 2D-quantitative structure-activity relationship (2D-QSAR) and 3D-pharmacophore confirmed the potential analgesic properties of the new target compounds.


Assuntos
Analgésicos/química , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/metabolismo , Pirimidinonas/química , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Humanos , Masculino , Camundongos , Pirimidinonas/metabolismo , Pirimidinonas/uso terapêutico , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Wistar
6.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202163

RESUMO

Lusianthridin is a phenanthrene derivative isolated from Dendrobium venustum. Some phenanthrene compounds have antiplatelet aggregation activities via undefined pathways. This study aims to determine the inhibitory effects and potential mechanisms of lusianthridin on platelet aggregation. The results indicated that lusianthridin inhibited arachidonic acid, collagen, and adenosine diphosphate (ADP)-stimulated platelet aggregation (IC50 of 0.02 ± 0.001 mM, 0.14 ± 0.018 mM, and 0.22 ± 0.046 mM, respectively). Lusianthridin also increased the delaying time of arachidonic acid-stimulated and the lag time of collagen-stimulated and showed a more selective effect on the secondary wave of ADP-stimulated aggregations. Molecular docking studies revealed that lusianthridin bound to the entrance site of the cyclooxygenase-1 (COX-1) enzyme and probably the active region of the cyclooxygenase-2 (COX-2) enzyme. In addition, lusianthridin showed inhibitory effects on both COX-1 and COX-2 enzymatic activities (IC50 value of 10.81 ± 1.12 µM and 0.17 ± 1.62 µM, respectively). Furthermore, lusianthridin significantly inhibited ADP-induced suppression of cAMP formation in platelets at 0.4 mM concentration (p < 0.05). These findings suggested that possible mechanisms of lusianthridin on the antiplatelet effects might act via arachidonic acid-thromboxane and adenylate cyclase pathways.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Fenantrenos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , AMP Cíclico , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Modelos Moleculares , Conformação Molecular , Fenantrenos/química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Relação Estrutura-Atividade
7.
Future Med Chem ; 13(13): 1091-1103, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34080888

RESUMO

Aim: This study investigated our Enzymelinks, COX-2-10aa-mPGES-1 and COX-2-10aa-PGIS, as cellular cross-screening targets for quick identification of lead compounds to inhibit inflammatory PGE2 biosynthesis while maintaining prostacyclin synthesis. Methods: We integrated virtual and wet cross-screening using Enzymelinks to rapidly identify lead compounds from a large compound library. Results: From 380,000 compounds virtually cross-screened with the Enzymelinks, 1576 compounds were identified and used for wet cross-screening using HEK293 cells that overexpressed individual Enzymelinks as targets. The top 15 lead compounds that inhibited mPGES-1 activity were identified. The top compound that specifically inhibited inflammatory PGE2 biosynthesis alone without affecting COX-2 coupled to PGI2 synthase (PGIS) for PGI2 biosynthesis was obtained. Conclusion: Enzymelink technology could advance cyclooxygenase pathway-targeted drug discovery to a significant degree.


Assuntos
Derivados de Benzeno/farmacologia , Ciclo-Oxigenase 1/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Oxirredutases Intramoleculares/metabolismo , Engenharia de Proteínas , Derivados de Benzeno/química , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia
8.
Biomed Pharmacother ; 140: 111770, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34119929

RESUMO

Our study has renewed interest in the genus Jasmine for the treatment of chronic inflammatory conditions. Aerial parts of Jasminum grandiflorum L. subsp. floribundum total methanolic extract (JTME) were tested for its therapeutic potential as an anti-inflammatory agent using two experimental models in rats; acetic acid (AA) induced ulcerative colitis and adjuvant induced arthritis. The administration of JTME showed anti-inflammatory activity in a dose dependent manner. JTME, 400 mg/kg was like prednisolone, 2 mg/kg p.o. (the reference drug), since it improved the tissues of the colon clinically, macro and microscopically (ulcer index), and histopathological (scoring). It reduced the intestinal expression of pro-inflammatory cytokines in the colonic mucosa; IFNγ, TNFα, IL-6, IL-1, and MPO. It also preserved tight junctions in intestinal epithelial cells by counter-regulating claudin-5 and occludin levels additionally, it had a potent antioxidant activity. The expressions of NF-κB p65, TNF-α and caspase-3 in rats administered AA (2 mL of 4% solution, once, intrarectally) were significantly increased, where the lowest expression was scored in JTME, 400 mg/kg group. In the adjuvant induced model of rheumatoid arthritis, the TJME, 400 mg/kg reduced the levels of cathepsin D, iNOS, NO, RF, CRP, CPP and elevated the total antioxidant capacity of tissues. Additionally, it maintained bones without histopathological lesions, articular cartilage damage, and inflammation of the synovial membrane and periarticular tissues, in contrast to arthritic rats. Finally, we report a new detailed study to validate the medicinal importance of Jasminum for the chronic inflammatory disorders with immune dysfunction with anti-inflammatory and antioxidant effects.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Jasminum , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Artrite Experimental/patologia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
9.
Molecules ; 26(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069658

RESUMO

Atherosclerotic cardiovascular disease is the leading cause of death in developed countries. Therefore, there is an increasing interest in developing new potent and safe antiplatelet agents. Coumarins are a family of polyphenolic compounds with several pharmacological activities, including platelet aggregation inhibition. However, their antiplatelet mechanism of action needs to be further elucidated. The aim of this study is to provide insight into the biochemical mechanisms involved in this activity, as well as to establish a structure-activity relationship for these compounds. With this purpose, the antiplatelet aggregation activities of coumarin, esculetin and esculin were determined in vitro in human whole blood and platelet-rich plasma, to set the potential interference with the arachidonic acid cascade. Here, the platelet COX activity was evaluated from 0.75 mM to 6.5 mM concentration by measuring the levels of metabolites derived from its activity (MDA and TXB2), together with colorimetric assays performed with the pure recombinant enzyme. Our results evidenced that the coumarin aglycones present the greatest antiplatelet activity at 5 mM and 6.5 mM on aggregometry experiments and inhibiting MDA levels.


Assuntos
Plaquetas/efeitos dos fármacos , Cumarínicos/farmacologia , Ciclo-Oxigenase 1/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Plaquetas/enzimologia , Plaquetas/metabolismo , Humanos , Técnicas In Vitro , Malondialdeído/metabolismo
10.
Biomed Pharmacother ; 139: 111678, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33964802

RESUMO

In this study we present design and synthesis of nineteen new nitric oxide-releasing indomethacin derivatives with 1,3-thiazolidine-4-one scaffold (NO-IND-TZDs) (6a-s), as a new safer and efficient multi-targets strategy for inflammatory diseases. The chemical structure of all synthesized derivatives (intermediaries and finals) was proved by NMR and mass spectroscopic analysis. In order to study the selectivity of NO-IND-TZDs for COX isoenzymes (COX-1 and COX-2) a molecular docking study was performed using AutoDock 4.2.6 software. Based on docking results, COX-2 inhibitors were designed and 6o appears as the most selective derivative which showed an improved selective index compared with indomethacin (IND) and diclofenac (DCF), used as reference drugs. The biological evaluation of 6a-s, using in vitro assays has included the anti-inflammatory and antioxidant effects as well as the nitric oxide (NO) release. Referring to the anti-inflammatory effects, the most active compound was 6i, which was more active than IND and aspirin (ASP) in term of denaturation effect, on bovine serum albumin (BSA), as indirect assay to predict the anti-inflammatory effect. An appreciable anti-inflammatory effect, in reference with IND and ASP, was also showed by 6k, 6c, 6q, 6o, 6j, 6d. The antioxidant assay revealed the compound 6n as the most active, being 100 times more active than IND. The compound 6n showed also the most increase capacity to release NO, which means is safer in terms of gastro-intestinal side effects. The ADME-Tox study revealed also that the NO-IND-TZDs are generally proper for oral administration, having optimal physico-chemical and ADME properties. We can conclude that the compounds 6i and 6n are promising agents and could be included in further investigations to study in more detail their pharmaco-toxicological profile.


Assuntos
Indometacina/análogos & derivados , Indometacina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Tiazolidinas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Aspirina/farmacologia , Simulação por Computador , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Diclofenaco/farmacologia , Desenho de Fármacos , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Humanos , Indometacina/química , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/toxicidade , Soroalbumina Bovina/química , Relação Estrutura-Atividade
11.
Bioorg Chem ; 113: 104948, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34052736

RESUMO

Various febuxostat derivatives comprising carboxamide functionalities and different substituted heterocycles were synthesized and evaluated for their biological activities as xanthine oxidase (XO) and cyclooxygenase (COX) inhibitors. All the tested compounds exhibited variable in vitro XO inhibitory activities (IC50 values 0.009-0.077 µM), among which the analog 17 has emerged as the most potent derivative (IC50 0.009 µM), representing nearly 3-times the potency of febuxostat (IC50 0.026 µM). The same analogs were further investigated for their in vitro COX-1 and COX-2 inhibitory activity, where fifteen analogs demonstrated recognizable COX-2 inhibitory potential (IC50 values range 0.04 - 0.1 µM), when correlated with celecoxib (IC50 0.05 µM), together with appreciable selectivity indices. Compounds 5a, 14b, 17, 19c, 19e and 21b that showed significant in vitro XO and/ or COX inhibitory potentials were further investigated for their in vivo hypouricemic as well as anti-inflammatory activities. Interestingly, the in vivo results were concordant with the collected in vitro data. Docking of compounds 5a, 14b, 17, 19c, 19e and 21b with the active sites of XO and COX-2 isozymes demonstrated superior binding profile compared with the reported ligands (febuxostat and celecoxib, respectively). Their docking scores were reasonable and cohering to a great extent with their corresponding in vitro IC50 values. Moreover, in silico computation of the predicted pharmacokinetic and toxicity properties (ADMET), together with the ligand efficiency (LE) of the same six compounds suggesting their liability to act as new orally active drug candidates with a predicted high safety profile.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores Enzimáticos/farmacologia , Febuxostat/farmacologia , Compostos Heterocíclicos/farmacologia , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Carragenina , Bovinos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Febuxostat/síntese química , Febuxostat/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Ovinos , Relação Estrutura-Atividade , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
12.
PLoS One ; 16(4): e0250638, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33891661

RESUMO

Prostaglandin E2 (PGE2) is known to have important roles in labor, but the detailed mechanism underlying the spontaneous human labor remains unknown. Here, we examined the involvement of prostaglandin biosynthetic enzymes and transporter in the accumulation of PGE2 in amniotic fluid in human labor. PGE2 and its metabolites were abundant in amniotic fluid in deliveries at term in labor (TLB), but not at term not in labor (TNL). In fetal-membrane Transwell assays, levels of PGE2 production in both maternal and fetal compartments were significantly higher in the TLB group than the TNL group. In fetal-membrane, the mRNA level of PTGES3, which encodes cytosolic prostaglandin E synthase (cPGES), was significantly higher in TLB than in TNL, but the mRNA levels of the other PGE2-synthase genes were not affected by labor. Moreover, the mRNA level of PTGS2, which encodes cyclooxygenase-2 (COX-2) in the amnion was significantly higher in TLB than in TNL. Western blot analyses revealed that the levels of COX-1 and COX-2 were comparable between the two groups, however, the level of cPGES was relatively higher in TLB than in TNL. COXs, cPGES, and prostaglandin transporter (SLCO2A1) proteins were all expressed in both chorionic trophoblasts and amniotic epithelium. These findings suggest that COXs, cPGES and SLCO2A1 contribute to PGE2 production from fetal-membrane in labor.


Assuntos
Âmnio/metabolismo , Dinoprostona/metabolismo , Membranas Extraembrionárias/metabolismo , Trabalho de Parto/metabolismo , Prostaglandina-E Sintases/metabolismo , Líquido Amniótico/metabolismo , Cromatografia Líquida de Alta Pressão , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/análise , Membranas Extraembrionárias/patologia , Feminino , Humanos , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Gravidez , Prostaglandina-E Sintases/genética , RNA Mensageiro/metabolismo , Espectrometria de Massas em Tandem , Regulação para Cima
13.
Biomolecules ; 11(3)2021 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800000

RESUMO

Cancer is a major burden of disease globally. Each year, tens of millions of people are diagnosed with cancer worldwide, and more than half of the patients eventually die from it. Significant advances have been noticed in cancer treatment, but the mortality and incidence rates of cancers are still high. Thus, there is a growing research interest in developing more effective and less toxic cancer treatment approaches. Curcumin (CUR), the major active component of turmeric (Curcuma longa L.), has gained great research interest as an antioxidant, anticancer, and anti-inflammatory agent. This natural compound shows its anticancer effect through several pathways including interfering with multiple cellular mechanisms and inhibiting/inducing the generation of multiple cytokines, enzymes, or growth factors including IκB kinase ß (IκKß), tumor necrosis factor-alpha (TNF-α), signal transducer, and activator of transcription 3 (STAT3), cyclooxygenase II (COX-2), protein kinase D1 (PKD1), nuclear factor-kappa B (NF-κB), epidermal growth factor, and mitogen-activated protein kinase (MAPK). Interestingly, the anticancer activity of CUR has been limited primarily due to its poor water solubility, which can lead to low chemical stability, low oral bioavailability, and low cellular uptake. Delivering drugs at a controlled rate, slow delivery, and targeted delivery are other very attractive methods and have been pursued vigorously. Multiple CUR nanoformulations have also been developed so far to ameliorate solubility and bioavailability of CUR and to provide protection to CUR against hydrolysis inactivation. In this review, we have summarized the anticancer activity of CUR against several cancers, for example, gastrointestinal, head and neck, brain, pancreatic, colorectal, breast, and prostate cancers. In addition, we have also focused on the findings obtained from multiple experimental and clinical studies regarding the anticancer effect of CUR in animal models, human subjects, and cancer cell lines.


Assuntos
Antineoplásicos/uso terapêutico , Curcumina/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Linhagem Celular Tumoral , Curcuma/química , Ciclo-Oxigenase 1/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Humanos , NF-kappa B/metabolismo , Extratos Vegetais/química , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPP/metabolismo
14.
Int Arch Allergy Immunol ; 182(9): 788-799, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33873179

RESUMO

INTRODUCTION: Epicutaneous (e.c.) allergen exposure is an important route of sensitization toward allergic diseases in the atopic march. Allergen sources such as house dust mites contain proteases that involve in the pathogenesis of allergy. Prostanoids produced via pathways downstream of cyclooxygenases (COXs) regulate immune responses. Here, we demonstrate effects of COX inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) on e.c. sensitization to protease allergen and subsequent airway inflammation in mice. METHODS: Mice were treated with NSAIDs during e.c. sensitization to a model protease allergen, papain, and/or subsequent intranasal challenge with low-dose papain. Serum antibodies, cytokine production in antigen-restimulated skin or bronchial draining lymph node (DLN) cells, and airway inflammation were analyzed. RESULTS: In e.c. sensitization, treatment with a nonspecific COX inhibitor, indomethacin, promoted serum total and papain-specific IgE response and Th2 and Th17 cytokine production in skin DLN cells. After intranasal challenge, treatment with indomethacin promoted allergic airway inflammation and Th2 and Th17 cytokine production in bronchial DLN cells, which depended modestly or largely on COX inhibition during e.c. sensitization or intranasal challenge, respectively. Co-treatment with COX-1-selective and COX-2-selective inhibitors promoted the skin and bronchial DLN cell Th cytokine responses and airway inflammation more efficiently than treatment with either selective inhibitor. CONCLUSION: The results suggest that the overall effects of COX downstream prostanoids are suppressive for development and expansion of not only Th2 but also, unexpectedly, Th17 upon exposure to protease allergens via skin or airways and allergic airway inflammation.


Assuntos
Alérgenos/imunologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Peptídeo Hidrolases/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Diferenciação Celular , Feminino , Imunização , Camundongos , Papaína/imunologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
15.
J Pharm Pharmacol ; 73(4): 553-559, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33793832

RESUMO

OBJECTIVE: To investigate the main chemical components and the anti-inflammatory activity of extracts of Adelia ricinella L. aerial parts. METHODS: Three extracts obtained by soxhlet extraction and ethanol/water mixtures were evaluated in their chemical composition by UPLC-DAD-MS/MS. The in vitro anti-inflammatory activity of the prepared extracts was assessed through three different assays: COX-1 and COX-2 enzymatic inhibition, cell-based COX assays on RAW264.7 macrophages (ATCC) measuring the COX-2 protein expression by Western blot and the measurement of the PGE2 concentration in the supernatants of the culture medium. Also was determinate the effect of the three extracts on the RAW 264.7 cell viability. KEY FINDINGS: Few differences in the phytochemical profile were found between the three prepared extracts, identifying a blend of thirteen flavonoids derived from luteolin and apigenin, with orientin as main constituent. Plant extracts (alcoholic and aqueous) did not affect the macrophage cell viability (IC50 > 256 µg/ml) and significantly reduced COX-1 and COX-2 enzyme activities. Additionally, COX-2 expression and PGE2 release were suppressed after 24 h of LPS stimulation and treatment with plant extracts (8-64 µg/ml). CONCLUSIONS: A. ricinella extracts showed the ability to reduce the inflammatory effect exerted by LPS in murine macrophages. However, further studies should confirm their anti-inflammatory activity.


Assuntos
Apigenina , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Euphorbiaceae/química , Flavonoides , Glucosídeos , Luteolina , Animais , Anti-Inflamatórios/farmacologia , Apigenina/isolamento & purificação , Apigenina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 1/análise , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Luteolina/isolamento & purificação , Luteolina/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Componentes Aéreos da Planta , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células RAW 264.7
16.
Int J Mol Sci ; 22(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33806238

RESUMO

In an intraocular inflammatory state, microglia residing in the retina become active and migrate inside the retina. In this study, we investigated whether cyclooxygenase-1 (COX-1) expressed by retinal microglia/macrophage can be a biomarker for the diagnosis of retinal diseases. COX-1 was immunopositive in microglia/macrophage and neutrophils, while COX-2 was immunopositive in astrocytes and neurons in the inner layer of normal retina. The number of COX-1 positive cells per section of the retinal tissue was 14 ± 2.8 (mean ± standard deviation) in normal mice, which showed significant increase in the lipopolysaccharide (LPS)-administrated model (62 ± 5.0, p = 8.7 × 10-9). In addition to microglia, we found neutrophils that were positive for COX-1. In the early stage of inflammation in the experimental autoimmune uveoretinitis (EAU), COX-1 positive cells, infiltrating from the ciliary body into the retinal outer nuclear layer, were observed. The number of infiltrating COX-1 positive cells correlated with the severity of EAU. Taken together, the increased number of COX-1 positive microglia/macrophage with morphological changes were observed in the retinas of retinal inflammatory disease models. This suggests that COX-1 can be a marker of disease-related activities of microglia/macrophage, which should be useful for the diagnosis of retinal diseases.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Macrófagos/patologia , Proteínas de Membrana/metabolismo , Microglia/patologia , Doenças Retinianas/patologia , Animais , Astrócitos/metabolismo , Biomarcadores , Feminino , Inflamação , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Neurônios/metabolismo , Neutrófilos/metabolismo , Tomografia de Coerência Óptica
17.
Cells ; 10(2)2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669841

RESUMO

Macrophages are professional antigen presenting cells with intense phagocytic activity, strategically distributed in tissues and cavities. These cells are capable of responding to a wide variety of innate inflammatory stimuli, many of which are signaled by lipid mediators. The distribution of arachidonic acid (AA) among glycerophospholipids and its subsequent release and conversion into eicosanoids in response to inflammatory stimuli such as zymosan, constitutes one of the most studied models. In this work, we used liquid and/or gas chromatography coupled to mass spectrometry to study the changes in the levels of membrane glycerophospholipids of mouse peritoneal macrophages and the implication of group IVA cytosolic phospholipase A2 (cPLA2α) in the process. In the experimental model used, we observed that the acute response of macrophages to zymosan stimulation involves solely the cyclooxygenase-1 (COX-1), which mediates the rapid synthesis of prostaglandins E2 and I2. Using pharmacological inhibition and antisense inhibition approaches, we established that cPLA2α is the enzyme responsible for AA mobilization. Zymosan stimulation strongly induced the hydrolysis of AA-containing choline glycerophospholipids (PC) and a unique phosphatidylinositol (PI) species, while the ethanolamine-containing glycerophospholipids remained constant or slightly increased. Double-labeling experiments with 3H- and 14C-labeled arachidonate unambiguously demonstrated that PC is the major, if not the exclusive source, of AA for prostaglandin E2 production, while both PC and PI appeared to contribute to prostaglandin I2 synthesis. Importantly, in this work we also show that the COX-1-derived prostaglandins produced during the early steps of macrophage activation restrict tumor necrosis factor-α production. Collectively, these findings suggest new approaches and targets to the selective inhibition of lipid mediator production in response to fungal infection.


Assuntos
Colina/metabolismo , Cromatografia Líquida/métodos , Ciclo-Oxigenase 1/metabolismo , Expressão Gênica/genética , Glicerofosfolipídeos/metabolismo , Espectrometria de Massas/métodos , Prostaglandinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Macrófagos/metabolismo , Camundongos
18.
Eur J Pharmacol ; 899: 174036, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33737009

RESUMO

Earlier we have shown that certain flavonoids (e.g., quercetin) are high-affinity reducing cosubstrates for cyclooxygenase (COX) 1 and 2. These compounds can bind inside the peroxidase active sites of COXs and donate an electron from one of their B-ring hydroxyl groups to hematin. Based on these earlier findings, it is postulated that some of the natural flavonoids such as galangin that are structural analogs of quercetin but lack the proper B-ring hydroxyl groups might function as novel inhibitors of COXs by blocking the effect of the reducing cosubstrates. This idea is tested in the present study. Computational docking analysis together with quantum chemistry calculation shows that galangin can bind inside the peroxidase active sites of COX-1 and COX-2 in a similar manner as quercetin, but it has little ability to effectively donate its electrons, thereby blocking the effect of the reducing cosubstrates like quercetin. Further experimental studies confirm that galangin can inhibit, both in vitro and in vivo, quercetin-mediated activation of the peroxidase activity of the COX-1/2 enzymes. The results of the present study demonstrate that galangin is a novel naturally-occurring inhibitor of COX-1 and COX-2, acting by blocking the function of the reducing cosubstrates at the peroxidase sites.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Flavonoides/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Domínio Catalítico , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase/química , Dinoprostona/metabolismo , Humanos , Ligantes , Macrófagos/enzimologia , Masculino , Proteínas de Membrana , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Células RAW 264.7 , Ratos Sprague-Dawley , Relação Estrutura-Atividade
19.
Eur J Pharmacol ; 900: 174020, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33741381

RESUMO

Gastric cancer is one of the most common and deadly cancers among men and women and is the third leading cause of cancer mortality worldwide. Thus, discovering and developing novel therapeutics for gastric cancer has become a global priority. In this study, we synthesized two novel anthraquinone-based aspirin derivatives, Asp-X3 and Asp-X3-CH3, with therapeutic potential for gastric cancer. The structures of the two compounds were determined by 1D, 2D-NMR, and High-Resolution Mass (HRSM). Asp-X3 and Asp-X3-CH3 could inhibit the growth of gastric cancer cells (SGC7901), yielding IC50 values 10-fold lower than that of Aspirin. Asp-X3 and Asp-X3-CH3 were less toxic to gastric mucosal cells, yielding IC50 values that were about 2-fold higher than the corresponding IC50 values determined with SGC7901 cells. Asp-X3-CH3 and Asp-X3 also induced SGC7901 cells to undergo apoptosis, yielding apoptotic rates that were about twice the rate induced by Aspirin. Asp-X3-CH3 did not cause significant loss of COX-1 expression in gastric mucosal cells, whereas Asp-X3 and Aspirin both caused significant loss of COX-1 expression as demonstrated by Western blot, consistent with their effects on the content of PGE2 in these cells as determined by ELISA assay. However, both Asp-X3-CH3 and Asp-X3 exerted a similar effect on the level of COX-2 in gastric cancer cells, causing as much as 90% and 95% reduction in COX-2 expression, respectively. Taken together, the results suggested that Asp-X3-CH3 and Asp-X3 were potentially better agents than Aspirin for the inhibition of gastric cancer cell growth, but Asp-X3-CH3 was more effective.


Assuntos
Antraquinonas/síntese química , Antraquinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Aspirina/análogos & derivados , Aspirina/farmacologia , Neoplasias Gástricas/prevenção & controle , Apoptose/efeitos dos fármacos , Aspirina/síntese química , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Mucosa Gástrica/citologia , Mucosa Gástrica/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Neoplasias Gástricas/induzido quimicamente , Relação Estrutura-Atividade
20.
Future Med Chem ; 13(7): 625-641, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33624540

RESUMO

New hexahydropyrimido[1,2-a]azepine derivatives bearing functionalized aryl and heterocyclic moieties were synthesized as anti-inflammatory agents with better safety profiles. All synthesized compounds were assessed in vitro for their COX-1 and COX-2 inhibition activities. The most selective compounds, 2f, 5 and 6, were further evaluated for their in vivo anti-inflammatory activity and PGE2 inhibitory activity. To rationalize their selectivity, molecular docking within COX-1 and COX-2 binding sites was performed. Their physicochemical properties and drug-like nature profile were also calculated. The good activity and selectivity of compounds 2f, 5 and 6 were rationalized using a molecular docking study and supported by in vivo studies. These promising findings are encouraging for performing future investigations of these derivatives.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Azepinas/farmacologia , Edema/tratamento farmacológico , Pirimidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Azepinas/síntese química , Azepinas/química , Carragenina , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Edema/induzido quimicamente , Edema/metabolismo , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-Atividade
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