RESUMEN
The olive oil sector is a fundamental food in the Mediterranean diet. It has been demonstrated that the consumption of extra virgin olive oil (EVOO) with a high content of phenolic compounds is beneficial in the prevention and/or treatment of many diseases. The main objective of this work was to study the relationship between the content of phenolic compounds and the in vitro neuroprotective and anti-inflammatory activity of EVOOs from two PDOs in the province of Granada. To this purpose, the amounts of phenolic compounds were determined by liquid chromatography coupled to mass spectrometry (HPLC-MS) and the inhibitory activity of acetylcholinesterase (AChE) and cyclooxygenase-2 (COX-2) enzymes by spectrophotometric and fluorimetric assays. The main families identified were phenolic alcohols, secoiridoids, lignans, flavonoids, and phenolic acids. The EVOO samples with the highest total concentration of compounds and the highest inhibitory activity belonged to the Picual and Manzanillo varieties. Statistical analysis showed a positive correlation between identified compounds and AChE and COX-2 inhibitory activity, except for lignans. These results confirm EVOO's compounds possess neuroprotective potential.
Asunto(s)
Fármacos Neuroprotectores , Aceite de Oliva , Fenoles , Aceite de Oliva/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fenoles/análisis , Fenoles/química , Fenoles/farmacología , España , Ciclooxigenasa 2/metabolismo , Acetilcolinesterasa/metabolismo , Cromatografía Líquida de Alta Presión , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Flavonoides/análisis , Flavonoides/farmacología , Flavonoides/químicaRESUMEN
Depression and anxiety disorders have their pathophysiologies linked to inflammation and oxidative stress. In this context, celecoxib (CLX) and etoricoxib (ETR) inhibit cyclooxygenase 2 (COX-2), an enzyme expressed by cells involved in the inflammatory process and found in the brain. Studies have been using CLX as a possible drug in the treatment of depression, although its mechanisms at the central nervous system level are not fully elucidated. In this study, the effects of CLX and ETR on behavioral, oxidative, and inflammatory changes induced by systemic exposure to Escherichia coli lipopolysaccharide (LPS) were evaluated in adult male swiss mice. For ten days, the animals received intraperitoneal injections of LPS at 0.5 mg/kg. From the sixth to the tenth day, one hour after LPS exposure, they were treated orally with CLX (15 mg/kg), ETR (10 mg/kg), or fluoxetine (FLU) (20 mg/kg). Twenty-four hours after the last oral administration, the animals underwent evaluation of locomotor activity (open field test), predictive tests for depressive-like behavior (forced swim and tail suspension tests), and anxiolytic-like effect (elevated plus maze and hole board tests). Subsequently, the hippocampus, prefrontal cortex and striatum were dissected for the measurement of oxidative and nitrosative parameters (malondialdehyde, nitrite, and glutathione) and quantification of pro-inflammatory cytokines (IL-1ß and IL-6). LPS induced depressive and anxious-like behavior, and treatment with CLX or ETR was able to reverse most of the behavioral changes. It was evidenced that nitrosative stress and the degree of lipid peroxidation induced by LPS were reduced in different brain areas after treatment with the drugs, as well as the endogenous defense system against free radicals was strengthened. CLX and ETR also significantly reduced LPS-induced cytokine levels. These data are expected to expand information on the role of inflammation in depression and anxiety and provide insights into possible mechanisms of COX-2 inhibitors in psychiatric disorders with a neurobiological basis in inflammation and oxidative stress.
Asunto(s)
Ansiedad , Conducta Animal , Celecoxib , Inhibidores de la Ciclooxigenasa 2 , Depresión , Lipopolisacáridos , Estrés Oxidativo , Animales , Masculino , Ratones , Lipopolisacáridos/farmacología , Estrés Oxidativo/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Depresión/tratamiento farmacológico , Depresión/inducido químicamente , Depresión/metabolismo , Ansiedad/tratamiento farmacológico , Ansiedad/inducido químicamente , Conducta Animal/efectos de los fármacos , Celecoxib/farmacología , Celecoxib/administración & dosificación , Etoricoxib/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/metabolismoRESUMEN
A high throughput method was developed to detect bioactive molecules with inhibitory activity over cyclooxygenase (COX-2) enzyme applying effect-directed analysis and planar chromatography hyphenated with bioassay and mass spectrometry. The assay was based on the indirect measurement of arachidonic acid transformation into prostaglandin with the colorimetric co-substrate N,N,N',N'-tetramethyl-p-phenylenediamine. Inhibitory zones were observed as colorless bands over a blue background. Using a central composite design the critical factors like substrate concentration, enzyme: substrate ratio, reaction time, and co-substrate concentration were optimized. Optimal conditions were achieved with 0.03 mg/mL of arachidonic acid, 0.15 U/mL of COX-2, and 8.21 mg/mL of chromogenic reagent. Method usefulness was challenged analyzing fresh Chiloe's giant garlic (Allium ampeloprasum L) ethanol: water (8:2 v/v) extract, finding COX-2 inhibitors that were preliminarily identified as the isomers γ-glutamyl-S-allyl-l-cysteine and γ-glutamyl-S-(trans-1-propenyl)-L- cysteine.
Asunto(s)
Bioensayo , Inhibidores de la Ciclooxigenasa 2 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2/farmacología , Cromatografía en Capa Delgada/métodos , Ácido Araquidónico , Espectrometría de Masas , Bioensayo/métodos , Extractos Vegetales/farmacología , Extractos Vegetales/químicaRESUMEN
Pulmonary tuberculosis (TB) inflammation is an underestimated disease complication which anti-inflammatory drugs may alleviate. This study explored the potential use of the COX-2 inhibitors acetylsalicylic acid (ASA) and celecoxib in 12 TB patients and 12 healthy controls using a whole-blood ex vivo model where TNFα, PGE2, and LTB4 plasma levels were quantitated by ELISA; we also measured COX-2, 5-LOX, 12-LOX, and 15-LOX gene expression. We observed a significant TNFα production in response to stimulation with LPS or M. tuberculosis (Mtb). Celecoxib, but not ASA, reduced TNFα and PGE2 production, while increasing LTB4 in patients after infection with Mtb. Gene expression of COX-2 and 5-LOX was higher in controls, while 12-LOX was significantly higher in patients. 15-LOX expression was similar in both groups. We concluded that COX-2 inhibitors downregulate inflammation after Mtb infection, and our methodology offers a straightforward time-efficient approach for evaluating different drugs in this context. Further research is warranted to elucidate the underlying mechanisms and assess the potential clinical benefit.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Humanos , Celecoxib/farmacología , Celecoxib/uso terapéutico , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Dinoprostona , Inmunidad , Inflamación/metabolismo , Leucotrieno B4/metabolismo , Mycobacterium tuberculosis/metabolismo , Tuberculosis/tratamiento farmacológico , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: Arylindole derivatives are promising scaffolds in the design of new drugs. These scaffolds exhibit a wide biological activity, including inhibition of COX-2, antitumor activity, receptor GABA agonism, and estrogen receptor modulation. OBJECTIVES: Taking this into account, this paper presents a study to understand the inhibitory action of certain 2-arylindole derivatives, specifically a series of 2,3-diarylindoles with IC50 values from 0.006 nM to 100 nM, on the COX-2 enzyme and supports its structural-activity relationship (SAR) through molecular docking simulations. METHODS: Applying molecular modelling, especially molecular docking, we assessed the SAR of a series of 2,3-arylindoles derivatives in the COX-2 enzyme. RESULTS: The results indicated that Gly 526 and Phe 381 residues are relevant for improving inhibitory activity on para-substituted 3-phenyl- compounds. Arg 120 was also demonstrated to be an important residue for COX-2 inhibition since it enables a π-cation interaction with the best compound in series A5 (experimental IC50 = 0.006 nM determined in advance). Furthermore, COX-2 presents flexibility in some regions of the active site to adequately accommodate 5-substituted compounds containing an indole ring. CONCLUSION: Therefore, such structural features can be used as support for further Structural-Based Drug Design (SBDD) and/or Ligand-Based Drug Design (LBDD) studies on new selective COX-2 inhibitors.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2 , Diseño de Fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Simulación del Acoplamiento Molecular , Ciclooxigenasa 2/metabolismo , Relación Estructura-Actividad , Modelos Moleculares , Estructura Molecular , Relación Dosis-Respuesta a DrogaRESUMEN
This article aims at reviewing celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) predominantly has two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role related to homeostatic effects in renal and platelets, while the latter is mainly responsible for the induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and have no side effects. In this sense, celecoxib is the only potent, selective COX-2 inhibitor that is still commercially available (within the "coxib" family). Thus, celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for the COX-2 enzyme. This review provides inhibition highlights that should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs), which act as COX-2 inhibitors with lesser side effects on the human body.
Asunto(s)
Celecoxib , Inhibidores de la Ciclooxigenasa 2 , Antiinflamatorios no Esteroideos/farmacología , Celecoxib/farmacología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2/farmacología , Humanos , IsoenzimasRESUMEN
Cyclooxygenase 2 (COX-2) is a well-established target for the design of anti-inflammatory intermediates. Celecoxib was selected as a template molecule to perform ligand-based virtual screening, i.e. to search for structures with similarity in shape and electrostatic potential, with a gradual increase in accuracy through the combined fitting of several steps using eight commercial databases. The molecules ZINC408709 and ZINC2090319 reproduced values within the limits established in an initial study of absorption and distribution in the body. No alert was fired for possible toxic groups when these molecules were subjected to toxicity prediction. Molecular docking results with these compounds showed a higher binding affinity in comparison to rofecoxib for the COX-2 target. Additionally, ZINC408709 and ZINC2090319 were predicted to be potentially biologically active. In in silico prediction of endocrine disruption potential, it was established that the molecule ZINC2090319 binds strongly to the target related to cardiovascular risk in a desirable way as a non-steroidal antagonist and ZINC408709 binds strongly to the target that is associated with the treatment of inflammatory pathologies and similar to celecoxib. Metabolites generated from these compounds are less likely to have side effects. Simulations were used to evaluate the interaction of compounds with COX-1 and COX-2 during 200 ns. Despite the differences, ZINC408709 molecule showed better stability for COX-2 during molecular dynamics simulation. In the calculations of free energy MM/PBSA, the molecule ZINC408709 ΔGbind value has a higher affinity to celecoxib and rofecoxib COX-2. This demonstrates that the selected substances can be considered as promising COX-2 inhibitors. Communicated by Ramaswamy H. Sarma.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2 , Simulación de Dinámica Molecular , Celecoxib/farmacología , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Ligandos , Simulación del Acoplamiento MolecularRESUMEN
Phytochemicals have been suggested as an effective strategy for cancer prevention. Within this context, triterpene betulinic acid (BA) exhibits several biological properties but its chemopreventive effect has not been fully demonstrated. The present study investigated the antigenotoxic potential of BA against doxorubicin (DXR)-induced genotoxicity using the mouse peripheral blood micronucleus assay, as well as its anticarcinogenic activity against 1,2dimethylhydrazine (DMH)-induced colorectal lesions in rats. Micronuclei (MN) assay and aberrant crypt foci assay were used to assess the antigenotoxic and the anticarcinogenic potential, respectively. The molecular mechanisms underlying the anticarcinogenic activity of BA were evaluated by assessing anti-inflammatory (COX-2) and antiproliferative (PCNA) pathways. The results demonstrated that BA at the dose of 0.5 mg/kg bodyweight exerted antigenotoxic effects against DXR, with a reduction of 70.2% in the frequencies of chromosomal damage. Animals treated with BA showed a 64% reduction in the number of preneoplastic lesions when compared to those treated with the carcinogen alone. The levels of COX-2 and PCNA expression in the colon were significantly lower in animals treated with BA and DMH compared to those treated with the carcinogen alone. The chemopreventive effect of BA is related, at least in part, to its antiproliferative and anti-inflammatory activity, indicating a promising potential of this triterpene in anticancer therapies, especially for colorectal cancer.
Asunto(s)
Anticarcinógenos/farmacología , Antimutagênicos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/efectos de los fármacos , Triterpenos Pentacíclicos/farmacología , Antígeno Nuclear de Célula en Proliferación/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/prevención & control , Ciclooxigenasa 2/metabolismo , Doxorrubicina/toxicidad , Inflamación/prevención & control , Masculino , Ratones , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/prevención & control , Transducción de Señal/efectos de los fármacos , Ácido BetulínicoRESUMEN
BACKGROUND: Penile cancer (PeCa) is a rare disease, but its incidence has increased worldwide, mostly in HPV+ patients. Nevertheless, there is still no targeted treatment for this carcinoma. OBJECTIVE: To predict the main signaling pathways involved in penile tumorigenesis and its potential drug targets. METHODS: Genome-wide copy number profiling was performed in 28 PeCa. Integration analysis of CNAs and miRNAs and mRNA targets was performed by DIANA-TarBase v.8. The potential impact of the miRNAs/target genes on biological pathways was assessed by DIANA-miRPath v.3.0. For each miRNA, KEGG pathways were generated based on the tarbase and microT-CDS algorithms. Pharmaco-miR was used to identify associations between miRNAs and their target genes to predict druggable targets. RESULTS: 269 miRNAs and 2,395 genes were mapped in cytobands with CNAs. The comparison of the miRNAs mapped at these cytobands and the miRNAs that were predicted to regulate the genes also mapped in these regions, resulted in a set of common 35 miRNAs and 292 genes. Enrichment pathway revealed their involvement in five top signaling pathways. EGFR and COX2 were identified as potential druggable targets. CONCLUSION: Our data indicate the potential use of EGFR and COX2 inhibitors as a target treatment for PeCa patients.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma/genética , Infecciones por Papillomavirus/genética , Neoplasias del Pene/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Carcinogénesis/genética , Carcinoma/tratamiento farmacológico , Carcinoma/patología , Carcinoma/virología , Ciclooxigenasa 2/genética , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Variaciones en el Número de Copia de ADN , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Infecciones por Papillomavirus/tratamiento farmacológico , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Neoplasias del Pene/tratamiento farmacológico , Neoplasias del Pene/patología , Neoplasias del Pene/virología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Mensajero/metabolismo , Transducción de Señal/genéticaRESUMEN
Congenital toxoplasmosis is represented by the transplacental passage of Toxoplasma gondii from the mother to the fetus. Our studies demonstrated that T. gondii developed mechanisms to evade of the host immune response, such as cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2) induction, and these mediators can be produced/stored in lipid droplets (LDs). The aim of this study was to evaluate the role of COX-2 and LDs during T. gondii infection in human trophoblast cells and villous explants. Our data demonstrated that COX-2 inhibitors decreased T. gondii replication in trophoblast cells and villous. In BeWo cells, the COX-2 inhibitors induced an increase of pro-inflammatory cytokines (IL-6 and MIF), and a decrease in anti-inflammatory cytokines (IL-4 and IL-10). In HTR-8/SVneo cells, the COX-2 inhibitors induced an increase of IL-6 and nitrite and decreased IL-4 and TGF-ß1. In villous explants, the COX-2 inhibitors increased MIF and decreased TNF-α and IL-10. Furthermore, T. gondii induced an increase in LDs in BeWo and HTR-8/SVneo, but COX-2 inhibitors reduced LDs in both cells type. We highlighted that COX-2 is a key factor to T. gondii proliferation in human trophoblast cells, since its inhibition induced a pro-inflammatory response capable of controlling parasitism and leading to a decrease in the availability of LDs, which are essentials for parasite growth.
Asunto(s)
Vellosidades Coriónicas/parasitología , Ciclooxigenasa 2/metabolismo , Gotas Lipídicas/metabolismo , Toxoplasma/crecimiento & desarrollo , Trofoblastos/parasitología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Vellosidades Coriónicas/inmunología , Vellosidades Coriónicas/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Proteínas de la Matriz Extracelular/metabolismo , Interacciones Huésped-Parásitos , Humanos , Interleucinas/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Nitritos/metabolismo , Toxoplasma/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Trofoblastos/inmunología , Trofoblastos/metabolismoRESUMEN
BACKGROUND: In this article, a series of 20 new thiosemicarbazone derivatives containing indole were synthesized and evaluated for their anti-inflammatory potential. METHODS: The compounds were obtained through a synthetic route of only two steps, with yields that varied between 33.6 and 90.4%, and characterized by spectroscopic and spectrometric techniques. RESULTS: An initial screening through the lymphoproliferation assay revealed that compounds LT76, LT81, and LT87 were able to inhibit lymphocyte proliferation, with CC50 of 0.56 ± 0.036, 0.9 ± 0.01 and 0.5 ± 0.07 µM, respectively, better results than indomethacin (CC50 > 12 µM). In addition, these compounds were able to suppress the in-vitro production of TNF-α and NO, in addition to stimulating the production of IL-4. Reinforcing in-vitro assays, the compounds were able to inhibit COX-2 similar to Celecoxib showing greater selectivity for this isoform (LT81 SI: 23.06 versus Celecoxib SI: 11.88). Animal studies showed that compounds LT76 (64.8% inhibition after 6 h), LT81 (89% inhibition after 6 h) and LT87 (100% inhibition after 4 h) were able to suppress edema in mice after inoculation carrageenan with greater potency than indomethacin, and immunohistochemistry revealed that the groups treated with LT76, LT81 and LT87 reduced the expression of COX-2, similar or better results when compared to indomethacin. Complementarily, in-silico studies have shown that these compounds have a good pharmacokinetic profile, for respecting the parameters of Lipinski and Veber, showing their good bioavailability. CONCLUSIONS: These results demonstrate the potency of thiosemicarbazone derivatives containing indole and confirm their importance as scaffolds of molecules with notorious anti-inflammatory activity.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Tiosemicarbazonas/farmacología , Animales , Carragenina/farmacología , Celecoxib/farmacología , Proliferación Celular/efectos de los fármacos , Edema/tratamiento farmacológico , Edema/metabolismo , Indoles/farmacología , Indometacina/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side effects of non-selective inhibitors of COX-1. Thus, the present study aims to identify new selective chemical entities for the COX-2 enzyme via molecular modeling approaches. The best pharmacophore model was used to identify compounds within the ZINC database. The molecular properties were determined and selected with Pearson's correlation for the construction of quantitative structure-activity relationship (QSAR) models to predict the biological activities of the compounds obtained with virtual screening. The pharmacokinetic/toxicological profiles of the compounds were determined, as well as the binding modes through molecular docking compared to commercial compounds (rofecoxib and celecoxib). The QSAR analysis showed a fit with R = 0.9617, R2 = 0.9250, standard error of estimate (SEE) = 0.2238, and F = 46.2739, with the tetra-parametric regression model. After the analysis, only three promising inhibitors were selected, Z-964, Z-627, and Z-814, with their predicted pIC50 (-log IC50) values, Z-814 = 7.9484, Z-627 = 9.3458, and Z-964 = 9.5272. All candidates inhibitors complied with Lipinski's rule of five, which predicts a good oral availability and can be used in in vitro and in vivo tests in the zebrafish model in order to confirm the obtained in silico data.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/farmacología , Inflamación/tratamiento farmacológico , Animales , Sitios de Unión , Células CACO-2 , Celecoxib/farmacología , Perros , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Lactonas/farmacología , Células de Riñón Canino Madin Darby , Simulación del Acoplamiento Molecular , Estructura Molecular , Permeabilidad , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Análisis de Regresión , Programas Informáticos , Sulfonas/farmacologíaRESUMEN
In this study, we investigated the effects and mechanisms of the pro-inflammatory cytokines IL-1ß and TNF-α on the proliferation and commitment phases of myoblast differentiation. C2C12 mouse myoblast cells were cultured to reach a proliferated or committed status and were incubated with these cytokines for the evaluation of cell proliferation, cyclooxygenase 2 (COX-2) expression, release of prostaglandins (PGs) and myokines, and activation of myogenic regulatory factors (MRFs). We found that inhibition of the IL-6 receptor reduced IL-1ß- and TNF-α-induced cell proliferation, and that the IL-1ß effect also involved COX-2-derived PGs. Both cytokines modulated the release of the myokines myostatin, irisin, osteonectin, and IL-15. TNF-α and IL-6 reduced the activity of Pax7 in proliferated cells and reduced MyoD and myogenin activity at both proliferative and commitment stages. Otherwise, IL-1ß increased myogenin activity only in committed cells. Our data reveal a key role of IL-6 and COX-2-derived PGs in IL-1ß and TNF-α-induced myoblast proliferation and support the link between TNF-α and IL-6 and the activation of MRFs. We concluded that IL-1ß and TNF-α induce similar effects at the initial stages of muscle regeneration but found critical differences between their effects with the progression of the process, bringing new insights into inflammatory signalling in skeletal muscle regeneration.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Interleucina-1beta/farmacología , Interleucina-6/metabolismo , Mioblastos/metabolismo , Prostaglandinas/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular , Inhibidores de la Ciclooxigenasa 2/farmacología , Diclofenaco/análogos & derivados , Diclofenaco/farmacología , Ratones , Desarrollo de Músculos/efectos de los fármacos , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Receptores de Interleucina-6/antagonistas & inhibidores , Regeneración/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The inflammatory response is the reaction of living tissue to an injury of a foreign nature, such as infection and irritants, and occurs as part of the body's natural defence response. Compounds capable of inhibiting cyclooxygenase (COX) enzymes, especially COX-2, have great potential as anti-inflammatory agents. Herein we present the regioselective synthesis of 49 novel compounds based on the 2-pyridone nucleus. The topical anti-inflammatory activity of seventeen compounds was evaluated in mice by croton oil (CO) induced ear edema assay. Most of the compounds exhibited a high level of in vivo anti-inflammatory activity, reducing ear edema and myeloperoxidase (MPO) activity. The most active compounds (2a and 7a) were inhibitors of COX enzymes. Compound 2a selectively inhibited the COX-2, while 7a was nonselective. Further, the compound 2a showed effective binding at the active site of COX-2 co-crystal by docking molecular study.
Asunto(s)
Antiinflamatorios/síntesis química , Piridonas/química , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Sitios de Unión , Dominio Catalítico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Edema/inducido químicamente , Edema/tratamiento farmacológico , Humanos , Ratones , Conformación Molecular , Simulación del Acoplamiento Molecular , Peroxidasa/metabolismo , Piridonas/metabolismo , Piridonas/uso terapéutico , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Canine leishmaniasis (CanL) is caused by the intracellular parasite Leishmania infantum. Prostaglandin E2 (PGE2 ) exerts potent regulatory effects on the immune system in experimental model Leishmania infection, but this influence has not yet been studied in CanL. In this study, PGE2 and PGE2 receptor levels and the regulatory effect of PGE2 on arginase activity, NO2 , IL-10, IL-17, IFN-γ, TNF-α and parasite load were evaluated in cultures of splenic leucocytes obtained from dogs with CanL in the presence of agonists and inhibitors. Our results showed that splenic leucocytes from dogs with CanL had lower EP2 receptor levels than those of splenic leucocytes from healthy animals. We observed that NO2 levels decreased when the cells were treated with a PGE2 receptor agonist (EP1/EP2/EP3) or COX-2 inhibitor (NS-398) and that TNF-α, IL-17 and IFN-γ cytokine levels decreased when the cells were treated with a PGE2 receptor agonist (EP2) or PGE2 itself. The parasite load in splenic leucocyte cell cultures from dogs with CanL decreased after stimulation of the cells with PGE2 . We conclude that Leishmania infection of dogs modulates PGE2 receptors and speculate that the binding of PGE2 to its receptors may activate the microbicidal capacity of cells.
Asunto(s)
Citocinas/inmunología , Dinoprostona/metabolismo , Enfermedades de los Perros/tratamiento farmacológico , Leishmania infantum/inmunología , Leishmaniasis/veterinaria , Receptores de Prostaglandina E/metabolismo , Animales , Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Dinoprostona/agonistas , Dinoprostona/antagonistas & inhibidores , Enfermedades de los Perros/inmunología , Enfermedades de los Perros/parasitología , Perros , Leishmaniasis/tratamiento farmacológico , Leishmaniasis/inmunología , Óxido Nítrico/análisis , Nitrobencenos/farmacología , Carga de Parásitos , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E/fisiología , Sulfonamidas/farmacología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
2-arylbenzofuran-containing compounds are chemical entities that can be naturally produced by several organisms. A wide-range of activities is described for several compounds of this kind and they are, therefore, valuable moieties for a lead finding from nature. Although there are in-vitro data about the activity of 2-arylbenzofuran-related compounds against cyclooxygenase (COX) enzymes, the molecular level of these COX-inhibiting constituents had not been deeply explored. Thus, 58 2-arylbenzofurans were initially screened through molecular docking within the active site of nine COX-2 crystal structures. The resulting docking scores were statistically analyzed and good reproducibility and convergence were found to discriminate the best-docked compounds. Discriminated compounds exhibited the best performance in molecular dynamics simulations as well as the most-favorable binding energies and the lowest in-vitro IC50 values for COX-2 inhibition. A three-dimensional quantitative activity-structure relationship (3D-QSAR) was also demonstrated, which showed some crucial structural requirements for enhanced enzyme inhibition. Therefore, four hits are proposed as lead structures for the development of COX-2 inhibitors based on 2-arylbenzofurans in further studies.
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Benzofuranos/química , Benzofuranos/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Animales , Dominio Catalítico , Celecoxib/química , Biología Computacional , Ciclooxigenasa 2/química , Imagenología Tridimensional , Concentración 50 Inhibidora , Ligandos , Ratones , Simulación de Dinámica Molecular , Distribución de Poisson , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Reproducibilidad de los Resultados , Electricidad Estática , TermodinámicaRESUMEN
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.
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Bignoniaceae/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Flavonoides/farmacología , Hiperalgesia/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/química , Modelos Animales de Enfermedad , Flavonoides/química , Hiperalgesia/inducido químicamente , Hiperalgesia/diagnóstico por imagen , Ácido Yodoacético/toxicidad , Actividad Motora/efectos de los fármacos , Especificidad de Órganos/efectos de los fármacos , Osteoartritis/inducido químicamente , Osteoartritis/diagnóstico por imagen , Extractos Vegetales/química , Ratas , Ratas WistarRESUMEN
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.
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Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Quinonas/química , Quinonas/farmacología , Sitios de Unión , Fenómenos Químicos , Humanos , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad CuantitativaRESUMEN
Os coxibes são uma nova geração de anti-inflamatórios não esteroidais, sendo seu principal mecanismo de ação a inibição seletiva da COX-2. Os fármacos são utilizados no tratamento da dor de osteoartrite (AO), no tratamento de neoplasias ou auxiliando no tratamento de dores crônicas, possibilitando um maior bem-estar animal. Objetivou-se nesta revisão de literatura salientar seu mecanismo de ação, as características fármaco-fisiológicas dos fármacos e seu uso empregado na Medicina Veterinária.(AU)
Coxibs are a new generation of nonsteroidal anti-inflammatory drugs, as their main mechanism of action is the selective inhibition of COX-2. The drugs are used in the treatment of osteoarthritis pain (OA), in the treatment of neoplasms or helping in the treatment of chronic pain, allowing greater animal welfare. The objective of this literature review was to emphasize its mechanism of action, the pharmacological and physiological characteristics of the drugs and its use in Veterinary Medicine.(AU)
Los coxibes son una nueva generación de antiinflamatorios no esteroides, siendo su principal mecanismo de acción la inhibición selectiva de la COX-2. Los fármacos se utilizan en el tratamiento del dolor de osteoartritis (AO), en el tratamiento de neoplasias o auxiliando en el tratamiento de dolores crónicos, posibilitando un mayor bienestar animal. Se objetivó en esta revisión de literatura resaltar su mecanismo de acción, las características fármaco-fisiológicas de los fármacos y su uso empleado en la Medicina Veterinaria.(AU)
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Animales , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
BACKGROUND: Aspirin is the oldest and possibly the most widely used pharmacologically active substance still used in allopathic medicine. Its effect on fever and inflammation has paved the way to its anti-thrombotic effect. Dilutions of aspirin have been tested for many years in the University of Bordeaux, in humans as well as in animal models. METHODS: This article is a review of the totality of articles published by the Laboratory of Hematology of the Faculty of Pharmacy of the University of Bordeaux, reporting different doses and dilutions of aspirin, different kinds of inhibitors, transgenic mice and animal models of disease such as portal hypertension and cirrhosis. RESULTS: Homeopathic dilutions of aspirin, notably 15 cH, have shown a pro-thrombotic effect in humans and in in-vivo animal studies. Longitudinal studies in rats have also shown an initial anti-thrombotic effect followed by a pro-thrombotic effect of aspirin several days after a single high-dose administration. This pro-thrombotic effect seems to act by inhibiting the cyclooxygenase (COX)-2 pathway in studies performed with COX selective inhibitors and in knock-out mice without COX-1 or COX-2. This effect may explain the thrombo-embolic complications described after aspirin withdrawal for the purposes of surgery or after non-compliance with anti-platelet therapy, and it may be beneficial in normalising primary haemostasis and decreasing haemorrhage in animal models of portal hypertension and cirrhosis. CONCLUSIONS: Aspirin 15 cH acts through the inhibition of the COX-2 pathway producing a clear pro-thrombotic effect. Further studies should clarify if the pro-thrombotic effect of aspirin withdrawal and the effect of aspirin 15 cH are related, as secondary effects of the same drug. Clarifying this last outcome may be of great significance to public health.