RESUMEN
This study was aimed to investigate the therapeutic effect and mechanism of AKHO on 5-fluorouracil (5-FU)-induced intestinal mucositis in mice. Mouse body weight, diarrhea score, and H&E staining were applied to judge the therapeutic effect of AKHO. 16S rDNA and nontargeted metabolomics have been used to study the mechanism. WB, ELISA, and immunohistochemistry were adopted to validate possible mechanisms. The results demonstrated that AKHO significantly reduced diarrhea scores and intestinal damage induced by 5-FU in mice. AKHO lowered the serum levels of LD and DAO, and upregulated the expressions of ZO-1 and occludin in the ileum. Also, AKHO upregulated the abundance of Lactobacillus in the gut and suppressed KEGG pathways such as cortisol synthesis and secretion and arachidonic acid metabolism. Further validation studies indicated that AKHO downregulated the expressions of prostaglandin E2 (PGE2), microsomal prostaglandin E synthase-1 (mPGES-1), and PGE2 receptor EP4, as well as upregulated the expression of glucocorticoid (GC) receptor (GR), leading to improved intestinal epithelial barrier function. Taken together, AKHO elicited protective effects against 5-FU-induced mucositis by regulating the expressions of tight junction proteins via modulation of GC/GR and mPGES-1/PGE2/EP4 pathway, providing novel insights into the utilization and development of this pharmaceutical/food resource.
Asunto(s)
Alpinia , Microbioma Gastrointestinal , Mucositis , Aceites Volátiles , Ratones , Animales , Mucositis/inducido químicamente , Mucositis/tratamiento farmacológico , Dinoprostona , Prostaglandina-E Sintasas/genética , Prostaglandina-E Sintasas/metabolismo , Aceites Volátiles/farmacología , Fluorouracilo/efectos adversos , DiarreaRESUMEN
The arachidonic acid pathway participates in immunosuppression in various types of cancer. Our previous observation detailed that microsomal prostaglandin E2 synthase 1 (mPGES-1), an enzyme downstream of cyclooxygenase 2 (COX-2), limited antitumor immunity in melanoma; in addition, genetic depletion of mPGES-1 specifically enhanced immune checkpoint blockade therapy. The current study set out to distinguish the roles of mPGES-1 from those of COX-2 in tumor immunity and determine the potential of mPGES-1 inhibitors for reinforcing immunotherapy in melanoma. Genetic deletion of mPGES-1 showed different profiles of prostaglandin metabolites from that of COX-2 deletion. In our syngeneic mouse model, mPGES-1-deficient cells exhibited similar tumorigenicity to that of COX-2-deficient cells, despite a lower ability to suppress PGE2 synthesis by mPGES-1 depletion, indicating the presence of factors other than PGE2 that are likely to regulate tumor immunity. RNA-sequencing analysis revealed that mPGES-1 depletion reduced the expressions of collagen-related genes, which have been found to be associated with immunosuppressive signatures. In our mouse model, collagen was reduced in mPGES-1-deficient tumors, and phenotypic analysis of tumor-infiltrating lymphocytes indicated that mPGES-1-deficient tumors had fewer TIM3+ exhausted CD8+ T cells compared with COX-2-deficient tumors. CAY10678, an mPGES-1 inhibitor, was equivalent to celecoxib, a selective COX-2 inhibitor, in reinforcing anti-PD-1 treatment. Our study indicates that mPGES-1 inhibitors represent a promising adjuvant for immunotherapies in melanoma by reducing collagen deposition and T-cell exhaustion. Significance: Collagen is a predominant component of the extracellular matrix that may influence the tumor immune microenvironment for cancer progression. We present here that mPGES-1 has specific roles in regulating tumor immunity, associated with several collagen-related genes and propose that pharmacologic inhibition of mPGES-1 may hold therapeutic promise for improving immune checkpoint-based therapies.
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Oxidorreductasas Intramoleculares , Melanoma , Animales , Ratones , Prostaglandina-E Sintasas/genética , Oxidorreductasas Intramoleculares/genética , Ciclooxigenasa 2/genética , Dinoprostona/metabolismo , Linfocitos T CD8-positivos/metabolismo , Agotamiento de Células T , Melanoma/tratamiento farmacológico , Ciclooxigenasa 1 , Colágeno , Inmunoterapia , Microambiente TumoralRESUMEN
Insensitivity and resistance to 5-fluorouracil (5FU) remain as major hurdles for effective and durable 5FU-based chemotherapy in colorectal cancer (CRC) patients. In this study, we identified prostaglandin E synthase (PTGES)/prostaglandin E2 (PGE2) axis as an important regulator for 5FU sensitivity in CRC cells. We found that PTGES expression and PGE2 production are elevated in CRC cells in comparison to normal colorectal epithelial cells. Depletion of PTGES significantly enhanced the inhibitory effect of 5FU on CRC cell viability that was fully reverted by exogenous supplement of PGE2. Inhibition of PTGES enzymatic function, by either inducing loss-of-function mutant or treatment with selective inhibitors, phenocopied the PTGES depletion in terms of 5FU sensitization. Mechanistically, PTGES/PGE2 axis modulates glycolysis in CRC cells, thereby regulating the 5FU sensitivity. Importantly, high PTGES expression is correlated with poor prognosis in 5FU-treated CRC patients. Thus, our study defines PTGES/PGE2 axis as a novel therapeutic target for enhancing the efficacy of 5FU-based chemotherapy in CRC.
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Neoplasias Colorrectales , Fluorouracilo , Humanos , Fluorouracilo/farmacología , Dinoprostona/metabolismo , Dinoprostona/farmacología , Dinoprostona/uso terapéutico , Prostaglandina-E Sintasas , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Línea Celular Tumoral , Resistencia a AntineoplásicosRESUMEN
Castanopsis tribuloides belongs to the oak species (Fagaceae) and it is commonly distributed in evergreen forests of Bangladesh, India, Myanmar, Nepal, China, and Thailand. Our present study aimed at uncovering the antipyretic potential of methanol extract of C. tribuloides bark (CTB) in the mice models. Baker's yeast pyrexia model was employed to determine the antipyretic potentials of the extract. Besides, molecular docking and dynamics simulation of CTB phenolic compounds were explored to validate the experimental results and gain insight into the possible antipyretic mechanism of action that can lead to the design and discovery of novel drugs against mPGES-1. The results revealed that CTB (400 mg/kg) significantly inhibited (P < 0.001) the elevated body temperature of mice since 0.5 h, which is more prominent than the standard. At dose 200 mg/kg, the bark extract also produced significant (P < 0.05) antipyretic activity since 2 h. HPLC-DAD analysis identified and quantified nine polyphenolic compounds from the extract, including rutin hydrate, (-) epicatechin, caffeic acid, catechin hydrate, catechol, trans-ferulic acid, p-coumaric acid, vanillic acid, and rosmarinic acid. Molecular docking study suggested probable competition of these phenolic compounds with glutathione, an essential cofactor for microsomal prostaglandin E synthase-1 (mPGES-1) activity. Additionally, RMSF, RMSD, Rg, and hydrogen bonds performed during MD simulations revealed that rutin hydrate (rich in CTB) bound to the mPGES-1 active site in a stable manner and thus inactivating mPGES-1. Therefore, it can be concluded that rutin hydrate reduces pyrexia in mice via downregulating PGE2 synthesis by inhibiting mPGES-1 activity.
Asunto(s)
Fagaceae , Fiebre/patología , Microsomas/efectos de los fármacos , Extractos Vegetales/farmacología , Prostaglandina-E Sintasas/efectos de los fármacos , Rutina/farmacología , Animales , Femenino , Masculino , Ratones , Simulación del Acoplamiento Molecular , Corteza de la Planta , Extractos Vegetales/química , Polifenoles/química , Polifenoles/farmacología , Rutina/químicaRESUMEN
Inflammation is closely linked to the abnormal phospholipid metabolism chain of cyclooxygenase-2/microsomal prostaglandin E2 synthase-1/prostaglandin E2 (COX-2/mPGES-1/PGE2). In clinical practice, non-steroidal anti-inflammatory drugs (NSAIDs) as upstream COX-2 enzyme activity inhibitors are widely used to block COX-2 cascade to relieve inflammatory response. However, NSAIDs could also cause cardiovascular and gastrointestinal side effects due to its inhibition on other prostaglandins generation. To avoid this, targeting downstream mPGES-1 instead of upstream COX is preferable to selectively block overexpressed PGE2 in inflammatory diseases. Some mPGES-1 inhibitor candidates including synthetic compounds, natural products and existing anti-inflammatory drugs have been proved to be effective in in vitro experiments. After 20 years of in-depth research on mPGES-1 and its inhibitors, ISC 27864 have completed phase II clinical trial. In this review, we intend to summarize mPGES-1 inhibitors focused on their inhibitory specificity with perspectives for future drug development.
Asunto(s)
Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Prostaglandina-E Sintasas/antagonistas & inhibidores , Prostaglandina-E Sintasas/metabolismo , Animales , HumanosRESUMEN
Prostaglandins are a group of important cell-signaling molecules involved in the regulation of ovarian maturation, oocyte development, egg laying and associated behaviors in invertebrates. However, the presence of prostaglandin E2 (PGE2), the key enzymes for PGE2 biosynthesis and its interference by drugs were not investigated previously in the ovary of ticks. The present study was undertaken to assess the modulation of the PGE2-mediated pathway in the eclosion blocking effect of flumethrin and terpenoid subfraction isolated from Artemisia nilagirica in Rhipicephalus annulatus ticks. The acaricidal activities and chemical profiling of the terpenoid subfraction were performed. The localization of the cyclooxygenase1 (COX1) and prostaglandin E synthase (PGES) enzymes and the quantification of PGE2 in the ovaries of the ticks treated with methanol (control), flumethrin and terpenoid subfraction were also undertaken. In addition, the vitellogenin concentration in hemolymph was also assayed. Both flumethrin and the terpenoid subfraction of A. nilagirica elicited a concentration-dependent inhibition of fecundity and blocking of hatching of the eggs. The COX1 could not be detected in the ovaries of treated and control ticks, while there was no significant difference observed in the concentration of vitellogenin (Vg) in them. The presence of PGES in the oocytes of control ticks was confirmed while the immunoreactivities against PGES were absent in the vitellogenic oocytes of ticks treated with flumethrin and terpenoid subfraction. The levels of PGE2 were below the detection limit in the ovaries of the flumethrin-treated ticks, while it was significantly lower in the ovaries of the terpenoid subfraction-treated ticks. Hence, the prostaglandin E synthase and PGE2 were identified as very important mediators for the signaling pathway for ovarian maturation and oviposition in ticks. In addition, the key enzyme for prostaglandin biosynthesis, PGES and the receptors for PGE2 can be exploited as potential drug targets for tick control. The detection of PGES by immunohistochemistry and quantification of PGE2 by LC-MSMS can be employed as valuable tools for screening newer compounds for their eclosion blocking acaricidal effects.
Asunto(s)
Artemisia/química , Dinoprostona/metabolismo , Piretrinas/farmacología , Rhipicephalus/efectos de los fármacos , Terpenos/aislamiento & purificación , Terpenos/farmacología , Animales , Anticuerpos/metabolismo , Femenino , Cromatografía de Gases y Espectrometría de Masas , Hemolinfa/metabolismo , Inmersión , Ovario/efectos de los fármacos , Ovario/enzimología , Peroxidasa/metabolismo , Prostaglandina-E Sintasas/metabolismo , Vitelogeninas/metabolismoRESUMEN
The multiple inhibition of biological targets involved in pro-inflammatory eicosanoid biosynthesis represents an innovative strategy for treating inflammatory disorders in light of higher efficacy and safety. Herein, following a multidisciplinary protocol involving virtual combinatorial screening, chemical synthesis, and in vitro and in vivo validation of the biological activities, we report the identification of 1,2,4-oxadiazole-based eicosanoid biosynthesis multi-target inhibitors. The multidisciplinary scientific approach led to the identification of three 1,2,4-oxadiazole hits (compounds 1, 2 and 5), all endowed with IC50 values in the low micromolar range, acting as 5-lipoxygenase-activating protein (FLAP) antagonists (compounds 1 and 2), and as a multi-target inhibitor (compound 5) of arachidonic acid cascade enzymes, namely cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1). Moreover, our in vivo results demonstrate that compound 5 is able to attenuate leukocyte migration in a model of zymosan-induced peritonitis and to modulate the production of IL-1ß and TNF-α. These results are of interest for further expanding the chemical diversity around the 1,2,4-oxadiazole central core, enabling the identification of novel anti-inflammatory agents characterized by a favorable pharmacological profile and considering that moderate interference with multiple targets might have advantages in re-adjusting homeostasis.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Desarrollo de Medicamentos , Eicosanoides/biosíntesis , Inhibidores Enzimáticos/farmacología , Oxadiazoles/farmacología , Peritonitis/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Araquidonato 5-Lipooxigenasa/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 1/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Masculino , Ratones , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Peritonitis/inducido químicamente , Prostaglandina-E Sintasas/antagonistas & inhibidores , Prostaglandina-E Sintasas/metabolismo , Relación Estructura-Actividad , ZimosanRESUMEN
The majority of anti-cancer therapies target the proliferating tumor cells, while the tumor stroma, principally unaffected, survives, and provide a niche for surviving tumor cells. Combining tumor cell and stroma-targeting therapies thus have a potential to improve patient outcome. The neuroblastoma stroma contains cancer-associated fibroblasts expressing microsomal prostaglandin E synthase-1 (mPGES-1). mPGES-1-derived prostaglandin E2 (PGE2 ) is known to promote tumor growth through increased proliferation and survival of tumor cells, immune suppression, angiogenesis, and therapy resistance, and we, therefore, hypothesize that mPGES-1 constitutes an interesting stromal target. Here, we aimed to develop a relevant in vitro model to study combination therapies. Co-culturing of neuroblastoma and fibroblast cells in 3D tumor spheroids mimic neuroblastoma tumors with regard to the cyclooxygenase/mPGES-1/PGE2 pathway. Using the spheroid model, we show that the inhibition of fibroblast-derived mPGES-1 enhanced the cytotoxic effect of doxorubicin and vincristine and significantly reduced tumor cell viability and spheroid growth. Cyclic treatment with vincristine in combination with an mPGES-1 inhibitor abrogated cell repopulation. Moreover, inhibition of mPGES-1 potentiated the cytotoxic effect of vincristine on established neuroblastoma allografts in mice. In conclusion, we established a 3D neuroblastoma model, highlighting the potential of combining stromal targeting of mPGES-1 with tumor cell targeting drugs like vincristine.
Asunto(s)
Antineoplásicos/farmacología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Animales , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Ratones , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neuroblastoma/metabolismo , Prostaglandina-E Sintasas/metabolismoRESUMEN
Application of allergens onto the sublingual epithelium is used to desensitize allergic individuals, a treatment known as sublingual immunotherapy. However, the response of sublingual epithelial cells to house dust mite allergen and potential tolerance-promoting adjuvants such as Toll-like receptor (TLR) ligands and calcitriol has not been investigated. In order to study this, primary sublingual epithelial cells were isolated from dogs and cultured in vitro. After 24-h incubation with a Dermatophagoides farinae extract, a Dermatophagoides pteronyssinus extract, TLR2 ligands (FSL-1, heat-killed Listeria monocytogenes, Pam3CSK4), a TLR3 ligand (poly I:C), a TLR4 ligand [lipopolysaccharide (LPS)], and calcitriol (1,25-dihydroxyvitamin D3), viability of the cells was analyzed using an MTT test, and their secretion of interleukin 6 (IL-6), IL-10, CXCL8, and transforming growth factor ß1 (TGF-ß1) was measured by enzyme-linked immunosorbent assay. Additionally, to evaluate its potential effect as an adjuvant, sublingual epithelial cells were incubated with calcitriol in combination with a D. farinae extract followed by measurement of CXCL8 secretion. Furthermore, the effect of D. farinae and calcitriol on the transcriptome was assessed by RNA sequencing. The viability of the sublingual epithelial cells was significantly decreased by poly I:C, but not by the other stimuli. CXCL8 secretion was significantly increased by D. farinae extract and all TLR ligands apart from LPS. Calcitriol significantly decreased CXCL8 secretion, and coadministration with D. farinae extract reduced CXCL8 concentrations to levels seen in unstimulated sublingual epithelial cells. Although detectable, TGF-ß1 secretion could not be modulated by any of the stimuli. Interleukin 6 and IL-10 could not be detected at the protein or at the mRNA level. It can be concluded that a D. farinae extract and TLR ligands augment the secretion of the proinflammatory chemokine CXCL8, which might interfere with sublingual desensitization. On the other hand, CXCL8 secretion was reduced by coapplication of calcitriol and a D. farinae extract. Calcitriol therefore seems to be a suitable candidate to be used as adjuvant during sublingual immunotherapy.
Asunto(s)
Alérgenos/administración & dosificación , Antígenos Dermatofagoides/administración & dosificación , Calcitriol/administración & dosificación , Interleucina-8/biosíntesis , Inmunoterapia Sublingual/métodos , Adyuvantes Inmunológicos/administración & dosificación , Animales , Células Cultivadas , Dermatophagoides farinae/inmunología , Perros , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Expresión Génica/efectos de los fármacos , Ligandos , Modelos Animales , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/inmunología , Mucosa Bucal/metabolismo , Prostaglandina-E Sintasas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Glucocorticoides/genética , Receptores Toll-Like/inmunologíaRESUMEN
Osteoarthritis (OA) is one of the most well-characterized joint diseases and is associated with chondrocyte inflammation, metalloproteinase upregulation and apoptosis. LI73014F2 is a novel composition prepared from aqueous extract of Terminalia chebula fruit, alcohol extract of Curcuma longa rhizome, and Boswellia serrata extract at 2:1:2 ratio. Earlier studies have shown that LI73014F2 inhibits cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) activities, and attenuates clinical symptoms in OA subjects. In the present study, we evaluated the protective anti-inflammatory and anti-apoptotic effects, as well as the underlying mechanisms, of LI73014F2 in interleukin (IL)-1ß-induced inflammation in human primary chondrocytes. Human chondrocytes were treated with LI73014F2 (0, 12.5, 25 and 50 µg/mL) in IL-1ß (10 ng/mL)-containing chondrocyte growth medium for 24 h. Cell viability was assessed using an MTT assay. The pro-inflammatory mediator, inflammatory cytokines, MMPs, apoptosis-related proteins, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways protein expression levels were detected by western blot analysis. The results demonstrated that LI73014F2 normalized the expressions of COX-2, mPGES-1, PGE2, 5-LOX, LTB4, IL-1ß, TNFα, IL-6, MMP-2, MMP-3, MMP-9, MMP-13, Bax/Bcl-2, cleaved caspase-9 and -3, cleaved PARP, phospho-NF-κB p65 and phospho-p38 MAPK proteins in IL-1ß-induced primary human chondrocytes. Moreover, the data suggested that LI73014F2 reduced IL-1ß-induced inflammation and apoptosis, at least partially via the inhibition of the NF-κB/MAPK signaling pathway. In conclusion, the present findings provide the molecular basis of the anti-OA efficacy of LI73014F2.
Asunto(s)
Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Condrocitos/efectos de los fármacos , Interleucina-1beta/farmacología , Osteoartritis/tratamiento farmacológico , Extractos Vegetales/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Boswellia/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Curcuma/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Citocinas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Interleucina-1beta/metabolismo , Leucotrieno B4/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaloproteasas/metabolismo , FN-kappa B/metabolismo , Prostaglandina-E Sintasas/metabolismo , Receptores de Prostaglandina E/metabolismo , Rizoma/química , Terminalia/químicaRESUMEN
Traditional folk medicine in Sri Lanka is mostly based on plants and plant-derived products, however, many of these medicinal plant species are scientifically unexplored. Here, we evaluated the anti-inflammatory and antimicrobial potency of 28 different extracts prepared from seven popular medicinal plant species employed in Sri Lanka. The extracts were subjected to cell-based and cell-free assays of 5-lipoxygenase (5-LO), microsomal prostaglandin E2 synthase (mPGES)-1, and nitric oxide (NO) scavenging activity. Moreover, antibacterial and disinfectant activities were assessed. Characterization of secondary metabolites was achieved by gas chromatography coupled to mass spectrometric (GC-MS) analysis. n-Hexane- and dichloromethane-based extracts of Garcinia cambogia efficiently suppressed 5-LO activity in human neutrophils (IC50 = 0.92 and 1.39 µg/mL), and potently inhibited isolated human 5-LO (IC50 = 0.15 and 0.16 µg/mL) and mPGES-1 (IC50 = 0.29 and 0.49 µg/mL). Lipophilic extracts of Pothos scandens displayed potent inhibition of mPGES-1 only. A methanolic extract of Ophiorrhiza mungos caused significant NO scavenging activity. The lipophilic extracts of G. cambogia exhibited prominent antibacterial and disinfectant activities, and GC-MS analysis revealed the presence of fatty acids, sesquiterpenes and other types of secondary metabolites. Together, our results suggest the prospective utilization of G. cambogia as disinfective agent with potent anti-inflammatory properties.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Plantas Medicinales/química , Humanos , Concentración 50 Inhibidora , Medicina Tradicional , Óxido Nítrico/metabolismo , Fitoquímicos/química , Fitoquímicos/farmacología , Prostaglandina-E Sintasas/metabolismo , Sri LankaRESUMEN
Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO), two key enzymes involved in pro-inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4-thiazolidinedione-based mPGES-1/5-LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent-based chemical route for the decoration of the 2,4-thiazolidinedione core, a large library of virtual compounds was built (â¼2.0×104 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid- and low- micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4-thiazolidinedione central core, facilitating the identification of novel anti-inflammatory agents endowed with a promising and safer pharmacological profile.
Asunto(s)
Antiinflamatorios/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Inhibidores Enzimáticos/farmacología , Prostaglandina-E Sintasas/antagonistas & inhibidores , Tiazolidinedionas/farmacología , Células A549 , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Prostaglandina-E Sintasas/metabolismo , Tiazolidinedionas/síntesis química , Tiazolidinedionas/químicaRESUMEN
Prostaglandin E2 (PGE2) is a lipid mediator of inflammation and cancer progression. It is mainly formed via metabolism of arachidonic acid by cyclooxygenases (COX) and the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). Widely used non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX activity, resulting in decreased PGE2 production and symptomatic relief. However, NSAIDs block the production of many other lipid mediators that have important physiological and resolving actions, and these drugs cause gastrointestinal bleeding and/or increase the risk for severe cardiovascular events. Selective inhibition of downstream mPGES-1 for reduction in only PGE2 biosynthesis is suggested as a safer therapeutic strategy. This review covers the recent advances in characterization of new mPGES-1 inhibitors in preclinical models and their future clinical applications.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Evaluación Preclínica de Medicamentos/métodos , Prostaglandina-E Sintasas/antagonistas & inhibidores , Animales , Ensayos Clínicos como Asunto , Humanos , Prostaglandina-E Sintasas/metabolismoRESUMEN
The side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in the cardiovascular system mainly result from its inhibitory effect on cyclooxygenase-2 (COX-2). Since NSAIDs are one of the most commonly used anti-inflammatory drugs in the clinic, it is necessary to identify new anti-inflammatory drugs that are safer than NSAIDs. Nardosinanone N (NAN), a compound isolated from the roots and rhizomes of Nardostachys chinensis, was evaluated for its anti-inflammatory effects using the lipopolysaccharide (LPS)-stimulated RAW264.7 cell line and rat peritoneal macrophage models. First, we found that NAN down regulated the levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS) and prostaglandin E2 (PGE2), but not cyclooxygenase-2 (COX-2). Additionally, NAN reduced the M1 macrophage phenotype and increased the M2 macrophage phenotype. Furthermore, mechanistic studies showed that NAN activated the nuclear factor-erythroid 2 -related factor 2 (Nrf2) signaling pathway, which, in turn, increased the expression of antioxidant protein heme oxygenase-1 (HO-1) to achieve its anti-inflammatory effect. Finally, Nrf2 siRNA and the HO-1 inhibitor significantly attenuated the anti-inflammatory effect of NAN. More interestingly, we found that NAN did not affect COX-2 expression and activity but reduced the PGE2 concentration by selective inhibition of microsomal prostaglandin E synthase-1 (mPGES-1). In conclusion, NAN may be a new anti-inflammatory drug that has fewer side effects than NSAIDs and can be a new potential Nrf2 activator and mPGES-1 inhibitor.
Asunto(s)
Compuestos Epoxi/farmacología , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Nardostachys/química , Preparaciones de Plantas/farmacología , Prostaglandina-E Sintasas/metabolismo , Terpenos/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Células Cultivadas , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Compuestos Epoxi/química , Expresión Génica/efectos de los fármacos , Macrófagos/clasificación , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Microsomas/efectos de los fármacos , Microsomas/enzimología , Estructura Molecular , Factor 2 Relacionado con NF-E2/genética , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Preparaciones de Plantas/química , Prostaglandina-E Sintasas/genética , Células RAW 264.7 , Ratas , Transducción de Señal/efectos de los fármacos , Terpenos/química , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Arachidonic acid (AA) metabolic enzymes including cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1) and cytochrome P450 (CYP) 4A11 play important roles in glioma angiogenesis. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. METHODS: A homology model of human CYP4A11 was constructed using SYBYL-X 2.0. Structure-based virtual screening against COX-2, mPGES-1 and CYP4A11was performed using the Surflex-Dock of the SYBYL suite. The candidates were further evaluated their antiangiogenic activities in a zebrafish embryo and rabbit corneal angiogenesis model. Laser doppler analysis was used to measure tumor perfusion. The expression of CD31 and α-SMA was measured by immunofluorescence. Western blot was used to measure the expression of HIF-1, Akt and p-Akt. The gene expression of FGF-2, G-CSF, PDGF, TGF-ß, Tie-2, VEGF, lncRNA NEAT1 and miR-194-5p were determined using qPCR. The production of FGF-2, TGF-ß and VEGF were analyzed using ELISA. Bioinformatic analysis and luciferase reporter assays confirmed the interaction between lncRNA NEAT1 and miR-194-5p. RESULTS: The nearly 36,043 compounds from the Traditional Chinese Medicine (TCM) database were screened against COX-2, mPGES-1 and CYP4A11 3D models, and the 17 top flavonoids were identified. In zebrafish screening, isoliquiritigenin (ISL) exhibited the most potent antiangiogenic activities with the EC50 values of 5.9 µM. Conversely, the antiangiogenic effects of ISL in the zebrafish and rabbit corneal models were partly reversed by 20-hydroxyeicosatetraenoic acid (20-HETE) or prostaglandin E2 (PGE2). ISL normalized glioma vasculature and improved the efficacy of temozolomide therapy in the rat C6 glioma model. Inhibition of COX-2, mPGES-1 and CYP4A by ISL decreased FGF-2, TGF-ß and VEGF production in the C6 and U87 glioma cells with p-Akt downregulation, which was reversed by Akt overexpression. Furthermore, ISL downregulated lncRNA NEAT1 but upregulated miR-194-5p in the U87 glioma cell. Importantly, lncRNA NEAT1 overexpression reversed ISL-mediated increase in miR-194-5p expression, and thereby attenuated FGF-2, TGF-ß and VEGF production. CONCLUSIONS: Reprogramming COX-2, mPGES-1 and CYP4A mediated-AA metabolism in glioma by flavonoid ISL inhibits the angiogenic Akt- FGF-2/TGF-ß/VEGF signaling through ceRNA effect of miR-194-5p and lncRNA NEAT1, and may serve as a novel therapeutic strategy for human glioma.
Asunto(s)
Chalconas/farmacología , Ciclooxigenasa 2/química , Citocromo P-450 CYP4A/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioma/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Prostaglandina-E Sintasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Neovascularización de la Córnea/tratamiento farmacológico , Neovascularización de la Córnea/metabolismo , Neovascularización de la Córnea/patología , Ciclooxigenasa 2/metabolismo , Citocromo P-450 CYP4A/metabolismo , Inhibidores Enzimáticos/farmacología , Glioma/irrigación sanguínea , Glioma/metabolismo , Glioma/patología , Humanos , Masculino , MicroARNs/genética , Prostaglandina-E Sintasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , Conejos , Ratas , Ratas Wistar , Células Tumorales Cultivadas , Pez CebraRESUMEN
Co-chaperon p23 has been well established as molecular chaperon for the heat shock protein 90 (Hsp90) that further leads to immorality in cancer cells by providing defense against Hsp90 inhibitors, and as stimulating agent for generating overexpressed antiapoptotic proteins, that is, Hsp70 and Hsp27. The natural compounds such as catechins from Camellia sinensis (green tea) are also well known for inhibition activity against various cancer. However, molecular interaction profile and potential lead bioactive compounds against co-chaperon p23 from green tea are not yet reported. To this context, we study the various secondary metabolites of green tea against co-chaperon p23 using structure-based virtual screening from Traditional Chinese Medicine (TCM) database. Following 26 compounds were obtained from TCM database and further studied for extra precision molecular docking that showed binding score between -10.221 and -2.276 kcal/mol with co-chaperon p23. However, relative docking score to known inhibitors, that is, ailanthone (-4.54 kcal/mol) and gedunin ( 3.60 kcal/mol) along with ADME profile analysis concluded epicatechin (-7.013 kcal/mol) and cis-theaspirone (-4.495 kcal/mol) as potential lead inhibitors from green tea against co-chaperone p23. Furthermore, molecular dynamics simulation and molecular mechanics generalized born surface area calculations validated that epicatechin and cis-theaspirone have significantly occupied the active region of co-chaperone p23 by hydrogen and hydrophobic interactions with various residues including most substantial amino acids, that is, Thr90, Ala94, and Lys95. Hence, these results supported the fact that green tea contained potential compounds with an ability to inhibit the cancer by disrupting the co-chaperon p23 activity.
Asunto(s)
Antineoplásicos Fitogénicos/química , Camellia sinensis/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Fitoquímicos/química , Prostaglandina-E Sintasas , Humanos , Prostaglandina-E Sintasas/antagonistas & inhibidores , Prostaglandina-E Sintasas/químicaRESUMEN
Cell signaling is necessary for the organs to co-ordinate with the whole body and it includes response to external stimuli, inflammation, hormonal secretions and other various metabolic functions. In the present study, we have focused on the inflammatory signals modulated by the reactive oxygen and nitrogen species (RONS). Under homeostatic conditions, these species turn on the COX-1-dependent arachidonic acid (AA) pathway towards the release of anti-inflammatory enzymes. However, the excess release of these ions induces negative effects in the form of inflammation by turning on the COX-2-dependent AA pathway to release pro-inflammatory enzymes. In the present study, we observed the shunting of the COX-2-dependent AA pathway towards the release of anti-inflammatory enzymes with the supplementation of organic dietary selenium in the form of seleniferous maize extracts. We observed that 500 nM selenium concentration in Se-maize extracts downregulated the COX-2 and mPGES-1 expressions by 3.8- and 3.2-fold and upregulated the GPx-1 and H-PGDS expressions by 5.0- and 5.4-fold, respectively. To facilitate more availability of Se from the dietary matrices, Se-maize extracts were incubated with rMETase. It was observed that the enzyme-treated cells increased the downregulation of COX-2 and mPGES-1 expressions by 24.8- and 21.0-fold and the upregulation of GPx-1 and H-PGDS expressions by 13.2- and 16.5-fold, respectively.
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Macrófagos/efectos de los fármacos , Prostaglandinas/metabolismo , Selenio/farmacología , Zea mays/química , Animales , Ácido Araquidónico/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Expresión Génica/efectos de los fármacos , Lipopolisacáridos/efectos adversos , Macrófagos/metabolismo , Ratones , Prostaglandina-E Sintasas/genética , Prostaglandina-E Sintasas/metabolismo , Células RAW 264.7 , Selenio/análisisRESUMEN
BACKGROUND: Bavachin is a natural product isolated from Psoralea corylifolia L. that has been applied as a traditional medicine in Asian countries. However, the anti-inflammatory effects of bavachin on LPS-induced inflammation and NLRP3 inflammasome activation by macrophages remain unclear. PURPOSE: We investigated the anti-inflammatory effects of bavachin on LPS-activated murine macrophage cell line J774A.1 cells and murine peritoneal macrophages. METHODS: J774A.1 cells and murine peritoneal macrophages were pre-treated with bavachin following LPS treatment. The concentrations of NO, PGE2, IL-6 and IL-12p40 in cell culture supernatant were analyzed. The expressions of iNOS, COX-2, mPGES-1 and MAPKs were analyzed using Western blotting, while NF-κB activity was detected using promoter reporter assay. To examine the activation of NLRP3 inflammasome, J774A.1 cells were incubated with LPS, and then treated with bavachin following treatment with ATP. The concentration of IL-1ß in the cell culture supernatant was measured. The expressions of NLRP3, ASC, caspase-1 and IL-1ß were analyzed using Western blotting. The formation of inflammasome complex was observed by immunofluorescence microscopy. RESULTS: Bavachin suppressed LPS-induced NO and PGE2 production, and decreased iNOS and mPGES-1 expression. Bavachin also reduced LPS-induced IL-6 and IL-12p40 production and decreased the activation of MAPKs and NF-κB. Additionally, bavachin suppressed NLRP3 inflammasome-derived IL-1ß secretion, decreased caspase-1 activation, repressed mature IL-1ß expression, and inhibited inflammasome complex formation. Furthermore, bavachin also suppressed the production of NO, IL-6 and IL-12p40 by LPS-stimulated murine peritoneal macrophages. CONCLUSION: Our experimental results indicated anti-inflammatory effects of bavachin exhibit attenuation of LPS-induced inflammation and inhibit activation of NLRP3 inflammasome in macrophages. These results suggest that bavachin might have potential in treating inflammatory and autoimmune diseases.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Flavonoides/farmacología , Inflamasomas/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Línea Celular , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Inflamasomas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos Peritoneales/metabolismo , Ratones , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Prostaglandina-E Sintasas/metabolismoRESUMEN
BACKGROUND: Cancer is one of the most life-threatening diseases worldwide. Since inflammation is considered to be one of the known characteristics of cancer, the activity of PGE2 has been paired with different tumorigenic steps such as increased tumor cell proliferation, resistance to apoptosis, increased invasiveness, angiogenesis and immunosuppression. OBJECTIVE: It has been successfully demonstrated that inhibition of mPGES-1 prevented inflammation in preclinical studies. However, despite the crucial roles of mPGEs-1 and PGE2 in tumorigenesis, there is not much in vivo study on mPGES-1 inhibition in cancer therapy. The specificity of mPGEs-1 enzyme and its low expression level under normal conditions makes it a promising drug target with a low risk of side effects. METHODS: A comprehensive literature search was performed for writing this review. An updated view on PGE2 biosynthesis, PGES isoenzyme family and its pharmacology and the latest information about inhibitors of mPGES-1 have been discussed. RESULTS: In this study, it was aimed to highlight the importance of mPGES-1 and its inhibition in inflammationrelated cancer and other inflammatory conditions. Information about PGE2 biosynthesis, its role in inflammationrelated pathologies were also provided. We kept the noncancer-related inflammatory part short and tried to bring together promising molecules or scaffolds. CONCLUSION: The information provided in this review might be useful to researchers in designing novel and potent mPGES-1 inhibitors for the treatment of cancer and inflammation.
Asunto(s)
Antiinflamatorios/química , Antineoplásicos/química , Inhibidores Enzimáticos/química , Prostaglandina-E Sintasas/antagonistas & inhibidores , Animales , Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Artritis/tratamiento farmacológico , Artritis/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Estructura Molecular , Terapia Molecular Dirigida , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/metabolismo , Prostaglandina-E Sintasas/genéticaRESUMEN
The polyphenolic extract (PE) from extra virgin olive oil (EVOO) has been shown to possess important anti-inflammatory and joint protective properties in murine models of rheumatoid arthritis (RA). This study was designed to evaluate the effects of PE on IL-1ß-activated human synovial fibroblasts SW982 cell line. PE from EVOO treatment inhibited IL-1ß-induced matrix metalloproteases (P<0·001), TNF-α and IL-6 production (P<0·001). Similarly, IL-1ß-induced cyclo-oxygenase-2 and microsomal PGE synthase-1 up-regulations were down-regulated by PE (P<0·001). Moreover, IL-1ß-induced mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB activation were ameliorated by PE (P<0·001). These results suggest that PE from EVOO reduces the production of proinflammatory mediators in human synovial fibroblasts; particularly, these protective effects could be related to the inhibition of MAPK and NF-κB signalling pathways. Taken together, PE from EVOO probably could provide an attractive complement in management of diseases associated with over-activation of synovial fibroblasts, such as RA.