RESUMEN
Despite vigorous efforts, the COVID-19 pandemic continues to take a toll on the global health. The contemporary therapeutic regime focused on the viral spike proteins, viral 3CL protease enzyme, immunomodulation, inhibition of viral replication, and providing a symptomatic relief encouraged the repurposing of drugs to meet the urgency of treatment. Similarly, the representative drugs that proved beneficial to alleviate SARS-CoV-1, MERS-CoV, HIV, ZIKV, H1N1, and malarial infection in the past presented a sturdy candidature for ameliorating the COVID-19 therapeutic doctrine. However, most of the deliberations for developing effective pharmaceuticals proved inconsequential, thereby encouraging the identification of new pathways, and novel pharmaceuticals for capping the COVID-19 infection. The COVID-19 contagion encompasses a burst release of the cytokines that increase the severity of the infection mainly due to heightened immunopathogenicity. The pro-inflammatory metabolites, COX-2, cPLA2, and 5-LOX enzymes involved in their generation, and the substrates that instigate the origination of the innate inflammatory response therefore play an important role in intensifying and worsening of the tissue morbidity related to the coronavirus infection. The deployment of representative drugs for inhibiting these overexpressed immunogenic pathways in the tissues invaded by coronaviruses has been a matter of debate since the inception of the pandemic. The effectiveness of NSAIDs such as Aspirin, Indomethacin, Diclofenac, and Celecoxib in COVID-19 coagulopathy, discouraging the SARS viral replication, the inflammasome deactivation, and synergistic inhibition of H5N1 viral infection with representative antiviral drugs respectively, have provided a silver lining in adjuvant COVID-19 therapy. Since the anti-inflammatory NSAIDs and COXIBs mainly function by reversing the COX-2 overexpression to modulate the overproduction of pro-inflammatory cytokines and chemokines, these drugs present a robust treatment option for COVID-19 infection. This commentary succinctly highlights the various claims that support the status of immunomodulatory NSAIDs, and COXIBs in the adjuvant COVID-19 therapy.
Asunto(s)
COVID-19/enzimología , Factores Inmunológicos/uso terapéutico , Prostaglandina-Endoperóxido Sintasas/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Quimioterapia Adyuvante/métodos , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Humanos , Factores Inmunológicos/farmacología , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/fisiología , Tratamiento Farmacológico de COVID-19RESUMEN
For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.
Asunto(s)
Sistema Nervioso Central/fisiopatología , Inflamación/fisiopatología , Lípidos de la Membrana/fisiología , Modelos Biológicos , Degeneración Nerviosa/fisiopatología , Enfermedades Neurodegenerativas/fisiopatología , Esfingolípidos/fisiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Ceramidas/fisiología , Eicosanoides/fisiología , Predicción , Homeostasis , Humanos , Inflamación/patología , Lipooxigenasa/fisiología , Lisofosfolípidos/fisiología , Degeneración Nerviosa/patología , Enfermedades Neurodegenerativas/patología , Neuroglía/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Fosfotransferasas (Aceptor de Grupo Alcohol)/fisiología , Prostaglandina-Endoperóxido Sintasas/fisiología , Esfingosina/análogos & derivados , Esfingosina/fisiologíaRESUMEN
BACKGROUND: Emergence of drug-resistant cancer phenotypes is a challenge for anti-cancer therapy. Cancer stem cells are identified as one of the ways by which chemoresistance develops. METHOD: We investigated the anti-inflammatory combinatorial treatment (DA) of doxorubicin and aspirin using a preclinical microfluidic model on cancer cell lines and patient-derived circulating tumour cell clusters. The model had been previously demonstrated to predict patient overall prognosis. RESULTS: We demonstrated that low-dose aspirin with a sub-optimal dose of doxorubicin for 72 h could generate higher killing efficacy and enhanced apoptosis. Seven days of DA treatment significantly reduced the proportion of cancer stem cells and colony-forming ability. DA treatment delayed the inhibition of interleukin-6 secretion, which is mediated by both COX-dependent and independent pathways. The response of patients varied due to clinical heterogeneity, with 62.5% and 64.7% of samples demonstrating higher killing efficacy or reduction in cancer stem cell (CSC) proportions after DA treatment, respectively. These results highlight the importance of using patient-derived models for drug discovery. CONCLUSIONS: This preclinical proof of concept seeks to reduce the onset of CSCs generated post treatment by stressful stimuli. Our study will promote a better understanding of anti-inflammatory treatments for cancer and reduce the risk of relapse in patients.
Asunto(s)
Antiinflamatorios/administración & dosificación , Aspirina/administración & dosificación , Doxorrubicina/administración & dosificación , Recurrencia Local de Neoplasia/prevención & control , Células Madre Neoplásicas/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Quimioterapia Combinada , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Interleucina-6/genética , Interleucina-6/fisiología , Microfluídica , Prostaglandina-Endoperóxido Sintasas/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
Urinary tract infection (UTI) is an extremely common infectious disease. Uropathogenic Escherichia coli (UPEC) is the predominant etiological agent of UTI. Asymptomatic bacteriuric E. coli (ABEC) strains successfully colonize the urinary tract resulting in asymptomatic bacteriuria (ABU) and do not induce symptoms associated with UTI. Oxylipids are key signaling molecules involved in inflammation. Based on the distinct clinical outcomes of E. coli colonization, we hypothesized that UPEC triggers the production of predominantly proinflammatory oxylipids and ABEC leads to production of primarily anti-inflammatory or proresolving oxylipids in the urinary tract. We performed quantitative detection of 39 oxylipid mediators with proinflammatory, anti-inflammatory, and proresolving properties, during UTI and ABU caused by genetically distinct E. coli strains in the murine urinary bladder. Our results reveal that infection with UPEC causes an increased accumulation of proinflammatory oxylipids as early as 6 h postinoculation, compared to controls. To the contrary, ABEC colonization leads to decreased accumulation of proinflammatory oxylipids at the early time point compared to UPEC infection but does not affect the level of proresolving oxylipids. This report represents the first comprehensive investigation on the oxylipidome during benign ABEC colonization observed in ABU and acute inflammation triggered by UPEC leading to UTI.
Asunto(s)
Infecciones por Escherichia coli/etiología , Mediadores de Inflamación/fisiología , Lípidos/fisiología , Vejiga Urinaria/microbiología , Infecciones Urinarias/etiología , Animales , Ácidos Grasos/análisis , Femenino , Lípidos/análisis , Lipooxigenasa/fisiología , Ratones , Ratones Endogámicos CBA , Prostaglandina-Endoperóxido Sintasas/fisiología , Vejiga Urinaria/químicaRESUMEN
Prostaglandin synthase (PGS) can catalyze the production of various types of prostaglandins and regulate the expression levels of related substances. The regulation mechanisms of the PGS gene are closely related with the occurrence and development of prostate diseases. However, few studies are reported on the regulation mechanisms of PGS in prostatic diseases, such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa), or on the relationship between PGS gene regulation and prostate diseases. This review aims to analyze their correlation and provide some ideas for the prevention and control of BPH and PCa by intervention of the prostaglandin synthase regulatory pathway.
Asunto(s)
Regulación de la Expresión Génica , Prostaglandina-Endoperóxido Sintasas/genética , Hiperplasia Prostática/prevención & control , Neoplasias de la Próstata/prevención & control , Humanos , Masculino , Prostaglandina-Endoperóxido Sintasas/fisiología , Hiperplasia Prostática/enzimología , Hiperplasia Prostática/genética , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genéticaRESUMEN
We tested the hypothesis that women exhibit greater vasodilator responses to ß-adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to ß-adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men (n = 29, 26 ± 1 yr) and women (n = 33, 25 ± 1 yr) during intra-arterial infusion of isoproterenol (ß-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [N(G)-monomethyl-l-arginine (l-NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow ÷ mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion (P < 0.01), and this effect was not different between men and women (P = 0.41). l-NMMA infusion had no effect on isoproterenol-mediated dilation in men (P > 0.99) or women (P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men (P < 0.01) and women (P = 0.04) and this rise was lost with subsequent l-NMMA infusion (men, P < 0.01; women, P < 0.05). ß-Adrenergic vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to ß-mediated vasodilation are not present. However, these data are the first to demonstrate ß-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease.
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Agonistas Adrenérgicos beta/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores Enzimáticos/farmacología , Isoproterenol/farmacología , Ketorolaco/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Vasodilatación/efectos de los fármacos , omega-N-Metilarginina/farmacología , Adulto , Femenino , Antebrazo/irrigación sanguínea , Humanos , Infusiones Intraarteriales , Masculino , Microcirculación/efectos de los fármacos , Microcirculación/fisiología , Prostaglandina-Endoperóxido Sintasas/fisiología , Factores Sexuales , Ultrasonografía Doppler , Vasodilatación/fisiologíaRESUMEN
KEY POINTS: In humans in vivo, the mechanisms behind ATP-mediated cutaneous vasodilatation along with whether and how ATP increases sweating remains uncertain. Recent work has implicated nitric oxide synthase (NOS), cyclooxygenase (COX) and/or adenosine in the modulation of cutaneous vasodilatation and sweat production during both local (i.e. localized heating) and whole-body heat stress (i.e. exercise-induced heat stress). We evaluated whether ATP-mediated cutaneous vasodilatation and sweating is mediated via NOS, COX and/or adenosine. We show that in humans in vivo, intradermal administration of ATP induces pronounced vasodilatation which is partially mediated by NOS, but neither COX nor adenosine influences ATP-mediated vasodilatation, and ATP alone does not induce an increase in sweating. These findings advance our basic physiological knowledge regarding control of skin blood flow and sweating, and provide insight into the mechanisms governing thermoeffector activity, which has major implications for whole-body heat exchange and therefore core temperature regulation in humans during heat stress. ABSTRACT: In humans in vivo, the mechanisms behind ATP-mediated cutaneous vasodilatation and whether and how ATP increases sweating remain uncertain. We evaluated whether ATP-mediated cutaneous vasodilatation and sweating is mediated via nitric oxide synthase (NOS), cyclooxygenase (COX) and/or adenosine-dependent mechanisms. Cutaneous vascular conductance (CVC, laser Doppler perfusion units/mean arterial pressure) and sweat rate (ventilated capsule) were evaluated at intradermal microdialysis forearm skin sites, each receiving pharmacological agents (two separate protocols). In Protocol 1 (n = 12), sites were perfused with: (1) lactated Ringer solution (Control), (2) 10 mm N(ω) -nitro-l-arginine (l-NNA, a NOS inhibitor), (3) 10 mm ketorolac (Ketorolac, a COX inhibitor) or (4) a combination of 10 mm l-NNA + 10 mm ketorolac (l-NNA + Ketorolac). In Protocol 2 (n = 8), sites were perfused with: (1) lactated Ringer solution (Control) or (2) 4 mm theophylline (Theophylline, an adenosine receptor inhibitor). At all sites, ATP was simultaneously perfused at 0.12, 1.2, 12, 120 and 1200 nm min(-1) (each for 20 min). Relative to CVC at the Control site with ATP infused at 120 nm min(-1) (71 ± 9% of max CVC), CVC at the Ketorolac site was comparable (64 ± 13% of max CVC, P = 0.407), but lower at l-NNA (51 ± 15% of max CVC, P = 0.040) and l-NNA + Ketorolac (51 ± 13% of max CVC, P = 0.049) sites. Conversely, across the four skin sites at any other ATP infusion rate (all P > 0.174), no differences in CVC were observed. Theophylline did not influence CVC at any ATP infusion rate (all P > 0.234). Furthermore, no ATP infusion rate elicited an increase in sweating from baseline at any skin site (all P > 0.235). We show that NOS, but neither COX nor adenosine receptors, modulates ATP-mediated cutaneous vasodilatation, whereas ATP does not directly increase sweating.
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Adenosina Trifosfato/fisiología , Óxido Nítrico Sintasa/fisiología , Prostaglandina-Endoperóxido Sintasas/fisiología , Piel/irrigación sanguínea , Piel/metabolismo , Sudoración/fisiología , Adenosina/fisiología , Administración Cutánea , Adolescente , Adulto , Femenino , Humanos , Masculino , Vasodilatación/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND: Disruption of the blood-brain barrier (BBB) occurs in many diseases and is often mediated by inflammatory and neuroimmune mechanisms. Inflammation is well established as a cause of BBB disruption, but many mechanistic questions remain. METHODS: We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in mice. BBB disruption was measured using (14)C-sucrose and radioactively labeled albumin. Brain cytokine responses were measured using multiplex technology and dependence on cyclooxygenase (COX) and oxidative stress determined by treatments with indomethacin and N-acetylcysteine. Astrocyte and microglia/macrophage responses were measured using brain immunohistochemistry. In vitro studies used Transwell cultures of primary brain endothelial cells co- or tri-cultured with astrocytes and pericytes to measure effects of LPS on transendothelial electrical resistance (TEER), cellular distribution of tight junction proteins, and permeability to (14)C-sucrose and radioactive albumin. RESULTS: In comparison to LPS-induced weight loss, the BBB was relatively resistant to LPS-induced disruption. Disruption occurred only with the highest dose of LPS and was most evident in the frontal cortex, thalamus, pons-medulla, and cerebellum with no disruption in the hypothalamus. The in vitro and in vivo patterns of LPS-induced disruption as measured with (14)C-sucrose, radioactive albumin, and TEER suggested involvement of both paracellular and transcytotic pathways. Disruption as measured with albumin and (14)C-sucrose, but not TEER, was blocked by indomethacin. N-acetylcysteine did not affect disruption. In vivo, the measures of neuroinflammation induced by LPS were mainly not reversed by indomethacin. In vitro, the effects on LPS and indomethacin were not altered when brain endothelial cells (BECs) were cultured with astrocytes or pericytes. CONCLUSIONS: The BBB is relatively resistant to LPS-induced disruption with some brain regions more vulnerable than others. LPS-induced disruption appears is to be dependent on COX but not on oxidative stress. Based on in vivo and in vitro measures of neuroinflammation, it appears that astrocytes, microglia/macrophages, and pericytes play little role in the LPS-mediated disruption of the BBB.
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Barrera Hematoencefálica/metabolismo , Células Endoteliales/metabolismo , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Estrés Oxidativo/fisiología , Prostaglandina-Endoperóxido Sintasas/fisiología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/inmunología , Astrocitos/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/inmunología , Línea Celular Transformada , Técnicas de Cocultivo , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/inmunología , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacosRESUMEN
BACKGROUND: Oxidative stress and inflammation are important factors contributing to the pathophysiology of numerous neurological disorders, including Alzheimer's disease, Parkinson's disease, acute stroke, and infections of the brain. There is well-established evidence that proinflammatory cytokines and glutamate, as well as reactive oxygen species (ROS) and nitric oxide (NO), are produced upon microglia activation, and these are important factors contributing to inflammatory responses and cytotoxic damage to surrounding neurons and neighboring cells. Microglial cells express relatively high levels of cytosolic phospholipase A2 (cPLA2), an enzyme known to regulate membrane phospholipid homeostasis and release of arachidonic acid (AA) for synthesis of eicosanoids. The goal for this study is to elucidate the role of cPLA2IV in mediating the oxidative and inflammatory responses in microglial cells. METHODS: Experiments involved primary microglia cells isolated from transgenic mice deficient in cPLA2α or iPLA2ß, as well as murine immortalized BV-2 microglial cells. Inhibitors of cPLA2/iPLA2/cyclooxygenase (COX)/lipoxygenase (LOX) were used in BV-2 microglial cell line. siRNA transfection was employed to knockdown cPLA2 expression in BV-2 cells. Griess reaction protocol was used to determine NO concentration, and CM-H2DCF-DA was used to detect ROS production in primary microglia and BV-2 cells. WST-1 assay was used to assess cell viability. Western blotting was used to assess protein expression levels. Immunocytochemical staining for phalloidin against F-actin was used to demonstrate cell morphology. RESULTS: In both primary and BV-2 microglial cells, stimulation with lipopolysaccharide (LPS) or interferon gamma (IFNγ) resulted in a time-dependent increase in phosphorylation of cPLA2 together with ERK1/2. In BV-2 cells, LPS- and IFNγ-induced ROS and NO production was inhibited by arachidonyl trifluoromethyl ketone (AACOCF3) and pyrrophenone as well as RNA interference, but not BEL, suggesting a link between cPLA2, and not iPLA2, on LPS/IFNγ-induced nitrosative and oxidative stress in microglial cells. Primary microglial cells isolated from cPLA2α-deficient mice generated significantly less NO and ROS as compared with the wild-type mice. Microglia isolated from iPLA2ß-deficient mice did not show a decrease in LPS-induced NO and ROS production. LPS/IFNγ induced morphological changes in primary microglia, and these changes were mitigated by AACOCF3. Interestingly, despite that LPS and IFNγ induced an increase in phospho-cPLA2 and prostaglandin E2 (PGE2) release, LPS- and IFNγ-induced NO and ROS production were not altered by the COX-1/2 inhibitor but were suppressed by the LOX-12 and LOX-15 inhibitors instead. CONCLUSIONS: In summary, the results in this study demonstrated the role of cPLA2 in microglial activation with metabolic links to oxidative and inflammatory responses, and this was in part regulated by the AA metabolic pathways, namely the LOXs. Further studies with targeted inhibition of cPLA2/LOX in microglia during neuroinflammatory conditions can be valuable to investigate the therapeutic potential in ameliorating neurological disease pathology.
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Citosol/enzimología , Lipooxigenasa/metabolismo , Microglía/enzimología , Óxido Nítrico/metabolismo , Fosfolipasas A2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Actinas/metabolismo , Animales , Línea Celular , Femenino , Inflamación/enzimología , Inflamación/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microglía/efectos de los fármacos , Fosfolipasas A2/genética , Cultivo Primario de Células , Prostaglandina-Endoperóxido Sintasas/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
AIMS: Current-induced vasodilation (CIV) is an axon-reflex response observed during monopolar current application such as iontophoresis. Cyclo-oxygenase derivates (COD) participate in CIV and act as sensitizing agents at the anodal level. Mechanisms involved during cathodal current application (CCA) are partially unknown. In a randomized double-blind crossover trial, we tested in 16 healthy subjects (i) the influence of the inter-stimulation interval (I-I) by comparing CIV following all-at-once 10 s CCA against 2 × 5 s CCA with intervals ranging from15 s-16 min and (ii) the participation of COD in CIV using 1 g aspirin or placebo intake. METHODS: Measurements were repeated 2 h and 14 days after treatment. Laser Doppler flowmetry assessed cutaneous blood flow, reported in multiples of baseline. RESULTS: Before treatment, peak vasodilation 10 min after the last current application (CVCstim2 ) increased compared with baseline whatever the I-I. Increase in CVCstim2 from baseline was greater for the 4 min (9.4 (5.3, 10.9) times; median (1(st) percentile, 3(rd) percentile)) and higher I-Is compared with all-at-once delivery (3.0 (2.1, 4.3) times, P < 0.05). The response was similar after placebo but aspirin abolished this vasodilation (increase by 1.2 (1.1, 1.3) times for all-at-once delivery and by 1.5 (1.3, 1.7) ± 0.3 times for 4 min interval, 2 h after aspirin intake) that recovered after 14 days. CONCLUSIONS: This confirms the participation of COD in CIV with CCA and their sensitizing action. This model can represent an attractive way to study the axon-reflex and sensitizing function of COD in humans.
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Aspirina/farmacología , Iontoforesis , Prostaglandina-Endoperóxido Sintasas/fisiología , Fenómenos Fisiológicos de la Piel , Piel/irrigación sanguínea , Vasodilatación , Aspirina/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Iontoforesis/efectos adversos , Iontoforesis/métodos , Flujometría por Láser-Doppler , Masculino , Microcirculación , Piel/efectos de los fármacos , Piel/enzimología , Fenómenos Fisiológicos de la Piel/efectos de los fármacos , Temperatura Cutánea , Vasodilatación/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND & AIMS: Microsomal prostaglandin E synthase-2 (mPGES-2) deletion does not influence in vivo PGE2 production and the function of this enzyme remains elusive. The present study was undertaken to investigate the role of mPGES-2 in streptozotocin (STZ)-induced type-1 diabetes and organ injuries. METHODS: mPGES-2 wild type (WT) and knockout (KO) mice were treated by a single intraperitoneal injection of STZ at the dose of 120 mg/kg to induce type-1 diabetes. Subsequently, glycemic status and organ injuries were evaluated. RESULTS: Following 4 days of STZ administration, mPGES-2 KO mice exhibited severe lethality in contrast to the normal phenotype observed in WT control mice. In a separate experiment, the analysis was performed at day 3 of the STZ treatment in order to avoid lethality. Blood glucose levels were similar between STZ-treated KO and WT mice. However, the livers of KO mice were yellowish with severe global hepatic steatosis, in parallel with markedly elevated liver enzymes and remarkable stomach expansion. However, the morphology of the other organs was largely normal. The STZ-treated KO mice displayed extensive hepatocyte apoptosis compared with WT mice in parallel with markedly enhanced inflammation and oxidative stress. More interestingly, a liver-specific 50% upregulation of GLUT2 was found in the KO mice accompanied with a markedly enhanced STZ accumulation and this induction of GLUT2 was likely to be associated with the insulin/SREBP-1c pathway. Primary cultured hepatocytes of KO mice exhibited an increased sensitivity to STZ-induced injury and higher cellular STZ content, which was markedly blunted by the selective GLUT2 inhibitor phloretin. CONCLUSIONS: mPGES-2 deletion enhanced STZ-induced liver toxicity possibly via GLUT2-mediated STZ uptake, independently of diabetes mellitus.
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Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/fisiopatología , Transportador de Glucosa de Tipo 2/fisiología , Prostaglandina-Endoperóxido Sintasas/deficiencia , Estreptozocina/efectos adversos , Animales , Apoptosis/fisiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Ciclooxigenasa 2/deficiencia , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/fisiología , Diabetes Mellitus Tipo 1/complicaciones , Modelos Animales de Enfermedad , Insulina/fisiología , Hígado/enzimología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/fisiología , Transducción de Señal/fisiología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/fisiologíaRESUMEN
Myocardial infarction (MI) is the main cause for the progression of the left ventricle towards congestive heart failure. The optimal healing after MI requires timely induction and resolution of inflammation. Primarily, there have been a number of strategies applied to inhibit the post-MI inflammation but approaches that focus on the resolution of inflammation have sparsely been used in the treatment of heart failure. The early attempts to inhibit post-MI inflammation resulted in adverse outcomes that were realized in heart failure trials. We provide here an overview on the cyclooxygenase (COX)- and lipoxygenase (LOX)-derived lipid mediators that are either impairing or resolving the post-MI inflammation. With the evolution of lipidomics there has been emerging novel bioactive-specialized lipid mediators that promise to resolve chronic inflammation rather than promoting inhibition. The current review is focused on post-MI immune cells kinetics and the unexplored array of lipid mediators that are coordinated by COX and LOX. Thus, an emphasis on COX and LOX poses key questions and potential for the development of novel targets in the heart failure treatment strategy. This updated dynamic approach aims to fuse basic pre-clinical discoveries and translational bioactive lipid-based resolvin discoveries that could be potentially used in the clinic for the treatment of heart failure.
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Inflamación/etiología , Infarto del Miocardio/complicaciones , Animales , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/prevención & control , Humanos , Inflamación/complicaciones , Inflamación/fisiopatología , Inflamación/terapia , Lípidos/fisiología , Lipooxigenasa/fisiología , Infarto del Miocardio/inmunología , Prostaglandina-Endoperóxido Sintasas/fisiología , Remodelación VentricularRESUMEN
OBJECTIVE: Cardiovascular diseases have high comorbidity with major depression. Endothelial dysfunction may explain the adverse cardiovascular outcome in depression; therefore, we analyzed it in vitro. In the chronic mild stress model, some rats develop depression-like symptoms (including "anhedonia"), whereas others are stress resilient. METHODS: After 8 weeks of chronic mild stress, anhedonic rats reduced their sucrose intake by 55% (7%), whereas resilient rats did not. Acetylcholine-induced endothelium-dependent relaxation of norepinephrine-preconstricted mesenteric arteries was analyzed in nonstressed, anhedonic, and resilient rat groups. RESULTS: Small resistance arteries from anhedonic rats were less sensitive to acetylcholine than those of the nonstressed and resilient groups (p = .029). Pathways of endothelium-dependent relaxation were altered in arteries from anhedonic rats. Nitric oxide (NO)-dependent relaxation and endothelial NO synthase expression were increased in arteries from anhedonic rats (0.235 [0.039] arbitrary units and 155.7% [8.15%]) compared with the nonstressed (0.135 [0.012] arbitrary units and 100.0% [8.08%]) and resilient (0.152 [0.018] arbitrary units and 108.1% [11.65%]) groups (p < .001 and p = .002, respectively). Inhibition of cyclooxygenase (COX) activity revealed increased COX-2-dependent relaxation in the anhedonic group. In contrast, endothelial NO synthase- and COX-independent relaxation to acetylcholine (endothelium-dependent hyperpolarization-like response) was reduced in anhedonic rats (p < .001). This was associated with decreased transcription of intermediate-conductance Ca-activated K channels. CONCLUSIONS: Our findings demonstrate that depression-like symptoms are associated with reduced endothelium-dependent relaxation due to suppressed endothelium-dependent hyperpolarization-like relaxation despite up-regulation of the NO and COX-2-dependent pathways in rat mesenteric arteries. These changes could affect peripheral resistance and organ perfusion in major depression.
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Depresión/fisiopatología , Endotelio Vascular/fisiopatología , Arterias Mesentéricas/fisiopatología , Estrés Psicológico/fisiopatología , Vasodilatación/fisiología , Acetilcolina/farmacología , Anhedonia/fisiología , Animales , Factores Biológicos/fisiología , Enfermedad Crónica , Constricción Patológica , Depresión/metabolismo , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa/fisiología , Norepinefrina/farmacología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Prostaglandina-Endoperóxido Sintasas/fisiología , Ratas , Ratas Wistar , Resiliencia Psicológica , Estrés Psicológico/metabolismo , Sacarosa/administración & dosificación , Resistencia Vascular/fisiología , Vasodilatación/efectos de los fármacosRESUMEN
Astrocytes are highly secretory cells, participating in rapid brain communication by releasing glutamate. Recent evidences have suggested that this process is largely mediated by Ca(2+)-dependent regulated exocytosis of VGLUT-positive vesicles. Here by taking advantage of VGLUT1-pHluorin and TIRF illumination, we characterized mechanisms of glutamate exocytosis evoked by endogenous transmitters (glutamate and ATP), which are known to stimulate Ca(2+) elevations in astrocytes. At first we characterized the VGLUT1-pHluorin expressing vesicles and found that VGLUT1-positive vesicles were a specific population of small synaptic-like microvesicles containing glutamate but which do not express VGLUT2. Endogenous mediators evoked a burst of exocytosis through activation of G-protein coupled receptors. Subsequent glutamate exocytosis was reduced by about 80% upon pharmacological blockade of the prostaglandin-forming enzyme, cyclooxygenase. On the other hand, receptor stimulation was accompanied by extracellular release of prostaglandin E2 (PGE2). Interestingly, administration of exogenous PGE2 produced per se rapid, store-dependent burst exocytosis of glutamatergic vesicles in astrocytes. Finally, when PGE2-neutralizing antibody was added to cell medium, transmitter-evoked exocytosis was again significantly reduced (by about 50%). Overall these data indicate that cyclooxygenase products are responsible for a major component of glutamate exocytosis in astrocytes and that large part of such component is sustained by autocrine/paracrine action of PGE2.
Asunto(s)
Astrocitos/fisiología , Exocitosis/fisiología , Ácido Glutámico/fisiología , Prostaglandinas/fisiología , Receptores Acoplados a Proteínas G/fisiología , Animales , Anticuerpos Bloqueadores/farmacología , Aspirina/farmacología , Células Cultivadas , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/antagonistas & inhibidores , Dinoprostona/farmacología , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Indometacina/farmacología , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/farmacología , Prostaglandina-Endoperóxido Sintasas/fisiología , Ratas , Transducción de Señal/fisiología , Transfección , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
Oxidized PLs (OxPLs) generated in health and disease are now recognized as important mediators of cellular signalling. There is an increasing body of evidence showing that PL peroxidation is not only increased in vascular disorders, but is also a physiological event of relevance to coagulation, innate immunity, and self-tolerance. Nonenzymatically formed OxPLs generated during chronic inflammation is an uncontrolled event, generating hundreds of diverse structures, and prone to more deleterious bioactivities. In contrast, enzymatic formation of OxPLs is tightly regulated, involving receptors and intracellular signaling, acting as part of the normal physiological response to injury in order to restore homeostasis. In the present review, the major nonenzymatic OxPLs structures found during vascular inflammation are summarized, along with a brief description of their known biological activities. Also, we review what is currently known about enzymatic formation of OxPLs by acutely activated immune cells and their signaling actions under homeostatic and pathological conditions.
Asunto(s)
Aterosclerosis/metabolismo , Oxidación-Reducción , Fosfolípidos/metabolismo , Vasculitis/metabolismo , Aterosclerosis/fisiopatología , Humanos , Lipooxigenasas/fisiología , Fosfolípidos/fisiología , Prostaglandina-Endoperóxido Sintasas/fisiología , Especies Reactivas de Oxígeno , Transducción de Señal/fisiología , Vasculitis/fisiopatologíaRESUMEN
Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. The finding of aspirin benefit at low-doses given once daily, used for cardioprevention, locates the antiplatelet effect of aspirin at the center of its antitumor efficacy. In fact, at low-doses, aspirin acts mainly by an irreversible inactivation of platelet cyclooxygenase (COX)-1 in the presystemic circulation, which translates into a long-lasting inhibition of platelet function. Given the short half-life of aspirin in the human circulation(approximately 20 min) and the capacity of nucleated cells to resynthesize the acetylated COX-isozyme(s), it seems unlikely that a nucleated cell could be the target of aspirin chemoprevention. These findings convincingly suggest that colorectal cancer and atherothrombosis may share a common mechanism of disease, i.e. platelet activation in response to epithelial(in tumorigenesis) and endothelial(in tumorigenesis and atherothrombosis) injury. Activated platelets may also enhance the metastatic potential of cancer cells (through a direct interaction and/or the release of soluble mediators or exosomes) at least in part by inducing the overexpression of COX-2. COX-independent mechanisms of aspirin, such as the inhibition of NF-kB signaling and Wnt/ß-catenin signaling and the acetylation of extra-COX proteins, have been suggested to play a role in its chemopreventive effects. However, their relevance remains to be demonstrated in vivo at clinical doses.
Asunto(s)
Anticarcinógenos/farmacología , Aspirina/farmacología , Neoplasias Colorrectales/prevención & control , Animales , Aspirina/farmacocinética , Plaquetas/fisiología , Inhibidores de la Ciclooxigenasa/farmacología , Humanos , Prostaglandina-Endoperóxido Sintasas/fisiologíaRESUMEN
Population-based studies have established that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), reduces the relative risk for developing colorectal cancer. These studies led to the identification of a molecular target, COX-2, that is involved in tumour promotion during colorectal cancer progression. Recent studies in humans indicate that therapy with specific COX-2 inhibitors might be an effective approach to colorectal cancer prevention and treatment.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Neoplasias Colorrectales/prevención & control , Inhibidores de la Ciclooxigenasa/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/enzimología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Modelos Animales de Enfermedad , Humanos , Isoenzimas/fisiología , Proteínas de la Membrana , Prostaglandina-Endoperóxido Sintasas/fisiología , Prostaglandinas/biosíntesis , Receptores de Prostaglandina E/fisiologíaRESUMEN
We investigated the mechanisms involved in the 5-hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in long-term-diabetic pithed rats. Diabetes was induced in rats by alloxan administration. Eight weeks later, the animals were anaesthetized and pithed. The action and mechanisms of 5-HT were analysed based on the pressor responses induced by sympathostimulation. In 8-week-diabetic animals, 5-HT (20 µg/kg/min) inhibits the pressor effect of sympathostimulation which is reproduced by two selective 5-HT(1A) and 5-HT(2) receptor agonists: 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT, 5 µg/kg/min) and α-methyl-5-HT (5 µg/kg/min). A bolus injection of 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 10 µg/kg), or L-arginine HCl, N(ω)-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg), an inhibitor of NO production, prior to the infusion of 8-OH-DPAT (5 µg/kg/min) reversed the inhibitory effect of 8-OH-DPAT. The inhibitory effect of infusion of α-methyl 5-HT (5 µg/kg/min) was abolished in the presence of indomethacin (2 mg/kg), a non-selective cyclooxygenase (COX) inhibitor, or FR 122047 (1.5 mg/kg) or nimesulide (1.5 mg/kg), two selective COX-1 and COX-2 inhibitors, respectively, in long-term-diabetic pithed rats. Our results indicate that 5-HT inhibition of the pressor responses induced by electrical stimulation is mediated both by the NO and COX pathways in long-term-diabetic rats.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Experimental/fisiopatología , Óxido Nítrico/fisiología , Prostaglandina-Endoperóxido Sintasas/fisiología , Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Aloxano , Animales , Masculino , NG-Nitroarginina Metil Éster/farmacología , Oxadiazoles/farmacología , Piperazinas/farmacología , Ratas , Ratas Wistar , Serotonina/análogos & derivados , Transducción de Señal , Sistema Nervioso Simpático/fisiología , Tiazoles/farmacologíaRESUMEN
Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Úlcera Péptica/inducido químicamente , Animales , Células Cultivadas , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/efectos adversos , Inhibidores de la Ciclooxigenasa/farmacología , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Flavonoides/farmacología , Humanos , Indometacina/farmacología , Isoenzimas/fisiología , Proteínas de la Membrana , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Neovascularización Patológica/enzimología , Nitrobencenos/farmacología , Úlcera Péptica/patología , Prostaglandina-Endoperóxido Sintasas/fisiología , Ratas , Sulfonamidas/farmacología , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Atherosclerosis is recognized as an inflammatory condition of the vessel wall, characterized by accumulation of inflammatory cells such as macrophages and T cells. There are accumulating evidences that chemokines, cytokines, and lipid mediators coordinately modulate platelet- or leukocyte-endothelial cell interactions, and contribute to the maintenance of vascular homeostasis. This review focuses on the role of lipid mediators, especially those derived from polyunsaturated fatty acids, in controlling vascular inflammation and the progression of atherosclerosis.