RESUMEN
Cholangiocarcinoma (CCA) is a cancer with a poor prognosis due to difficulties in diagnosis and limited treatment options, highlighting the urgent need for new targeted therapies. In a clinical setting, we found that leukotriene levels in bile were higher than in serum. Immunohistochemical analysis of surgically resected samples also revealed that CysLT receptor 1 (CysLTR1) was more highly expressed in CCA than in normal bile duct tissue, prompting us to investigate leukotriene as a potential therapeutic target in CCA. In vitro studies using CCA cell lines expressing CysLTR1 showed that leukotriene D4, a major ligand of CysLTR1, promoted cell proliferation, with increased phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Additionally, treatment with two clinically available anti-allergic drugs-zileuton, an inhibitor of CysLT formation, and montelukast, a CysLTR1 inhibitor-had inhibitory effects on cell proliferation and migratory capacity, accompanied by the reduced phosphorylation of AKT and ERK1/2. Furthermore, the simultaneous administration of both drugs synergistically enhanced the inhibitory effect on cell proliferation. Our study suggests that use of these drugs may represent a novel approach to treat CCA through drug repositioning.
Asunto(s)
Neoplasias de los Conductos Biliares , Proliferación Celular , Colangiocarcinoma , Hidroxiurea , Antagonistas de Leucotrieno , Quinolinas , Receptores de Leucotrienos , Sulfuros , Humanos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Proliferación Celular/efectos de los fármacos , Receptores de Leucotrienos/metabolismo , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Línea Celular Tumoral , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Sulfuros/farmacología , Quinolinas/farmacología , Hidroxiurea/análogos & derivados , Hidroxiurea/farmacología , Hidroxiurea/uso terapéutico , Acetatos/farmacología , Acetatos/química , Masculino , Ciclopropanos/farmacología , Ciclopropanos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Femenino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Progresión de la Enfermedad , Leucotrienos/metabolismo , Fosforilación/efectos de los fármacos , Anciano , Leucotrieno D4/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacosRESUMEN
BACKGROUNDS & AIM: Placental insufficiency is a serious complication that affects pregnancy and fetal growth. Cyclophosphamide (CYC) is considered one of the chemotherapeutic agents. Unfortunately, CYC not only affects tumor cells but also affects healthy cells causing multiple injuries including the placenta. The present study aimed to evaluate the effect of cysteinyl leukotriene receptor antagonist; montelukast (MK), on CYC-induced placental injury in rats. MATERIALS AND METHODS: Forty-eight female Wister rats were randomly divided into 8 experimental groups. Group 1: control pregnant group; Group 2: MK 5 mg-treated pregnant rats; Group 3: MK 10 mg-treated pregnant rats; Group 4: MK 20 mg-treated pregnant rats; Group 5: pregnant rats received CYC (20 mg/kg, i.p); Group 6: pregnant rats received MK 5 mg and CYC; Group 7: pregnant rats received MK 10 mg and CYC; Group 8: pregnant rats received MK 20 mg and CYC. Placental malondialdehyde (MDA), reduced glutathione (GSH), total antioxidant capacity (TAC), placental growth factor (PlGF), and Nod-like receptor p3 (NLRP3) inflammasome were measured. Histological changes, interleukin-1ß (IL-1ß), and cleaved caspase-3 immuno-expressions were also evaluated. RESULTS: CYC showed a significant decrease in placental GSH, TAC, and PlGF with a significant increase in placental MDA, NLRP3, and immuno-expression of IL-1ß and caspase-3. MK showed significant improvement in all oxidative stress (MDA, GSH and TAC), inflammatory (NLRP3 and IL-1ß), and apoptotic (caspase-3) parameters. CONCLUSION: According to the findings, MK was proved to have a possible protective role in CYC-induced placental injury via modulation of NLRP3/IL-1ß signaling pathway with anti-oxidant, anti-inflammatory, and anti-apoptotic effects.
Asunto(s)
Acetatos , Ciclofosfamida , Ciclopropanos , Interleucina-1beta , Antagonistas de Leucotrieno , Proteína con Dominio Pirina 3 de la Familia NLR , Placenta , Quinolinas , Ratas Wistar , Transducción de Señal , Sulfuros , Animales , Femenino , Embarazo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Ciclofosfamida/toxicidad , Ciclofosfamida/efectos adversos , Quinolinas/farmacología , Quinolinas/uso terapéutico , Acetatos/uso terapéutico , Acetatos/farmacología , Interleucina-1beta/metabolismo , Placenta/efectos de los fármacos , Placenta/patología , Placenta/metabolismo , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Transducción de Señal/efectos de los fármacos , Ratas , Factor de Crecimiento Placentario/metabolismo , Estrés Oxidativo/efectos de los fármacos , Inflamasomas/metabolismo , Apoptosis/efectos de los fármacosRESUMEN
Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively treat respiratory conditions by targeting cysteinyl leukotriene receptors, CysLT1 and CysLT2 subtypes. This review explores the multifaceted effects of LTs, extending beyond bronchoconstriction. CysLT receptors are not only present in the respiratory system but are also crucial in neuronal signaling pathways. LTRAs modulate these receptors, influencing downstream signaling, calcium levels, inflammation, and oxidative stress (OS) within neurons hinting at broader implications. Recent studies identify novel molecular targets, sparking interest in repurposing LTRAs for therapeutic use. Clinical trials are investigating their potential in neuroinflammation control, particularly in Alzheimer's disease (AD) and Parkinson's diseases (PD). However, montelukast, a long-standing LTRA since 1998, raises concerns due to neuropsychiatric adverse drug reactions (ADRs). Despite widespread use, understanding montelukast's metabolism and underlying ADR mechanisms remains limited. This review comprehensively examines LTRAs' diverse biological effects, emphasizing non-bronchoconstrictive activities. It also analyses plausible mechanisms behind LTRAs' neuronal effects, offering insights into their potential as neurodegenerative disease modulators. The aim is to inform clinicians, researchers, and pharmaceutical developers about LTRAs' expanding roles, particularly in neuroinflammation control and their promising repurposing for neurodegenerative disease management.
Asunto(s)
Antagonistas de Leucotrieno , Receptores de Leucotrienos , Humanos , Antagonistas de Leucotrieno/uso terapéutico , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/efectos adversos , Animales , Receptores de Leucotrienos/metabolismo , Sulfuros/uso terapéutico , Sulfuros/farmacología , Sulfuros/efectos adversos , Acetatos/uso terapéutico , Acetatos/farmacología , Acetatos/efectos adversos , Neurotransmisores/metabolismo , Transducción de Señal/efectos de los fármacos , Ciclopropanos , QuinolinasRESUMEN
Schistosomiasis remains the most devastating neglected tropical disease, affecting over 240 million people world-wide. The disease is caused by the eggs laid by mature female worms that are trapped in host's tissues, resulting in chronic Th2 driven fibrogranulmatous pathology. Although the disease can be treated with a relatively inexpensive drug, praziquantel (PZQ), re-infections remain a major problem in endemic areas. There is a need for new therapeutic drugs and alternative drug treatments for schistosomiasis. The current study hypothesized that cysteinyl leukotrienes (cysLTs) could mediate fibroproliferative pathology during schistosomiasis. Cysteinyl leukotrienes (cysLTs) are potent lipid mediators that are known to be key players in inflammatory diseases, such as asthma and allergic rhinitis. The present study aimed to investigate the role of cysLTR1 during experimental acute and chronic schistosomiasis using cysLTR1-/- mice, as well as the use of cysLTR1 inhibitor (Montelukast) to assess immune responses during chronic Schistosoma mansoni infection. Mice deficient of cysLTR1 and littermate control mice were infected with either high or low dose of Schistosoma mansoni to achieve chronic or acute schistosomiasis, respectively. Hepatic granulomatous inflammation, hepatic fibrosis and IL-4 production in the liver was significantly reduced in mice lacking cysLTR1 during chronic schistosomiasis, while reduced liver pathology was observed during acute schistosomiasis. Pharmacological blockade of cysLTR1 using montelukast in combination with PZQ reduced hepatic inflammation and parasite egg burden in chronically infected mice. Combination therapy led to the expansion of Tregs in chronically infected mice. We show that the disruption of cysLTR1 is dispensable for host survival during schistosomiasis, suggesting an important role cysLTR1 may play during early immunity against schistosomiasis. Our findings revealed that the combination of montelukast and PZQ could be a potential prophylactic treatment for chronic schistosomiasis by reducing fibrogranulomatous pathology in mice. In conclusion, the present study demonstrated that cysLTR1 is a potential target for host-directed therapy to ameliorate fibrogranulomatous pathology in the liver during chronic and acute schistosomiasis in mice.
Asunto(s)
Acetatos , Ciclopropanos , Modelos Animales de Enfermedad , Ratones Noqueados , Quinolinas , Receptores de Leucotrienos , Esquistosomiasis mansoni , Sulfuros , Animales , Receptores de Leucotrienos/metabolismo , Ratones , Ciclopropanos/uso terapéutico , Ciclopropanos/farmacología , Acetatos/uso terapéutico , Acetatos/farmacología , Sulfuros/uso terapéutico , Sulfuros/farmacología , Esquistosomiasis mansoni/tratamiento farmacológico , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/parasitología , Quinolinas/uso terapéutico , Quinolinas/farmacología , Femenino , Schistosoma mansoni/inmunología , Enfermedad Crónica , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Hígado/parasitología , Hígado/patología , Hígado/metabolismo , Hígado/inmunología , Ratones Endogámicos C57BL , Praziquantel/uso terapéutico , Praziquantel/farmacología , Linfocitos T Reguladores/inmunologíaRESUMEN
Montelukast and zafirlukast, cysteinyl leukotriene receptor antagonists (LTRAs), trigger apoptosis and inhibit cell proliferation of triplenegative breast cancer MDAMB231 cells. By contrast, only zafirlukast induces G0/G1 cell cycle arrest. The present study compared the effects of these drugs on proteins regulating cell proliferation, apoptosis, autophagy, and endoplasmic reticulum (ER) and oxidative stress using reverse transcriptionquantitative PCR, western blotting and flow cytometry. The expression of proliferating markers, Ki67 and proliferating cell nuclear antigen, was decreased by both drugs. Zafirlukast, but not montelukast, decreased the expression of cyclin D1 and CDK4, disrupting progression from G1 to S phase. Zafirlukast also increased the expression of p27, a cell cycle inhibitor. Both drugs decreased the expression of antiapoptotic protein Bcl2 and ERK1/2 phosphorylation, and increased levels of the autophagy marker LC3II and DNA damage markers, including cleaved PARP1, phosphorylated (p)ATM and phistone H2AX. The number of caspase 3/7positive cells was greater in montelukasttreated cells compared with zafirlukasttreated cells. Montelukast induced higher levels of the ER stress marker CHOP compared with zafirlukast. Montelukast activated PERK, activating transcription factor 6 (ATF6) and inositolrequiring enzyme type 1 (IRE1) pathways, while zafirlukast only stimulated ATF6 and IRE1 pathways. GSK2606414, a PERK inhibitor, decreased apoptosis mediated by montelukast, but did not affect zafirlukastinduced cell death. The knockdown of CHOP by small interfering RNA reduced apoptosis triggered by montelukast and zafirlukast. In conclusion, the effects on cell cycle regulator proteins may contribute to cell cycle arrest caused by zafirlukast. The greater apoptotic effects of montelukast may be caused by the higher levels of activated caspase enzymes and the activation of three pathways of ER stress: PERK, ATF6, and IRE1.
Asunto(s)
Acetatos , Apoptosis , Autofagia , Ciclopropanos , Daño del ADN , Estrés del Retículo Endoplásmico , Indoles , Quinolinas , Sulfuros , Sulfonamidas , Humanos , Sulfuros/farmacología , Ciclopropanos/farmacología , Quinolinas/farmacología , Apoptosis/efectos de los fármacos , Acetatos/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Línea Celular Tumoral , Autofagia/efectos de los fármacos , Sulfonamidas/farmacología , Indoles/farmacología , Femenino , Daño del ADN/efectos de los fármacos , Fenilcarbamatos/farmacología , Compuestos de Tosilo/farmacología , Proliferación Celular/efectos de los fármacos , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Endorribonucleasas/metabolismo , Endorribonucleasas/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Factor de Transcripción CHOP/metabolismo , Factor de Transcripción CHOP/genética , Ciclo Celular/efectos de los fármacos , Antagonistas de Leucotrieno/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
Background and Objectives: The influence of montelukast (MK), an antagonist of cysLT1 leukotriene receptors, on lung lesions caused by experimental diabetes was studied. Materials and Methods: The study was conducted on four groups of six adult male Wistar rats. Diabetes was produced by administration of streptozotocin 65 mg/kg ip. in a single dose. Before the administration of streptozotocin, after 72 h, and after 8 weeks, the serum values of glucose, SOD, MDA, and total antioxidant capacity (TAS) were determined. After 8 weeks, the animals were anesthetized and sacrificed, and the lungs were harvested and examined by optical microscopy. Pulmonary fibrosis, the extent of lung lesions, and the lung wet-weight/dry-weight ratio were evaluated. Results: The obtained results showed that MK significantly reduced pulmonary fibrosis (3.34 ± 0.41 in the STZ group vs. 1.73 ± 0.24 in the STZ+MK group p < 0.01) and lung lesion scores and also decreased the lung wet-weight/dry-weight (W/D) ratio. SOD and TAS values increased significantly when MK was administered to animals with diabetes (77.2 ± 11 U/mL in the STZ group vs. 95.7 ± 13.3 U/mL in the STZ+MK group, p < 0.05, and 25.52 ± 2.09 Trolox units in the STZ group vs. 33.29 ± 1.64 Trolox units in the STZ+MK group, respectively, p < 0.01), and MDA values decreased. MK administered alone did not significantly alter any of these parameters in normal animals. Conclusions: The obtained data showed that by blocking the action of peptide leukotrienes on cysLT1 receptors, montelukast significantly reduced the lung lesions caused by diabetes. The involvement of these leukotrienes in the pathogenesis of fibrosis and other lung diabetic lesions was also demonstrated.
Asunto(s)
Acetatos , Ciclopropanos , Diabetes Mellitus Experimental , Pulmón , Quinolinas , Ratas Wistar , Sulfuros , Ciclopropanos/uso terapéutico , Animales , Quinolinas/uso terapéutico , Quinolinas/farmacología , Acetatos/uso terapéutico , Acetatos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Masculino , Ratas , Pulmón/efectos de los fármacos , Fibrosis Pulmonar/tratamiento farmacológico , Antagonistas de Leucotrieno/uso terapéutico , Antagonistas de Leucotrieno/farmacología , Estreptozocina , Glucemia/análisis , Glucemia/efectos de los fármacosRESUMEN
INTRODUCTION: Post-market monitoring has shown a potential link between the use of leukotriene-modifying agents (LTRAs) and an increased risk of neuropsychiatric events, such as depression. However, observational studies have produced inconsistent findings, offering no definitive conclusions. OBJECTIVE: To assess the potential correlation between LTRAs exposure and depression in US adults. METHOD: This cross-sectional study, based on population data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016 cycle. The Patient Health Questionnaire-9 was used to assess depression. Multivariable regression was used to evaluate the association between LTRAs exposure and depression. Sensitivity and subgroup analyses were conducted, with the calculation of the E-value. Network pharmacology was employed to investigate the influence of LTRAs on mechanisms of depression. RESULTS: Among the 9414 participants, 595 (6.3 %) were classified as having depression. LTRAs exposure was associated with a higher prevalence of depression (16.9 % vs. 6.0 %). The multivariable logistic regression results showed that LTRAs use increased the risk of depression (OR = 1.70; 95 % CI, 1.05-2.75). An association between LTRAs exposure and depression was found in sensitivity analyses conducted regardless of multivariable linear regression with the PHQ-9 score as a continuous variable (ß = 0.97; 95 % CI, 0.44-1.50) or multivariable logistic regression with the PHQ-9 cut-off of 5 (OR = 1.52; 95 % CI, 1.08-2.14). The association between LTRAs and depression was stable in the different subgroups. CONCLUSION: LTRAs exposure is positively associated with depression in US adults. Therefore, the risk for depression in patients receiving long-term LTRAs treatment should be considered.
Asunto(s)
Depresión , Encuestas Nutricionales , Humanos , Estudios Transversales , Masculino , Femenino , Persona de Mediana Edad , Adulto , Depresión/epidemiología , Depresión/inducido químicamente , Estados Unidos/epidemiología , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/efectos adversos , Prevalencia , Factores de Riesgo , AncianoRESUMEN
BACKGROUND AND AIMS: The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. METHODS: The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. RESULTS: Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. CONCLUSIONS: ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.
Asunto(s)
Aldehído Deshidrogenasa Mitocondrial , Trampas Extracelulares , Leucotrieno C4 , Daño por Reperfusión Miocárdica , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Aldehído Deshidrogenasa Mitocondrial/genética , Aldehído Deshidrogenasa Mitocondrial/metabolismo , Benzamidas , Benzodioxoles , Modelos Animales de Enfermedad , Trampas Extracelulares/metabolismo , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Leucotrieno C4/antagonistas & inhibidores , Leucotrieno C4/metabolismo , Ratones Noqueados , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Neutrófilos/metabolismo , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Infarto del Miocardio con Elevación del ST/metabolismoRESUMEN
BACKGROUND: Emerging literature has suggested the antiepileptic activity of cysteine leukotriene receptor (CysLTR) antagonists in experimental animals of epilepsy. Leukotrienes are substances that cause inflammation and affect brain activity, blood flow, oxidation, and inflammation in the brain. These processes are related to epilepsy and its complications. CysLTR antagonists are drugs that prevent leukotrienes from working. They may be useful for treating epilepsy, especially for people who do not respond to other drugs. Therefore, the current study aims to systematically review the potential anti-seizure effect of CysLTR antagonists in experimental studies. METHOD: We systematically reviewed the online databases using online databases such as Google Scholar, science direct, and PubMed until December 2022 to identify experimental studies assessing the anti-seizure activity of CysLTR antagonists. The Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) was used to evaluate the risk of bias (RoB) of the included studies. RESULTS: Initially we identified 3823 studies. After screening using inclusion and exclusion criteria, 8 studies were finally included in the current study. All included studies, reported that CysLTR antagonists reduced the intensity of seizures in animal models of epilepsy. CONCLUSION: In conclusion, CysLTR antagonists could be a potential therapeutic approach for the treatment of epilepsy. However, further preclinical and clinical studies are required to confirm their efficacy, safety, and mechanism of anti-seizure activity.
Asunto(s)
Cisteína , Epilepsia , Humanos , Animales , Cisteína/uso terapéutico , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/complicaciones , Leucotrienos , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , InflamaciónRESUMEN
BACKGROUND: Declined kidney function associated with hypertension is a danger for cognitive deficits, dementia, and brain injury. Cognitive decline and vascular dementia (VaD) are serious public health concerns, which highlights the urgent need for study on the risk factors for cognitive decline. Cysteinyl leukotriene (CysLT1) receptors are concerned with regulating cognition, motivation, inflammatory processes, and neurogenesis. OBJECTIVE: This research aims to examine the consequence of montelukast (specific CysLT1 antagonist) in renovascular hypertension 2-kidney-1-clip-2K1C model-triggered VaD in experimental animals. METHODS: 2K1C tactics were made to prompt renovascular hypertension in mature male rats. Morris water maze was employed to measure cognition. Mean arterial pressure (MAP), serum nitrite levels, aortic superoxide content, vascular endothelial activity, brain's oxidative stress (diminished glutathione, raised lipid peroxides), inflammatory markers (IL-10, IL-6, TNF-α), cholinergic activity (raised acetylcholinesterase), and cerebral injury (staining of 2, 3, 5- triphenylterazolium chloride) were also examined. RESULTS: Montelukast in doses of 5.0 and 10.0 mg kg-1 was used intraperitoneally as the treatment drug. Along with cognitive deficits, 2K1C-operated rats showed elevated MAP, endothelial dysfunction, brain oxidative stress, inflammation, and cerebral damage with diminished serum nitrite/nitrate. Montelukast therapy significantly and dose-dependently mitigated the 2K1Chypertension- provoked impaired behaviors, biochemistry, endothelial functions, and cerebral infarction. CONCLUSION: The 2K1C tactic caused renovascular hypertension and associated VaD, which was mitigated via targeted regulation of CysLT1 receptors by montelukast administration. Therefore, montelukast may be taken into consideration for the evaluation of its complete potential in renovascular-hypertension-induced VaD.
Asunto(s)
Acetatos , Ciclopropanos , Demencia Vascular , Modelos Animales de Enfermedad , Endotelio Vascular , Hipertensión Renovascular , Antagonistas de Leucotrieno , Estrés Oxidativo , Quinolinas , Receptores de Leucotrienos , Sulfuros , Animales , Acetatos/farmacología , Quinolinas/farmacología , Masculino , Demencia Vascular/fisiopatología , Demencia Vascular/tratamiento farmacológico , Demencia Vascular/metabolismo , Demencia Vascular/psicología , Antagonistas de Leucotrieno/farmacología , Estrés Oxidativo/efectos de los fármacos , Hipertensión Renovascular/fisiopatología , Hipertensión Renovascular/tratamiento farmacológico , Hipertensión Renovascular/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Endotelio Vascular/metabolismo , Receptores de Leucotrienos/metabolismo , Mediadores de Inflamación/metabolismo , Cognición/efectos de los fármacos , Ratas Wistar , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Ratas , Aprendizaje por Laberinto/efectos de los fármacosRESUMEN
Leukotrienes are important icosanoids group involved in a lot of normal and pathological states. Montelukast (MK) is a selective cysteinyl leukotriene receptor (Cys LT1) antagonist. Purpose. The purpose of the study is to observe the influence of MK on renal damage caused by experimental diabetes in rats. The experiment was carried out on four groups of adult male Wistar rats. Lot I was a witness and received 1.5ml of physiological saline ip. in unique dose on the first day of the experiment. Lots II and III have been caused experimental diabetes by streptozotocin (STZ) administration of 60mg/kg ip. in the unique dose. Lot III also received MK daily 10mg/kg/day daily 8weeks.Lot IV received only MK 10mg/kg/day daily 8 weeks. After eight weeks all animals were anesthetized and were sacrificed. The following pathological modifications were observed: tubular injury, glomerular hypertrophy and lesions, leukocytes infiltration. Obtained data showed that MK has significantly reduced the intensity of glomerular lesions (score 3.50+/-0.21 in STZ lot vs. 2.50+/-0.17 in STZ+MK lot p<0.01) and tubular damages. Renal interstitial leukocyte infiltration in animals with diabetes has been also reduced by MK. MK has a partially protective action against the lesions produced by experimental diabetes.
Asunto(s)
Diabetes Mellitus Experimental , Quinolinas , Ratas , Masculino , Animales , Ratas Wistar , Antagonistas de Leucotrieno/farmacología , Riñón , Leucotrienos , Acetatos/farmacología , Quinolinas/farmacología , Ciclopropanos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patologíaRESUMEN
We present an optimized protocol set to study the production of drug metabolites in different in vitro systems. We detail the necessary steps to identify the metabolites of xenobiotics produced in different metabolic-competent systems, from purified enzymes to primary cell cultures. It is coupled to a high-resolution mass spectrometry analytical approach and can be adapted to study any xenobiotic. This protocol was optimized using montelukast, an antagonist of the cysteinyl leukotriene receptor 1, widely used for asthma management. For complete details on the use and execution of this protocol, please refer to Marques et al. (2022).1.
Asunto(s)
Acetatos , Antagonistas de Leucotrieno , Antagonistas de Leucotrieno/farmacología , Cultivo Primario de Células , Acetatos/farmacología , Espectrometría de MasasRESUMEN
BACKGROUND: Lung cancer is a major threat to public health and remains difficult to treat. Repositioning of existing drugs has emerged as a therapeutic strategy in lung cancer. Clinically, low-dose montelukast has been used to treat asthma. OBJECTIVE: We evaluated the potential of using montelukast to treat lung cancer. METHODS: Migration was detected using wound-healing and Transwell assays, the expression of CysLT1 using western blotting, and subcellular localization of CysLT1 using immunofluorescence. CRISPR/Cas9 technology was used to further investigate the function of CysLT1. RESULTS: Subcellular localization staining showed that the CysLT1 distribution varied in murine and human lung cancer cell lines. Furthermore, montelukast suppressed CysLT1 expression in lung cancer cells. The treated cells also showed weaker migration ability compared with control cells. Knockout of CysLT1 using CRISPR/Cas9 editing in A549 cells further impaired the cell migration ability. CONCLUSION: Montelukast inhibits the migration of lung cancer cells by suppressing CysLT1 expression, demonstrating the potential of using CysLT1 as a therapeutic target in lung cancer.
Asunto(s)
Antagonistas de Leucotrieno , Neoplasias Pulmonares , Humanos , Animales , Ratones , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Acetatos/farmacología , Acetatos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Movimiento CelularRESUMEN
The role of chronic inflammation and arachidonic acid (AA) metabolism in tumor progression has been well characterized for variety of cancers, with compelling data for colon cancer. Several preclinical and clinical studies primarily focused on inhibiting the cyclooxygenase pathways using NSAIDs and aspirin for colon cancer prevention. However, emerging evidence clearly supports the pro-tumorigenic role of 5-lipoxygenase and its downstream leukotriene pathway within AA metabolism. As discussed in the current issue, targeting the leukotriene pathway by cysteinyl leukotriene receptor antagonist (LTRA) montelukast suppressed formation of aberrant crypt foci (ACF) and cell proliferation in colonic epithelium, suggesting the potential of LTRAs for colon cancer prevention. Although this is a short clinical chemoprevention trial to explore the effects of LTRAs against ACF development, it is a significant and timely study opening avenues to further explore the possibilities of using LTRAs in other inflammation-associated precancerous lesions as well. In this spotlight commentary, we highlight the implications of their data and the opportunities for developing LTRAs as potential candidates for colorectal cancer interception. See related article by Higurashi et al., p. 661.
Asunto(s)
Focos de Criptas Aberrantes , Neoplasias del Colon , Focos de Criptas Aberrantes/patología , Antiinflamatorios no Esteroideos/uso terapéutico , Araquidonato 5-Lipooxigenasa/farmacología , Ácido Araquidónico/metabolismo , Aspirina/farmacología , Quimioprevención , Colon/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Humanos , Inflamación/patología , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Leucotrienos/farmacología , Prostaglandina-Endoperóxido Sintasas/farmacologíaRESUMEN
AIMS: Montelukast (MNK), a leukotriene receptor antagonist, has proven its antioxidant/anti-inflammatory capacity to guard against diabetes-induced complications and to enhance metformin antidiabetic effect. Nevertheless, here we evaluated the involvement of endoplasmic reticulum (ER) stress and insulin signaling cascade in the effect of MNK and/or dapagliflozin (DAPA) using the soleus muscle of type 2 diabetic (T2D)/insulin resistant (IR) rats. MAIN METHODS: To induce T2D/IR, rats were fed a westernized diet (WD) for 8 weeks followed by a sub-diabetogenic dose of streptozotocin (STZ). Animals were divided into control (receiving normal diet; ND), diabetic untreated, and diabetic treated for 4 weeks with DAPA, MNK, or their combination (DAPA+MNK). Blood glucose and serum lipid profile were determined, and the soleus muscle was tested for ER stress-induced IR, besides histopathological examination. KEY FINDINGS: Treatment with DAPA, MNK, and especially their combination decreased the fasting plasma levels of glucose and insulin while improving insulin sensitivity and lipid profile. This was achieved via the activation of insulin signaling IRS-1/AKT/GLUT4 pathway in the soleus muscle consequent to the deactivation of the ER stress response elements, namely IRE1α, ATF6, and PERK to suppress p-JNK and p-eIF2α. SIGNIFICANCE: Improved insulin signaling along with the deactivation of the ER stress response by MNK comparable to the DAPA are partly responsible for the enhanced soleus muscle insulin sensitivity, effects that nominate MNK as an add-on to DAPA to enhance its antidiabetic efficacy.
Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Metformina , Acetatos/farmacología , Animales , Antioxidantes/farmacología , Compuestos de Bencidrilo , Glucemia/metabolismo , Ciclopropanos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplásmico , Endorribonucleasas/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Glucósidos , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Antagonistas de Leucotrieno/farmacología , Metformina/farmacología , Músculo Esquelético/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinolinas , Ratas , Elementos de Respuesta , Estreptozocina/farmacología , SulfurosRESUMEN
BACKGROUND: Arachidonic acid (AA), which is metabolized via the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways, was found to be associated with venous thromboembolism (VTE). Metabolites of the LOX pathway include cysteinyl (Cys) Leukotrienes (LT), potent proinflammatory mediators, which have also been implicated in cardiovascular disease. OBJECTIVE: The purpose of this study was to examine if cysteinyl leukotriene receptor blockade by montelukast, lowers the risk of VTE. METHODS: We conducted a retrospective cohort study examining VTE risk among COPD patients from the United States Department of Veterans Affairs. We use propensity score matching and Cox survival models to estimate the hazard ratio comparing montelukast exposure to non-exposure. Montelukast exposure was associated with a 15.9% reduction in risk of VTE compared to those unexposed (HR= 0.841; 95% CI= (0.758-0.934)). CONCLUSION: The results of this study demonstrate that targeting LTs might be beneficial for VTE prophylaxis using the clinically available LT inhibitor, montelukast. Importantly, further research on LTs is warranted to fully understand and validate this relationship.
Asunto(s)
Quinolinas , Tromboembolia Venosa , Acetatos/farmacología , Acetatos/uso terapéutico , Ciclopropanos , Humanos , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Leucotrienos , Quinolinas/farmacología , Quinolinas/uso terapéutico , Receptores de Leucotrienos/metabolismo , Estudios Retrospectivos , Sulfuros , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/prevención & controlRESUMEN
BACKGROUND: Cyclooxygenase (COX) and Lipoxygenase (LOX) enzymes catalyze the production of pain mediators like Prostaglandins (PGs) and Leukotrienes (LTs), respectively from arachidonic acid. INTRODUCTION: The COX and LOX enzyme modulators are responsible for the major PGs and LTs mediated complications like asthma, osteoarthritis, rheumatoid arthritis, cancer, Alzheimer's disease, neuropathy and Cardiovascular Syndromes (CVS). Many synthetic Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) used in the treatment have serious side effects like nausea, vomiting, hyperacidity, gastrointestinal ulcers, CVS, etc. Methods: The natural inhibitors of pain mediators have great acceptance worldwide due to fewer side effects on long-term uses. The present review is an extensive study of the advantages of plantbased vs synthetic inhibitors. RESULTS: These natural COX and LOX inhibitors control inflammatory response without causing side-effect-related complicacy. CONCLUSION: Therefore, the natural COX and LOX inhibitors may be used as alternative medicines for the management of pain and inflammation due to their less toxicity and resistivity.
Asunto(s)
Inhibidores de la Ciclooxigenasa , Antagonistas de Leucotrieno , Inhibidores de la Lipooxigenasa , Humanos , Antiinflamatorios no Esteroideos/efectos adversos , Inhibidores de la Ciclooxigenasa/farmacología , Dolor , Inhibidores de la Lipooxigenasa/farmacología , Antagonistas de Leucotrieno/farmacología , Manejo del DolorRESUMEN
Leukotrienes are pro-inflammatory lipid mediators generated by 5-lipoxygenase aided by the 5-lipoxygenase-activating protein (FLAP). BRP-201, a novel benzimidazole-based FLAP antagonist, inhibits leukotriene biosynthesis in isolated leukocytes. However, like other FLAP antagonists, BRP-201 fails to effectively suppress leukotriene formation in blood, which limits its therapeutic value. Here, we describe the encapsulation of BRP-201 into poly(lactide-co-glycolide) (PLGA) and ethoxy acetalated dextran (Ace-DEX) nanoparticles (NPs), aiming to overcome these detrimental pharmacokinetic limitations and to enhance the bioactivity of BRP-201. NPs loaded with BRP-201 were produced via nanoprecipitation and the physicochemical properties of the NPs were analyzed in-depth using dynamic light scattering (size, dispersity, degradation), electrophoretic light scattering (effective charge), NP tracking analysis (size, dispersity), scanning electron microscopy (size and morphology), UV-VIS spectroscopy (drug loading), an analytical ultracentrifuge (drug release, degradation kinetics), and Raman spectroscopy (chemical attributes). Biological assays were performed to study cytotoxicity, cellular uptake, and efficiency of BRP-201-loaded NPs versus free BRP-201 to suppress leukotriene formation in primary human leukocytes and whole blood. Both PLGA- and Ace-DEX-based NPs were significantly more efficient to inhibit leukotriene formation in neutrophils versus free drug. Whole blood experiments revealed that encapsulation of BRP-201 into Ace-DEX NPs strongly increases its potency, especially upon pro-longed (≥ 5 h) incubations and upon lipopolysaccharide-challenge of blood. Finally, intravenous injection of BRP-201-loaded NPs significantly suppressed leukotriene levels in blood of mice in vivo. These results reveal the feasibility of our pharmacological approach using a novel FLAP antagonist encapsulated into Ace-DEX-based NPs with improved efficiency in blood to suppress leukotriene biosynthesis.
Asunto(s)
Antagonistas de Leucotrieno/farmacología , Leucotrienos , Nanopartículas/química , Animales , Femenino , Voluntarios Sanos , Humanos , Leucotrienos/biosíntesis , Leucotrienos/metabolismo , Masculino , RatonesRESUMEN
Autophagy is an important cellular mechanism for maintaining cellular homeostasis, and its impairment correlates highly with age and age-related diseases. Retinal pigment epithelial (RPE) cells of the eye represent a crucial model for studying autophagy, as RPE functions and integrity are highly dependent on an efficient autophagic process. Cysteinyl leukotriene receptor 1 (CysLTR1) acts in immunoregulation and cellular stress responses and is a potential regulator of basal and adaptive autophagy. As basal autophagy is a dynamic process, the aim of this study was to define the role of CysLTR1 in autophagy regulation in a chronobiologic context using the ARPE-19 human RPE cell line. Effects of CysLTR1 inhibition on basal autophagic activity were analyzed at inactive/low and high lysosomal degradation activity with the antagonists zafirlukast (ZTK) and montelukast (MTK) at a dosage of 100 nM for 3 hours. Abundances of the autophagy markers LC3-II and SQSTM1 and LC3B particles were analyzed in the absence and presence of lysosomal inhibitors using western blot analysis and immunofluorescence microscopy. CysLTR1 antagonization revealed a biphasic effect of CysLTR1 on autophagosome formation and lysosomal degradation that depended on the autophagic activity of cells at treatment initiation. ZTK and MTK affected lysosomal degradation, but only ZTK regulated autophagosome formation. In addition, dexamethasone treatment and serum shock induced autophagy, which was repressed by CysLTR1 antagonization. As a newly identified autophagy modulator, CysLTR1 appears to be a key player in the chronobiological regulation of basal autophagy and adaptive autophagy in RPE cells.
Asunto(s)
Autofagia/efectos de los fármacos , Células Epiteliales/metabolismo , Receptores de Leucotrienos/efectos de los fármacos , Epitelio Pigmentado de la Retina/efectos de los fármacos , Acetatos/farmacología , Western Blotting , Línea Celular , Supervivencia Celular/efectos de los fármacos , Fenómenos Cronobiológicos , Ciclopropanos/farmacología , Humanos , Indoles/farmacología , Antagonistas de Leucotrieno/farmacología , Estrés Oxidativo/fisiología , Fenilcarbamatos/farmacología , Quinolinas/farmacología , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/metabolismo , Sulfuros/farmacología , Sulfonamidas/farmacologíaRESUMEN
Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established ex vivo model of organotypic slice co-cultures of the mesocortical dopaminergic system (prefrontal cortex (PFC) and substantia nigra/ventral tegmental area (SN/VTA) complex), the influence of GPR17 ligands on neurite outgrowth from SN/VTA to the PFC was investigated. The growth-promoting effects of Montelukast (MTK; GPR17- and cysteinyl-leukotriene receptor antagonist), the glial cell line-derived neurotrophic factor (GDNF) and of two potent, selective GPR17 agonists (PSB-16484 and PSB-16282) were characterized. Treatment with MTK resulted in a significant increase in mean neurite density, comparable with the effects of GDNF. The combination of MTK and GPR17 agonist PSB-16484 significantly inhibited neuronal growth. qPCR studies revealed an MTK-induced elevated mRNA-expression of genes relevant for neuronal growth. Immunofluorescence labelling showed a marked expression of GPR17 on NG2-positive glia. Western blot and RT-qPCR analysis of untreated cultures suggest a time-dependent, injury-induced stimulation of GPR17. In conclusion, MTK was identified as a stimulator of neurite fibre outgrowth, mediating its effects through GPR17, highlighting GPR17 as an interesting therapeutic target in neuronal regeneration.