RESUMEN
OBJECTIVE: Vortioxetine has demonstrated safety and efficacy in improving symptoms of major depressive disorder (MDD), including overall functioning in real-world settings. This is the first study in a real-life clinical setting in India to evaluate effectiveness and safety of vortioxetine in patients with MDD. METHODS: This interventional, open-label study consisted of a 12-week treatment period with flexible doses of vortioxetine (5-20 mg/day) in adult patients (aged 18-65 years) with a confirmed MDD diagnosis. Effectiveness outcomes included change from baseline to week 12 in Patient Health Questionnaire-9 (PHQ-9) and Clinical Global Impression-Severity (CGI-S) scores, along with CGI-Improvement (CGI-I) scores at week 12, using a mixed model for repeated measures. Adverse events (AEs) were recorded for safety outcome assessments. RESULTS: Of 395 patients who received vortioxetine, 42.3% were women mean age 38.9 years; 322 patients completed the study. Significant improvement in depressive symptoms was observed in change from baseline to week 12 least squares (LS) mean (SE) PHQ-9 total score (-9.36 [0.276]; p<.0001) and CGI-S score (-2.14 [0.065]; p<.0001). LS mean (SE) CGI-I score showed significant improvement at week 12 (1.93 [0.067]; p<.0001). Subgroup analysis across age, sex, disease severity, and body mass index showed significant improvements in depression symptoms and severity. A total of 35.4% (n = 140) of patients experienced treatment-emergent AEs (mostly mild-moderate); nausea and pruritus were the most frequent (6.6%, n = 26 each). CONCLUSION: Safety and effectiveness of vortioxetine in improving symptoms of MDD over a 12-week period was demonstrated in a real-life clinical setting in India. CLINICAL TRIAL REGISTRATION INFORMATION: Open-label, flexible-dose study of vortioxetine in patients with major depressive disorder in India; Clinical Trials.gov ID: NCT04288895; https://www.clinicaltrials.gov/study/NCT04288895.
Asunto(s)
Trastorno Depresivo Mayor , Piperazinas , Vortioxetina , Humanos , Vortioxetina/administración & dosificación , Vortioxetina/efectos adversos , Vortioxetina/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Adulto , Femenino , Masculino , Persona de Mediana Edad , India , Piperazinas/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Adolescente , Anciano , Adulto Joven , Resultado del Tratamiento , Antidepresivos/efectos adversos , Antidepresivos/administración & dosificación , Antidepresivos/uso terapéutico , Sulfuros/efectos adversos , Sulfuros/administración & dosificación , Sulfuros/uso terapéuticoRESUMEN
Rhabdomyosarcoma (RMS) represents one of the most lethal soft-tissue sarcomas in children. The toxic trace element arsenic has been reported to function as a radiosensitizer in sarcomas. To investigate the role of arsenic sulfide (As4S4) in enhancing radiation sensitization in RMS, this study was conducted to elucidate its underlying mechanism in radiotherapy. The combination of As4S4 and radiotherapy showed significant inhibition in RMS cells, as demonstrated by the cell counting kit-8 (CCK-8) assay and flow cytometry. Subsequently, we demonstrated for the first time that As4S4, as well as the knockdown of NFATc3 led to double-strand break (DSB) through increased expression of RAG1. In vivo experiment confirmed that co-treatment efficiently inhibited RMS growth. Furthermore, survival analysis of a clinical cohort consisting of 59 patients revealed a correlation between NFATc3 and RAG1 expression and overall survival (OS). Cox regression analysis also confirmed the independent prognostic significance of NFATc3 and RAG1.Taken together, As4S4 enhances radiosensitivity in RMS via activating NFATc3-RAG1 mediated DSB. NFATc3 and RAG1 are potential therapeutic targets. As4S4 will hopefully serve as a prospective radio-sensitizing agent for RMS.
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Arsenicales , Roturas del ADN de Doble Cadena , Factores de Transcripción NFATC , Tolerancia a Radiación , Rabdomiosarcoma , Sulfuros , Humanos , Roturas del ADN de Doble Cadena/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de la radiación , Sulfuros/farmacología , Sulfuros/uso terapéutico , Rabdomiosarcoma/metabolismo , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/radioterapia , Rabdomiosarcoma/patología , Rabdomiosarcoma/genética , Línea Celular Tumoral , Masculino , Femenino , Arsenicales/farmacología , Arsenicales/uso terapéutico , Animales , Tolerancia a Radiación/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Ratones , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Ratones Desnudos , Niño , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Ratones Endogámicos BALB CRESUMEN
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.
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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
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
Membranous nephropathy (MN) is a common immune-mediated glomerular disease that requires the development of safe and highly effective therapies. Celastrol (CLT) has shown promise as a therapeutic molecule candidate, but its clinical use is currently limited due to off-target toxicity. Given that excess levels of reactive oxygen species (ROS) contributing to podocyte damage is a key driver of MN progression to end-stage renal disease, we rationally designed ROS-responsive cationic polymeric nanoparticles (PPS-CPNs) with a well-defined particle size and surface charge by employing poly(propylene sulfide)-polyethylene glycol (PPS-PEG) and poly(propylene sulfide)-polyethylenimine (PPS-PEI) to selectively deliver CLT to the damaged glomerulus for MN therapy. Experimental results show that PPS-CPNs successfully crossed the fenestrated endothelium, accumulated in the glomerular basement membrane (GBM), and were internalized by podocytes where rapid drug release was triggered by the overproduction of ROS, thereby outperforming nonresponsive CLT nanotherapy to alleviate subepithelial immune deposits, podocyte foot process effacement, and GBM expansion in a rat MN model. Moreover, the ROS-responsive CLT nanotherapy was associated with significantly lower toxicity to major organs than free CLT. These results suggest that encapsulating CLT into PPS-CPNs can improve efficacy and reduce toxicity as a promising treatment option for MN.
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Glomerulonefritis Membranosa , Nanopartículas , Triterpenos Pentacíclicos , Podocitos , Especies Reactivas de Oxígeno , Animales , Especies Reactivas de Oxígeno/metabolismo , Nanopartículas/química , Glomerulonefritis Membranosa/tratamiento farmacológico , Glomerulonefritis Membranosa/patología , Ratas , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacología , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Polietilenglicoles/química , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Ratas Sprague-Dawley , Humanos , Masculino , Polímeros/química , Polímeros/farmacología , Sulfuros/química , Sulfuros/farmacología , Sulfuros/uso terapéutico , Polietileneimina/química , Portadores de Fármacos/químicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Realgar, a traditional mineral Chinese medicine, has been used in China for more than 2000 years. It has been recorded in many ancient and modern works that it has anti-cancer and anti-tumor effects. Of course, colon cancer is also within the scope of its treatment. Realgar needs to be processed into realgar decoction pieces by water grinding before being used for medicine. To ensure the consistency of efficacy and quality of realgar decoction pieces, modern methods need to be used for further quality control. AIM OF THE STUDY: The research of traditional mineral Chinese medicine is relatively difficult, and the related research is less. The purpose of this study is to control the quality of realgar decoction pieces by modern analytical technology and analyze its components. On this basis, its anti-colon cancer activity was discussed. MATERIALS AND METHODS: Several batches of realgar decoction pieces were analyzed by XRD, and the components of realgar decoction pieces were obtained. The quality control fingerprints of realgar decoction pieces were established by processing XRD spectra and similarity evaluation. Then, the effects of realgar decoction pieces on apoptosis of CT26 and HTC-116 cells were observed in vitro by Hoechst 33258 staining, flow cytometry, measurement of mitochondrial membrane potential and Western blot; In vivo, the mouse model of tumor-in-situ transplantation of colon cancer was established, and the related indexes were observed. RESULT: The explorations showed that the XRD Fourier fingerprints of realgar decoction pieces samples that had the same phase revealed 10 common peaks, respectively. The similarity evaluation of the established XRD Fourier fingerprint was greater than 0.900. We also demonstrated that realgar decoction pieces can promote apoptosis and inhibit tumor growth in colon cancer cells, its activating effect on p53 protein, and its safety when used within reasonable limits. CONCLUSION: The quality control of realgar decoction pieces by XRD is scientific and has the inhibitory effect on colon cancer, which has the development potential.
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Apoptosis , Neoplasias del Colon , Animales , Apoptosis/efectos de los fármacos , Ratones , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Humanos , Sulfuros/farmacología , Sulfuros/uso terapéutico , Arsenicales/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Línea Celular Tumoral , Ratones Endogámicos BALB C , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Masculino , Control de Calidad , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéuticoRESUMEN
Development of novel functional foods is trending as one of the hot topics in food science and food/beverage industries. In the present study, the anti-diabetic, anti-hyperlipidemic and histo-protective effects of the extra virgin olive oil (EVOO) enriched with the organosulfur diallyl sulfide (DAS) (DAS-rich EVOO) were evaluated in alloxan-induced diabetic mice. The ingestion of EVOO (500µL daily for two weeks) attenuated alloxan-induced elevated glucose, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), urea and creatinine. It also normalized the levels of triglycerides (TG), total cholesterols (TC), low-density lipoprotein-cholesterol (LDL-c) and their consequent atherogenic index of plasma (AIP) in diabetic animals. Additionally, EVOO prevented lipid peroxidation (MDA) and reduced the level of hydrogen peroxide (H2O2) in diabetic animals. Concomitantly, it enhanced the activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), reducing thereby tissue oxidative stress injury. The overall histologic (pancreas, liver, and kidney) alterations were also improved after EVOO ingestion. The manifest anti-diabetic, lipid-lowering and histo-protective properties of EVOO were markedly potentiated with DAS-rich EVOO suggesting possible synergistic interactions between DAS and EVOO lipophilic bioactive ingredients. Overall, EVOO and DAS-rich EVOO show promise as functional foods and/or adjuvants for the treatment of diabetes and its complications.
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Compuestos Alílicos , Diabetes Mellitus Experimental , Hipoglucemiantes , Hipolipemiantes , Aceite de Oliva , Sulfuros , Animales , Aceite de Oliva/química , Aceite de Oliva/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Compuestos Alílicos/farmacología , Compuestos Alílicos/uso terapéutico , Sulfuros/farmacología , Sulfuros/uso terapéutico , Sulfuros/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Ratones , Hipolipemiantes/farmacología , Masculino , Antioxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Páncreas/efectos de los fármacos , Páncreas/patología , Páncreas/metabolismo , Glutatión Peroxidasa/metabolismo , Catalasa/metabolismo , Peróxido de Hidrógeno/metabolismo , Superóxido Dismutasa/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Alanina Transaminasa/sangre , Alanina Transaminasa/metabolismo , Aspartato Aminotransferasas/metabolismo , Aspartato Aminotransferasas/sangre , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
Ticks, particularly Rhipicephalus annulatus, pose significant threats to livestock, causing economic losses and transmitting various infectious diseases. This study aimed to evaluate the potential acaricidal properties of garlic oil and its nanoemulsion against ticks infesting cattle, Rhipicephalus annulatus through the evaluation of mortality rate and morphological changes of the treated ticks. The study also included prevalence, risk factors, and molecular confirmation of tick species. Genetic characterization confirmed the identity of R. annulatus. Our results revealed a high prevalence of R. annulatus (46.9%) with a higher risk in male cattle (50%) than females (44.9%) and a nonsignificant high infection (49.1%) in animals ≤ 1 year old. The acaricidal efficiency of garlic oil and its nanoemulsion was concentration and time-dependent. The high concentration of garlic oil (20â¯mg/L) induced complete mortality within 48â¯hours. The nanoemulsion formulation enhanced efficacy, particularly at 5â¯mg/L, which exhibited rapid and substantial acaricidal activity. Scanning electron microscopy revealed morphological alterations induced by garlic oil and its nanoemulsion, including changes to the anterior capitulum, dorsal, and ventral cuticles. The study contributes to the exploration of effective, safe, and eco-friendly alternatives for tick control. Further research is warranted to validate their efficacy under diverse conditions and assess practical strategies.
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Acaricidas , Enfermedades de los Bovinos , Emulsiones , Rhipicephalus , Infestaciones por Garrapatas , Animales , Acaricidas/farmacología , Infestaciones por Garrapatas/veterinaria , Infestaciones por Garrapatas/parasitología , Infestaciones por Garrapatas/tratamiento farmacológico , Infestaciones por Garrapatas/prevención & control , Enfermedades de los Bovinos/parasitología , Enfermedades de los Bovinos/tratamiento farmacológico , Femenino , Bovinos , Masculino , Rhipicephalus/efectos de los fármacos , Sulfuros/farmacología , Sulfuros/uso terapéutico , Compuestos Alílicos/farmacología , Ajo/químicaRESUMEN
Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.
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Modelos Animales de Enfermedad , Daño por Reperfusión Miocárdica , Sulfuros , Animales , Porcinos , Sulfuros/farmacología , Sulfuros/administración & dosificación , Sulfuros/uso terapéutico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Oclusión Coronaria/tratamiento farmacológico , Oclusión Coronaria/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Glutatión Peroxidasa/metabolismo , Miocardio/metabolismo , Miocardio/patología , Masculino , MolibdenoRESUMEN
Acute lung injury (ALI) is a major cause of acute respiratory failure with a high morbidity and mortality rate, and effective therapeutic strategies for ALI remain limited. Inflammatory response is considered crucial for the pathogenesis of ALI. Garlic, a globally used cooking spice, reportedly exhibits excellent anti-inflammatory bioactivity. However, protective effects of garlic against ALI have never been reported. This study aimed to investigate the protective effects of garlic oil (GO) supplementation on lipopolysaccharide (LPS)-induced ALI models. Hematoxylin and eosin staining, pathology scores, lung myeloperoxidase (MPO) activity measurement, lung wet/dry (W/D) ratio detection, and bronchoalveolar lavage fluid (BALF) analysis were performed to investigate ALI histopathology. Real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to evaluate the expression levels of inflammatory factors, nuclear factor-κB (NF-κB), NLRP3, pyroptosis-related proteins, and H2S-producing enzymes. GO attenuated LPS-induced pulmonary pathological changes, lung W/D ratio, MPO activity, and inflammatory cytokines in the lungs and BALF. Additionally, GO suppressed LPS-induced NF-κB activation, NLRP3 inflammasome expression, and inflammatory-related pyroptosis. Mechanistically, GO promoted increased H2S production in lung tissues by enhancing the conversion of GO-rich polysulfide compounds or by increasing the expression of H2S-producing enzymes in vivo. Inhibition of endogenous or exogenous H2S production reversed the protective effects of GO on ALI and eliminated the inhibitory effects of GO on NF-κB, NLRP3, and pyroptotic signaling pathways. Overall, these findings indicate that GO has a critical anti-inflammatory effect and protects against LPS-induced ALI by suppressing the NF-κB/NLRP3 signaling pathway via H2S generation.
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Lesión Pulmonar Aguda , Compuestos Alílicos , Sulfuro de Hidrógeno , Lipopolisacáridos , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Transducción de Señal , Sulfuros , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/prevención & control , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , FN-kappa B/metabolismo , Piroptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Compuestos Alílicos/farmacología , Compuestos Alílicos/uso terapéutico , Sulfuros/farmacología , Sulfuros/uso terapéutico , Masculino , Sulfuro de Hidrógeno/metabolismo , Ratones , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ajo/química , Antiinflamatorios/farmacología , Ratones Endogámicos C57BL , Suplementos DietéticosRESUMEN
OBJECTIVES: Montelukast is a well-known leukotriene receptor antagonist commonly used in treating allergic rhinitis and asthma. Omega-3 fatty acid is also known as an antiallergic and immunomodulator molecule. This study aimed to elucidate the efficacy of systemic montelukast and omega-3 fatty acid treatment in allergic rhinitis models in Wistar Hannover rats. METHODS: This research was conducted on 28 healthy Wistar Hannover rats weighing 250-350â¯g. After establishing the allergic rhinitis model, nasal symptoms were observed and scored, and the nasal mucosa of all rats was investigated histologically. Light microscopy was utilized to evaluate the degree of ciliary loss, goblet cell hyperplasia, vascular congestion, vascular proliferation, inflammatory cell infiltration, eosinophil infiltration, and hypertrophy in chondrocytes. RESULTS: As a result of the analysis of the data obtained from the study, it was determined that typical allergic rhinitis symptoms such as nasal scratching and sneezing were significantly reduced in the rats in the montelukast and omega-3 treated group, and these symptoms did not increase after repeated intranasal OVA-protease applications. Histological examinations after fish oil treatment did not reveal typical inflammatory changes in allergic rhinitis. None of the rats in the montelukast and omega-3 groups had any increase in goblet cells, whereas 14.3% of the rats in the control group and 28.6% of the rats in the allergic rhinitis group had mild increase. Last but not least, 71.4% of rats in the allergic rhinitis group had a moderate increase. The difference between the groups was statistically significant (pâ¯<â¯0.001). CONCLUSION: Regarding the outcomes of this research, it was observed that w-3 fatty acids had antiallergic effects, both histopathological and clinical, in the allergic rhinitis model. We believe that further randomized controlled trials incorporating larger cohorts are warranted to verify the use of omega-3 fatty acids in treating allergic rhinitis. The level of evidence of this article is Level 2.
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Acetatos , Ciclopropanos , Modelos Animales de Enfermedad , Ácidos Grasos Omega-3 , Aceites de Pescado , Antagonistas de Leucotrieno , Ovalbúmina , Quinolinas , Ratas Wistar , Rinitis Alérgica , Sulfuros , Animales , Ciclopropanos/uso terapéutico , Sulfuros/uso terapéutico , Acetatos/uso terapéutico , Quinolinas/uso terapéutico , Ácidos Grasos Omega-3/uso terapéutico , Rinitis Alérgica/tratamiento farmacológico , Rinitis Alérgica/patología , Ratas , Antagonistas de Leucotrieno/uso terapéutico , Aceites de Pescado/uso terapéutico , Masculino , Resultado del Tratamiento , Mucosa Nasal/patología , Mucosa Nasal/efectos de los fármacosRESUMEN
IMPORTANCE: Pediatric obstructive sleep apnea (OSA) is a common disease that can have significant negative impacts on a child's health and development. A comprehensive evaluation of different pharmacologic interventions for the treatment of OSA in children is still lacking. OBJECTIVE: This study aims to conduct a comprehensive systematic review and network meta-analysis of pharmacological interventions for the management of obstructive sleep apnea in pediatric population. DATA SOURCES: PubMed, Web of Science, Embase, The Cochrane Library, and CNKI were searched from 1950 to November 2022 for pediatric OSA. STUDY SELECTION: Multiple reviewers included Randomized controlled trials (RCTs) concerning drugs on OSA in children. DATA EXTRACTION AND SYNTHESIS: Multiple observers followed the guidance of the PRISMA NMA statement for data extraction and evaluation. Bayesian network meta-analyses(fixed-effect model) were performed to compare the weighted mean difference (WMD), logarithmic odds ratios (log OR), and the surface under the cumulative ranking curves (SUCRA) of the included pharmacological interventions. Our protocol was registered in PROSPERO website (CRD42022377839). MAIN OUTCOME(S) AND MEASURE(S): The primary outcomes were improvements in the apnea/hypopnea index (AHI), while secondary outcomes included adverse events and the lowest arterial oxygen saturation (SaO2). RESULTS: 17 RCTs with a total of 1367 children with OSA aged 2-14 years that met the inclusion criteria were eventually included in our systematic review and network meta-analysis. Ten drugs were finally included in the study. The results revealed that Mometasone + Montelukast (WMD-4.74[95%CrIs -7.50 to -2.11], Budesonide (-3.45[-6.86 to -0.15], and Montelukast(-3.41[-5.45 to -1.39] exhibited significantly superior therapeutic effects compared to the placebo concerning apnea hypopnea index (AHI) value with 95%CrIs excluding no effect. Moreover, Mometasone + Montelukast achieved exceptionally high SUCRA values for both AHI (85.0 %) and SaO2 (91.0 %). CONCLUSIONS AND RELEVANCE: The combination of mometasone furoate nasal spray and oral montelukast sodium exhibits the highest probability of being the most effective intervention. Further research is needed to investigate the long-term efficacy and safety profiles of these interventions in pediatric patients with OSA.
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Ciclopropanos , Metaanálisis en Red , Apnea Obstructiva del Sueño , Sulfuros , Humanos , Apnea Obstructiva del Sueño/tratamiento farmacológico , Niño , Ciclopropanos/uso terapéutico , Ciclopropanos/efectos adversos , Sulfuros/uso terapéutico , Quinolinas/uso terapéutico , Quinolinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Acetatos/uso terapéutico , Acetatos/efectos adversos , Furoato de Mometasona/uso terapéutico , Furoato de Mometasona/administración & dosificación , Teorema de BayesRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: In China, the Chinese patent drug Realgar-Indigo naturalis Formula (RIF) is utilized for the therapy of acute promyelocytic leukemia (APL). Comprising four traditional Chinese herb-Realgar, Indigo naturalis, Salvia miltiorrhiza, and Pseudostellaria heterophylla-it notably includes tetra-arsenic tetra-sulfide, indirubin, tanshinone IIa, and total saponins of Radix Pseudostellariae as its primary active components. Due to its arsenic content, RIF distinctly contributes to the therapy for APL. However, the challenge of arsenic resistance in APL patients complicates the clinical use of arsenic agents. Interestingly, RIF demonstrates a high remission rate in APL patients, suggesting that its efficacy is not significantly compromised by arsenic resistance. Yet, the current state of research on RIF's ability to reverse arsenic resistance remains unclear. AIM OF THE STUDY: To investigate the mechanism of different combinations of the compound of RIF in reversing arsenic resistance in APL. MATERIALS AND METHODS: The present study utilized the arsenic-resistant HL60-PMLA216V-RARα cell line to investigate the effects of various RIF compounds, namely tetra-arsenic tetra-sulfide (A), indirubin (I), tanshinone IIa (T), and total saponins of Radix Pseudostellariae (S). The assessment of cell viability, observation of cell morphology, and evaluation of cell apoptosis were performed. Furthermore, the mitochondrial membrane potential, changes in the levels of PMLA216V-RARα, apoptosis-related factors, and the PI3K/AKT/mTOR pathway were examined, along with autophagy in all experimental groups. Meanwhile, we observed the changes about autophagy after blocking the PI3K or mTOR pathway. RESULTS: Tanshinone IIa, indirubin and total saponins of Radix Pseudostellariae could enhance the effect of tetra-arsenic tetra-sulfide down-regulating PMLA216V-RARα, and the mechanism was suggested to be related to inhibiting mTOR pathway to activate autophagy. CONCLUSIONS: We illustrated that the synergistic effect of different compound combinations of RIF can regulate autophagy through the mTOR pathway, enhance cell apoptosis, and degrade arsenic-resistant PMLA216V-RARα.
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Abietanos , Arsénico , Arsenicales , Medicamentos Herbarios Chinos , Leucemia Promielocítica Aguda , Saponinas , Humanos , Arsénico/efectos adversos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/inducido químicamente , Fosfatidilinositol 3-Quinasas , Arsenicales/farmacología , Arsenicales/uso terapéutico , Sulfuros/farmacología , Sulfuros/uso terapéutico , Saponinas/uso terapéuticoRESUMEN
INTRODUCTION: Myocardial injury is a serious complication in sepsis with high mortality. Zero-valent iron nanoparticles (nanoFe) displayed novel roles in cecal ligation and puncture (CLP)-induced septic mouse model. Nonetheless, its high reactivity makes it difficult for long-term storage. OBJECTIVES: To overcome the obstacle and improve therapeutic efficiency, a surface passivation of nanoFe was designed using sodium sulfide. METHODS: We prepared iron sulfide nanoclusters and constructed CLP mouse models. Then the effect of sulfide-modified nanoscale zero-valent iron (S-nanoFe) on the survival rate, blood routine parameters, blood biochemical parameters, cardiac function, and pathological indicators of myocardium was observed. RNA-seq was used to further explore the comprehensive protective mechanisms of S-nanoFe. Finally, the stability of S-nanoFe-1d and S-nanoFe-30 d, together with the therapeutic efficacy of sepsis between S-nanoFe and nanoFe was compared. RESULTS: The results revealed that S-nanoFe significantly inhibited the growth of bacteria and exerted a protective role against septic myocardial injury. S-nanoFe treatment activated AMPK signaling and ameliorated several CLP-induced pathological processes including myocardial inflammation, oxidative stress, mitochondrial dysfunction. RNA-seq analysis further clarified the comprehensive myocardial protective mechanisms of S-nanoFe against septic injury. Importantly, S-nanoFe had a good stability and a comparable protective efficacy to nanoFe. CONCLUSIONS: The surface vulcanization strategy for nanoFe has a significant protective role against sepsis and septic myocardial injury. This study provides an alternative strategy for overcoming sepsis and septic myocardial injury and opens up possibilities for the development of nanoparticle in infectious diseases.
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Lesiones Cardíacas , Sepsis , Ratones , Animales , Hierro , Miocardio/patología , Lesiones Cardíacas/tratamiento farmacológico , Lesiones Cardíacas/complicaciones , Lesiones Cardíacas/patología , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sulfuros/uso terapéuticoRESUMEN
Cisplatin, a chemotherapy medication employed in the treatment of various solid tumors, is constrained in its clinical application due to nephrotoxicity. Diallyl trisulfide (DATS), a compound derived from garlic that possessed anticancer and antioxidant properties, can be combined with cisplatin without hindering its antitumor effects. The present investigation examined the defensive properties of DATS and its active metabolites against renal dysfunction caused by cisplatin. We created a mouse model to study renal injury caused by cisplatin and assessed kidney histology, immunochemistry, and serum cytokines. DATS treatment effectively reduced the pathological changes caused by cisplatin by decreasing the levels of renal function markers BUN, CRE, cystatin C, NGAL, inflammatory factors TNF-α, IL-6, and the protein expression of α-SMA, NF-κB, KIM-1. A pharmacokinetic evaluation of DATS found that allyl methyl sulfone (AMSO2) was the most abundant and persistent metabolite of DATS in vivo. Then, we examined the impact of AMSO2 on cell viability, apoptosis, ROS generation, and MAPK/NF-κB pathways in HK-2 cells treated with cisplatin. Cotreatment with AMSO2 effectively hindered the HK-2 cells alterations induced by cisplatin. Furthermore, AMSO2 mitigated oxidative stress through the modulation of MAPK and NF-κB pathways. Our findings indicated that DATS and its active derivative AMSO2 attenuated cisplatin-induced nephrotoxicity. DATS shows potential as a viable treatment for nephrotoxicity caused by cisplatin.
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Compuestos Alílicos , Cisplatino , Dimetilsulfóxido , Sulfonas , Ratones , Animales , Cisplatino/farmacología , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Compuestos Alílicos/farmacología , Compuestos Alílicos/uso terapéutico , Sulfuros/uso terapéutico , Sulfuros/farmacología , Apoptosis , Antioxidantes/farmacologíaRESUMEN
Copper sulfide nanoparticles (CuS NPs) have attracted growing interest in biomedical research due to their remarkable properties, such as their high photothermal and thermodynamic capabilities, which are ideal for anticancer and antibacterial applications. This comprehensive review focuses on the current state of antitumor and antibacterial applications of CuS NPs. The initial section provides an overview of the various approaches to synthesizing CuS NPs, highlighting the size, shape and composition of CuS NPs fabricated using different methods. In this review, the mechanisms underlying the antitumor and antibacterial activities of CuS NPs in medical applications are discussed and the clinical challenges associated with the use of CuS NPs are also addressed.
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Infecciones Bacterianas , Nanopartículas , Neoplasias , Humanos , Cobre/uso terapéutico , Fototerapia , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Sulfuros/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Antibacterianos/uso terapéuticoRESUMEN
Various organosulfur compounds, such as dimethyl trisulfide (DMTS), display anti-inflammatory properties. We aimed to examine the effects of DMTS on acute pancreatitis (AP) and its mechanism of action in both in vivo and in vitro studies. AP was induced in FVB/n mice or Wistar rats by caerulein, ethanol-palmitoleic acid, or L-ornithine-HCl. DMTS treatments were administered subcutaneously. AP severity was assessed by pancreatic histological scoring, pancreatic water content, and myeloperoxidase activity measurements. The behaviour of animals was followed. Pancreatic heat shock protein 72 (HSP72) expression, sulfide, and protein persulfidation were measured. In vitro acinar viability, intracellular Ca2+ concentration, and reactive oxygen species production were determined. DMTS dose-dependently decreased the severity of AP. It declined the pancreatic infiltration of leukocytes and cellular damage in mice. DMTS upregulated the HSP72 expression during AP and elevated serum sulfide and low molecular weight persulfide levels. DMTS exhibited cytoprotection against hydrogen peroxide and AP-inducing agents. It has antioxidant properties and modulates physiological but not pathophysiological Ca2+ signalling. Generally, DMTS ameliorated AP severity and protected pancreatic acinar cells. Our findings indicate that DMTS is a sulfur donor with anti-inflammatory and antioxidant effects, and organosulfur compounds require further investigation into this potentially lethal disease.
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Pancreatitis , Ratas , Ratones , Animales , Pancreatitis/patología , Ratas Wistar , Enfermedad Aguda , Páncreas/metabolismo , Sulfuros/farmacología , Sulfuros/uso terapéutico , Sulfuros/metabolismo , Antioxidantes/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/metabolismo , Ceruletida/farmacologíaRESUMEN
INTRODUCTION: Montelukast is a leukotriene inhibitor that is widely used to treat chronic asthma and allergic rhinitis. The drug interferes with molecular signaling pathways produced by leukotrienes in a variety of cells and tissues throughout the human body that lead to tightening of airway muscles, production of aberrant pulmonary fluid (airway edema), and in some cases, pulmonary inflammation. AREAS COVERED: Montelukast has also been noted to have anti-inflammatory properties, suggesting it may have a role in the treatment of coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has been noted to induce misfiring of the immune system in some patients. A literature search of PubMed was performed to identify all relevant studies of montelukast and SARS-CoV-2 through 27 January 2023. EXPERT OPINION: Montelukast has been the subject of small studies of SARS-CoV-2 and will be included in a large, randomized, double-blind, placebo-controlled study of outpatients with COVID-19 sponsored by the United States National Institutes of Health known as Accelerating COVID-19 Therapeutic Interventions and Vaccines-6. This paper reviews what is known about montelukast, an inexpensive, well-tolerated, and widely available medication, and examines the rationale for using this drug to potentially treat patients with COVID-19.
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Asma , COVID-19 , Quinolinas , Humanos , Antagonistas de Leucotrieno/uso terapéutico , SARS-CoV-2 , Asma/tratamiento farmacológico , Acetatos/uso terapéutico , Quinolinas/uso terapéutico , Quinolinas/farmacología , Ciclopropanos/uso terapéutico , Sulfuros/uso terapéutico , Método Doble Ciego , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: Evaluate the long-term safety and efficacy of vortioxetine in the management of major depressive disorder (MDD) in two open-label one-year studies, including a post-hoc analysis of its effects on symptoms related to anhedonia. METHODS: Both studies were 52-week, open-label, flexible-dose extension studies to evaluate the safety and efficacy of vortioxetine in adult patients with MDD following prior double-blind studies. Patients in the first study (NCT00761306) were flexibly treated with vortioxetine 5 or 10 mg/day (N = 74), and patients in the second study (NCT01323478) received vortioxetine 15 or 20 mg/day (N = 71). RESULTS: The safety and tolerability profile of vortioxetine was similar between the two studies; treatment-emergent adverse events with the highest incidence were nausea, dizziness, headache, and nasopharyngitis. Across both studies, improvements achieved during the preceding double-blind studies period were maintained, and additional improvements were observed with open-label treatment. Patients showed a mean ± SD reduction (improvement) in Montgomery and Åsberg Depression Rating Scale (MADRS) total score from open-label baseline to Week 52 of 4.3 ± 9.2 points in the 5-10 mg study, and 10.9 ± 10.0 in the 15-20 mg study. Post-hoc MMRM analyses of MADRS anhedonia factor scores also showed continued improvements over long-term treatment; patients showed a mean ± SE reduction from an open-label baseline to Week 52 of 3.10 ± 0.57 points in the 5-10 mg study, and 5.62 ± 0.60 in the 15-20 mg study. CONCLUSIONS: Data from both studies confirm the safety and efficacy of flexibly dosed vortioxetine over 52 weeks of treatment and demonstrate that MADRS anhedonia factor scores continue to improve with long-term maintenance treatment.
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Trastorno Depresivo Mayor , Adulto , Humanos , Vortioxetina/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Anhedonia , Inhibidores Selectivos de la Recaptación de Serotonina , Piperazinas/uso terapéutico , Sulfuros/uso terapéuticoRESUMEN
Triple-negative breast cancer (TNBC) is considered more aggressive with a poorer prognosis than other breast cancer subtypes. Through systemic bioinformatic analyses, we established the ferroptosis potential index (FPI) based on the expression profile of ferroptosis regulatory genes and found that TNBC has a higher FPI than non-TNBC in human BC cell lines and tumor tissues. To exploit this finding for potential patient stratification, we developed biologically amenable phototheranostic iron pyrite FeS2 nanocrystals (NCs) that efficiently harness near-infrared (NIR) light, as in photovoltaics, for multispectral optoacoustic tomography (MSOT) and photothermal ablation with a high photothermal conversion efficiency (PCE) of 63.1%. Upon NIR irradiation that thermodynamically enhances Fenton reactions, dual death pathways of apoptosis and ferroptosis are simultaneously triggered in TNBC cells, comprehensively limiting primary and metastatic TNBC by regulating p53, FoxO, and HIF-1 signaling pathways and attenuating a series of metabolic processes, including glutathione and amino acids. As a unitary phototheranostic agent with a safe toxicological profile, the nanocrystal represents an effective way to circumvent the lack of therapeutic targets and the propensity of multisite metastatic progression in TNBC in a streamlined workflow of cancer management with an integrated image-guided intervention.