Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.261
Filtrar
1.
Adv Ther ; 41(4): 1728-1745, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38460107

RESUMO

INTRODUCTION: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety. METHODS: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases). RESULTS: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition. CONCLUSIONS: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04742699.


Assuntos
Azepinas , Indenos , Piridinas , Pirimidinas , Distúrbios do Início e da Manutenção do Sono , Triazóis , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Japão , Estudos Prospectivos
2.
J Investig Med High Impact Case Rep ; 12: 23247096241231641, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38344974

RESUMO

The Von-Hippel-Lindau (VHL) gene, acting as a tumor suppressor, plays a crucial role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Approximately 90% of individuals with advanced ccRCC exhibit somatic mutations in the VHL gene. Belzutifan, orally administered small-molecule inhibitor of hypoxia-induced factor-2α, has demonstrated promising efficacy in solid tumors associated with germline loss-of-function mutations in VHL, including ccRCC. However, its impact on cases with somatic or sporadic VHL mutations remains unclear. Here, we present 2 cases where belzutifan monotherapy was employed in patients with advanced ccRCC and somatic loss-of-function mutations in VHL. Both patients exhibited a swift and sustained response, underscoring the potential role of belzutifan as a viable option in second or subsequent lines of therapy for individuals with somatic VHL mutations. Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.


Assuntos
Carcinoma de Células Renais , Carcinoma , Indenos , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Mutação
3.
Biomed Pharmacother ; 172: 116229, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38330708

RESUMO

Reperfusion stands as a pivotal intervention for ischemic heart disease. However, the restoration of blood flow to ischemic tissue always lead to further damage, which is known as myocardial ischemia/reperfusion injury (MIRI). Ramelteon is an orally administered drug used to improve sleep quality, which is famous for its high bioadaptability and absence of notable addictive characteristics. However, the specific mechanism by which it improves MIRI is still unclear. Sirtuin-3 (Sirt3), primarily located in mitochondria, is crucial in mitigating many cardiac diseases, including MIRI. Based on the structure of Sirt3, we simulated molecular docking and identified several potential amino acid binding sites between it and ramelteon. Therefore, we propose a hypothesis that ramelteon may exert cardioprotective effects by activating the Sirt3 signaling pathway. Our results showed that the activation levels and expression level of Sirt3 were significantly decreased in MIRI tissue and H2O2 stimulated H9C2 cells, while ramelteon treatment upregulated Sirt3 activity and expression. After treat with 3-TYP, a classic Sirt3 activity inhibitor, we constructed myocardial ischemia/reperfusion surgery in vivo and induced H9C2 cells with H2O2 in vitro. The results showed that the myocardial protection and anti-apoptotic effects of ramelteon were antagonized by 3-TYP, indicating that the activation of Sirt3 is a key mechanism for ramelteon to exert myocardial protection. In summary, our results confirm a novel mechanism by which ramelteon improves MIRI by activating Sirt3 signaling pathway, providing strong evidence for the treatment of MIRI with ramelteon.


Assuntos
Indenos , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Sirtuína 3 , Humanos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Peróxido de Hidrogênio , Simulação de Acoplamento Molecular , Miócitos Cardíacos , Apoptose
4.
Biomed Pharmacother ; 172: 116261, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38340397

RESUMO

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with a pathogenesis that remains incompletely understood, resulting in limited treatment options. MCC950, a highly specific NLRP3 inflammasome inhibitor, effectively suppresses the activation of NLRP3, thus reducing the production of caspase-1, the pro-inflammatory cytokines IL-1ß and IL-18. This review highlights the pivotal role of NLRP3 inflammasome activation pathways in the pathogenesis of SLE and discusses the potential therapeutic application of MCC950 in SLE. Notably, it comprehensively elucidates the mechanism of MCC950 targeting the NLRP3 pathway in SLE treatment, outlining its potential role in regulating autophagy and necroptosis. The insights gained contribute to a deeper understanding of the value of MCC950 in SLE therapy, serving as a robust foundation for further research and potential clinical applications.


Assuntos
Doenças Autoimunes , Indenos , Lúpus Eritematoso Sistêmico , Humanos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Furanos/uso terapêutico , Indenos/uso terapêutico , Sulfonamidas
5.
Angew Chem Int Ed Engl ; 63(13): e202316133, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38279624

RESUMO

Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising for a range of selective oxidations, practical use of enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering and practical application of a non-heme iron and α-ketoglutarate-dependent dioxygenase for the direct stereo- and regio-selective hydroxylation of a non-native fluoroindanone en route to the oncology treatment belzutifan, replacing a five-step chemical synthesis with a direct enantioselective hydroxylation. Mechanistic studies indicated that formation of the desired product was limited by enzyme stability and product overoxidation, with these properties subsequently improved by directed evolution, yielding a biocatalyst capable of >15,000 total turnovers. Highlighting the industrial utility of this biocatalyst, the high-yielding, green, and efficient oxidation was demonstrated at kilogram scale for the synthesis of belzutifan.


Assuntos
Indenos , Oxigenases de Função Mista , Oxirredução , Hidroxilação , Biocatálise
7.
J Neural Eng ; 21(1)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38295418

RESUMO

Objective.the P300-based brain-computer interface (BCI) establishes a communication channel between the mind and a computer by translating brain signals into commands. These systems typically employ a visual oddball paradigm, where different objects (linked to specific commands) are randomly and frequently intensified. Upon observing the target object, users experience an elicitation of a P300 event-related potential in their electroencephalography (EEG). However, detecting the P300 signal can be challenging due to its very low signal-to-noise ratio (SNR), often compromised by the sequence of visual evoked potentials (VEPs) generated in the occipital regions of the brain in response to periodic visual stimuli. While various approaches have been explored to enhance the SNR of P300 signals, the impact of VEPs has been largely overlooked. The main objective of this study is to investigate how VEPs impact P300-based BCIs. Subsequently, the study aims to propose a method for EEG spatial filtering to alleviate the effect of VEPs and enhance the overall performance of these BCIs.Approach.our approach entails analyzing recorded EEG signals from visual P300-based BCIs through temporal, spectral, and spatial analysis techniques to identify the impact of VEPs. Subsequently, we introduce a regularized version of the xDAWN algorithm, a well-established spatial filter known for enhancing single-trial P300s. This aims to simultaneously enhance P300 signals and suppress VEPs, contributing to an improved overall signal quality.Main results.analyzing EEG signals shows that VEPs can significantly contaminate P300 signals, resulting in a decrease in the overall performance of P300-based BCIs. However, our proposed method for simultaneous enhancement of P300 and suppression of VEPs demonstrates improved performance in P300-based BCIs. This improvement is verified through several experiments conducted with real P300 data.Significance.this study focuses on the effects of VEPs on the performance of P300-based BCIs, a problem that has not been adequately addressed in previous studies. It opens up a new path for investigating these BCIs. Moreover, the proposed spatial filtering technique has the potential to further enhance the performance of these systems.


Assuntos
Interfaces Cérebro-Computador , Cicloexilaminas , Potenciais Evocados Visuais , Indenos , Potenciais Evocados , Eletroencefalografia/métodos , Potenciais Evocados P300/fisiologia , Algoritmos
8.
ChemMedChem ; 19(5): e202300379, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38235922

RESUMO

The ligand-sensing transcription factor retinoid X receptor (RXR) is the universal heterodimer partner of nuclear receptors and involved in multiple physiological processes. Its pharmacological modulation holds therapeutic potential in cancer and neurodegeneration but many available RXR ligands lack specificity. The sesquiterpenoid valerenic acid has been identified as RXR agonist with unprecedented subtype and homodimer preference. Here, we identified simplified mimetics of the complex natural product by rational design and virtual screening that exhibited similar activity profiles on RXR and informed about structural elements contributing to the favorable activity.


Assuntos
Indenos , Sesquiterpenos , Receptores X de Retinoides , Receptores do Ácido Retinoico/química , Sesquiterpenos/farmacologia
9.
Toxicol Lett ; 393: 57-68, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38219808

RESUMO

Dicyclopentadiene (DCPD) was investigated in a 14-day oral rat toxicity study based on the OECD 407 guideline in combination with plasma metabolomics. Wistar rats received the compound daily via gavage at dose levels of 0, 50 and 150 mg/kg bw. The high dose induced transient clinical signs of toxicity and in males only reduced body weight gain. High dose liver changes were characterized by altered clinical chemistry parameters in both sexes and pathological changes in females. In high dose males an accumulation of alpha-2 u-globulin in the kidney was noted. Comparing the DCPD metabolome with previously established specific metabolome patterns in the MetaMap® Tox data base suggested that the high dose would result in liver enzyme induction leading to increased breakdown of thyroid hormones for males and females. An indication for liver toxicity in males was also noted. Metabolomics also suggested an effect on the functionality of the adrenals in high dose males, which together with published data, is suggestive of a stress related effect in this organ. The results of the present 14-day combined toxicity and metabolome investigations were qualitatively in line with literature data from subchronic oral studies in rats with DCPD. Importantly no other types of organ toxicity, or hormone dysregulation beyond the ones associated with liver enzyme induction and stress were indicated, again in line with results of published 90-day studies. It is therefore suggested that short term "smart" studies, combining classical toxicity with 'omics technologies, could be a 2 R (refine and reduce) new approach method allowing for the reduction of in vivo toxicity testing.


Assuntos
Indenos , Metaboloma , Masculino , Feminino , Ratos , Animais , Ratos Wistar , Testes de Toxicidade
10.
Bioorg Med Chem Lett ; 99: 129622, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38244940

RESUMO

Alzheimer's disease (AD) remains an incurable neurodegenerative condition that poses a threat to humanity. Immune signaling in the brain, particularly the NLR family pyrin domain containing 3 (NLRP3), is currently targeted for AD treatment. Based on the crystal structure of the NACHT domain of NLRP3 and its renowned inhibitor MCC950, we designed and synthesized nineteen sulfonylurea compounds and evaluated their capacity to inhibit caspase-1 and interleukin-1ß (IL-1ß). Of these, nine were selected for measuring their IC50 for caspase-1 and cytotoxicity analysis. Finally, three compounds were chosen to assess their inhibitory effect on IL-1ß in mice. The results showed that compound 5m had a superior ability to reduce IL-1ß levels in the brain compared to MCC950 at a lower dosing concentration, indicating that 5m has the potential to penetrate the blood-brain barrier (BBB) and inhibit inflammation both in vitro and in vivo. Docking studies of compound 5m on NLRP3 revealed a binding mode similar to MCC950. These findings suggest that compound 5m holds promise as an NLRP3 inhibitor for AD treatment.


Assuntos
Doença de Alzheimer , Indenos , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Caspases , Furanos/farmacologia , Furanos/uso terapêutico , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico , Naftalenos/farmacologia , Naftalenos/uso terapêutico
11.
Chemosphere ; 350: 141118, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38199501

RESUMO

The use of long-residual herbicides can have adverse effects on terrestrial ecosystems. This study assessed the acute and chronic toxicity and avoidance behavior of Eisenia andrei earthworms exposed to nominal concentrations of clomazone, indaziflam, and sulfentrazone, using recommended commercial formulations for sugarcane cultivation. The formulations included Gamit® 360 CS (360 g L-1 of the active ingredient - a.i. - clomazone), Boral® 500 SC (500 g L-1 of a.i. sulfentrazone), and Alion® (500 g L-1 of a.i. indaziflam). Boral® 500 SC induced avoidance at concentrations as low as 1 mg kg-1, while Gamit® 360 CS and Alion® exhibited higher avoidance at 50-75 mg kg-1 and 75-100 mg a.i. kg-1, respectively. Reproduction tests showed significant impacts from Gamit® 360 CS (EC50: 0.572 mg kg-1, EC10: 0.2144 mg kg-1) and Boral® 500 SC (EC50: 0.3941 mg kg-1, EC10: 0.134 mg kg-1). Acute toxicity tests indicated moderate toxicity for Gamit® 360 CS (LC50: 184.12 mg kg-1) and Boral® 500 SC (LC50: 1000 mg kg-1). Gamit® 360 CS reduced biomass at all concentrations, while Boral® 500 SC influenced only at higher levels (500 and 1000 mg kg-1). Results suggest significant acute risks with Gamit® 360 CS, while chronic exposure raises concerns for both Gamit® 360 CS and Boral® 500 SC, indicating potential long-term risks. Alion®'s acute effects were inconclusive, but chronic exposure hints at a possible risk. These findings provide crucial insights for environmental agencies establishing protective limits against herbicide exposure to non-target soil invertebrates.


Assuntos
Herbicidas , Indenos , Oligoquetos , Poluentes do Solo , Sulfonamidas , Triazinas , Triazóis , Animais , Herbicidas/toxicidade , Ecossistema , Poluentes do Solo/toxicidade
12.
PLoS Negl Trop Dis ; 18(1): e0011825, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38190386

RESUMO

Snake envenoming is a major, but neglected, tropical disease. Among venomous snakes, those inducing neurotoxicity such as kraits (Bungarus genus) cause a potentially lethal peripheral neuroparalysis with respiratory deficit in a large number of people each year. In order to prevent the development of a deadly respiratory paralysis, hospitalization with pulmonary ventilation and use of antivenoms are the primary therapies currently employed. However, hospitals are frequently out of reach for envenomated patients and there is a general consensus that additional, non-expensive treatments, deliverable even long after the snake bite, are needed. Traumatic or toxic degenerations of peripheral motor neurons cause a neuroparalysis that activates a pro-regenerative intercellular signaling program taking place at the neuromuscular junction (NMJ). We recently reported that the intercellular signaling axis melatonin-melatonin receptor 1 (MT1) plays a major role in the recovery of function of the NMJs after degeneration of motor axon terminals caused by massive Ca2+ influx. Here we show that the small chemical MT1 agonists: Ramelteon and Agomelatine, already licensed for the treatment of insomnia and depression, respectively, are strong promoters of the neuroregeneration after paralysis induced by krait venoms in mice, which is also Ca2+ mediated. The venom from a Bungarus species representative of the large class of neurotoxic snakes (including taipans, coral snakes, some Alpine vipers in addition to other kraits) was chosen. The functional recovery of the NMJ was demonstrated using electrophysiological, imaging and lung ventilation detection methods. According to the present results, we propose that Ramelteon and Agomelatine should be tested in human patients bitten by neurotoxic snakes acting presynaptically to promote their recovery of health. Noticeably, these drugs are commercially available, safe, non-expensive, have a long bench life and can be administered long after a snakebite even in places far away from health facilities.


Assuntos
Antivenenos , Indenos , Mordeduras de Serpentes , Humanos , Camundongos , Animais , Antivenenos/uso terapêutico , Mordeduras de Serpentes/complicações , Mordeduras de Serpentes/tratamento farmacológico , Receptores de Melatonina/uso terapêutico , Venenos de Serpentes , Recuperação de Função Fisiológica , Cálcio , Serpentes , Bungarus
13.
Plant J ; 117(2): 616-631, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37910396

RESUMO

The membrane-bound heterotrimeric G-proteins in plants play a crucial role in defending against a broad range of pathogens. This study emphasizes the significance of Extra-large Gα protein 2 (XLG2), a plant-specific G-protein, in mediating the plant response to Sclerotinia sclerotiorum, which infects over 600 plant species worldwide. Our analysis of Arabidopsis G-protein mutants showed that loss of XLG2 function increased susceptibility to S. sclerotiorum, accompanied by compromised accumulation of jasmonic acid (JA) during pathogen infection. Overexpression of the XLG2 gene in xlg2 mutant plants resulted in higher resistance and increased JA accumulation during S. sclerotiorum infection. Co-immunoprecipitation (co-IP) analysis on S. sclerotiorum infected Col-0 samples, using two different approaches, identified 201 XLG2-interacting proteins. The identified JA-biosynthetic and JA-responsive proteins had compromised transcript expression in the xlg2 mutant during pathogen infection. XLG2 was found to interact physically with a JA-responsive protein, Coronatine induced 1 (CORI3) in Co-IP, and confirmed using split firefly luciferase complementation and bimolecular fluorescent complementation assays. Additionally, genetic analysis revealed an additive effect of XLG2 and CORI3 on resistance against S. sclerotiorum, JA accumulation, and expression of the defense marker genes. Overall, our study reveals two independent pathways involving XLG2 and CORI3 in contributing resistance against S. sclerotiorum.


Assuntos
Aminoácidos , Proteínas de Arabidopsis , Arabidopsis , Ascomicetos , Proteínas Heterotriméricas de Ligação ao GTP , Indenos , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Plantas/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Doenças das Plantas/genética
14.
Int Immunopharmacol ; 126: 111236, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38039716

RESUMO

Epilepsy is one of the most common serious chronic brain disorders, affecting up to 70 million people worldwide. Vascular disruption, including blood-brain barrier impairment and pathological angiogenesis, exacerbates its occurrence. However, its underlying mechanisms remain elusive. MCC950 is a specific small-molecule inhibitor that selectively blocks NLRP3 inflammatory vesicle activation across the blood-brain barrier, limits downstream IL-1ß maturation and release, and exerts therapeutic effects across multiple diseases. In the present study, an epilepsy model was established by intraperitoneal administration of Kainic acid to adult male C57BL/6J wild-type mice. The results revealed that the epilepsy susceptibility of MCC950-treated mice was decreased, and neural damage following seizure episodes was reduced. In addition, immunofluorescence staining, RT-qPCR, and Western blot demonstrated that MCC950 inhibited the expression of the NLRP3 inflammasome and its related proteins in microglia, whereas microangiogenesis was found to be increased in the cerebral cortex and hippocampus of epileptic mice, and these effects could be reversed by MCC950. Furthermore, neurobehavioral impairment was observed in the epileptic mouse model, and MCC950 similarly alleviated the aforementioned pathological process. To the best of our knowledge, this is the first study to establish that pathological microangiogenesis is associated with NLRP3/IL-1ß signaling pathway activation in a Kainic acid-induced epilepsy mouse model and that MCC950 administration attenuates the above-mentioned pathological changes and exerts neuroprotective effects. Therefore, MCC950 is a promising therapeutic agent for the treatment of epilepsy.


Assuntos
Epilepsia , Indenos , Humanos , Adulto , Masculino , Animais , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonas/uso terapêutico , Sulfonas/farmacologia , Piroptose , Ácido Caínico , Camundongos Endogâmicos C57BL , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacologia , Inflamassomos/metabolismo , Transdução de Sinais , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Furanos/uso terapêutico , Furanos/farmacologia , Indenos/uso terapêutico
15.
J Pineal Res ; 76(1): e12925, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37986632

RESUMO

Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.


Assuntos
Isquemia Encefálica , Indenos , AVC Isquêmico , Melatonina , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Animais , Camundongos , AVC Isquêmico/tratamento farmacológico , Receptor MT1 de Melatonina/agonistas , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais , Melatonina/farmacologia , Isquemia Encefálica/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Camundongos Knockout , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo
16.
J Pineal Res ; 76(1): e12921, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37846173

RESUMO

Evidence suggests that the neuroprotective effects of melatonin involve both receptor-dependent and -independent actions. However, little is known about the effects of melatonin receptor activation on the kainate (KA) neurotoxicity. This study examined the effects of repeated post-KA treatment with ramelteon, a selective agonist of melatonin receptors, on neuronal loss, cognitive impairment, and depression-like behaviors following KA-induced seizures. The expression of melatonin receptors decreased in neurons, whereas it was induced in astrocytes 3 and 7 days after seizures elicited by KA (0.12 µg/µL) in the hippocampus of mice. Ramelteon (3 or 10 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) mitigated KA-induced oxidative stress and impairment of glutathione homeostasis and promoted the nuclear translocation and DNA binding activity of Nrf2 in the hippocampus after KA treatment. Ramelteon and melatonin also attenuated microglial activation but did not significantly affect astroglial activation induced by KA, despite the astroglial induction of melatonin receptors after KA treatment. However, ramelteon attenuated KA-induced proinflammatory phenotypic changes in astrocytes. Considering the reciprocal regulation of astroglial and microglial activation, these results suggest ramelteon inhibits microglial activation by regulating astrocyte phenotypic changes. These effects were accompanied by the attenuation of the nuclear translocation and DNA binding activity of nuclear factor κB (NFκB) induced by KA. Consequently, ramelteon attenuated the KA-induced hippocampal neuronal loss, memory impairment, and depression-like behaviors; the effects were comparable to those of melatonin. These results suggest that ramelteon-mediated activation of melatonin receptors provides neuroprotection against KA-induced neurotoxicity in the mouse hippocampus by activating Nrf2 signaling to attenuate oxidative stress and restore glutathione homeostasis and by inhibiting NFκB signaling to attenuate neuroinflammatory changes.


Assuntos
Indenos , Melatonina , Camundongos , Animais , Melatonina/farmacologia , Melatonina/metabolismo , Receptores de Melatonina/metabolismo , Ácido Caínico/toxicidade , Ácido Caínico/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Hipocampo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Glutationa/metabolismo , DNA
17.
J Mol Graph Model ; 127: 108691, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38086144

RESUMO

Dye-sensitized solar cells (DSSCs) are promising third-generation photovoltaic cell technology owing to their easy fabrication, flexibility and better performance under diffuse light conditions. Natural pigment sensitizers are abundantly available and environmentally friendliness. However, narrow absorption spectra of natural pigments result in low efficiencies of the DSSCs. Therefore, combining two or more pigments with complementary absorption spectra is considered an appropriate method to broaden the absorption band and boost efficiency. This study reports three complex molecules: brazilin-betanidin-oxane (Braz-Bd-oxane), brazilin-betanidin-ether (Braz-Bd-ether) and brazilein-betanidin-ether (Braze-Bd-ether), obtained from the etherification and bi-etherification reactions of brazilin dye and brazilein dye with betanidin dye. The equilibrium geometrical structure properties, frontier molecular orbital, electrostatic surface potential, reorganization energy, chemical reactivities, and non-linear optical properties of the studied dyes were investigated using density functional theory (DFT)/B3LYP methods, with 6-31+G(d,p) basis sets and LANL2DZ for light atom and heavy atoms respectively. The optical-electronic properties were calculated using TD-DFT/B3LYP/6-31+G(d,p) for isolated dye and TD-DFT/CAM-B3LYP/6-31G(d,p)/LANL2DZ for dyes@(TiO2)9H4. The results reveal that spectra for Braz-Bd-oxane and Braze-Bd-ether complexes red-shifted compared to the individually selected dyes. The simulated absorption spectra of the adsorbed dyes on (TiO2)9H4 are red-shifted compared to the free dye. Moreover, Braz-Bd-oxane and Braz-Bd-ether exhibit better charge transfer and photovoltaic properties than the selected natural dyes forming these complexes. Based on the dyes' optoelectronic properties and photovoltaic properties, the designed molecules Braz-Bd-oxane and Braze-Bd-ether are considered better candidates to be used as photosensitizers in dye solar cells.


Assuntos
Benzopiranos , Corantes , Indenos , Energia Solar , Modelos Moleculares , Corantes/química , Betacianinas , Teoria da Densidade Funcional , Éteres
18.
ChemMedChem ; 18(21): e202300404, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37697963

RESUMO

Retinoid X receptors (RXR) are ligand-sensing transcription factors with a unique role in nuclear receptor signaling as universal heterodimer partners. RXR modulation holds potential in cancer, neurodegeneration and metabolic diseases but adverse effects of RXR activation and lack of selective modulators prevent further exploration as therapeutic target. The natural product valerenic acid has been discovered as RXR agonist with unprecedented preference for RXR subtype and homodimer activation. To capture structural determinants of this activity profile and identify potential for optimization, we have studied effects of structural modification of the natural product on RXR modulation and identified an analogue with enhanced RXR homodimer agonism.


Assuntos
Indenos , Sesquiterpenos , Indenos/farmacologia , Receptores X de Retinoides/metabolismo , Receptores Citoplasmáticos e Nucleares
19.
Acta Neuropathol Commun ; 11(1): 155, 2023 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-37749707

RESUMO

Inflammasomes, primarily responsible for the activation of IL-1ß, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1ß to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1ß in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1ß prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1ß expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1ß. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1ß release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases.


Assuntos
Neoplasias Encefálicas , Indenos , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Inflamassomos , Astrócitos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sulfonamidas/farmacologia , Microambiente Tumoral
20.
J Enzyme Inhib Med Chem ; 38(1): 2247579, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37587873

RESUMO

Angiogenesis plays an important role in tumour generation and progression, which is used to supply nutrients and metastasis. Herein, a series of novel dihydro-1H-indene derivatives were designed and evaluated as tubulin polymerisation inhibitors by binding to colchicine site, exhibiting anti-angiogenic activities against new vessel forming. Through structure-activity relationships study, compound 12d was found to be the most potent derivative possessing the antiproliferative activity against four cancer lines with IC50 values among 0.028-0.087 µM. Compound 12d bound to colchicine site on tubulin and inhibited tubulin polymerisation in vitro. In addition, compound 12d induced cell cycle arrest at G2/M phase, stimulated cell apoptosis, inhibited tumour metastasis and angiogenesis. Finally, the results of in vivo assay suggested that compound 12d could prevent tumour generation, inhibit tumour proliferation and angiogenesis without obvious toxicity. Collectively, all these findings suggested that compound 12d is a novel tubulin polymerisation inhibitor deserving further research.


Assuntos
Indenos , Moduladores de Tubulina , Moduladores de Tubulina/farmacologia , Tubulina (Proteína) , Colchicina
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...