RESUMO
We report herein the potential of colony-stimulating factor-1 receptor (CSF1R) inhibitors as therapeutic agents in neuroinflammatory diseases, with a focus on Alzheimer's disease (AD). Employing a carefully modified scaffold, N-(4-heterocycloalkyl-2-cycloalkylphenyl)-5-methylisoxazole-3-carboxamide, we identify highly selective and potent CSF1R inhibitorsâ7dri and 7dsi. Molecular docking studies shed light on the binding modes of these key compounds within the CSF1R binding site. Remarkably, kinome-wide selectivity assessment underscores the impressive specificity of 7dri for CSF-1R. Notably, 7dri emerges as a potent CSF-1R inhibitor with favorable cellular activity and minimal cytotoxicity among the synthesized compounds. Demonstrating efficacy in inhibiting CSF1R phosphorylation in microglial cells and successfully mitigating neuroinflammation in an in vivo LPS-induced model, 7dri establishes itself as a promising antineuroinflammatory agent.
Assuntos
Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Fator Estimulador de Colônias de Macrófagos , Fosforilação , Simulação de Acoplamento Molecular , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
This study explores the potential of CSF-1R inhibitors as therapeutic agents for neurodegenerative diseases. CSF-1R, a receptor tyrosine kinase primarily expressed in macrophage lineages, plays a pivotal role in regulating various cellular processes. Recent research highlights the significance of CSF-1R inhibition in mitigating neuroinflammation, particularly in Alzheimer's disease, where microglial overactivation contributes to neurodegeneration. The research reveals a series of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide CSF-1R inhibitors, where compounds 7d, 7e, and 9a exhibit outstanding inhibitory activities and selectivity, with IC50 values of 33, 31, and 64 nM, respectively. These most promising compounds in this series were profiled for cellular potency and subjected to in vitro pharmacokinetic profiling. These inhibitors exhibit minimal cytotoxicity, even at higher concentrations, and possess promising blood-brain barrier permeability, making them potential candidates for central nervous system diseases. The investigation into the in vitro ADME properties, including plasma and microsomal stability, reveals that these CSF-1R inhibitors maintain their structural integrity and plasma concentration. This resilience positions them for further development as therapeutic agents for neurodegenerative diseases.
Assuntos
Isoxazóis , Doenças Neurodegenerativas , Receptor de Fator Estimulador de Colônias de Macrófagos , Humanos , Receptor de Fator Estimulador de Colônias de Macrófagos/química , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Barreira Hematoencefálica/metabolismo , Receptores Proteína Tirosina Quinases , Inibidores EnzimáticosRESUMO
We have been developing new inhibitors for c-Jun N-terminal kinase 3 (JNK3) as a potential treatment for Alzheimer's disease (AD). We identified potential JNK3 inhibitors through pharmacodynamic optimization studies, including benzimidazole compounds 2 and 3, but their unreliable pharmacokinetic properties led us to develop carbamate inhibitors 2h and 3h. In vitro studies validated carbamate inhibitors 2h and 3h as potent and highly selective JNK3 inhibitors with favorable pharmacokinetic profiles. Oral administration of 2h and 3h to both APP/PS1 and 3xTg AD mouse models improved cognitive function, indicating their potential as effective treatments for Alzheimer's disease. Carbamate JNK3 inhibitor 3h, in particular, restored cognitive function to near-normal levels in the 3xTg mice model of AD and led to pTau reduction in the hippocampal tissues of 3xTg-AD mice during in vivo behavioral evaluations. We intend to further develop these carbamate JNK3 inhibitors in preclinical studies as a potential first-in-class treatment for AD.
Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Modelos Animais de Doenças , Cognição , Camundongos TransgênicosRESUMO
JNK3 is a key factor driving the pathophysiology of neuronal apoptosis. Since demonstrating the therapeutic potential of JNK3 inhibitors in Alzheimer's disease, we aimed to broaden their chemical diversity for drug development. In continuation with our previous research, a series of compounds with the tetrahydrocyclopenta[d]imidazole scaffold as a core moiety was developed as JNK3 inhibitors based on in silico modeling analysis. The biochemical kinase assay results revealed that the JNK3 inhibitory effects and isoform selectivity of the compounds developed in this study were significantly higher than that of previously developed inhibitors. In particular, the IC50 values of compounds 18c, 19c, 22b, and 26c, which exhibited excelled isoform selectivity, against JNK3 were 0.716, 0.564, 0.379, and 0.779 nM, respectively, which were more potent than those of any known JNK3 inhibitors. Additionally, compounds 18c, 18c, 22b, and 22c effectively protected the neuronal cells against amyloid beta-induced apoptosis. Docking studies indicated that the tetrahydrocyclopenta[d]imidazole scaffold retained all the optimal interactions. Meanwhile, BBB PAMPA and ADME prediction suggested that the tested compounds had a favorable BBB permeability and pharmacokinetic profile. Therefore, the tetrahydrocyclopenta[d]imidazole scaffold is a promising candidate for developing JNK3 inhibitors. In particular, compound 22b is a potential starting point for the preclinical optimization of novel JNK3 inhibitors.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Simulação de Acoplamento Molecular , Peptídeos beta-Amiloides , Imidazóis/farmacologia , Doença de Alzheimer/tratamento farmacológicoRESUMO
Despite innumerable efforts to develop effective therapeutics, it is difficult to achieve breakthrough treatments for Alzheimer's disease (AD), and the main reason is probably the absence of a clear target. Here, we reveal c-Jun N-terminal kinase 3 (JNK3), a protein kinase explicitly expressed in the brain and involved in neuronal apoptosis, with a view toward providing effective treatment for AD. For many years, we have worked on JNK3 inhibitors and have discovered 2-aryl-1-pyrimidinyl-1H-imidazole-5-yl acetonitrile-based JNK3 inhibitors with superb potency (IC50 < 1.0 nM) and excellent selectivity over other protein kinases including isoforms JNK1 (>300 fold) and JNK2 (â¼10 fold). Based on in vitro biological activity and DMPK properties, the lead compounds were selected for further in vivo studies. We confirmed that repeat administration of JNK3 inhibitors improved cognitive memory in APP/PS1 and the 3xTg mouse model. Overall, our results show that JNK3 could be a potential target protein for AD.
Assuntos
Doença de Alzheimer , Imidazóis , Proteína Quinase 10 Ativada por Mitógeno , Inibidores de Proteínas Quinases , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Apoptose/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Isoformas de Proteínas/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Modelos Animais de DoençasRESUMO
Ligamentum flavum hypertrophy (LFH) is a known contributor to lumbar spinal canal stenosis (LSCS). However, the clinical significance and quantitative role of LFH compared to other components, such as disc bulging and facet hypertrophy, have not yet been examined. We investigated the correlation between the quantitative radiological factors, clinical symptoms, and outcomes in patients with LSCS. In total, 163 patients diagnosed with single-level (L4-L5) stenosis were included. The patients were divided into 2 groups according to claudication severity: >100 m for mild (n = 92) and < 100 m for severe (n = 71). The visual analog scale (VAS) was used to quantify back and leg pain, and the Oswestry Disability Index (ODI) and Short form-36 (SF-36) physical component summary (PCS) scores, and Macnab criteria were evaluated as clinical factors 6 months after treatment. We measured the baseline canal cross-sectional area, ligamentum flavum (LF) area, disc herniation area, dural sac area, fat area, and LF thickness using MRI. A comparative analysis was performed to evaluate the association between radiologic and clinical factors. Additionally, further comparative analyses between the types of surgeries were performed. Among various radiologic factors, the baseline LF thickness (odds ratio [OR] 1.73; 95% confidence interval [CI] 1.25-2.41) was the only major contributing factor to the severity of claudication in the multivariate logistic regression analysis. The types of surgery (decompression alone vs fusion) did not significantly differ in terms of their clinical outcomes, including back and leg VAS, ODI, SF-36 PCS, and satisfaction with the MacNab classification. LF thickness is a major factor contributing to claudication severity.
Assuntos
Dor Crônica , Ligamento Amarelo , Estenose Espinal , Dor nas Costas , Constrição Patológica , Humanos , Hipertrofia , Claudicação Intermitente/etiologia , Perna (Membro) , Ligamento Amarelo/cirurgia , Canal Medular , Estenose Espinal/complicações , Estenose Espinal/diagnóstico por imagem , Estenose Espinal/cirurgiaRESUMO
Long-term exposure to fine particles (PM2.5), ultrafine particles (UFPs), and volatile organic compounds (VOCs) emissions from cooking has been linked to adverse human health effects. Here, we measured the real-time number size distribution of particles emitted when cooking two served food in Chinese restaurants and estimated the emission rate of UFPs and PM2.5. Experiments were conducted under a control hood, and both online measurement and offline analysis of PM2.5 were carried out. The measured emission rates of PM2.5 generated from deep-frying and grilling were 0.68 ± 0.11 mg/min and 1.58 ± 0.25 mg/min, respectively. Moreover, the UFPs emission rate of deep-frying (4.3 × 109 #/min) is three times higher than that of grilling (1.4 × 109 #/min). Additionally, the PM2.5 emission of deep-frying was comprised of a considerable amount of α-Fe2O3 (5.7% of PM2.5 total mass), which is more toxic than other iron oxide species. A total of six carcinogenic HAPs were detected, among which formaldehyde, acrolein, and acetaldehyde were found to exceed the inhalation reference concentration (RfC) for both cooking methods. These findings can contribute to future evaluation of single particle and HAPs emission from cooking to better support toxicity assessment.
Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Nanopartículas , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , China , Culinária/métodos , Monitoramento Ambiental/métodos , Humanos , Ferro/análise , Nanopartículas/análise , Tamanho da Partícula , Material Particulado/análise , RestaurantesRESUMO
Fms-like tyrosine kinase 3 (FLT3) has been verified as a therapeutic target for acute myeloid leukaemia (AML). In this study, we report a series of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazol-5-yl benzamide and phenyl urea derivatives as potent FLT3 inhibitors based on the structural optimisation of previous FLT3 inhibitors. Derivatives were synthesised as benzamide 8a-k, 8n-z, and phenyl urea 8l-m, with various substituents. The most potent inhibitor, 8r, demonstrated strong inhibitory activity against FLT3 and FLT3 mutants with a nanomolar IC50 and high selectivity profiles over 42 protein kinases. In addition, these type II FLT3 inhibitors were more potent against FLT3 mutants correlated with drug resistance. Overall, we provide a theoretical basis for the structural optimisation of novel benzimidazole analogues to develop strong inhibitors against FLT3 mutants for AML therapeutics.
Assuntos
Benzimidazóis/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
c-Jun N-terminal kinase (JNK) plays an important role in cell death caused by various stimuli. Because the isoform JNK3 is mainly expressed in the brain, it is believed to play a pivotal role in various neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), which still lack plausible therapeutics. To develop a novel and selective JNK3 inhibitor, we conducted a decadal review (2011 to 2021) of published articles on JNK inhibitors, particularly those focusing on a structural perspective and docking insights. We observed the structures of three isoforms of JNK, namely holo-proteins and co-crystal structures, with JNK3 inhibitors and summarized the significant structural aspects of selective JNK3 inhibitors as AD therapeutics.
RESUMO
As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we prepared a series of five 6-dihydroxy-1H-benzo[d]imidazoles as JNK3 inhibitors and found them have potential as neuroprotective agents. Following a previous lead scaffold, benzimidazole moiety was modified with various aryl groups and hydroxylation, and the resulting compounds exhibited JNK3 inhibitory activity with improved potency and selectivity. Out of 37 analogues synthesized, (S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)-5,6-dihydroxy-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino) piperidin-1-yl)methanone (35b) demonstrated the highest JNK3 inhibition (IC50 = 9.7 nM), as well as neuroprotective effects against Aß-induced neuronal cell death. As a protein kinase inhibitor, it also showed excellent selectivity over other protein kinases including isoforms JNK1 (>1000 fold) and JNK2 (-10 fold).
Assuntos
Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/toxicidade , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Proteína Quinase 10 Ativada por Mitógeno/química , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Neurônios/patologia , Síndromes Neurotóxicas/prevenção & controle , Fragmentos de Peptídeos/toxicidade , RatosRESUMO
The lacking of laboratory black carbon (BC) samples have long challenged the corresponding toxicological research; furthermore, the toxicity tests of engineered carbon nanoparticles were unable to reflect atmospheric BC. As a simplified approach, we have synthesized artificial BC (aBC) for the purpose of representing atmospheric BC. Surface chemical properties of aBC were controlled by thermal treatment, without transforming its physical characteristics; thus, we were able to examine the toxicological effects on A549 human lung cells arising from aBC with varying oxidation surface properties. X-ray photoelectron spectroscopy, as well as Raman and Fourier transform infrared spectroscopy, verified the presence of increased amounts of oxygenated functional groups on the surface of thermally-treated aBC, indicating aBC oxidization at elevated temperatures; aBC with increased oxygen functional group content displayed increased toxicity to A549 cells, specifically by decreasing cell viability to 45% and elevating reactive oxygen species levels up to 294% for samples treated at 800 °C.
RESUMO
Polo-like kinase 1 (PLK1) plays an important role in cell cycle progression and proliferation in cancer cells. PLK1 also contributes to anticancer drug resistance and is a valuable target in anticancer therapeutics. To identify additional effective PLK1 inhibitors, we performed QSAR studies of two series of known PLK1 inhibitors and proposed a new structure based on a hybridized 3D-QSAR model. Given the hybridized 3D-QSAR models, we designed and synthesized 4-benzyloxy-1-(2-arylaminopyridin-4-yl)-1H-pyrazole-3-carboxamides, and we inspected its inhibitory activities to identify novel PLK1 inhibitors with decent potency and selectivity.
Assuntos
Proteínas de Ciclo Celular/química , Técnicas de Química Sintética , Desenho de Fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Proteínas Proto-Oncogênicas/química , Relação Quantitativa Estrutura-Atividade , Proteínas de Ciclo Celular/antagonistas & inibidores , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinase 1 Polo-LikeRESUMO
Lichens, composite organisms resulting from the symbiotic association between the fungi and algae, produce a variety of secondary metabolites that exhibit pharmacological activities. This study aimed to investigate the anti-inflammatory activities of the secondary metabolite atraric acid produced by Heterodermia hypoleuca. The results confirmed that atraric acid could regulate induced pro-inflammatory cytokine, nitric oxide, prostaglandin E2, induced nitric oxide synthase and cyclooxygenase-2 enzyme expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Meanwhile, atraric acid downregulated the expression of phosphorylated IκB, extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NFκB) signaling pathway to exhibit anti-inflammatory effects in LPS-stimulated RAW264.7 cells. Based on these results, the anti-inflammatory effect of atraric acid during LPS-induced endotoxin shock in a mouse model was confirmed. In the atraric acid treated-group, cytokine production was decreased in the peritoneum and serum, and each organ damaged by LPS-stimulation was recovered. These results indicate that atraric acid has an anti-inflammatory effect, which may be the underlying molecular mechanism involved in the inactivation of the ERK/NFκB signaling pathway, demonstrating its potential therapeutic value for treating inflammatory diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Ascomicetos/química , Hidroxibenzoatos/farmacologia , Extratos Vegetais/farmacologia , Choque Séptico/tratamento farmacológico , Animais , Citocinas/metabolismo , Feminino , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos BALB C , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Choque Séptico/induzido quimicamente , Transdução de Sinais/efeitos dos fármacosRESUMO
We designed and synthesized 1-pyrimidinyl-2-aryl-4, 6-dihydropyrrolo [3,4-d] imidazole-5(1H)-carboxamide derivatives as selective inhibitors of c-Jun-N-terminal Kinase 3 (JNK3), a target for the treatment of neurodegenerative diseases. Based on the compounds found in previous studies, a novel scaffold was designed to improve pharmacokinetic characters and activity, and compound 18a, (R)-1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-4,6-dihydro pyrrolo [3,4-d]imidazole-5(1H)-carboxamide, showed the highest IC50 value of 2.69 nM. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases, having mild activity against JNK2, RIPK3, and GSK3ß, which also known to involve in neuronal apoptosis.
Assuntos
Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Sítios de Ligação , Imidazóis/química , Proteína Quinase 10 Ativada por Mitógeno/química , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologiaRESUMO
3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives were designed and synthesised as selective inhibitors of JNK3, a target for the treatment of neurodegenerative diseases. Following previous studies, we have designed JNK3 inhibitors to reduce the molecular weight and successfully identified a lead compound that exhibits equipotent activity towards JNK3. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases. Among the derivatives, the IC50 value of 8a, (R)-2-(1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-5-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)acetonitrile exhibited 227 nM, showing the highest inhibitory activity against JNK3.
Assuntos
Descoberta de Drogas , Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Relação Dose-Resposta a Droga , Humanos , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
This study investigates a new air-washing cleaning system that directly injects compressed air on the filter surface for filter regeneration in a fabric filter (FF) dust collector. A pilot-scale FF is designed to test the new system and to compare it with the conventional pulse-jet cleaning system with regard to filter clogging by fume particles. A pleated filter with a filtration area of 2.4â¯m2 is installed in the FF and a thermal steel spraying gun is used to supply the fume particles. Pressure drop and particle emission concentration are monitored to examine the effect of the new system on filter regeneration and collection efficiency. The results show that the air-washing cleaning is effective for filter regeneration, as it allows the FF to operate stably for a long time, whereas the pulse-jet cleaning fails to achieve filter regeneration, resulting in a continuously increasing pressure drop. In addition, air-washing cleaning shows better performance on collection efficiency than the pulse-jet cleaning method, as it reduces the outlet particulate matter concentration to less than half that of the pulse-jet cleaning.
RESUMO
Titanium and titanium alloys are promising implant metallic materials because of their high strengths, low elastic moduli, high corrosion resistances, and excellent biocompatibilities. A large difference in elastic modulus between the implant material and bone leads to a stress shielding effect, which increases the probability of implant separation or decrease in the bone density around it. Thus, a lower elastic modulus is required for a better implant metallic material. ß titanium has a lower elastic modulus and high strength and can reduce the probability of the stress shielding effect. In this study, the applicability of the Ti-39Nb-6Zr+0.45Al alloy, obtained by adding a small amount of aluminum to the Ti-39Nb-6Zr alloy, as a biomedical implant material was evaluated. The mechanical properties and biocompatibility of the alloy were evaluated. The biocompatibility of Ti-39Nb-6Zr+0.45Al was similar to that of Ti-39Nb-6Zr according to in vitro and in vivo experiments. In addition, the biological corrosion resistances were evaluated through a corrosion test using a 0.9% NaCl solution, which is equivalent to physiological saline. The corrosion resistance was improved by the addition of Al. The yield strength of the Ti-39Nb-6Zr+0.45Al alloy was improved by approximately 20%. The excellent biocompatibility confirmed its feasibility for use as a biomedical implant material.
RESUMO
Spinal stenosis is a common condition in elderly individuals. Many patients are unresponsive to the conventional treatment. If the transforaminal epidural block does not exert a sufficient treatment effect, percutaneous transforaminal epidural adhesiolysis (PTFA) through the safe-triangle approach using an inflatable balloon catheter can reduce the patients' pain and improve their functional capacity. We aimed to evaluate the safety and efficacy of the Kambin's-triangle approach for PTFA using an inflatable balloon catheter and compare this approach to the traditional safe-triangle approach. Thirty patients with chronic unilateral L5 radiculopathy were divided into two groups: the safe-triangle-approach and Kambin's-triangle-approach groups, with 15 patients each. The success rate of the procedure was assessed. Pain and dysfunction were assessed using the Numerical Rating Scale and Oswestry Disability Index, respectively, before the procedure and at 1 and 3 months after the procedure. The success rate of the procedure was high in both the groups, with no significant difference between the groups. The Numerical Rating Scale and Oswestry Disability Index scores significantly decreased 3 months after the procedure in both the groups, with no significant difference between the groups. For patients in whom the safe-triangle approach for PTFA is difficult, the Kambin's-triangle approach could be an alternative.
RESUMO
Particulate matter (PM) from cooking is considered one of the most harmful indoor air pollutants causing numerous adverse health effects, and it is essential to comprehend the characteristics of the particles generated from cooking to prevent these problems. In this study, we investigated PM from the pan-frying of salmon using number concentration and developed emission rates as a function of time for ultrafine particles (UFPsâ¯<â¯100â¯nm) and accumulation mode particles (AMPs 0.1-1⯵m). The newly defined emission rates vary significantly with time and are very different from the conventionally determined rates that do not consider the variation of particle concentration with time. The emission rate of UFPs decreased over time after a sharp rise, whereas that of AMPs continued to increase, resulting in a change in the proportions of UFPs and AMPs in the total PM from 93 to 7% to 72 and 28%, respectively. Particle-particle interactions such as coagulation and coalescence were observed between primary particles via high resolution transmission electron microscopy (HR-TEM), which is a plausible reason for the decreasing emission rate of UFPs with time. The emission rate as a function of time can serve as a tool to estimate PM from cooking, as well as to monitor the change trends through phenomena such as agglomeration.
Assuntos
Poluentes Atmosféricos , Monitoramento Ambiental , Animais , Culinária , Tamanho da Partícula , Material ParticuladoRESUMO
Nicotine, a nicotinic acetylcholine receptor agonist, produces the reinforcing effects of tobacco dependence by potentiating dopaminergic and glutamatergic neurotransmission. Non-nicotine alkaloids in tobacco also contribute to dependence by activating the cholinergic system. However, glutamatergic neurotransmission in the dorsal striatum associated with behavioral changes in response to cigarette smoking has not been investigated. In this study, the authors investigated alterations in glutamate levels in the rat dorsal striatum related to behavioral alterations after repeated administration of cigarette smoke condensate (CSC) using the real-time glutamate biosensing and an open-field behavioral assessment. Repeated administration of CSC including 0.4 mg nicotine (1.0 mL/kg/day, subcutaneous) for 14 days significantly increased extracellular glutamate concentrations more than repeated nicotine administration. In parallel with the hyperactivation of glutamate levels, repeated administration of CSC-evoked prolonged hypersensitization of psychomotor activity, including locomotor and rearing activities. These findings suggest that the CSC-induced psychomotor activities are closely associated with the elevation of glutamate concentrations in the rat dorsal striatum.