Microglial activation drives neuroinflammation, a key factor in many neurological diseases. The purinergic system is a major regulator of inflammatory responses and represents a promising target for controlling neuroinflammation. Capsaicin, a bioactive compound found in chili peppers, exhibits significant anti-inflammatory and antioxidant properties. This study aimed to investigate the modulatory effects of capsaicin on microglial activation and purinergic system regulation. For this, BV-2 microglial cells were exposed to lipopolysaccharide (1 μg/mL) and treated with capsaicin (25 and 50 μM) for 24 hours. Cell viability was assessed by MTT and trypan blue assays. Cell cycle and apoptosis were evaluated by flow cytometry. Nitric oxide, reactive species and malondialdehyde levels were evaluated as markers of oxidative stress. Activities of NTPDase, 5'-nucleotidase (5’-NT), and adenosine deaminase (ADA) were evaluated. Gene expression of inflammatory mediators and purinergic receptors were analyzed by qRT-PCR, and molecular docking analyses were performed. As a result, capsaicin decreased the expression of pro-inflammatory mediators (NLRP3, CASP-1, IL-1β, IL-6, and TNF-α), increased IL-10 expression, and attenuated oxidative stress. It reduced NTPDase, 5'-NT, and ADA activities, downregulated P2X7 and A2A receptor expression, and upregulated A1 receptor expression. Molecular docking revealed that capsaicin has a high affinity for the A1 and A2A receptors, as well as for ADA. Collectively, these findings suggest that capsaicin exerts neuroprotective effect by suppressing pro-inflammatory signaling, enhancing anti-inflammatory responses, reducing oxidative stress, and modulating key components of the purinergic system, including ectoenzyme activities and P2X7, A1, and A2A receptor expression. Graphical Abstract Lipopolysaccharide (LPS) activates microglia via the NLRP3 pathway, increasing pro-inflammatory cytokines, purinergic receptors expression (P2X7 and A2A), and the activity of CD39, CD73, and ADA. Capsaicin mitigates this inflammatory profile by inhibiting NLRP3 signaling, reducing pro-inflammatory cytokine expression and modulating purinergic signaling toward an anti-inflammatory profile. Illustrations were obtained from Servier Medical Art ( https://smart.servier.com/ ), licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0).

Background/Objectives: Major depressive disorder (MDD) is a debilitating illness, and chronic stress is a contributing factor for depressive symptoms. However, despite intense research, the mechanisms of MDD remain substantially unidentified. Quercetin is a powerful flavonoid and could be used as a possible therapeutic strategy for depression. Acknowledging the potential benefits of quercetin, this study investigated its effect alone or in association with the standard drug tranylcypromine (TCP) in a rodent model of chronic restraint stress (CRS). Methods: Adult male rats were subjected to a CRS model consisting of an immobilization session of 4 h daily during 14 consecutive days. Quercetin (50 mg/kg, gavage) was administered for 45 days. TCP (10 mg/kg, gavage) was administered for 14 days. Behavioral tasks were conducted to assess locomotor functions, memory, anhedonia, depression-like behaviors, and anxiety-like behaviors. The activity, gene expression, and protein density of acetylcholinesterase (AChE) were investigated. Results: Behavioral tasks showed that the CRS model effectively induced stable behavioral changes. CRS did not alter locomotor function assessed by the open field test (OFT) or anhedonia behavior assessed by the sucrose preference test (SPT). CRS increased total fecal count, which was prevented by quercetin administration in rats. TCP and the association of quercetin and TCP increased the recognition index in comparison with the CRS group in the novel object recognition (NOR) test and improved the swimming and immobility times in comparison to stressed animals in the forced swim test (FST). All treatments were able to decrease the anxiety index assessed by the elevated plus maze (EPM) test. The activity, gene expression, and protein density of AChE were increased in the CRS model compared to control males. Overall, quercetin and TCP proved to reverse CRS-induced alterations in these parameters. Conclusions: Quercetin mitigated cognitive deficits, behavioral impairments, and neurochemical alterations induced by the CRS model, especially in association with TCP, supporting its potential as a promising therapeutic agent for depression.

Quercetin has therapeutic potential in the recovery of musculoskeletal injuries; however, when administered orally, this polyphenol exhibits low absorption. Its skin penetration can be enhanced by nanostructured lipid carriers loaded with quercetin (NLC-Q) applied in combination with pulsed therapeutic ultrasound (PTU). However, different intensities of 1 MHz ultrasound may compromise the physicochemical properties of NLC-Q, and this interaction has not yet been evaluated. The aim of this study was to assess the effects of different 1 MHz PTU intensities on the physicochemical properties of a gel containing nanostructured lipid carriers loaded with quercetin (NLC-Q). NLC-Q was developed using the high shear rate method. PTU (1 MHz, for 5 min, 20% duty cycle) was applied to the gel at intensities of 0.1, 0.2, 0.4, and 0.6 W/cm2 SATA (spatial average temporal average intensity). Physicochemical properties (pH, temperature, mean particle size, polydispersity index, and concentrations of quercetin within the nanostructured lipid carriers) were evaluated before and after the application of different PTU intensities. Intensities of 0.1 and 0.2 W/cm2 SATA did not alter the physicochemical properties of NLC-Q, while intensities of 0.4 and 0.6 W/cm2 SATA increased particle size by 14% and 44%, respectively (P < 0.001). These intensities also increased the polydispersity index by 28% and 88% (P < 0.001). PTU intensities above 0.4 W/cm2 SATA lead to instability of NLC-Q within the gel, which does not favor the topical delivery of the active ingredient. La quercetina posee un reconocido potencial terapéutico en la recuperación de lesiones musculoesqueléticas; sin embargo, presenta baja biodisponibilidad cuando administrada por vía oral. Su penetración cutánea puede ser mejorada mediante la aplicación tópica de transportadores lipídicos nanoestructurados cargados con quercetina (NLC-Q), en combinación con ultrasonido terapéutico pulsado (UTP). No obstante, diferentes intensidades de ultrasonido a 1 MHz podrían comprometer las propiedades fisicoquímicas de los NLC-Q, una interacción que aún no ha sido completamente evaluada. El objetivo de este estudio fue analizar los efectos de distintas intensidades del UTP (1 MHz) sobre las propiedades fisicoquímicas de un gel que contiene NLC-Q. Los NLC-Q fueron elaborados mediante el método de alta tasa de cizallamiento. El UTP (1 MHz, 5 minutos, ciclo de trabajo del 20%) se aplicó al gel a intensidades de 0,1, 0,2, 0,4 y 0,6 W/cm² SATA (intensidad espacial y temporal media). Se evaluaron las propiedades fisicoquímicas —pH, temperatura, tamaño medio de partícula, índice de polidispersión y concentración de quercetina encapsulada— antes y después de la aplicación de cada intensidad. Las intensidades de 0,1 y 0,2 W/cm² SATA no alteraron significativamente las propiedades de los NLC-Q. Sin embargo, las intensidades de 0,4 y 0,6 W/cm² SATA aumentaron el tamaño de las partículas en un 14% y 44%, respectivamente (P < 0,001), así como el índice de polidispersión en un 28% y 88% (P < 0,001). Intensidades superiores a 0,4 W/cm² SATA del UTP promovieron la inestabilidad de los NLC-Q en el gel, lo que podría comprometer su eficacia como sistema de administración tópica del principio activo. A quercetina tem potencial terapêutico na recuperação de lesões musculoesqueléticas, mas, por via oral, esse polifenol apresenta baixa absorção. Sua penetração na pele pode ser potencializada por carreadores lipídicos nanoestruturados carregados com quercetina (NLC-Q) aplicados em associação com o ultrassom terapêutico pulsado (PTU). No entanto, diferentes intensidades do ultrassom de 1 MHz podem comprometer as propriedades físico-químicas das NLC-Q, porém esta interação ainda não foi avaliada. O objetivo desta pesquisa foi avaliar os efeitos de diferentes intensidades do PTU de 1 MHz nas propriedades físico-químicas de um gel contendo carreadores lipídicos nanoestruturados carregados com quercetina (NLC-Q). As NLC-Q foram desenvolvidas pelo método de alta taxa de cisalhamento. O PTU (1 MHz, por 5 min, ciclo de trabalho de 20%) foi aplicado ao gel nas intensidades de 0,1, 0,2, 0,4 e 0,6 W/ cm2 SATA (intensidade espacial média-temporal). As propriedades físico-químicas (pH, temperatura, tamanho médio das partículas, índice de polidispersão e as concentrações de quercetina contidas nos carreadores lipídicos nanoestruturados) foram avaliados antes e após as aplicações das diferentes intensidades do PTU. As intensidades de 0,1 e 0,2 W/cm2 SATA não alteraram as propriedades físico-químicas das NLC-Q, enquanto as intensidades de 0,4 e 0,6 W/cm2 SATA aumentaram o tamanho das partículas respectivamente em 14% e 44% (P < 0,001). Essas intensidades também aumentaram o índice de polidispersão em 28% e 88% (P < 0,001). Intensidades maiores que 0,4 W/cm2 SATA do PTU promovem a instabilidade das NLC-Q contido no gel, o que não favorece a administração tópica do ingrediente ativo.

A quercetina tem potencial terapêutico na recuperação de lesões musculoesqueléticas, mas, por via oral, esse polifenol apresenta baixa absorção. Sua penetração na pele pode ser potencializada por carreadores lipídicos nanoestruturados carregados com quercetina (NLC-Q) aplicados em associação com o ultrassom terapêutico pulsado (PTU). No entanto, diferentes intensidades do ultrassom de 1 MHz podem comprometer as propriedades físico-químicas das NLC-Q, porém esta interação ainda não foi avaliada. O objetivo desta pesquisa foi avaliar os efeitos de diferentes intensidades do PTU de 1 MHz nas propriedades físico-químicas de um gel contendo carreadores lipídicos nanoestruturados carregados com quercetina (NLC-Q). As NLC-Q foram desenvolvidas pelo método de alta taxa de cisalhamento. O PTU (1 MHz, por 5 min, ciclo de trabalho de 20%) foi aplicado ao gel nas intensidades de 0,1, 0,2, 0,4 e 0,6 W/ cm2 SATA (intensidade espacial média-temporal). As propriedades físico-químicas (pH, temperatura, tamanho médio das partículas, índice de polidispersão e as concentrações de quercetina contidas nos carreadores lipídicos nanoestruturados) foram avaliados antes e após as aplicações das diferentes intensidades do PTU. As intensidades de 0,1 e 0,2 W/cm2 SATA não alteraram as propriedades físico-químicas das NLC-Q, enquanto as intensidades de 0,4 e 0,6 W/cm2 SATA aumentaram o tamanho das partículas respectivamente em 14% e 44% (P < 0,001). Essas intensidades também aumentaram o índice de polidispersão em 28% e 88% (P < 0,001). Intensidades maiores que 0,4 W/cm2 SATA do PTU promovem a instabilidade das NLC-Q contido no gel, o que não favorece a administração tópica do ingrediente ativo.