RESUMEN
The l -arginine ( l -Arg)/nitric oxide/cyclic GMP/potassium channel (K ATP ) pathway and opioid receptors are known to play critical roles in pain perception and the antinociceptive effects of various compounds. While there is evidence suggesting that the analgesic effects of rutin may involve nitric oxide modulation, the direct link between rutin and the l -Arg/nitric oxide/cyclic GMP/K ATP pathway in the context of pain modulation requires further investigation. The antinociceptive effect of rutin was studied in male NMRI mice using the formalin test. To investigate the role of the l -Arg/nitric oxide/cyclic GMP/K ATP pathway and opioid receptors, the mice were pretreated intraperitoneally with different substances. These substances included l -Arg (a precursor of nitric oxide), S-nitroso- N -acetylpenicillamine (SNAP, a nitric oxide donor), N(gamma)-nitro- l -arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase), sildenafil (an inhibitor of phosphodiesterase enzyme), glibenclamide (a K ATP channel blocker), and naloxone (an opioid receptor antagonist). All pretreatments were administered 20â min before the administration of the most effective dose of rutin. Based on our investigation, it was found that rutin exhibited a dose-dependent antinociceptive effect. The administration of SNAP enhanced the analgesic effects of rutin during both the initial and secondary phases. Moreover, L-NAME, naloxone, and glibenclamide reduced the analgesic effects of rutin in both the primary and secondary phases. In conclusion, rutin holds significant value as a flavonoid with analgesic properties, and its analgesic effect is directly mediated through the nitric oxide/cyclic GMP/K ATP channel pathway.
Asunto(s)
Analgésicos , Arginina , GMP Cíclico , Canales KATP , NG-Nitroarginina Metil Éster , Óxido Nítrico , Receptores Opioides , Rutina , Transducción de Señal , Animales , Masculino , Ratones , Arginina/farmacología , Óxido Nítrico/metabolismo , Rutina/farmacología , Analgésicos/farmacología , Transducción de Señal/efectos de los fármacos , Receptores Opioides/metabolismo , Receptores Opioides/efectos de los fármacos , Canales KATP/metabolismo , GMP Cíclico/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Gliburida/farmacología , Citrato de Sildenafil/farmacología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Naloxona/farmacología , Sulfonas/farmacología , Piperazinas/farmacología , Purinas/farmacología , S-Nitroso-N-Acetilpenicilamina/farmacología , Dolor/tratamiento farmacológico , Dolor/metabolismo , Antagonistas de Narcóticos/farmacología , Relación Dosis-Respuesta a Droga , Donantes de Óxido Nítrico/farmacologíaRESUMEN
BACKGROUND: Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor-κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti-inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti-inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms. METHODS AND RESULTS: Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanized at either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory-related gene expression, and elevated serum interleukin-6 levels at 4 days after MI were significantly attenuated by esaxerenone. In vitro experiments using mouse macrophage-like cell line RAW264.7 cells demonstrated that esaxerenone- and spironolactone-attenuated lipopolysaccharide-induced interleukin-6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65-STAT3 interaction, leading to a subsequent increase in interleukin-6 promoter activity, which was reversed by esaxerenone. CONCLUSIONS: Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti-inflammatory properties exerted by modulating the transcriptional activity of the MR-p65-STAT3 complex. These results suggest that the MR-p65-STAT3 complex can be a novel therapeutic target for treating MI.
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Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Antagonistas de Receptores de Mineralocorticoides , Infarto del Miocardio , Receptores de Mineralocorticoides , Factor de Transcripción STAT3 , Sulfonas , Factor de Transcripción ReIA , Animales , Factor de Transcripción STAT3/metabolismo , Masculino , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/genética , Antagonistas de Receptores de Mineralocorticoides/farmacología , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/prevención & control , Infarto del Miocardio/genética , Factor de Transcripción ReIA/metabolismo , Células RAW 264.7 , Sulfonas/farmacología , Transducción de Señal/efectos de los fármacos , Fibrosis , Transcripción Genética/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Antiinflamatorios/farmacología , Interleucina-6/metabolismo , Interleucina-6/genética , PirrolesRESUMEN
The synthetic auxin 2,4-D and the 4-hydroxyphenylpyruvate dioxygenase inhibitor pyrasulfotole are phloem-mobile post-emergence herbicides, the latter applied in co-formulation with either bromoxynil (a contact herbicide causing leaf desiccation) or MCPA (another synthetic auxin). Previous studies have shown a wide range of 2,4-D translocation phenotypes in resistant populations of the agricultural weed Raphanus raphanistrum, but it was hypothesised that enhanced movement out of the apical meristem could contribute to resistance. Little is known about pyrasulfotole translocation or the effect of bromoxynil on pyrasulfotole movement. Therefore, the behaviour of pyrasulfotole and 2,4-D applied to the growing point of susceptible and resistant R. raphanistrum seedlings was assessed, along with the effect of bromoxynil on pyrasulfotole translocation. The small amount of herbicide directly contacting the growing point after spraying was sufficient to induce herbicide symptoms, and there was no enhancement of translocation away from the growing point in either pyrasulfotole- or 2,4-D-resistant populations. Bromoxynil had a slightly inhibitory effect on pyrasulfotole translocation in some populations, somewhat negating the minor differences observed among populations when pyrasulfotole was applied alone. Resistance to pyrasulfotole could not explained by enhanced metabolism or vacuolar sequestration of the herbicide. Overall, differential translocation in either the treated leaves or apical meristems does not appear to be a major determinant of resistance to pyrasulfotole or 2,4-D.
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Ácido 2,4-Diclorofenoxiacético , Resistencia a los Herbicidas , Herbicidas , Raphanus , Herbicidas/farmacología , Ácido 2,4-Diclorofenoxiacético/farmacología , Raphanus/efectos de los fármacos , Raphanus/metabolismo , Plantones/efectos de los fármacos , Plantones/metabolismo , Pironas/farmacología , Transporte Biológico , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacología , Isoxazoles , Nitrilos , SulfonasRESUMEN
The pharmacokinetic profile of selected NSAIDs in southern black rhinoceros (Diceros bicornis minor) were studied. Phenylbutazone (PBZ), meloxicam (MEL), and firocoxib (FIR) were administered orally to five captive, black rhinoceros, and blood was collected at predetermined time points for NSAID quantification and noncompartmental pharmacokinetic (PK) analysis. Phenylbutazone 4.0 mg/kg PO q12h for three doses, MEL 0.3 mg/kg PO q24h administered twice, and a single oral dose of FIR 0.1 mg/kg, were tested with a minimum washout time of 2 wk. PBZ reached a median (range) peak concentration (Cmax) of 9.42 (2.74-11.5) g/ml at a mean (range) time (Tmax) of 6.00 (4.00 to >12.00) h, and the median (range) elimination half-life (T1/2) was 6.07 (3.95-6.49) h. Phenylbutazone pharmacokinetic parameters for black rhinoceros in this study were similar to domestic horses. Meloxicam reached a median (range) Cmax of 0.576 (0.357-0.655) µg/ml at a median (range) time (Tmax) of 6.00 (4.00-12.00) h; the median (range) T1/2 of MEL was 14.0 (12.4-17.9) h. These results demonstrate that once-daily administration of MEL at 0.3 mg/kg resulted in a serum concentration of greater than 0.200 µg/ml from 2 to 24 h in four animals, which is within the analgesic range (0.200-0.400 µg/ml) for this drug in other species postulated by other studies. A single dose of firocoxib (0.1 mg/kg) reached a median (range) peak concentration (Cmax) of 15.7 (9.65-17.3) ng/ml at a median (range) Tmax of 4.00 (4.00-6.00) h. The median (range) elimination T1/2 of FIR was 4.96 (4.47-6.51) h, which is faster than in the horse. The data suggest that extrapolation from equine FIR dosage recommendations is inappropriate for black rhinoceros.
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4-Butirolactona , Antiinflamatorios no Esteroideos , Meloxicam , Perisodáctilos , Fenilbutazona , Sulfonas , Animales , Meloxicam/farmacocinética , Meloxicam/administración & dosificación , Meloxicam/sangre , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/sangre , 4-Butirolactona/farmacocinética , 4-Butirolactona/análogos & derivados , 4-Butirolactona/administración & dosificación , 4-Butirolactona/sangre , Perisodáctilos/sangre , Fenilbutazona/farmacocinética , Fenilbutazona/administración & dosificación , Fenilbutazona/sangre , Masculino , Femenino , Semivida , Sulfonas/farmacocinética , Sulfonas/administración & dosificación , Sulfonas/sangre , Administración Oral , Área Bajo la CurvaRESUMEN
A novel nanofibrous double-layered biosorbent was fabricated by electrospinning polyethersulfone (PES) doped with a natural deep eutectic solvent (DES), composed of choline chloride (ChCl) and caffeic acid (CFA) in a 3:1 molar ratio, onto a bacterial cellulose (BC) substrate. The pristine PES/DES@BC biosorbent was employed in a thin film-solid phase microextraction (TF-SPME) to extract 12 multiclass pesticides from water. Characterization techniques, including ATR-FTIR, FT-NMR, SEM, and nitrogen adsorption/desorption isotherms, confirmed the nanofibrous structure of the electrospun PES-DES and BC biopolymer. The method was validated for matrix effect, specificity, reproducibility, limits of quantification (0.03-0.10 µg/L), and enrichment factor (7-14). Matrix-match calibration linearity ranged from 0.03 to 500 µg/L, with determination coefficients (r²) between 0.9884 and 0.9994. Intra-day and inter-day relative standard deviations (RSDs) were 1.2-3.6 % and 7.0-9.3 %, respectively. The composition of the biosorbent and the fabrication reproducibility across different batches were also thoroughly examined. The accuracy was evaluated by measuring extraction recoveries in six environmental water samples, which ranged from 75 to 105 % (RSDs < 9.0 %). Furthermore, the sustainability of the method was evaluated with the Analytical Eco-Scale and Analytical Greenness metrics. To our knowledge, this study represents the first synthesis and combination of [ChCl:[CFA] DES with PES to create a double-layered nanofiber biosorbent, as well as its application for extracting various pesticide groups from water samples.
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Celulosa , Disolventes Eutécticos Profundos , Nanocompuestos , Plaguicidas , Polímeros , Microextracción en Fase Sólida , Sulfonas , Contaminantes Químicos del Agua , Nanocompuestos/química , Celulosa/química , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/química , Polímeros/química , Plaguicidas/análisis , Plaguicidas/aislamiento & purificación , Disolventes Eutécticos Profundos/química , Reproducibilidad de los Resultados , Microextracción en Fase Sólida/métodos , Sulfonas/química , Límite de Detección , Nanofibras/química , Adsorción , Tecnología Química Verde/métodosRESUMEN
Exposure to bisphenol A (BPA) during gestation and lactation is considered to be a potential risk factor for autism spectrum disorder (ASD) in both humans and animals. As a novel alternative to BPA, 4-hydroxy-4'-isopropoxydiphenylsulfone (BPSIP) is frequently detected in breast milk and placental barrier systems, suggesting potential transmission from the mother to offspring and increased risk of exposure. Gestation and lactation are critical periods for central nervous system development, which are vulnerable to certain environmental pollutants. Herein, we investigated the behavioral impacts and neurobiological effects of early-life exposure to BPSIP (0.02, 0.1, and 0.5 mg/kg body weight/day) in mice offspring. Behavioral studies indicated that BPSIP exposure induced ASD-like behaviors, including elevated anxiety-related behavior and decreased spatial memory, in both male and female pups. A distinct pattern of reduced social novelty was observed only in female offspring, accompanied by significant alterations in antioxidant levels. Transcriptome analysis demonstrated that differentially expressed genes (DEGs) were mainly enriched in pathways related to behaviors and neurodevelopment, which were consistent with the observed phenotype. Besides, a decrease in the protein levels of complex IV (COX IV) across all tested populations suggests a profound impact on mitochondrial function, potentially leading to abnormal energy metabolism in individuals with autism. Additionally, changes in synaptic proteins, evidenced by alterations in synapsin 1 (SYN1) and postsynaptic density protein-95 (PSD95) levels in the cerebellum and hippocampus, support the notion of synaptic involvement. These findings suggest that BPSIP may induce sex-specific neurotoxic effects that involve oxidative stress, energy generation, and synaptic plasticity.
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Trastorno del Espectro Autista , Animales , Trastorno del Espectro Autista/inducido químicamente , Ratones , Femenino , Conducta Animal/efectos de los fármacos , Masculino , Embarazo , SulfonasRESUMEN
Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARß/δ activation. Here, we assessed the impact of central leptin administration and PPARß/δ inhibition on cardiac function. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARß/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARß/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARß/δ signaling is intact. The protective effects of leptin are lost by PPARß/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARß/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity.
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Leptina , PPAR delta , PPAR-beta , Animales , Leptina/farmacología , Leptina/metabolismo , PPAR-beta/metabolismo , PPAR-beta/agonistas , PPAR delta/metabolismo , PPAR delta/agonistas , Ratas , Masculino , Corazón/efectos de los fármacos , Ratas Wistar , Atrofia , Frecuencia Cardíaca/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Sulfonas , TiofenosRESUMEN
The aim of this study was to evaluate the chondrogenic potential of chondrocyte transplants cultured in vitro on polyethersulfone (PES) membranes. Forty-eight rabbits (96 knee joints) were used in the project. The synthetic, macro-porous PES membranes were used as scaffolds. Fragments of articular cartilage were harvested from non-weight-bearing areas of the joints of the animals. Chondrocytes were isolated and then cultivated on PES scaffolds for 3 weeks. The animals were divided into four groups. All the lesions in the articular cartilage were full thickness defects. In Group I, autogenic chondrocytes on PES membranes were transplanted into the defect area; in Group II, allogenic chondrocytes on PES membranes were transplanted into the defect area; in Group III, pure PES membranes were transplanted into the defect area; and in Group IV, lesions were left untreated. Half of the animals from each group were terminated after 8 weeks, and the remaining half were terminated 12 weeks postoperatively. The samples underwent macroscopic evaluation using the Brittberg scale and microscopic evaluation using the O'Driscoll scale. The best regeneration was observed in Groups II and I. In Group I, the results were achieved with two surgeries, while in Group II, only one operation was needed. This indicates that allogenic chondrocytes do not require two surgeries, highlighting the importance of further in vivo studies to better understand this advantage. The success of the study and the desired properties of PES scaffolds are attributed mainly to the presence of sulfonic groups in the structure of the material. These groups, similar to chondroitin sulfate, which naturally occurs in hyaline cartilage, likely enable mutual affinity between the scaffold and cells and promote scaffold colonization by the cells.
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Cartílago Articular , Condrocitos , Polímeros , Regeneración , Sulfonas , Andamios del Tejido , Trasplante Homólogo , Animales , Condrocitos/citología , Andamios del Tejido/química , Conejos , Sulfonas/química , Polímeros/química , Condrogénesis , Ingeniería de Tejidos/métodos , Trasplante Autólogo , Células CultivadasRESUMEN
Thyroid hormones play a crucial role in numerous physiological processes, including reproduction. Bisphenol S (BPS) is a structural analog of Bisphenol A known for its toxic effects. Interference of this substitute with normal thyroid function has been described. To investigate the effect of thyroid disruption on ovarian development following maternal exposure to BPS, female rats were exposed, daily, to either AT 1-850 (a thyroid hormone receptor antagonist) (10 nmol/rat) or BPS (0.2 mg/kg) during gestation and lactation. The effects on reproductive outcome, offspring development, histological structures, hormone levels, oxidative status, cytoskeleton proteins expression, and oocyte development gene expression were examined. Our results are in favor of offspring ovarian development disruption due to thyroid disturbance in adult pregnant females. During both fetal and postnatal stages, BPS considerably altered the histological structure of the thyroid tissue as well as oocyte and follicular development, which led to premature ovarian failure and stimulation of oocyte atresia, being accompanied with oxidative stress, hypothalamic-pituitary-ovarian axis disorders, and cytoskeletal dynamic disturbance. Crucially, our study underscores that BPS may induce reproductive toxicity by blocking nuclear thyroid hormone receptors, evidenced by the parallelism and the perfect meshing between the data obtained following exposure to AT 1-850 and those after the treatment by this substitute.
Asunto(s)
Exposición Materna , Ovario , Fenoles , Sulfonas , Glándula Tiroides , Femenino , Animales , Fenoles/toxicidad , Sulfonas/toxicidad , Ratas , Ovario/efectos de los fármacos , Glándula Tiroides/efectos de los fármacos , EmbarazoRESUMEN
Passive sampling is a crucial method for evaluating concentrations of hydrophilic organic compounds in the aquatic environment, but it is insufficiently understood to what extent passive samplers capture the intermittent emissions that frequently occur for this group of compounds. In the present study, silicone sheets and styrene-divinyl benzene-reversed phase sulfonated extraction disks with and without a polyethersulfone membrane were exposed under semi-field conditions in a 31 m3 flume at three different flow velocities. Natural processes and spiking/dilution measures caused aqueous concentrations to vary strongly with time. The data were analyzed using two analytical models that account for these time-variable concentrations: a sampling rate model and a diffusion model. The diffusion model generally gave a better fit of the data than the sampling rate model, but the difference in residual errors was quite small (median errors of 19 vs. 25% for silicone and 22 vs. 25% for SDB-RPS samplers). The sampling rate model was therefore adequate enough to evaluate the time-integrative capabilities of the samplers. Sampler performance was best for SDB-RPS samplers with a polyethersulfone membrane, despite the occurrence of lag times for some compounds (0.1 to 0.4 days). Sampling rates for this design also spanned a narrower range (80 to 110 mL/day) than SDB-RPS samplers without a membrane (100 to 660 mL/day). The effect of biofouling was similar for all compounds and was consistent with a biofouling layer thickness of 150 µm.
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Monitoreo del Ambiente , Interacciones Hidrofóbicas e Hidrofílicas , Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/análisis , Monitoreo del Ambiente/métodos , Sulfonas/química , Sulfonas/análisis , PolímerosRESUMEN
Many environmental pollutants have neurotoxic effects, but the initial molecular events involved in these effects are unclear. Here, zebrafish were exposed to the neurotoxicant bisphenol S (BPS, 1, 10, or 100 µg/L) from the embryonic stage to the larval stage to explore the ability of BPS to interfere with energy metabolism in the brain. BPS, which is similar to a glucose transporter 1 (GLUT1) inhibitor, inhibited GLUT1 function but increased mitochondrial activity in the brains of larval zebrafish. Interestingly, GLUT1 inhibitor treatment and BPS exposure did not reduce energy production in the brain; instead, they increased ATP production by inducing the preferential use of ketone bodies. Moreover, BPS promoted the protein expression of the purinergic 2X receptor but inhibited the purinergic 2Y-mediated phosphatidylinositol signaling pathway, indicating that excess ATP acts as a neurotransmitter to activate the purinergic 2X receptor under the BPS-induced restriction of GLUT1 function. BPS-induced inhibition of GLUT1 increased the number of neurons but promoted apoptosis by activating ATP-purinergic 2X receptors in the brain, causing ATP excitatory neurotoxicity. Our data reveal a potential neurotoxic mechanism induced by BPS that may represent a new adverse outcome pathway.
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Adenosina Trifosfato , Encéfalo , Transportador de Glucosa de Tipo 1 , Fenoles , Pez Cebra , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Adenosina Trifosfato/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Fenoles/toxicidad , Sulfonas/toxicidadRESUMEN
Recently, there has been increasing concern regarding the emergence of bisphenol S analogues (BPSs) due to their potential toxicity. However, their exposure levels and associated health risks in susceptible populations remain unknown. In our study, we analyzed bisphenol A (BPA), along with 11 common BPA analogues (BPAs), and nine emerging BPSs in urine samples collected from 381 pregnant women in South China. All nine BPSs were first detected in pregnant women's urine. In addition to BPA, two BPAs, three BPSs including Diphenylsulfone (DPS), Bis(phenylsulfonyl)phenol (DBSP) and Bis(3-allyl-4-hydroxyphenyl)sulfone (TGSA), were identified as the predominant bisphenols, with detection frequencies ranging from 53-100 %. BPA still exhibited the highest median concentration at 0.624 ng/mL, followed by DPS (0.169 ng/mL), BPS (0.063 ng/mL) and DBSP (0.023 ng/mL). Importantly, mothers with higher levels of BPA, DBSP, DPS, and TGSA in their urine are statistically more likely to give birth to premature infants with shorter lengths at birth or smaller head circumference (p < 0.05). Although the median exposure to 21 bisphenols did not exceed the tolerable daily intake (TDI) of BPA, it did surpass the recently proposed BPA TDI (0.2 ng/kg bw/day) by a factor ranging from 1.1-99 times. This study signifies the first report unveiling the prevalence of multiple bisphenols, particularly emerging BPSs, in the urine of pregnant women in South China.
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Fenoles , Sulfonas , Humanos , Femenino , Fenoles/orina , Fenoles/toxicidad , Embarazo , Sulfonas/toxicidad , China , Adulto , Adulto Joven , Compuestos de Bencidrilo/orina , Exposición Materna/efectos adversos , Contaminantes Ambientales/orina , Contaminantes Ambientales/toxicidadRESUMEN
During the inflammatory storm of sepsis, a significant quantity of neutrophil extracellular traps (NETs) are generated, which act as a double-edged sword and not only impede the invasion of foreign microorganisms but also exacerbate organ damage. This study provides evidence that NETs can cause damage to alveolar epithelial cells in vitro. The sepsis model developed in this study showed a significant increase in NETs in the bronchoalveolar lavage fluid (BALF). The development of NETs has been shown to increase the lung inflammatory response and aggravate injury to alveolar epithelial cells. Bay-117082, a well-known NF-κB suppressor, is used to modulate inflammation. This analysis revealed that Bay-117082 efficiently reduced total protein concentration, myeloperoxidase activity, and inflammatory cytokines in BALF. Moreover, Bay-117082 inhibited the formation of NETs, which in turn prevented the activation of the pore-forming protein gasdermin D (GSDMD). In summary, these results indicated that excessive NET production during sepsis exacerbated the onset and progression of acute lung injury (ALI). Therefore, Bay-117082 could serve as a novel therapeutic approach for ameliorating sepsis-associated ALI.
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Trampas Extracelulares , Péptidos y Proteínas de Señalización Intracelular , Proteína con Dominio Pirina 3 de la Familia NLR , Nitrilos , Proteínas de Unión a Fosfato , Sepsis , Sulfonas , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Animales , Sepsis/inmunología , Sepsis/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sulfonas/farmacología , Sulfonas/uso terapéutico , Nitrilos/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Ratones , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Masculino , Ratones Endogámicos C57BL , Humanos , Neutrófilos/inmunología , Regulación hacia Abajo , Citocinas/metabolismo , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , GasderminasRESUMEN
Sepsis-induced intestinal injury is a common complication that increases the morbidity and mortality associated with sepsis. UCP2, a mitochondrial membrane protein, is involved in numerous cellular processes, including metabolism, inflammation, and pyroptosis. According to our previous studies, UCP2 expression increases in septic intestinal tissue. However, its function in intestinal damage is not known. This work investigated UCP2's role in intestinal injury caused by sepsis. A sepsis mouse model was established in wild-type and UCP2-knockout (UCP2-KO) animals using cecal ligation and puncture (CLP). MCC950, an NLRP3 inflammasome inhibitor, was injected intraperitoneally 3 h before CLP surgery. Overall, significantly higher levels of UCP2 were observed in the intestines of septic mice. UCP2-KO mice subjected to CLP exhibited exacerbated intestinal damage, characterized by enhanced mucosal erosion, inflammatory cell infiltration, and increased intestinal permeability. Furthermore, UCP2 knockout significantly increased oxidative stress, inflammation, and pyroptosis in the CLP mouse intestines. Interestingly, MCC950 not only inhibited pyroptosis but also reversed inflammation, oxidative stress as well as damage to intestinal tissues as a result of UCP2 knockout. Our results highlighted the protective functions of UCP2 in sepsis-associated intestinal injury through modulation of inflammation and oxidative stress via NLRP3 inflammasome-induced pyroptosis.
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Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Sepsis , Proteína Desacopladora 2 , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína Desacopladora 2/metabolismo , Proteína Desacopladora 2/genética , Sepsis/complicaciones , Sepsis/inmunología , Sepsis/metabolismo , Ratones , Masculino , Inflamasomas/metabolismo , Modelos Animales de Enfermedad , Sulfonamidas/farmacología , Estrés Oxidativo , Indenos , Furanos/farmacología , Sulfonas/farmacología , Intestinos/patología , Intestinos/inmunología , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunologíaRESUMEN
To enhance the stability and adsorption performance of chitosan in Cr(VI)-contaminated acidic wastewater, a novel EDAC-modified-EDTA-crosslinked chitosan derivative (CSEC) was synthesized via a one-pot method with chitosan, 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC), and Na2EDTA as raw materials. To further improve the mechanical strength and separation performance of CSEC, a novel composite bead (CSEP) of CSEC and imidazolium-functionalized polysulfone (IMPSF) was prepared through a phase inversion method. The chemical composition and microstructure of CSEC and CSEP were characterized by FESEM, FTIR, NMR and XPS techniques. The maximum adsorption capacities of CSEC and CSEP for Cr(VI) were 145.96 and 135.82 mg g-1 at pH 3, respectively, and the equilibrium time for Cr(VI) adsorption by CSEC and CSEP was 5 min and 8 h, respectively. The adsorption process of Cr(VI) by both CSEC and CSEP was exothermic and spontaneous. Compared to CSEC, CSEP has significantly enhanced resistance to interference from coexisting anions. The removal mechanism of Cr(VI) by CSEP might involve redox reaction as well as electrostatic attraction between Cr(VI) oxyanions and various nitrogen cations, including protonated amino groups, guanidinium groups, protonated tertiary amine groups, and imidazolium cations. The CSEP beads have potential application value in the treatment of acidic wastewater containing Cr(VI).
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Quitosano , Cromo , Imidazoles , Polímeros , Sulfonas , Contaminantes Químicos del Agua , Purificación del Agua , Quitosano/química , Cromo/aislamiento & purificación , Cromo/química , Sulfonas/química , Adsorción , Contaminantes Químicos del Agua/química , Contaminantes Químicos del Agua/aislamiento & purificación , Imidazoles/química , Polímeros/química , Purificación del Agua/métodos , Concentración de Iones de Hidrógeno , Cinética , Aguas Residuales/química , Carbodiimidas/química , Agua/química , Soluciones , MicroesferasRESUMEN
Bisphenol S (BPS) is widely used in the manufacture products and increase the risk of cardiovascular diseases. The effect of the association between obesity and BPS on cardiac outcomes is still unknown. Male C57BL/6 mice were divided into standard chow diet (SC; 15 kJ/g), standard chow diet + BPS (SCB), high-fat diet (HF; 21 kJ/g), and high-fat diet + BPS (HFB). Over 12 weeks, the groups were exposed to BPS through drinking water (dose: 25 µg/kg/day) and/or a HF diet. We evaluated: body mass (BM), total cholesterol, systolic blood pressure (SBP), left ventricle (LV) mass, and cardiac remodeling. In the SCB group, BM, total cholesterol, and SBP increase were augmented in relation to the SC group. In the HF and HFB groups, these parameters were higher than in the SC and SCB groups. Cardiac hypertrophy was evidenced by augmented LV mass and wall thickness, and ANP protein expression in all groups in comparison to the SC group. Only the HFB group had a thicker LV wall than SCB and HF groups, and increased cardiomyocyte area when compared with SC and SCB groups. Concerning cardiac fibrosis, SCB, HF, and HFB groups presented higher interstitial collagen area, TGFß, and α-SMA protein expression than the SC group. Perivascular collagen area was increased only in the HF and HFB groups than SC group. Higher IL-6, TNFα, and CD11c protein expression in all groups than the SC group evidenced inflammation. All groups had elevated CD36 and PPARα protein expression in relation to the SC group, but only HF and HFB groups promoted cardiac steatosis with increased perilipin 5 protein expression than the SC group. BPS exposure alone promoted cardiac remodeling with pathological concentric hypertrophy, fibrosis, and inflammation. Diet-induced remodeling is aggravated when associated with BPS, with marked hypertrophy, alongside fibrosis, inflammation, and lipid accumulation.
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Cardiomegalia , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Fenoles , Animales , Masculino , Dieta Alta en Grasa/efectos adversos , Cardiomegalia/inducido químicamente , Cardiomegalia/patología , Ratones , Fenoles/toxicidad , Remodelación Ventricular/efectos de los fármacos , SulfonasRESUMEN
Biocatalytic membranes have great potential in various industrial sectors, with the immobilization of enzymes being a crucial stage. Immobilizing enzymes through covalent bonds is a complex and time-consuming process for large-scale applications. Polydopamine (PDA) offers a more sustainable and eco-friendly alternative for enzyme immobilization. Therefore, surface modification with polydopamine as mussel-inspired antifouling coatings has increased resistance to fouling. In this study, α-amylase enzyme was covalently bound to a bioactive PDA-coated polyethersulfone (PES) membrane surface using cyanuric chloride as a linker. The optimal activity of α-amylase enzyme immobilized on PES/PDA membrane was obtained at temperature and pH of 55°C and 6.5, respectively. The immobilized enzyme can be reused up to five reaction cycles with 55â¯% retention of initial activity. Besides, it maintained 60â¯% of its activity after being stored for five weeks at 4°C. Additionally, the immobilized enzyme demonstrated increased Michaelis constant and maximum velocity values during starch hydrolysis. The results of the biofouling experiment of various membranes in a dead-end cell demonstrated that the PES membrane's water flux increased from 6722.7 Lmh to 7560.2 Lmh after PDA modification. Although α-amylase immobilization reduced the flux to 7458.5 Lmh due to enhanced hydrophilicity, compared to unmodified membrane. The findings of this study demonstrated that the membrane produced through co-deposition exhibited superior hydrophilicity, enhanced coating stability, and strong antifouling properties, positioning it as a promising candidate for industrial applications.
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Estabilidad de Enzimas , Enzimas Inmovilizadas , Indoles , Membranas Artificiales , Polímeros , Sulfonas , alfa-Amilasas , Indoles/química , Polímeros/química , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/metabolismo , Sulfonas/química , alfa-Amilasas/metabolismo , alfa-Amilasas/química , Concentración de Iones de Hidrógeno , Incrustaciones Biológicas/prevención & control , Temperatura , Hidrólisis , TriazinasRESUMEN
RESEARCH QUESTION: Does the NOD-like receptor protein 3 (NLRP3) inflammasome have an effect in adenomyosis? DESIGN: Fresh-frozen endometrial tissues and paraffin specimens were obtained from endometrial tissues from patients with adenomyosis and controls. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were applied to assess expression of the NLRP3 inflammasome components. Primary eutopic endometrial stromal cells were isolated from the uteri of patients with adenomyosis. After NLRP3 was knocked down using small interfering RNA, proliferation, invasion and epithelial-mesenchymal transition (EMT) were evaluated using EdU, CCK8, transwell assays and western blot. Importantly, a mouse model of adenomyosis was established to evaluate the effects of the NLRP3 inhibitor MCC950 on the formation of adenomyosis. RESULTS: Expression of the NLRP3 inflammasome components was elevated in the ectopic or eutopic endometrium of patients with adenomyosis. NLRP3 knockdown inhibited migration, invasion and EMT in endometrial cells and primary endometrial cells (P < 0.0001). MCC950, which blocks the NLRP3 inflammasome, reduced migration and invasion of endometrial cells (P < 0.01) and primary endometrial cells (P < 0.0001) considerably. Importantly, in the mouse model of adenomyosis, MCC950 had a mitigating effect on the severity of adenomyosis (P < 0.01). CONCLUSIONS: NLRP3 was found to enhance migration, invasion and EMT of human endometrial cells in adenomyosis. Notably, the NLRP3 inhibitor MCC950 reduced migration and invasion of endometrial cells effectively. Furthermore, in the mouse model of adenomyosis, MCC950 exhibited a therapeutic effect by alleviating the severity of adenomyosis.
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Adenomiosis , Movimiento Celular , Endometrio , Transición Epitelial-Mesenquimal , Indenos , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Sulfonamidas , Femenino , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Humanos , Adenomiosis/metabolismo , Adenomiosis/patología , Adenomiosis/tratamiento farmacológico , Animales , Sulfonamidas/farmacología , Movimiento Celular/efectos de los fármacos , Indenos/farmacología , Ratones , Endometrio/metabolismo , Endometrio/patología , Endometrio/efectos de los fármacos , Inflamasomas/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Furanos/farmacología , Sulfonas/farmacología , Adulto , Proliferación Celular/efectos de los fármacos , Persona de Mediana EdadRESUMEN
Defense against intracellular acidification of breast cancer tissue depends on net acid extrusion via Na+,HCO3--cotransporter NBCn1/Slc4a7 and Na+/H+-exchanger NHE1/Slc9a1. NBCn1 is increasingly recognized as breast cancer susceptibility protein and promising therapeutic target, whereas evidence for targeting NHE1 is discordant. Currently, selective small molecule inhibitors exist against NHE1 but not NBCn1. Cellular assays-with some discrepancies-link NHE1 activity to proliferation, migration, and invasion; and disrupted NHE1 expression can reduce triple-negative breast cancer growth. Studies on human breast cancer tissue associate high NHE1 expression with reduced metastasis and-in some molecular subtypes-improved patient survival. Here, we evaluate Na+/H+-exchange and therapeutic potential of the NHE1 inhibitor cariporide/HOE-642 in murine ErbB2-driven breast cancer. Ex vivo, cariporide inhibits net acid extrusion in breast cancer tissue (IC50 = 0.18 µM) and causes small decreases in steady-state intracellular pH (pHi). In vivo, we deliver cariporide orally, by osmotic minipumps, and by intra- and peritumoral injections to address the low oral bioavailability and fast metabolism. Prolonged cariporide administration in vivo upregulates NBCn1 expression, shifts pHi regulation towards CO2/HCO3--dependent mechanisms, and shows no net effect on the growth rate of ErbB2-driven primary breast carcinomas. Cariporide also does not influence proliferation markers in breast cancer tissue. Oral, but not parenteral, cariporide elevates serum glucose by â¼1.5 mM. In conclusion, acute administration of cariporide ex vivo powerfully inhibits net acid extrusion from breast cancer tissue but lowers steady-state pHi minimally. Prolonged cariporide administration in vivo is compensated via NBCn1 and we observe no discernible effect on growth of ErbB2-driven breast carcinomas.