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2.
Environ Health Perspect ; 132(9): 97011, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39298647

RESUMO

BACKGROUND: A broad suite of bisphenol S (BPS) derivatives as alternatives for BPS have been identified in various human biological samples, including 4-hydroxyphenyl 4-isopropoxyphenylsulfone (BPSIP) detected in human umbilical cord plasma and breast milk. However, very little is known about the health outcomes of prenatal BPS derivative exposure to offspring. OBJECTIVES: Our study aimed to investigate the response of hepatic cholesterol metabolism by sex in offspring of dams exposed to BPSIP. METHODS: Pregnant ICR mice were exposed to 5µg/kg body weight (BW)/day of BPSIP, BPS, or E2 through drinking water from gestational day one until the pups were weaned. The concentration of BPSIP, BPS, or E2 in the plasma and liver of pups was determined by liquid chromatography-tandem mass spectrometry. Metabolic phenotypes were recorded, and histopathology was examined for liver impairment. Transcriptome analysis was employed to characterize the distribution and expression patterns of differentially expressed genes across sexes. The metabolic regulation was validated by quantitative real-time PCR, immunohistochemistry, and immunoblotting. The role of estrogen receptors (ERs) in mediating sex-dependent effects was investigated using animal models and liver organoids. RESULTS: Pups of dams exposed to BPSIP showed a higher serum cholesterol level, and liver cholesterol levels were higher in females and lower in males than in the controls. BPSIP concentration in the male liver was 1.22±0.25 ng/g and 0.69±0.27 ng/g in the female liver. Histopathology analysis showed steatosis and lipid deposition in both male and female offspring. Transcriptome and gene expression analyses identified sex-specific differences in cholesterol biosynthesis, absorption, disposal, and efflux between pups of dams exposed to BPSIP and those in controls. In vivo, chromatin immunoprecipitation analysis revealed that the binding of ERα protein to key genes such as Hmgcr, Pcsk9, and Abcg5 was attenuated in BPSIP-exposed females compared to controls, while it was enhanced in males. In vitro, the liver organoid experiments demonstrated that restoration of differential expression induced by BPSIP in key genes, such as Hmgcr, Ldlr, and Cyp7a1, to levels comparable to the controls was only achieved when treated with a combination of ERα agonist and ERß agonist. DISCUSSION: Findings from this study suggest that perinatal exposure to BPSIP disrupted cholesterol metabolism in a sex-specific manner in a mouse model, in which ERα played a crucial role both in vivo and in vitro. Therefore, it is crucial to systematically evaluate BPS derivatives to protect maternal health during pregnancy and prevent the transmission of metabolic disorders across generations. https://doi.org/10.1289/EHP14643.


Assuntos
Colesterol , Fígado , Camundongos Endogâmicos ICR , Fenóis , Animais , Feminino , Masculino , Camundongos , Colesterol/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Gravidez , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Sulfonas/toxicidade , Exposição Materna
3.
J Hazard Mater ; 479: 135704, 2024 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-39217924

RESUMO

Bisphenol S (BPS) is widely used in plastic products, food packaging, electronic products, and other applications. In recent years, BPS emissions have increasingly impacted aquatic ecosystems. The effects of BPS exposure on aquatic animal health have been documented; however, our understanding of its toxicology remains limited. This study aimed to explore the mechanisms of lipid metabolism disorders, oxidative stress, and autophagy dysfunction induced in freshwater crayfish (Procambarus clarkii) by exposure to different concentrations of BPS (0 µg/L, 1 µg/L, 10 µg/L, and 100 µg/L) over 14 d. The results indicated that BPS exposure led to oxidative stress by inducing elevated levels of reactive oxygen species (ROS) and inhibiting the activity of antioxidant-related enzymes. Additionally, BPS exposure led to increased lipid content in the serum and hepatopancreas, which was associated with elevated lipid-related enzyme activity and increased expression of related genes. Furthermore, BPS exposure decreased levels of phosphatidylcholine (PC) and phosphatidylinositol (PI), disrupted glycerophospholipid (GPI) metabolism, and caused lipid deposition in the hepatopancreatic. These phenomena may have occurred because BPS exposure reduced the transport of fatty acids and led to hepatopancreatic lipid deposition by inhibiting the transport and synthesis of PC and PI in the hepatopancreas, thereby inhibiting the PI3K-AMPK pathway. In conclusion, BPS exposure induced oxidative stress, promoted lipid accumulation, and led to autophagy dysfunction in the hepatopancreas of freshwater crayfish. Collectively, our findings provide the first evidence that environmentally relevant levels of BPS exposure can induce hepatopancreatic lipid deposition through multiple pathways, raising concerns about the potential population-level harm of BPS and other bisphenol analogues.


Assuntos
Astacoidea , Autofagia , Metabolismo dos Lipídeos , Estresse Oxidativo , Fenóis , Sulfonas , Poluentes Químicos da Água , Animais , Astacoidea/efeitos dos fármacos , Astacoidea/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Fenóis/toxicidade , Sulfonas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Hepatopâncreas/efeitos dos fármacos , Hepatopâncreas/metabolismo , Hepatopâncreas/patologia
4.
Environ Sci Pollut Res Int ; 31(43): 55663-55675, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39240436

RESUMO

Given the increasing concern about chemical exposure from textiles, our study examines the risks of dermal exposure to bisphenol A (BPA), bisphenol S (BPS), bisphenol B (BPB) and bisphenol F (BPF) from conventional and recycled textiles for adults, aiming to obtain new data, assess exposure, and evaluate the impact of washing on bisphenol levels. A total of 57 textile samples (33 from recycled and 24 from conventional material) were subjected to ultrasound-assisted extraction (UAE) followed by ultra-high performance liquid chromatography with tandem mass spectrometry analysis (UHPLC-MS/MS). The BPA and BPS concentrations varied widely (BPA: < 0.050 to 625 ng/g, BPS: 0.277-2,474 ng/g). The median BPA content in recycled textiles (13.5 ng/g) was almost twice as high as that of 7.66 ng/g in conventional textiles. BPS showed a median of 1.85 ng/g in recycled textiles and 3.42 ng/g in conventional textiles, indicating a shift from BPA to BPS in manufacturing practices. Simulated laundry experiments showed an overall reduction in bisphenols concentrations after washing. The study also assessed potential health implications via dermal exposure to dry and sweat-wet textiles compared to a tolerable daily intake (TDI) of 0.2 ng/kg bw/day for BPA set by the European Food Safety Authority (EFSA). Exposure from dry textiles remained below this threshold, while exposure from wet textiles often exceeded it, indicating an increased risk under conditions that simulate sweating or humidity. By finding the widespread presence of bisphenols in textiles, our study emphasises the importance of being aware of the potential risks associated with recycling materials as well as the benefits.


Assuntos
Compostos Benzidrílicos , Fenóis , Têxteis , Fenóis/análise , Humanos , Reciclagem , Vestuário , Sulfonas
5.
J Chromatogr A ; 1735: 465267, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39241404

RESUMO

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.


Assuntos
Celulose , Solventes Eutéticos Profundos , Nanocompostos , Praguicidas , Polímeros , Microextração em Fase Sólida , Sulfonas , Poluentes Químicos da Água , Nanocompostos/química , Celulose/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/química , Polímeros/química , Praguicidas/análise , Praguicidas/isolamento & purificação , Solventes Eutéticos Profundos/química , Reprodutibilidade dos Testes , Microextração em Fase Sólida/métodos , Sulfonas/química , Limite de Detecção , Nanofibras/química , Adsorção , Química Verde/métodos
6.
Pestic Biochem Physiol ; 204: 106072, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39277417

RESUMO

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.


Assuntos
Ácido 2,4-Diclorofenoxiacético , Resistência a Herbicidas , Herbicidas , Raphanus , Herbicidas/farmacologia , Ácido 2,4-Diclorofenoxiacético/farmacologia , Raphanus/efeitos dos fármacos , Raphanus/metabolismo , Plântula/efeitos dos fármacos , Plântula/metabolismo , Pironas/farmacologia , Transporte Biológico , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacologia , Isoxazóis , Nitrilas , Sulfonas
7.
J Am Heart Assoc ; 13(18): e030941, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39248263

RESUMO

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.


Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Antagonistas de Receptores de Mineralocorticoides , Infarto do Miocárdio , Receptores de Mineralocorticoides , Fator de Transcrição STAT3 , Sulfonas , Fator de Transcrição RelA , Animais , Fator de Transcrição STAT3/metabolismo , Masculino , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/genética , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Camundongos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/genética , Fator de Transcrição RelA/metabolismo , Células RAW 264.7 , Sulfonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fibrose , Transcrição Gênica/efeitos dos fármacos , Miocárdio/metabolismo , Miocárdio/patologia , Anti-Inflamatórios/farmacologia , Interleucina-6/metabolismo , Interleucina-6/genética , Pirróis
8.
J Zoo Wildl Med ; 55(3): 547-554, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39255195

RESUMO

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.


Assuntos
4-Butirolactona , Anti-Inflamatórios não Esteroides , Meloxicam , Perissodáctilos , Fenilbutazona , Sulfonas , Animais , Meloxicam/farmacocinética , Meloxicam/administração & dosagem , Meloxicam/sangue , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , 4-Butirolactona/farmacocinética , 4-Butirolactona/análogos & derivados , 4-Butirolactona/administração & dosagem , 4-Butirolactona/sangue , Perissodáctilos/sangue , Fenilbutazona/farmacocinética , Fenilbutazona/administração & dosagem , Fenilbutazona/sangue , Masculino , Feminino , Meia-Vida , Sulfonas/farmacocinética , Sulfonas/administração & dosagem , Sulfonas/sangue , Administração Oral , Área Sob a Curva
9.
Behav Pharmacol ; 35(7): 399-407, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39230435

RESUMO

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 20 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.


Assuntos
Analgésicos , Arginina , GMP Cíclico , Canais KATP , NG-Nitroarginina Metil Éster , Óxido Nítrico , Receptores Opioides , Rutina , Transdução de Sinais , Animais , Masculino , Camundongos , Arginina/farmacologia , Óxido Nítrico/metabolismo , Rutina/farmacologia , Analgésicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptores Opioides/metabolismo , Receptores Opioides/efeitos dos fármacos , Canais KATP/metabolismo , GMP Cíclico/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Glibureto/farmacologia , Citrato de Sildenafila/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Naloxona/farmacologia , Sulfonas/farmacologia , Piperazinas/farmacologia , Purinas/farmacologia , S-Nitroso-N-Acetilpenicilamina/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Antagonistas de Entorpecentes/farmacologia , Relação Dose-Resposta a Droga , Doadores de Óxido Nítrico/farmacologia
10.
Environ Sci Technol ; 58(36): 15984-15996, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39194383

RESUMO

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.


Assuntos
Transtorno do Espectro Autista , Animais , Transtorno do Espectro Autista/induzido quimicamente , Camundongos , Feminino , Comportamento Animal/efeitos dos fármacos , Masculino , Gravidez , Sulfonas
11.
Environ Res ; 261: 119781, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39142458

RESUMO

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.


Assuntos
Cardiomegalia , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Fenóis , Animais , Masculino , Dieta Hiperlipídica/efeitos adversos , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Camundongos , Fenóis/toxicidade , Remodelação Ventricular/efeitos dos fármacos , Sulfonas
12.
Biochim Biophys Acta Mol Basis Dis ; 1870(7): 167450, 2024 10.
Artigo em Inglês | MEDLINE | ID: mdl-39111631

RESUMO

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 ∼1.5 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.


Assuntos
Neoplasias da Mama , Proliferação de Células , Guanidinas , Receptor ErbB-2 , Trocador 1 de Sódio-Hidrogênio , Sulfonas , Guanidinas/farmacologia , Feminino , Animais , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/antagonistas & inibidores , Trocador 1 de Sódio-Hidrogênio/metabolismo , Trocador 1 de Sódio-Hidrogênio/antagonistas & inibidores , Trocador 1 de Sódio-Hidrogênio/genética , Camundongos , Humanos , Sulfonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Simportadores de Sódio-Bicarbonato/metabolismo , Simportadores de Sódio-Bicarbonato/genética , Simportadores de Sódio-Bicarbonato/antagonistas & inibidores , Linhagem Celular Tumoral , Concentração de Íons de Hidrogênio
13.
Reprod Biomed Online ; 49(4): 104319, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39121559

RESUMO

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.


Assuntos
Adenomiose , Endométrio , Indenos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Adulto , Animais , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Adenomiose/metabolismo , Adenomiose/patologia , Adenomiose/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Endométrio/metabolismo , Endométrio/patologia , Endométrio/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Furanos/farmacologia , Indenos/farmacologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Sulfonamidas/farmacologia , Sulfonas/farmacologia
14.
Environ Sci Pollut Res Int ; 31(39): 52596-52614, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39153066

RESUMO

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.


Assuntos
Exposição Materna , Ovário , Fenóis , Sulfonas , Glândula Tireoide , Feminino , Animais , Fenóis/toxicidade , Sulfonas/toxicidade , Ratos , Ovário/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Gravidez
15.
Environ Sci Pollut Res Int ; 31(39): 51844-51857, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39129044

RESUMO

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.


Assuntos
Monitoramento Ambiental , Interações Hidrofóbicas e Hidrofílicas , Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Monitoramento Ambiental/métodos , Sulfonas/química , Sulfonas/análise , Polímeros
16.
Environ Sci Technol ; 58(35): 15463-15474, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39167196

RESUMO

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.


Assuntos
Trifosfato de Adenosina , Encéfalo , Transportador de Glucose Tipo 1 , Fenóis , Peixe-Zebra , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Trifosfato de Adenosina/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Fenóis/toxicidade , Sulfonas/toxicidade
17.
J Hazard Mater ; 478: 135431, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39128146

RESUMO

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.


Assuntos
Fenóis , Sulfonas , Humanos , Feminino , Fenóis/urina , Fenóis/toxicidade , Gravidez , Sulfonas/toxicidade , China , Adulto , Adulto Jovem , Compostos Benzidrílicos/urina , Exposição Materna/efeitos adversos , Poluentes Ambientais/urina , Poluentes Ambientais/toxicidade
18.
J Enzyme Inhib Med Chem ; 39(1): 2387417, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39163165

RESUMO

Papain-like protease (PLpro) is an attractive anti-coronavirus target. The development of PLpro inhibitors, however, is hampered by the limitations of the existing PLpro assay and the scarcity of validated active compounds. We developed a novel in-cell PLpro assay based on BRET and used it to evaluate and discover SARS-CoV-2 PLpro inhibitors. The developed assay demonstrated remarkable sensitivity for detecting the reduction of intracellular PLpro activity while presenting high reliability and performance for inhibitor evaluation and high-throughput screening. Using this assay, three protease inhibitors were identified as novel PLpro inhibitors that are structurally disparate from those previously known. Subsequent enzymatic assays and ligand-protein interaction analysis based on molecular docking revealed that ceritinib directly inhibited PLpro, showing high geometric complementarity with the substrate-binding pocket in PLpro, whereas CA-074 methyl ester underwent intracellular hydrolysis, exposing a free carboxyhydroxyl group essential for hydrogen bonding with G266 in the BL2 groove, resulting in PLpro inhibition.


Assuntos
Simulação de Acoplamento Molecular , Pirimidinas , SARS-CoV-2 , Sulfonas , Humanos , SARS-CoV-2/enzimologia , SARS-CoV-2/efeitos dos fármacos , Sulfonas/farmacologia , Sulfonas/química , Pirimidinas/química , Pirimidinas/farmacologia , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/química , Técnicas de Transferência de Energia por Ressonância de Bioluminescência , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade
19.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(4): 845-852, 2024 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-39170016

RESUMO

Objective: To design and prepare a high efficiency bilirubin adsorbent with good mechanical properties and biocompatibility. Methods: In this study, quaternary ammonium pyridine was designed and synthesized, and then modified polyether sulfone microspheres, or PES/p(4-VP-co-N-VP)@6 microspheres, were prepared by phase conversion and electrostatic spraying. The morphology of the polymer components and the microspheres were studied by means of nuclear magnetic resonance (NMR) spectroscopy and scanning electron microscopy. The basic properties of the microspheres and their bilirubin adsorption efficiency were tested, and the adsorption mechanism was further explored. Blood cell counts and the clotting time of the microspheres were also measured. Results: The diameter of the modified polyether sulfone microspheres prepared in the study was approximately 700-800 µm. Compared with the original PES microspheres, the surface and internal structure of PES/p(4-VP-co-N-VP)@6 microspheres did not change significantly, and they also had a loose porous structure, with some micropores scattered around in addition to irregular large pores. Compared with the control group, the bilirubin removal effect of the modified microspheres was (94.91±0.73)% after static adsorption in bilirubin PBS buffer solution for 180 min, with the difference being statistically significant (P<0.0001). According to the findings for the clotting time, the activated partial thromboplastin time (APTT) of the blank plasma group, the control PES group, and the modified PES microsphere group were (27.57±1.25) s, (28.47±0.45) s, and (30.4±0.872) s, respectively, and the difference between the experimental group and the other two groups was statistically significant (P<0.01, P<0.05). There was no significant change in red blood cell and white blood cell counts. Conclusion: The microspheres prepared in the study have high efficiency in bilirubin adsorption, excellent mechanical properties and thermal stability, and good blood biocompatibility, and are expected to be used in the clinical treatment of patients with liver failure.


Assuntos
Bilirrubina , Microesferas , Polímeros , Sulfonas , Sulfonas/química , Polímeros/química , Adsorção , Bilirrubina/sangue , Humanos
20.
Biomolecules ; 14(8)2024 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-39199415

RESUMO

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.


Assuntos
Leptina , PPAR delta , PPAR beta , Animais , Leptina/farmacologia , Leptina/metabolismo , PPAR beta/metabolismo , PPAR beta/agonistas , PPAR delta/metabolismo , PPAR delta/agonistas , Ratos , Masculino , Coração/efeitos dos fármacos , Ratos Wistar , Atrofia , Frequência Cardíaca/efeitos dos fármacos , Miocárdio/metabolismo , Miocárdio/patologia , Sulfonas , Tiofenos
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