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1.
Environ Geochem Health ; 46(4): 135, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38483670

RESUMO

Some Polycyclic Aromatic Compounds (PACs) such as nitrated-PAHs (NPAHs), oxygenated-PAHs (OPAHs) and methyl-PAHs (MPAHs) have attracted significant concern due to derivatives have greater potential to be more toxic at low environmental concentrations compared to their PPAHs, particularly in petrochemical industrial region and its surrounding areas surface soils in China. Hence, this article provides an insight into the fate, sources, impacts, and relevance to the external environment of PAH-derivatives based on important emissions source. Moreover, prospective health risk due to their exposure has also been discussed. In this study, the concentration (10-3 ng/g) of Æ©18PPAHs, Æ©11MPAHs, Æ©12NPAHs, and Æ©4OPAHs in the park were 9.67 ± 1.40, 3.24 ± 0.54, 0.03 ± 0.02 and 0.19 ± 0.65, respectively, which were 4.47, 3.89, 2.04 and 1.17 times than of them surrounding the region. A decreasing trend of the low molecular weight (2-4Rings) contribution to the total amount of PAHs, while the fraction of high molecular weight (5-6Rings) species showed the opposite trend. According to the principal component analysis (PCA) and diagnostic ratios indicated PAHs in the soil samples have mixed sources from industrial activities, solid fuel combustion, and heavy traffic. Despite the high concentrations of MPAHs and OPAHs, the toxicity equivalency quotients (TEQs) of them were not calculated due to the lack of toxic equivalent factors (TEF), thus current studies on PAH and derivatives could have underestimated their exposure risks. The quality and sustainable management of soils are crucial for human health and sustainable development, while there is lack of public awareness of the severe issue of soil pollution. It is recommended to conduct more intensive monitoring and regional assessments in the future.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Compostos Policíclicos , Poluentes do Solo , Humanos , Compostos Policíclicos/análise , Monitoramento Ambiental , Solo , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/análise , China , Poluentes do Solo/toxicidade , Poluentes do Solo/análise , Medição de Risco
2.
Int J Mol Sci ; 25(5)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38473969

RESUMO

A theoretical molecular simulation study of the encapsulation of gaseous SO2 at different temperature conditions in a type II porous liquid is presented here. The system is composed of cage cryptophane-111 molecules that are dispersed in dichloromethane, and it is described using an atomistic modelling of molecular dynamics. Gaseous SO2 tended to almost fully occupy cryptophane-111 cavities throughout the simulation. Calculations were performed at 300 K and 283 K, and some insights into the different adsorption found in each case were obtained. Simulations with different system sizes were also studied. An experimental-like approach was also employed by inserting a SO2 bubble in the simulation box. Finally, an evaluation of the radial distribution function of cryptophane-111 and gaseous SO2 was also performed. From the results obtained, the feasibility of a renewable separation and storage method for SO2 using porous liquids is mentioned.


Assuntos
Simulação de Dinâmica Molecular , Compostos Policíclicos , Porosidade
3.
J Ethnopharmacol ; 326: 117996, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38431110

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis, the dried and ripe fruit of the magnolia family plant Schisandra chinensis (Turcz.) Baill, was commonly used in traditional analgesic prescription. Studies have shown that the extract of Schisandra chinensis (SC) displayed analgesic activity. However, the analgesic active component and the exact mechanisms have yet to be revealed. AIM OF THE STUDY: The present study was to investigate the anti-nociceptive constituent of Schisandra chinensis, assess its analgesic effect, and explore the potential molecular mechanisms. MATERIALS AND METHODS: The effects of a series of well-recognized compounds from SC on glycine receptors were investigated. The analgesic effect of the identified compound was evaluated in three pain models. Mechanistic studies were performed using patch clamp technique on various targets expressed in recombinant cells. These targets included glycine receptors, Nav1.7 sodium channels, Cav2.2 calcium channels et al. Meanwhile, primary cultured spinal dorsal horn (SDH) neurons and dorsal root ganglion (DRG) neurons were also utilized. RESULTS: Schisandrin B (SchB) was a positive allosteric modulator of glycine receptors in spinal dorsal horn neurons. The EC50 of SchB on glycine receptors in spinal dorsal horn neurons was 2.94 ± 0.28 µM. In three pain models, the analgesic effect of SchB was comparable to that of indomethacin at the same dose. Besides, SchB rescued PGE2-induced suppression of α3 GlyR activity and alleviated persistent pain. Notably, SchB could also potently decrease the frequency of action potentials and inhibit sodium and calcium channels in DRG neurons. Consistent with the data from DRG neurons, SchB was also found to significantly block Nav1.7 sodium channels and Cav2.2 channels in recombinant cells. CONCLUSION: Our results demonstrated that, Schisandrin B, the primary lignan component of Schisandra chinensis, may exert its analgesic effect by acting on multiple ion channels, including glycine receptors, Nav1.7 channels, and Cav2.2 channels.


Assuntos
Lignanas , Compostos Policíclicos , Schisandra , Receptores de Glicina , Lignanas/farmacologia , Dor , Canais de Cálcio Tipo N , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Canais de Sódio , Ciclo-Octanos
4.
Phytomedicine ; 126: 155372, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38382281

RESUMO

BACKGROUND: Renal fibrosis is a common pathway that drives the advancement of numerous kidney maladies towards end-stage kidney disease (ESKD). Suppressing renal fibrosis holds paramount clinical importance in forestalling or retarding the transition of chronic kidney diseases (CKD) to renal failure. Schisandrin A (Sch A) possesses renoprotective effect in acute kidney injury (AKI), but its effects on renal fibrosis and underlying mechanism(s) have not been studied. STUDY DESIGN: Serum biochemical analysis, histological staining, and expression levels of related proteins were used to assess the effect of PKCß knockdown on renal fibrosis progression. Untargeted metabolomics was used to assess the effect of PKCß knockdown on serum metabolites. Unilateral Ureteral Obstruction (UUO) model and TGF-ß induced HK-2 cells and NIH-3T3 cells were used to evaluate the effect of Schisandrin A (Sch A) on renal fibrosis. PKCß overexpressed NIH-3T3 cells were used to verify the possible mechanism of Sch A. RESULTS: PKCß was upregulated in the UUO model. Knockdown of PKCß mitigated the progression of renal fibrosis by ameliorating perturbations in serum metabolites and curbing oxidative stress. Sch A alleviated renal fibrosis by downregulating the expression of PKCß in kidney. Treatment with Sch A significantly attenuated the upregulated proteins levels of FN, COL-I, PKCß, Vimentin and α-SMA in UUO mice. Moreover, Sch A exhibited a beneficial impact on markers associated with oxidative stress, including MDA, SOD, and GSH-Px. Overexpression of PKCß was found to counteract the renoprotective efficacy of Sch A in vitro. CONCLUSION: Sch A alleviates renal fibrosis by inhibiting PKCß and attenuating oxidative stress.


Assuntos
Ciclo-Octanos , Nefropatias , Lignanas , Compostos Policíclicos , Obstrução Ureteral , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Nefropatias/tratamento farmacológico , Rim , Fibrose , Obstrução Ureteral/patologia , Estresse Oxidativo
5.
Cancer Med ; 13(2): e6942, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38376003

RESUMO

OBJECTIVE: The purpose of this study is to explore the biological mechanism of Schizandrin A (SchA) inducing non-small cell lung cancer (NSCLC) apoptosis. METHODS: The reverse molecular docking tool "Swiss Target Prediction" was used to predict the targets of SchA. Protein-protein interaction analysis was performed on potential targets using the String database. Functional enrichment analyses of potential targets were performed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The conformation of SchA binding to target was simulated by chemical-protein interactomics and molecular docking. The effect of SchA on the expression and phosphorylation level of EGFR was detected by Western blot. Lipofectamine 3000 and EGFR plasmids were used to overexpress EGFR. Apoptosis was tested with Annexin V-FITC and propidium iodide staining, and cell cycle was detected by propidium iodide staining. RESULTS: The "Swiss Target Prediction" database predicted 112 and 111 targets based on the 2D and 3D structures of SchA, respectively, of which kinases accounted for the most, accounting for 24%. Protein interaction network analyses showed that molecular targets such as ERBB family and SRC were at the center of the network. Functional enrichment analyses indicated that ERBB-related signaling pathways were enriched. Compound-protein interactomics and molecular docking revealed that SchA could bind to the ATP-active pocket of the EGFR tyrosine kinase domain. Laboratory results showed that SchA inhibited the phosphorylation of EGFR. Insulin could counteract the cytotoxic effect of SchA. EGFR overexpression and excess EGF or IGF-1 had limited impacts on the cytotoxicity of SchA. CONCLUSIONS: Network pharmacology analyses suggested that ERBB family members may be the targets of SchA. SchA can inhibit NSCLC at least in part by inhibiting EGFR phosphorylation, and activating the EGFR bypass can neutralize the cytotoxicity of SchA.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ciclo-Octanos , Lignanas , Neoplasias Pulmonares , Compostos Policíclicos , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Simulação de Acoplamento Molecular , Propídio/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Apoptose
6.
J Chromatogr A ; 1718: 464723, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38341899

RESUMO

The scientific literature is replete with analytical methods for the analysis of homocyclic aromatic compounds especially polycyclic aromatic hydrocarbons and their alkylated analogs. However, there is a paucity of methods for the analysis of nitrogen-, sulfur- and oxygen-containing polycyclic aromatic compounds (PACs). The lack of commercially available analytical standards, the presence of many structural derivatives and isomers and lack of certified reference materials all contribute to the inherent challenges in measuring these compounds. Gas chromatography coupled with a tandem mass spectrometer was used to develop two multiple reaction monitoring methods to detect and quantify fifty-three non-halogenated and halogenated hetero-polycyclic aromatic compounds (HPACs). Because of their greater polarity, strongly non-polar solvents typically employed to extract homocyclic PACs from sediment samples did not yield acceptable recoveries of our target analytes. By adding ethyl acetate to dichloromethane (50:50), recoveries of our target analytes using accelerated solvent extraction increased markedly. The performance characteristics of the validated method including accuracy [> than 67% for 46 (out of 53) analytes], inter- and intra-day precision [<30% for all analytes, (expressed as relative standard deviation)], limits of detection (0.1 to 2.3 ng/g) and quantitation (1.5 to 7.6 ng/g) imply that the method is fit for its intended purpose. A sediment sample from a known contaminated site in Canada was analyzed for both homo- and hetero-PACs. Measured concentrations of Σ27HPAC (7.3 µg/g, dry weight) were significantly smaller (p<0.05) than Σ16PAHs (80.9 µg/g, dry weight) and Σ30Alkylated-PAHs (14.2 µg/g, dry weight). These results suggest that the developed method is an effective and efficient approach for the targeted analysis of HPACs and their halogenated derivatives in sediment samples.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Compostos Policíclicos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Espectrometria de Massas , Hidrocarbonetos Policíclicos Aromáticos/análise , Cromatografia Gasosa
7.
Int J Mol Sci ; 25(4)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38396934

RESUMO

The quantitative structure-activity relationship (QSAR) is one of the most popular methods for the virtual screening of new drug leads and optimization. Herein, we collected a dataset of 955 MIC values of pleuromutilin derivatives to construct a 2D-QSAR model with an accuracy of 80% and a 3D-QSAR model with a non-cross-validated correlation coefficient (r2) of 0.9836 and a cross-validated correlation coefficient (q2) of 0.7986. Based on the obtained QSAR models, we designed and synthesized pleuromutilin compounds 1 and 2 with thiol-functionalized side chains. Compound 1 displayed the highest antimicrobial activity against both Staphylococcus aureus ATCC 29213 (S. aureus) and Methicillin-resistant Staphylococcus aureus (MRSA), with minimum inhibitory concentrations (MICs) < 0.0625 µg/mL. These experimental results confirmed that the 2D and 3D-QSAR models displayed a high accuracy of the prediction function for the discovery of lead compounds from pleuromutilin derivatives.


Assuntos
Diterpenos , Staphylococcus aureus Resistente à Meticilina , Compostos Policíclicos , Antibacterianos/química , Relação Quantitativa Estrutura-Atividade , Staphylococcus aureus , Diterpenos/química , Compostos Policíclicos/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular
8.
J Hazard Mater ; 467: 133646, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38330651

RESUMO

The exposure of terrestrial organisms to soils freshly contaminated by polycyclic aromatic compounds (PACs, including PAHs and polar-PACs) is known to cause significant toxicity effects. However, historically contaminated soils, such as former coking plant soils, usually induce a limited toxic impact, due to the "aging" phenomenon which is the result of several processes causing a reduction of PAC availability over time. For a better understanding of these behaviors, this study aimed to compare the toxic responses of terrestrial organisms exposed to aged contaminated soils and their counterparts submitted to a moderate heating process applied to increase PAC availability. Two aged "raw" soils (limited PAC availability) were selected for their representativeness of former industrial soils in terms of PAC contamination. These soils were submitted either to moderate heating (expected PAC availability increase) or solvent-extraction (expected PAC removal). Physico-chemical parameters, contamination levels and availability were determined for these three soil modalities. Additionally, standardized limit bioassays on plants and earthworms were performed to assess soil ecotoxicity. The findings demonstrated that historically contaminated soils exposed to moderate heating induced the highest ecotoxic responses from terrestrial organisms. Heating increased PAC (bio)availability, without modifying any other soil physico-chemical properties. These results pointed out the importance of considering the contamination availability parameter in risk evaluation and also provide a possible tool for protective long-term risk assessment.


Assuntos
Coque , Hidrocarbonetos Policíclicos Aromáticos , Compostos Policíclicos , Poluição Ambiental , Hidrocarbonetos Policíclicos Aromáticos/análise , Solo/química
9.
Int J Biol Macromol ; 262(Pt 1): 130257, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38423904

RESUMO

The genus Schisandra, a member of the Magnoliaceae family, is a well-known tonic traditional Chinese medicine with a long history of traditional medicinal and functional food used in China. Polysaccharides are one of its main active constituents, which have a wide range of bioactivities, such as anti-inflammatory, anti-tumor, neuroprotection, anti-diabetes, hepatoprotection, immunomodulation, and anti-fatigue. In this paper, we review the extraction, isolation, purification, structural characterization, bioactivities, as well as structure-activity relationship of polysaccharides from the genus Schisandra. In conclusion, we hope that this review could provide reference for the subsequent research on structural, bioactivities, development and application of the genus Schisandra polysaccharides.


Assuntos
Ciclo-Octanos , Lignanas , Compostos Policíclicos , Schisandra , Schisandra/química , Polissacarídeos/química , Extratos Vegetais/química , Antioxidantes
10.
Aquat Toxicol ; 269: 106863, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38422926

RESUMO

The potential for oil spills poses a threat to marine organisms, the toxicity of which has been attributed primarily to polycyclic aromatic compounds (PACs). Predictive tools such as the target lipid model (TLM) have been developed to forecast and assess these risks. The aim of the present study was to characterize the cardiotoxicity of 10 structurally diverse PACs in American lobster (Homarus americanus) larvae by assessing heart rate following a 48 h exposure in a passive dosing system, and subsequently use the TLM framework to calculate a critical target lipid body burden (CTLBB) for bradycardia. Exposure to 8 of the 10 PACs resulted in concentration-dependent bradycardia, with phenanthrene causing the greatest effect. The TLM was able to effectively characterize bradycardia in American lobsters, and the cardiotoxic CTLBB value determined in this study is among the most sensitive endpoints included in the CTLBB database. This study is one of the first to apply the TLM to a cardiac endpoint and will improve predictive models for assessing sublethal impacts of oil spills on American lobster populations.


Assuntos
Compostos Policíclicos , Poluentes Químicos da Água , Animais , Nephropidae , Bradicardia , Larva , Poluentes Químicos da Água/toxicidade , Lipídeos
11.
Chem Biol Interact ; 391: 110906, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38340974

RESUMO

Wuzhi capsule (WZC), a commonly used Chinese patent medicine to treat various types of liver dysfunction in China, increases the exposure of tacrolimus (TAC) in liver transplant recipients. However, this interaction has inter-individual variability, and the underlying mechanism remains unclear. Current research indicates that CYP3A4/5 and drug transporters influence the disposal of both drugs. This study aims to evaluate the association between TAC dose-adjusted trough concentration (C/D) and specific genetic polymorphisms of CYP3A4/5, drug transporters and pregnane x receptor (PXR), and plasma levels of major WZC components, deoxyschisandrin and γ-schisandrin, in liver transplant patients receiving both TAC and WZC. Liquid chromatography-tandem-mass spectrometry was used to detect the plasma levels of deoxyschisandrin and γ-schisandrin, and nine polymorphisms related to metabolic enzymes, transporters and PXR were genotyped by sequencing. A linear mixed model was utilized to assess the impact of the interaction between genetic variations and WZC components on TAC lnC/D. Our results indicate a significant association of TAC lnC/D with the plasma levels of deoxyschisandrin and γ-schisandrin. Univariate analysis demonstrated three polymorphisms in the genes ABCB1 (rs2032582), ABCC2 (rs2273697), ABCC2 (rs3740066), and PXR (rs3842689) interact with both deoxyschisandrin and γ-schisandrin, influencing the TAC lnC/D. In multiple regression model analysis, the interactions between deoxyschisandrin and both ABCB1 (rs2032582) and ABCC2 (rs3740066), post-operative day (ß < 0.001, p < 0.001), proton pump inhibitor use (ß = -0.152, p = 0.008), body mass index (ß = 0.057, p < 0.001), and ABCC2 (rs717620, ß = -0.563, p = 0.041), were identified as significant factors of TAC lnC/D, accounting for 47.89% of the inter-individual variation. In summary, this study elucidates the influence of the interaction between ABCB1 and ABCC2 polymorphisms with WZC on TAC lnC/D. These findings offer a scientific basis for their clinical interaction, potentially aiding in the individualized management of TAC therapy in liver transplant patients.


Assuntos
Ciclo-Octanos , Medicamentos de Ervas Chinesas , Transplante de Rim , Lignanas , Transplante de Fígado , Compostos Policíclicos , Humanos , Tacrolimo/uso terapêutico , Imunossupressores/uso terapêutico , Citocromo P-450 CYP3A/genética , Polimorfismo Genético , Genótipo , Proteína 2 Associada à Farmacorresistência Múltipla , Interações Medicamentosas , Polimorfismo de Nucleotídeo Único
12.
Environ Sci Pollut Res Int ; 31(11): 17472-17480, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38342836

RESUMO

China, one of the two dechlorane plus (DP) producers, might have become a major area of DP pollution. The environmental contamination status of DP in sediments across the whole of China has not yet been studied. In the current study, the pollution levels, spatial distribution, and compositions of DP were investigated comprehensively in surface sediments from 173 black-odorous urban rivers across China for the first time. Total DP concentrations varied from not-detected to 39.71 ng/g dw, with an average concentration of 3.20 ± 4.74 ng/g dw, which was polluted by local emission sources and presented significant differences among different sampling cities. Among the seven administrative regions of China, DP concentrations were the highest in South China and showed a decreasing trend from southeastern coastal areas to northwest inland regions. Spearman's correlation analysis suggested that the gross industrial output, gross domestic product, and daily wastewater treatment capacity were not the principal factors controlling the spatial distribution of DP. The fanti values (the concentration ratios of anti-DP to the sum of anti-DP and syn-DP) varied from 0.19 to 0.88, with those in most sediments falling in the range of DP technical product (0.60 ~ 0.80), suggesting no apparent stereoselective enrichment occurred. Moreover, the anti-Cl11-DP was detected in sediments (n.d. ~ 0.40 ng/g dw), which showed significantly and insignificantly positive correlation with the anti-DP levels and fanti, respectively, implying it might mainly originate from the byproduct of DP technical product rather than the dechlorination of anti-DP.


Assuntos
Retardadores de Chama , Hidrocarbonetos Clorados , Compostos Policíclicos , Poluentes Químicos da Água , Sedimentos Geológicos , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Retardadores de Chama/análise , Hidrocarbonetos Clorados/análise , Compostos Policíclicos/análise , Rios , China
13.
J Med Chem ; 67(5): 3692-3710, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38385364

RESUMO

Herein, we report the hit-to-lead identification of a drug-like pleuromutilin conjugate 16, based on a triaromatic hit reported in 2020. The lead arose as the clear candidate from a hit-optimization campaign in which Gram-positive antibacterial activity, solubility, and P-gp affinity were optimized. Conjugate 16 was extensively evaluated for its in vitro ADMET performance which, apart from solubility, was overall on par with lefamulin. This evaluation included Caco-2 cell permeability, plasma protein binding, hERG inhibition, cytotoxicity, metabolism in microsomes and CYP3A4, resistance induction, and time-kill kinetics. Intravenous pharmacokinetics of 16 proved satisfactory in both mice and pigs; however, oral bioavailability was limited likely due to insufficient solubility. The in vivo efficacy was evaluated in mice, systemically infected with Staphylococcus aureus, where 16 showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead 16 has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections.


Assuntos
Diterpenos , Compostos Policíclicos , Infecções Estafilocócicas , Humanos , Animais , Camundongos , Suínos , Antibacterianos/uso terapêutico , Antibacterianos/farmacocinética , Células CACO-2 , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Disponibilidade Biológica , Compostos Policíclicos/farmacologia , Testes de Sensibilidade Microbiana
14.
Chemosphere ; 352: 141240, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38266881

RESUMO

Creosote has been used in Sweden as a wood preservative in buildings since the 19th century. These buildings can function as workplaces, homes, and cultural buildings to which the public has access. Creosote contains polycyclic aromatic hydrocarbons (PAH) which are well known carcinogens. To understand exposure and risks in an indoor environment, it is important to determine air levels of parent PAHs as well as the more toxic nitrated and oxygenated PAH derivatives (NPAH, OPAH). This study aims to investigate indoor air levels of polycyclic aromatic compounds (PACs) e.g., PAH, NPAH, OPAH and dibenzothiophenes in buildings containing creosote sources and whether these levels pose a health risk. Four cultural buildings were studied, all located within a radius of 130 m. Two were known to have creosote sources, and two had not. Polyurethane foam passive air samplers (PUF-PAS) were used to indicate possible point sources. PUF-PAS measurements were performed for one month in each building winter and summer. Simultaneously, PAC outdoor level measurements were performed. Buildings with creosote impregnated constructions had notably higher indoor air levels of PAC (31-1200 ng m-3) compared to the two buildings without creosote sources (14-45 ng m-3). The PAH cancer potency (sum of benzo[a]pyrene equivalents (BaPeq)) was more than one order of magnitude higher in the buildings containing creosote impregnated wood compared to reference buildings. The highest value was 5.1 BaPeq ng m-3 which was significantly higher than the outdoor winter measurement (1.3 BaPeq ng m-3). Fluoranthene and phenanthrene, with significant distribution in gas phase, but also several particulate NPAHs contributed significantly to the total cancer risk. Thus, creosote containing buildings can still contaminate the indoor air with PACs despite being over a hundred years old. The PUF-PAS was shown to be a good tool providing quantitative/semiquantitative measures of PACs exposure in indoor microenvironments.


Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Neoplasias , Hidrocarbonetos Policíclicos Aromáticos , Compostos Policíclicos , Humanos , Monitoramento Ambiental , Poluentes Atmosféricos/análise , Creosoto , Poluição do Ar em Ambientes Fechados/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Microambiente Tumoral
15.
Artigo em Inglês | MEDLINE | ID: mdl-38262768

RESUMO

The platensimycin (PTM), platencin (PTN), and platensilin (PTL) family of natural products continues to inspire the discovery of new chemistry, enzymology, and medicine. Engineered production of this emerging family of natural products, however, remains laborious due to the lack of practical systems to manipulate their biosynthesis in the native-producing Streptomyces platensis species. Here we report solving this technology gap by implementing a CRISPR-Cas9 system in S. platensis CB00739 to develop an expedient method to manipulate the PTM, PTN, and PTL biosynthetic machinery in vivo. We showcase the utility of this technology by constructing designer recombinant strains S. platensis SB12051, SB12052, and SB12053, which, upon fermentation in the optimized PTM-MS medium, produced PTM, PTN, and PTL with the highest titers at 836 mg L-1, 791 mg L-1, and 40 mg L-1, respectively. Comparative analysis of these resultant recombinant strains also revealed distinct chemistries, catalyzed by PtmT1 and PtmT3, two diterpene synthases that nature has evolved for PTM, PTN, and PTL biosynthesis. The ΔptmR1/ΔptmT1/ΔptmT3 triple mutant strain S. platensis SB12054 could be envisaged as a platform strain to engineer diterpenoid biosynthesis by introducing varying ent-copalyl diphosphate-acting diterpene synthases, taking advantage of its clean metabolite background, ability to support diterpene biosynthesis in high titers, and the promiscuous tailoring biosynthetic machinery. ONE-SENTENCE SUMMARY: Implementation of a CRISPR-Cas9 system in Streptomyces platensis CB00739 enabled the construction of a suite of designer recombinant strains for the overproduction of platensimycin, platencin, and platensilin, discovery of new diterpene synthase chemistries, and development of platform strains for future diterpenoid biosynthesis engineering.


Assuntos
Adamantano , Aminobenzoatos , Aminofenóis , Anilidas , Produtos Biológicos , Diterpenos , Compostos Policíclicos , Streptomyces , Fermentação , Vias Biossintéticas , Diterpenos/metabolismo
16.
Chemosphere ; 351: 141257, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38244871

RESUMO

Airborne polycyclic aromatic hydrocarbons (PAHs) and their derivatives are of particular concern for population health due to their abundance and toxicity via inhalation. Lung toxicity testing includes exposing lung epithelial cell lines to PAHs in a culture medium containing inorganic species, lipids, proteins, and other biochemicals where the cell response is influenced among others by the toxic chemical accessibility in the medium. While inhalation bioaccessibility of PAHs and other toxicants was previously studied in surrogate lung fluids, studies measuring bioaccessibility in cell culture media are rare. In this work, a method was developed to characterize PAH bioaccessibility in a culture medium used for mouse lung epithelial (FE1) cells. Further, the optimised method was tested using commercially available standard reference material of urban particulate matter (PM) as well as polyurethane foam passive air samplers (PUF-PAS). The method provided a high precision and recovery of analytes, indicating no losses during sample processing and analysis. PAHs had non-linear concentration-responses, with the culture medium approaching saturation with PM concentration of 500 µg mL-1. The results showed that phenanthrene, a 3-ring PAH, was significantly more bioaccessible than ≥4-ring congeners in the culture medium (up to ∼2.5 folds; p < 0.05). Finally, using pre-deployed PUF-PAS from a residential and an industrial site, five PAHs were found in the culture medium, including naphthalene, phenanthrene, anthracene, fluoranthene, and pyrene. This work provides a proof of concept to enable future studies to assess the inhalation bioaccessibility of polycyclic aromatic compounds and other airborne pollutants collected using PUF-PAS.


Assuntos
Poluentes Atmosféricos , Fenantrenos , Hidrocarbonetos Policíclicos Aromáticos , Compostos Policíclicos , Animais , Camundongos , Hidrocarbonetos Policíclicos Aromáticos/análise , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Material Particulado/toxicidade , Material Particulado/análise , Fenantrenos/análise , Compostos Policíclicos/análise , Técnicas de Cultura de Células , Monitoramento Ambiental/métodos
17.
Clin Ther ; 46(2): 96-103, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38195348

RESUMO

PURPOSE: Methicillin-resistant Staphylococcus aureus infections are increasing in prevalence in patients with cystic fibrosis (CF) and are associated with worsening lung function and increased mortality. Lefamulin is a pleuromutilin antimicrobial approved to treat community-acquired bacterial pneumonia based on potent in vitro activity and clinical efficacy. This Phase I, open-label, randomized crossover study assessed the safety and pharmacokinetic profile of oral and intravenous (IV) lefamulin in adults with CF. METHODS: The study comprised 2 dosing periods in which adults with CF (N = 13) received a single dose of lefamulin via a 150-mg IV infusion or 600-mg immediate-release orally administered tablet, separated by a 4- to 7-day washout period. Pharmacokinetic and safety parameters were assessed after lefamulin treatment. FINDINGS: Single doses of lefamulin administered via oral tablet or IV infusion resulted in comparable drug exposure, and sputum analysis suggested rapid penetration of lefamulin into the lung. Comparison of the present results with those obtained from prior single-dose studies of healthy volunteers indicate no meaningful difference in the pharmacokinetic properties of lefamulin in patients with CF. Treatment-emergent adverse events were consistent with previous reports, and the majority were mild in severity. IMPLICATIONS: These results show similar lefamulin pharmacokinetic and safety profiles between patients with CF and healthy volunteers receiving the same oral and IV doses, suggesting no need for lefamulin dose adjustment in patients with CF and indicating the potential of lefamulin as therapy for lung infections in patients with CF. CLINICALTRIALS: gov identifier: NCT05225805.


Assuntos
Fibrose Cística , Diterpenos , Staphylococcus aureus Resistente à Meticilina , Pneumonia , Compostos Policíclicos , Tioglicolatos , Adulto , Humanos , Antibacterianos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/induzido quimicamente , Estudos Cross-Over , Pneumonia/tratamento farmacológico , Comprimidos/farmacocinética
18.
J Mater Chem B ; 12(4): 1043-1051, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38214029

RESUMO

Coronene diimide functionalized with 4-(2-nitrovinyl)phenyl (CDI 2) serves as a precursor for generating a stable radical anion (CDI 2˙-) using H2S as a reductant in 40% H2O-THF solution in the NIR region with stability up to >50 min. The optical, cyclic voltammetry (CV), current-voltage (I-V) and electron paramagnetic resonance (EPR) studies revealed the formation of the radical anion (CDI 2˙-). The addition of a strong oxidant NOBF4 quenches the radical anion (CDI 2˙-). The aggregation studies revealed that CDI 2 exists in the aggregated state in 40% H2O-THF solution, which points to the possibility of stabilization of the radical anion in the aggregates. The radical anion (CDI 2˙-) was explored for the detection of 58.27 pM H2O2 in aqueous medium with the naked eye colour change from green to light yellow. The biochemical assay involving the radical anion (CDI 2˙-) and glucose oxidase (GOx) enzyme can be used for the detection of 16 pM (UV-vis method) and 82.4 pM (fluorescence method) glucose. The naked eye colour change from green to light yellow (daylight) and a colorless non-fluorescent solution to a green fluorescent solution (365 nm) allow the detection of 1 nM glucose.


Assuntos
Glucose , Peróxido de Hidrogênio , Compostos Policíclicos , Ânions , Espectroscopia de Ressonância de Spin Eletrônica
19.
Org Biomol Chem ; 22(5): 1038-1046, 2024 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-38197499

RESUMO

This paper describes a simple and practical protocol for the direct synthesis of acyclic and cyclic quinone derivatives via an acid-promoted nickel(II)-catalyzed inner rim C-H oxidation of cyclotriveratrylene (CTV) and its analogues. The cyclic quinone derivatives resulted from trimethoxy-cyclotriveratrylene (TCTV) through C-C bond formation via intramolecular ipso substitution followed by subsequent anionic rearrangement containing stereo-vicinal quaternary centers. The DFT calculations strongly support the experimental findings and reveal the role of Brønsted acids in the C-H bond activation of CTV. All the newly synthesized compounds were screened for their in vitro anti-cancer activity using colorimetric SRB assay analysis. Among them, compounds 3a, 3d, 3h, 4a, 4b, 4c and 4e exhibited moderate anticancer activity against A549, HCT-116, PC-3, MDA-MB-231, HEK-293 and SW620 human cancer cell lines.


Assuntos
Antineoplásicos , Compostos Policíclicos , Humanos , Quinonas/farmacologia , Células HEK293 , Antineoplásicos/química , Catálise
20.
ACS Chem Neurosci ; 15(3): 593-607, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38214579

RESUMO

Objective: Schisandrin B (Sch B) is a bioactive dibenzocyclooctadiene derizative that is prevalent in the fruit of Schisandra chinensis. Numerous studies have demonstrated that Sch B has a neuroprotective action by reducing oxidative stress and effectively preventing inflammation. It follows that Sch B is a potential treatment for Alzheimer's disease (AD). However, the drug's solubility, bioavailability, and lower permeability of the blood-brain barrier (BBB) can all reduce its efficacy during the therapy process. Therefore, this study constructed borneol-modified schisandrin B micelles (Bor-Sch B-Ms), which increase brain targeting by accurately delivering medications to the brain, effectively improving bioavailability. High therapeutic efficacy has been achieved at the pathological site. Methods: Bor-Sch B-Ms were prepared using the thin film dispersion approach in this article. On the one hand, to observe the targeting effect of borneol, we constructed a blood-brain barrier (BBB) model in vitro and studied the ability of micelles to cross the BBB. On the other hand, the distribution of micelle drugs and their related pharmacological effects on neuroinflammation, oxidative stress, and neuronal damage were studied through in vivo administration in mice. Results: In vitro studies have demonstrated that the drug uptake of bEnd.3 cells was increased by the borneol alteration on the surface of the nano micelles, implying that Bor-Sch B-Ms can promote the therapeutic effect of N2a cells. This could result in more medicines entering the BBB. In addition, in vivo studies revealed that the distribution and circulation time of medications in the brain tissue were significantly higher than those in other groups, making it more suitable for the treatment of central nervous system diseases. Conclusion: As a novel nanodrug delivery system, borneol modified schisandrin B micelles have promising research prospects in the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Canfanos , Lignanas , Compostos Policíclicos , Camundongos , Animais , Micelas , Doença de Alzheimer/tratamento farmacológico , Células Endoteliais , Ciclo-Octanos
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