RESUMEN
OBJECTIVES: To investigate the toxicokinetic differences of 3,4-methylenedioxy-N-methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after single and continuous administration of MDMA, providing reference data for the forensic identification of MDMA. METHODS: A total of 24 rats in the single administration group were randomly divided into 5, 10 and 20 mg/kg experimental groups and the control group, with 6 rats in each group. The experimental group was given intraperitoneal injection of MDMA, and the control group was given intraperitoneal injection of the same volume of normal saline as the experimental group. The amount of 0.5 mL blood was collected from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. In the continuous administration group, 24 rats were randomly divided into the experimental group (18 rats) and the control group (6 rats). The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5, 7, 9, 11, 13, 15, 17 mg/kg per day, respectively, while the control group was given the same volume of normal saline as the experimental group by intraperitoneal injection. On the eighth day, the experimental rats were randomly divided into 5, 10 and 20 mg/kg dose groups, with 6 rats in each group. MDMA was injected intraperitoneally, and the control group was injected intraperitoneally with the same volume of normal saline as the experimental group. On the eighth day, 0.5 mL of blood was taken from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels, and statistical software was employed for data analysis. RESULTS: In the single-administration group, peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration, respectively, with the largest detection time limit of 12 h. In the continuous administration group, peak concentrations were reached at 30 min and 1.5 h after administration, respectively, with the largest detection time limit of 10 h. Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows: T=10.362C-1.183, R2=0.974 6; T=7.397 3C-0.694, R2=0.961 5 (T: injection time; C: concentration ratio of MDMA to MDA in plasma). CONCLUSIONS: The toxicokinetic data of MDMA and its metabolite MDA in rats, obtained through single and continuous administration, including peak concentration, peak time, detection time limit, and the relationship between concentration ratio and administration time, provide a theoretical and data foundation for relevant forensic identification.
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3,4-Metilenodioxianfetamina , Anfetaminas , N-Metil-3,4-metilenodioxianfetamina , Ratas , Animales , Anfetamina , N-Metil-3,4-metilenodioxianfetamina/toxicidad , 3,4-Metilenodioxianfetamina/análisis , Toxicocinética , Solución SalinaRESUMEN
Recently we published in this journal an enantioselective high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitative determination of 3,4-methylenedioxymethamphetamine (MDMA) and its major phase-1 metabolites, 4-hydroxy-3-methoxyamphetamine (HMA), 4-hydroxy-3-methoxymethamphetamine (HMMA) and 3,4-methylenedioxyamphetamine (MDA) in human plasma, sweat, oral fluid and urine. Since we did not achieve simultaneous enantioseparation of all 4 compounds with a single chiral column, two amylose-based chiral columns were used alternatively. Further optimization of the mobile phase in the present study enabled baseline separation of all four pairs of enantiomers on a single Lux AMP column. In addition, by optimization of the column dimension and applied flow-rate it became possible to complete the separation within 6â¯minutes. These new methods were applied to the analysis of human plasma, oral fluid and urine. While results on the concentration of MDMA and its metabolites in various biological fluids were reported in our recent publication, in the present study an attempt was made to hydrolyze glucuronides in urine samples by using alternatively, hydrochloric acid or glucuronidase and to evaluate the effect of hydrolysis on the concentration and enantiomeric distribution of hydroxy metabolites of MDMA such as HMA and HMMA.
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3,4-Metilenodioxianfetamina , Lactatos , Metanfetamina , N-Metil-3,4-metilenodioxianfetamina , Humanos , N-Metil-3,4-metilenodioxianfetamina/orina , Cromatografía Líquida de Alta Presión , Espectrometría de Masas en Tándem , Cromatografía Liquida , Estereoisomerismo , 3,4-Metilenodioxianfetamina/orinaRESUMEN
On 7 October 2023, Israel faced an unexpected attack by Hamas, causing over 1,200 deaths and injuring more than 9,000 individuals. This report delves into the rapid medical response spearheaded by Israel's civilian Emergency Medical Service, Magen David Adom (MDA), during this crisis. Utilizing data from MDA's electronic database, 4,097 dispatch records from the day were analyzed. Of these, 39.3% were directly related to the attack. EMS teams faced multiple challenges, including handling an overwhelming number of casualties and navigating active combat zones, which impeded safe access to victims, posed significant risks to teams' safety, and constrained patient evacuation strategies. This incident underscores the importance of reinforcing healthcare resilience, particularly emphasizing the need for centralizing various aspects of response efforts. These include streamlined communication, national coordination of pre-hospital resources, and systemic management of patient evacuations. Moreover, providing substantial support for EMS personnel, who operated in highly challenging conditions, is imperative.
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3,4-Metilenodioxianfetamina , Servicios Médicos de Urgencia , Incidentes con Víctimas en Masa , Humanos , Israel , Atención a la SaludRESUMEN
Amphetamine-type stimulants are the third most widely consumed category of illicit drugs worldwide. Faced with the growing problem of amphetamine-type stimulants, numerous qualitative and quantitative techniques have been developed to detect amphetamine (AMP), methamphetamine (MET), MDMA, MDEA or MDA in biological matrices, including hair. Hair analysis is widely used in forensic medicine, but one of its main drawbacks remains external contamination. In this study, we investigated the possibility of hair contamination through external exposure to blood containing AMP, MET MDMA, MDEA or MDA at 2 ng/mL; 20 ng/mL; 200 ng/mL or 2000 ng/mL after 6 h, 1, 3, 7 or 14 days of contact protected from light at room temperature (RT or 20 °C) or at 4 °C. Dried extracts of hair samples were analyzed by UPLC-MS/MS after extensive washings in several baths of water, methanol and acetone before grounding. At the end of our study, contamination of hair was observed from 6 h of contact with all tested amphetamine-type stimulants. The concentrations found in hair ranged from 3 ± 1 to 1464 ± 10 pg/mg, 5 ± 1 to 5070 ± 160 pg/mg, 3 ± 1 to 1269 ± 60 pg/mg, 4 ± 1 to 1860 ± 113 pg/mg and from 8 ± 1 to 1041 ± 44 pg/mg for AMP, MET, MDMA, MDEA and MDA, respectively. Possibly due to its low polar surface area, MET was the most prone to contaminate. As anticipated, hair contamination was mainly dependent on the concentration of all molecules in the contaminating blood, reaching the SOHT cut-off of 200 pg/mg when amphetamine-type stimulants are at toxic or lethal concentrations in the blood. These observations call for caution in interpreting exposure to these substances in such forensic situations.
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3,4-Metilenodioxianfetamina/análogos & derivados , Estimulantes del Sistema Nervioso Central , Metanfetamina , N-Metil-3,4-metilenodioxianfetamina , Anfetaminas/análisis , Cromatografía Liquida , Espectrometría de Masas en Tándem , Detección de Abuso de Sustancias/métodos , Estimulantes del Sistema Nervioso Central/análisis , Cabello/químicaRESUMEN
Biomethanation of carbon dioxide (CO2) from flue gas is a potential enabler of the green transition, particularly when integrated with the power-to-gas chain. However, challenges arise in achieving synthetic natural gas quality when utilizing CO2 from diluted carbon sources, and the high costs of CO2 separation using amine-based solutions make large-scale implementation unfeasible. We propose an innovative continuous biomethanation system that integrates carbon capture and CO2 stripping through microbial utilization, eliminating expenses with the stripper. Stable continuous biomethane production (83-92 % methane purity) was achieved from flue gas-CO2 using a biocompatible aqueous n-methyldiethanolamine (MDEA) solution (50 mmol/L) under mesophilic and hydrogen-limiting conditions. MDEA was found to be recalcitrant to biodegradation and could be reused after regeneration. Demonstrating the microbial ability to simultaneously strip and convert the captured CO2 and regenerate MDEA provides a new pathway for valorization of flue gas CO2.
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3,4-Metilenodioxianfetamina/análogos & derivados , Dióxido de Carbono , Gas Natural , Dióxido de Carbono/metabolismo , EtanolaminasRESUMEN
PURPOSE: Several epidemiological studies have linked lead (Pb) exposure to induced oxidative stress and the promotion of inflammatory response. We performed a within-subjects study (repeated measures study) to evaluate the relationship between the concentration of blood lead (B-Pb) and toenail lead (T-Pb) and circulating markers of inflammation. METHODS: We evaluated the associations between B-Pb concentrations and T-Pb concentrations and circulating markers of inflammation, soluble intracellular adhesion molecule-1 (s-ICAM-1), soluble vascular adhesion molecule-1 (s-VCAM-1), and high-sensitivity C-reactive protein (hs-CRP) on 158 traffic enforcers from the Metropolitan Manila Development Authority (MMDA) traffic enforcer's health study. Linear mixed-effects models with random subject-specific intercepts were fitted to estimate the association between B-Pb and T-Pb exposure and circulating markers of inflammation, adjusting for confounding factors. RESULTS: Traffic enforcers were middle-aged men (89.4%) with a mean age (± SD) of 37.1 years ± 8.9 years and had a total of 293 valid markers of inflammation measurements. B-Pb concentration was related to increased hs-CRP levels. A 10% increase in B-Pb was associated with a 5.7% increase in hs-CRP level [95% confidence interval (95% CI): 1.3-10.1]. However, B-Pb was not associated with s-ICAM-1 and s-VCAM-1. Furthermore, no associations were observed between T-Pb and all the circulating markers of inflammation. CONCLUSIONS: Low-level B-Pb may increase hs-CRP among traffic enforcers. Moreover, the study suggests that Pb via the oxidative and inflammation pathways may have an essential role in the development of cardiovascular disease. Furthermore, MMDA and the Department of Labor and Employment can use our study's findings as evidence to conduct routine screening of blood heavy metals, especially Pb, among MMDA and other traffic enforcers as part of their yearly medical examination.
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3,4-Metilenodioxianfetamina/análogos & derivados , Proteína C-Reactiva , Plomo , Masculino , Persona de Mediana Edad , Humanos , Adulto , Proteína C-Reactiva/análisis , Filipinas/epidemiología , Molécula 1 de Adhesión Celular Vascular , Molécula 1 de Adhesión Intercelular , Inflamación/epidemiología , BiomarcadoresRESUMEN
Infectious bursal disease (IBD) is a viral disease that affects the ability of chickens to produce humoral immune responses. One way to prevent the disease is the passage of maternally derived antibodies (MDA) from dams to offsprings via the yolk. Despite sanitary measures, which include immunization with genogroup 1 (G1) vaccines, infections with IBDV genogroup 4 (G4) in young animals have been detected. The aim of this study was to determine whether a local IBDV isolate belonging to G4 could evade the immunity generated by MDAs. Twelve-day-old animals positive for MDA, were inoculated with G1 or G4 isolates or phosphate buffered saline (PBS) as a control. After 1 wk, the animals were sacrificed and the following parameters were evaluated: bursa-body (BB) ratio, viral load, and histologic damage in the bursa of Fabricius. Results showed that G4-infected animals had significant differences in the BB ratio compared to the PBS group. In addition, viral load was significantly higher in the G4 group than in the G1 group. Histologic damage in the bursa of Fabricius was detected only in G4-infected MDA chickens. Our results suggest that infection with G4 local isolate can circumvent the immunity generated by MDA and, furthermore, that G4 isolate does not differ in its pathogenicity from G1 isolate, which underlines the need to include variant strains in vaccine formulations to reduce potential losses caused by these viruses.
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3,4-Metilenodioxianfetamina , Virus de la Enfermedad Infecciosa de la Bolsa , Animales , Pollos , Anticuerpos , Inmunización/veterinariaRESUMEN
Zearalenone (ZEA) has adverse effects on human and animal health, and finding effective strategies to combat its toxicity is essential. The probiotic Bacillus velezensis A2 shows various beneficial physiological functions, including the potential to combat fungal toxins. However, the detailed mechanism by which the Bacillus velezensis A2 strain achieves this protective effect is not yet fully revealed. This experiment was based on transcriptome data to study the protective mechanism of Bacillus velezensis A2 against ZEA-induced damage to IPEC-J2 cells. The experiment was divided into CON, A2, ZEA, and A2+ZEA groups. This research used an oxidation kit to measure oxidative damage indicators, the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) method to detect cell apoptosis, flow cytometry to determine the cell cycle, and transcriptome sequencing to screen and identify differentially expressed genes. In addition, gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were adopted to screen out relevant signaling pathways. Finally, to determine whether A2 can alleviate the damage caused by ZEA to cells, the genes and proteins involved in inflammation, cell apoptosis, cell cycles, and related pathways were validated using a quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot methods. Compared with the CON group, the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in the ZEA group increased significantly (p < 0.01), while the levels of antioxidant enzyme activity, total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-PX), total antioxidant capacity (T-AOC), and catalase (CAT) decreased significantly (p < 0.01). Compared with the ZEA group, the A2+ZEA group showed a significant decrease in ROS and MDA levels (p < 0.01), while the levels of T-SOD, GSH-PX, T-AOC, and CAT increased significantly (p < 0.01). TUNEL and cell cycle results indicated that compared with the ZEA group, the A2+ZEA group demonstrated a significant decrease in the cell apoptosis rate (p < 0.01), and the cell cycle was restored. Combining transcriptome data, qRT-PCR, and Western blot, the results showed that compared with the CON group, the mRNA and protein expression levels of Wnt10 and ß-catenin increased significantly (p < 0.01), while the expression level of FRZB decreased significantly (p < 0.01); compared with the ZEA group, the expression levels of these mRNA and proteins were reversed. Bacillus velezensis A2 can increase the antioxidant level, reduce inflammatory damage, decrease cell apoptosis, and correct the cell cycle when that damage is being caused by ZEA. The protective mechanism may be related to the regulation of the Wnt/FRZB cell/ß-catenin signaling pathway.
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3,4-Metilenodioxianfetamina , Bacillus , Zearalenona , Animales , Humanos , Zearalenona/toxicidad , Antioxidantes , Especies Reactivas de Oxígeno , beta Catenina , Vía de Señalización Wnt , Anticuerpos , ARN Mensajero , Superóxido DismutasaRESUMEN
Disulfiram (DSF) is used to treat nonsmall cell lung cancer (NSCLC). DSF significantly increases expression of programmed deathligand 1 (PDL1), which may enhance immunosuppression and immune escape of tumors. Therefore, the present study aimed to investigate the role of combined treatment of DSF and antiPDL1 in NSCLC resistance. The viability and apoptosis of A549 cells were detected by the Cell Counting Kit8 assay and flow cytometry, respectively. The expression levels of ATPase coppertransporting ß (ATP7B) and PDL1 in A549 cells were detected by reverse transcriptionquantitative PCR and western blot analysis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) in A549 cells were detected by respective assay kits. The expression levels of cuproptosisassociated proteins ferredoxin1 (FDX1), ATP7B, solute carrier family 31 member 1 (SLC31A1), succinate dehydrogenase B (SDHB), PDL1 and hypoxia inducible factor (HIF)1A were analyzed by western blotting in A549 cells. DSF inhibited the viability of A549 cells and promoted expression levels of ATP7B and PDL1 at both mRNA and protein levels in A549 cells. The viability of cisplatin (DPP)treated A549 cells was increased following DSF treatment. JQ1 (a PDL1 inhibitor) suppressed the viability of DPPtreated A549 cells pretreated with DSF. DSF increased expression levels of ATP7B and PDL1. The combination treatment of DSF and JQ1 in A549 cells increased levels of ROS and MDA, as well as expression levels of FDX1 and SLC31A1; however, combination treatment decreased levels of SOD, as well as expression levels of ATP7B, SDHB, PDL1, and HIF1A. PX478 (an HIF1 inhibitor) acted with DSF to enhance the inhibitory effects on the viability and on the induction of apoptosis of A549 cells. PX478 upregulated the levels of ROS and MDA, while it downregulated levels of SOD in DSFtreated A549 cells. PX478 promoted expression levels of FDX1 and SLC31A1, while it suppressed expression levels of ATP7B, PDL1, and HIF1A in DSFtreated A549 cells. In conclusion, the combined treatment of A549 cells with antiPDL1 and DSF enhanced the effect of cuproptosis on the inhibition of NSCLC cell viability.
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3,4-Metilenodioxianfetamina , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Disulfiram/farmacología , Especies Reactivas de Oxígeno , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Transducción de Señal , Superóxido DismutasaRESUMEN
A new class of synthetic cannabinoids called OXIZIDs has emerged in recent years. This class consists of compounds with oxindole cores and hydrazide/hydrazone linker moieties and has often been described as being designed to circumvent a Chinese class-wide ban that was effective as of 1 July 2021. However, through hair testing of nightclub attendees in New York City-a high-risk population for recreational drug use-we have evidence suggesting exposures to an OXIZID called BZO-4en-POXIZID (4en-pentyl MDA-19) prior to the effective ban. Through analysis of 6 cm segmented hair samples from attendees collected in 2021, we detected five cases of exposure. Specifically, we detected a cluster of three cases based on hair samples collected on 20 June 2021, and then two additional cases from samples collected on 16 July 2021. Four of these hair samples were long enough to analyze two 6 cm hair segments (representing approximately two 6-month timeframes) and three of four of these cases tested positive for repeated exposure (for an estimated exposure over 6 months prior to hair collection). All cases included young adult females reporting past-year cannabis use but all tested negative for tetrahydrocannabinol exposure. Three cases also reported past-year use of cocaine, ecstasy, and/or ketamine, and four cases tested positive for exposure to cocaine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), methamphetamine and/or eutylone. These subjects were exposed to BZO-4en-POXIZID-likely as an adulterant in other drugs, and these cases are among the first documented cases which occurred approximately half a year before the Chinese legislative ban.
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3,4-Metilenodioxianfetamina , Cocaína , Drogas Ilícitas , Metanfetamina , N-Metil-3,4-metilenodioxianfetamina , Femenino , Adulto Joven , Humanos , Ciudad de Nueva York/epidemiología , Drogas Ilícitas/análisis , N-Metil-3,4-metilenodioxianfetamina/análisis , Metanfetamina/análisis , 3,4-Metilenodioxianfetamina/análisis , Cocaína/análisisRESUMEN
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common type of non-small cell lung cancer, and any change of miRNAs expression will affect the degree of target regulation, thus affecting intracellular homeostasis. This study verified that miR-186-5p could inhibit the proliferation, migration and invasion of LUAD cells by regulating PRKAA2. METHODS: Previous investigations found that the expression of miR-186-5p was markedly suppressed in LUAD. Bioinformatics method is used to predict the target protein related to ferroptosis downstream and inquire about its expression level in LUAD and its influence on the survival of patients. Double luciferase verified the binding site of PRKAA2 and miR-186-5p. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression of PRKAA2. The effects of miR-186-5p of LUAD cells as well as the mechanism by which miR-186-5p inhibits Fer-1's sensitivity to ferroptosis were confirmed by EdU, Transwell, and scratch assays. The effect of miR-186-5p on the amount of reactive oxygen species (ROS) in LUAD cells was discovered using ROS experiment. Malondialdehyde (MDA) and glutathione (GSH) experiments were used to detect the effects of miR-186-5p and PRKAA2 on ferroptosis index of LUAD cells. The concentration of lipid ROS (L-ROS) in LUAD cells were measured using the L-ROS tests to determine the effects of miR-186-5p and PRKAA2. RESULTS: The expression of PRKAA2 is up-regulated, and a high level of PRKAA2 expression was associated with a poor prognosis for patients with LUAD. Overexpression of miR-186-5p decreased the gene and protein expression of PRKAA2. By promoting ferroptosis, miR-186-5p overexpression prevented lung cancer cells from proliferating, invading, and migrating. ROS could be produced in higher amounts in LUAD cells due to miR-186-5p. Overexpression of miR-186-5p and knockdown PRKAA2 up-regulated MDA content and reduced GSH content in LUAD cells, respectively. miR-186-5p could increase the content of L-ROS and promote the ferroptosis sensitivity of LUAD cells by targeting PRKAA2. CONCLUSIONS: miR-186-5p promotes ferroptosis of LUAD cells through targeted regulation of PRKAA2, thus inhibiting the proliferation, invasion and migration of LUAD.â©.
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3,4-Metilenodioxianfetamina , Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Ferroptosis , Neoplasias Pulmonares , MicroARNs , Humanos , Neoplasias Pulmonares/genética , Ferroptosis/genética , Especies Reactivas de Oxígeno , Adenocarcinoma del Pulmón/genética , MicroARNs/genética , Proliferación Celular/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Proteínas Quinasas Activadas por AMPRESUMEN
Diabetic retinopathy (DR) is a leading cause of vision impairment in the working-age population worldwide. Various modes of photoreceptor cell death contribute to the development of DR, including apoptosis and autophagy. However, whether ferroptosis is involved in the pathogenesis of photoreceptor degeneration in DR is still unclear. High-glucose (HG)-stimulated 661W cells and diabetic mice models were used for in vitro and in vivo experiments, respectively. The levels of intracellular iron, glutathione (GSH), reactive oxygen species (ROS), lipid peroxidation (MDA), and ferroptosis-related proteins (GPX4, SLC7A11, ACSL4, FTH1, and NCOA4) were quantified to indicate ferroptosis. The effect of ferroptosis inhibition was also assessed. Our data showed the levels of iron, ROS, and MDA were enhanced and GSH concentration was reduced in HG-induced 661W cells and diabetic retinas. The expression of GPX4 and SLC7A11 was downregulated, while the expression of ACSL4, FTH1, and NCOA4 was upregulated in the 661W cells cultured under HG conditions and in the photoreceptor cells in diabetic mice. Furthermore, the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1) obviously alleviated ferroptosis-related changes in HG-cultured 661W cells and in retinal photoreceptor cells in diabetic mice. Taken together, our findings suggest that ferroptosis is involved in photoreceptor degeneration in the development of the early stages of DR.
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3,4-Metilenodioxianfetamina , Diabetes Mellitus Experimental , Retinopatía Diabética , Ferroptosis , Animales , Ratones , Diabetes Mellitus Experimental/tratamiento farmacológico , Especies Reactivas de Oxígeno , Retinopatía Diabética/tratamiento farmacológico , Glutatión , Hierro , Factores de TranscripciónRESUMEN
Increasing amounts of experimental studies have shown that circular RNAs (circRNAs) play important regulatory roles in human diseases through interactions with related microRNAs (miRNAs). CircRNAs have become new potential disease biomarkers and therapeutic targets. Predicting circRNA-disease association (CDA) is of great significance for exploring the pathogenesis of complex diseases, which can improve the diagnosis level of diseases and promote the targeted therapy of diseases. However, determination of CDAs through traditional clinical trials is usually time-consuming and expensive. Computational methods are now alternative ways to predict CDAs. In this study, a new computational method, named PCDA-HNMP, was designed. For obtaining informative features of circRNAs and diseases, a heterogeneous network was first constructed, which defined circRNAs, mRNAs, miRNAs and diseases as nodes and associations between them as edges. Then, a deep analysis was conducted on the heterogeneous network by extracting meta-paths connecting to circRNAs (diseases), thereby mining hidden associations between various circRNAs (diseases). These associations constituted the meta-path-induced networks for circRNAs and diseases. The features of circRNAs and diseases were derived from the aforementioned networks via mashup. On the other hand, miRNA-disease associations (mDAs) were employed to improve the model's performance. miRNA features were yielded from the meta-path-induced networks on miRNAs and circRNAs, which were constructed from the meta-paths connecting miRNAs and circRNAs in the heterogeneous network. A concatenation operation was adopted to build the features of CDAs and mDAs. Such representations of CDAs and mDAs were fed into XGBoost to set up the model. The five-fold cross-validation yielded an area under the curve (AUC) of 0.9846, which was better than those of some existing state-of-the-art methods. The employment of mDAs can really enhance the model's performance and the importance analysis on meta-path-induced networks shown that networks produced by the meta-paths containing validated CDAs provided the most important contributions.
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3,4-Metilenodioxianfetamina , MicroARNs , Humanos , ARN Circular , Área Bajo la Curva , MicroARNs/genética , ARN Mensajero/genéticaRESUMEN
Herein, a novel Ag NP substrate doped with Au nanobipyramids was designed and fabricated via a convenient procedure of galvanic reaction for the identification and classification of amphetamine-type stimulants (ATS) in oral fluids in combination with surface enhanced Raman scattering (SERS). The substrate was shown to have a three-dimensional nanostructure, high SERS activity, and good stability. In combination with SERS, the Ag NP substrate doped with Au nanobipyramids was able to detect ultra-low traces of ATS, including amphetamine, methylamphetamine (MA), 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxymethylamphetamine (MDMA) in oral fluid with limit of detection (LOD) and limit of determination quantitation (LOQ) as low as 10-9 mg/mL, which is much better than the current spectroscopic techniques. The equations between concentration and peaks intensity for quantitative analysis displied good doublelogarithmic linear relations and reliability figures of merit at nanogram concentration level in compartion with GC-MS method. The approach can be broadly applied to the ultra-low trace detection of ATS in oral fluid and would be particularly useful for the analyses of nitrogenous organic compounds.
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3,4-Metilenodioxianfetamina , Estimulantes del Sistema Nervioso Central , Metanfetamina , Anfetamina , Reproducibilidad de los Resultados , Compuestos de NitrógenoRESUMEN
OBJECTIVES: Trans-fatty acids (TFAs), primarily derived from the food industry's production processes, have become a globally recognized public health issue due to the detrimental impact they have on human well-being. Secoisolariciresinol diglucoside (SDG) is a polyphenolic compound derived from flax lignans, possessing antioxidative properties. This study aims to investigate the protective effect of SDG on kidney oxidative damage in offspring of mice caused by maternal exposure to TFA during pregnancy and lactation. METHODS: A total of 30 c57BL/6 female rats were randomly divided into 5 groups: a control group, a TFA-exposed group, a low-(TFA+LSDG) group, a medium-(TFA+MSDG) group, and a high-(TFA+HSDG) group (n=6 in each group). With the exception of the control group, the maternal mice in the remaining 4 groups received a daily oral gavage of TFA at a dosage of 60 mg/(kg·BW) throughout the experimental period. The mothers in the control group were administered physiological saline via oral gavage once daily. Meanwhile, the 3 SDG intervention groups were provided with ad libitum access to SDG feed containing 10 mg/kg (low), 20 mg/kg (medium), and 30 mg/kg (high) of SDG. The female mice were conceived overnight. If the vaginal plug appeared in the next morning, the female mice were conceived and included in the experimental stage until the end of the 21th day lactation period. The body weight and kidney mass of offspring were recorded, and the kidney coefficient was calculated. The kidney was detected by HE staining to observe the histopathological changes, and the level of reactive oxidative species (ROS) was detected by fluorescence probe-dihydroethidium (DHE) staining; the expression levels of total superoxide dismutase (T-SOD) and malondialdehyde (MDA) in renal homogenate were detected, and the expression of nuclear factor E2-related fator2 (Nrf2) and hemeoxygenase-1 (HO-1) protein was analyzed by immunohistochemistry (IHC) staining. The mRNA expressions of Nrf2 and HO-1 were detected by real-time PCR, and the protein expression of Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase-1 (GPx-1), Nrf2 and HO-1 were detected by Western blotting. RESULTS: Compared with the control group, the kidney coefficient in the TFA-exposed group was increased, the morphology and structure of kidney tissue was abnormal; the activity of T-SOD enzyme was decreased, and the content of MDA was increased, the level of ROS was increased; the expressions of Cu/Zn-SOD, Mn-SOD, GPx1 protein were decreased, and the mRNA and protein expressions of Nrf2 and HO-1 were decreased, there were all significant difference (all P<0.05). Compared with the TFA-exposed group, the ROS levels were reduced, and the T-SOD enzyme activity as well as the protein expression of Cu/Zn-SOD, GPx-1, Mn-SOD, Nrf2 and HO-1 were up-regulated in the low, middle and high dose SDG intervention groups; the kidney coefficient and MDA content were decreased in the middle and high dose SDG groups; the Nrf2 mRNA expression in the high dose SDG group was up-regulated, there were all significant difference (all P<0.05). CONCLUSIONS: Maternal exposure to TFA during pregnancy and lactation can lead to oxidative damage in the kidney of offspring, and the SDG intervention may alleviate TFA-induced oxidative damage by up-regulating the expression of Nrf2 and HO-1 signal pathway.
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3,4-Metilenodioxianfetamina , Ácidos Grasos trans , Humanos , Embarazo , Femenino , Ratones , Ratas , Animales , Ácidos Grasos trans/toxicidad , Exposición Materna , Factor 2 Relacionado con NF-E2 , Especies Reactivas de Oxígeno , Riñón , Superóxido Dismutasa , Estrés OxidativoRESUMEN
Objectives: Excessive inflammatory responses and reactive oxygen species (ROS) formation play pivotal roles in the pathogenesis of sepsis. Penfluroidol (PF), an oral long-acting antipsychotic drug, has been suggested to possess diverse biological properties, including antischizophrenia, antitumour effect, and anti-inflammatory activity. The purpose of this research was to explore the anti-inflammatory and antioxidative effects of penfluroidol on lipopolysaccharide (LPS)-related macrophages. Methods: The viability of RAW264.7 and THP-1 cells was measured by Enhanced Cell Counting Kit-8 (CCK-8). The production of nitric oxide was evaluated by the Nitric Oxide Assay Kit. The generation of pro-inflammatory monocytes was detected by qRT-PCR (quantitative real-time PCR) and ELISA (enzyme-linked immunosorbent assay). Oxidative stress was assessed by measuring ROS, malondialdehyde (MDA), and superoxide dismutase (SOD) activity. The protein expression of the Nrf2/HO-1/NLRP3 inflammasome was detected by western blotting. Results: Our results indicated that no cytotoxic effect was observed when RAW264.7 and THP-1 cells were exposed to PF (0-1 µm) and/or LPS (1 µg/ml) for 24 hr. The data showed that LPS, which was repressed by PF, facilitated the generation of the pro-inflammatory molecules TNF-α and IL-6. In addition, LPS contributed to increased production of intracellular ROS compared with the control group, whereas the administration of PF effectively reduced LPS-related levels of ROS. Moreover, LPS induced the generation of MDA and suppressed the activities of SOD. However, PF treatment strongly decreased LPS-induced MDA levels and increased SOD activities in the RAW264.7 and THP-1 cells. Furthermore, our research confirmed that penfluroidol repressed the secretion of pro-inflammatory molecules by limiting the activation of the NLRP3 inflammasome and reducing oxidative effects via the Nrf2/HO-1 signaling pathway. Conclusion: Penfluroidol attenuated the imbalance of the inflammatory response by suppressing the activation of the NLRP3 inflammasome and reduced oxidative stress via the Nrf2/HO-1 signaling pathway in LPS-induced macrophages.
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3,4-Metilenodioxianfetamina , Lipopolisacáridos , Inflamasomas , Macrófagos , Factor 2 Relacionado con NF-E2 , Óxido Nítrico , Proteína con Dominio Pirina 3 de la Familia NLR , Estrés Oxidativo , Especies Reactivas de Oxígeno , Transducción de Señal , Superóxido Dismutasa , Células THP-1 , Células RAW 264.7 , Humanos , Animales , RatonesRESUMEN
This review focuses on the effects and mechanisms of action of amphetamine-type stimulants (ATS) and their adverse effects on the cardiovascular, nervous, and immune systems. ATS include amphetamine (AMPH), methamphetamine (METH, "crystalmeth," or "ice"), methylenedioxymethamphetamine (MDMA, "ecstasy," or "Molly"), MDMA derivatives (e.g., methylenedioxyamphetamine [MDA] and methylenedioxy-N-ethylamphetamine [MDEA]), khat, and synthetic cathinones. The first section of this paper presents an overview of the historical aspects of ATS use, their initial clinical use, and regulations. The second part reviews the acute and chronic impact and the most salient clinical effects of ATS on the central nervous and cardiovascular systems, skin, and mouth. The chemical structure, pharmacokinetics, and classic and non-canonical pharmacological actions are covered in the third section, briefly explaining the mechanisms involved. In addition, the interactions of ATS with the central and peripheral immune systems are reviewed. The last section presents data about the syndemic of ATS and opioid use in the North American region, focusing on the increasing adulteration of METH with fentanyl.
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3,4-Metilenodioxianfetamina , Estimulantes del Sistema Nervioso Central , Metanfetamina , N-Metil-3,4-metilenodioxianfetamina , Humanos , Anfetamina/efectos adversos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Estimulantes del Sistema Nervioso Central/efectos adversos , Metanfetamina/efectos adversosRESUMEN
BACKGROUND: Effective mass drug administration (MDA) is the cornerstone in the elimination of lymphatic filariasis (LF) and a critical component in combatting all neglected tropical diseases for which preventative chemotherapy is recommended (PC-NTDs). Despite its importance, MDA coverage, however defined, is rarely investigated systematically across time and geography. Most commonly, investigations into coverage react to unsatisfactory outcomes and tend to focus on a single year and health district. Such investigations omit more macro-level influences including sociological, environmental, and programmatic factors. The USAID NTD database contains measures of performance from thousands of district-level LF MDA campaigns across 14 years and 10 West African countries. Specifically, performance was measured as an MDA's epidemiological coverage, calculated as persons treated divided by persons at risk. This analysis aims to explain MDA coverage across time and geography in West Africa using sociological, environmental, and programmatic factors. METHODOLOGY: The analysis links epidemiological coverage data from 3,880 LF MDAs with contextual, non-NTD data via location (each MDA was specific to a health district) and time (MDA month, year). Contextual data included rainfall, temperature, violence or social unrest, COVID-19, the 2014 Ebola outbreak, road access/isolation, population density, observance of Ramadan, and the number of previously completed MDAs. PRINCIPAL FINDINGS: We fit a hierarchical linear regression model with coverage as the dependent variable and performed sensitivity analyses to confirm the selection of the explanatory factors. Above average rainfall, COVID-19, Ebola, violence and social unrest were all significantly associated with lower coverage. Years of prior experience in a district and above average temperature were significantly associated with higher coverage. CONCLUSIONS/SIGNIFICANCE: These generalized and context-focused findings supplement current literature on coverage dynamics and MDA performance. Findings may be used to quantify typically anecdotal considerations in MDA planning. The model and methodology are offered as a tool for further investigation.
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3,4-Metilenodioxianfetamina , COVID-19 , Filariasis Linfática , Filaricidas , Fiebre Hemorrágica Ebola , Humanos , Filariasis Linfática/tratamiento farmacológico , Filariasis Linfática/epidemiología , Filariasis Linfática/prevención & control , Administración Masiva de Medicamentos , Filaricidas/uso terapéutico , Fiebre Hemorrágica Ebola/tratamiento farmacológico , África Occidental/epidemiología , Enfermedades Desatendidas/epidemiología , 3,4-Metilenodioxianfetamina/uso terapéuticoRESUMEN
BACKGROUND: Ferroptosis, as a unique form of cell death, plays crucial negative roles in tumorigenesis and progression. This study aimed to investigate the role and molecular mechanism of TEA domain transcription factor 1 (TEAD1) in HCC and its effect on sorafenib-induced ferroptosis. METHODS: TEAD1 expression was analyzed in HCC tissues using quantitative PCR, and western blot. The effects on cell proliferation, migration and invasion were determined by CCK-8, wound healing and Transwell assays. Intracellular iron, reactive oxygen species (ROS), malondialdehyde (MDA) and GSH measurement was used to assess ferroptosis. Chromatin immunoprecipitation and luciferase reporter gene assays were performed to verify the relationship between TEAD1 and solute carrier family 3 member 2 (SLC3A2). Expression of mTOR, ribosomal protein S6, glutathione peroxidase 4 (GPX4) and SLC3A2 was analyzed by western blot. Tumor xenografts were used assess the effect of TEAD1 on tumor growth in vivo. RESULTS: TEAD1 was more abundant in HCC compared with normal tissues. Overexpression of TEAD1 enhanced the proliferation, migration, and invasion of HCC cells, while knockdown of TEAD1 inhibited these cell behaviors. Further, TEAD1 inhibited ferroptosis, which was demonstrated by decreased intracellular Fe2+ content, ROS, and MDA levels, and increased GSH activity. Mechnistically, TEAD1 promotes the transcription of SLC3A2 and activates the mTOR signaling. Additionally, silenced TEAD1 restrained tumor growth and enhance sorafenib-induced antitumor activity in vivo. CONCLUSIONS: TEAD1 confers resistance of HCC cells to ferroptosis, thereby promoting the progression of HCC, suggesting the potential value of TEAD1 in the diagnosis and treatment of HCC.
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3,4-Metilenodioxianfetamina , Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Especies Reactivas de Oxígeno , Sorafenib/farmacología , Factores de Transcripción de Dominio TEARESUMEN
The high-production-volume chemical 4,4'-methylenedianiline (4,4'-MDA) is an aromatic amine used to manufacture 4,4'-methylenedianiline diisocyanate for polyurethane production. Based on 4,4'-MDA's octanol/water partition coefficient (KOW ) and correlations with the transpiration stream concentration factor (TSCF), significant plant uptake and root-to-shoot transfer are predicted. However, most correlations between KOW and TSCF were developed for neutral organics and may not be applicable for ionizable bases such as 4,4'-MDA. To investigate, TSCF values for 4,4'-MDA were measured using pressure chamber and intact plant approaches for tomato, soybean, and wheat (intact plants only). 14 C-labeled 4,4'-MDA was used to increase analytical sensitivity and facilitate measurement of distribution within plant tissues. The TSCF of 14 C-MDA determined using the pressure chamber method was 0.04 ± 0.00 for tomato and 0.17 ± 0.10 for soybean. These values were lower than predicted from log KOW and within the range of values for 14 C-pyrene also measured in our study (0.14 ± 0.00 for tomato and 0.16 ± 0.09 for soybean). The TSCF values calculated from measurements made from intact plants grown to maturity were statistically equivalent to those obtained from the pressure chamber method for soybean and tomato. The distributions of 14 C within the three plants species were similar, with the roots > leaves ≈ stems > fruit. The log root concentration factors for 4,4'-MDA ranged from 3.68 to 4.33 for the three plant species. This finding indicates that the aromatic amine sorption to root materials is much greater than would be predicted based on its log KOW and may be the reason for the limited root-to-shoot transfer observed in the pressure chamber and intact plant studies. Environ Toxicol Chem 2023;42:655-662. © 2023 SETAC.