查找使用阿拉丁产品的科研文献

Ethanol potentiates mirtazapine-induced cardiotoxicity by inducing dysfunctional autophagy via HMGB1-dependent Akt/mTOR signaling pathway

Rongzhe Zhu,Xiaochen Liu,Qiupeng Xue,Xiaoru Dong,Tianyi Zhang,Yan Jiang

Previous surveys have revealed that mirtazapine (MIR), one of the most commonly prescribed antidepressants, is associated with a higher risk of adverse cardiac events compared with other newer antidepressants. Chronic ethanol (EtOH) abuse could also lead to myocardial injuries. Concerning the common comorbidity of major depression and alcohol dependence, combined consumption of MIR and EtOH might be prevalent in patients with depression, resulting in an additive or synergistic cardiotoxic effect. To this end, the present study evaluated cardiotoxicity induced by MIR-plus-EtOH in vivo (male C57BL/6J mice) and in vitro (H9c2 cardiomyoblasts), Further research on the role of autophagy and underlying signaling pathway were carried out in H9c2 cells. We found that EtOH exacerbated MIR-induced cardiotoxicity both in vivo and in vitro . Furthermore, EtOH significantly potentiated MIR-induced dysfunctional autophagy as reflected by upregulated protein levels of LC3-II, p62, Beclin1 and LAMP-1. Pharmacological inhibition of autophagy by 3-methyladenine alleviated MIR-plus-EtOH-induced myocardial injury. High mobility group box 1 (HMGB1) is a positive regulator of autophagy. In our work, HMGB1 knockdown decreased autophagosome accumulation and boosted viability in H9c2 cells. Additionally, HMGB1 blockage markedly upregulated p-Akt/Akt and p-mTOR/mTOR levels which were suppressed in MIR-plus-EtOH treated cells. In general, the present study demonstrates that EtOH potentiates MIR-induced cardiotoxicity which might be attributed to dysfunctional autophagy via inhibiting Akt/mTOR signaling pathway, while HMGB1 knockdown might contribute to improve autophagy flux.

Environmentally relevant concentrations of antidepressant mirtazapine impair the neurodevelopment of zebrafish (Danio rerio)

Jie Zhou,Yanbin Zhao,Jiayin Dai,Kun Zhang

Mirtazapine is a commonly prescribed antidepressant and has been found widespread in aquatic environments. However, its toxicities to aquatic organisms has rarely been explored. Herein, we conducted a comprehensive study on the developmental effects of mirtazapine on early life stages of zebrafish at environmentally relevant concentrations (3.9 ng/L and 43.5 ng/L). Out of the endpoints measured, spontaneous contraction of embryos at 24 h post fertilization (hpf) and hatching rate and heart rate of embryos at 50 hpf and 56 hpf, respectively, were significantly affected. In light-dark transition behavior test, mirtazapine significantly reduced the swimming frequency and swimming speed of embryos at both concentrations of 3.9 ng/L and 43.5 ng/L. Furthermore, the total swimming distances in dark conditions were also significantly reduced. Transcriptomic analysis was further conducted. It demonstrated that the decreased neural activities in embryos may be associated with altered epinephrine and neuregulin signaling. The present results fill a data gap regarding the exposure of fish to mirtazapine at environmentally relevant concentrations and provide new insights into the neurotoxic mechanisms of mirtazapine exposure.

Detection of antidepressants in wastewater from four provinces of China by UPLC-MS/MS to assess the regional prevalence of depression

Moying Yang,Yan Yao,Haotian Shen,Fei Teng,Yunuo Liu,Yuyang Ma,Bin Di,Mengxiang Su

Depression has gradually become a serious public health problem. Traditionally, data on depression are mainly derived from questionnaires or antidepressant prescriptions, and these methods may suffer from update delays and survey bias, resulting in a low actual prevalence of depression. To monitor the prevalence of depression in near real-time, this study developed an analytical method of UPLC-MS/MS by wastewater-based epidemiology to detect 10 typical antidepressants and metabolites in four provinces of China. The method has high sensitivity in that the lower limit of quantification was 2 ng/L. And the method provides recoveries and matrix effects ranging from 85.12 % to 102.98 % and 84.95 % to 112.75 %, respectively. The results showed that among the four provinces, the highest average detected concentration of antidepressants was in Jiangsu (91.82 ± 150.46 ng/L), followed by Guangxi (76.06 ± 130.44 ng/L), Anhui (61.53 ± 94.09 ng/L), and Hainan (27.87 ± 28.33 ng/L). Most wastewater treatment facilities had antidepressants such as venlafaxine, fluvoxamine, and agomelatine. The average back-calculated consumption of venlafaxine and fluvoxamine was 815.88 ± 2015.96 mg/day/1000 inh and 497.02 ± 405.21 mg/day/1000 inh, respectively. Based on this study, the estimated prevalence in the population over 15 in Jiangsu, Anhui, and Hainan was finally determined to be 4.90 %, 5.36 %, and 2.93 %, indicating regional diversity. This study offered a workable way to track the prevalence of depression using wastewater-based epidemiology, which aided public health agencies in comprehending the state of depression prevalence.

Highly selective N-glucuronidation of four piperazine-containing drugs by UDP-glucuronosyltransferase 2B10

Danyi Lu,Dong Dong,Baojian Wu

Ultrasound-assisted low-density solvent dispersive liquid–liquid microextraction for the simultaneous determination of 12 new antidepressants and 2 antipsychotics in whole blood by gas chromatography–mass spectrometry

Xiujuan Chen,Shuiqing Zheng,Jian Le,Zheyuan Qian,Runsheng Zhang,Zhanying Hong,Yifeng Chai

Antidepressant drugs are widely used in the treatment of different psychiatric disorders, as well as in conjunction with antipsychotics for the treatment of major depressive disorder. In this study, a simple and rapid ultrasound-assisted low-density solvent dispersive liquid–liquid microextraction (UA-LDS-DLLME) method was developed for the simultaneous determination of 12 new antidepressants (norfluoxetine, fluoxetine, fluvoxamine, agomelatine, mirtazapine, moclobemide, melitracen, N-desmethylmirtazapine, maprotiline, sertraline, citalopram, paroxetine) and 2 antipsychotics (clozapine and haloperidol) in human whole blood by gas chromatography–mass spectrometry (GC–MS). Different parameters affecting the UA-LDS-DLLME were optimized and the optimal conditions were as follows: 100   μL of toluene as extraction solvent, extraction pH 12 and 3   min of ultrasound stirring. Good linearity ( R 2   ≥   0.991) was obtained at the concentration range of 15–1500   ng/mL for norfluoxetine, fluoxetine, fluvoxamine, melitracen, maprotiline and citalopram, and 5–500   ng/mL for agomelatine, mirtazapine, moclobemide, N-desmethylmirtazapine, sertraline, paroxetine, clozapine and haloperidol. The intra-day and inter-day precision were all less than 10%, and accuracy of intra-day and inter-day were in the range of −12.7% to 7.9% and −13.9 to 11.8%, respectively. The extraction recoveries of most analytes were more than 60%. The UA-LDS-DLLME/GC–MS method was demonstrated with acceptable precision, accuracy and good specificity for the simultaneous determination of 12 antidepressants and 2 antipsychotics, and has been successfully applied in a real case.

N-glucuronidation catalyzed by UGT1A4 and UGT2B10 in human liver microsomes: Assay optimization and substrate identification

Danyi Lu,Qian Xie,Baojian Wu

N -glucuronidation is an important pathway for metabolism and disposition of tertiary amines in humans. This reaction is mainly catalyzed by the enzymes UGT1A4 and UGT2B10. However, the metabolic patterns of UGT1A4- and UGT2B10-mediated N -glucuronidation are not fully clear. In this study, we first optimized in vitro reaction conditions for N -glucuronidation by using specific substrates (i.e., trifluoperazine for UGT1A4, cotinine and amitriptyline for UGT2B10). Furthermore, we found that hepatic N -glucuronidation showed significant species differences. In addition, UGT1A4 and UGT2B10 were primarily responsible for N -glucuronidation of many tertiary amines, including asenapine, loxapine, clozapine, chlorpromazine, dothiepin, doxepin, mirtazapine, mianserin, chlorcyclizine, cyclizine, promethazine, cyclobenzaprine, imatinib, retrorsine, strychnine and brucine. In conclusion, this study provides an in vitro assay system for evaluating N -glucuronidation of amines. Also, UGT1A4- and UGT2B10-mediated N -glucuronidation might play significant roles in metabolism and detoxification of tertiary amines in humans.