基于代谢组学分析策略的玉米中多类别农兽药共残留非靶向筛查

目的 建立基于代谢组学分析策略的玉米中多类别农兽药共残留非靶向筛查的新方法。方法 在高效液相色谱-串联质谱(high performance liquid chromatography-tandem mass spectrometer, HPLC-MS/MS)全扫描模式下检测玉米样品, 从而获取代谢组学数据。将该数据上传至Workflow4Metabolomics平台, 经过色谱峰处理后获得包含1447个变量的数据矩阵, 再通过主成分分析、正交偏最小二乘判别分析、成对t检验和浓度倍数变化分析, 挑选出符合条件的变量。通过数据库比对, 最终确定能够代表残留农兽药的“标志化合物”的特征变量。结果 借助HPLC-MS/MS的正离子模式, 采用代谢组学分析策略, 从124种添加农兽药中筛查出其中109种(检出限为0.3~1.5 μg/kg), 筛查率达88%。结论 代谢组学分析策略能够高效的实现玉米中残留农兽药的非靶向筛查, 为污染物非靶向筛查提供了一种新的思路。     

超高效液相色谱-四极杆串联离子阱质谱法同时检测动物源性食品中26种新型抗病毒药物

目的 建立一种超高效液相色谱-四极杆串联离子阱质谱法(ultra performance liquid chromatography quadrupole tandem ion trap-mass spectrometry, UPLC-MS/MS)同时检测动物源性食品中多种抗病毒药物的方法。方法 样品经三氯乙酸-乙腈(20:80, V:V)溶液提取, Captive EMR-Lipid净化柱净化, 采用Waters BEH C18色谱柱分离, UPLC-MS/MS检测, 多反应监测-信息关联扫描-增强子离子扫描(multiple response monitoring-information dependent acquisition-enhanced product ion, MRM-IDA-EPI)确证, 外标法定量。结果 26种抗病毒药物定量限为0.1~5.0 μg/kg, 相关系数均高于0.99, 回收率范围为71%~97%, 相对标准偏差为1.3%~10.7%。结论 采用新型通过型净化技术及四极杆串联离子阱质谱法, 可同时对26种抗病毒药物进行定性、定量检测; 采用二级全扫描谱图与谱库检索比对, 实现了化合物的确证分析。     

超高效液相色谱-四极杆-飞行时间质谱法快速筛查畜禽类产品中50种违禁药物残留

建立了超高效液相色谱-四极杆-飞行时间质谱（UPLC-Q-TOF/MS）快速筛查畜禽类产品中50种违禁药物残留的检测方法。畜禽类产品经β-葡萄糖醛酸酶/芳基硫酸酯酶酶解,依次用乙酸乙酯-叔丁基甲醚提取后,利用HLB净化,采用UPLC-Q-TOF/MS电喷雾正离子模式检测。通过建立在线谱库检索的方法实现50种违禁药物的快速筛选和准确定性,再结合同位素内标法实现准确定量。目标物质量浓度在2~200 μg/L范围内线性关系良好,相关系数均大于0.99,检出限为0.1~0.5 μg/kg,定量限为0.3~1.5 μg/kg,三个不同浓度的加标回收率在81.74%~114.22%之间,相对标准偏差为1.41%~8.91%。研究建立的筛查数据库在无需标准品的情况下实现了50种违禁药物的快速筛查、定性确证和定量分析。该方法适用于畜禽类产品中低浓度的违禁药物残留量的快速筛查和准确定量。     

膀胱癌化疗药物增敏机制研究进展

近年来化疗耐药严重制约着膀胱癌的治疗效果,术后复发率和转移率居高不下。因此,逆转膀胱癌化疗耐药性,寻找有效的化疗增敏靶点并探究其机制十分重要。目前临床上多采用经尿道膀胱肿瘤切除术,术后选择辅助化疗药物进行治疗,常用化疗药物包括顺铂、吉西他滨、阿霉素、表柔比星等。目前实现这些药物化疗增敏的靶点基因和分子在膀胱癌细胞中呈现不同的表达状态,且通过这些靶点实现增敏的机制也各有不同。本文将就膀胱癌化疗药物增敏靶点及机制的研究进展进行综述,以期为膀胱癌的化疗增敏探索新的思路。     

The Importance of Platelets Response during Antiplatelet Treatment after Ischemic Stroke—Between Benefit and Risk: A Systematic Review

Ischemic stroke is a disease related to abnormal blood flow that leads to brain dysfunction. The early and late phases of the disease are distinguished. A distinction is made between the early and late stages of the disease, and the best effect in treating an ischemic stroke is usually achieved within the first hours after the onset of symptoms. This review looked at studies platelet activity monitoring studies to determine the risks and benefits of various approaches including antiplatelet therapy. A study was conducted on recently published literature based on PRISMA. This review includes 32 research articles directly addressing the importance of monitoring platelet function during antiplatelet therapy (dual or monotherapy) after ischemic stroke. In patients with transient ischemic attack or ischemic stroke, antiplatelet therapy can reduce the risk of stroke by 11–15%, assuming that patients respond well. Secondary prevention results are dependent on platelet reactivity, meaning that patients do not respond equally to antiplatelet therapy. It is very important that aspirin-resistant patients can benefit from the use of dual antiplatelet therapy. The individualized approach to secondary stroke prevention is to administer the most appropriate drug at the correct dose and apply the optimal therapeutic procedure to the individual patient.     

EAPB0503, an Imidazoquinoxaline Derivative Modulates SENP3/ARF Mediated SUMOylation,and Induces NPM1c Degradation in NPM1 Mutant AML

Nucleophosmin-1 (NPM1) is a pleiotropic protein involved in numerous cellular processes. NPM1 shuttles between the nucleus and the cytoplasm, but exhibits a predominant nucleolar localization, where its fate and functions are exquisitely controlled by dynamic post-translational modifications (PTM). Sentrin/SUMO Specific Peptidase 3 (SENP3) and ARF are two nucleolar proteins involved in NPM1 PTMs. SENP3 antagonizes ARF-mediated NPM1 SUMOylation, to promote ribosomal biogenesis. In Acute Myeloid Leukemia (AML), NPM1 is frequently mutated, and exhibits an aberrant cytoplasmic localization (NPM1c). NPM1c mutations define a separate AML entity with good prognosis in some AML patients, rendering NPM1c as a potential therapeutic target. SENP3-mediated NPM1 de-SUMOylation induces resistance to therapy in NPM1c AML. Here, we demonstrate that the imidazoquinoxaline EAPB0503 prolongs the survival and results in selective reduction in the leukemia burden of NPM1c AML xenograft mice. Indeed, EAPB0503 selectively downregulates HDM2 expression and activates the p53 pathway in NPM1c expressing cells, resulting in apoptosis. Importantly, we unraveled that NPM1c expressing cells exhibit low basal levels of SUMOylation paralleled with high SENP3 and low ARF basal levels. EAPB0503 reverted these molecular players by inducing NPM1c SUMOylation and ubiquitylation, leading to its proteasomal degradation. EAPB0503-induced NPM1c SUMOylation is concurrent with SENP3 downregulation and ARF upregulation in NPM1c expressing cells. Collectively, these results provide a strong rationale for testing therapies modulating NPM1c post-translational modifications in the management of NPM1c AML.     

Novel Design of Neuropeptide-Based Drugs with β-Sheet Breaking Potential in Amyloid-Beta Cascade: Molecular and Structural Deciphers

Our work discusses the investigation of 75 peptide-based drugs with the potential ability to break the β-sheet structures of amyloid-beta peptides from senile plaques. Hence, this study offers a unique insight into the design of neuropeptide-based drugs with β-sheet breaker potential in the amyloid-beta cascade for Alzheimer’s disease (AD). We started with five peptides (¹⁵QKLVFF²⁰, ¹⁶KLVFF²⁰, ¹⁷LVFF²⁰, ¹⁶KLVF¹⁹ and ¹⁵QKLV¹⁸), to which 14 different organic acids were attached at the N-terminal. It was necessary to evaluate the physiochemical features of these sequences due to the biological correlation with our proposal. Hence, the preliminary analysis of different pharmacological features provided the necessary data to select the peptides with the best biocompatibility for administration purposes. Our approaches demonstrated that the peptides ¹⁷LVFF²⁰, NA-¹⁷LVFF²⁰, ¹⁶KLVF¹⁹ and NA-¹⁶KLVF¹⁹ (NA-nicotinic acid) have the ability to interfere with fibril formation and hence improve the neuro and cognitive functions. Moreover, the peptide conjugate NA-¹⁶KLVF¹⁹ possesses attractive pharmacological properties, demonstrated by in silico and in vitro studies. Tandem mass spectrometry showed no fragmentation for the spectra of ¹⁶KLVF¹⁹. Such important results suggest that under the action of protease, the peptide cleavage does not occur at all. Additionally, circular dichroism confirmed docking simulations and showed that NA-¹⁶KLVF¹⁹ may improve the β-sheet breaker mechanism, and thus the entanglement process of amyloid-beta peptides can be more effective.     

All the players in the game: driving home the global commitment for legitimate drugs

Substandard, falsified, and counterfeit medications are a concern for the industry and for the public’s health. Data collection and research on these illegitimate drugs must continue to be a priority and common recommendations must be implemented immediately. The health of the public continues to be at risk, and as such global consensus and collaboration must be swift. Process improvements and policy decisions can support expert recommendations while technology and research continue to drive home change. Addressing counterfeit and substandard drugs is cost effective, feasible, and the right thing to do.