In Vitro Biotransformation Studies of 2‑Oxo-clopidogrel: Multiple Thiolactone Ring-Opening Pathways Further Attenuate Prodrug Activation

The biotransformation of clopidogrel has been under extensive investigation to address the observed high clinical variability and resistance of its antithrombotic prodrug therapy. Clopidogrel (M0) is first activated to its thiolactone intermediate, 2-oxo-clopidogrel (M2), by hepatic cytochrome P450 (P450) enzymes. Subsequent P450-catalyzed <i>S</i>-oxidation is followed by thioester hydrolysis, which cleaves the thiolactone ring and yields a sulfenic acid intermediate (M12); this intermediate is reduced to the final active metabolite (M13). The aim of the present study is to characterize the metabolic fates of M2 more comprehensively with focus on the thiolactone ring-opening pathways. It was found that the bioactivating <i>S</i>-oxidation confers on the thiolactone moiety not only one electrophilic site at the carbonyl <i>C</i>-atom (Site A), but also a second one at the allylic bridge <i>C</i>-atom (Site B). Both sites can react with H₂O or other nucleophiles, like glutathione (GSH), leading to different thiolactone ring-opening pathways. In addition to the pharmacologically desired A-H₂O pathway leading to M13 formation, the A-GSH pathway leads to the formation of a glutathione conjugate (GS-3), the B-H₂O pathway leads to the formation of a desulfurized hydroxyl metabolite (M17), and the B-GSH pathway leads to the formation of a desulfurized glutathione conjugate (GS-2). These results demonstrate the reactive nature of the electrophilic thiolactone <i>S</i>-oxide intermediate (M11) and suggest that M13 formation from M2 might be accompanied by more attenuating pathways than previously reported. The research presented here may facilitate future studies exploring the clinical antithrombotic response to clopidogrel as well as the susceptibility to the adverse effect of clopidogrel and its close prodrug analogues

Identification of the Significant Involvement and Mechanistic Role of CYP3A4/5 in Clopidogrel Bioactivation

The clinical response to the antiplatelet prodrug clopidogrel is associated with high intersubject variability and a certain level of therapeutic resistance. Previous studies have suggested that genetic polymorphism of CYP2C19 might be one determinant of clopidogrel efficacy and led to the CYP2C19 genotype-tailored antithrombotic therapy. However, evidence against the role of CYP2C19 from multiple studies implied the involvement of other factors. Here, we report that prodrug activation of the thiophene motif in clopidogrel is attenuated by heavy metabolic attrition of the piperidine motif. CYP3A4/5 was identified to be the enzyme metabolizing the piperidine motif. Inhibiting CYP3A4/5-mediated attrition was shown to potentiate active metabolite formation, which was found to be catalyzed by multiple CYP enzymes. Identifying the significant involvement of CYP3A4/5 and characterizing its mechanistic role in clopidogrel bioactivation might assist future pharmacogenomic studies in exploring the full mechanism underlying clopidogrel efficacy

Deuterated Clopidogrel Analogues as a New Generation of Antiplatelet Agents

Clopidogrel (CPG) is an antithrombotic prodrug that needs hepatic cytochrome P450 (CYP) enzymes for its bioactivation. The clinical effects of CPG have been associated with high intersubject variability and a certain level of resistance. Recently, comprehensive biotransformation studies of CPG support that the observed clinical uncertainty stems from the low bioactivation efficiency, which is attributed to extensive attritional metabolism (e.g., hydrolysis of the methyl ester functionality and oxidation of the piperidine moiety). With the goal of potentiating the desired thiophene 2-oxidation through minimal structural modification, we have adopted the strategy of <i>targeted metabolism shift</i> and have designed and synthesized deuterated piperidine analogues of CPG. In vitro studies showed that the prodrug activation percentages have been significantly increased for the deuterated analogues as a result of stability enhancement of the piperidine moiety. In a pharmacological study with a rat model, oral administration of the deuterated analogues also demonstrated higher inhibitory activity than that of CPG against adenosine diphosphate (ADP) induced platelet aggregation. These deuterated analogues represent a new generation of antiplatelet agents with the potential to overcome the major clinical drawbacks of CPG

Oxygen-Incorporated MoS₂ Nanosheets with Expanded Interlayers for Hydrogen Evolution Reaction and Pseudocapacitor Applications

Two-dimensional transition-metal dichalcogenides (TMDs) nanosheets have attracted tremendous research interest. Engineering the structure of MoS₂ may result in desirable performance for energy applications. In this work, oxygen-incorporated MoS₂ nanosheets with expanded interlayers have been synthesized by a solvothermal reaction. The oxygen-incorporated MoS₂ nanosheets with rich defects demonstrate excellent hydrogen evolution reaction activity with a small Tafel slope of 42 mV decade^–1 as well as excellent long-term stability. Interestingly, a large expanded ∼8.40 Å interlayer of (002) faces can be achieved by controlling the reaction time. This material also shows excellent long-term cycling stability (up to 20 000 cycles) as well as high specific capacitance for pseudocapacitors. We believe that the structural modification strategy can be applied for other TMDs to further optimize the performance for various applications

From Waste to Wealth: Novel Approach for Recovery of Metals from Spent Lithium-Ion Batteries Using Biological Waste

This study used tea waste (TW) as an environmentally friendly reducing agent to extract spent lithium-ion batteries in the H2SO4 solvent, thereby replacing highly explosive H2O2. The leaching parameters, including TW dosage, leaching temperature, H2SO4 concentration, leaching time, liquid–solid ratio, and stirring speed, were systematically optimized to achieve over 98% leaching efficiency of Ni, Mn, Co, and Li from the spent cathode material. The leaching kinetics study indicated that the H2SO4-TW leaching process was influenced by internal diffusion. The Box–Behnken experimental design was employed to optimize the leaching results, a proposition was made for a model that predicts the efficiencies of metal leaching. The regenerated cathode material demonstrated exceptional electrochemical performance. Contrary to the traditional biomass-reducing agents, the reduction performance of TW at low temperatures is derived from the catechins; meanwhile, at high temperatures, it is derived from the decomposition of cellulose. The oxidation process of catechins involves the oxidation of hydroxyl groups to carboxyl groups or the generation of adjacent quinone structures that form gallic acid derivatives. Using TW to extract metals from spent LIBs is an efficient, environmentally friendly, and sustainable approach to reducing the environmental impact of both waste sources

Convenient Method for the Synthesis of a Flexible Cyclic Polyamide for Selective Targeting of <i>c‑myb</i> G‑quadruplex DNA

A convenient efficient method for synthesis of a flexible cyclic polyamide (<b>cβ</b>, <b>1</b>) was developed through cyclodimerization. Electrospray ionization mass spectrometry and nuclear magnetic resonance results showed that <b>1</b> selectively binds to the <i>c-myb</i> G-quadruplex with high affinity, and there was no binding with the ILPR, <i>bcl-2</i>, and <i>c-kit</i> G-quadruplexes. This is the first time that a flexible cyclic polyamide was found to have high selectivity for the <i>c-myb</i> G-quadruplex

Additional file 1 of Circular RNA circPTPRF promotes the progression of GBM via sponging miR-1208 to up-regulate YY1

Supplementary Table S1. Relationship of circPTPRF expression to clinical features of glioma patients

Engineering Ion Diffusion by CoS@SnS Heterojunction for Ultrahigh-Rate and Stable Potassium Batteries

Transitional metal sulfides (TMSs) are considered as promising anode candidates for potassium storage because of their ultrahigh theoretical capacity and low cost. However, TMSs suffer from low electronic, ionic conductivity and significant volume expansion during potassium ion intercalation. Here, we construct a carbon-coated CoS@SnS heterojunction which effectively alleviates the volume change and improves the electrochemical performance of TMSs. The mechanism analysis and density functional theory (DFT) calculation prove the acceleration of K-ion diffusion by the built-in electric field in the CoS@SnS heterojunction. Specifically, the as-prepared material maintains 81% of its original capacity after 2000 cycles at 500 mA g–1. In addition, when the current density is set at 2000 mA g–1, it can still deliver a high discharge capacity of 210 mAh g–1. Moreover, the full cell can deliver a high capacity of 400 mAh g–1 even after 150 cycles when paired with a perylene-3,4,9,10-tetracarboxydiimide (PTCDI) cathode. This work is expected to provide a material design idea dealing with the unstable and low rate capability problems of potassium-ion batteries

Data_Sheet_1_Trends of Tourette Syndrome in children from 2011 to 2021: A bibliometric analysis.PDF

ObjectiveAnalyze the research status of Tourette Syndrome (TS) in children by CiteSpace and determine the current research hotspots and frontiers.Materials and methodsWe chose publications indexed in the Web of Science Core Collection (WoSCC) database for studies related to TS in children from 2011 to 2021. We built online cooperation maps of countries/regions, institutions, authors, journals, references, and keywords by CiteSpace, and identified hotspots and frontiers of study for children’s TS.ResultsA total of 1,232 publications about TS in children were downloaded from the WoSCC. The USA (414) was the country with the highest rate of production, and University College London (87) was the institution that had the highest publication rate. Andrea Eugenio Cavanna was the most prolific author (39 papers). There was inactive cooperation between institutions, countries/regions, and authors. The Journal of European Child & Adolescent Psychiatry was the most active journal. Hot topics focused on epidemiology, comorbidities, deep brain stimulation, behavioral therapy, basal ganglia, pharmacological treatment, and risk factors of TS in children.ConclusionAccording to the CiteSpace results, this study found that authors, countries/regions, and institutions were not actively working together. Current research hotspots mainly consist of epidemiology, comorbidities, deep brain stimulation, behavior therapy, and basal ganglia. The main research trends include comorbidities, pharmacological treatment, and risk factors. Therefore, international cooperation should be strengthened in the future, and it should be mindful of the psychiatric comorbidities of TS, the choice of intervention measures, and early warning of risk factors.</p

Additional file 2 of Circular RNA circPTPRF promotes the progression of GBM via sponging miR-1208 to up-regulate YY1

Supplementary Table S2. Clinical information of the primary glioma stem-like cells