Could chroman-4-one derivative be a better inhibitor of PTR1? – Reason for the identified disparity in its inhibitory potency in Trypanosoma brucei and Leishmania major

Most notable Kinetoplastids are of the genus Trypanosoma and Leishmania, affecting several millions of humans in Africa and Latin America. Current therapeutic options are limited by several drawbacks, hence the need to develop more efficacious inhibitors. An investigation to decipher the mechanism behind greater inhibitory potency of a chroman-4-one derivative (compound 1) in Trypanosoma brucei pteridine reductase 1 (TbPTR1) and Leishmania major pteridine reductase 1 (LmPTR1) was performed. Estimation of ΔG_bind revealed that compound 1 had a greater binding affinity in TbPTR1 with a ΔG_bind value of −49.0507 Kcal/mol than −29.2292 Kcal/mol in LmPTR1. The ΔGbind in TbPTR1 were predominantly contributed by “strong” electrostatic energy compared to the “weak” van der Waals in LmPTR1. In addition to this, the NADPH cofactor contributed significantly to the total energy of TbPTR1. A characteristic weak aromatic π interaction common in PTR1 was more prominent in TbPTR1 than LmPTR1. The consistent occurrence of high-affinity conventional hydrogen bond interactions as well as a steady interaction of crucial active site residues like Arg14/Arg17, Ser95/Ser111, Phe97/Phe113 in TbPTR1/LmPTR1 with chroman-4-one moiety equally revealed the important role the moiety played in the activity of compound 1. Overall, the structural and conformational analysis of the active site residues in TbPTR1 revealed them to be more rigid than LmPTR1. This could be the mechanism of interaction TbPTR1 employs in exerting a greater potency than LmPTR1. These findings will further give insight that will be assistive in modifying compound 1 for better potency and the design of novel inhibitors of PTR1.     

Rational Designs for Lithium-Sulfur Batteries with Low Electrolyte/Sulfur Ratio

Lithium-sulfur batteries (LSBs) are considered a promising next-generation energy storage device owing to their high theoretical energy density. However, their overall performance is limited by several critical issues such as lithium polysulfide (PS) shuttles, low sulfur utilization, and unstable Li metal anodes. Despite recent huge progress, the electrolyte/sulfur ratio (E/S) used is usually very high (≥20 µL mg⁻¹), which greatly reduces the practical energy density of devices. To push forward LSBs from the lab to the industry, considerable attention is devoted to reducing E/S while ensuring the electrochemical performance. To date, however, few reviews have comprehensively elucidated the possible strategies to achieve that purpose. In this review, recent advances in low E/S cathodes and anodes based on the issues resulting from low E/S and the corresponding solutions are summarized. These will be beneficial for a systematic understanding of the rational design ideas and research trends of low E/S LSBs. In particular, three strategies are proposed for cathodes: preventing PS formation/aggregation to avoid inadequate dissolution, designing multifunctional macroporous networks to address incomplete infiltration, and utilizing an imprison strategy to relieve the adsorption dependence on specific surface area. Finally, the challenges and future prospects for low E/S LSBs are discussed.     

TiO2/MXene-Assisted LDI-MS for Urine Metabolic Profiling in Urinary Disease

Cancer remains an intractable medical problem. Rapid diagnosis and identification of cancer are critical to differentiate it from nonmalignant diseases. High-throughput biofluid metabolic analysis has potential for cancer diagnosis. Nevertheless, the present metabolite analysis method does not meet the demand for high-throughput screening of diseases. Herein, a high-throughput, cost-effective, and noninvasive urine metabolic profiling method based on TiO₂/MXene-assisted laser desorption/ionization mass spectrometry (LDI-MS) is presented for the efficient screening of bladder cancer (BC) and nonmalignant urinary disease. Combined with machine learning, TiO₂/MXene-assisted LDI-MS enables high diagnostic accuracy (96.8%) for the classification of patient groups (including 47 BC and 46 ureteral calculus (UC) patients) from healthy controls (113 cases). In addition, BC patients can also be identified from noncancerous UC individuals with an accuracy of 88.3% in the independent test cohort. Furthermore, metabolite variations between BC and UC individuals are investigated based on relative quantification, and related pathways are also discussed. These results suggest that this method, based on urine metabolic patterns, provides a potential tool for rapidly distinguishing urinary diseases and it may pave the way for precision medicine.     

A volatolomic approach using cerumen as biofluid to diagnose bovine intoxication by Stryphnodendron rotundifolium

An innovative volatolomic approach employs the detection of biomarkers present in cerumen (earwax) to identify cattle intoxication by Stryphnodendron rotundifolium Mart., Fabaceae (popularly known as barbatimão). S. rotundifolium is a poisonous plant with the toxic compound undefined and widely distributed throughout the Brazilian territory. Cerumen samples from cattle of two local Brazilian breeds (‘Curraleiro Pé-Duro’ and ‘Pantaneiro’) were collected during an experimental intoxication protocol and analyzed using headspace (HS)/GC–MS followed by multivariate analysis (genetic algorithm for a partial least squares, cluster analysis, and classification and regression trees). A total of 106 volatile organic metabolites were identified in the cerumen samples of bovines. The intoxication by S. rotundifolium influenced the cerumen volatolomic profile of the bovines throughout the intoxication protocol. In this way, it was possible to detect biomarkers for cattle intoxication. Among the biomarkers, 2-octyldecanol and 9-tetradecen-1-ol were able to discriminate all samples between intoxicated and nonintoxicated bovines. The cattle intoxication diagnosis by S. rotundifolium was accomplished by applying the cerumen analysis using HS/GC–MS, in an easy, accurate, and noninvasive way. Thus, the proposed bioanalytical chromatography protocol is a useful tool in veterinary applications to determine this kind of intoxication.     

An improved LC–MS/MS method for determination of docetaxel and its application to population pharmacokinetic study in Chinese cancer patients

Because of its unpredictable side effects and efficacy, the anticancer drug docetaxel (DTX) requires improved characterisation of its pharmacokinetic profiles through population pharmacokinetic studies. A sensitive and rugged LC–MS/MS method for the detection of DTX in human plasma was developed and optimised using paclitaxel as an internal standard (IS). The plasma samples underwent rapid extraction using hybrid solid-phase extraction-protein precipitation. The analyte and IS were separated with an isocratic system on a Zorbax Eclipse Plus C₁₈ column using water containing 0.05% acetic acid along with 20 μM of sodium acetate and methanol (30/70, v/v) as the mobile phase. Quantification was performed using a triple quadrupole mass spectrometer through multiple reaction monitoring in positive mode, using the m/z 830.3 → 548.8 and m/z 876.3 → 307.7 transitions for DTX and paclitaxel, respectively. The range of the calibration curve was 1–500 ng/mL for DTX, and the linear correlation coefficient was >0.99. The accuracies ranged from −4.6 to 4.2%, and the precision was no higher than 7.0% for the analytes. No significant matrix effect was observed. Both DTX and the IS showed considerable recovery. This method was finally applied to the establishment of a population pharmacokinetic model to optimise the clinical use of DTX.     

A dried blood spot assay with HPLC–MS/MS for the determination of larotrectinib in mouse blood and its application to a pharmacokinetic study

Larotrectinib is a first-generation tropomyosin kinase inhibitor, approved for the treatment of solid tumors. In this paper, we present a validated dried blood spot (DBS) method for the quantitation of larotrectinib from mouse blood using HPLC–MS/MS, which was operated under multiple reaction monitoring mode. To the DBS disc cards, acidified methanol enriched with internal standard (IS; enasidenib) was added and extracted using tert-butyl methyl ether as an extraction solvent with sonication. Chromatographic separation of larotrectinib and the IS was achieved on an Atlantis dC₁₈ column using 10 mm ammonium formate–acetonitrile (30:70, v/v) delivered at a flow-rate of 0.80 ml/min. Under these optimized conditions, the retention times of larotrectinib and the IS were ~0.93 and 1.37 min, respectively. The total run time was 2.50 min. Larotrectinib and the IS were analyzed using positive ion scan mode and parent–daughter mass to charge ion (m/z) transitions of 429.1 → 342.1 and 474.1 → 267.1, respectively, were used for the quantitation. The calibration range was 1.06–5,080 ng/ml. No matrix effect or carryover was observed. Hematocrit did not influence DBS larotrectinib concentrations. All of the validation parameters met the acceptance criteria. The applicability of the validated method was shown in a mouse pharmacokinetic study.     

Change of evaporation rate of single monocomponent droplet with temperature using time-resolved phase rainbow refractometry

Droplet evaporation characterization, although of great significance, is still challenging. The recently developed phase rainbow refractometry (PRR) is proposed as an approach to measuring the droplet temperature, size as well as evaporation rate simultaneously, and is applied to a single flowing n-heptane droplet produced by a droplet-on-demand generator. The changes of droplet temperature and evaporation rate after a transient spark heating are reflected in the time-resolved PRR image. Results show that droplet evaporation rate increases with temperature, from ?1.28$\times {10}^{?8}$ m²/s at atmospheric 293 K to a range of (?1.5, ?8)$\times {10}^{?8}$ m²/s when heated to (294, 315) K, agreeing well with the Maxwell and Stefan–Fuchs model predictions. Uncertainty analysis suggests that the main source is the indeterminate gradient inside droplet, resulting in an underestimation of droplet temperature and evaporation rate. With the demonstration on simultaneous measurements of droplet refractive index as well as droplet transient and local evaporation rate in this work, PRR is a promising tool to investigate single droplet evaporation in real engine conditions.     

Definition and detection of data-based uniqueness in evaluating bilinear (two-way) chemical measurements

Multivariate curve resolution methods, frequently used in analyzing bilinear data sets, result in ambiguous decomposition in general. Implementing the adequate constraints may lead to reduce the so-called rotational ambiguity drastically, and in the most favorable cases to the unique solution. However, in some special cases, non-negativity constraint as minimal information of the system is a sufficient condition to resolve profiles uniquely. Although, several studies on exploring the uniqueness of the bilinear non-negatively constrained multivariate curve resolution methods have been made in the literature, it has still remained a mysterious question. In 1995, Manne published his profile-based theorems giving the necessary and sufficient conditions of the unique resolution. In this study, a new term, i.e., data-based uniqueness is defined and investigated in details, and a general procedure is suggested for detection of uniquely recovered profile(s) on the basis of data set structure in the abstract space. Close inspection of Borgen plots of these data sets leads to realize the comprehensive information of local rank, and these argumentations furnish a basis for data-based uniqueness theorem. The reported phenomenon and its exploration is a new stage (it can be said fundament) in understanding and describing the bilinear (matrix-type) chemical data in general.     

Salting‐out‐assisted liquid–liquid extraction with acetonitrile for the determination of trimetazidine in rat plasma using liquid chromatography–mass spectrometry

A high‐throughout bioanalytical method based on salting‐out‐assisted liquid/liquid extraction (SALLE) method with acetonitrile and mass spectrometry‐compatible salts followed by LC‐MS/MS analysis of trimetazidine in rat plasma is presented. It required only 50 μL of plasma and allows the use of minimal volumes of organic solvents. The seamless interface of SALLE and LC‐MS eliminated the drying‐down step and the extract was diluted and injected into an LC‐MS/MS system with a cycle time of 2.5 min/sample. The retention times of trimetazidine and IS were approximately 1.1 and 1.7 min, respectively. Calibration curves were linear over the concentration range of 0.1–100 ng/mL, which can be extended to 500 ng/mL by dilution. The intra‐ and inter‐batch precision, accuracy and the relative standard deviation were all <15%. This method was successfully applied to determine trimetazidine concentrations in rat plasma. Copyright © 2014 John Wiley & Sons, Ltd.     

Metabolic profiles of dioscin in rats revealed by ultra‐performance liquid chromatography quadrupole time‐of‐flight mass spectrometry

Dioscin (DIS), one of the most abundant bioactive steroidal saponins in Dioscorea sp., is used as a complementary medicine to treat coronary disease and angina pectoris in China. Although the pharmacological activities and pharmacokinetics of DIS have been well demonstrated, information regarding the final metabolic fates is very limited. This study investigated the in vivo metabolic profiles of DIS after oral administration by ultra‐performance liquid chromatography quadrupole time‐of‐flight mass spectrometry method. The structures of the metabolites were identified and tentatively characterized by means of comparing the molecular mass, retention time and fragmentation pattern of the analytes with those of the parent compound. A total of eight metabolites, including seven phase I and one phase II metabolites, were detected and tentatively identified for the first time. Oxidation, deglycosylation and glucuronidation were found to be the major metabolic processes of the compound in rats. In addition, a possible metabolic pathway on the biotransformation of DIS in vivo was proposed. This study provides valuable and new information on the metabolism of DIS, which will be helpful for further understanding its mechanism of action. Copyright © 2015 John Wiley & Sons, Ltd.