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Thymus species (Lamiaceae), commonly referred to as thyme, have gained popularity due to their utilisation in traditional medicine for various ailments such as gastrointestinal disorders, colds, upper respiratory infections, vomiting, jaundice, oral hygiene and oral ulcers. Nevertheless, a significant number of Thymus species remain unexplored in terms of their bioactivity and phenolic content. In the present study, a thorough chemical analysis of endemic Thymus canoviridis methanol (METC)-water extracts (WETC) and Thymus pubescens var. pubescens methanol (METP)-water extracts (WETP) was carried out by Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). In addition, the inhibitory effect and antioxidant properties of these extracts on the enzymes acetylcholinesterase (AChE), α -glycosidase and carbonic anhydrase II (CA II) were also evaluated. The antioxidant potential was assessed using six assays, namely DPPH, ABTS, DMPD, FRAP, CUPRAC and Fe3+ reducing assays. Our results suggest that the methanol extract from these two plants exhibits a higher level of antioxidant activity. Furthermore, WETP inhibited all enzymes in the best way. According to the UPLC-MS/MS analysis results, rosmarinic acid showed its highest content in METC (18285.55 µg/g extract), WETC (27.98 µg/g extract) and METP (2910.59 µg/g extract), while WETP (69.76 µg/g extract) and the following total amounts of phenolic compounds were METC 20726.55 µg/g extract, METP 5887.20 µg/g extract, WETP 348.98 µg/g extract, WETC 68.56 µg/g extract. It is consistent with the analytical result, total phenolic content, and activity ranking in antioxidant assays. Regard to the results of the molecular docking studies, there is a high binding affinity between the CA II enzyme and cyanidin-3- O -glycoside, between the AChE and keracyanin chloride, and between α -glycosidase enzyme and rosmarinic acid. The extracts were discovered to exhibit various biological activities, such as antioxidant, antidiabetic, anti-Alzheimer's disease, and antiglaucoma properties. [Display omitted] • Antioxidant and antimicrobial activities of Thymus species were evaluated using several bioassays. • Comprehensive metabolic profiling of Thymus species was relaized by UPLC-MS/MS. • Anti-Alzheimer, antidiabetic, anti-glaucoma effects of Thymus species were determined and compared to standards. • High binding affinity was detected between CA II enzyme-cyanidin-3- O -glucoside, AChE-keracyanin chloride, and α -glycosidase-rosmarinic acid. [ABSTRACT FROM AUTHOR]

Acylcarnitines are metabolic intermediates of fatty acids and branched-chain amino acids having vital biofunctions and pathophysiological significances. Here, we developed a high-throughput method for quantifying hundreds of acylcarnitines in one run using ultrahigh performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). This enabled simultaneous quantification of 1136 acylcarnitines (C0–C26) within 10-min with good sensitivity (limit of detection < 0.7 fmol), linearity (correlation coefficient > 0.992), accuracy (relative error < 20%), precision (coefficient of variation (CV), CV < 15%), stability (CV < 15%), and inter-technician consistency (CV < 20%, n = 6). We also established a quantitative structure-retention relationship (goodness of fit > 0.998) for predicting retention time (t R) of acylcarnitines with no standards and built a database of their multiple reaction monitoring parameters (t R , ion-pairs, and collision energy). Furthermore, we quantified 514 acylcarnitines in human plasma and urine, mouse kidney, liver, heart, lung, and muscle. This provides a rapid method for quantifying acylcarnitines in multiple biological matrices. [Display omitted] • A sensitive 10-min method for simultaneous quantification of multiple acylcarnitines. • Quantification of 514 acylcarnitines in multiple biofluids and tissues for molecular phenotyping. • Quantitative structure-retention relationship and database of MRM parameters (t R , ion-pairs, and CE) for 1136 acylcarnitines. [ABSTRACT FROM AUTHOR]

Onion has been historically valued for its various health promoting activities. It has been traditionally used to treat various infectious diseases and alleviate the symptoms of several respiratory ailments. However, the therapeutic potential of the plant against respiratory viruses remains meager. This study aimed to investigate the metabolic profiles of bulb extracts of four onion cultivars (red, copper-yellow, golden yellow and white onions) using UPLC-MS/MS combined to chemometrics. Further, the extracts were assessed for their potential anti-COVID-19 activity against the omicron sub-variant BA.5 of SARS-CoV-2. A total of 81 metabolites of diverse chemical classes were identified including amino acids and peptides, flavonoids, phenolic acids, saponins and fatty acids. The four cultivars displayed significant variations in their chemical composition, with copper-yellow onion exhibiting the richest metabolic profile which distinguished it from the others. Except for white onion, the tested cultivars displayed promising anti-COVID-19 activities (IC 50 9.78–16.39 μg/mL) and effectively downregulated viral RNA dependent RNA polymerase (RdRp) and envelope (E) genes. Multivariate analysis revealed potential anti-COVID-19 bioactive metabolites. Among them, chlorogenic, caffeic acids, and kaempferol effectively inhibited viral RdRp and E genes in vitro , with a % downregulation of (86 %, 79 %), (80 %, 73 %), and (82 %, 70 %), respectively, at 30 μg/mL. The results from in vitro testing were corroborated by molecular docking and dynamics studies as the compounds showed significant interactions with the viral target proteins forming stable protein-ligand complexes. This study increments the value of metabolomics as a promising tool for cultivar differentiation. Conjointly, it lays the groundwork for future research into the anti-COVID-19 potential of onion as a valuable source of bioactive compounds. [Display omitted] • UPLC-MS analysis combined to chemometrics allowed efficient metabolic profiling of bulb extracts of four onion cultivars (red, copper-yellow, golden yellow and white onions). • The tested cultivars exhibited significant variations in their chemical profiles, with copper-yellow onion displaying the richest metabolic profile which distinguished it from others. • Red, copper-yellow, and golden yellow onions displayed promising anti-COVID-19 potentials against the omicron subvariant BA.5. • The coefficient plot revealed potential anti-COVID-19 bioactive metabolites among which caffeic, chlorogenic acids and kaempferol efficiently inhibited viral RdRp and E genes in vitro. • Molecular docking and dynamics studies on the biomarkers corroborated the findings of in vitro testing. [ABSTRACT FROM AUTHOR]

The use of kinetic modeling data for the extraction of bioactive compounds is essential for food industries. This work aimed to investigate which mathematical model best fits the extraction of bioactive compounds from camu-camu peel and to evaluate the effect of drying by hot air convection (60 ºC). Four mathematical models (parabolic diffusion, power law, hyperbolic and pseudo-second order) were applied to assess the extraction conditions. To describe the kinetics and data modeling the peels went through ultrasound-assisted extraction (UAE) for 1 h, 6 h, 12 h, and 24 h with water and water-ethanol (50:50 v/v) as solvents. The hyperbolic and pseudo-second order mathematical models presented the best fitting to the experimental data with lower values of γ ², MSE, RMSE, and NRMSE, in addition to values closer to 1 for EF. The extracts went through UPLC-MS/MS and nine compounds were identified in the peels: cyanidin 3-o-glucoside, delphinidin, quercetin, myricetin, rutin, gallic acid, chlorogenic acid p-coumaric and ellagic acid. Therefore, dried camu-camu peels still have antioxidant potential, especially when extracted for 12 h with water-ethanol (50:50 v/v) as solvent. [Display omitted] • The selection of fruits was based on the color of the peel: green and red. • Extraction was performed in an ultrasonic bath in indirect contact. • Best results were obtained with ethanol/water (v/v) and extraction times of 12 and 24 h. • Hyperbolic and pseudo-second kinetic model presented the best fits. • The use of UPLC-MS/MS resulted in the determination of 9 bioactive compounds types. [ABSTRACT FROM AUTHOR]

Taraxacum mongolicum Hand.-Mazz. (TM) is a commonly used Chinese herbal medicine. Phenolic natural products are one of its main active components, which have a relationship with its biological activities. Previous studies have reported certain differences in the biological activities of different parts of TM. The present study aims to quantitatively analyze 130 phenolic metabolites in the roots, leaves and flowers of TM using UPLC-QTRAP-MS/MS. The method detected seventy-five metabolites in roots, seventy-three in leaves and eighty-two in flowers. Additionally, the differential metabolites and metabolic pathways were further studied using statistical analysis methods. Four, nine, and ten differential metabolites were detected upon comparison between the leaves and roots, flowers and roots, and flowers and leaves, while the three parts compared together showed twelve differential metabolites. Differences in metabolic pathways were determined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) based pathway analysis. Our results indicated that differential production of phenolic metabolites exists in TM roots, leaves and flowers, which may explain differences in efficacy of different parts. Therefore, it is recommended to use TM roots, leaves, and flowers separately. It is also worth noting that TM flowers had the highest content of phenolic metabolites. Furthermore, caftaric acid and delphinidin 3- O -glucoside may be used as chemical markers to identify different source parts of TM powder. [Display omitted] • Differential production of phenolic metabolites exists in Taraxacum mongolicum roots, leaves and flowers. • Taraxacum mongolicum flowers have the highest content of phenolic metabolites. • Caftaric acid and delphinidin 3- O -glucoside can be used as chemical markers to identify the different parts. • The different parts of Taraxacum mongolicum may have different trends in metabolic pathways. [ABSTRACT FROM AUTHOR]

An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous quantitation of doxorubicin (DOX) and sorafenib (SOR) in rat plasma. Chromatographic separation was performed using a reversed-phase column C 18 (1.7 μm, 1.0 × 100 mm Acquity UPLC BEH™). The gradient mobile phase system consisted of water containing 0.1% acetic acid (mobile phase A) and methanol (mobile phase B) with a flow rate of 0.40 mL/min over 8 min. Erlotinib (ERL) was used as an internal standard (IS). The quantitation of conversion of [M + H]+, which was the protonated precursor ion, to the corresponding product ions was performed using multiple reaction monitoring (MRM) with a mass-to-charge ratio (m / z) of 544 > 397.005 for DOX, 465.05 > 252.03 for SOR, and 394 > 278 for the IS. Different parameters were used to validate the method including accuracy, precision, linearity, and stability. The developed UPLC–MS/MS method was linear over the concentration ranges of 9–2000 ng/mL and 7–2000 ng/mL with LLOQ of 9 and 7 ng/mL for DOX and SOR, respectively. The intra-day and inter-day accuracy, expressed as % relative standard deviation (RSD%), was below 10% for both DOX and SOR in all QC samples that have drug concentrations above the LLOQ. The intra-day and inter-day precision, expressed as percent relative error (Er %), was within the limit of 15.0% for all concentrations above LLOQ. Four groups of Wistar rats (250–280 g) were used to conduct the pharmacokinetic study. Group I received a single intraperitoneal (IP) injection of DOX (5 mg/kg); Group II received a single oral dose of SOR (40 mg/kg), Group III received a combination of both drugs; and Group IV received sterile water for injection IP and 0.9% w/v sodium chloride solution orally to serve as a control. Non-compartmental analysis was used to calculate the different pharmacokinetic parameters. Data revealed that coadministration of DOX and SOR altered some of the pharmacokinetic parameters of both agents and resulted in an increase in the Cmax and AUC and reduction in the apparent clearance (CL/F). In conclusion, our newly developed method is sensitive, specific, and can reliably be used to simultaneously determine DOX and SOR concentrations in rat plasma. Moreover, the results of the pharmacokinetic study suggest that coadministration of DOX and SOR might cause an increase in exposure of both drugs. [ABSTRACT FROM AUTHOR]

Dendrobium officinale (DO) is a perennial herb that has been utilized medicinal and edible purposes for thousands of years, often transforming into 'Fengdou' after drying. Despite its long-standing use, the specific phenolic components present during DO processing have remained elusive. This study established a method for the simultaneous and accurate quantification of 27 phenolic compounds during DO processing employing ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), with 8 reference-free components optimized through an online strategy. Furthermore, correlation analysis and molecular docking were conducted to further screened and validated 6 phenolics with α-glucosidase inhibitory activity, including vanillin, p -coumaric acid, 4-hydroxybenzaldehyde, resveratrol, coniferyl alcohol, and dihydropinosylvin. Notably, resveratrol exhibited the lowest binding energy at −7.7 kcal/mol among these compounds. These findings significantly contribute to the development of the deep-processing techniques for DO and the hypoglycaemic functional food industry by providing data that support the elucidation of medicinal substances in DO. • Twenty-seven phenolic compounds in DO were quantification employing UPLC-MS/MS. • Online strategies were used to optimize the parameters of reference-free compounds • Correlation analysis showed 6 phenolics with α-glucosidase inhibitory activity. • Molecular docking indicated resveratrol showed the lowest binding energy. [ABSTRACT FROM AUTHOR]

Phytic acid (IP6) and its degradation products lower myo-inositol phosphates exert different impacts on nutrient bioavailability and product quality characteristics. However, information regarding the occurrence of IP6 and its degradation products is scarce. In this work, simultaneous determination of IP6 and its degradation products in soybeans was developed, with emphasis on analysis by UPLC-MS/MS and a BEH Amide column both with hybrid surface technology. The retention and analyte/metal surface interactions issues were effectively addressed without ion-pairing reagents addition or derivatization. This method was applied to analyze soybeans from China. Total contents were 0.44–13.2 mg/g, and IP6 and its degradation product myo-inositol pentakisphosphate (IP5) were the predominant analytes, accounting for over 99%. Accession type significantly affected IP5 content, and landraces had significantly higher IP5 than cultivars. Geographically, the lowest IP6 was concentrated in the Huanghuaihai region. Significant correlations existed between IP6 and longitude, altitude, and annual cumulative sunshine hours. This study provides comprehensive insights into the IP6 and its degradation product profile in soybeans, which will benefit breeding soybeans based on specific requirements. • Analysis of IP1–6 was improved by UPLC-MS/MS and an amide column both with the HST • The retention was increased without ion-pairing reagents addition or derivatization • IP6 and IP5 were the predominant analytes, both accounting for over 99% • Landraces had significantly higher contents of IP5 than cultivars • IP6 was significantly correlated with certain geographical and climatic factors [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as icotinib, osimertinib, and aumolertinib have emerged as promising treatment options for EGFR mutated Non-small cell lung cancer (NSCLC) patients. Additionally, anlotinib, an anti-angiogenic agent targeting VEGFR, FGFR, and PDGFR, has been used in combination with EGFR-TKIs in NSCLC cases. A method utilizing ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated for quantifying icotinib, osimertinib, aumolertinib and anlotinib simultaneously in clinical TDM. The chromatographic separation was performed using a Kinetex C18 column (100 mm × 2.1 mm) and an elution gradient of ammonium acetate in water acidified with 0.1 % formic acid and in acetonitrile. The assay was validated over a linear range of 4–2000 ng/mL for icotinib, 2–1000 ng/mL for osimertinib, 1–500 ng/mL for aumolertinib, and 0.8–400 ng/mL for anlotinib, following the guidelines on bioanalytical methods by FDA. The quantification method exhibited satisfactory performance in terms of selectivity, accuracy (from 91.3 % to 107 %), precision (intra- and inter-day coeffficients of variation ranged from 0.944 % to 7.48 %), linearity, recovery (from 86.0 % to 91.9 %), matrix effect (IS-normalized matrix factors were from 96.7 % to 102 %), and stability. Overall, the method proved to be sensitive, reliable, and straightforward, enabling successful simultaneous determination of blood concentrations of icotinib, osimertinib, aumolertinib, and anlotinib in patients. The validity of the method has been confirmed across various instruments. • Develop and validate a UPLC-MS/MS method for the determination of four TKIs in human plasma. • Validate the concentration determination method across different instruments. • The method was utilized in Chinese NSCLC patients, fulfilling the requirement for TDM. [ABSTRACT FROM AUTHOR]

Pharmaceutical care is important for mental health during the perinatal period, which is often characterized by insomnia. In recent years, prescriptions of melatonin receptor agonists (MRAs) and dual orexin receptor antagonists (DORAs) for insomnia have increased; however, their use during the perinatal period has scarcely been reported. In the present study, we developed a UPLC-MS/MS method for the quantification of ramelteon, its metabolite M-II, suvorexant, and lemborexant in human plasma and breast milk to accumulate information on the safety and transfer of MRAs and DORAs into breast milk. Samples of MRAs (ramelteon and M-II) in plasma and breast milk were prepared using liquid–liquid extraction (LLE) with ethyl acetate. For DORAs (suvorexant and lemborexant), LLE with ethyl acetate was applied to plasma samples. For breast milk samples, significant ion suppression was observed for LLE with ethyl acetate. Solid-phase extraction (SPE) cartridges capable of removing phospholipids improved the matrix effects. Finally, protein precipitation with methanol and an SPE cartridge, InertSep® Phospholipid Remover, were selected for breast milk sample preparation. An ACQUITY UPLC BEH C18 column was used for analyte separation. MRAs and DORAs were eluted using isocratic and gradient elution, respectively, and analyzed using electrospray ionization in the positive mode with multiple reaction monitoring. The range of calibration curve for MRAs and DORAs was 0.1–25 and 0.5–50 ng/ml, respectively. Both the plasma and breast milk samples exhibited good linearity over this range. The method was validated by evaluating its accuracy and precision, matrix effect, recovery, carry-over, stability, and dilution integrity. The validated method was successfully applied to clinical samples donated by breastfeeding women and the milk/plasma (M/P) ratio and relative infant dose (RID) of lemborexant (one case) and suvorexant (two cases) were estimated. The M/P ratio of lemborexant was <1, and the RID was 1.05 %. The M/P ratio of suvorexant was <0.1, and RID was 0.11–0.20 %. This method will be useful for future studies evaluating the safety of these drugs during breastfeeding. ● A UPLC-MS/MS method was devised for MRA and DORA in plasma and breast milk. ● Sample preparation procedures were established considering the matrix effect. ● The method was successfully applied to quantitate DORAs in clinical samples. ● The M/P ratios and RIDs of DORAs were estimated from the quantified data. [ABSTRACT FROM AUTHOR]

Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) who are resistant to or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. Given that ponatinib can induce significant cardiotoxicity when taken, and that most Chinese medicines have cardioprotective effects, it is possible to administer them in combination in clinic to alleviate adverse effects. The quantitative determination of ponatinib and its metabolite N-desmethyl ponatinib was optimized and fully verified by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). And the drug-drug interactions (DDI) of ponatinib with lycopene and shikonin, both in vivo and in vitro , were studied. The results of bioanalytical methodology showed that ponatinib and N-desmethyl ponatinib had good linearity in plasma samples, and their selectivity, accuracy, precision, stability, matrix effect and recovery were all satisfied with the need of quantitative analysis of samples. In animal experiments, compared with the control group, lycopene and shikonin significantly changed the pharmacokinetic parameters of ponatinib, including AUC (0-t) , AUC (0-∞) and CL z/F , while having no effect on the pharmacokinetic parameters of N-desmethyl ponatinib. In vitro interaction studies indicated that lycopene showed mixed inhibition mechanism on ponatinib metabolism in both rat liver microsomes (RLM) and human liver microsomes (HLM). And, shikonin displayed mixed inhibition mechanism in RLM and competitive inhibition mechanism in HLM, respectively. In summary, the UPLC-MS/MS method can accurately and sensitively quantify ponatinib and N-desmethyl ponatinib, and provide further reference for clinical drug combination between ponatinib and lycopene or shikonin. • The UPLC-MS/MS analysis method of ponatinib and N -desmethyl ponatinib was verified. • The DDI of ponatinib with lycopene and shikonin was studied for the first time. • Both lycopene and shikonin have inhibitory effects on ponatinib metabolism. [ABSTRACT FROM AUTHOR]

Hibiscus sabdariffa L. (roselle) is a medicinal and edible plant which rich in anthocyanins with potent antioxidant properties. To enhance the stability of roselle anthocyanins, they were encapsulated in nanocapsules composed of carboxymethyl chitosan (CMC), chitosan hydrochloride (CHC), and β-lactoglobulin (β-Lg). In vitro simulated digestion assays evaluated the impact of various core-to-wall ratios and β-Lg concentrations on the bioaccessibility of seven anthocyanins. Nanocapsules with a core-to-wall ratio of 1:2 and β-Lg at 10 mg/mL exhibited the highest encapsulation efficiency (EE). Cyanidin-3-glucoside had the highest EE , while cyanidin-3-sambubioside showed the outstanding retention rate. Furthermore, simulated digestion experiments combined with molecular docking revealed that peonidin-3-glucoside and petunidin-3-glucoside likely interact with and bind to the outer β-Lg layer of the nanocapsules, increasing their release during in vitro digestion. This study demonstrates that encapsulating roselle anthocyanins in CMC, CHC, and β-Lg nanocapsules significantly enhances their bioaccessibility. Graphical abstract Roselle anthocyanins were encapsulated in nanocapsules using six different material concentrations. The encapsulation properties were evaluated to identify the optimal formulation with favorable particle characteristics and maximum bioaccessibility. During in vitro simulated digestion, changes in seven anthocyanins were monitored, highlighting cyanidin-3-sambubioside's high retention rate. Molecular docking analysis revealed that additional hydrophobic bonds enhance the binding of peonidin-3-glucoside and petunidin-3-glucoside to β-lactoglobulin in the capsule shell. [Display omitted] • C3G exhibited the highest encapsulation efficiency among quantified anthocyanins. • Hydroxyl groups in B-ring may increase the environmental sensitivity of D3G. • C3S showed the high retention rate during simulated digestion. • Hydrophobic bonds facilitate interaction of PEO and PET with β-lactoglobulin. [ABSTRACT FROM AUTHOR]

• The first UPLC-MS/MS method for analyzing furmonertinib in human plasma and cerebrospinal fluid. • The method was proved to be efficient and robust with high sensitivity and selectivity. • We firstly reported the penetration rates of furmonertinib in human cerebrospinal fluid. • Furmonertinib was proved to be penetrated with high concentration in cerebrospinal fluid. Furmonertinib (AST2818) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) being developed for the treatment of patients with EGFR mutation-positive non-small cell lung cancer. Quantification of furmonertinib in plasma and cerebrospinal fluid (CSF) can be used to assess penetration of furmonertinib into the central nervous system (CNS). This paper described ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) methods for quantification of furmonertinib in human plasma and CSF. Sample separation was achieved on a Kinetex C 18 column (100 mm × 2.1 mm, 2.6 μm) after simple protein precipitation with acetonitrile. The mobile phase was composed of acetonitrile and 5 mM ammonium acetate with 0.2 % formic acid in water. Quantitative ion pairs were m / z 569.3 → 72.2 for furmonertinib and m / z 526.5 → 72.2 for aumolertinib, which was used as the internal standard (IS). The calibration curves showed good linearity (r2 > 0.99) over concentration range of 0.5–200 ng/mL(plasma sample) and 0.05–30 ng/mL(CSF sample). The precision (RSD) was ≤7.86 %, and the accuracy fell within the range of 96.2 %–109.3 %, all meeting acceptance criteria. The matrix effect was from 94.3 % to 102.1 %. The recovery of analytes fell within the range of 93.3 %–98.9 %. The established analytical methods showed great sensitivity, simplicity, accuracy and reliability for the analysis of furmonertinib in human plasma and CSF. This assay would be helpful to predict the effectiveness and toxicities of furmonertinib in the pursuit of precision medicine for lung cancer patients. [ABSTRACT FROM AUTHOR]

[Display omitted] • An UPLC-MS/MS method is established to determine three components of BDE. • PK study of three components of BDE is conducted in normal and AA rats. • PK study of three components of BDE is conducted in normal and inflammatory cell. • It has laid the foundation for the development and utilization of BDE. Biancaea decapetala (Roth) O.Deg. (Fabaceae), traditionally utilized by the Hmong for treating rheumatoid arthritis (RA), has its pharmacokinetic behavior under disease conditions largely unexplored. In view of this, a UPLC-MS/MS method was established for the determination of protosappanin B (PTB), protosappanin B-3- O-β-D -glucoside (PTD), and 3-deoxysappanchalcone (3-DSC), key bioactive components of the herb, in rat plasma and RAW264.7 cells to explore the effect of disease state on the pharmacokinetic profiles changes of these three components in vitro and in vivo. These components were detected using multiple reaction monitoring (MRM) process in positive and negative mode. Each calibration curve had a high R 2 value of > 0.99. The intra- and inter-day precisions of PTD, PTB, 3-DSC were all < 15 %, and accuracy ranged from 85 % to 115 %. The RSD values pertaining to stability, recovery, matrix effect, and stability remained below 15.0 %. It was successfully applied for the investigation of the pharmacokinetics of these three components in rat plasma and RAW264.7 cells after administration of Biancaea decapetala extracts (BDE). In rat pharmacokinetic experiments, significant differences were observed in the AUC (0-t) , MRT (0-t) , and Cl z / F values of PTD, PTB, 3-DSC between adjuvant-induced arthritis (AA) and normal rats. In cellular pharmacokinetic experiments, comparison with the normal group revealed increased AUC (0-t) and MRT (0-t) for these three components in the LPS-induced inflammatory cell model, along with decreased Cl z / F , which was consistent with in vivo experimental outcomes. These findings suggest an increased absorption rate and a decreased elimination rate of the three components of BDE in AA rats and inflammatory cells, indicating a potential alteration in the rate and extent of drug metabolism. This study provided a theoretical reference for further clarification of its pharmacodynamic basis. [ABSTRACT FROM AUTHOR]

• Freshwater eutrophication contributes to the increase of Harmful algal blooms. • Stability of anatoxin-a and saxitoxin in water was studied during 24 h. • Zebrafish larvae exposed to anatoxin-a and saxitoxin showed hypolocomotion. • Anatoxin-a significantly increased methionine and glutamate levels in zebrafish. • Saxitoxin enhanced 3-methoxytyramine levels, impacting in behavior and metabolism. Global warming due to climate change, as well as freshwater eutrophication caused by anthropogenic activities are responsible, among other factors, for an increasing occurrence of harmful algal blooms (HABs) in aquatic systems. These can lead to the generation of cyanotoxins, secondary metabolites coming from cyanobacteria, producing adverse effects in living organisms including death. This research aims to study the effects that two neurotoxins, anatoxin-a (ATX-a) and saxitoxin (STX), have on living organisms. Once the stability of both compounds in water was determined for a 24 h period using ultra-high-performance liquid chromatography coupled to a triple quadrupole mass spectrometer (UPLC-MS/MS), zebrafish larvae were exposed to different levels of toxins (1 ng L −1, 10 ng L −1, 100 ng L −1 and 1 μg L −1) during 24 h. Behavioral studies including vibrational startle response (VSR), habituation to vibrational stimuli, basal locomotor activity (BLM) and visual motor response (VMR) were performed using Danio Vision system, and neurotransmitters (NTs) from 15-head pools of control and exposed zebrafish larvae were extracted and analyzed by UPLC-MS/MS. Both compounds induced hypolocomotion in the individuals, while 10 and 100 ng L −1 of ATX-a significantly increased methionine (120 % and 126 %, respectively) and glutamate levels (118 % and 129 %, respectively). Saxitoxin enhanced 3-metoxytyramine (3-MT) levels at 1 ng L −1 by 185 %. The findings of this study show that both studied cyanotoxins influence the behavior of zebrafish larvae as well as their metabolism. [ABSTRACT FROM AUTHOR]

Alternaria toxins (ATs) are produced from Alternaria species that result in crop losses and harmful impacts on human health. A stable isotope dilution LC–MS/MS method was established to quantify four ATs in 15 food commodities: alternariol (AOH), alternariol monomethyl ether (AME), tentoxin (TEN), and tenuazonic acid (TeA). Based on systematically optimization of detection conditions and pre-processing steps, the limits of detection and limits of quantification of the four ATs ranged from 0.1 to 10 μg/kg and 0.2 to 30 μg/kg, respectively. The results showed that the recoveries of the four ATs were 72.0%–119.1%. The intra-precision and inter-precision ranged from 0.7% to 11.1% and 1.1% to 13.1%, respectively. The method was successfully applied to the determination of four ATs in 35 food samples, suggesting that this method could provide meaningful occurrence data to support the assessment of emerging ATs in food commodities. • A new method for the quantification of four Alternaria toxins on diverse food matrices was developed. • A solid phase extraction method was optimized on 15 food commodities screening. • The susceptibility of raw-food material and their derivatives to ATs contamination were confirmed. • High incidence and levels of TeA and TEN were found in 35 food samples screening. • TeA contents were high in dried wolfberry, dried chilli, sunflower seed, tomato sauces and wheat. [ABSTRACT FROM AUTHOR]

Immunosuppressive drugs (ISDs) are given to avoid the allograft rejection after transplantation. The concentrations of ISDs should be closely monitored owing to their wide inter-individual variability in its pharmacokinetics and narrow therapeutic window. Currently, the whole blood concentration measurement is the major approach of therapeutic drug monitoring of clinical ISDs in organ transplantation. Its correlation with the efficacy of ISDs remains elusive. While the acute rejection after transplantation may occur even when whole-blood ISDs concentrations are within the target range. Since the site of action of ISDs are within the lymphocyte, direct measurement of drug exposure in target cells may more accurately reflect the clinical efficacy of ISDs. Although several methods have been developed for the peripheral blood mononuclear cells (PBMCs) extraction and drug concentration measurement, the complex pre-processing has limited the study of the relationship between intracellular ISDs concentrations and the occurrence of rejection. In this study, the extraction of ISDs in PBMCs was carried out by the liquid-liquid extraction with low temperature purification, without centrifugation. The lower limit of quantitation were 0.2 ng/mL for cyclosporine A, tacrolimus and sirolimus, 1.0 ng/mL for mycophenolic acid, and the within-run and between-run coefficient of variations were both less than 12.4 %. The calibration curves of mycophenolic acid had a linear range (ng/mL): 1.0–128.0 (r2 = 0.9992). The calibration curves of other three ISDs had a linear range (ng/mL): 0.2–20.48 (r2 > 0.9956). A total of 157 clinical samples were analyzed by the UPLC-MS/MS for ISDs concentration in blood or plasma ([ISD] blood or plasma) and the concentration within PBMCs ([ISD] PBMC). Although there was strong association between [ISD] PBMC and [ISD] blood or plasma , the large discrepancies between concentration within [ISD] blood or plasma and [ISD] PBMC were observed in a small proportion of clinical samples. The developed method with short analysis time and little amounts of blood sample can be successfully applied to therapeutic drug monitoring of ISDs in PBMCs for analysis of large numbers of clinical samples and is helpful to explore the clinical value of ISDs concentration in PBMCs. • A new pretreatment method is for determination of immunosuppressive drugs in PBMCs. • Only at least 0.8 mL of clinical whole blood sample was needed for assay. • The method can be applied to analysis of four immunosuppressive drugs in PBMCs. • It is easy operation, cost-saving and ideal for high-throughput analysis. [ABSTRACT FROM AUTHOR]

Both sedative and antipathogenic drugs are often found to be illegally used in aquaculture, but there is a lack of simultaneous monitoring methods. A method for simultaneously monitoring multiple prohibited drugs in various aquatic product samples was developed in this work, including fish, shrimp, crab, and shellfish. Sulfonic acid-functionalized magnetic graphitic carbon nitride (S-MGCN) was synthesized and validated to efficiently co-extract all targets (adsorption efficiency over 90.07%) through various adsorption mechanisms such as electrostatic interaction, hydrogen bonding, and π-π interaction while demonstrating good sample matrix purification ability (matrix effect below 13.60%). A new magnetic solid-phase extraction method based on S-MGCN was subsequently established. Coupled with UPLC-MS/MS, the detection limits were 0.030.075 μg /kg, and the recoveries ranged from 88.76% to 111.74% with the RSDs lower than 14.60%, indicating that the developed method has good sensitivity, accuracy, and precision. Further validation of its practicality was achieved through actual sample analysis. [Display omitted] • High throughput screening of multi-prohibited drugs in various aquatic samples was realized. • S-MGCN provides fast and efficient extraction of targets through multiple adsorption mechanisms. • S-MGCN exhibited good purification ability for sample matrix and reusability. • The accuracy and sensitivity of the method are equivalent to or better than existing methods. • The good practicality of the developed method was verified by testing actual samples. [ABSTRACT FROM AUTHOR]

• A rapid and sensitive UPLC-MS/MS method for determination of PEC in rat plasma and tissues. • The method involves a simple processing procedure with high sensitivity. • The analyte underwent extremely low bioavailability and high exposure in GI tract, liver and kidney. Pectolinarigenin (PEC), a natural flavonoid isolated from Cirsium japonicum , exhibits promising therapeutic potential for multiple cancers. In present study, a simple and sensitive UPLC-MS/MS method was established for the quantification of PEC in rat plasma and tissues. The assay procedure involved a one-step protein precipitation with tadalafil as the internal standard, and separation on a Welch Xtimate UHPLC C 18 column by gradient elution of acetonitrile/aqueous formic acid (0.1 %, v/v) at a flow rate of 0.2 m L·min−1. The detection was conducted using multiple-reaction monitoring via an electrospray ionization source in positive ionization mode. The established method was proved to be highly sensitive with a good linearity (R2 > 0.99) in respective concentration range (0.1–100 ng·mL−1 in plasma and 1–10,000 ng·mL−1 in tissues) and acceptable extraction recovery (≥71.17 %), matrix effect and stability, which was applied to study the pharmacokinetics and tissue distribution of PEC after intravenous (100 μg·kg−1) and oral administration (10, 20 and 40 mg·kg−1). PEC was promptly absorbed (T max ≤ 0.222 h) and maintained at a low level with slow elimination (t 1/2 z ≥ 14.47 h) in rats after oral administration, resulting in extremely low bioavailability (0.56–0.68 %). However, PEC is widely distributed in rat tissues with high exposure in GI tract, liver and kidney. The bioavailability and tissue affinity were firstly revealed, which would guide directions for further development of PEC as an anti-tumor drug candidate. [ABSTRACT FROM AUTHOR]

• Combining UPLC-MS/MS and DESI-MSI for metabolomics research. • The decrease of DCA in colon tissue of STC rats was proved by DESI-MSI. • SHTB inhibited the ileum ASBT and OST-α/β to regulate BA transport in STC rats. • SHTB alleviated STC by improving BA metabolism. Slow transit constipation (STC) is a common intestinal disorder. Some studies reported that Shouhui Tongbian Capsule (SHTB) can effectively mitigate STC symptoms. A detailed understanding of the changes in the endogenous metabolite profile of rats is crucial for a more accurate comprehension of the molecular pathological characteristics of SHTB in treating STC. In the present study, a method integrating metabolomics based on Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and Desorption electrospray ionization (DESI)-mass spectrometry imaging (MSI) was proposed to investigate serum, feces and colon tissue metabolic alterations of STC rats induced by diphenoxylate and the effect of SHTB treatment on metabolism. Then, Enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) analysis for verifying the potential mechanism of SHTB in treating STC. As a result, we first indicated that SHTB significantly improved intestinal peristalsis and low fecal water content in STC rats. Furthermore, after treatment with SHTB, the thickness of muscle layers was increased, demonstrated SHTB's effectiveness in reducing intestinal injury in STC rats. Besides, bile acid (BA) metabolomics based on UPLC-MS/MS revealed significant increase in serum levels of Cholic acid (CA), Deoxycholic acid (DCA), Chenodeoxycholic acid (CDCA), Ursodeoxycholic acid (UDCA), and Glycolithocholic acid (GLCA), whereas the contents of CA and DCA in feces were significantly decreased in STC rats. Nonetheless, they returned to the control levels after the SHTB administration. ELISA results showed that SHTB significantly hindered the excessive reabsorption of BAs by inhibiting apical sodium-dependent bile acid transporter (ASBT), organic solute transporter alpha (OSTα) and organic solute transporter beta (OSTβ) in the ileum tissue of STC rats. Furthermore, the DESI-MSI analysis revealed that SHTB remarkably enhanced DCA in the colon tissue of STC rats. The WB results indicated that SHTB reinstated Takeda G-protein–coupled receptor 5 (TGR5) expression, a receptor for BAs and a key regulator of colonic motility. Consequently, DCA exerted its effects on TGR5, leading to the promotion of colonic motility. This study provided more comprehensive and detailed information about the BA metabolomics in the serum, feces and colon of STC rats. These findings highlighted the promising potential of metabolomics based on UPLC-MS/MS and DESI-MSI method for application in the study of STC diseases. [ABSTRACT FROM AUTHOR]

• A validated UPLC-MS/MS assay for the measurement of taletrectinib in dog plasma. • Low sample volume is needed, as well as simple sample preparation by protein precipitation. • A high sensitivity (LLOQ 0.2 ng/mL) was achieved. • Excellent linearity was achieved between 0.2–200 ng/mL. • The assay was successfully applied to a pharmacokinetic study in dogs. Taletrectinib is a potent selective ROS and pan-NTRK tyrosine kinase inhibitor (TKI) and has been developed to treat non-small cell lung cancer (NSCLC). To facilitate pharmacokinetic and toxicokinetic studies of taletrectinib, we developed a procedure for ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to detect the plasma level of taletrectinib in dogs. This assay procedure was validated in compliance with FDA guidance. The dog plasma samples were spiked with internal standard (IS), followed by protein precipitation, and analyzed using a Waters ACQUITY BEH C 18 column coupled to a Thermo triple quadrupole mass spectrometer. Separation was executed using the acetonitrile-0.1 % formic acid solution with gradient elution, at a flow rate of 0.4 mL/min. Taletrectinib and IS were monitored by multiple reaction monitoring (MRM) with m / z 406.2 > 349.2 and m / z 441.2 > 138.1, respectively. The procedure demonstrated excellent linearity with a correlation coefficient greater than 0.999 within the concentration range of 0.2–200 ng/mL. The inter- and intra-day accuracy ranged from −5.25 % to 5.26 %, and the precision was below 6.39 %. Acetonitrile-mediated protein precipitation showed high extraction efficiency and a recovery above 85 %. The procedure was then applied to quantify taletrectinib in beagle dog plasma after oral and intravenous doses and achieved success. The obtained pharmacokinetic parameters indicated high bioavailability of taletrectinib (>85 %) and extensive tissue distribution (>40 L/kg). [ABSTRACT FROM AUTHOR]

[Display omitted] • The first UPLC-MS/MS method for analyzing BPI-460372 and its metabolites in human plasma. • The method is sensitive, simple, accurate, and reliable. • It can provide support further clinical studies and pharmacokinetic analysis. In cancer development and progression, the Hippo signaling pathway functions. The transcriptional enhanced associate domain (TEAD) stands out as a pivotal transcription factor within this pathway, and the suppression of TEAD represents a promising approach for cancer treatment. The primary aim of the study was to establish an analytical method for the concurrent quantification of a novel TEAD target inhibitor, BPI-460372, and its principal metabolites, BPI-460444 and BPI-460456, in human plasma. The chromatographic separation utilized a XSelect™ HSS C 18 column (2.1 × 100 mm, 2.5 µm), while quantification was conducted on a SCIEX API 4000 mass spectrometer. 22 plasma samples were tested via the developed method. The calibration curve for BPI-460372 exhibited linearity from 2 to 2000 ng/mL, while its metabolites BPI-460444 and BPI-460456 had linearity between 1 and 1000 ng/mL (r > 0.99). The precision (RSD) was ≤ 17.1 %, and the accuracy (RE) fell within the range of −17.7 % to 15.0 %, all meeting acceptance criteria. The matrix effect was from 101.0 % to 105.8 %. The extraction recovery of analytes fell within the range of 96.8 % to 104.1 % with an RSD of less than 7.4 %. The developed method was effectively utilized in an advanced solid tumor patient, and the concentration trends of the three analytes in plasma were found to be largely consistent. The established analytical method showed great sensitivity, simplicity, accuracy, and reliability for the rapid and simultaneous analysis of the TEAD target inhibitor BPI-460372, alongside its major metabolites BPI-460444 and BPI-460456 in human plasma. This analytical method provided essential support for future clinical investigations and pharmacokinetic analysis. [ABSTRACT FROM AUTHOR]

Fuzuloparib is a novel orally bioactive poly-ADP-ribose polymerase inhibitor (PARPi), which was approved by the Chinese Regulatory Agency (CRA) in 2020 for the treatment of platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancers. This study firstly presents a rapid and accurate ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for analyzing the levels of fuzuloparib and its major metabolite (SHR165202), and to investigate drug-drug interaction between fuzuloparib and curcumin in vitro and in vivo studies. After protein precipitation with acetonitrile, mobile phase consisted of acetonitrile and 0.1 % formic acid with a gradient elution was used to successfully separate fuzuloparib, SHR165202 and talazoparib (internal standard, IS). The results indicated that fuzuloparib and SHR165202 had good linearity over the calibration range of 2–50 ng/mL and 1–20 ng/mL, respectively. The precision, accuracy, stability, matrix effect, and extraction recovery required for methodological validation all complied with the requirements of the Bioanalytical Method Validation Guidelines. In vitro microsome incubation experiments, curcumin exhibited inhibitory effect on fuzuloparib in both rat liver microsomes (RLM) and human liver microsomes (HLM) with half-maximal inhibitory concentration (IC 50) value of 10.54 μM and 47.64 μM, respectively, and the corresponding mechanism was non-competitive. Furthermore, the inhibitory mechanism of curcumin on fuzuloparib was validated through molecular docking. In pharmacokinetic experiments in rats, curcumin significantly altered the plasma exposure of fuzuloparib, resulting in significant increases in AUC (0-t) and C max of fuzuloparib and a significant decrease in CL z/F. Moreover, the metabolite SHR165202 showed significant increases in AUC (0-t) , AUC (0-∞) , T max and C max and a significant decrease in CL z/F. This further supports the notion that curcumin could inhibit the metabolism of fuzuloparib. Therefore, when co-administering fuzuloparib and curcumin in clinic, it is recommended to monitor plasma levels of fuzuloparib and pay close attention to adverse effects. If necessary, the dose of fuzuloparib needs to be reduced. • An UPLC-MS/MS assay for the determination of fuzuloparib and its metabolite SHR165202 was developed and used to study DDIs. • Inhibitory effect of curcumin on fuzuloparib was found. • Verified the inhibitory mechanism of curcumin on fuzuloparib. [ABSTRACT FROM AUTHOR]

• The method successfully separated Obeticholic acid from its stereo isomeric metabolites. • The method successfully separated the interferors with close retention time in blank plasma from the target analytes. • The amount of plasma required for detection was reduced. • The sensitivity was higher and the quantitation limit was lower. • The method has been verified by a complete methodology and applied in portraying the pharmacokinetics of Obeticholic acid and its two active metabolites in healthy subjects. Obeticholic acid (OCA), a semisynthetic bile acid derivative, was approved for its therapeutic use in primary biliary cirrhosis. OCA has a enterohepatic circulation and host-gut microbiota metabolic interaction, which produce various metabolites. Such metabolites, especially structural isomers of OCA, together with the need to achieve idea lower limit of quantitation (LLOQ) with minimum matrix interference, bring about significant difficulties to the bioanalysis of OCA. Herein, by applying a combination of solid-phase extraction (SPE) and ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), we introduced an approach for the bioanalysis of OCA along with its two major metabolites—glyco-OCA (GOA) and tauro-OCA (TOA) in human plasma, the full validation results of which showed excellent performance. The quantitative range is 0.2506 ∼ 100.2 ng/mL for OCA, 0.2500 ∼ 100.0 ng/mL for GOA, as well as 0.1250 ∼ 50.00 ng/mL for TOA, respectively. This method was successfully applied to the pharmacokinetic studies in healthy subjects following administration of OCA tablets. [ABSTRACT FROM AUTHOR]

Paçoca is a typical Brazilian confectionery of Indigenous origin prepared by mixing ground roasted peanuts, sugar, and salt. A total of 52 samples of paçoca (37 pressed, 15 cooked), produced and sold in the state of São Paulo, were evaluated for aflatoxin content (AFB 1 , AFB 2 , AFG 1 and AFG 2), moisture content and water activity. The microbiological quality was assessed by counting mesophilic aerobic bacteria, fungal and yeast counts, most likely number of thermotolerant coliforms and Escherichia coli and Salmonella sp. The limit of quantification (LOQ) by Ultra Performance Liquid Chromatography coupled to the Mass Spectrometer (UPLC-MS/MS) ranged from 0.29 μg kg−1 for AFB 1 and AFG 2 ; 0.36 μg kg−1 for AFG 1 and 0.37 μg kg−1 for AFB 2. The recovery averages were 89.2, 83.5, 80.5 and 82.8% for AFB 1 , AFB 2 , AFG 1 and AFG 2. 71% of the samples showed aflatoxin contamination, ranging from 0.29 to 38.8 μg kg−1 (mean of 7.06 μg kg−1). Six samples (16%) exceeded the limit value tolerated by the Brazilian guideline for AFT (20 μg kg−1). The mean AFT content in cooked paçocas (19.55 μg kg−1) was higher than the levels in pressed paçocas (9.08 μg kg−1) (p < 0.05). AFB 1 had a higher incidence in the two groups of paçocas (75% pressed and 60% cooked). The mean moisture content and water activity of cooked paçocas (8.86% and 0.7081) were higher than those of pressed paçocas (2.08% and 0.4863). Twenty-one samples (56%) showed fungal and yeast contamination ranging from 1.0 to 4.25 log CFU g−1. The total count of aerobic mesophilic bacteria in cooked paçocas (4.85 log CFU g−1) was also higher than in pressed paçocas (2.77 log CFU g−1) (p < 0.05). E. coli was confirmed in these samples in the range of 3.0–160 NMP g−1. Salmonella sp. was detected in 2 samples of pressed paçocas, indicating poor hygiene, inefficient heat treatment or possible cross-contamination. The results of this study demonstrate the need for greater control of the paçoca production chain through the adoption of Good Manufacturing Practices and process control, to prevent exposure of the population to aflatoxins and possible pathogenic microorganisms. • Paçoca is a typical Brazilian sweet prepared with roasted and ground peanuts, sugar and salt. • Paçoca-type peanut confectionery may be contaminated with aflatoxins. • The paçocas production process requires aflatoxin control. • Aflatoxins represent a chemical hazard in the production of paçoca-type peanut confectionary. [ABSTRACT FROM AUTHOR]

Recently, amino acid derivatives gradually gained attention, but studies on N-lactoyl-leucine (Lac-Leu) and N-lactoyl-isoleucine (Lac-Ile) are limited. This study aims to explore the contributions of Lac-Leu and Lac-Ile to soy sauce. Lac-Leu and Lac-Ile were synthesized via enzymatic synthesis method catalyzed by Tgase. The mixed solutions containing Lac-Leu were found to have greater taste improvement than those containing Lac-Ile. Sensory evaluation indicated the sour, bitter, and astringent taste of Lac-Leu in water as well as its kokumi, astringent, and umami-enhancing taste in MSG solution. The taste threshold and umami-enhancing threshold of Lac-Leu measured by TDA and cTDA, respectively, were 0.08 mg/mL and 0.16 mg/mL. Molecular docking of Lac-Leu and Lac-Ile with the kokumi receptor CaSR and the umami receptors T1R1 and T1R3 indicated that Lac-Leu had higher affinities with receptors than Lac-Ile. These findings demonstrated the underlying contribution Lac-Leu made to soy sauce, indicating its potential to improve the flavor quality of soy sauce. • An enzymatic synthesis method of N-lactoyl leucine was established and optimized. • The taste characteristics of N-lactoyl leucine was investigated. • The thresholds of N-lactoyl leucine were determined by TDA and cTDA. • The taste mechanism of N-lactoyl leucine was explored by molecular docking. [ABSTRACT FROM AUTHOR]

Adjuvants play a crucial role in optimizing and improving the efficacy of herbicides. Therefore, adding appropriate adjuvants to herbicides is an important part of weed control. The aim of this study was to investigate the synergistic effect and underlying mechanism of action of three commercial adjuvants (Hasuteng, Penwubao, and Zhenxiao IV) in conjunction with pinoxaden for controlling Lolium multiflorum Lam. The results of synergic effect, which were determined by dose‒response assay showed that the addition of Hasuteng and Penwubao could significantly enhance the efficacy of pinoxaden and decrease the ED 50 (the herbicide dose resulting in 50% weed control) on L. multiforum while being safe to wheat. Hasuteng and Penwubao were further selected to investigate the underlying mechanisms by which adjuvants enhanced the efficacy of pinoxaden. The results indicated that the addition of Hasuteng and Penwubao significantly reduced the surface tension and shortened the drying time of the pinoxaden solution; moreover, it significantly increased both expanded diameter and maximum retention. Additionally, ultra high performance liquid chromatography-tandem mass spectrometry (UPLC‒MS/MS) analysis was used to evaluate the recovery rate, absorption level, and rainfastness. These two adjuvants could improve the absorption and metabolism levels of L. multiforum to pinoxaden. However, Hasuteng and Penwubao did not improve the rainfastness of pinoxaden. In summary, Hasuteng and Penwubao enhance the efficacy of pinoxaden by improving its physical properties and absorption level. The studies present a novel approach for enhancing the utilization rate of pinoxaden and provide theoretical guidance toward effectively reducing herbicide application in wheat fields. [Display omitted] • Adjuvants showed a synergistic effect of pinoxaden for controlling Lolium multiforum. • Synergistic effect was achieved by enhancing the physical properties of pinoxaden. • The synergistic effect was related to the increase in the absorption level. • A UPLC‒MS/MS method for detecting pinoxaden residue in Lolium spp. was established. [ABSTRACT FROM AUTHOR]

• UPLC-MS/MS tannins profiling of ethyl acetate extract of C. sieberiana root bark. • 23 flavan-3-ol metabolites newly described in C. sieberiana. • 3 flavan-3-ols reported for the first time in the literature. • Anthelmintic properties of C. sieberiana extracts in Larval Migration Inhibition test. • Validation of C. sieberiana as anthelmintic drug to slow down the infection dynamic. Helminth infections of livestock result in economic losses around the globe. The majority of the people in West Africa treats such infections with medicinal plants related to the local traditional medicine. In a previous ethnomedicinal survey carried out in the north of Togo, traditional healers frequently cited Cassia sieberiana DC to treat helminth infections. The aim of the present study was to validate the traditional application of C. sieberiana root bark as a dewormer and to analyse the metabolite composition in preparations with this activity. Two tannin-rich fractions (FrE14 and FrE15) obtained from ethyl acetate extract were submitted to UPLC-MS analysis. The anthelmintic activity of C. sieberiana extracts and tannins-rich fractions was investigated on the small ruminant parasite Haemonchus contortus using Larval Migration Inhibition tests. The ethyl acetate, butanol and aqueous extracts significantly disrupted larval migration of Haemonchus contortus L3 with inhibition of 30.3%, 22.2% and 26.5% respectively at 2.5 mg/mL, as compared to negative control. The two tannin-rich fractions, FrE14 and FrE15 presented larval migration inhibition of 6.5% and 20.7% respectively at the same concentration. From these two fractions, 28 flavan-3-ols were identified including 3 monomers (catechin, epicatechin and epiafzelechin), 22 dimers (7 homodimers and 15 heterodimers) as well as 3 newly described trimers consisting of (epi)afzelechin, (ent)cassiaflavan or (epi)guibourtidinol subunits. [ABSTRACT FROM AUTHOR]

Alternaria mycotoxins are of concern due to its adverse health effect, they affect various cereal crops and grain-based food along with modified forms that contribute to overall exposure. This study aimed to determine the frequency and level of exposure to Alternaria mycotoxins (tenuazonic acid, TeA; alternariol, AOH; alternariol monomethyl ether, AME; tentoxin, TEN; and altenuene, ALT) in human urine from Beijing adults. A total of 2212 urine samples were collected and analyzed for five mycotoxins using LC–ESI–MS/MS. More than 98% of the samples had at least one Alternaria mycotoxin detected. Among the mycotoxins, AME had the highest detection rate (96.0%), followed by TeA (70.5%). The calculated average daily intake values of AME (12.5 ng/kg b.w.) was 5 times the TTC value (2.5 ng/kg b.w.) set by the EFSA, indicating the potential health risks associated with mycotoxins. Immediate attention and subsequent actions should be taken to identify the sources of mycotoxins and the corresponding exposure pathways to humans in the investigated regions. [Display omitted]. [ABSTRACT FROM AUTHOR]

The current study coupled fabric phase sorptive extraction (FPSE) with ultraperformance liquid chromatography method with electrospray ionization and tandem mass detection (UPLC-ESI-MS/MS) for fast and sensitive determination of tadalafil (TAD) in a bioequivalence study. Fabric phase sorptive extraction allowed direct extraction of TAD from the sample matrix with improved selectivity, repeatability, and recoveries. A sol–gel Carbowax 20 M (CX-20 M) coated FPSE membrane revealed the best extraction efficiency for TAD because of its strong affinity for analytes via intermolecular interactions, high mass transfer rate to FPSE membrane, and high permeability. An automated multiple reaction monitoring (MRM) optimizer was employed for the best selection of the precursor and product ions, ion breakdown profile, the fine adjustment of the fragmentor voltages for each precursor ions, and the collision energies for the product ions. The chromatographic separation was conducted using a mobile phase A: 5.0 mM ammonium acetate with 0.1 % formic acid in water and mobile phase B: formic acid (0.1%) in acetonitrile in ratio (55:45, v/v) through isocratic elution mode on an Agilent EclipsePlus C18 (50 × 2.1 mm, 1.8 μm) column and the flow rate was adjusted at 0.4 mL min−1. The total run time per sample was 1.0 min. The method was validated by FDA standards for bioanalytical method validation over a concentration range of 0.1–100 ng mL−1 with a correlation coefficient of 0.9993 and the lower limit of quantitation (LLOQ) was 0.1 ng mL−1 in rat plasma. Intra- and inter-assay precision (%RSD) were lower than 4.1% and accuracy (%RE) was within 2.4%. The developed FPSE-UPLC-ESI-MS/MS method was effectively used in a randomized, two-way, single-dose, crossover study to compare the bioequivalence of two TAD formulations from different companies in male rats and verified to be bioequivalent. [ABSTRACT FROM AUTHOR]

A 3-step load-wash-elute solid-phase extraction tandem dedicated clean-up cartridge prior to UPLC-MS/MS for the simultaneous determination of bongkretic acid, isobongkretic acid and toxoflavin in food is presented in this work. The 3-step load-wash-elute SPE strategy with PRiME HLB, eliminating conditioning and equilibration, and coupled with dedicated purification cartridge, PriboFast MFC 336, was used as a tandem cartridge for sample pretreatment. Various sample pretreatment conditions including sample extractant, the tandem cartridge, the optimizatioin of PRiME HLB SPE conditions and PriboFast MFC 336 purification conditions, as well as MS/MS conditions and HPLC conditions were systematically investigated. Under the optimal experimental conditions, high sensitivity (LODs: 0.030–0.040 μg kg−1, LOQs: 0.090–0.12 μg kg−1), acceptable recoveries (83 %–96 %) and good precisions (r2 < 6.0 %) were obtained. The method was successfully applied to 90 food samples, bongkretic acid and isobongkretic acid were detected simultaneously in a dried black fungus, whereas toxoflavin was not detected in any of the samples. • Simultaneous detection of bongkretic acid, isobongkretic acid and toxoflavin in foods. • A possible cleavage mechanism of toxoflavin were presented and explained. • A 3-step load-wash-elute SPE cartridge tandem dedicated clean-up cartridge was used. • The method can be applied in relevant foods with satisfactory accuracy and precison. • For the first time, BA and IBA were detected simultaneously in a dried black fungus. [ABSTRACT FROM AUTHOR]

Baru nut is a tree nut obtained through sustainable extraction from the Brazilian Cerrado. It is an important economic source for rural communities and for environmental preservation of the region. The aim of this study was to evaluate the mycoflora and mycotoxins contamination in70 roasted baru nut samples available in the Brazilian market. For mycotoxin determination, an analytical method using a miniaturized Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method and ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was validated. Filamentous fungi were enumerated by spread-plate in Dichloran Rose Bengal Chloramphenicol agar and identification was performed by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF/MS) and D2 ribosomal ribonucleic acid region sequencing. Among the analyzed baru nut samples, six (8.5%) showed contamination by alternariol with concentration levels ranging between 12.2 and 148.2 μg kg−1. Fumonisins B1 (242.7 μg kg−1) and B2 (27.6 μg kg−1) were found in one (1.4%) sample. No other mycotoxins, including regulated aflatoxins, were found. Eleven fungal strains were isolated and Penicillium spp. was the most frequently isolated genus. All fungal strains were identified to the genus level. None of the isolated fungal strains showed mycotoxigenic potential. Baru nuts comply with mycotoxin regulations, displaying lower contamination levels than other nuts. These findings support rural economic growth, sustainable harvesting practices, and the conservation of the Cerrado's native flora. • Fungal contamination was found in 14.3% of Brazilian roasted baru nuts. • Penicillium spp. was the most frequent fungal genus isolated. • Regulated aflatoxins were not found. • Alternariol was found in 8.5% of the samples. • Fumonisins (B1 and B2) were found in 1.4% of the samples. [ABSTRACT FROM AUTHOR]

Co-extraction of multiple types of target substances is the key to achieve high throughput detection. In this work, PDA@MOF-808/PAN NFsM was prepared by co -modified polyacrylonitrile nanofiber membrane (PAN NFsM) with polydopamine (PDA) and metal-organic framework-808 (MOF-808), and its potential as a solid-phase extraction (SPE) adsorbent was investigated by using the most typical nine veterinary drug residues in eggs and chicken as model target substances. The results show that PDA@MOF-808/PAN NFsM could effectively co-extract all the target substances (adsorption efficiency ranged from 81.46 % to 96.78 %), and had good capability of sample matrix purification (matrix effect was lower than −15.26 %), so a new SPE method has been established. Combined with UPLC-MS/MS, the detection limits were 0.3 to 3.1 μg/kg, the recoveries were between 71.02 % and 106.48 %, and the relative standard deviations were lower than 12.03 %, indicating that the method has considerable good sensitivity, accuracy and precision. • High throughput screening of a variety of veterinary drugs in chicken and egg samples was achieved. • PDA@MOF/PAN NFsM provides fast and efficient extraction of targets through multiple adsorption mechanisms. • PDA@MOF/PAN NFsM exhibited good purification ability for sample matrix. • The accuracy and sensitivity of this method both meet the requirements of practical applications. • The good practicality of the developed method was verified by testing actual samples. [ABSTRACT FROM AUTHOR]

Ademetionine 1,4-Butanedisulfonate (SAMe) is widely used as a prescription drug to treat cholestasis associated with liver disease, and is also used to treat depression, Alzheimer's disease and other diseases. Currently, the main way to produce SAMe is by fermentation of S-adenosylmethionine synthetase（SAMS）. However, during the fermentation process, host cells produce contaminants unrelated to the treatment. Among them, host cell protein (HCP), which is co-purified with the drug, is the main impurity in the production process. HCP-induced antigenic reactions can lead to allergies or other adverse reactions and affect drug quality, efficacy, and safety. Enzyme-linked immunosorbent assay (ELISA) and mass spectrometry (MS) are currently used as the main analytical methods for measuring HCP. The ELISA method may ignore some HCPs with low immunogenicity, while mass spectrometry is primarily employed for the characterization of proteomes. Orthogonal methods can more effectively evaluate impurities in drugs. In this study, ELISA was initially utilized to quantify the content of Saccharomyces cerevisiae host protein in 11 batches of SAMe active pharmaceutical ingredient (API) from two suppliers, then the above APIs were qualitatively analyzed by MS method. Following the identification of surrogate peptide of SAMS, an Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry（UPLC-MS/MS）method was established and validated, the SAMS protein residues in 11 batches of samples were subsequently determined. The results demonstrated that the levels of Saccharomyces cerevisiae host protein and SAMS in the samples were both low, with values below 20 ppm and 1.19 ppm, respectively. The qualitative results also indicate that the types of peptide residues in the samples are more diverse than those of protein residues. Furthermore, residues of proteins and peptides can be detected in all samples, which underscores the importance of evaluating the HCP in API. This study employs a range of complementary detection methods to conduct a comprehensive and sensitive evaluation of total HCP and specific proteins in drugs, thereby guiding more informed assessments of the risks posed by HCP impurities in raw materials during pharmaceutical processes. [Display omitted] • ELISA and MS methods orthogonally used to quantify and qualify protein impurities. • The developed UPLC-MS/MS method accurately measures a major host cell protein. • This method was successfully applied to evaluate active pharmaceutical ingredient. • Results show protein impurities types varied greatly, with content under 20 ppm. [ABSTRACT FROM AUTHOR]

Moutan Cortex, is the root bark of Paeonia suffruticosa Andrews, which is classified into three specifications according to whether or not it is peeled and cored: Liandanpi, Guadanpi and whole root. In this study, the cork layer, cortex, phloem and xylem of P. suffruticosa fresh root were precisely separated by laser microdissection technique. UPLC-Q-Orbitrap-MS and UPLC-QQQ-MS techniques were used to analyse the differences in the chemical composition of different tissue parts of P. suffruticosa fresh root and Liandanpi, and to determine the optimal processing method of P. suffruticosa root. As a result, a total of 90 compounds were characterised, among which the cork layer had more types and higher contents of chemical constituents, and the xylem had fewer types and lower contents of chemical constituents. The proportion of xylem is larger, while the type and content of active ingredients is smaller. Therefore, the processing method of removing the wood core and retaining the cork bark can be used in the processing of Moutan Cortex. In this study, laser microdissection and ultra performance liquid chromatography-mass spectrometry were used to provide a theoretical basis for optimising the processing method of Moutan Cortex to enhance its pharmacological effects. • Accurate separation of different parts of P. suffruticosa root by LMD. • Characterization of different parts of P. suffruticosa root using UPLC-Q-Orbitrap-MS. • A total of 90 compounds were identified. • Quantitative analysis of four components in P. suffruticosa root using UPLC-QQQ-MS. • Determined the optimal processing method for P. suffruticosa root. [ABSTRACT FROM AUTHOR]

[Display omitted] • 550 metabolites were identified from the CPSDF in vitro digestion. • Phenolic acids are the most abundant and diverse components of bound polyphenols in CPSDF. • The most significant increase in the 5,7,8,3′,4′-pentamethoxyflavanone after digestion. • Oral-to-gastric digestion resulted in upregulation of 97.14% of differential metabolites. • The α-amylase inhibitory activity of CPSDF after gastric digestion was similar to control. Dietary fiber from coffee peel is rich in bound polyphenols good for human health due to the antioxidant activity. In this study, we evaluated the bound polyphenol release conditions and activities in coffee peel soluble dietary fiber (CPSDF) in the process of in vitro simulation digestion. The CPSDF structure became loose and porous due to simulated digestion but retained the polysaccharide backbone. Widely-targeted metabolomics analysis identified 550 metabolites, with phenolic acids and flavonoids being main differentially expressed metabolites in digested products (82.18% in total). The most significant increase in the 5,7,8,3′,4′-pentamethoxyflavanone content and decrease in the 3,5-dihydroxyacetophenone content were observed after digestion (undigested vs S-intestine). Additionally, the changes in antioxidant and enzyme inhibitory activities followed the same pattern as that observed for total phenolic content. The enzyme inhibitory and antioxidant activities of gastric digestion products were greater than those of the oral and small intestinal digestion products. The present work provided the theoretical foundation for developing high-value CPSDF products and reusing coffee peel waste. [ABSTRACT FROM AUTHOR]

• DNDI-6148 is a new potential oral compound for cutaneous leishmaniasis treatment. • First validated UPLC-MS/MS methods to quantify DNDI-6148 in multiple biomatrices. • Enzymatic digestion of mouse tissue was superior over mechanical homogenization. • Protein precipitation yielded reproducible recoveries, with no matrix effects. • Successfully applied the methods on samples obtained from Leishmania -infected mice. DNDI-6148 is a promising new oral drug for the treatment of cutaneous leishmaniasis (CL), a parasitic neglected tropical disease that affects impoverished populations worldwide. Preclinical target site pharmacokinetics (PK) studies are necessary to evaluate the actual exposure to DNDI-6148 of Leishmania parasites in the skin. To facilitate these investigations, we have developed and validated a reversed phase ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method to quantify DNDI-6148 in relevant target site PK samples, adhering to the relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M10 guideline on bioanalytical method validation. Full validation was performed for the surrogate biomatrices human K 2 EDTA plasma, enzymatic digestion buffer and skin microdialysate. Partial validation was conducted for mouse K 2 EDTA plasma and tissues. The tissue samples, including mouse skin, liver and spleen, were homogenized using a collagenase A-based enzymatic homogenization workflow. This method was found to be 2.9-fold more effective in extracting DNDI-6148 from skin than the commonly used mechanical homogenization. Protein precipitation was subsequently carried out for all biomatrices. A surrogate biomatrix was used for each method and the range was specifically developed for its intended application, resulting in a linear concentration range of 5.00–2000 ng/mL, 2.00–1000 ng/mL, and 3.00–600 ng/mL for human K 2 EDTA plasma, enzymatic digestion buffer and microdialysate, respectively. Each biomatrix had intra- and inter-run accuracy and precision within 15 % for all concentration levels. Matrix effects did not affect the determination of DNDI-6148, since the stable isotopically-labelled internal standard for DNDI-6148 effectively compensated for these matrix effects. Total recovery across all methods was between 73.5 % and 81.3 % (CV ≤4.5 %). DNDI-6148 was stable under various conditions in all the tested biomatrices. However, a decrease in its concentration was observed during homogenization, for which the internal standard corrected adequately. The suitability of the method for use in future preclinical research involving DNDI-6148 was demonstrated in a preclinical target site PK study using a CL-infected murine model. [ABSTRACT FROM AUTHOR]

Over the past two decades, concerns have arisen about the efficacy and safety of medicinal plants, highlighting good agricultural practices and quality control. This study aimed to validate a multi-residue analysis method for detecting 268 pesticides in Mikania glomerata tincture, using direct injection and UPLC-MS/MS, per SANTE guidelines. The validation of the method involved evaluating the linearity of analytical curves in terms of the determination coefficient r2 and residuals (%), as well as the limits of quantification (LOQ), matrix effects, precision (expressed as the coefficient of variation, CV), and accuracy (determined as the recovery percentage). The parameters and acceptance criteria were assessed based on SANTE guidelines. The method was then applied to analyse commercial samples of M. glomerata tincture, and traces of carbendazim and dimethomorph were detected. This study underscores the need for regulatory measures to enhance agricultural practices, thereby ensuring the safety and efficacy of medicinal plants. [Display omitted] • The development of a new analytical method for the chemical quality control of medicinal plants. • The validation of a method for detecting 268 pesticides in Mikania glomerata tincture using UPLC-MS/MS per SANTE guidelines. • The detection of carbendazim and dimethomorph in samples of M. glomerata tincture marketed in Brazil. [ABSTRACT FROM AUTHOR]

Trimethylamine (TMA) and trimethylamine- N -oxide (TMAO) play a crucial role in many biochemical processes within diverse organisms including animals, plants, fungi and bacteria. Studies have linked these metabolites with cardiovascular and kidney diseases; however, emerging evidence demonstrates their protective properties. Owing to these controversies and co-existence of these metabolites in biological samples, it is crucial to accurately quantify these metabolites to associate their concentrations with various physiological and pathophysiological conditions to elucidate their potential roles. We reported interferences on TMA quantification without derivatizing the analyte. A combined sample preparation method, including sample derivatization with ethyl bromoacetate and use of ion pairing reagent (sodium heptanesulfonate), minimized these interferences and provided improved accuracy and precision for simultaneous quantification of TMA and TMAO. The linearity for TMAO ranged from 0.01 µM to 300 µM and 0.1 µM - 300 µM for TMA. With the application of this method, we reported that the circulating concentrations of TMA was 4 times higher in male mice (33.1 ± 5.9 µmol/L) compared to females (8.3 ± 1.39 µmol/L), whereas TMAO levels were 6 times lower in male (7.2 ± 0.4 µmol/L) than female mice (42.1 ± 4.5 µmol/L). In contrast, concentrations of TMA and TMAO in the colonic tissue did not differ significantly between males and females. The robust analytical method for simultaneously quantifying TMA and TMAO presents a significant value in facilitating investigations on TMA and TMAO biology. [Display omitted] • Ethyl bromoacetate derivatization better separates TMA and TMAO transition. • Ion pairing using sodium heptane sulfonate enhances method sensitivity. • Circulating levels of TMA and TMAO differ between male and female mice. • Colonic tissue levels of TMA and TMAO are comparable between two sexes. [ABSTRACT FROM AUTHOR]

Suxiao Jiuxin pill (SJP) was a commonly-used traditional Chinese medicine for treating cardiovascular diseases. It was composed of the rhizome of Ligusticum chuanxiong Hort. and Borneolum Syntheticum. The distribution of SJP in vivo was still ambiguous. A UPLC-MS/MS coupled with GC-MS method was developed to quantify twenty-one chemical ingredients in multiple tissues from rat after administration of SJP. Protein precipitation and liquid-liquid microextraction were both utilized in sample pretreatment. All analytes were detected under acceptable specificity, linearity (correlation coefficient > 0.992), sensitivity (LLOQ < 12.5 ng/mL), precision (RSD < 14.8 %), accuracy (RE < ±14.6 %), extraction recovery (between 52.8 % and 124.1 %), matrix effect (ranged from 60.5 % and 149.7 %) and stability (RE < ±16.0 %). The established method was successfully applied in the tissue distribution study of SJP in rats. As a result, the distribution characteristics of ten analytes were clearly elucidated, including borneol, isoborneol, ligustilide, senkyunolide A, ferulic acid, senkyunolide I, levistolide A, neocnidilide, senkyunolide H and angelicide. The information provided by this research was greatly meaningful for the active chemical ingredient exploration and clinical application of SJP. • A method was developed to determine compounds from SJP in rat tissue. • An integrated quantification method was developed by combing UPLC-MS/MS and GC-MS. • This study provides comprehensive characteristic of tissue distribution of SJP. [ABSTRACT FROM AUTHOR]

• A method based on UPLC-MS/MS was developed for the determination of 8 QPCs and 4 POs in environment. • This universal analytical method is available for varied environmental samples. • Real sample analysis indicated QPCs and POs were detected in each environmental samples. • QPCs were first tentatively detected in wastewater, sludge, and road dust. Quaternary phosphonium compounds (QPCs) and phosphine oxides (POs) are emerging contaminants that are attracting increasing attention. In the present study, a method for the quantification of QPCs and POs in multiple environmental media was developed using ultrahigh performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Analytes were extracted from water samples using solid phase extraction, and for the solid samples, ultrasonic extraction was employed. Compared with analytical methods established by previous studies, the approach developed in this study is more suitable for the quantitative analysis of compounds along with high sensitivity. The method quantification limit reached 0.12–2.55 ng⋅L–1 in water samples and 0.004–0.10 ng⋅g–1 in solid samples. The recoveries of target analytes spiked at low, medium and high concentrations in water and solid samples were in the range of 56.4–120 %, with relative standard deviations below 20 % (n = 6). Furthermore, the validated method succeeded in applying to analyse of eight QPCs and four POs in real environmental samples. At least five QPCs and two POs were detected in each environmental medium. This quantitative method would assist in further investigations on the occurrence, migration and the source of QPCs and POs. [ABSTRACT FROM AUTHOR]

In traditional Chinese medicine (TCM), Yigong San (YGS) is mainly used to treat dyspepsia caused by deficiency of spleen and stomach qi. Although the chemical composition and bioactivity of YGS has been well studied, the main in vivo compounds and their distribution in tissues still need to be made clearer. To elucidate the pharmacokinetic profiles and tissue distribution of eight main compounds of YGS in rats, and provide a reference for clinical application and new drug development. UPLC-Q-Exactive-Orbitrap-MS was used to qualitatively characterize the parent compounds and their metabolites in the plasma of rats after oral administration of YGS. A sensitive, reliable, and accurate ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method using UPLC-AB Sciex QTRAP 5500 MS was established to quantitatively determine eight main compounds of YGS in rat plasma and tissues, including liquiritin, isoliquiritin, hesperidin, ginsenosides Rb 1 , Re and Rg 1 , atractylenolides I and II. The mean area under the concentration-time curve (AUC) values of ginsenoside Rb 1 , hesperidin, and liquiritin at low, medium, and high doses were greater than 150 ng h/mL. The elimination half-life (t 1/2) values of ginsenoside Rb 1 , atractylenolides I and II (low and medium doses) were longer than 10 h. Peak time (T max) values of all compounds were shorter than 10 h. Except for atractylenolides, the maximum concentration (C max) values of the compounds were greater than 10 ng/mL. The eight compounds were detected in the heart, brain, liver, spleen and kidney at 0.25 h after oral administration. Liquiritin and isoliquiritin had higher exposure in the liver and heart. Hesperidin and ginsenosides Rb 1 , Re, and Rg 1 are mainly distributed in the spleen and kidney. Atractylenolides I and II are mainly distributed in spleen, liver and kidney. All main compounds of YGS, i.e., liquiritin, isoliquiritin, hesperidin, ginsenosides Rb 1 , Re, and Rg 1 , and atractylenolides I and II are absorbed into plasma and widely distributed in various tissues. Among them, hesperidin, ginsenoside Rb 1 , and atractylenolide I are main in vivo compounds. They are mainly distributed in spleen, liver and kidney. The results of this study provide a basis for further in-depth development and application of YGS. [Display omitted] • Characterizing the in vivo parent compounds and their metabolites of YGS. • Investigating the pharmacokinetics and tissue distribution of eight main compounds of YGS in rats. • All eight main compounds of YGS are absorbed into plasma and widely distributed in various tissues. • Hesperidin, ginsenoside Rb 1 , and atractylenolide I are main in vivo compounds. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicines (TCMs) are popular in clinic because of their safety and efficacy. They contain abundant natural active compounds, which are important sources of new drug discovery. However, how to efficiently identify active compounds from complex ingredients remains a challenge. In this study, a method combining UHPLC-MS/MS characterization and in silico screening was developed to discover compounds with dopamine D2 receptor (D2R) activity in Stephania epigaea (S. epigaea). By combining the compounds identified in S. epigaea by UHPLC-MS/MS with reported compounds, a virtual library of 80 compounds was constructed for in silico screening. Potentially active compounds were chosen based on screening scores and subsequently tested for in vitro activity on a transfected cell line CHO-K1-D2 model using label-free cellular phenotypic assay. Three D2R agonists and five D2R antagonists were identified. (-)-Asimilobine, N -nornuciferine and (-)-roemerine were reported for the first time as D2R agonists, with EC 50 values of 0.35 ± 0.04 μM, 1.37 ± 0.10 μM and 0.82 ± 0.22 μM, respectively. Their target specificity was validated by desensitization and antagonism assay. (-)-Isocorypalmine, (-)-tetrahydropalmatine, (-)-discretine, (+)-corydaline and (-)-roemeroline showed strong antagonistic activity on D2R with IC 50 values of 92 ± 9.9 nM, 1.73 ± 0.13 μM, 0.34 ± 0.02 μM, 2.09 ± 0.22 μM and 0.85 ± 0.08 μM, respectively. Their kinetic binding profiles were characterized using co-stimulation assay and they were both D2R competitive antagonists. We docked these ligands with human D2R crystal structure and analyzed the structure-activity relationship of aporphine-type D2R agonists and protoberberine-type D2R antagonists. These results would help to elucidate the mechanism of action of S. epigaea for its analgesic and sedative efficacy and benefit for D2R drug design. This study demonstrated the potential of integrating UHPLC-MS/MS with in silico and in vitro screening for accelerating the discovery of active compounds from TCMs. • Three D2R agonists in Stephania epigaea were reported for the first time. • UPLC-MS and in silico screening were combined to discover active compounds. • The effective components of Stephania epigaea analgesia were revealed. [ABSTRACT FROM AUTHOR]

• First reported determination of eupafolin by UPLC-MS/MS in rat plasma. • First reported pharmacokinetics of eupafolin in rats. • The bioavailability of eupafolin was relatively low (8.3%). In this experiment, a rapid and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technology was established and validated for the quantitation and pharmacokinetic analysis of eupafolin in rat plasma, utilizing licochalcone B as internal standard (IS). After liquid–liquid extraction of the analyte samples by ethyl acetate, chromatographic separation was achieved using a UPLC HSS T3 column under gradient elution conditions, with the mobile phase consisting of acetonitrile and water (with 0.1 % formic acid). Eupafolin was quantified by multiple reaction monitoring (MRM) in electrospray positive-ion mode (ESI+), employing the mass transition m / z 315.2 → 300.3 for eupafolin and m / z 285.4 → 270.3 for IS. Eupafolin demonstrated excellent linear relationship (r > 0.99) over the concentration range of 1.25–1250 ng/mL, with the lower limit of quantification (LLOQ) of the UPLC-MS/MS assay determined as 1.25 ng/mL. Method validation followed the bioanalytical method validation criteria outlined by the FDA. The accuracy of eupafolin ranged from 86.7 % to 111.2 %, and the precision was less than 12 %. The matrix effect was observed at 92.8 %-98.6 %, while the recoveries exceeded 83.2 %. The established UPLC-MS/MS assay was successfully employed for the pharmacokinetic evaluation of eupafolin in rats. The half-lives (t 1/2z) were determined to be 1.4 ± 0.4 h and 2.5 ± 1.4 h for intravenous and oral administration, respectively. Notably, the bioavailability of eupafolin was relatively low (8.3 %). The optimized UPLC-MS/MS technology showed highly sensitive, selective, and effective, rendering it suitable for the pharmacokinetics of eupafolin in preclinical practice. [ABSTRACT FROM AUTHOR]

[Display omitted] • Anisaldehyde based DES-DLLME method was optimized for the determination of parabens and bisphenols for the first time. • The developed DES-DLLME method, followed by UPLC–MS/MS was applied for analysis of the studied analytes in 80 food products. • The ecological impact of the proposed method was investigated using three assessment tools. • The proposed method is eco-friendly, rapid, cost-effectiveness and capable of analyzing the analytes without imparting any detrimental effects on human health and the environment. A rapid and environmentally friendly method based on dispersive liquid–liquid microextraction (DLLME) technique, coupled with UPLC–MS/MS analysis was employed for simultaneous determination of selected bisphenols and parabens residues in food products. In this research, anisaldehyde and decanoic acid with a molar ration of 3:1 was prepared as a natural deep eutectic extracting solvent. Various extraction parameters such as the volume of the natural deep eutectic solvent, vortex duration, centrifugation duration, sample volume and pH were systematically explored and optimized. Determination coefficients of ≥0.9990 were achieved for the analyzed compounds under the optimal conditions. The limits detection were in the range of 0.0005 to 0.02 µg/L, while extraction recoveries ranged from 97.8 % to 100.2 % with relative standard deviations (%RSD) not exceeding 6.8 %. To assess the practical applicability of the proposed method, it was employed for the determination of five parabens and three bisphenols in eighty food products including soft drinks, energy drinks, sauces and juices collected from the Saudi market. The environmental implications of the proposed method were assessed using the following evaluation tools, Eco-Scale Assessment (ESA), Green Analytical Procedure Index (GAPI) and Analytical GREEnness metric (AGREE). To the best of our knowledge, this is the first study to determine the investigated analytes using anisaldehyde based deep eutectic solvent. [ABSTRACT FROM AUTHOR]

A novel analytical strategy was proposed to simultaneously quantify two advanced glycation end products (AGEs) including Nε-(Carboxymethyl)lysine (CML), Nε-(Carboxyethyl)lysine (CEL) and eight heterocyclic amines (HAs) including IQ, MeIQ, MeIQx, 4,8-DiMeIQx, 7,8-DiMeIQx, PhIP, Harman, and Norharman. The procedure was based on a two-step extraction, solid phase extraction (SPE) purification followed by ultra performance liquid chromatography tandem mass spectrometry. The established method showed a good linearity (R2 ≥ 0.9950), rapid processing time (8 min per sample), satisfactory recoveries (matrix spiked recoveries range from 72.2% to 119.6%) and precision (intra-day and inter-day RSDs were <19.3%). The limit of quantification (LOQ) and limit of detection (LOD) resulted to be between 0.05–15 ng/g and 0.2–50 ng/g, respectively. The validated technique was further applied to determine HAs and AGEs in eight stewed meat product samples consumed in Shanghai, with the amount of HAs and AGEs ranging from 2.851 to 18.289 ng/g and 118.158–543.493 ng/g, respectively. • The extraction, purification, and determination parameters were optimized. • UPLC-MS/MS was used to simultaneously analyze 8 HAs and 2 AGEs. • The method was with low solvent consumption and good precise. • This method was successfully applied in stewed meat products. [ABSTRACT FROM AUTHOR]

• A new magnetic cationic schiff base polymer was first prepared. • The magnetic cationic polymer was used as sorbent to extract AVMs effectively by multiple interactions. • A MSPE-UPLC-MS/MS methodfor determination of trace AVMs insecticides was developed. • The method was successfully applied to the detection of AVMs in surface water and milk. Herein, a magnetic cationic Schiff base polymeric material (Fe 3 O 4 @SiO 2 - Schiff -TAPB-DA) was fabricated simply and rapidly, which was explored as a magnetic adsorbent for magnetic solid-phase extraction (MSPE) for enriching seven avermectins insecticides in surface water and milk matrices combined with ultra-high performance liquid chromatography mass spectrometry (UPLC-MS/MS). Under the optimized pretreatment and instrumental parameters, the analytes showed good linearity in the range of 0.5–200.0 ng·mL−1 with a correlation coefficient (R2) greater than 0.9990 and high precision. The limits of detection for the analytes were 0.004–0.047 μg· L −1 for surface water sample and 0.008–0.250 μg·kg−1 for milk samples. Satisfactory recoveries of spiked target compounds were in the range of 82.25- 100.87 % for surface water sample and 72.73- 119.62 % for milk samples. The results indicated powerfully Fe 3 O 4 @SiO 2 - Schiff -TAPB-DA was of significant potential as an MSPE adsorbent for the detection of avermectin insecticides in surface water and milk, which provides a quick and efficient idea for enriching avermectins insecticides in complicated matrices. [Display omitted] [ABSTRACT FROM AUTHOR]

Apixaban is an oral anticoagulant that directly inhibits the target Factor Xa (FXa). In this study, we focused on the in vivo and in vitro effects of adagrasib and asciminib on apixaban metabolism, to discover potential drug-drug interactions (DDI) and explore their inhibitory mechanisms. The levels of apixaban and its metabolite, O-desmethyl-apixaban (M2), were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In vitro evaluation, the maximum half inhibitory concentration (IC 50) of adagrasib in rat liver microsomes (RLM) and human liver microsomes (HLM) against apixaban was 7.99 μM and 117.40 μM, respectively. The IC 50 value of asciminib against apixaban in RLM and HLM was 4.28 μM and 18.42 μM, respectively. The results of the analysis on inhibition mechanisms showed that adagrasib inhibited the metabolism of apixaban through a non-competitive mechanism, while asciminib inhibited the metabolism of apixaban through a mixed mechanism. Moreover, the interaction of apixaban with adagrasib and asciminib in Sprague-Dawley (SD) rats was also investigated. It was found that the pharmacokinetic characteristics of apixaban were significantly changed when combined with these two antitumor drugs, where AUC (0-t) , AUC (0-∞) , t 1/2 , T max , and C max were increased, while CL z /F was significantly decreased. But both drugs did not appear to affect the metabolism of M2 in a significant way. Consistent results from in vitro and in vivo demonstrated that both adagrasib and asciminib inhibited the metabolism of apixaban. It provided reference data for the future clinical individualization of apixaban. • Establishment of UPLC-MS/MS method to evaluate the concentration of apixaban and M2 in rat plasma. • To evaluate the inhibitory effect of adagrasib and asciminib on apixaban metabolism. • Potential drug interactions of adagrasib and asciminib on apixaban. [ABSTRACT FROM AUTHOR]

• An UPLC-MS/MS 5-window-method enduring 22 min has been optimized. • This sensitive and accurate method allows to quantify 23 pesticides in human urine. • The optimization includes 3 further pesticide groups: neonicotinoids, carbamates and triazoles. • Pesticides still in use and others already banned by legislations are included. • This method is optimal as a HBM tool for health risk assessment in large population surveys. An accurate and sensitive method for the determination of a total of 23 pesticides and their metabolites in human urine has been optimised. The methodology is based on a previously published method based on solid-phase extraction with methanol and acetone followed by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) in the selected reaction mode (SRM) with both positive and negative electrospray ionization (ESI+/-). The detection settings of the previous method, which allowed to determine the metabolites from 6 organophosphate and 2 pyrethroid pesticides, were optimised in order to include further pesticide groups, such as 11 neonicotinoids, 3 carbamates/thiocarbamates and 2 triazoles. The 5-windows method enduring 22 min was optimized with acceptable results in relation to accuracy (recoveries >75 %), precision (coefficients of variation <26 %) and linearity (R2> 0.9915). The limits of detection ranged between 0.012 ng/mL and 0.058 ng/mL. Samples from the German External Quality Assessment Scheme (G-EQUAS) encompassing 2 pyrethroids, 2 organophosphate and one neonicotinoid (6-chloronicotinic acid, a common metabolite of imidacloprid and acetamiprid) were analysed, and the latter, included in this newest optimization, provided good reference results. The method is optimal as a human biomonitoring tool for health risk assessment in large population surveys. [ABSTRACT FROM AUTHOR]