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Aim: We aimed to establish and validate a simple and sensitive UPLC–MS/MS method for the determination of UNC1999, a dual inhibitor against EZH1 and EZH2 in plasma samples. Materials & methods: UNC1999 in rat plasma was processed with protein precipitation method and then separated on a C18column and detected under positive ionization mode. The method presented good linearity over the range of 1.0–2000 ng/ml with good accuracy and precision. UNC1999 was absorbed slowly and achieved a maximum concentration of 118.8 ± 12.0 ng/ml 1.5 h after oral administration. Conclusion: The method provides a favorable character in selectivity, linearity, accuracy, precision, recovery, matrix effects and stabilities and was suitable for describing the pharmacokinetic profile of UNC1999.

Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been described to partially overlap with Kawasaki disease (KD) with regard to clinical symptoms, but they are unlikely to share the same disease entity. We conducted a systematic review and meta-analysis to characterize the laboratory parameters of MIS-C compared with those of KD and Kawasaki disease shock syndrome (KDSS). Databases were searched for studies on laboratory parameters of MIS-C (hematology, inflammatory markers, cardiac markers, and biochemistry) through May 31, 2021. Twelve studies with 3073 participants yielded 969 MIS-C patients. In terms of hematology, MIS-C patients had lower levels of leukocytes, absolute lymphocyte count and platelet count (PLT) than KD patients and had similar absolute neutrophil count (ANC) and hemoglobin (Hb) levels. In terms of inflammatory markers, MIS-C patients had higher levels of C-reactive protein, D-dimer and ferritin than KD patients and had similar levels of procalcitonin and erythrocyte sedimentation rate (ESR). In terms of cardiac markers, MIS-C patients had higher CPK levels than KD patients. The levels of N-terminal pro-brain natriuretic peptide, troponin and aspartate aminotransferase were not significantly different between MIS-C and KD patients. In terms of biochemistry, MIS-C patients had lower levels of albumin, sodium and alanine aminotransferase and higher levels of creatinine than KD patients. In addition, MIS-C patients had lower levels of PLT, Hb and ESR and higher levels of ANC than KDSS patients. Measurement of laboratory parameters might assist clinicians with accurate evaluation of MIS-C and further mechanistic research.

VS-5584 is a small-molecular compound that showed equivalent activity against mTOR and all class I PI3K isoforms and demonstrated preclinical activity in diverse cancer cell lines and xenograft tumor model, and rational combination of VS-5584 and other target therapies achieved promising outcomes in oncology. In the present study, we established and validated a simple and sensitive UPLC-MS/MS method for the determination of VS-5584 in plasma samples. VS-5584 was separated via an Acquity UPLC BEH C18 column, with a mobile phase composed of acetonitrile and 0.2% formic acid in water (40 : 60). The calibration curve displayed a good linearity in the range of 1.0–1000 ng/mL, with satisfactory accuracy (−13.6%

Aim: GW788388 is a selective and orally active TGF-β1 receptor inhibitor that shows potent activity in renal fibrosis. We aimed to establish and validate a simple and sensitive ultra-performance LC–MS/MS method for the determination of GW788388 in plasma samples. Methodology & results: GW788388 in rat plasma was processed with protein precipitation method and then separated on a C18 column. The calibration curve presented a good linearity in the range of 1.0–1200 ng/ml, with satisfactory accuracy (relative error, [-17.5% < relative error

Aim: Capmatinib is an orally bioavailable mesenchymal-epithelial transition factor inhibitor with anticancer activity, which has proved preclinical activity in multiple cancer trials. The present study aimed to develop a fast and reliable assay approach to quantify capmatinib in rat plasma. Methodology & results: After protein precipitation with acetonitrile, the chromatographic separation was achieved with an Acquity UPLC BEH C18 column, and subsequently detected with positive electrospray ionization via a triple quadrupole tandem mass spectrometer. The target quantitative ion pairs m/z 412.99 → 381.84 for capmatinib and 387.00 → 355.81 for the internal standard, respectively. The calibration curve for the assay was linear over the range of 1.0–4000 ng/ml. Conclusion: The method shows an excellent performance in linearity, accuracy, precision, stability, and has been successfully applied to a pharmacokinetic study after oral administration of capmatinib at three doses (5, 10 and 20 mg/kg) in rats.

The suitability of biochar (BC) as a container substrate depends on the BC mix ratio and plant species. Mixes with mixed hardwood BC (20%, 40%, 60%, and 80%, by volume) and vermicompost (VC, 5%, 10%, 15%, and 20%, by volume) were evaluated as container substrates on basil (Ocimum basilicum L.) and tomato (Solanum lycopersicum L. &lsquo, Roma&rsquo, ) plants compared to a commercial peat-based substrate (CS). The CS made up the rest of the volume when BC and VC did not add up to 100%. The total porosity of all mixes with BC, VC, and CS (BC:VC:CS mixes) was similar to the control. Mixes with 80% BC had lower container capacity than the control. At 9 weeks after transplanting, the leachate pH of all the BC:VC:CS mixes was higher than that of the control, except for mixes of 20%BC and 5%VC with the rest (75%) being CS (20BC:5VC:75CS) and 20BC:10VC:70CS with tomato plants. The soil plant analysis development (SPAD) readings in BC:VC:CS mixes were similar to or higher than the control except for tomato plants in 80BC:5VC:15CS, 80BC:15VC:5CS, and 80BC:20VC:0CS mixes. Plants in BC:VC:CS mixes had similar growth indexes and total dry weight with respect to those in 100% CS, with the root DW of basil plants in 60BC:15VC:25CS being the highest among all treatments. Therefore, the BC (20%, 40%, 60%, or 80%, by volume) and VC (5%, 10%, 15%, or 20%, by volume) mixes had the potential to replace CS for container-grown plants, with the estimate wholesale price for 80BC:5VC:15CS was only 61.6% that of the control.

PH-797804 is a selective p38 MAPK inhibitor currently evaluated in clinical trials. This study described a validated UPLC-MS/MS combined with one-step protein precipitation extraction method for determination of PH-797804 in rat plasma. After protein precipitation with acetonitrile, the plasma sample was analyzed by a Waters Acquity UPLC BEH C18 column, with acetonitrile/0.1% formic acid (70:30) as the mobile phase. Mass spectrometric detection was conducted with a Waters TQ-S mass spectrometer via electrospray, positive-mode ionization, with target quantitative ion pairs of m/z 476.895 → 126.860 for PH-797804, and 482.726 → 269.707 for regorafenib (internal standard). The assay showed a good linearity over the range of 1.0–1600 ng/mL, with acceptable accuracy (RE from −7.8% to 8.5%) and precision (RSD within 8.4%) values. Recovery from plasma was 81.4–90.2% and matrix effect was negligible (93.3–95.4%). The validated method presented a quantification method of PH-797804 in detail for the first time and utilized for a pharmacokinetic study at three dose concentrations after oral administration in Wistar rats. The pharmacokinetic profiles of PH-797804 showed a linear relationship between drug concentration and dose, which provided dosage and safety information on further clinical studies.

Spiders are the most successful insect predators given that they use their venom containing insecticidal peptides as biochemical weapons for preying. Due to the high specificity and potency of peptidic toxins, discoveries of insecticidal toxins from spider venom have provided an opportunity to obtain natural compounds for agricultural applications without affecting human health. In this study, a novel insecticidal toxin (μ-NPTX-Nc1a) was identified and characterized from the venom of Nephila clavata. Its primary sequence is GCNPDCTGIQCGWPRCPGGQNPVMDKCVSCCPFCPPKSAQG which was determined by automated Edman degradation, cDNA cloning, and MS/MS analysis. BLAST search indicated that Nc1a shows no similarity with known peptides or proteins, indicating that Nc1a belongs to a novel family of insecticidal peptide. Nc1a displayed inhibitory effects on NaV and KV channels in cockroach dorsal unpaired median neurons. The median lethal dose (LD50) of Nc1a on cockroach was 573 ng/g. Herein, a study that identifies a novel insecticidal toxin, which can be a potential candidate and/or template for the development of bioinsecticides, is presented.

We report the development and validation of a rapid, specific, and sensitive liquid chromatographic–tandem mass spectrometric (LC–MS–MS) method for analysis and pharmacokinetic study, in rats, of hyperoside and isoquercitrin, two bioactive structural isomers present in the leaves of Apocynum venetum L. After simple deproteinization by addition of acetonitrile, the analytes were separated on a C18 column. Detection was by tandem mass spectrometry in multiple reaction monitoring mode. The method was linear over the concentration range 3.9–195 ng mL−1 for both hyperoside and isoquercitrin. Intra-day and inter-day precision for both hyperoside and isoquercitrin were

A sensitive fluorescence liquid chromatographic analytical method was developed for the simultaneous determination of carnosine enantiomers in rat plasma. The method was applied to pharmacokinetic studies. Chiral separation of carnosine enantiomers was achieved by pre-column derivatization with o-phthaldialdehyde and the thiol N-acety-l-cysteine as derivating reagents. They were separated on an ODS column and detected by fluorescence detection (λex = 350 nm, λem = 450 nm). γ-Aminobutyric acid was used as internal standard. The method was linear up to 6,000 ng mL−1 for l-carnosine, 4,000 ng mL−1 for d-carnosine. Low limit of quantitation (LLOQ) was 40 ng mL−1 for each isomer. The relative standard deviations obtained for intra- and inter-day precision were lower than 12% and the recoveries were higher than 75% for both enantiomers. The method was applied to a stereoselective study on the pharmacokinetics of carnosine after oral administration with a single dose (carnosine, 75 mg kg−1 for each isomer) to a rat. The initial data indicated that l-carnosine had a larger value of the highest plasma concentration than d-carnosine (C max 5,344 vs. 1,914 ng mL−1), and that of l-carnosine had a lower value of AUC(0−∞) and t 1/2(h) (AUC(0−∞) 5,306 vs. 6,321 ng h mL−1, t 1/2 1.43 vs. 3.37 h). Our results indicated that the pharmacokinetic of l-carnosine and d-carnosine revealed enantioselective properties significantly.

Despite growing interest in the protective role that dietary antioxidant vitamins may have in the development of type 2 diabetes (T2D), little epidemiological evidence is available in non-Western populations especially about the possible mediators underlying in this role. The present study aimed to investigate the association of vitamin C and vitamin E intakes with T2D risk in Chinese adults and examine the potential mediators. 178 incident T2D cases among 3483 participants in the Harbin People Health Study (HPHS), and 522 newly diagnosed T2D among 7595 participants in the Harbin Cohort Study on Diet, Nutrition and Chronic Non-communicable Diseases (HDNNCDS) were studied. In the multivariable-adjusted logistics regression model, the relative risks (RRs) were 1.00, 0.75, and 0.76 (Ptrend = 0.003) across tertiles of vitamin C intake in the HDNNCDS, and this association was validated in the HPHS with RRs of 1.00, 0.47, and 0.46 (Ptrend = 0.002). The RRs were 1.00, 0.72, and 0.76 (Ptrend = 0.039) when T2D diagnosed by haemoglobin A1c in the HDNNCDS. The mediation analysis discovered that insulin resistance (indicated by homeostasis model assessment) and oxidative stress (indicated by plasma total antioxidative capacity) partly mediated this association. But no association was evident between vitamin E intake and T2D. In conclusion, our research adds further support to the role of vitamin C intake in reducing the development of T2D in the broader population studied. The results also suggested that this association was partly mediated by inhibiting or ameliorating oxidative stress and insulin resistance.