Inhibitory effect of imperatorin on dabrafenib metabolism in vitro and in vivo.

Dabrafenib is a BRAF inhibitor that has been demonstrated to be efficacious in the treatment of melanoma and non-small-cell lung cancer patients with BRAF V600E mutations. The objective of this study was to investigate the effects of 51 traditional Chinese medicines on the metabolism of dabrafenib and to further investigate the inhibitory effect of imperatorin. The quantification of dabrafenib and its metabolite hydroxy-dabrafenib was carried out using a sensitive, rapid, and accurate assay method based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results of in vitro experiments showed that 20 drugs inhibited the metabolism of dabrafenib by more than 80%. In a further study of imperatorin on dabrafenib, the half-maximal inhibitory concentration (IC50) values of imperatorin on dabrafenib were 0.22 µM and 3.68 µM in rat liver microsomes (RLM) and human liver microsomes (HLM), respectively, while the inhibition mechanisms were non-competitive and mixed type inhibition, respectively. The results of in vivo experiments demonstrated that in the presence of imperatorin, the AUC(0-t), AUC(0-∞), Cmax, and Tmax of dabrafenib were increased by 2.38-, 2.26-, 1.05-, and 6.10-fold, respectively, while CLz/F was decreased by 67.9%. In addition, Tmax of hydroxy-dabrafenib was increased by 1.4-fold. The results of the research showed that imperatorin had a consistent inhibitory effect on dabrafenib in vitro and in vivo. When the concurrent use of dabrafenib and imperatorin is unavoidable, clinicians should closely monitor for potential adverse events and make timely adjustments to the administered dosage.

Simultaneous measurement of COVID-19 treatment drugs (nirmatrelvir and ritonavir) in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study.

PAXLOVID™ (Co-packaging of Nirmatrelvir with Ritonavir) has been approved for the treatment of Coronavirus Disease 2019 (COVID-19). The goal of the experiment was to create an accurate and straightforward analytical method using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to simultaneously quantify nirmatrelvir and ritonavir in rat plasma, and to investigate the pharmacokinetic profiles of these drugs in rats. After protein precipitation using acetonitrile, nirmatrelvir, ritonavir, and the internal standard (IS) lopinavir were separated using ultra performance liquid chromatography (UPLC). This separation was achieved with a mobile phase composed of acetonitrile and an aqueous solution of 0.1% formic acid, using a reversed-phase column with a binary gradient elution. Using multiple reaction monitoring (MRM) technology, the analytes were detected in the positive electrospray ionization mode. Favorable linearity was observed in the calibration range of 2.0-10000 ng/mL for nirmatrelvir and 1.0-5000 ng/mL for ritonavir, respectively, within plasma samples. The lower limits of quantification (LLOQ) attained were 2.0 ng/mL for nirmatrelvir and 1.0 ng/mL for ritonavir, respectively. Both drugs demonstrated inter-day and intra-day precision below 15%, with accuracies ranging from -7.6% to 13.2%. Analytes were extracted with recoveries higher than 90.7% and without significant matrix effects. Likewise, the stability was found to meet the requirements of the analytical method under different conditions. This UPLC-MS/MS method, characterized by enabling accurate and precise quantification of nirmatrelvir and ritonavir in plasma, was effectively utilized for in vivo pharmacokinetic studies in rats.

[Effects of water level on soil seed bank in the floodplain wetland of Juzhang River, China]. / 水位变化对沮漳河河漫滩湿地土壤种子库的影响.

Aiming to understand the responses of soil seed bank to different water levels, we investigated vegetation and soil seed bank along a water level gradient (frequently flooded area, unflooded area) on the floodplain wetland of Juzhang River. We used the structural equation model to explore the direct and indirect effects of water level on soil seed bank, and used non-metric multidimensional scaling (NMDS) to assess the role of soil seed bank for vegetation regeneration. The results showed that the density of transient and persistent seed banks at unflooded area was 36.9% and 7.8% higher than that of frequently flooded area, respectively. Shannon index and Pielou index of seed bank and vegetation were significantly affected by water level and sampling location. Water level significantly affected the similarity between seed bank and aboveground vegetation, and the similarity of persistent seed bank with aboveground vegetation was significantly higher than that with transient seed bank. Structural equation model showed that water level had a direct effect on seed bank density, and indirect effects on density and richness of seed bank via affecting soil pH and NH4+-N content. NMDS results showed that there was no significant difference in the composition of the persistent seed bank and vegetation community in autumn under different water levels, but water level significantly changed the community composition of transient seed bank. Transient seed bank was affected by the vegetation and soil property, while persistent seed bank was determined by aboveground vegetation and water level. Although soil seed bank had low regeneration potential for the vegetation communities in floodplain wetlands, soil seed bank could not be neglected during the restoration of propagule diversity after disturbance in wetlands. Persistent seed bank would be an importance source of diversity of propagules for floodplain wetlands restoration following disturbance.

Seven-year long-term inoculation with Funneliformis mosseae increases maize yield and soil carbon storage evidenced by in situ 13C-labeling in a dryland.

Arbuscular mycorrhizal fungi (AMF) establish symbiotic relationships with roots of most plants, contributing to plant water uptake and soil carbon (C) sequestration. However, the interactive contribution and of long-term field AMF inoculation and water conservation on maize yield and soil organic carbon (SOC) sequestration in drylands remain largely unknown. After 7-year long-term field inoculation with AMF Funneliformis mosseae, AMF suppression by fungicide benomyl, and no-AMF/no-benomyl control, and two water conservation practices of half-film and full-film mulching (∼50 % and ∼100 crop planted area covered with plastic film), this study thus applied in situ 13CO2-C labeling and high-throughput sequencing to quantify newly photosynthetically assimilated C into different soil C pools including soil aggregates and respiration, and their effects on maize growth and productivity. Results showed that 7-year long-term AMF inoculation significantly increased the relative abundance of F. mosseae in rhizosphere soil and root AMF colonization, indicating that F. mosseae successfully dominated in AMF communities. Compared to no-AMF/no-benomyl control, AMF colonization significantly increased shoot biomass and maize yield by 17.9 % and 20.3 % while mitigated the less water conservation effects of half-film mulching on maize performance. The SOC content under field AMF inoculation SOC was increased from 7.9 to 8.4 g kg-1 and also the mean weight diameter of aggregates (1.21 to 1.35), e.g. aggregate stability. After 1 and/or 40 days 13C labeling, the enhanced 13C translocations into macro-aggregates with decreased 13C emissions from microbial decomposition under field AMF inoculation had contributed to SOC conservation in bulk soil. These results suggest that AMF inoculation in dryland crops is promising to increase crop yield while promoting more atmospheric CO2 fixation in soil aggregates. A long-term field AMF inoculation will enhance our understanding of applying beneficial mycorrhizal fungi to enhance soil C sequestration and also crop yield via plant-fixed atmospheric CO2 in semi-arid and arid farmlands.

Heat-sealable, transparent, and degradable arabinogalactan/polyvinyl alcohol films with UV-shielding, antibacterial, and antioxidant properties.

Petroleum-based packaging materials are nondegradable and unsustainable and thus are harmful to the environment. Renewable packaging films prepared from bio-based raw materials are promising alternatives to petroleum-based packaging materials. In this study, colorless and transparent bio-based films were successfully cast using a solution containing a mixture of arabinogalactan (AG) and poly (vinyl alcohol) (PVA). Vanillin was incorporated into the mixture to endow the films with UV-shielding, antioxidant, and antibacterial properties. The morphological, physical, antioxidant, and antibacterial properties of the blend films were then characterized. At an AG:PVA weight ratio of 1:3, and the vanillin content was 0.15 %, the tensile strength of the AG/PVA/Vanillin (APV) films reached ~28 MPa, while their elongation at break reached ~475 %. The addition of vanillin significantly affected the antioxidant and antibacterial properties of the blend films, which exhibited superb UV barrier capacity. The APV films exhibited extremely low oxygen transmittance, delaying the onset of mold/rot in strawberries and reducing their weight loss. Because of the heat sealability of the blend films, they can be used for encapsulating various substances, such as concentrated laundry liquid. Moreover, the blend films were recyclable and biodegradable. Thus, these films have great potential for applications that require sustainable packaging.

Advances in contezolid: novel oxazolidinone antibacterial in Gram-positive treatment.

PURPOSE: The principal objective of this project was to review and thoroughly examine the chemical characteristics, pharmacological activity, and quantification methods associated with contezolid. METHODS: The article was based on published and ongoing preclinical and clinical studies on the application of contezolid. These studies included experiments on the physicochemical properties of contezolid, in vitro antimicrobial research, in vivo antimicrobial research, and clinical trials in various phases. There were no date restrictions on these studies. RESULTS: In June 2021, contezolid was approved for treating complicated skin and soft tissue infections. The structural modification of contezolid has resulted in better efficacy compared to linezolid. It inhibits bacterial growth by preventing the production of the functional 70S initiation complex required to translate bacterial proteins. The current evidence has indicated a substantial decline in myelosuppression and monoamine oxidase inhibition without impairing its antibacterial properties. Contezolid was found to have a more significant safety profile and to be metabolised by flavin monooxygenase 5, reducing the risk of harmful effects due to drug-drug interactions. Adjusting doses is unnecessary for patients with mild to moderate renal or hepatic insufficiency. CONCLUSION: As an oral oxazolidinone antimicrobial agent, contezolid is effective against multi-drug resistant Gram-positive bacteria. The introduction of contezolid provided a new clinical option.

CYP3A4 and CYP2C19 genetic polymorphisms and myricetin interaction on tofacitinib metabolism.

Tofacitinib can effectively improve the clinical symptoms of rheumatoid arthritis (RA) patients. In this current study, a recombinant human CYP2C19 and CYP3A4 system was operated to study the effects of recombinant variants on tofacitinib metabolism. Moreover, the interaction between tofacitinib and myricetin was analyzed in vitro. The levels of M9 (the main metabolite of tofacitinib) was detected by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The findings revealed that 11 variants showed significant changes in the levels of M9 compared to CYP3A4.1, while the other variants didn't reveal any remarkable significances. Compared with CYP2C19.1, 11 variants showed increases in the levels of M9, and 10 variants showed decreases. Additionally, it was demonstrated in vitro that the inhibition of tofacitinib by myricetin was a non-competitive type in rat liver microsomes (RLM) and human liver microsomes (HLM). However, the inhibitory mechanism was a competitive type in CYP3A4.18, and mixed type in CYP3A4.1 and .28, respectively. The data demonstrated that gene polymorphisms and myricetin had significant effects on the metabolism of tofacitinib, contributing to important clinical data for the precise use.

Effects of two commonly used antidepressants amitriptyline and fluoxetine on the pharmacokinetics of abrocitinib in rats.

Abrocitinib is approved to treat moderate-to-severe atopic dermatitis and eliminated mainly through cytochrome P450 (CYP450) enzyme. Two commonly used antidepressants, amitriptyline and fluoxetine, could inhibit the activities of CYP2C19 and CYP3A4. In this study, we developed a new and quick ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantitatively analyzing the plasma concentration of abrocitinib, and further investigated the effects of amitriptyline or fluoxetine on the pharmacokinetics of abrocitinib in rats. The selectivity, linearity, recovery, accuracy, precision, matrix effect and stability of UPLC-MS/MS assay were satisfied according to the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Our result showed that when co-administered with amitriptyline and fluoxetine, the CLz/F of abrocitinib was reduced by 44.4 % and 33.3 %, respectively, while the AUC(0-t) of abrocitinib was increased by 77.7 % and 49.4 %, respectively. It indicated that amitriptyline and fluoxetine could significantly increase the plasma concentration of abrocitinib in rats. Thus, dose adjustment of abrocitinib may be required when it is combined with amitriptyline or fluoxetine in ongoing clinical practice.

Quantitative investigation of drug-drug interaction between bergenin and vilazodone in rats through UPLC-MS/MS assay.

In this study, we firstly established and verified a method by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for the analysis of vilazodone and its metabolite M10 in rat plasma, then this method was used to explore the pharmacokinetics of vilazodone and M10 present or absence of 80 mg/kg bergenin in rats. Protein precipitation with acetonitrile was used to prepare the samples in this research. The mobile phase for liquid chromatography was consisted of 0.1% formic acid aqueous solution and acetonitrile. Brexpiprazole was used as the internal standard (IS), and the multiple reaction monitoring (MRM) mode was used for detection. The verification items required by the US Food and Drug Administration (FDA) guidelines such as selectivity, sensitivity, linearity, stability, recovery and matrix effect of this method were all met the standards. Besides, rats were used to explore the drug-drug interaction between vilazodone and bergenin, which were divided into two groups, and separately gavaged with the same-volume of carboxymethyl cellulose sodium (CMC-Na) solution and 80 mg/kg bergenin, respectively. The results showed that bergenin significantly affected the metabolism of vilazodone. It suggested that there was a potential drug-drug interaction between bergenin and vilazodone in rats. In clinical application, we should pay attention to the dose of vilazodone when in combination with bergenin.

Genetic variants, haplotype determination, and function of novel alleles of CYP2B6 in a Han Chinese population.

Amino acid variants in protein may result in deleterious effects on enzymatic activity. In this study we investigate the DNA variants on activity of CYP2B6 gene in a Chinese Han population for potential use in precision medicine. All exons in CYP2B6 gene from 1483 Chinese Han adults (Zhejiang province) were sequenced using Sanger sequencing. The effects of nonsynonymous variants on recombinant protein catalytic activity were investigated in vitro with Sf12 system. The haplotype of novel nonsynonymous variants with other single nucleotide variants in the same allele was determined using Nanopore sequencing. Of 38 alleles listed on the Pharmacogene Variation Consortium, we detected 7 previously reported alleles and 18 novel variants, of which 11 nonsynonymous variants showed lower catalytic activity (0.00-0.60) on bupropion compared to CYP2B6*1. Further, these 11 novel star-alleles (CYP2B6*39-49) were assigned by the Pharmacogene Variation Consortium, which may be valuable for pharmacogenetic research and personalized medicine.

Differential inhibition of sildenafil and macitentan on saxagliptin metabolism.

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

Simultaneous determination of iguratimod and its metabolite in rat plasma using a UPLC-MS/MS method: Application for drug-drug interaction.

This aim of the work was to establish an acceptable sensitive assay based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for quantitatively analyzing the plasma concentrations of iguratimod (IGR) and its metabolite M2 in rats, and to further investigate the effect of fluconazole on the pharmacokinetics of IGR and M2. The mobile phase consisted of acetonitrile and water with 0.1% formic acid, was used to separate IGR, M2 and internal standard (IS) fedratinib on a UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm) with the flow rate of 0.4 mL/min. Positive ion mode and multiple reaction monitoring (MRM) were used to construct the quantitative analysis. The calibration standard of IGR and M2 covered 2-10000 and 1-1000 ng/mL respectively, with the lower limit of quantification (LLOQ) as 2 ng/mL and 1 ng/mL respectively. In addition, selectivity, recovery, accuracy, precision, matrix effect and stability of the method validation program were well accepted in this work. Subsequently, this approach was used to assess the effect of fluconazole on the pharmacokinetics of IGR and M2 in rats. In the presence of 20 mg/kg fluconazole (experimental group), we found the main pharmacokinetic parameters were significantly altered when compared with 2.5 mg/kg IGR alone (control group). Among them, AUC(0-∞) and Cmax of IGR in the experimental group was 1.43 and 1.08 times higher than that of the control group, respectively. Moreover, we also found that the other main pharmacokinetic parameters of M2 had no significant changes, except t1/2z and Tmax. In conclusion, fluconazole significantly altered the main pharmacokinetics of IGR and M2 in rats. It implys that we should pay more attention to the adverse reaction of IGR when the concomitant use of fluconazole and IGR occur in the future clinical practice.

In-depth theoretical analysis of the influence of an external electric field on charge transport parameters.

It is important to develop materials with environmental stability and long device shelf life for use in organic field-effect transistors (OFETs). The microscopic, molecular-level nature of the organic layer in OFETs is not yet well understood. The stability of geometric and electronic structures and the regulation of the external electric field (EEF) on the charge transport properties of four typical homogeneous organic semiconductors (OSCs) were investigated by density functional theory (DFT). The results showed that under the EEF, the structural changes in single-bond linked oligomers were more sensitive and complex than those of condensed molecules, and there were non-monotonic changes in their reorganization energy (λ) during charge transport under an EEF consisting of decreases and then increases (Series D). The change in λ under an EEF can be preliminarily and qualitatively determined by the change in the frontier molecular orbitals (FMOs) - the number of C-atoms with nonbonding characteristics. For single-bonded molecules, the transfer integral is basically unchanged under a low EEF, but it will greatly change at a high EEF. Because the structure and properties of the molecule will greatly change under different EEFs, the effect of an EEF should be fully considered when determining the intrinsic mobility of OSCs, which could cause a deviation 0.3-20 times in mobility. According to detailed calculations, one heterogeneous oligomer, TH-BTz, was designed. Its λ can be greatly reduced under an EEF, and the change in the energy level of FMOs can be adjusted to different degrees. This study provides a reasonable idea for verification of the experimental mobility value and also provides guidance for the directional design of stable high-mobility OSCs.

High-Performance Flexible Ionically Conductive Superhydrophobic Papers via Deep Eutectic Polymer-Enhanced Interfacial Interactions.

Endowing paper with highly flexible, conductive, and superhydrophobic properties will effectively expand its applications in fields such as green packaging, smart sensing, and paper-based electronics. Herein, a multifunctional superhydrophobic paper is reported in which a highly flexible transparent conductive substrate is prepared by introducing a hydrophobic deep eutectic polymer into the ethylcellulose network via a matrix swelling-polymerization strategy, and then the substrate is modified using fluorinated silica to impart superhydrophobicity. By introducing soft deep eutectic polymers, (1) the superhydrophobic paper can efficiently dissipate energy during deformation, (2) intrinsically ion-conducting deep eutectic polymers can endow the material with good electrical sensing properties, and (3) meanwhile, enhanced interfacial interactions can anchor inorganic particles, thereby improving the coating stability. The prepared superhydrophobic paper has an ultrahigh water contact angle (contact angle ≈ 162.2°) and exhibits a stable electrical response signal to external deformation/pressure, and the electrical properties are almost unaffected by external water molecules. In addition, the superhydrophobic paper was able to withstand 5000 bending-recovery cycles at a large angle of 150°, exhibiting stable electrical performance. The design concepts demonstrated here will provide insights into the development of superhydrophobic paper-based flexible electronic devices.

Effects of myricetin and quercetin on ticagrelor metabolism and the underlying mechanism.

The aim of this study was to investigate the potential drug-drug interactions (DDIs) between ticagrelor and other drugs as well as their underlying mechanisms. Rat liver microsome (RLM) reaction system was used to screen potential DDIs in vitro, and ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was applied to detect the levels of ticagrelor and AR-C124910XX, the main metabolite of ticagrelor. A total of 68 drugs were screened, 11 of which inhibited the production of AR-C124910XX to 20% or less, especially two flavonoids (myricetin and quercetin). The half-maximal inhibitory concentration (IC50) of myricetin on ticagrelor was 11.51 ± 0.28 µM in RLM and 17.96 ± 0.54 µM in human liver microsome (HLM). The IC50 of quercetin in inhibiting ticagrelor in RLM and HLM was 16.92 ± 0.49 µM and 60.15 ± 0.43 µM, respectively. They all inhibited the metabolism of ticagrelor through a mixed mechanism. In addition, Sprague-Dawley (SD) rats were used to study the interactions of ticagrelor with selected drugs in vivo. We found that the main pharmacokinetic parameters including AUC (0-t), AUC (0-∞) and Cmax of ticagrelor were significantly increased when ticagrelor was combined with these two flavonoids. Our results suggested that myricetin and quercetin of flavonoids both had significant effects on the metabolism of ticagrelor, providing reference data for the clinical individualized medication of ticagrelor.

The Pharmacokinetic Interaction of Tirabrutinib with Voriconazole, Itraconazole, and Fluconazole in SD Rats by UPLC-MS/MS.

BACKGROUND: Tirabrutinib is an orally effective, approved, and highly selective second-generation Bruton's tyrosine kinase (BTK) inhibitor for the treatment of recurrent or refractory primary central nervous system lymphoma (PCNSL). OBJECTIVE: This study aimed to develop an ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) method for the determination of tirabrutinib concentration in rat plasma, where zanubrutinib was used as an internal standard (IS). This method was also applied to study whether tirabrutinib would interact with voriconazole, itraconazole, and fluconazole in rats, providing a reference value for clinical medication guidance. METHODS: In the current study, the organic solvent protein precipitation method was used to treat plasma samples, which is simple and reproducible. Tirabrutinib (m/z 455.32 → 320.21) and zanubrutinib (m/z 472.13 → 455.04) were separated on a Waters Acquity BEH C18 column (2.1 × 50 mm, 1.7 µm) and detected by multiple reaction monitoring (MRM) in positive ionization mode. RESULTS: The method showed good linearity in the range of 5-3000 ng/mL for tirabrutinib with the lower limit of quantification (LLOQ) of 5 ng/mL. The recovery and matrix effects were 85.7-91.0% and 102.0-113.3%, respectively. The accuracy, precision, stability, and carry-over effect were also acceptable. The method could also be used for determining the pharmacokinetic interaction of tirabrutinib in rats. The results showed AUC0→∞ of tirabrutinib to be increased by 139.3% and 83.9% in the presence of voriconazole and fluconazole, respectively, while itraconazole had little effect. CONCLUSION: It is necessary to monitor the concentration of tirabrutinib in patients when it is combined with voriconazole and fluconazole to achieve a better therapeutic effect and reduce the risk of adverse reaction. Further research should be conducted in the future.

Inhibitory effects of the main metabolites of Apatinib on CYP450 isozymes in human and rat liver microsomes.

PURPOSE: The inhibitory effect of Apatinib on cytochrome P450 (CYP450) enzymes has been studied. However, it is unknown whether the inhibition is related to the major metabolites, M1-1, M1-2 and M1-6. METHODS: A 5-in-1 cocktail system composed of CYP2B6/Cyp2b1, CYP2C9/Cyp2c11, CYP2E1/Cyp2e1, CYP2D6/Cyp2d1 and CYP3A/Cyp3a2 was used in this study. Firstly, the effects of APA and its main metabolites on the activities of HLMs, RLMs and recombinant isoforms were examined. The reaction mixture included HLMs, RLMs or recombinant isoforms (CYP3A4.1, CYP2D6.1, CYP2D6.10 or CYP2C9.1), analyte (APA, M1-1, M1-2 or M1-6), probe substrates. The reactions were pre-incubated for 5 min at 37 °C, followed by the addition of NAPDH to initiate the reactions, which continued for 40 min. Secondly, IC50 experiments were conducted to determine if the inhibitions were reversible. The reaction mixture of the "+ NADPH Group" included HLMs or RLMs, 0 to 100 of µM M1-1 or M1-2, probe substrates. The reactions were pre-incubated for 5 min at 37 °C, and then NAPDH was added to initiate reactions, which proceeded for 40 min. The reaction mixture of the "- NADPH Group" included HLMs or RLMs, probe substrates, NAPDH. The reactions were pre-incubated for 30 min at 37 °C, and then 0 to 100 µM of M1-1 or M1-2 was added to initiate the reactions, which proceeded for 40 min. Finally, the reversible inhibition of M1-1 and M1-2 on isozymes was determined. The reaction mixture included HLMs or RLMs, 0 to 10 µM of M1-1 or M1-2, probe substrates with concentrations ranging from 0.25Km to 2Km. RESULTS: Under the influence of M1-6, the activity of CYP2B6, 2C9, 2E1 and 3A4/5 was increased to 193.92%, 210.82%, 235.67% and 380.12% respectively; the activity of CYP2D6 was reduced to 92.61%. The inhibitory effects of M1-1 on CYP3A4/5 in HLMs and on Cyp2d1 in RLMs, as well as the effect of M1-2 on CYP3A in HLMs, were determined to be noncompetitive inhibition, with the Ki values equal to 1.340 µM, 1.151 µM and 1.829 µM, respectively. The inhibitory effect of M1-1 on CYP2B6 and CYP2D6 in HLMs, as well as the effect of M1-2 on CYP2C9 and CYP2D6 in HLMs, were determined to be competitive inhibition, with the Ki values equal to 12.280 µM, 2.046 µM, 0.560 µM and 4.377 µM, respectively. The inhibitory effects of M1-1 on CYP2C9 in HLMs and M1-2 on Cyp2d1 in RLMs were determined to be mixed-type, with the Ki values equal to 0.998 µM and 0.884 µM. The parameters could not be obtained due to the atypical kinetics of CYP2E1 in HLMs under the impact of M1-2. CONCLUSIONS: M1-1 and M1-2 exhibited inhibition for several CYP450 isozymes, especially CYP2B6, 2C9, 2D6 and 3A4/5. This observation may uncover potential drug-drug interactions and provide valuable insights for the clinical application of APA.

Green, recyclable, mechanically robust, wet-adhesive and ionically conductive cellulose-based bioplastics enabled by supramolecular covalent hydrophobic eutectic networks.

The development of novel cellulose-based bioplastics (CBPs) is highly desirable because CBPs are green, rationally use resources, and lead to a reduction in environmental pollution compared to alternative materials. However, incorporating high transparency, water resistance, mechanical robustness, wet-adhesion, ionic conductivity and recyclability into CBP remains a challenge. In this paper, novel CBPs with supramolecular covalent networks are fabricated by introducing polymerizable hydrophobic deep eutectic solvents (HDES) into ethylcellulose (EC) networks through in situ plasticization followed by a rapid photopolymerization process. The excellent molecular interfacial compatibility enables EC to be loaded with a high content of poly(HDES), while allowing high transparency (more than 90 %) of the prepared CBPs. Multiple intermolecular interactions provide CBPs with mechanical robustness, water resistance, and underwater adhesion, and CBPs can be readily recovered by the solvent in a closed loop. Moreover, CBPs possess inherent ionic conductivities, and using them as green substrates, personalized electroluminescent devices can be successfully constructed. The method proposed in this paper provides a new strategy for the preparation of multifunctional CBPs, which will greatly enrich their applications in self-adhesive materials, green flexible electronics and other package materials.

Inhibitory effect of napabucasin on arbidol metabolism and its mechanism research.

As a broad-spectrum antiviral, and especially as a popular drug for treating coronavirus disease 2019 (COVID-19) today, arbidol often involves drug-drug interactions (DDI) when treating critical patients. This study established a rapid and effective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to detect arbidol and its metabolite arbidol sulfoxide (M6-1) levels in vivo and in vitro. In this study, a 200 µL incubation system was used to study the inhibitory effect of the antitumor drug napabucasin on arbidol in vitro, with IC50 values of 2.25, 3.91, and 67.79 µM in rat liver microsomes (RLMs), human liver microsomes (HLMs), and CYP3A4.1, respectively. In addition, we found that the mechanism of inhibition was non-competitive inhibition in RLM and mixed inhibition in HLM. In pharmacokinetic experiments, it was observed that after gavage administration of 48 mg/kg napabucasin and 20 mg/kg arbidol, napabucasin inhibited the metabolism of arbidol in vivo and significantly changed the pharmacokinetic parameters of arbidol, such as AUC(0-t) and AUC(0-∞), in rats. We also found that napabucasin increased the AUC(0-t) and AUC(0-∞) of M6-1, the main metabolite of arbidol. This study provides a reference for the combined use of napabucasin and arbidol in clinical practice.

Research and Design of Aggregation-Regulated Thermally Activated Delayed Fluorescence Materials for Time-Resolved Two-Photon Excited Fluorescence Imaging and Biological Monitoring.

Exploring the nature of aggregation-regulated thermally activated delayed fluorescence (TADF) and proposing effective design strategies for two-photon excited TADF materials for time-resolved biological imaging and monitoring are urgent and encouraging. In this work, it is found that the aggregation effect not only plays an important role in decreasing the internal conversion decay rate but also strongly influences the singlet-triplet excited-state energy difference as well as the intersystem crossing rate. It is proposed that the transformation from prompt fluorescence materials to long lifetime TADF or phosphorescence materials can be accomplished by regulating the position of substituent groups, which provides an effective method to design and develop long afterglow materials. Then, a high-performance TADF compound with a large two-photon absorption cross section in the biological window (112 GM/775 nm), high TADF efficiency (nearly 100%), and long fluorescence lifetime (50.75 µs) has been designed, which demonstrates the potential application in time-resolved two-photon excited fluorescence imaging and biological detection.