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"Sun, Sen"
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Physcion inhibition of CYP2C9, 2D6 and 3A4 in human liver microsomes
The effect of the active ingredients in traditional Chinese medicines on the activity of cytochrome P450 enzymes (CYP450s) is a critical factor that should be considered in TCM prescriptions. Physcion, the major active ingredient of
spp. (Polygonaceae), possesses wide pharmacological activities.
The effect of physcion on CYP450 activity was investigated to provide a theoretical basis for use.
The experiments were conducted in pooled human liver microsomes (HLMs). The activity of CYP450 isoforms was evaluated with corresponding substrates and probe reactions. Blank HLMs were set as negative controls, and typical inhibitors were employed as positive controls. The inhibition model was fitted with Lineweaver Burk plots. The concentration (0, 2.5, 5, 10, 25, 50 and 100 μM physcion) and time-dependent (0, 5, 10, 15 and 30 min) effects of physcion were also assessed.
Physcion suppressed CYP2C9, 2D6 and 3A4 in a concentration-dependent manner with IC
values of 7.44, 17.84 and 13.50 μM, respectively. The inhibition of CYP2C9 and 2D6 was competitive with the
values of 3.69 and 8.66 μM, respectively. The inhibition of CYP3A4 was non-competitive with a
value of 6.70 μM. Additionally, only the inhibition of CYP3A4 was time-dependent with the
and
parameters of 3.10 μM
and 0.049 min
, respectively.
The inhibition of CYP450s by physcion should be considered in its clinical prescription, and the study design can be employed to evaluate the interaction of CYP450s with other herbs.
Journal Article
Ischemia-free liver transplantation improves the prognosis of recipients using functionally marginal liver grafts
Background/Aims: The shortage of donor liver hinders the development of liver transplantation. This study aimed to clarify the poor outcomes of functionally marginal liver grafts (FMLs) and provide evidence for the improvement of ischemia-free liver transplantation (IFLT) after FML transplantation.Methods: Propensity score matching was used to control for confounding factors. The outcomes of the control group and FML group were compared to demonstrate the negative impact of FMLs on liver transplantation patients. We compared the clinical improvements of the different surgical types. To elucidate the underlying mechanism, we conducted bioinformatic analysis based on transcriptome and single-cell profiles.Results: FMLs had a significantly greater hazard ratio (HR: 1.969, P=0.018) than did other marginal livers. A worse 90-day survival (Mortality: 12.3% vs. 5.0%, P=0.007) was observed in patients who underwent FML transplantation. Patients who received FMLs had a significant improvement in overall survival after IFLT (Mortality: 10.4% vs 31.3%, P=0.006). Pyroptosis and inflammation were inhibited in patients who underwent IFLT. The infiltration of natural killer cells was lower in liver grafts from these patients. Bulk transcriptome profiles revealed a positive relationship between IL-32 and Caspase 1 (R=0.73, P=0.01) and between IL-32 and Gasdermin D (R=0.84, P=0.0012).Conclusions: FML is a more important negative prognostic parameter than other marginal liver parameters. IFLT might ameliorate liver injury in FMLs by inhibiting the infiltration of NK cells, consequently leading to the abortion of IL-32, which drives pyroptosis in monocytes and macrophages.
Journal Article
UDE-based Nonlinear Path-following Control of Autonomous Underwater Vehicles With Multiple Uncertainties and Input Saturation
This paper proposes a novel UDE-based nonlinear path-following (PF) control scheme for the underactuated autonomous underwater vehicle (AUV) with multiple uncertainties and input saturation. Firstly, to overcome the drawback of dependence on the accurate mathematical model, the unknown time-varying sideslip angular speed in the error dynamic model is treated as kinematic uncertainty, and the linear superposition of parameter uncertainties, environmental perturbations, and other unmodeled dynamics is regarded as lumped dynamic uncertainty. Both kinematic and dynamic uncertainties are estimated and compensated by the designed uncertainty and disturbance estimators (UDEs). Secondly, a novel augmented backstepping controller based on the estimates generated by UDEs is proposed to achieve PF control of the underactuated AUV. The nonlinear tracking differentiator (NTD) is adopted to prevent the “explosion of complexity” inherent in the traditional back-stepping method, and the auxiliary dynamical system is utilized to solve the issue of input saturation. Lastly, the stability analysis of the entire enclosed-loop framework is presented. Simulations and comparative analyses are presented to demonstrate the effectiveness and robustness of the presented strategy.
Journal Article
Sub-ppm acetic acid gas sensor based on In2O3 nanofibers
Metal oxide semiconductor sensors based on nanocrystalline In2O3 and its composites are found to be very sensitive in detecting low-concentration (~ 5 ppm) gases such as ozone, nitrogen dioxide, formaldehyde and butane. Here, we successfully obtained fiber-shaped In2O3 crystalline nanofibers via electrospun and calcination routes. The gas sensing properties of the In2O3 nanofibers were studied by exposing them to the acetic acid vapor with different concentrations from 500 ppb to 2000 ppm at the optimum operating temperature (250 °C). The device possesses ultra-high response of 66.7 toward 2000 ppm acetic acid vapor, low response and recovery times of 25 s and 37 s (100 ppm), respectively, and significant selectivity to acetic acid at 100 ppm. In particular, the sensor based on In2O3 nanofibers has very low detection limit and can reach 500 ppb. Therefore, the presented In2O3 nanofiber sensor can be used in practice in acetic acid detection area in the future.
Journal Article
Analysis and Optimization of Station Taxi Transfer Efficiency Based on Queuing Theory
Nowadays, the pace of life is accelerating, and people are paying great attention to the efficiency and quality of travel. This article uses some unreasonable phenomena in the station taxi transfer area to study the relevant knowledge of queuing theory to establish the taxi transfer efficiency of the city’s external transportation hub Optimize the model, take transfer waiting time and operating cost as evaluation indicators, and verify with examples. The results show that the optimization model is feasible, and the queuing time and the total cost per unit time under the optimization scheme are significantly reduced, which improves the efficiency of passengers changing taxis. Finally, it evaluates the optimization results proposed above.
Journal Article
Pharmacokinetic study on the co-administration of abemaciclib and astragaloside IV in rats
The co-administration of abemaciclib and astragaloside IV might occur in the treatment of breast cancer.
This study evaluates the interaction between abemaciclib and astragaloside IV in rats and describes the potential mechanism.
Male Sprague Dawley rats were randomly divided into four groups: single dose of abemaciclib (control), abemaciclib + 50 mg/kg/d astragaloside IV, abemaciclib + 100 mg/kg/d astragaloside IV, and abemaciclib + 150 mg/kg/d astragaloside IV. Abemaciclib and astragaloside IV were orally administrated, and astragaloside IV was pre-administrated for 7 d in the co-administrated groups. The pharmacokinetics and transport of abemaciclib were assessed in the absence or presence of astragaloside IV. In mechanism, the activity of CYP3A4 was estimated in human liver microsomes in the presence of astragaloside IV.
Astragaloside IV significantly increased the C
max
(from 991.5 ± 116.99 up to 2308.5 ± 55.29 μg/L) and AUC (from 24.49 ± 2.86 up to 66.14 ± 1.17 μg/mL × h) and prolonged the t
1/2
(from 19.85 ± 4.65 up to 66.17 ± 28.73 h) of abemaciclib, and the effect was enhanced with the increasing astragaloside IV concentration. Astragaloside IV also suppressed the transport of abemaciclib with the efflux ratio decreasing to 1.35. Astragaloside IV suppressed the activity of CYP3A4 with an IC
50
value of 21.78 μM.
The co-administration of abemaciclib and astragaloside IV induced the increasing systemic exposure of abemaciclib through the inhibition of CYP3A4. Further clinical validations could be carried out according to the study design of the present investigation.
Journal Article
COLEC12high tumor-associated macrophages orchestrate lenvatinib resistance and cancer stemness in hepatocellular carcinoma via paracrine NRG1-HER2/HER3 signaling
Background/Aims: Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood.Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort.Results: Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models.Conclusions: Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.
Journal Article
Iridescent Features Correlating with Periodic Assemblies in Custom-Crystallized Arylate Polyesters
In this study, five different aryl polyesters, i.e., poly(ethylene terephthalate) (PET), poly(trimethylene terephthalate) (PTT), poly(octamethylene terephthalate) (POT), poly(nonamethylene terephthalate) (PNT), and poly(decamethylene terephthalate) (PDT), upon crystallization at a suitable temperature range, all exhibit ring-banded spherulites with universal characteristics. Previous research has revealed some fundamental mechanisms underlying the formation of periodic hierarchical structures. Additionally, this study further explored correlations among micro/nanocrystal assemblies in the top surface and internal grating architectures and the structural iridescent properties. The interior lamellar assembly of arylate polyesters’ banded spherulites is shown to exhibit periodic birefringence patterns that are highly reminiscent of those found in a variety of biological structures, with the capacity for iridescence from light interference. A laser diffraction analysis was also used to support confirmation of this condition, which could result in an arc diffraction pattern indicative of the presence of ringed spherulites. Among the five arylate polyesters, only PET is incapable of regularly producing ring-banded morphology, and thus cannot produce any iridescent color.
Journal Article
Pyrolysis Kinetics and Combustion Behaviors of a High-Nitrogen Compound, 4,4′-Azobis(1,2,4-triazole)
To study the thermal decomposition behavior of 4,4′-azobis(1,2,4-triazole) (ATRZ), the non-isothermal thermal decomposition kinetics of ATRZ were studied using the thermogravimetric–differential scanning calorimetry (TG–DSC) method. The TG–DSC of ATRZ was analyzed at heating rates of 5, 10, 15, and 20 K·min−1 in an argon atmosphere. The thermal decomposition kinetic parameters at peak temperature (Tp), such as apparent activation energy (Ea) and pre-exponential factor (lgA) of ATRZ, were calculated using the Kissinger, Ozawa, and Satava–Sestak methods. Ea and lgA calculated using the Kissinger, Ozawa, and Satava–Sestak methods are very close, at 780.2 kJ·mol−1/70.5 s−1, 751.1 kJ·mol−1/71.8 s−1, and 762.1 kJ·mol−1/71.8 s−1, respectively. Using a combination of three methods, the reaction mechanism function g(α) of ATRZ was obtained. The results show that the decomposition temperature of ATRZ is about 310 °C, and the decomposition is rapidly exothermic. The pyrolysis path of ATRZ was investigated through a pyrolysis-gas chromatography mass spectrometry (PY-GC/MS) experiment. ATRZ has three different decomposition paths and finally generates N2, HC-N-CH, N≡C-N, and HC=N-C≡N. The laser ignition combustion duration of ATRZ was 0.5033 s and the peak temperature was 1913 °C. The laser ignition combustion duration of ATRZ+CL-20 was 1.0277 s and the peak temperature was 2105 °C. The rapid energy release rate of ATRZ promotes the combustion energy release of CL-20.
Journal Article