Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes

Cytochrome p450 (CYP450) enzymes are predominantly involved in Phase I metabolism of xenobiotics. In this study, the CYP450 isoforms involved in xanthotoxol metabolism were identified using recombinant CYP450s. In addition, the inhibitory effects of xanthotoxol on eight CYP450 isoforms and its pharmacokinetic parameters were determined using human liver microsomes. CYP1A2, one of CYP450s, played a key role in the metabolism of xanthotoxol compared to other CYP450s. Xanthotoxol showed stronger inhibition on CYP3A4 and CYP1A2 compared to other isoenzymes with the IC50 of 7.43 μM for CYP3A4 and 27.82 μM for CYP1A2. The values of inhibition kinetic parameters (Ki) were 21.15 μM and 2.22 μM for CYP1A2 and CYP3A4, respectively. The metabolism of xanthotoxol obeyed the typical monophasic Michaelis-Menten kinetics and Vmax, Km, and CLint values were calculated as 0.55 nmol·min−1·mg−1, 8.46 μM, and 0.06 mL·min−1·mg−1. In addition, the results of molecular docking showed that xanthotoxol was bound to CYP1A2 with hydrophobic and π-π bond and CYP3A4 with hydrogen and hydrophobic bond. We predicted the hepatic clearance (CLh) and the CLh value was 15.91 mL·min−1·kg−1 body weight. These data were significant for the application of xanthotoxol and xanthotoxol-containing herbs

Land use change on the surface area and the influence on carbon

China has diversified landforms, the three-dimensional space area check is more accurate to help determine China’s land use change and the caused carbon variations. This study explored a new method to check China’s surface area and examine the terrestrial carbon changes for the period of 2000–2020. The results show that China’s surface area increased by 13.9% compared with the planar area, with the increased area measuring 133 × 104 km2. The south and the west, especially the southwest, usually have a high area increasing rate. Woodland has the highest area increasing rate for all the provinces. 10% of the land had its land use type changed. Cropland, grassland and unused show total land area decrease, woodland, water, and impervious all increased. The mean increasing rate of land transfer on surface area varied between 1.39% and 38.84%. The total amount of land use-type change caused carbon loss reached −5907.44 × 104 t, of −3168.97 × 104 t from vegetation storage loss, −2738.77 × 104 t from NPP and water. There were only seven provinces show carbon increase, which were more located in the west. Per unit of woodland loss will cause higher carbon release than other land use types. Land use control need to be further strengthened, especially for the protection of woodland at mountain regions

Nrf2 expression and function, but not MT expression, is indispensable for sulforaphane-mediated protection against intermittent hypoxia-induced cardiomyopathy in mice

We reported previously that nuclear factor erythroid 2-related factor 2 (Nrf2) and metallothionein (MT) play critical roles in preventing intermittent hypoxia (IH)-induced cardiomyopathy. In addition, positive feedback regulation between Nrf2 and MT is required for the efficient compensative responses of the heart to IH. As an activator of Nrf2, sulforaphane (SFN) has attracted attention as a potential protective agent against cardiovascular disease. Here, we investigated whether SFN can up-regulate cardiac Nrf2 expression and function, as well as MT expression, to prevent IH-induced cardiomyopathy, and if so, whether Nrf2 and MT are indispensable for this preventive effect. Nrf2-knock-out (Nrf2-KO) or MT-KO mice and their wild-type (WT) equivalents were exposed to IH for 4 weeks with or without SFN treatment. SFN almost completely prevented IH-induced cardiomyopathy in WT mice, and this preventive effect was abolished in Nrf2-KO mice but retained in MT-KO mice. In IH-exposed WT mice, SFN induced significant increases in the expression levels of Nrf2 and its downstream antioxidant target genes, as well as those of MT, but these effects were not seen in IH-exposed Nrf2-KO mice. By contrast, KO of MT did not affect the ability of SFN to up-regulate the expression of Nrf2 and its downstream antioxidant targets. These results suggest that SFN-induced MT expression is Nrf2-dependent, and SFN prevents IH-induced cardiomyopathy in a Nrf2-dependent manner, for which MT is dispensable. This study provides important information that is relevant to the potential use of SFN to prevent IH-induced cardiomyopathy. Keywords: Intermittent hypoxia, Cardiomyopathy, Nuclear factor erythroid 2-related factor 2, Metallothionein, Sulforaphan

Abnormal alterations in the Ca2+/CaV1.2/calmodulin/caMKII signaling pathway in a tremor rat model and in cultured hippocampal neurons exposed to Mg2+-free solution

Voltage-dependent calcium channels (VDCCs) are key elements in epileptogenesis. There are several binding-sites linked to calmodulin (CaM) and several potential CaM-dependent protein kinase II (CaMKII)-mediated phosphorylation sites in CaV1.2. The tremor rat model (TRM) exhibits absence-like seizures from 8 weeks of age. The present study was performed to detect changes in the Ca(2+)/CaV1.2/CaM/CaMKII pathway in TRMs and in cultured hippocampal neurons exposed to Mg(2+)-free solution. The expression levels of CaV1.2, CaM and phosphorylated CaMKII (p-CaMKII; Thr-286) in these two models were examined using immunofluorescence and western blotting. Compared with Wistar rats, the expression levels of CaV1.2 and CaM were increased, and the expression of p-CaMKII was decreased in the TRM hippocampus. However, the expression of the targeted proteins was reversed in the TRM temporal cortex. A significant increase in the expression of CaM and decrease in the expression of CaV1.2 were observed in the TRM cerebellum. In the cultured neuron model, p-CaMKII and CaV1.2 were markedly decreased. In addition, neurons exhibiting co-localized expression of CaV1.2 and CaM immunoreactivities were detected. Furthermore, intracellular calcium concentrations were increased in these two models. For the first time, o the best of our knowledge, the data of the present study suggested that abnormal alterations in the Ca(2+)/CaV1.2/CaM/CaMKII pathway may be involved in epileptogenesis and in the phenotypes of TRMs and cultured hippocampal neurons exposed to Mg(2+)-free solution

Psychometric evaluation of the Chinese version of the Person-Centred Care Assessment Tool

OBJECTIVE: This study aims to test a Chinese cross-cultural adaptation of the English version of the Person-Centred Care Assessment Tool (P-CAT) and evaluate its psychometric properties. DESIGN: P-CAT was translated/back-translated using established procedures before the psychometric evaluation of the Chinese version was made. SETTING: Two hospitals covering urban and suburban areas of Kunming in the Yunnan province of China. PARTICIPANTS: 152 female hospital staff completed the survey. MAIN OUTCOME MEASURES: Construct validity and reliability, including internal consistency and test-retest reliability, were assessed among a sample of hospital staff. RESULTS: The factor analysis resulted in a two-component solution that consisted of two subscales. The corrected item-total correlations for all of the items ranged from 0.14 to 0.44, with six items not meeting the cut-off level for item-total correlation (>0.3). The Chinese P-CAT demonstrated strong reliability, with a Cronbach's alpha of 0.91-0.94 for the scales and a test-retest reliability coefficient of 0.88 for the overall scale scores. The intraclass correlation was 0.92 (95% CI 0.90 to 0.95). CONCLUSION: P-CAT appears to be a promising measure for evaluating staff perceptions of person-centredness in Chinese hospital environments. The results show that P-CAT can be a useful tool for improving the quality of healthcare in terms of person-centred care in the Chinese context

Psychometric evaluation of the Chinese version of the Person-centred Climate Questionnaire - Staff version (PCQ-S)

OBJECTIVES: The aim of the study was to evaluate the psychometric properties of a Chinese translation of the English version of the Person-centred Climate Questionnaire - Staff version (PCQ-S) for Chinese palliative care staff in a hospital context.DESIGN: This was a cross-sectional design. The 14-item English PCQ-S was translated and backtranslated using established procedures. Construct validity and reliability including internal consistency and test-retest reliability were assessed among hospital staff. Construct validity was tested using principal component analysis (PCA), internal consistency was assessed using Cronbach's alpha, and test-retest reliability was evaluated with the weighted kappa (Kp), Pearson correlation coefficient (r) and intra-class correlation coefficient (ICC).SETTING: This study was conducted in three hospitals in Kunming, the capital of Yunnan province in south-west China.PARTICIPANTS: A sample of hospital staff (n=163) on duty in the palliative care departments of three hospitals in Kunming consented to participate in the study.RESULTS: The 14-item Chinese PCQ-S consists of the three subscales also present in other language versions. It showed strong internal consistency, with a Cronbach's alpha of 0.94 for the total scale, 0.87 for the safety subscale, 0.90 for the everydayness subscale and 0.88 for the community subscale. The Chinese PCQ-S had high test-retest reliability as evidenced by a high Kp coefficient and a high correlation coefficient for all scales between test and retest scores, on 'a climate of safety' (Kp=0.77, r=0.88, p<0.01), 'a climate of everydayness' (Kp=0.82, r=0.91, p<0.01), 'a climate of community' (Kp=0.75, r=0.79, p<0.01), and on overall scale scores (Kp=0.85, r=0.93, p<0.01). The ICC to evaluate the test-retest reliability was 0.97 (95% CI 0.95 to 0.98).CONCLUSIONS: The Chinese version of the PCQ-S showed satisfactory reliability and validity for assessing staff perceptions of person-centred care in Chinese hospital environments