•Drugs can be detected in hair root in 15 min after administration.•Quetiapine level in hair roots were positively correlated with doses within 24 h.•Hair root analysis may be a good choice to detect ...acute poisoning.
This study investigated the kinetics of quetiapine and its metabolite 7-hydroxyquetiapine in guinea pig blood and hair roots during the whole time course of absorption and elimination after intragastric administration of three dosages (25 mg/kg, 50 mg/kg, 100 mg/kg). The mean maximum concentration (Cmax) values of quetiapine in the blood of the low-, medium- and high-dose groups were 334.4, 849.0, and 2751.1 ng/mL, respectively, and those of 7-hydroxyquetiapine were 75.6, 175.5, and 173.7 ng/mL, respectively. The corresponding mean Cmax values of quetiapine in hair roots were 2.0, 5.9, and 14.7 ng/mg, and those of 7-hydroxyquetiapine were 1.0, 1.8, and 6.4 ng/mg. The mean half-lives of quetiapine at the three dosages in blood were 3.8 h, 5.0 h, and 6.0 h, and those in hair roots were 48.2 h, 41.5 h, and 162.3 h; for 7-hydroxyquetiapine, the values were 2.9 h, 4.1 h, and 4.2 h in blood and 77.1 h, 103.6 h, and 385.9 h in hair roots. The levels of quetiapine in blood and hair roots were higher than those of 7-hydroxyquetiapine, and there were significant positive correlations (p<0.05) between the concentrations of quetiapine and 7-hydroxyquetiapine in hair roots and the respective doses within 24 h and 48 h. Quetiapine and 7-hydroxyquetiapine could still be detected in some guinea pigs even after 28 days, which means that drugs remain in the hair roots longer than in the blood. This finding shows that hair roots could be a good alternative or supplemental matrix to common biological samples such as blood and urine, as hair roots substantially extend the detection window from days to months. Moreover, quetiapine and 7-hydroxyquetiapine were detected within 15min after administration in hair roots, which also suggests that the drug enters the hair roots quickly. Therefore, hair root analysis may be a good choice to detect acute poisoning and single-dose administration if other matrices are unavailable or to provide complementary information for other matrices.
The importance of intratumoral heterogeneity has been highlighted by the identification and characterization of cancer stem cells (CSCs). Based on the differential responsiveness to a Sox2 reporter, ...SRR2, we had found a novel dichotomy in esophageal squamous cell carcinoma (ESCC) cells, with reporter‐responsive (RR) cells showing more CSC‐like features than reporter‐unresponsive (RU) cells. Specifically, RR cells exhibited significantly higher tumorsphere formation capacity, proportions of CD44High cells, chemoresistance to cisplatin, and tumorigenic potential in vivo. H2O2, a potent inducer of oxidative stress and reactive oxygen species, was found to induce a conversion from RU to RR cells; importantly, converted RR cells acquired CSC‐like features. The PI3K/AKT/c‐MYC signalling axis is important in this context, since pharmacologic blockade of PI3K‐AKT or siRNA knockdown of c‐MYC effectively inhibited the RR phenotype and its associated CSC‐like features, as well as the H2O2‐induced RU/RR conversion. In a cohort of 188 ESCC patient samples, we found a significant correlation between strong c‐MYC expression and a short overall survival (p = .009). In conclusion, we have described a novel intratumoral heterogeneity in ESCC. The identification of the PI3K/AKT/c‐MYC axis as a driver of CSC‐like features carries therapeutic implications. Stem Cells 2016;34:2040–2051
Oxidative stress induced by H2O2 promotes RU/RR conversion and the acquisition of CSC‐like properties. (A) Reactive oxygen species (ROS) induced by H2O2 (500 μM for 24 hours) was measured by flow cytometry. (B) H2O2‐induced RU/RR conversion in KYSE150‐RU cells, as indicated by the increase of GFP‐positive cells and luciferase activity. Representative flow cytometry data at Day 4 was shown in the left panel. Note that cells grown at a 100% confluence were used in this assay. (C) Flow cytometry was performed to measure GFP expression and ROS levels to determine the effect of N‐Acetyl‐Cysteine (NAC), an antioxidant agent, on oxidative stress‐induced RU/RR conversion. Median ROS values are indicated by bidirectional arrows. (D) Tumorsphere formation assay was used to evaluate H2O2‐induced CSC‐like properties. The RU cells used in this assay were treated with different concentrations of H2O2 for four cycles, each cycle includes a 24 hours H2O2 treatment and a recovery phase for 3 days. Images were taken at ×100 magnification. (E) RU cells were treated with 300 μM H2O2 for 48 hours or left untreated, and CD44 expression was measured using flow cytometry. The size of the CD44High cell population was compared in untreated RU cells and the converted RR cells (Conv. RR). All data are presented as mean ± SD, *p < .05, **p < .01, ***p < .001, Student's t test.
The emergence of novel drugs and the continuous expansion of the scope of the types of drugs under control have greatly increased requests for screening of a range of drugs in hair. Here, a ...multi-analyte method for the detection and quantification of 88 psychotropic drugs in the hair of addicts in drug abstinence was developed and fully validated using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Hair samples (25 mg) were washed, cut into pieces, cryogenically ground and extracted in methanol. The extracted analytes were separated on an Allure PFP Propyl column (100 × 2.1 mm, 5 mm inside diameter, Restek, USA) and analyzed by LC-MS-MS in multiple reaction monitoring modes. The limits of detection and the limits of quantification ranged from 0.1 to 20 pg/mg and 0.2 to 50 pg/mg, respectively. The intra- and inter-assay precisions (relative standard deviation (RSD)) of all analyses ranged from 0.9% to 14.9% and 1.9% to 15.9%, respectively. Accuracy values were 100 ± 20%. The extraction recovery of quality control samples ranged from 50.9% to 99.6% for all analytes. The matrix effects for all analytes ranged from 46.8% to 99.7%. The method was successfully used to analyze 1,865 hair samples from addicts in drug rehabilitation at their own communities. Among the samples, 129 cases were positive; the majority of positive cases were from males (78.29%), 92.25% of whom were >35 years old. Traditional drugs, like methamphetamine and opioids, accounted for most positive cases, and 27 of the abstinence cases with a use history of methamphetamine were still positive. In addition to abused drugs, like methamphetamine, morphine and cocaine, the sedative-hypnotic and psychotherapeutic drugs, including clonazepam, alprazolam, estazolam, zolpidem and quetiapine, were detected in 26% of the hair samples, suggesting that these addicts may have insomnia and mental problems such as depression and psychosis, probably due to the long-term effects of drugs and withdrawal reactions. Three synthetic cannabinoids were also detected in four (2.7%) cases. A total of 37 cases were positive for methadone, tramadol and dextromethorphan, reflecting a new trend of alternative drug use when traditional drugs were not easy to obtain during the coronavirus disease 2019 outbreak.
We show that in a setting with a strong concern for controlling shareholder entrenchment, firms with multiple large shareholders (MLS) are more likely to experience stock price crashes. As a result, ...when anticipating future revelations of bad news concerning corporate misconduct on information disclosure, large shareholders can exploit their information advantage and initiate their sales ex ante as far as eight quarters ahead. The positive association between MLS and crashes is more pronounced in the presence of noncontrolling shareholders' sales. Also, the positive predictive power of MLS on crash risk is more potent in firms with weak internal or external governance.
Impaired macroautophagy/autophagy and high levels of glycolysis are prevalent in liver cancer. However, it remains unknown whether there is a regulatory relationship between autophagy and glycolytic ...metabolism. In this study, by utilizing cancer cells with basal or impaired autophagic flux, we demonstrated that glycolytic activity is negatively correlated with autophagy level. The autophagic degradation of HK2 (hexokinase 2), a crucial glycolytic enzyme catalyzing the conversion of glucose to glucose-6-phosphate, was found to be involved in the regulation of glycolysis by autophagy. The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. In a tissue microarray of human liver cancer, the combination of high HK2 expression and high SQSTM1 expression was shown to have biological and prognostic significance. Furthermore, 3-BrPA, a pyruvate analog targeting HK2, significantly decreased the growth of autophagy-impaired tumors in vitro and in vivo (p < 0.05). By demonstrating the regulation of glycolysis by autophagy through the TRAF6- and SQSTM1-mediated ubiquitination system, our study may open an avenue for developing a glycolysis-targeting therapeutic intervention for treatment of autophagy-impaired liver cancer.
Bioactive metabolites in
are of particular interest as an immunostimulant. Methyl jasmonate (MeJA) plays an important role in the elicitation of metabolite biosynthesis. Here, we explored the ...response of metabolites to MeJA elicitation in
adventitious roots and multiple shoots. The results showed that the biomass, polysaccharide, and lobetyolin content of adventitious roots exhibited the highest increases with 100 µmol·L
MeJA at the 16th day of subculture, whereas the atractylenolide III (a terpenoid) content increased extremely with 50 µmol·L
MeJA treatment at the 7th day of subculture. In addition, the biomass and lobetyolin content significantly increased at the 4th day after treatment. Similarly, the polysaccharide and lobetyolin content increased in multiple shoots. Further identification of different metabolites responding to MeJA by ¹H-NMR showed an extremely significant increase of the lobetyolinin level, which coincided with lobetyolin. Accordingly, the precursor, fatty acids, showed a highly significant decrease in their levels. Furthermore, a significant increase in β-d-fructose-butanol glycoside was detected, which was accompanied by a decrease in the sucrose level. Accordingly, the enzyme genes responsible for terpenoid and carbohydrate biosynthesis,
, and
, were up regulated. In conclusion, MeJA promoted culture growth and accelerated bioactive metabolite accumulation by regulating the expression of the metabolite biosynthesis related genes,
and
in
.
This paper examines the relationship between number of topic-specific board meetings and quality of corporate governance. The quality of corporate governance is estimated by CEO turnover-performance ...and compensation-performance sensitivities. Information about topic-specific meetings is collected from the reports of independent directors of Chinese listed firms. We find that more frequent discussions of growth strategies related to the use of IPO proceeds, investment and acquisitions increase CEO compensation-performance sensitivity. By contrast, more discussions about the nomination of directors and top management are likely to reduce the sensitivities of both CEO turnover and compensation to performance. Our findings shed light on what makes boards efficient, and how board monitoring of assorted decisions modifies the relationship between CEO interests and firm performance.
Hair testing is well established for the assessment of past drug exposure; however, more research is needed to understand drug incorporation mechanisms and drug entry pathways into hair.
In this ...study, a micro-segmental LC-MS/MS method was used to analyze a 0.4 mm segment of hair after a single oral administration of zolpidem. Five single hairs were plucked at 1 day, 3 days, 7 days, and 28 days after administration from the vertex posterior of three subjects, and 5 single hairs were also plucked from the parietal, left temporal, and right temporal regions of the head at 28 days.
Proximal S1 (0-0.4 mm) in hair plucked at 1 day had the highest level of zolpidem at 1.5-2.4 pg/mm; much lower concentrations (< 1 pg/mm) were detected at proximal S2-S8 (0.4-3.2 mm). The drug concentration decreased gradually in S1 for 7 days after drug intake and disappeared by 28 days, suggesting that the drug from the bloodstream initially combined with the hair follicle and then gradually moved to the hair tip as the hair grew. The zolpidem concentration-hair segment profiles exhibited a large peak (root side) and a small peak (tip side) for the four sampling times in all three subjects, indicating that drug incorporation in the hair bulb occurred mainly from the blood but probably also entered the hair through sweat and sebum. Zolpidem was also detected in all hairs from the vertex posterior in all three subjects but was not detected in 1 hair from the parietal region and 2 hairs from the left temporal region. The consistency in drug detection, drug concentration level, and peak position was better in hair from the vertex posterior than from the other three regions, indicating that the vertex posterior is a suitable sampling region for estimating drug intake.
•A LC–MS/MS method for determination of 12 psychotropic drugs in hair is developed.•Quetiapine and its metabolite were detected in hair root 5 min post administration.•Higher quetiapine levels ...occurred in black hair root than that of other colors.•Hair root may be a good specimen for proving acute quetiapine poisoning.
A rapid, sensitive liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for the determination and quantification of 12 psychotropic drugs and metabolites in hair was developed and validated. After freeze grinding with methanol, the supernatant was determined by LC–MS/MS using an Allure PFPPropyl column (100 × 2.1 mm, 5 μm) with a gradient elution of acetonitrile and 10 mmol/L ammonium acetate with 0.1% formic acid, and in the subsequent analysis using multiple reaction monitoring (MRM) mode, two ion transitions were monitored for each analyte. The limits of detection ranged from 0.002 to 0.05 ng/mg, and the limits of quantitation were in the range of 0.005–0.1 ng/mg. Good linearity (r > 0.995) was observed for all analytes over the linear range. Acceptable intraday and interday precision (RSD ≤ 20%) and accuracy (85.3%–112.9%) were achieved. This method of detection was applied to the analysis of guinea pig hair roots after a single dose of quetiapine. Quetiapine and 7-hydroxyquetiapine were both detected in guinea pig hair roots from 5 min post administration. The concentration of quetiapine (10.3–1733.8 ng/mg) was much higher than that of 7-hydroxyquetiapine (0.1–40.6 ng/mg) in the hair roots of guinea pigs, and higher concentrations of quetiapine and 7-hydroxyquetiapine occurred in black hair root than in that of white and brown. The animal experiment demonstrated that hair roots may be a good specimen for proving acute quetiapine poisoning when other biological matrices are not available.
Abstract
This study investigated the distribution of quetiapine and 7-hydroxyquetiapine in guinea pig hair roots and shafts after five repeated intragastric administrations at three doses (5, 10 and ...25 mg/kg) by segmental analysis to explore the mechanism of drug entry and retention in hair. Hair root samples were collected after 7, 10, 14, 21, 28 and 35 d in area A after the first dose, and a hair shaft was plucked 35 d after the first dose. The maximum concentrations of quetiapine in hair roots in the low-, medium- and high-dose groups occurred at 50, 74 and 98 h after the first administration, and the maximum concentrations were 0.71 ng/mg (range: 0.54–0.84 ng/mg), 6.72 ng/mg (range: 4.59–9.75 ng/mg) and 12.72 ng/mg (range: 10.74–15.76 ng/mg), respectively. The maximum concentrations of 7-hydroxyquetiapine in the low-, medium- and high-dose groups were 0.67 ng/mg (0.23–1.15 ng/mg), 1.07 ng/mg (0.44–1.19 ng/mg) and 3.92 ng/mg (0.656.14 ng/mg), respectively, at 26 h. The maximum concentrations of quetiapine and 7-hydroxyquetiapine in hair roots were significantly positively correlated with the dose (n = 18; r2 = 0.84; P < 0.0001 for quetiapine and n = 18; r2 = 0.61; P = 0.0001 for 7-hydroxyquetiapine). The concentrations of quetiapine and 7-hydroxyquetiapine in hair roots were higher than those in hair shafts 10 d after administration, indicating drug and metabolite entry into the hair through the roots in the first few days after administration. The highest concentrations of quetiapine in the hair shaft in the low-, medium- and high-dose groups were found at the hair ends, and 7-hydroxyquetiapine in the hair shaft showed no obvious peak concentration. Combined with previous studies, we think, by analyzing the drug concentrations in the hair roots and shaft, that the most important way for drugs to enter into and be retained in hair is that the drug enters the hair through the blood circulation from hair root, then spreads and redistributes as the hair grows.
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