Subvacuum environment-enhanced cell migration promotes wound healing without increasing hypertrophic scars caused by excessive cell proliferation.

Cell migration and proliferation are conducive to wound healing; however, regulating cell proliferation remains challenging, and excessive proliferation is an important cause of scar hyperplasia. Here, we aimed to explore how a subvacuum environment promotes wound epithelisation without affecting scar hyperplasia. Human immortalized keratinocyte cells and human skin fibroblasts were cultured under subvacuum conditions (1/10 atmospheric pressure), and changes in cell proliferation and migration, target protein content, calcium influx, and cytoskeleton and membrane fluidity were observed. Mechanical calcium (Ca2+ ) channel blockers were used to prevent Ca2+ influx for reverse validation. A rat wound model was used to elucidate the mechanism of the subvacuum dressing in promoting healing. The subvacuum environment was observed to promote cell migration without affecting cell proliferation; intracellular Ca2+ concentrations and PI3K, p-PI3K, AKT1, p-AKT 1 levels increased significantly. The cytoskeleton was depolymerized, pseudopodia were reduced or absent, and membrane fluidity increased. The use of Ca2+ channel blockers weakened or eliminated these changes. Animal experiments confirmed these phenomena and demonstrated that subvacuum dressings can effectively promote wound epithelisation. Our study demonstrates that the use of subvacuum dressings can enhance cell migration without affecting cell proliferation, promote wound healing, and decrease the probability of scar hyperplasia.

[Accumulation Effects and Health Risks of Heavy Metals in Rice in Location-based Cadmium Anomaly Area in Liuzhou].

In order to explore the migration and transformation characteristics of soil heavy metals in rice in an area of ground source cadmium anomaly and to evaluate the safe planting of rice, a total of 91 pairs of soil and rice samples were collected from paddy fields in the typical area of Liuzhou city, Guangxi province, and the contents of heavy metals such as Cd, soil pH, and organic matter were tested. The results showed that:① Cd, Cu, Ni, and Zn in the paddy field exceeded the background values of 92.31%, 34.07%, 36.26%, and 90.11%, respectively. Compared with the screening values in the Soil Environmental Quality Agricultural Land Soil Pollution Risk Control Standard, Cd and Zn exceeded 30.53% and 25.26%, respectively. Super standard points were mainly distributed in Fushi Town. ② Cd and Ni exceeded 35.16% and 3.30%, respectively, and Daliang town had the highest Cd enrichment coefficient and Cd exceeded rate. ③ Correlation analysis showed that soil pH was the main influencing factor of heavy metals in rice, and Cd and Ni had similar pollution sources in rice. ④ The results of rice health risk assessment showed that the THQ value of rice Cd in Daliang town was greater than 1.0, indicating the potential health risk of rice Cd in this area. The TTHQ values were all greater than 1.0, indicating that the risks to children were higher than those to adult women, which were higher than those of adult men, showing that reasonable dietary structure is crucial to prevent heavy metal intake in different ages and genders. Therefore, there are certain risks in rice planting in the Liuzhou area of ground source cadmium anomaly, which need to be controlled using different safety utilization measures.

High Glucose Activated Cardiac Fibroblasts by a Disruption of Mitochondria-Associated Membranes.

Cardiac fibrosis is evident even in the situation without a significant cardiomyocyte loss in diabetic cardiomyopathy and a high glucose (HG) level independently activates the cardiac fibroblasts (CFs) and promotes cell proliferation. Mitochondrial respiration and glycolysis, which are key for cell proliferation and the mitochondria-associated membranes (MAMs), are critically involved in this process. However, the roles and the underlying mechanism of MAMs in the proliferation of HG-induced CFs are largely unknown. The proliferation and apoptosis of CFs responding to HG treatment were evaluated. The MAMs were quantified, and the mitochondrial respiration and cellular glycolytic levels were determined using the Seahorse XF analyzer. The changes of signal transducer and activator of transcription 3 (STAT3) and mitofusin-2 (MFN2) in responding to HG were also determined, the effects of which on cell proliferation, MAMs, and mitochondrial respiration were assessed. The effects of STAT3 on MFN2 transcription was determined by the dual-luciferase reporter assay (DLRA) and chromatin immunoprecipitation (CHIP). HG-induced CFs proliferation increased the glycolytic levels and adenosine triphosphate (ATP) production, while mitochondrial respiration was inhibited. The MAMs and MFN2 expressions were significantly reduced on the HG treatment, and the restoration of MFN2 expression counteracted the effects of HG on cell proliferation, mitochondrial respiration of the MAMs, glycolytic levels, and ATP production. The mitochondrial STAT3 contents were not changed by HG, but the levels of phosphorylated STAT3 and nuclear STAT3 were increased. The inhibition of STAT3 reversed the reduction of MFN2 levels induced by HG. The DLRA and CHIP directly demonstrated the negative regulation of MFN2 by STAT3 at the transcription levels via interacting with the sequences in the MFN2 promoter region locating at about -400 bp counting from the start site of transcription. The present study demonstrated that the HG independently induced CFs proliferation via promoting STAT3 translocation to the nucleus, which switched the mitochondrial respiration to glycolysis to produce ATP by inhibiting MAMs in an MFN2-depression manner.

Adenoma miss rate determined by very shortly repeated colonoscopy: Retrospective analysis of data from a single tertiary medical center in China.

Adenoma miss rate (AMR) has been calculated in several tandem colonoscopy studies, but it costs overmuch to carry out a clinical trial.We aimed to put forward AMR by taking advantage of retrospective data, and to judge the comparability between AMRs from prospective and retrospective data.Data of the patients accepting repeated colonoscopies during January to September 2016 was retrospectively collected and analyzed. Information was recorded, including bowel preparation quality of the first colonoscopy, size, location, histology and whether missed within the first colonoscopy of each single adenoma. AMR was compared by different risk factors through χ test and multivariable logistic regression.Around 267 adenomas were detected during 309 pairs of repeated colonoscopies, of which 66 were missed during the first colonoscopies. AMRs of the lesions small in size, nonadvanced in histology, in poor bowel preparation context and located in the proximal colon, were significantly higher than the opposite ones, and old age and male were related to adenoma missing (P < .05). In multivariable logistic regression analysis, adenoma-related factors (diminutive in size, poor bowel preparation and located in ascending colon, transverse colon or sigmoid colon), and patient-related factors (older than 60 years, male and poor bowel preparation) were found to be independently associated with missing adenomas (P < .05).AMR of retrospective data is comparable to that of tandem studies. Several risk factors influence AMR dramatically, which should be paid attention to.

Identification and characterization of human UDP-glucuronosyltransferases responsible for xanthotoxol glucuronidation.

1. Xanthotoxol is a furanocoumarin that possesses many pharmacological activities and in this study its in vitro glucuronidation was studied. 2. Xanthotoxol can be rapidly metabolized to a mono-glucuronide in both human intestine microsomes (HIM) and human liver microsomes (HLM); the structure of the metabolite was confirmed by NMR spectroscopy. 3. Reaction phenotyping with 12 commercial recombinant human UGTs, as well as with the Helsinki laboratory UGT1A10 that carry a C-terminal His-tag (UGT1A10-H), revealed that UGT1A10-H catalyzes xanthotoxol glucuronidation at the highest rate, followed by UGT1A8. The other enzymes, namely UGT1A3, UGT1A1, UGT1A6, UGT1A10 (commercial), and UGT2B7 displayed moderate-to-low reaction rates. 4. In kinetic analyses, HIM exhibited much higher affinity for xanthotoxol, along with high Vmax and mild substrate inhibition, whereas the kinetics in HLM was biphasic. UGT1A1 (high Km value), UGT1A10-H (low Km value), and UGT1A8 exhibited mild substrate inhibition. 5. Considering the above findings and the current knowledge on UGTs expression in HIM, it is likely that UGT1A10 is mainly responsible for xanthotoxol glucuronidation in the human small intestine, with some contribution from UGT1A1. In the liver, this reaction is mainly catalyzed by UGT1A1 and UGT2B7. 6. Glucuronidation appears to be the major metabolic pathway of xanthotoxol in human.

The inhibition of UDP-glucuronosyltransferases (UGTs) by vitamin A.

1. The exposed level of vitamin A in plasma might be exceeded due to the both inadvertent and clinical utilization. The adverse effects of vitamin A have been frequently reported, however, the mechanism remains unclear. The inhibition of vitamin A on the activity of UDP-glucuronosyltransferases (UGTs) was determined using in vitro incubation system to explain the adverse effects of vitamin A from a new perspective. 2. UGT supersomes catalyzed glucuronidation of 4-methylumbelliferone (4-MU), trifluoperazine (TFP), and cotinine was used as the probe reaction to evaluate the inhibition of vitamin A toward UGT isoforms, and 100 µM of vitamin A significantly inhibited the activity of all the tested UGT isoforms. Vitamin A exerted competitive inhibition on the activity of UGT1A1, 2B4, 2B7, and 2B15, and the inhibition kinetic parameters (Ki) were calculated to be 31.1, 16.8, 2.2, and 11.6 µM for UGT1A1, 2B4, 2B7, and 2B15. In silico docking method was used to try to elucidate the inhibition mechanism of vitamin A toward UGT2B7. The results showed the significant contribution of hydrogen bonds and hydrophobic interaction on the UGT2B7 inhibition by vitamin A. 3. The present study provides a new perspective for the adverse effects of vitamin A through reporting the inhibition of vitamin A on the activity of important phase II drug-metabolizing enzymes UGTs, which benefits our deep understanding of mechanism of vitamin A's adverse effects when high exposure of vitamin A occurs.

Microscope-assisted endoscopic interlaminar ligation of spinal arteriovenous fistulas: technical note.

Spinal dural arteriovenous fistulas (SDAVFs) are the most common type of spinal arteriovenous malformations, and microsurgical ligation is the treatment modality most frequently used for these lesions. Developments in endoscopic techniques have made endoscopy an even less invasive alternative to routine microsurgical approaches in spine surgery, but endoscopic management of SDAVF or other intradural spinal lesions has not been reported to date. The authors describe the use of a microscope-assisted endoscopic interlaminar approach for the ligation of the proximal draining vein of an L-1 SDAVF in a 58-year-old man. A complete cure was confirmed by postoperative angiography. The postoperative course was uneventful, and short-term follow-up showed improvements in the patient's neurological function. The authors conclude that the endoscopic interlaminar approach with microscope assistance is a safe, minimally invasive, innovative technique for the surgical management of SDAVFs in selected patients.

A population-based study on health-related quality of life among urban community residents in Shenyang, Northeast of China.

BACKGROUND: Due to the rising standard of living environment and advances in public health and medical care in China, it has been a tendency in recent years that health-related quality of life (HRQoL) has been increasingly acknowledged in community health management. However, large-scale population-based study on evaluating HQRoL in northeast of China was not conducted. This article aims to investigate the HRQoL in community residents in Northeast China and explore the associated factors. METHODS: Stratified multiple-stage sampling method was used in the cross-sectional survey to investigate HRQoL of community residents in northeast of China. Univariate analysis and multiple linear regressions were used to analyze the factors associated to HRQoL of the community residents. RESULTS: The results were confirmed that HRQoL in general population was well performed for the first time in northeast of China in a large scale population. Community residents had better mental health than physical health. The factors influencing HRQoL included gender, age, educational level, marital status, ethnic group, chronic disease status, having breakfast frequency weekly and sleep quality. However, drinking and smoking habits did not affect residents' HRQoL. CONCLUSIONS: In this study, the result of the large-scale survey was satisfactory in northeast of China, providing HRQoL status of community residents. Policies on specific health management in community public health would emphasize on lifestyle behaviors especially eating habits in order to improving HRQoL.

Minimally invasive removal of lumbar intradural extramedullary lesions using the interlaminar approach.

OBJECT Posterior midline laminectomy or hemilaminectomy has been successfully applied as the standard microsurgical technique for the treatment of spinal intradural pathologies. However, the associated risks of postoperative spinal instability increase the need for subsequent fusion surgery to prevent potential long-term spinal deformity. Continuous efforts have been made to minimize injuries to the surrounding tissue resulting from surgical manipulations. The authors report here their experiences with a novel minimally invasive surgical approach, namely the interlaminar approach, for the treatment of lumbar intraspinal tumors. METHODS A retrospective review was conducted of patients at the Second Affiliated Hospital of Zhejiang University School of Medicine who underwent minimally invasive resection of lumbar intradural-extramedullary tumors. By using an operative microscope, in addition to an endoscope when necessary, the authors were able to treat all patients with a unilateral, paramedian, bone-sparing interlaminar technique. Data including preoperative neurological status, tumor location, size, pathological diagnosis, extension of resections, intraoperative blood loss, length of hospital stay, and clinical outcomes were obtained through clinical and radiological examinations. RESULTS Eighteen patients diagnosed with lumbar intradural-extramedullary tumors were treated from October 2013 to March 2015 by this interlaminar technique. A microscope was used in 15 cases, and the remaining 3 cases were treated using a microscope as well as an endoscope. There were 14 schwannomas, 2 ependymomas, 1 epidermoid cyst, and 1 enterogenous cyst. Postoperative radiological follow-up revealed complete removal of all the lesions and no signs of bone defects in the lamina. At clinical follow-up, 14 of the 18 patients had less pain, and patients' motor/sensory functions improved or remained normal in all cases except 1. CONClUSIONS When meeting certain selection criteria, intradural-extramedullary lumbar tumors, especially schwannomas, can be completely and safely resected through a less-invasive interlaminar approach using a microscope, or a microscope in addition to an endoscope when necessary. This approach was advantageous because it caused even less bone destruction, resulting in better postoperative spinal stability, no need for facetectomy and fusion, and quicker functional recovery for the patients. Individualized surgical planning according to preoperative radiological findings is key to a successful microsurgical resection of these lesions through the interlaminar space.

Comparison of two dose-response relationship of noise exposure evaluation results with high frequency hearing loss.

BACKGROUND: Complex noise and its relation to hearing loss are difficult to measure and evaluate. In complex noise measurement, individual exposure results may not accurately represent lifetime noise exposure. Thus, the mean L Aeq,8 h values of individuals in the same workgroup were also used to represent L Aeq,8 h in our study. Our study aimed to explore whether the mean exposure levels of workers in the same workgroup represented real noise exposure better than individual exposure levels did. METHODS: A cross-sectional study was conducted to establish a model for cumulative noise exposure (CNE) and hearing loss in 205 occupational noise-exposed workers who were recruited from two large automobile manufacturers in China. We used a personal noise dosimeter and a questionnaire to determine the workers' occupational noise exposure levels and exposure times, respectively. A qualified audiologist used standardized audiometric procedures to assess hearing acuity after at least 16 h of noise avoidance. RESULTS: We observed that 88.3% of workers were exposed to more than 85 dB(A) of occupational noise (mean: 89.3 ± 4.2 dB(A)). The personal CNE (CNEp) and workgroup CNE (CNEg) were 100.5 ± 4.7 dB(A) and 100.5 ± 2.9 dB(A), respectively. In the binary logistic regression analysis, we established a regression model with high-frequency hearing loss as the dependent variable and CNE as the independent variable. The Wald value was 5.014 with CNEp as the independent variable and 8.653 with CNEg as the independent variable. Furthermore, we found that the figure for CNEg was more similar to the stationary noise reference than CNEp was. The CNEg model was better than the CNEp model. In this circumstance, we can measure some subjects instead of the whole workgroup and save manpower. CONCLUSIONS: In a complex noise environment, the measurements of average noise exposure level of the workgroup can improve the accuracy and save manpower.

Identification and characterization of human UDP-glucuronosyltransferases responsible for the glucuronidation of fraxetin.

Fraxetin, a major constituent of the traditional medicine plant Fraxinus rhynchophylla Hance (Oleaceae), has been found to possess multiple bioactivities. However, the metabolic pathway(s) of fraxetin in human tissues has not been reported yet. This study aimed to characterize the glucuronidation pathway(s) of fraxetin in human tissues. Fraxetin could be metabolized to two glucuronides in human liver microsomes (HLMs). These two glucuronides were biosynthesized and characterized as 7-O-glucuronide (7-O-G) and 8-O-glucuronide (8-O-G). UGT1A1, -1A6, -1A7, -1A8, -1A9 and -1A10 participated in the formation of 7-O-G, while the formation of 8-O-G was catalyzed selectively by UGT1A6 and UGT1A9. UGT1A9 showed the highest catalytic activities in the formation of 7-O-G and 8-O-G. Both kinetic characterization and inhibition assays demonstrated that UGT1A9 played important roles in fraxetin glucuronidations in HLMs, especially in the formation of the major metabolite 8-O-G. Furthermore, the intrinsic clearance of fraxetin in both human liver microsomes and UGT1A9 was greater than that of 7,8-dihydroxylcoumarin, revealing that the addition of a C-6 methoxy group led to the higher metabolic clearance. In summary, the glucuronidation pathways of fraxetin in human liver microsomes were well-characterized, and UGT1A9 was the major isoform responsible for the glucuronidations of fraxetin.

Glucuronidation of the broad-spectrum antiviral drug arbidol by UGT isoforms.

OBJECTIVES: The aim of this work was to identify the uridine glucuronosyltransferase (UGT) isoforms involved in the metabolism of the broad-spectrum antiviral drug arbidol. METHODS: A human liver microsome (HLM) incubation system was employed to catalyse the formation of arbidol glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards arbidol was screened. A combination of kinetic analysis and chemical inhibition study was used to determine the UGT isoforms involved in arbidol's glucuronidation. KEY FINDINGS: The arbidol glucuronide was detected when arbidol was incubated with HLMs in the presence of UDP-glucuronic acid. The Eadie-Hofstee plot showed that glucuronidation of arbidol was best fit to the Michaelis-Menten kinetic model, and K(m) and apparent V(max) were calculated to be 8.0 ± 0.7 µm and 2.03 ± 0.05 nmol/min/mg protein, respectively. Assessment of a panel of recombinant UGT isoforms revealed that UGT1A1, UGT1A3 and UGT1A9 could catalyse the glucuronidation of arbidol. Kinetic analysis and chemical inhibition study demonstrated that UGT1A9 was the predominant UGT isoform involved in arbidol glucuronidation in HLMs. CONCLUSIONS: The major contribution of UGT1A9 towards arbidol glucuronidation was demonstrated in this study.

Inhibitory effects of sanguinarine on human liver cytochrome P450 enzymes.

Sanguinarine (SAG) has been recognized as an anticancer drug candidate. However, the drug-drug interactions (DDI) potential for SAG via the inhibition against human cytochrome P450 (CYP) enzymes remains unclear. In the present study, the inhibitory effects of SAG on seven major human CYP isoforms 1A2, 2A6, 2E1, 2D6, 2C8, 2C9 and 3A4 were investigated with human liver microsomes (HLM). The results showed that SAG was a potent noncompetitive inhibitor of CYP2C8 activity (Ki=8.9 µM), and competitive inhibitor of CYP1A2, CYP2C9 and CYP3A4 activities (Ki=2.7, 3.8 and 2.0 µM, respectively). Furthermore, SAG exhibited time- and NADPH-dependent inhibition towards CYP1A2 and CYP3A4 with KI/kinact values of 13.3/0.087 and 5.58/0.029 min(-1) µM(-1), respectively. Weak inhibition of SAG against CYP2E1, CYP2D6 and CYP2A6 was also observed. In vitro-in vivo extrapolation (IV-IVE) from HLM data showed that more than 35.9% of CYP1A2, CYP2C9, CYP2C8 and CYP3A4 activities in vivo could be inhibited by SAG, suggesting that harmful DDIs could occur when SAG or its medical preparations are co-administered with drugs primarily cleared by these CYP isoforms. Further in vivo studies are needed to evaluate the clinical significance of the data presented herein.

Deep understanding of the interaction between thienorphine and UDP-glucuronosyltransferase (UGT) isoforms.

Thienorphine has been demonstrated to be a potent, long-acting partial opioid agonist. It is being developed as a good candidate to treat opioid dependence. The thienorphine's glucuronide was detected after thienorphine was incubated with human liver microsomes (HLMs). Recombinant UGT isoforms screening experiment and enzyme kinetic study showed that UGT1A1 completely contributed to the glucuronidation of thienorphine. Among the tested UGT isoforms, UGT1A3 and UGT2B7 were inhibited by thienorphine, with other UGT isoforms negligibly influenced. The inhibition type is competitive, and inhibition kinetic parameters (K(i)) were 1.65 and 5.27 µM for UGT1A3 and UGT2B7, respectively. However, due to low plasma concentration of thienorphine, in vivo drug-drug interaction might not occur.

The role of serum albumin in the metabolism of Boc5: molecular identification, species differences and contribution to plasma metabolism.

Boc5, the first nonpeptidic agonist of Glucagon-like peptide-1 receptor, has been recognized as a potential candidate for treatment of diabetes. However, the metabolic behaviors of this novel molecule in both human and experimental animals remain unclear. This study aimed to explore the metabolic behaviors of Boc5 in biological preparations from human, pig and rat. Boc5 was found to be very stable in liver microsomes of human, pig and rat, but it can be degraded to two metabolites in plasma from all three species, via the successive hydrolysis of the C-22 esters. Chemical inhibition studies using selective esterase inhibitors and assays with purified enzymes suggested that Boc5 hydrolysis in human was totally mediated by human serum albumin (HSA) rather than esterases. ESI-TOF-MS/MS analysis revealed that Lys525 of HSA could be modified by treatment with Boc5, strongly suggesting the pseudo-esterase activity of albumin. Studies on species differences in this albumin-mediated metabolism showed large species differences in degradation rate of Boc5, the half lives of Boc5 in plasma from three various species varied from 23.5 h to 83.1h, but they were much closer to the half lives of Boc5 in corresponding serum albumins, implying the predominant role of serum albumin in plasma metabolism of Boc5. Additionally, the effects of various ligands including fatty acids and several drugs with unambiguous binding sites on HSA, on the pseudo-esterase activity of HSA, were also investigated using both experimental and molecular modelling studies. These results showed that the binding of various ligands to HSA could significantly affect the pseudo-esterase activity of HSA towards Boc5, due to the ligand-induced conformation changes of HSA.

Identification of UDP-glucuronosyltransferase isoforms involved in hepatic and intestinal glucuronidation of phytochemical carvacrol.

1. Carvacrol (2-methyl-5-(1-methylethyl)-phenol), one of the main components occurring in many essential oils of the family Labiatae, has been widely used in food, spice and pharmaceutical industries. 2. The carvacrol glucuronidation was characterized by human liver microsomes (HLMs), human intestinal microsomes (HIMs) and 12 recombinant UGT (rUGT) isoforms. 3. One metabolite was identified as a mono-glucuronide by liquid chromatography/mass spectrometry with HLMs, HIMs, rUGT1A3, rUGT1A6, rUGT1A7, rUGT1A9 and rUGT2B7. 4. The study with a chemical inhibition, rUGT, and kinetics study demonstrated that rUGT1A9 was the major isozyme responsible for glucuronidation in HLMs, and rUGT1A7 played a major role for glucuronidation in HIMs.

Investigation of UDP-glucuronosyltransferases (UGTs) inhibitory properties of carvacrol.

UDP-glucuronosyltransferases (UGTs), the most important phase II drug metabolizing enzymes (DMEs), could metabolize many drugs and various endogenous substances including bilirubin, steroid hormones, thyroid hormones, bile acids and fat-soluble vitamins. Evaluation of the inhibitory effects of compounds on UGTs is clinically important because inhibition of UGT isoforms could not only result in serious drug-drug interactions (DDIs), but also induce metabolic disorders of endogenous substances. The aim of the present study was to investigate the inhibitory effects of carvacrol on major UGT isoforms. The results showed that carvacrol could inhibit the activity of UGT1A9 with negligible effects on other UGT isoforms. When 4-methylumbelliferone (4-MU) was used as a nonspecific probe substrate and recombinant UGT enzymes were utilized as an enzyme resource, the inhibition of UGT1A9 was best fit to the competitive type and the inhibition kinetic parameter (K(i)) was calculated to be 5.7 µM. Furthermore, another specific probe substrate, propofol, was employed to determine the inhibitory kinetics of UGT1A9, and the results demonstrated that the inhibitory type was noncompetitive. The inhibition kinetic parameter (K(i)) was determined to be 25.0 µM. Because this substrate-dependent inhibition of UGT1A9 might confuse the in vitro-in vivo extrapolation, these in vitro inhibition kinetic parameters should be interpreted with special caution.

Identification of CYP isoforms involved in the metabolism of thymol and carvacrol in human liver microsomes (HLMs).

Carvacrol and thymol are phenolic compounds with similar structures isolated from many aromatic plants, and have been demonstrated to exert multiple pharmacological effects. The metabolic and pharmacokinetic behaviour of thymol and carvacrol has received much attention. Carvacrol and thymol have been demonstrated to undergo phase I metabolism such as hydroxylation reaction. However, drug-metabolizing enzymes involved in this process remain unclear. Given that cytochrome P450s (CYPs) are involved in most phase I metabolism, the aim of the present study was to investigate the role of CYPs in the metabolism of thymol and carvacrol. After incubation with human liver microsomes (HLMs) in the presence of NADPH, a new metabolite and two metabolites were detected for thymol and carvacrol, respectively. A combination of chemical inhibition studies and assays with recombinant CYP isoforms demonstrated that CYP2A6 was the predominant drug-metabolizing enzyme involved in the metabolism of thymol and carvacrol. All these results remind the researchers that special attention should be paid on pharmacokinetic and clinical outcomes when thymol or carvacrol was co-administrated with other compounds mainly undergoing CYP2A6-mediated metabolism.

Noise exposure assessment with task-based measurement in complex noise environment.

BACKGROUND: Task-based measurement (TBM) is a method to assess the eight-hour A-weighted equivalent noise exposure level (L(Aeq.8h)) besides dosimeter. TBM can be better used in factories by non-professional workers and staffs. However, it is still not clear if TBM is equal or similar with dosimeter for L(Aeq.8h) measurement in general. This study considered the measurement with dosimeter as real personal noise exposure level (PNEL) and assessed the accuracy of TBM by comparing the consistencies of TBM and dosimeter in L(Aeq.8h) measurement. METHODS: The study was conducted in one automobile firm among 387 workers who are exposed to unstable noise. Dosimeters and TBM were used to compare the two strategies and assess the degree of agreement and causes of disagreement. Worker's PNEL was measured via TBM for noise; the real PNEL was also recorded. The TBM for noise was computed with task/position noise levels measured via sound level meter and workers' exposure information collected via working diary forms (WDF) filled by participants themselves. Full-shift noise exposure measurement via personal noise dosimeters were taken as the real PNEL. General linear model (GLM) was built to analyze the accuracy of TBM for noise and the source of difference between TBM for noise and real PNEL. RESULTS: The L(Aeq.8h) with TBM were slightly higher than the real PNELs, except the electricians. Differences of the two values had statistical significance in stamping workers (P < 0.001), assembly workers (P = 0.015) and welding workers (P = 0.001). The correlation coefficient of L(Aeq.8h) with TBM and real PNELs was 0.841. Differences of the two results were mainly affected by real PNEL (F = 11.27, P = 0.001); and work groups (F = 3.11, P < 0.001) divided by jobs and workshops were also independent factors. PNEL of workers with fixed task/position ((86.53 ± 8.82) dB(A)) was higher than those without ((75.76 ± 9.92) dB(A)) (t = 8.84, P < 0.01). Whether workers had fixed task/position was another factor on the accuracy of TBM for noise (F = 4.36, P = 0.038). CONCLUSION: TBM for noise has acceptable accuracy on workers' PNEL measurement. The accuracy is affected by job categories, workshops and variability of task/position. TBM for noise can yield a relatively conservative result of worker's PNEL in most cases, so it can be used to measure and assess workers' real PNEL.

Inhibitory potential of chlormadinone acetate (CMA) on five important UDP-glucuronosyltransferases in human liver.

Chlormadinone acetate (CMA), a derivative of 17-a-hydroxyprogesterone, has been widely used as an orally effective progestogen in hormone replacement therapy (HRT). Glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs) is one of the major steps responsible for the metabolism of many drugs, environmental chemicals and endogenous compounds. Pharmacokinetic behaviours of drugs could be altered by inhibition of these UGT isoforms, and the search for drugs that potentially inhibit these UGT isoforms is very significant from a clinical point of view. In the present study, inhibition of five important UGT isoforms in human liver (UGT1A1, 1A3, 1A6, 1A9 and 2B7) by CMA was investigated using 4-MU as nonspecific substrate and recombinant UGT isoforms as enzyme sources. The results showed that CMA exhibited inhibitory effects on UGT1A3 (IC50 = 8.6 +/- 1.4 microM) and UGT2B7 (IC50 = 14.2 +/- 3.8 microM), with other UGT isoforms negligibly influenced. Lineweaver-Burk and Dixon plots showed that CMA noncompetitively inhibited UGT1A3 and UGT2B7. The Ki value was calculated to be 36.9 microM and 4.1 microM for UGT1A3 and UGT2B7, respectively. Considering that UGT1A3 and UGT2B7 are involved in the metabolism of many drugs, special attentions should be paid when CMA was co-administered with the drugs which mainly underwent UGT1A3, 2B7-mediated metabolism.