In Vitro and In Vivo Studies of Metabolic Activation of Marrubiin, a Bioactive Constituent from Marrubium Vulgare.

Marrubiin, a furanoid compound, is a well-known diterpenoid lactone isolated from Marrubium vulgare, which displays a wide spectrum of pharmacological effects and potential hepatotoxicity. Considering that marrubiin contains a structural alert, furan ring, metabolic activation may be one of the major metabolic pathways, and the reactive metabolite may be involved in the hepatotoxicity. The present study was carried out to investigate the bioactivation mechanism of marrubiin in rats and humans. Marrubiin was initially metabolized into cis-butene-1,4-dial intermediate, which was readily trapped by glutathione (GSH) and N-acetyl-lysine (NAL) in the microsomal incubations supplemented with NADPH. A total of nine conjugates were detected and identified by high-resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. M1-M3 and M6 and M7 were characterized as mono-GSH conjugates, and M4 and M5 were identified as bis-GSH conjugates. M8 and M9 were identified as NAL conjugates. In rat bile, five GSH conjugates (M1-M3; M6 and M7) were detected. M1, M8, and M9 were chemically synthesized, and their structures were characterized by 13C NMR. Sulfaphenazole, ticlopidine, and ketoconazole displayed significant inhibitory effect on the bioactivation of marrubiin. Further phenotyping revealed that CYP2C9, CYP2C19, and CYP3A4 were the primary enzymes catalyzing the bioactivation of marrubiin. The current study provides evidence for the CYP-dominated bioactivation of marrubiin to the corresponding cis-butene-1,4-dial intermediate, which enables us to better understand the potential side effects caused by marrubiin.

Silibinin suppresses epithelial-mesenchymal transition in human non-small cell lung cancer cells by restraining RHBDD1.

BACKGROUND: Rhomboid domain containing 1 (RHBDD1) plays a crucial role in tumorigenesis. Silibinin, which is a natural extract from milk thistle, has shown anti-tumor effects against various tumors. Here, we investigate whether silibinin affects the function of RHBDD1 in non-small cell lung cancer (NSCLC) cell proliferation, migration and invasion. METHODS: The Oncomine database and an immunohistochemistry (IHC) assay were used to determine the RHBDD1 expression levels in lung cancer tissues. The associations between RHBDD1 and overall survival rate or clinicopathological parameters were respectively assessed using the Kaplan-Meier overall survival analysis or Chi-squared test. CCK-8 and Transwell assays were applied to analyze cell proliferation, migration and invasion. A549 cells were incubated with increasing concentrations of silibinin. RHBDD1 knockdown and overexpression were achieved via transfection with si-RHBDD1 or RHBDD1 overexpression plasmid, respectively. Western blotting was performed to measure the expressions of epithelial-mesenchymal transition (EMT) markers. RESULTS: We found that overexpression of RHBDD1 in lung cancer tissues correlates with a poor prognosis of survival. Clinical specimen analysis showed that upregulation of RHBDD1 correlates remarkably well with TNM stage and lymph node metastasis. Silibinin suppresses A549 cell proliferation, migration, invasion and EMT in a dose-dependent manner. Importantly, RHBDD1 was downregulated in silibinin-treated A549 cells. RHBDD1 overexpression reversed the suppressive effects of silibinin on A549 cell proliferation, migration, invasion and EMT expression, while its knockdown enhanced them. CONCLUSIONS: These findings shown an anti-tumor impact of silibinin on NSCLC cells via repression of RHBDD1.

T-2 toxin cytotoxicity mediated by directly perturbing mitochondria in human gastric epithelium GES-1 cells.

T-2 toxin is one of the most toxic trichothecenes and harmful to human health and animal husbandry. The mechanism underlying its growth suppression remains unclear, especially for mitochondrial damage in human gastric epithelial cells. In the present study, we investigated cell death caused by T-2 toxin in a human gastric epithelial cell line (GES-1) and the possible mechanism of T-2-induced cytotoxicity. T-2 strongly reduced the viability of GES-1 cells in a time- and dose-dependent manner within a small range of concentrations. However, when the concentrations of T-2 were >40 nM, there was no concentration dependence, only time dependence. Moreover, T-2 induced apoptosis, with the activation of caspase-3 in GES-1 and mitochondrial membrane potential (MMP) decrease and cytochrome c release. T-2 also resulted in the accumulation of reactive oxygen species (ROS) and DNA damage with a positive signal of p-H2A.X in GES-1 cells. While T-2 caused a MMP decrease, DNA damage and cell death were not blocked by pretreatment with 3 mM glutathione (GSH), a typical scavenger of ROS. The induction of mitochondrial permeability transition pore (mPTP) regulators voltage-dependent anion channel (VDAC1) and cyclophilin D (CypD) were also observed in T-2-treated cells. Interestingly, cyclosporine A (CsA), a CypD inhibitor, significantly reversed the drop in MMP and the DNA damage, as well as ROS accumulation caused by T-2. Additionally, GES-1 cell death could also be protected to some extent by 4, 4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS), an inhibitor of VDAC1, especially the combination of CsA and DIDS, and 3 mM GSH could further enhance the effect of CsA + DIDS on cell viability. In conclusion, our present findings indicate that the T-2 induced MMP decrease, DNA damage and cell death, as well as ROS accumulation in GES-1 cells, starts with T-2 directly perturbing the mitochondria triggering ROS generation by acting on CypD and VDAC1. This study presents a new viewpoint for evaluating the toxicity of T-2 toxin.

Catalyst-free direct cross-dehydrogenative coupling of imidazoheterocycles with glyoxal hydrates: an efficient approach to 1,2-diketones.

An efficient and convenient methodology for catalyst-free cross-dehydrogenative coupling of imidazoheterocycles with glyoxal hydrates in good yields was developed. This methodology exhibits a broad substrate scope and excellent functional group tolerance and offers a straightforward means to produce different heterocycles such as imidazoheterocyclic quinoxaline, imidazoheterocyclic hydantoin and imidazoheterocyclic α-keto ketamine under relatively mild conditions. Biological evaluation showed that the most potent compound 3m possesses significant in vitro antiproliferative activities against human-derived lung cancer cell lines with an IC50 value of 14.8 µM.

Epidemiological features and spatial clusters of hand, foot, and mouth disease in Qinghai Province, China, 2009-2015.

BACKGROUND: Hand, Foot, and Mouth Disease (HFMD) is most frequently caused by Enterovirus71 (EV-A71) or Coxsackie virus A16 (CV-A16), infants and young children are at greatest risk. Describing the epidemiology of HFMD can help develop and better target interventions, including the use of pediatric EV-A71 vaccination. METHODS: We obtained data from the national surveillance system for HFMD cases with onset dates from 2009 to 2015. We defined probable cases as patient with skin papular or vesicular rashes on the hands, feet, mouth, or buttocks and confirmed cases as patients with the above symptoms along with laboratory-based enterovirus detection. We generated overall and age-specific annual incidence rates and described the temporal variability and seasonality of HFMD in Qinghai Province. We identified spatial clustering of HFMD incidence at the county level using the Local Indicator of Spatial Associationand an alpha level of 0.05. RESULTS: During the study period, 14,480 HFMD probable or confirmed cases were reported in Qinghai Province. Of the 2158 (14.9%) with laboratory confirmation, 924 (42.6%) were caused by CV-A16 and 830 (38.2%) were caused by EV-A71. The majority (89%) of all case-patients were ≤ 5 years of age and male (61.5%). The overall mean annual HFMD incidence rate was 36.4 cases per 100,000 populations, while the incidence rate for children ≤5 years of age was 379.5 cases per 100,000. Case reports peaked during the months of May through July. HFMD was predominantly caused by EV-A71, except in 2010 and 2014 when CV-A16 was the predominant causative agent. High incidence rates of HFMD were clustered (Moran's I = 0.59, P < 0.05) in the eastern region of the province. CONCLUSION: HFMD remains an important cause of childhood disease in Qinghai Province, occurring in an acyclical pattern of increased incidence, primarily due to CV-A16 circulation every three years. Incidence is also seasonal and tends to spatially cluster in the eastern region of the province. Since approximately 40% of confirmed HFMD cases were due to EV-A71, EV-A71 vaccination is likely to have a positive impact on the HFMD disease burden. Routine analysis of local surveillance data is crucial for describing disease occurrence and changes in etiology.

Copper-catalyzed chalcogenation of imidazoheterocycles with sulfur/selenium powder and coumarinyl triflates.

An efficient and convenient copper-catalyzed chalcogenation of imidazoheterocycles with sulfur/selenium powder and coumarinyl triflates has been described. This procedure provides a wide range of structurally diverse coumarinylthio-/coumarinylseleno-substituted imidazoheterocycles in good yields and with good functional group tolerance. Biological evaluation showed that the newly synthesized compound 6d possesses significant in vitro antiproliferative activities against human-derived esophageal, breast, stomach, and prostate cancer cell lines compared with the positive control, 5-fluorouracil.

Effects of cytochrome P450 3A4 and non-genetic factors on initial voriconazole serum trough concentrations in hematological patients with different cytochrome P450 2C19 genotypes.

1. Polymorphisms of cytochrome P450 2C19 (CYP2C19) is an important factor contributing to variability of voriconazole pharmacokinetics. Polymorphisms of CYP3A4, CYP3A5, CYP2C9 and non-genetic factors such as age, gender, body mass index (BMI), transaminase levels, concomitant medications might also affect voriconazole initial steady serum trough concentration (VICmin) in haematological patients, but the effects were not clear. 2. Eighteen single-nucleotide polymorphisms in CYP2C19, CYP3A4, CYP3A5, CYP2C9 were genotyped. Patients were stratified into two groups according to CYP2C19 genotype. Group 1 were patients with CYP2C19*2 or CYP2C19*3, and Group 2 were homozygous extensive metabolizers. The effects were studied in different groups. VICmin was adjusted on daily dose (VICmin/D) for overcoming effect of dose. 3. A total of 106 blood samples from 86 patients were included. In final optimal scaling regression models, polymorphisms of rs4646437 (CYP3A4), age, BMI was identified to be factors of VICmin/D in Group 1 (R2 = .255, p < .001). Only age was confirmed as a factor of VICmin/D in Group 2 (R2 = 0.144, p = .021). 4. Besides polymorphisms of CYP2C19, in individualized medication of voriconazole in haematological patients, polymorphisms of CYP3A4, and non-genetic factors as BMI, age should also be taken into account, especially for individuals with CYP2C19*2 or CYP2C19*3.

Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM-Chk1/2-Cdc25C pathway.

Jaridonin, a novel diterpenoid from Isodon rubescens, has been shown previously to inhibit proliferation of esophageal squamous cancer cells (ESCC) through G2/M phase cell cycle arrest. However, the involved mechanism is not fully understood. In this study, we found that the cell cycle arrest by Jaridonin was associated with the increased expression of phosphorylation of ATM at Ser1981 and Cdc2 at Tyr15. Jaridonin also resulted in enhanced phosphorylation of Cdc25C via the activation of checkpoint kinases Chk1 and Chk2, as well as in increased phospho-H2A.X (Ser139), which is known to be phosphorylated by ATM in response to DNA damage. Furthermore, Jaridonin-mediated alterations in cell cycle arrest were significantly attenuated in the presence of NAC, implicating the involvement of ROS in Jaridonin's effects. On the other hand, addition of ATM inhibitors reversed Jaridonin-related activation of ATM and Chk1/2 as well as phosphorylation of Cdc25C, Cdc2 and H2A.X and G2/M phase arrest. In conclusion, these findings identified that Jaridonin-induced cell cycle arrest in human esophageal cancer cells is associated with ROS-mediated activation of ATM-Chk1/2-Cdc25C pathway.

ALDH2*2 Allele is a Negative Risk Factor for Cerebral Infarction in Chinese Women.

Unlike its reported role in the cardiovascular diseases, little information is available for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the cerebrovascular function. We investigated the different effects of ALDH2 genotypes on the risk of cerebral infarction between the genders, because different genders had different smoking and/or dinking status which are also risk factors for cerebral infarction. 247 healthy Chinese Han people (controls, group 1), 287 Chinese Han male patients with cerebral infarction (group 2), and 82 Chinese Han female patients with cerebral infarction (group 3) were involved in this study. The frequencies of the ALDH2*2 allele in group 3 were significantly higher than those in other groups (with P = 0.001 and P = 0.002, respectively). The difference of ALDH2*2 allele frequency between group 1 and group 2 was not significant (P = 0.652). After adjustment for smoking and drinking status, the male patients without smoking or drinking status (group 4) had higher ALDH2*2 allele frequency than group 1, but the difference was still not significant (P = 0.139). Thus, we conclude that ALDH2*2 allele may be a significant negative risk factor for cerebral infarction in Chinese women [odds ratio (OR) = 2.207, 95% CI 1.416-3.439]. But for Chinese male patients, the negative effects of ALDH2*2 allele on cerebral infarction which might be concealed by other risk factors were not significant.

[Jaridonin induces apoptosis in human esophageal cancer cells by depleting GSH and inducing DNA damage].

OBJECTIVE: The aim of this study was to explore the molecular mechanism of apoptosis in esophageal cancer cells induced by Isodon rubescens. METHODS: The DNA-damage effect of Jaridonin was detected by single cell gel electrophoresis (SCGE). The p53 protein was determined by Western blot. GSH assay kit was employed to determine the GSH content in human esophageal cancer EC-1 cells. Intracellular levels of hydrogen peroxide (H2O2) or superoxide (O(2).-) were determined using the redox-sensitive probes 2', 7'-dichlorodihydrofluorescein diacetate (DCF) or dihydroethidium (DHE), and the fluorescence signal was assayed by fluorescence microscopy and by flow cytometry. RESULTS: Jaridonin induced DNA damage in EC-1 cells remarkably. The olive tail moments (OTM) of control and 20, 40 µmol/L Jaridonin were 3.2, 45.2 and 89.0, respectively. Compared with the control, the differences were significant (P < 0.01 for both). Jaridonin resulted in extensive p53 up-regulation in the EC-1 cells. More importantly, the p53 up-regulation occurred as early as 2 h after Jaridonin incubation, and in a time-dependent manner (P < 0.05). p53 siRNA transfection inhibited apoptosis in the EC-1 cells, and the Jaridonin-induced apoptosis rate was reduced from 38.5% to 8.8%. Intracellular level of H2O2 was increased by Jaridonin, whereas the level of O(2).- was barely changed. The GSH content in EC-1 cells was reduced from (10.3 ± 1.6) nmol/mg protein to (4.6 ± 2.1) nmol/mg protein after 20 µmol/L Jaridonin incubation for 8 h, and it was further reduced with the increase of Jaridonin concentration. Jaridonin induced DNA damage, H2O2 accumulation and apoptosis were significantly attenuated in the presence of GSH, but Jaridonin showed little effect on normal human liver L-02 cells. CONCLUSIONS: Jaridonin selectively induces apoptosis in esophageal cancer EC-1 cells through H2O2-mediated DNA damage by depleting GSH.

Individuals having variant genotypes of cytochrome P450 2C19 are at increased risk of developing primary liver cancer in Han populations, without infection with the hepatitis virus.

Recently, many researchers have reported that the genetic polymorphisms of CYP2C19 may account for the interpatient variability of the clinical course in cancers including primary liver cancer (PLC). Besides the genetic polymorphisms of CYP2C19, hepatitis viruses (HV, including HAV, HBV, HCV, HDV, HEV, especially HBV and/or HCV) also account for the interpatient variability of the clinical course in PLC. This research covered the above two factors and divided the patients with PLC into two groups (one group with HBV infection and another without any HV infection) to find out whether the genetic polymorphisms of CYP2C19 have different effects in the progressing of PLC in different groups of patients. Eight hundred sixty-four cancer-free Han people (controls, named group 1), 207 Han PLC patients with HBV infection (group 2), and 55 Han PLC patients without any HV infection (group 3) were involved in this study. A wild-type allele (CYP2C19*1) and two mutated alleles (CYP2C19*2 and CYP2C19*3) were identified. The frequencies of the mutant alleles and genotypes were then compared with each other. The frequencies of the homozygous and heterozygous variant genotypes (*2/*2, *2/*3, *3/*3) in group 3 (25.5 %) were significantly higher than those in other groups (11.9 % in group 1 and 13.5 % in group 2, P = 0.014, 95 % confidence interval (CI)). The differences were statistically significant between group 1 and group 3 (P = 0.004, 95 % CI), but they were not statistically significant between group 1 and group 2 (P = 0.527, 95 % CI). Thus, we conclude that people which were not infected with HV but with the homozygous or heterozygous variant genotypes (*2/*2, *2/*3, *3/*3) of CYP2C19 may have higher possibilities of getting PLC than people with other allelic genotypes (*1/*1, *1/*2, *1/*3) (odds ratio (OR) = 2.523, 95 % CI = 1.329 ~ 4.788). However, in patients with HBV infection, the genetic polymorphisms of CYP2C19 did not seem to be an important factor in the risk of developing PLC (OR = 1.156, 95 % CI = 0.738 ~ 1.810).

A novel method for the diagnosis of atherosclerosis based on nanotechnology.

Cardiovascular disease (CVD) is a global health concern, presenting significant risks to human health. Atherosclerosis is among the most prevalent CVD, impacting the medium and large arteries in the kidneys, brain, heart, and other vital organs, as well as the lower limbs. As the disease progresses, arterial obstruction can result in heart attacks and strokes. Therefore, patients with atherosclerosis should receive accurate diagnosis and timely therapeutic intervention. With the advancements in nanomedicine, researchers have proposed new research strategies and methods for atherosclerosis imaging. This paper summarizes some current research findings on the use of nanomaterials in diagnosing atherosclerosis and offers insights for optimizing the imaging applications of nanomaterials in the future.

Motivating health workers for the provision of directly observed treatment to TB patients in rural China: does cash incentive work? A qualitative study.

As a key component of DOTS (directly observed treatment, short course) strategy, DOT is essential in the prevention of drug-resistant tuberculosis. However, DOT had very poor implementation in rural areas of China. One major reason to this problem was the lack of incentives for DOT providers. In 2005, the Chinese Minister of Health released an incentive strategy that aimed to improve the DOT performance of rural health workers by providing allowances. Our study used a qualitative method to explore the practical impact of this incentive strategy in motivating rural DOT providers, and searched for other potential incentive measures as well. A total of 16 focus group discussions were carried out among 102 rural health workers in eight counties of China. A semi-structured theme outline was used to collect the perception, attitude and experiences of health workers toward the DOT implementation as well as the cash incentive strategy. Findings showed that DOT allowance had some incentive effect to DOT providers, but its extent was circumscribed by the small amount and operational problems. Raising DOT allowance and removing existing barriers to DOT provision might result in a greater motivational impact, particularly in less developed areas of China, where health workers were more likely to encounter financial and other obstacles in delivering DOT services to TB patients in rural areas.

High-throughput identification and determination of antifungal triazoles in human plasma using UPLC-QDa.

Triazoles are common agents for invasive fungal infections, while therapeutic drug monitoring is needed to improve antifungal efficacy and reduce toxicity. This study aimed to exploit a simple and reliable liquid chromatography-mass spectrometry method for high-throughput monitoring of antifungal triazoles in human plasma using UPLC-QDa. Triazoles in plasma were separated by chromatography on a Waters BEH C18 column and detected using positive ions electrospray ionization fitted with single ion recording. M+ for fluconazole (m/z 307.11) and voriconazole (m/z 350.12), M2+ for posaconazole (m/z 351.17), itraconazole (m/z 353.13) and ketoconazole (m/z 266.08, IS) were selected as representative ions in single ion recording mode. The standard curves in plasma showed acceptable linearities over 1.25-40 µg/mL for fluconazole, 0.47-15 µg/mL for posaconazole and 0.39-12.5 µg/mL for voriconazole and itraconazole. The selectivity, specificity, accuracy, precision, recovery, matrix effect, and stability met acceptable practice standards under Food and Drug Administration method validation guidelines. This method was successfully applied to the therapeutic monitoring of triazoles in patients with invasive fungal infections, thereby guiding clinical medication.

Impact of SLCO4C1 Genotypes, Creatinine, and Spironolactone on Digoxin Population Pharmacokinetic Variables in Patients With Cardiac Insufficiency.

PURPOSE: This study aimed to utilize a population pharmacokinetic method to obtain information about the influence of covariates on the in vivo behavior of digoxin in patients with cardiac insufficiency. METHODS: A total of 228 therapeutic drug monitoring concentrations were retrospectively collected from 176 inpatients. The patients were randomly divided into a modeling group (n = 126) and a validation group (n = 50). The first-order absorption one-compartment model was used to develop a population pharmacokinetic model from a nonlinear mixed effects modeling approach. Sixteen single nucleotide polymorphisms involved in the pharmacokinetic variables of digoxin were identified by using the MassARRAY system. Various demographic parameters, biochemical test values, concomitant medications, and genetic variants were investigated. FINDINGS: The typical population value of digoxin CL/F was 5.06 L/h, and the volume of distribution was 211.82 L. The drug CL/F was significantly related to serum creatinine, in a combination of spironolactone and SLCO4C1 genotypes of 2 variants (rs3114660 and rs3114661). Results of model evaluation and internal/external validation indicated a stable and precise performance of the final model. IMPLICATIONS: For the first time, 2 single nucleotide polymorphisms (rs3114660 and rs3114661) in SLCO4C1 were found to significantly affect the elimination of digoxin in vivo. The final population model may be useful for the individualized dosing of digoxin for patients with cardiac insufficiency.

The Synergistic Antitumor Activity of Chidamide in Combination with Bortezomib on Gastric Cancer.

PURPOSE: The aim of this study was to investigate the antitumor effect of chidamide in combination with bortezomib on gastric cancer cell lines. MATERIALS AND METHODS: First, the sensitivity and IC50 values of chidamide and bortezomib in several gastric cancer cell lines (MGC-803, BGC-823, SGC-7901, and MKN45) were measured using the CCK-8 assay. Then, the relatively insensitive gastric cancer cell lines (MGC-803 and BGC-823) were treated with low concentrations of chidamide alone, bortezomib alone, or chidamide and bortezomib combination to detect the effects on cell proliferation, apoptosis, migration, and invasion. Finally, the inhibitory effect of the combined chidamide and bortezomib treatment on MGC-803 cells was verified in vivo through tumor formation experiments in nude mice. RESULTS: Compared with low-dose chidamide or bortezomib alone, the low-dose drug combination significantly inhibited the proliferation, migration, and invasion of MGC-803 and BGC-823 cells and induced apoptosis of the cells. The effects of the low-dose chidamide and bortezomib combination reduced the growth on gastric cancer in vivo were investigated by using a subcutaneous tumor mouse model. CONCLUSION: Our results suggest that the combination of chidamide and bortezomib can significantly reduce the proliferation, invasion, and migration of MGC-803 and BGC-823 cells, providing a framework for the clinical evaluation of combined therapies for gastric cancers.

An Exploratory Study of Influenza Vaccination Coverage in Healthcare Workers in a Western Chinese City, 2018-2019: Improving Target Population Coverage Based on Policy Interventions.

Objectives: To evaluate a policy-based intervention to increase seasonal-influenza-vaccination coverage in healthcare workers in Xining, a city in Western China. Methods: From October 2018 to March 2019, we implemented a free vaccination policy in healthcare workers in Xining. A face-to-face interview with the head of the infection control department and an online survey for medical staff in four tertiary medical facilities was conducted to understand both the implementation of the free policy and influenza vaccination coverage. Possible factors for influenza vaccination among healthcare workers (physician, nurses working on the front-line, HCWs) were investigated by multivariate-logistic regression. Results: Coverage in two hospitals that implemented the free vaccination policy was 30.5% and 25.9%, respectively, which was statistically different to hospitals that did not implement the free policy (7.2% and 8.7%, respectively) (χ2 = 332.56, p < 0.0001). Among vaccinated healthcare workers, 65.5% and 48.6% reported their main reasons for vaccination were a convenient vaccination service and awareness of the free vaccination policy. The reasons for not being vaccinated among the 3389 unvaccinated healthcare workers included: the inconvenient vaccination service (33.8%), believing vaccination was unnecessary (29.7%), concerns about adverse reactions to the vaccine (28.8%), and having to pay for the vaccine (25.6%). Conclusions: Implementing the free vaccination policy, combined with improving the accessibility of the vaccination service, increased seasonal-influenza vaccination-coverage in healthcare workers in Xining.

Association between the UGT1A1*28 allele and hyperbilirubinemia in HIV-positive patients receiving atazanavir: a meta-analysis.

Objectives The uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)*28 allele in HIV-positive patients receiving atazanavir (ATV) might be associated with the risk of hyperbilirubinemia. Owing to mixed and inconclusive results, a meta-analysis was conducted to systematically summarize and clarify this association.Methods Based on a comprehensive search of PubMed, Embase and Web of Science databases, studies investigating the association between UGT1A1 alleles and hyperbilirubinemia was retrieved. We evaluated the strength of this relationship using odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity analysis was performed by removing each study one at a time and calculating the pooled ORs of the remaining studies to test the robustness of the meta-analysis results. The Q statistic and the I2 index statistic were used to assess heterogeneity. Publication bias was evaluated using Orwin's fail-safe N test.Results A total of six individual studies were included in this meta-analysis. A significantly increased risk of hyperbilirubinemia was observed in HIV-positive patients receiving ATV with the UGT1A1*1/*28 or UGT1A1*28/*28 genotype, and the risk was higher with the UGT1A1*28/*28 genotype than with the UGT1A1*1/*28 genotype. (UGT1A1*28/*28 versus UGT1A1*1/*28: OR = 3.69, 95%CI = 1.82-7.49; UGT1A1*1/*28 versus UGT1A1*1/*1: OR = 3.50, 95%CI = 1.35-9.08; UGT1A1*28/*28 versus UGT1A1*1/*1: OR = 10.07, 95%CI = 4.39-23.10). All of the pooled ORs were not significantly affected by the remaining studies and different modeling methods, indicating robust results.Conclusions This meta-analysis suggests that the UGT1A1*28 allele represents a biomarker for an increased risk of hyperbilirubinemia in HIV-positive patients receiving ATV.

Effect of nitrogen co-doping with ruthenium on the catalytic performance of Ba/Ru-N-MC catalysts for ammonia synthesis.

Nitrogen co-doping with ruthenium mesoporous carbons (Ru-N-MC) was prepared by co-impregnation of sucrose and urea on a RuCl3/SiO2 template followed by a thermal carbonization process. The turnover frequency (TOF) of the Ba/Ru-N-MC catalyst in ammonia synthesis is 0.16 s-1 under reaction conditions of 400 °C, pressure of 10 MPa and space velocity of 10 000 h-1. The superior catalytic performance of the Ba/Ru-N-MC is proposed to originate from the strong metal-support interaction between Ru nanoparticles (NPs) and carbon support. In addition to the activity, the Ba/Ru-N-MC catalyst exhibits a long-term stability for 35 h without significant deactivation.