Mechanism of anti-hyperuricemia of isobavachin based on network pharmacology and molecular docking.

BACKGROUND: Hyperuricemia is a more popular metabolic disease caused by a disorder of purine metabolism. Our previous study firstly screened out a natural product Isobavachin as anti-hyperuricemia targeted hURAT1 from a Chinese medicine Haitongpi (Cortex Erythrinae). In view of Isobavachin's diverse pharmacological activities, similar to the Tranilast (as another hURAT1 inhibitor), our study focused on its potential targets and molecular mechanisms of Isobavachin anti-hyperuricemia based on network pharmacology and molecular docking. METHODS: First of all, the putative target genes of compounds were screen out based on the public databases with different methods, such as SwissTargetPerdiction, PharmMapper and TargetNet,etc. Then the compound-pathways were obtained by the compounds' targets gene from David database for Gene Ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. The cross pathways of compound-pathways and the diseases pathways of hyperuricemia from Comparative Toxicogenomics Database were be considered as the compound-disease pathways. Next, based on the compound-disease pathways and the PPI network, the core targets were identified based on the retrieved disease-genes. Finally, the compound-target-pathway-disease network was constructed by Cytoscape and the mechanism of isobavachin anti-hyperuricemia was discussed based on the network analysis. RESULTS: Our study demonstrated that there were five pathways involved in Isobavachin against hyperuricemia, including Drug metabolism-other enzymes, Metabolic pathways, Bile secretion, Renin-angiotensin system and Renin secretion. Among the proteins involved in these pathways, HPRT1, REN and ABCG2 were identified as the core targets associated with hyperuricemia, which regulated the five pathways mentioned above. It is quite different from that of Tranilast, which involved in the same pathways except Bile secretion instead of purine metabolism. CONCLUSION: This study revealed Isobavachin could regulate the pathways including Drug metabolism-other enzymes, Metabolic pathways, Bile secretion, Renin-angiotensin system, Renin secretion by core targets HPRT1, REN and ABCG2, in the treatment of hyperuricemia effect. Among them, the Bile secretion regulated by ABCG2 probably would be a novel pathway. Our work provided a theoretical basis for the pharmacological study of Isobavachin in lowering uric acid and further basic research.

Reciprocal positive regulation between BRD4 and YAP in GNAQ-mutant uveal melanoma cells confers sensitivity to BET inhibitors.

Uveal melanoma (UM) is the most common intraocular cancer in adults. UMs are usually initiated by a mutation in GNAQ or GNA11 (encoding Gq or G11, respectively), unlike cutaneous melanomas (CMs), which usually carry a BRAF or NRAS mutation. Currently, there are no clinically effective targeted therapies for UM carrying Gq/11 mutations. Here, we identified a causal link between Gq activating mutations and hypersensitivity to bromodomain and extra-terminal (BET) inhibitors. BET inhibitors transcriptionally repress YAP via BRD4 regardless of Gq mutation status, independently of Hippo core components LATS1/2. In contrast, YAP/TAZ downregulation reduces BRD4 transcription exclusively in Gq-mutant cells and LATS1/2 double knockout cells, both of which are featured by constitutively active YAP/TAZ. The transcriptional interdependency between BRD4 and YAP identified in Gq-mutated cells is responsible for the preferential inhibitory effect of BET inhibitors on the growth and dissemination of Gq-mutated UM cells compared to BRAF-mutated CM cells in both culture cells and animal models. Our findings suggest BRD4 as a viable therapeutic target for Gq-driven UMs that are addicted to unrestrained YAP function.

PTEN loss confers sensitivity to rapalogs in clear cell renal cell carcinoma.

Rapalogs (everolimus and temsirolimus) are allosteric mTORC1 inhibitors and approved agents for advanced clear cell renal cell carcinoma (ccRCC), although only a subset of patients derive clinical benefit. Progress in genomic characterization has made it possible to generate comprehensive profiles of genetic alterations in ccRCC; however, the correlations between recurrent somatic mutations and rapalog efficacy remain unclear. Here, we demonstrate by using multiple patient-derived ccRCC cell lines that compared to PTEN-proficient cells, PTEN-deficient cells exhibit hypersensitivity to rapalogs. Rapalogs inhibit cell proliferation by inducing G0/G1 arrest without inducing apoptosis in PTEN-deficient ccRCC cell lines. Using isogenic cell lines generated by CRISPR/Cas9, we validate the correlation between PTEN loss and rapalog hypersensitivity. In contrast, deletion of VHL or chromatin-modifying genes (PBRM1, SETD2, BAP1, or KDM5C) fails to influence the cellular response to rapalogs. Our mechanistic study shows that ectopic expression of an activating mTOR mutant (C1483F) antagonizes PTEN-induced cell growth inhibition, while introduction of a resistant mTOR mutant (A2034V) enables PTEN-deficient ccRCC cells to escape the growth inhibitory effect of rapalogs, suggesting that PTEN loss generates vulnerability to mTOR inhibition. PTEN-deficient ccRCC cells are more sensitive to the inhibitory effects of temsirolimus on cell migration and tumor growth in zebrafish and xenograft mice, respectively. Of note, PTEN protein loss as detected by immunohistochemistry is much more frequent than mutations in the PTEN gene in ccRCC patients. Our study suggests that PTEN loss correlates with rapalog sensitivity and could be used as a marker for ccRCC patient selection for rapalog therapy.

Nickel(II)-Catalyzed [3 + 2] Cycloaddition of Nitrones and Allenoates to Access N-Vinylindoles and N-Vinylpyrroles.

A variety of N-vinylindoles and N-vinylpyrroles were prepared in moderate to good yields through the nickel(II)-catalyzed [3 + 2] cycloaddition of α,ß-unsaturated nitrones with allenoates under mild reaction conditions. A rational mechanism for the formation of N-vinylindoles was proposed based on the 18O-labeled experiments and key intermediates detected by high-resolution mass spectrometry trace experiments. The present method highlights a nickel(II)-controlled cyclization, atom-economical reaction, broad substrate scope, good functional group tolerance, and high Z-stereoselectivity for the enamine bond.

Multicenter analysis and a rapid screening model to predict early novel coronavirus pneumonia using a random forest algorithm.

ABSTRACT: Early determination of coronavirus disease 2019 (COVID-19) pneumonia from numerous suspected cases is critical for the early isolation and treatment of patients.The purpose of the study was to develop and validate a rapid screening model to predict early COVID-19 pneumonia from suspected cases using a random forest algorithm in China.A total of 914 initially suspected COVID-19 pneumonia in multiple centers were prospectively included. The computer-assisted embedding method was used to screen the variables. The random forest algorithm was adopted to build a rapid screening model based on the training set. The screening model was evaluated by the confusion matrix and receiver operating characteristic (ROC) analysis in the validation.The rapid screening model was set up based on 4 epidemiological features, 3 clinical manifestations, decreased white blood cell count and lymphocytes, and imaging changes on chest X-ray or computed tomography. The area under the ROC curve was 0.956, and the model had a sensitivity of 83.82% and a specificity of 89.57%. The confusion matrix revealed that the prospective screening model had an accuracy of 87.0% for predicting early COVID-19 pneumonia.Here, we developed and validated a rapid screening model that could predict early COVID-19 pneumonia with high sensitivity and specificity. The use of this model to screen for COVID-19 pneumonia have epidemiological and clinical significance.

Hepatocellular carcinoma progression in hepatitis B virus-related cirrhosis patients receiving nucleoside (acid) analogs therapy: A retrospective cross-sectional study.

BACKGROUND: Antiviral therapy cannot completely block the progression of hepatitis B to hepatocellular carcinoma (HCC). Furthermore, there are few predictors of early HCC progression and limited strategies to prevent progression in patients with HBV-related cirrhosis who receive nucleos(t)ide analog (NA) therapy. AIM: The study aim was to clarify risk factors and the diagnostic value of alpha-fetoprotein (AFP) for HCC progression in NA-treated hepatitis B virus (HBV)-related cirrhosis patients. METHODS: In this retrospective cross-sectional study, we analyzed the clinical data of 266 patients with HBV-related cirrhosis who received NA treatment between February 2014 and April 2020 at Zhejiang Provincial People's Hospital. The patients were divided into two groups, 145 who did not progress to HCC (No-HCC group), and 121 who progressed to HCC during NA treatment (HCC group). The logistic regression analysis was used to analyze the risk factors of HCC progression. The diagnostic value of AFP for HCC was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: Univariate analysis showed that age ≥ 60 years (P = 0.001), hepatitis B and alcoholic etiology (P = 0.007), smoking history (P < 0.001), family history of HBV-related HCC (P = 0.002), lamivudine resistance (P = 0.011), HBV DNA negative (P = 0.023), aspartate aminotransferase > 80 U/L (P = 0.002), gamma-glutamyl transpeptidase > 120 U/L (P = 0.001), alkaline phosphatase > 250 U/L (P = 0.001), fasting blood glucose (FBG) ≥ 6.16 (mmol/L) (P = 0.001) and Child-Pugh class C (P = 0.005) were correlated with HCC progression. In multivariate analysis, age ≥ 60 years [hazard ratio (HR) = 3.089, 95% confidence interval (CI): 1.437-6.631, P = 0.004], smoking history (HR = 4.001, 95%CI: 1.836-8.716, P < 0.01), family history of HBV-related HCC (HR = 6.763, 95%CI: 1.253-36.499, P < 0.05), lamivudine resistance (HR = 2.949, 95%CI: 1.207-7.208, P = 0.018), HBV DNA negative (HR = 0.026, 95%CI: 0.007-0.139, P < 0.01), FBG ≥ 6.16 mmol/L (HR = 7.219, 95%CI: 3.716-14.024, P < 0.01) were independent risk factors of HCC progression. ROC of AFP for diagnosis of HCC was 0.746 (95%CI: 0.674-0.818). A cutoff value of AFP of 9.00 ug/L had a sensitivity of 0.609, and specificity of 0.818 for diagnosing HCC. CONCLUSION: Age ≥ 60 years, smoking history, family history of HCC, lamivudine resistance, HBV DNA negative, FBG ≥ 6.16 mmol/L were risk factors of HCC progression. Serum AFP had limited diagnostic value for HCC.

A rapid screening model for early predicting novel coronavirus pneumonia in Zhejiang Province of China: a multicenter study.

Novel coronavirus pneumonia (NCP) has been widely spread in China and several other countries. Early finding of this pneumonia from huge numbers of suspects gives clinicians a big challenge. The aim of the study was to develop a rapid screening model for early predicting NCP in a Zhejiang population, as well as its utility in other areas. A total of 880 participants who were initially suspected of NCP from January 17 to February 19 were included. Potential predictors were selected via stepwise logistic regression analysis. The model was established based on epidemiological features, clinical manifestations, white blood cell count, and pulmonary imaging changes, with the area under receiver operating characteristic (AUROC) curve of 0.920. At a cut-off value of 1.0, the model could determine NCP with a sensitivity of 85% and a specificity of 82.3%. We further developed a simplified model by combining the geographical regions and rounding the coefficients, with the AUROC of 0.909, as well as a model without epidemiological factors with the AUROC of 0.859. The study demonstrated that the screening model was a helpful and cost-effective tool for early predicting NCP and had great clinical significance given the high activity of NCP.

Constructed Wetland Revealed Efficient Sulfamethoxazole Removal but Enhanced the Spread of Antibiotic Resistance Genes.

Constructed wetlands (CWs) could achieve high removal efficiency of antibiotics, but probably stimulate the spread of antibiotic resistance genes (ARGs). In this study, four CWs were established to treat synthetic wastewater containing sulfamethoxazole (SMX). SMX elimination efficiencies, SMX degradation mechanisms, dynamic fates of ARGs, and bacterial communities were evaluated during the treatment period (360 day). Throughout the whole study, the concentration of SMX in the effluent gradually increased (p < 0.05), but in general, the removal efficiency of SMX remained at a very high level (>98%). In addition, the concentration of SMX in the bottom layer was higher compared with that in the surface layer. The main byproducts of SMX degradation were found to be 4-amino benzene sulfinic acid, 3-amino-5-methylisoxazole, benzenethiol, and 3-hydroxybutan-1-aminium. Temporally speaking, an obvious increase of sul genes was observed, along with the increase of SMX concentration in the bottom and middle layers of CWs. Spatially speaking, the concentration of sul genes increased from the surface layer to the bottom layer.

Serum Proteomic Changes as Candidate Biomarkers of Intermediate Liver Fibrosis in Chronic Hepatitis B Infection.

Chronic hepatitis B (CHB) is a major global health burden. Liver fibrosis, an insidious process, is the main histopathological change in CHB that might lead to the end-stage liver disease if left untreated. The intermediate liver fibrosis (S2) is the optimal time to start antiviral therapy. The aim of the present study was to examine the proteomic changes in patients with CHB at different fibrotic stages, with a view to identify future serum biomarkers for S2. Ninety CHB patients were grouped into mild (S0-1), intermediate (S2), and severe liver fibrosis (S3-4) (61 men and 29 women; age 25-63 years). Isobaric tagging for relative and absolute quantitation was applied to screen proteins differentially expressed among the patient groups. Another 46 patients with CHB (age 25-59 years; 31 men and 15 women), and 16 healthy controls (age 26-61 years; 11 men and 5 women) were enrolled in a validation group. Enzyme-linked immunosorbent assay was used to verify the diagnostic value of the candidate biomarkers. We found 139 proteins that were differentially expressed between various fibrotic stage-paired comparisons. Five protein candidates were selected as potential biomarkers of S2 for further verification. Notably, ficolin-2 (FCN2) and carboxypeptidase B2 (CPB2) showed differential expression between patients and healthy controls. In conclusion, serum proteomic changes reported here offer new molecular leads for future research on biomarker candidates to identify liver fibrotic stages in CHB. In particular, FCN2 and CPB2 warrant further research on their possible mechanistic involvement in CHB pathogenesis.

Identification of potential metabolic biomarkers of cerebrospinal fluids that differentiate tuberculous meningitis from other types of meningitis by a metabolomics study.

Tuberculous meningitis (TBM) is caused by tuberculosis infection of of the meninges, which are the membrane systems that encircle the brain, with a high morbidity and mortality rate. It is challenging to diagnose TBM among other types of meningitis, such as viral meningitis, bacterial meningitis and cryptococcal meningitis. We aimed to identify metabolites that are differentially expressed between TBM and the other types of meningitis by a global metabolomics analysis. The cerebrospinal fluids (CSF) from 50 patients with TBM, 17 with viral meningitis, 17 with bacterial meningitis, and 16 with cryptococcal meningitis were analyzed using ultra high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). A total of 1161 and 512 features were determined in positive and negative electrospray ionization mode, respectively. A clear separation between TBM and viral, bacterial or cryptococcal meningitis was achieved by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) analysis. Potential metabolic markers and related pathways were identified, which were mainly involved in the metabolism of amino acid, lipids and nucleosides. In summary, differential metabolic profiles of the CSF exist between TBM and other types of meningitis, and potential metabolic biomarkers were identified to differentiate TBM from other types of meningitis.

Old age and hydrocephalus are associated with poor prognosis in patients with tuberculous meningitis: A retrospective study in a Chinese adult population.

Tuberculous meningitis (TBM) is the most common form of central nervous system tuberculosis with a very poor prognosis. We aimed at assessing risk factors related to the prognosis of patients with TBM.Forty-five inpatients with TBM in our institution from January 2013 to December 2015 were enrolled retrospectively. The good or poor prognosis in the patients was defined, based on Glasgow Outcome Scale System at discharge. Patients with a GOS score less than 5 were defined as "poor prognosis." Univariate and multivariate logistic regression analyses were performed to assess the predictors for TBM outcome.Among 45 TBM patients, 35 (77.8%) and 10 (22.2%) were in good, poor prognoses, respectively. Old age, disturbance of consciousness, moderate to severe electroencephalogram abnormality, hydrocephalus, remarkable increase of protein (≥ 236 mg/dL) and white blood cell counts (≥ 243 /µL) in cerebral spinal fluid were associated with poor prognosis. Multivariate analysis indicated that old age (odds ratio (OR) = 18.395, P = .036) and hydrocephalus (OR = 32.995, P = .049) were independent factors for a poor outcome of TBM.In conclusion, old age and hydrocephalus are the predictors for poor prognosis of TBM. Patients with these risk factors should be treated promptly with a special care paid to improve their outcomes.

Peliosis hepatis: 2 case reports of a rare liver disorder and its differential diagnosis.

RATIONALE: Peliosis hepatis (PH) is a rare tumor-like liver lesion composed of multiple blood-filled cavities within the liver parenchyma. It is hard to differentiate PH from other liver lesions by imaging, such as carcinoma, metastases, or abscess. PATIENT CONCERNS: Here, we reported 2 cases that presented with liver lesions under ultrasound and computed tomography (CT) scanning, without any history of liver diseases or drug usage traced back. DIAGNOSES: Liver biopsy and laparoscopy were processed, and the lesions were eventually diagnosed as PH by histopathology, which microscopically presented with multiple sinusoidal dilatations with blood-filled cystic spaces. INTERVENTIONS: After the liver biopsy or laparoscopy, the patients were discharged and followed up in the clinic. OUTCOMES: Both patients were followed up for at least 1 year with good recovery. LESSONS: PH should always be recognized in the differentiation of liver lesions, particularly indistinctive lesion(s) without any history of liver-related diseases.

Standardized myrtol attenuates lipopolysaccharide induced acute lung injury in mice.

CONTEXT: Standardized myrtol, an essential oil containing primarily cineole, limonene and α-pinene, has been used for treating nasosinusitis, bronchitis and chronic obstructive pulmonary disease (COPD). OBJECTIVE: To investigate the effects of standardized myrtol in a model of acute lung injury (ALI) induced by lipopolysaccharides (LPS). MATERIALS AND METHODS: Male BALB/c mice were treated with standardized myrtol for 1.5 h prior to exposure of atomized LPS. Six hours after LPS challenge, lung injury was determined by the neutrophil recruitment, cytokine levels and total protein concentration in the bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung tissue. Additionally, pathological changes and NF-κB activation in the lung were examined by haematoxylin and eosin staining and western blot, respectively. RESULTS: In LPS-challenged mice, standardized myrtol at a dose of 1200 mg/kg significantly inhibited the neutrophile counts (from 820.97 ± 142.44 to 280.42 ± 65.45, 103/mL), protein concentration (from 0.331 ± 0.02 to 0.183 ± 0.01, mg/mL) and inflammatory cytokines level (TNF-α: from 6072.70 ± 748.40 to 2317.70 ± 500.14, ng/mL; IL-6: from 1184.85 ± 143.58 to 509.57 ± 133.03, ng/mL) in BALF. Standardized myrtol also attenuated LPS-induced MPO activity (from 0.82 ± 0.04 to 0.48 ± 0.06, U/g) and pathological changes (lung injury score: from 11.67 ± 0.33 to 7.83 ± 0.79) in the lung. Further study demonstrated that standardized myrtol prevented LPS-induced NF-κB activation in lung tissues. DISCUSSION AND CONCLUSION: Together, these data suggest that standardized myrtol has the potential to protect against LPS-induced airway inflammation in a model of ALI.

[Small RNA interference-mediated ADP-ribosylation factor 6 silencing inhibits proliferation, migration and invasion of human prostate cancer PC-3 cells].

OBJECTIVE: To investigate the effects of silencing ADP-ribosylation factor 6 (Arf6) on the proliferation, migration, and invasion of prostate cancer cell line PC-3 and the possible molecular mechanisms. METHODS: Three Arf6-specific small interfering RNA (siRNA) were transfected into cultured prostate cancer cell line PC-3. Arf6 expression was examined by real-time PCR and Western blotting. MTT assay, wound healing assay, and Transwell migration and invasion assay were used to observe the effect of Arf6 silencing on the proliferation, migration, and invasion ability of PC-3 cells. The levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), ERK1/2, p-AKT, AKT and Rac1 were detected by Western blotting. RESULTS: Transfection of siRNA-3 resulted in significantly decreased Arf6 mRNA and protein expression with inhibition rates of (91.88±3.13)% and (86.37±0.57)%, respectively. Arf6 silencing by siRNA-3 markedly suppressed the proliferation, migration and invasion of PC-3 cells and reduced the expression levels of p-ERK1/2 and Rac1. CONCLUSION: Silencing of Arf6 efficiently inhibits the proliferation, migration, and invasion of PC-3 cells in vitro, and the underlying mechanisms may involve the down-regulation of p-ERK1/2 and Rac1.

The Significance of Ultrasound in Determining Whether SHPT Patients Are Sensitive to Calcitriol Treatment.

This study was to explore the significance of ultrasound in determining whether the patients with secondary hyperparathyroidism (SHPT) are sensitive to calcitriol treatment. According to the decrease value of parathyroid hormone (PTH), 42 SHPT patients were divided into two groups: drug susceptible group and drug insusceptible group. These 42 SHPT patients' ultrasound images were retrospectively analyzed. The morphology, size, number, blood flow, elastic modulus, and perfusion of the parathyroid glands were correlated with drug therapeutic outcome (oral calcitriol). Most SHPT patients with drug susceptible showed volume <438.50 mm(3) and number ≤2, with 0-1 structural and vascular patterns, associated with Relative Maximum Intensity (RIMAX) <1.59 and elastic modulus <18.8 kPa, whereas most SHPT patients with drug insusceptible showed volume ≥438.50 mm(3) and number ≥3, with 2-3 structural and vascular patterns, associated with Relative Maximum Intensity (RIMAX) ≥1.59 and elastic modulus ≥18.8 kPa. Therefore, ultrasonography in SHPT allows an accurate definition of the morphology, size, number, blood flow, elastic modulus, and perfusion of the parathyroid glands and is useful in determining whether SHPT patients are sensitive to calcitriol treatment.

Smooth muscle cells of penis in the rat: noninvasive quantification with shear wave elastography.

PURPOSE: Smooth muscle cells (SMCs) of cavernosum play an important role in erection. It is of great significance to quantitatively analyze the level of SMCs in penis. In this study, we investigated the feasibility of shear wave elastography (SWE) on evaluating the level of SMCs in penis quantitatively. MATERIALS AND METHODS: Twenty healthy male rats were selected. The SWE imaging of penis was carried out and then immunohistochemistry analysis of penis was performed to analyze the expression of alpha smooth muscle actin in penis. The measurement index of SWE examination was tissue stiffness (TS). The measurement index of immunohistochemistry analysis was positive area percentage of alpha smooth muscle actin (AP). RESULTS: Sixty sets of data of TS and AP were obtained. The results showed that TS was significantly correlated with AP and the correlation coefficient was -0.618 (p < 0.001). The result of TS had been plotted against the AP measurements. The relation between the two results has been fitted with quadric curve; the goodness-of-fit index was 0.364 (p < 0.001). CONCLUSIONS: The level of SMCs in penis was successfully quantified in vivo with SWE. SWE can be used clinically for evaluating the level of SMCs in penis quantitatively.

Molecular epidemiology and mechanisms of tigecycline resistance in clinical isolates of Acinetobacter baumannii from a Chinese university hospital.

Because of its remarkable ability to acquire antibiotic resistance and to survive in nosocomial environments, Acinetobacter baumannii has become a significant nosocomial infectious agent worldwide. Tigecycline is one of the few therapeutic options for treating infections caused by A. baumannii isolates. However, tigecycline resistance has increasingly been reported. Our aim was to assess the prevalence and characteristics of efflux-based tigecycline resistance in clinical isolates of A. baumannii collected from a hospital in China. A total of 74 A. baumannii isolates, including 64 tigecycline-nonsusceptible A. baumannii (TNAB) and 10 tigecycline-susceptible A. baumannii (TSAB) isolates, were analyzed. The majority of them were determined to be positive for adeABC, adeRS, adeIJK, and abeM, while the adeE gene was found in only one TSAB isolate. Compared with the levels in TSAB isolates, the mean expression levels of adeB, adeJ, adeG, and abeM in TNAB isolates were observed to increase 29-, 3-, 0.7-, and 1-fold, respectively. The efflux pump inhibitors (EPIs) phenyl-arginine-ß-naphthylamide (PAßN) and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) could partially reverse the resistance pattern of tigecycline. Moreover, the tetX1 gene was detected in 12 (18.8%) TNAB isolates. To our knowledge, this is the first report of the tetX1 gene being detected in A. baumannii isolates. ST208 and ST191, which both clustered into clonal complex 92 (CC92), were the predominant sequence types (STs). This study showed that the active efflux pump AdeABC appeared to play important roles in the tigecycline resistance of A. baumannii. The dissemination of TNAB isolates in our hospital is attributable mainly to the spread of CC92.

Praeruptorin D and E attenuate lipopolysaccharide/hydrochloric acid induced acute lung injury in mice.

Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury.

Multi-class method for determination of veterinary drug residues and other contaminants in infant formula by ultra performance liquid chromatography-tandem mass spectrometry.

A rapid, simple and generic analytical method which was able to simultaneously determine 220 undesirable chemical residues in infant formula had been developed. The method comprised of extraction with acetonitrile, clean-up by low temperature and water precipitation, and analysis by ultra performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS-MS) using multiple reaction monitoring (MRM) mode. Most fat materials in acetonitrile extract were eliminated by low temperature clean-up. The water precipitation, providing a necessary and supplementary cleanup, could avoid losses of hydrophobic analytes (avermectins, ionophores). Average recoveries for spiked infant formula were in the range from 57% to 147% with associated RSD values between 1% and 28%. For over 80% of the analytes, the recoveries were between 70% and 120% with RSD values in the range of 1-15%. The limits of quantification (LOQs) were from 0.01 to 5 µg/kg, which were usually sufficient to verify the compliance of products with legal tolerances. Application of this method in routine monitoring programs would imply a drastic reduction of both effort and time.

Mollugin inhibits the inflammatory response in lipopolysaccharide-stimulated RAW264.7 macrophages by blocking the Janus kinase-signal transducers and activators of transcription signaling pathway.

Mollugin, a kind of naphthohydroquinone, is a major constituent isolated from Rubia cordifolia L. and demonstrated to possess anti-inflammatory activity in recent reports. However, the effects and mechanism of action of mollugin in inflammation have not been fully defined. The present study was therefore designed to investigate whether mollugin suppresses the inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Mollugin attenuated the LPS-induced expression of nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß and IL-6 but augmented the expression of tumor necrosis factor (TNF)-α. Mollugin did not inhibit the degradation of inhibitory kappa B (IκB)-α or the nuclear translocation of p65 nuclear factor-kappa B (NF-κB) but rather enhanced the phosphorylation of p65 subunits evoked by LPS. Mollugin did not inhibit the phosphorylation of extracellular-signal-related kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK) 1/2 either. Mollugin significantly reduced the LPS-mediated phosphorylation of Janus kinase (JAK) 2, signal transducers and activators of transcription (STAT) 1 and STAT3. Molecular docking analysis showed that mollugin binds to JAK2 in a manner similar to that of AG490, a specific JAK2 inhibitor. We conclude that mollugin may be a JAK2 inhibitor and inhibits LPS-induced inflammatory responses by blocking the activation of the JAK-STAT pathway.