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Aims: To compare the efficacy and safety of vonoprazan-based versus proton pump inhibitor (PPI)-based triple therapy in the eradication of Helicobacter pylori ., Methods: We performed a systematic search in PubMed, Embase, and the Cochrane Library databases for relevant randomized controlled trials up to March 2019. Studies were included if they compared the efficacy and safety of H. pylori eradication of vonoprazan-based and PPI-based triple therapy., Results: Three studies with 897 patients were evaluated in this meta-analysis. The H. pylori eradication rate of vonoprazan-based triple therapy was higher than that of PPI-based triple therapy as first-line regimens (intention-to-treat analysis: pooled eradication rates, 91.4% vs 74.8%; odds ratio [OR], 3.68; 95% confidence interval (CI): [1.87-7.26]; P <0.05). The incidence of adverse events in vonoprazan-based triple therapy was lower than that in PPI-based triple therapy (pooled incidence, 32.7% vs 40.5%; OR, 0.71; 95%CI: [0.53-0.95]; P <0.05)., Conclusions: Efficacy of vonoprazan-based triple therapy is superior to that of PPI-based triple therapy for first-line H. pylori eradication. Additionally, vonoprazan-based triple therapy is better tolerated than PPI-based triple therapy.

Aims: To identify and characterize the top-cited articles in the field of islet transplantation., Methods: We used the Science Citation Index Expanded database to identify the most frequently cited articles published after 1900. Articles were evaluated using the following characteristics: citation number, publication year, study design, references, country and institution of origin, authorship, and journal. Keyword analysis and citation networks were used to analyze research trends., Results: The most frequently cited articles received between 146 and 2988 citations; the median was 291. All of the most frequently cited articles were published between 1972 and 2012, and 85 articles were published after 1990. The most popular study design involved basic science (75 articles). The leading countries were the United States (US) and Canada, and the leading institutions were the University of Alberta, Canada, and the University of Minnesota, in the US. Journals specializing in diabetes or transplantation published more than half of the articles (n = 53, 52%), with the journal Diabetes publishing the largest number (n = 30). No association was found between a journal's impact factor and the number of top-cited articles it published. There was no correlation between the number of citations and the number of years since publication, authors, participating institutions, or countries involved. Top-cited articles focused on 2 themes: the use of antirejection immunotherapy or biocompatible encapsulations to prolong graft survival, and assessments of the efficacy of islet transplants, in particular, islet allografts., Conclusions: Our study can help researchers to identify and decipher the characteristics of top-cited articles in the field of islet transplantation. Just as clinically successful allografts are carried out using the Edmonton protocol, autografts and xenografts should be similarly strengthened to solve problems relating to immune rejection and islet sources, respectively.

1. Our objective is to investigate the alterations of hepatic drug transporters and metabolizing enzymes in hypercholesterolemia. Male Sprague-Dawley rats were fed high-cholesterol chows for 8 weeks to induce hypercholesterolemia. Protein levels of hepatic drug transporters and metabolizing enzymes were analyzed by iTRAQ labeling coupled with LC TRIPLE-TOF. 2. Total 239 differentially expressed proteins were identified using proteomic analysis. Among those, protein levels of hepatic drug transporters (MRP2, ABCD3, OAT2, SLC25A12, SCL38A3, SLC2A2 and SLC25A5) and metabolizing enzymes (CYP2B3, CYP2C7, CYP2C11, CYP2C13, CYP4A2 and UGT2B) were markedly reduced, but the levels of CYP2C6 and CYP2E1 were increased in hypercholesterolemia group compared to control. Decreased expressions of drug transporters MRP2 and OAT2 were further confirmed by real time quantitative PCR (RT-qPCR) and western blot. 3. Ingenuity pathway analysis revealed that these differentially expressed proteins were regulated by various signaling pathways including nuclear receptors and inflammatory cytokines. One of the nuclear receptor candidates, liver X receptor alpha (LXRα), was further validated by RT-qPCR and western blot. Additionally, LXRα agonist T0901317 rescued the reduced expressions of MRP2 and OAT2 in HepG2 cells in hypercholesterolemic serum treatment. 4. Our present results indicated that hypercholesterolemia affected the expressions of various drug transporters and metabolizing enzymes in liver via nuclear receptors pathway. Especially, decreased function of LXRα contributes to the reduced expressions of MRP2 and OAT2.

Objectives: The aim of this study is to compare the quantity and quality of scientific publications in transplantation fields that were written by researchers from Mainland China, Japan, South Korea and Taiwan in the East Asia region., Settings: East Asia., Participants and Outcome Measures: Articles except editorials, conference abstracts, letters, news and corrections published in 25 transplantation journals from 2006 to 2015 were screened with the Web of Science database. The number of total and annual articles, article types (study design and transplantation site), impact factor, citations and articles in the high-impact journals was determined to assess the quantity and quality of transplantation research from East Asia. The correlation of socioeconomic factors and annual publications was also analysed., Results: From 2006 to 2015, there were 47 141 articles published in transplantation journals, of which researchers from Japan published 3694 articles, followed by Mainland China, South Korea and Taiwan with 2778, 1643 and 951 articles, respectively. Similar trends were observed in accumulated impact factor, accumulated citations, articles in the high-impact journals and articles on transplantation site. Publications from Japan had the highest average impact factor and citation, while those from Mainland China had the lowest. Additionally, in terms of study design, authors from Mainland China contributed to most clinical trials and randomised controlled trials, but authors from Japan contributed to most case reports. The annual numbers of articles from Mainland China and South Korea increased linearly (p<0.05), but those from Japan and Taiwan remained stable for the period studied. The annual numbers of articles from Mainland China and South Korea were positively correlated with gross domestic product (p<0.05)., Conclusions: Transplantation research productivity in East Asia is highly skewed, with gross domestic product having a significant positive correlation. Mainland China still lags far behind Japan in most bibliometric indicators; thus, there is vast room for improvement., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

BCR-ABL tyrosine kinase inhibitor imatinib fails to eradicate leukemia stem cells (LSCs), the underlying mechanisms maintaining CML LSCs remain poorly understood. Here, we showed that transient inhibition of miR-21 by antagomiR-21 markedly increased imatinib-induced apoptosis in CML, but not normal CD34+ stem/progenitor cells. Furthermore, PI3K inhibitors also significantly sensitized CML CD34+ cells to imatinib-induced apoptosis. MiR-21 or PI3K inhibitor in combination with imatinib treatment significantly decreased AKT phosphorylation and c-Myc expression than either agent did alone, but did not affect Bim and Bcl-6 expresssion. These findings indicate that miR-21 is required for maintaining the imatinib-resistant phenotype of CML CD34+ cells through PI3K/AKT signaling pathway, thus providing the basis for a promising therapeutic approach to eliminate CML LSCs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

1.Gallic acid is a main polyphenol in various fruits and plants. Inhibitory characteristics of gallic acid on CYP3A4 were still unclear. The objective of this work is hence to investigate inhibitory characteristics of gallic acid on CYP3A4 using testosterone as the probe substrate in human liver microsomes (HLMs) and recombinant CYP3A4 (rCYP3A4) systems. 2.Gallic acid caused concentration-dependent loss of CYP3A4 activity with IC50 values of 615.2 μM and 669.5 μM in HLM and rCYP3A4 systems, respectively. IC50-shift experiments showed that pre-incubation with gallic acid in the absence of NADPH contributed to 12- or 14-fold reduction of IC50 in HLM and rCYP3A4 systems, respectively, supporting a time-dependent inhibition. In HLM, time-dependent inactivation variables KI and Kinact were 485.8 μM and 0.05 min(-1), respectively. 3.Compared with the presence of NADPH, pre-incubation of gallic acid in the absence of NADPH markedly increased its inhibitory effects in HLM and rCYP3A4 systems. Those results indicate that CYP3A4 inactivation by gallic acid was independent on NADPH and was mainly mediated its oxidative products. 4.In conclusion, we showed that gallic acid weakly and time-dependently inactivated CYP3A4 via its oxidative products.

Aims: Neurodegenerative diseases are the leading cause of morbidity and mortality worldwide. Several studies have shown that tetramethylpyrazine (TMP) is an effective therapy for neurodegenerative diseases and that it acts by inhibiting the activation of microglial cells in response to inflammatory stimuli. However, the molecular mechanisms underlying the action of TMP remain unknown., Main Methods: Proteomic analysis was used to generate novel insights into the mechanism by which TMP inhibits microglial activation, and western blotting was used to validate candidate proteins., Key Findings: To identify candidate proteins affected by TMP in lipopolysaccharide-activated microglia, we performed proteomic analysis using iTRAQ labelling coupled with LC TRIPLE-TOF, and we identified 5187 unique proteins. Among these, 266 proteins were differentially expressed and considered putative candidate proteins. Protein annotation revealed that the differentially expressed proteins, such as inducible nitric oxide synthase (iNOS) and ERO1-like protein (ERO1L), might be involved in reducing cellular oxidation in response to stress. Ingenuity pathway analysis revealed that the differentially expressed proteins were involved in a variety of signalling pathways, including liver X receptor/retinoid X receptor (LXR/RXR) activation and the production of nitric oxide and reactive oxygen species in macrophages. Furthermore, one of the differentially expressed protein candidates detected by iTRAQ, iNOS, was confirmed by western blotting., Significance: Our data suggest that iTRAQ technology is an effective tool to study the mechanism by which TMP inhibits activated microglia. TMP decreased the expression of LXR/RXR-mediated iNOS, which reduced microglial activation in response to inflammatory stimuli., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) cells are insensitive to BCR-ABL tyrosine kinase inhibitor imatinib, the underlying mechanisms remain largely unknown. Here, we showed that imatinib treatment induced significant upregulation of miR-21 and downregulation of PTEN in Ph+ ALL cell line Sup-b15. Transient inhibition of miR-21 resulted in increased apoptosis, PTEN upregulation and AKT dephosphorylation, whereas ectopic overexpression of miR-21 further conferred imatinib resistance. Furthermore, knockdown of PTEN protected the cells from imatinib-induced apoptosis achieved by inhibition of miR-21. Additionally, PI3K inhibitors also notably enhanced the effects of imatinib on Sup-b15 cells and primary Ph+ ALL cells similar to miR-21 inhibitor. Therefore, miR-21 contributes to imatinib resistance in Ph+ ALL cells and antagonizing miR-21 demonstrates therapeutic potential by sensitizing the malignancy to imatinib therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The maternal effect of different Se source in offspring of young broiler breeders has been reported, but the lasting maternal effect of different sources of Se on offspring of breeders has received limited attention, so this study was conducted to investigate the effects of different maternal Se sources on Se retention, antioxidant status, and meat quality of 56-d-old offspring of broiler breeders. A total of two hundred forty 39-wk-old Lingnan Yellow broiler breeders were randomly distributed into 2 treatments, each of which was replicated 3 times with 40 birds per replicate, with a 14-d pretreatment and 56-d trial period. The treatments were fed a basal corn-soybean diet (0.04 mg∙kg⁻¹ Se) supplemented with 0.3 mg∙kg⁻¹ sodium selenite (SS) or selenomethionine (Se-Met). Fertile eggs were collected for incubation, after which 180 healthy chicks from each treatment were selected and randomly allocated into 3 replicates, with 60 birds per replicate. All the chicks were fed the same basal diet (0.04 mg∙kg⁻¹ Se) for 56 d. The Se concentrations in serum and tissues (liver, kidney, and breast muscle) of the 56-d-old offspring were significantly (P < 0.01) increased by maternal Se-Met intake compared with maternal SS intake. The antioxidant status of the 56-d-old offspring was greatly improved by maternal Se-Met supplementation in contrast with maternal SS supplementation, which was shown by increased glutathione peroxidase activity in serum and breast muscle (P < 0.01), glutathione concentration in serum (P < 0.05), and total antioxidant capability in pancreas (P < 0.01), as well as cytosolic glutathione peroxidase mRNA abundance in breast muscle, liver (P < 0.01), and pancreas (P < 0.05). The maternal Se-Met treatment was more effective in maintaining the shape of liver and pancreas cells, cell nuclei, chromatin, as well as cell membrane structure, and more organelles were observed in liver cells. The maternal Se-Met treatment had significant (P < 0.05) reduced the 48-h drip loss of 56-d-old offspring in comparison with maternal SS treatment. The results suggest that maternal Se-Met diet is superior to maternal SS diet in increasing Se retention and improving antioxidant status and meat quality of 56-d-old offspring., (© 2014 Poultry Science Association Inc.)

The present study is to elucidate the mechanisms underlying Gleevec-induced apoptosis of chronic myeloid leukemia (CML) K562 cells in vitro. The apoptotic cell death and cell cycle distribution after Gleevec treatment and the effect of PDCD4 siRNA on Gleevec-induced apoptosis of K562 cells were analyzed by flow cytometry. The effect of Gleevec on p-Crkl, caspase-3, PARP and PDCD4 protein levels, and the knockdown efficacy of PDCD4 siRNA were detected by Western blotting. The results showed that Gleevec dramatically suppressed the phosphorylation level of Crkl in a dose-dependent manner and induced significant apoptosis and G0/G1 cell cycle arrest of K562 cells in time- and dose-dependent manners. In addition, Gleevec activated caspase-3 and its downstream substrates PARP, and the caspase pan inhibitor Z-VAD-FMK (50 micromol x L(-1)) markedly reduced Gleevec-induced apoptosis from 47.97% +/- 10.56% to 31.05% +/- 9.206% (P < 0.05). Moreover, Gleevec significantly increased the protein expression of programmed cell death 4 (PDCD4). PDCD4 knockdown by siRNA reduced Gleevec-induced apoptosis from 46.97% +/- 14.32% to 42.8% +/- 11.43%. In summary, Gleevec induced apoptosis in K562 cells via caspase-3 activation.

Conventional chemotherapy against hepatocellular carcinoma typically causes various side effects. Our previous study showed that cecropin of Musca domestica can induce apoptosis in human hepatocellular carcinoma BEL-7402 cells in vitro. However, whether cecropin inhibits BEL-7402 cell in vivo and the question of possible side effects remained undentified. The present study confirmed tumor-inhibitory effects of cecropin in vivo, and furthermore strongly suggested that cecropin cytotoxicity in BEL-7402 cells in vivo may be mainly derived from its pro-apoptotic action. Specifically, we found that cecropin exerted no obvious side effects in tumor-bearing mice as it had no significant hematoxicity as well as visceral toxicity. Therefore, cecropin may be a potential candidate for further investigation as an antitumor agent against hepatocellular carcinoma.

Aim: The aim of this study is to explore the underlying molecular mechanism of curcumin-induced apoptosis in human hepatocellular carcinoma (HCC) Huh7 cells., Main Methods: Fas and FasL mRNA expression was analyzed by reverse transcription PCR. Western blot was applied to detect the protein expression of Bcl-2 family members, MAPK family members, c-Jun, c-Fos, ATF-2, caspase-3, PARP, TNF receptor family members and the respective ligands. Apoptotic cells were assayed with annexin V/PI double staining and flow cytometry., Key Findings: Curcumin treatment resulted in a fast and significant increase of Fas and Fas ligand (FasL) along with activation of caspase-3 and cleavage of PARP in Huh7 cells. Inhibition of caspase-3 activity by the specific inhibitor Z-DEVD-FMK rescued Huh7 cells from curcumin-induced apoptosis. Neutralization of FasL significantly protected the cells from curcumin-induced caspase-3 activation and apoptosis in a dose-dependent manner. Moreover, p38 was rapidly activated in response to curcumin, and inactivation of p38 by pharmacologic inhibitor SB203580 dramatically suppressed curcumin-induced FasL expression and apoptosis., Significance: Our results demonstrated that curcumin induces apoptosis through p38-denpendent up-regulation of FasL in Huh7 cells., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This study was designed to explore the effects of Musca domestica antimicrobial peptides cecropin on the adhesion and migration of human hepatocellular carcinoma BEL-7402 cells. The adhesive and migratory capacities were determined by adhesion assay and transwell assay, respectively. The changes in microvilli of tumor cells were determined by scanning electron microscopy (SEM). Western blotting and quantitative polymerase chain reaction (qPCR) were carried out to determine the expression levels of proteins related to adhesion and migration, such as matrix metalloproteinase-2 (MMP2), tissue inhibitors of metalloproteinase-2 (TIMP2), and epithelial cadherin (E-cadherin). We found that Musca domestica cecropin inhibited the adhesion and migration of BEL-7402 cells, which also displayed curling microvilli, increased ball structures on cell surface, gradually broken connections between tumor cells, and even disappeared microvilli on some cells. The expression of MMP2 was significantly reduced after cecropin treatment, while the levels of TIMP2 and E-cadherin were significantly increased. These results suggest that Musca domestica cecropin inhibits the adhesion and migration of human hepatocellular carcinoma BEL-7402 cells by destroying the microvilli of tumor cells and changing the expression of MMP2, TIMP2 and E-cadherin.

Objective: To determine the accuracy of nonattenuation corrected (NAC) F-fluorodeoxyglucose positron emission tomography (F-FDG PET) images in the evaluation of solitary pulmonary lesion as compared with more established methods., Methods: Fifty-six patients received F-FDG PET/CT for diagnosing solitary pulmonary nodules or mass lesions based on histopathology (n=39) and clinical follow-up (n=17). Visual pulmonary lesion FDG uptake was graded by consensus of two nuclear medicine physicians on both attenuation corrected (AC) [absent, less than mediastinal blood pool (MBP), equal to MBP, greater than MBP] and NAC (absent, less than skin, equal to skin, greater than skin) images. Standardized uptake values (SUV) were also measured from AC images. SUV, visual AC, and visual NAC methods' diagnostic performances were compared, distinguishing benign from malignant pulmonary nodules., Results: There were 34 malignant and 22 benign lesions. Lesion diameter varied from 5 to 100 mm (mean ± SD, 24.0 ± 17.9 mm). The NAC, AC, and SUV method sensitivities and specificities were 100/64%, 91/59%, and 79/77%, respectively. For lesions less than 3 cm, NAC, AC, and SUV methods yielded accuracies of 85%, 78%, and 73%, respectively. The NAC method was the most sensitive and accurate especially for small nodules., Conclusion: Visual assessment of NAC F-FDG PET images alone may provide a more accurate characterization of solitary pulmonary lesions.