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We aim to study the effects of CYP2D6 variants and drug-drug interaction on the metabolism of dacomitinib. CYP2D6 variants were incubated with 25-1000 μM dacomitinib for 40 min at 37 °C, and the reaction was terminated by cooling to -80 °C immediately. For an in vivo experiment, 18 male Sprague-Dawley rats were randomly divided into three groups ( n = 6): a single dose of 5 mg/kg dacomitinib (group A), a single dose of 6 mg/kg trazodone (group B), and a combined group (group C). Processed samples were analyzed by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS.) The relative clearance of dacomitinib was reduced for most of the variants. Moreover, the inhibitory potency of classic CYP inhibitors on dacomitinib metabolism was significantly different among the main subtypes of CYP2D6. Interestingly, compared with gefitinib, even the same CYP2D6 variants showed significant differences in metabolic activity, suggesting that the activity of CYP2D6 has strong variability. In addition, the interaction between trazodone and dacomitinib was determined both in vitro and in vivo. When dacomitinib was given in combination with trazodone, the blood exposure to these two drugs increased remarkably. The mechanistic study revealed that the interaction followed the noncompetitive inhibition. We demonstrated that the activity of CYP2D6 variants to metabolize dacomitinib was significantly reduced. In combination with the CYP2D6 inhibitor, the degree of activity inhibition of different variants obviously differed. When trazodone and dacomitinib were used in combination, the body exposure to the two drugs increased significantly. This study provides data for the precise use of dacomitinib in clinical settings.

Background: Increasing evidence suggested N 6 -methyladenosine (m 6 A) modification is crucial for male germline development. However, m 6 A modification of lncRNAs gains a little attention in amphibians in recent years. Xenopus laevis (X. laevis) was chosen to be an ideal model organism for testing environmental endocrine disrupting chemicals (EDCs) exposure and resultant effects. Atrazine (AZ) as an endocrine disrupt can effect development of testis in amphibians. Our previous study revealed that m 6 A is a highly conserved modification across the species., Results: The results of m 6 A sequences showed that m 6 A-methylated lncRNAs enriched in intergenic region in testes of X. laevis. We further examined the differential expression of lncRNAs m 6 A sites in testes of AZ-exposed and compared with that in animals from control group. The results indicated that up to 198 differentially methylated m 6 A sites were detected within 188 lncRNAs, in which 89 significantly up-methylated sites and 109 significantly down-methylated sites. Data from KEGG pathway analysis indicated that AZ-affected lncRNAs m 6 A sites were mainly involved in 10 pathways in which 3 mutual pathways were found in the result of differentially m 6 A-methylated mRNAs., Conclusions: These findings suggested that differentially m 6 A-methylated lncRNAs and these 3 pathways may act on regulatory roles in abnormal testis development of AZ-exposed X. laevis. This study for the first time provides insights into the profile of lncRNAs m 6 A modifications in amphibian species., (© 2021. The Author(s).)

Objective: The study was aimed to investigate the effects and potential mechanisms of Dexmedetomidine (Dex) on hypoxia/reoxygenation (H/R) injury in human renal tubular epithelial HK-2 cells., Materials and Methods: In this experimental study, HK-2 cells were divided into four groups: control group, Dex group, H/R group, and Dex+H/R group. The cells in control group received no treatment, and cells in Dex group were only treated with 0.1 nmol/L Dex. The cells in H/R group and Dex+H/R group were all treated with H/R (hypoxia for 24 hours and normoxia for 4 hours), and only the cells in Dex+H/R group were pre-administrated with 0.1 nmol/L Dex. Following treatments at 37˚C for 28 hours, cell viability and apoptosis were measured by MTT assay and flow cytometry, respectively. Also, the expressions of hypoxia-inducible factor 1 (HIF-1α), glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), caspase-12 and cleaved caspase-3 were determined by western blot., Results: The cell viability was significant decreased in H/R group compared with control group (P<0.05), while was significantly increased in Dex+H/R group compared with that in H/R group (P<0.05). However, the change tendency of the cell apoptosis was opposite to that of cell viability. Compared with H/R group, the expression of HIF-1α was evidently up-regulated, while GRP78, CHOP, capase-12 and cleaved caspase-3 expressions were all obviously downregulated in Dex+H/R group (P<0.05). In addition, the concentrations of malondialdehyde (MDA) in H/R group and Dex+H/R group were 1.68 ± 0.22 nmol/mgprot and 0.85 ± 0.16 nmol/mgprot, respectively. The superoxide dismutase (SOD) activity was higher in Dex+H/R group (121 ± 11 U/L), which which was more than twice larger than that in H/R group (57 ± 10 U/L)., Conclusion: Dex could promote cell viability and inhibit apoptosis through up-regulating HIF-1α, reducing endoplasmic reticulum (ER) stress and mediating oxidative stress, thus ameliorating the H/R injury., Competing Interests: There is no conflict of interest in this study., (Copyright© by Royan Institute. All rights reserved.)

Background/aims: We recently described a novel regulatory role for histone deacetylase 2 (HDAC2) in protecting endothelial cells from oxidized low-density lipoprotein (OxLDL)-induced injury. In this study, we examined the effects of endothelial-specific HDAC2 overexpression on endothelial-dependent vasorelaxation and atherogenesis in vivo., Methods: Endothelial-specific HDAC2-overexpressing transgenic mice (HDAC2-Tg) were generated under control of the Tie2 promoter. An atherosclerosis model was produced by injecting HDAC2-Tg and wild-type (WT) mice with adeno-associated virus encoding a PCSK9 gain-of-function mutant under control of a liver-specific promoter and feeding them a high-fat diet for 12 weeks. Aortic stiffness in vivo was determined by measuring pulse wave velocity. Wire myography was used to measure endothelium dependent (acetylcholine) and independent (sodium nitroprusside) relaxation in isolated mice aortas. Atherosclerotic plaque burden in aortas was determined by Oil Red O staining and protein expression was determined by western blotting., Results: At baseline, HDAC2-Tg mice had normal mean arterial blood pressure (MAP) and body weight, but pulse wave velocity (PWV), an inverse measure of vascular health and stiffness, was decreased, suggesting that their vessels were more compliant. Moreover, basal nitric oxide production was enhanced in the vessels of HDAC2-Tg mice as compared to that in WT controls, although no significant differences in acetylcholine (endothelial component)- or sodium nitroprusside (non-endothelial component)-mediated relaxation were observed. However, after exposure to OxLDL, aortas from HDAC2-Tg mice exhibited greater acetylcholine-induced relaxation than did those from WT mice. Thus, endothelial-specific vasodilator production was enhanced despite oxidative injury. Atherosclerosis induction in WT mice led to a significant increase in PWV, but in HDAC2-Tg mice, PWV and MAP remained unchanged. Further, aortic rings from HDAC2-Tg exhibited better endothelial-dependent vascular relaxation than did those from WT mice, but not when treated with nitric oxide synthase inhibitor L-NAME. Finally, plaque burden, determined by Oil red O staining, was significantly increased in WT, but not HDAC2-Tg mice, subjected to the atherogenic model. Deletion of endothelial HDAC2 led to impaired endothelial cell-dependent vascular relaxation and increased PWV, compared with those in littermate controls., Conclusion: HDAC2 protects against endothelial dysfunction and atherogenesis induced by oxidized lipids. Hence, overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis. HDAC2-Tg mice provide an opportunity to determine the role of endothelial HDAC2 in vascular endothelial homeostasis., Competing Interests: The authors have no conflicts of interest to disclose., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Rechargeable aqueous Zn/manganese dioxide (Zn/MnO 2 ) batteries are attractive energy storage technology owing to their merits of low cost, high safety, and environmental friendliness. However, the β-MnO 2 cathode is still plagued by the sluggish ion insertion kinetics due to the relatively narrow tunneled pathway. Furthermore, the energy storage mechanism is under debate as well. Here, β-MnO 2 cathode with enhanced ion insertion kinetics is introduced by the efficient oxygen defect engineering strategy. Density functional theory computations show that the β-MnO 2 host structure is more likely for H + insertion rather than Zn 2+ , and the introduction of oxygen defects will facilitate the insertion of H + into β-MnO 2 . This theoretical conjecture is confirmed by the capacity of 302 mA h g -1 and capacity retention of 94% after 300 cycles in the assembled aqueous Zn/β-MnO 2 cell. These results highlight the potentials of defect engineering as a strategy of improving the electrochemical performance of β-MnO 2 in aqueous rechargeable batteries., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Primordial germ cells (PGCs) as the precursors of germ cells are responsible for transmitting genetic information to the next generation. Visualization of teleost PGCs in vivo is essential to research the origination and development of germ cells and facilitate further manipulation on PGCs isolation, cryopreservation, and surrogate breeding. In this study, artificially synthesized mRNAs constructed by fusing fluorescent protein coding region to the 3' untranslated region (3'UTR) of nanos3 or vasa (mCherry-Smnanos3 3'UTR or mCherry-Smvasa 3'UTR mRNA) were injected into turbot (Scophthalmus maximus) fertilized eggs for tracing PGCs. The results demonstrated that the fluorescent PGCs differentiated from somatic cells and aligned on both sides of the trunk at the early segmentation period, then migrated and located at the dorsal part of the gut where the gonad would form. In the same way, we also found that the zebrafish (Danio rerio) vasa 3'UTR could trace turbot PGCs, while the vasa 3'UTR s of marine medaka (Oryzias melastigma) and red seabream (Pagrus major) failed, although they could label the marine medaka PGCs. In addition, through comparative analysis, we discovered that some potential sequence elements in the3 'UTRs of nanos3 and vasa, such as GCACs, 62-bp U-rich regions and nucleotide 187-218 regions might be involved in PGCs stabilization. The results of this study provided an efficient, rapid, and specific non-transgenic approach for visualizing PGCs of economical marine fish in vivo.

Background: Renal ischemia/reperfusion (IR) can induce acute kidney injury (AKI), which often progresses to chronic kidney disease (CKD). Dexmedetomidine (Dex), a highly selective α2 adrenergic receptor (α2-AR) agonist, protects against acute renal IR-induced injury. However, the effects of Dex on the transition of AKI to CKD remain unclear. Therefore, we investigated the mechanisms of Dex on renal fibrosis., Methods: Adult male C57BL/6 mice were pretreated with Dex, a specific α2A-adrenergic receptor (AR) blocker (BRL-44408), or a cell senescence inhibitor (rapamycin) in a surgical bilateral renal IR model. The diagnoses of AKI and chronic renal fibrosis were performed by histopathological staining and western blotting. Histopathological changes, cell senescence, tubular fibrotic markers, and the expression of inflammatory factors were studied., Results: Pretreatment with Dex alleviated renal IR-induced AKI and chronic tubulointerstitial fibrosis in later stages. Similar to the effects of rapamycin, pretreatment with Dex also decreased the number of senescent tubular cells and weakened the protein expression of senescence-associated markers such as p53, p21, and p16. Furthermore, the expression of inflammatory markers was also decreased in Dex-treated IR mice; and these protective effects of Dex could be abolished by treatment with the specific α2A-AR blocker, BRL-44408., Conclusions: The administration of a single dose of Dex protects against AKI and CKD. Dex inhibits tubular cell senescence and inflammation as well as improves renal fibrosis to moderate the AKI-to-CKD transition. The renal protective potential of Dex may provide a novel treatment strategy for high-risk renal injury patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To compare dexmedetomidine combined with isoflurane versus isoflurane anesthesia on brain injury after cardiac surgery., Design: A prospective, randomized, single-blind study., Setting: University hospital., Participants: Adult patients undergoing elective valve replacement surgery., Interventions: Ninety-seven patients scheduled for valve replacement surgery were randomly divided into 2 groups: dexmedetomidine and isoflurane (Dex-Iso, n = 50) and isoflurane alone (Iso, n = 47). Dexemedetomidine was infused at 0.6 μg/kg as a bolus, followed with 0.2 μg/kg/h until the end of surgery., Measurements and Main Results: Jugular blood samples were drawn for analysis of matrix metalloproteinase-9 (MMP-9) and glial fibrillary acidic protein (GFAP) levels on time points of: T1 (before induction); T2 (5 minutes after cardiopulmonary bypass [CPB] onset); T3 (after CPB off); T4 (the first day after operation); T5 (the second day after operation). Plasma lactate levels in arterial and jugular venous blood also were quantified. The difference between arterial and jugular bulb venous blood lactate levels (AVDL) was calculated. An antisaccadic eye movement (ASEM) test was carried out on the day before the operation and the seventh day postoperatively. In both groups, serum MMP-9 and GFAP concentrations increased after CPB, with the peak values occurring after CPB. At time point T5, MMP-9 and GFAP levels were close to those at T1. MMP-9 concentrations in the Dex-Iso group were lower than the Iso group at T3 and T4. GFAP concentrations in the Dex-Iso group were lower at T3 but were higher than the Iso group at T2. No significant differences were found in AVDL between the 2 groups perioperatively except at T2. The ASEM scores decreased significantly postoperatively. There was no significant difference in the ASEM scores between the 2 treatment groups before and after the operation., Conclusions: The use of dexmedetomidine decreased the biochemical markers of brain injury but did not improve the neuropsychological test result after cardiac surgery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

RNF43 is a novel tumor suppressor protein and known to be expressed in a multitude of tissue and dysregulated in cancers of these organs including ovarian and colorectal tissues. RNF43 expression has been shown to be expressed in mutated forms in several pancreatic cell lines. RNF43, by virtue of being an ubiquitin ligase, has the potential to ubiquitinylate membrane receptors like frizzled that subserves sensing Wnt soluble signals at the cell membrane. Thus, normally, RNF43 downregulates Wnt signaling by removing frizzled receptor from the membrane. In the present study, the expression of the tumor suppressor RNF43 was examined in human patient samples of pancreatic ductal adenocarcinoma (PDAC). Reduced levels of expression of RNF43 in PDAC were demonstrated by Western blotting. We incorporated membrane biotinylation assay to examine the expression of frizzled6 receptor in the membrane and demonstrated that it is significantly increased in PDAC tissues. This may be responsible for enhanced Wnt/beta-catenin signaling and provides the first level of evidence of a possible role of this well-known pathway in pancreatic exocrine carcinogenesis. We have utilized appropriate controls to ensure the true positivity of the findings of the present study. The contribution of Wnt/beta-catenin/RNF43 pathway in pancreatic carcinogenesis may provide for utilization of pharmacologic resources for precision-based approaches to treat pancreatic ductal adenocarcinoma.

The aim of the study is to identify the differentially expressed microRNAs (miRNAs) between hepatocellular carcinoma (HCC) samples and controls and provide new diagnostic potential miRNAs for HCC. The miRNAs expression profile data GSE20077 included 7 HCC samples, 1 HeLa sample and 3 controls. Differentially expressed miRNAs (DE-miRNAs) were identified by t-test and wilcox test. The miRNA with significantly differential expression was chosen for further analysis. Target genes for this miRNA were selected using TargetScan and miRbase database. STRING software was applied to construct the target genes interaction network and topology analysis was carried out to identify the hub gene in the network. And we identified the mechanism for affecting miRNA function. A total of 54 differentially expressed miRNAs were identified, in which there were 13 miRNAs published to be related to HCC. The differentially expressed hsa-miR-106b was chosen for further analysis and PTPRT (Receptor-type tyrosine-protein phosphatase T) was its potential target gene. The target genes interaction network was constructed among 33 genes, in which PTPRT was the hub gene. We got the conclusion that the differentially expressed hsa-miR-106b may play an important role in the development of HCC by regulating the expression of its potential target gene PT-PRT.

Objective: To investigate the quality of life ( QOL) and its influencing factors among men who have sex with men ( MSM) in Chongqing city., Methods: Snowball sampling and internet investigation techniques were applied to recruit MSM and 803 MSM in Chongqing were collected. The WHOQOL-BREF and SSRS questionnaire were used among MSM., Results: Scores of the physiological domain, psychological domain, social relation domain, environmental domain and total score of QOL were (14. 03 +/- 2. 14) (13.38 +/- 2.44), (13.45 +/- 2.88), (12.52 +/- 2.48) and (13.29 +/- 2.05), respectively. Except for the environmental domain, scores of other domains of MSM were lower than that of common residents. The factors of social support and the domains of the quality of life were positive correlation. The multivariate analysis indicated that the main factors involved in influenced the QOL of the MSM were monthly income and scores of total social support. Frequency of condom, objective support, presence of regular homo-sex partners, the number of friends in gay circles, presence of regular sexual partner, the situation of only child,utilization of support, profession, knowing the VCT or not,native place had impacts on a few domains of the QOL., Conclusion: According to different demographic characteristics, and combining HIV health education and psychological intervention is helpful to improve the quality of life among MSM.