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BACKGROUND & AIMS Hepatic ischemia-reperfusion injury (IRI) is a common complication of hepatectomy and liver transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. The regulator of G-protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates G-protein and mitogen-activated protein kinase (MAPK) signaling pathways. However, the role of RGS14 in hepatic IRI remains unclear. APPROACH & RESULTS We found that RGS14 expression increased in mice subjected to hepatic IR surgery and during hypoxia reoxygenation in hepatocytes. We constructed global RGS14 knockout (RGS14-KO) and hepatocyte-specific RGS14 transgenic (RGS14-TG) mice to establish 70% hepatic IRI models. Histological H&E staining, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), expression of inflammatory factors, and apoptosis were used to assess liver damage and function in these models. We found that RGS14 deficiency significantly aggravated IR-induced liver injury and activated hepatic inflammatory responses and apoptosis in vivo and in vitro. Conversely, RGS14 overexpression exerted the opposite effect of the RGS14-deficient models. Phosphorylation of transforming growth factor-β-activated kinase 1(TAK1) and its downstream effectors JNK and p38 increased in the liver tissues of RGS14-KO mice, but was repressed in those of RGS14-TG mice. Furthermore, inhibition of TAK1 phosphorylation rescued the effect of RGS14 deficiency on JNK and p38 activation, thus blocking the inflammatory responses and apoptosis. CONCLUSIONS RGS14 plays a protective role in hepatic IR by inhibiting the activation of the TAK1-JNK/p38 signaling pathway. This may be a potential therapeutic strategy for reducing incidences of hepatic IRI in the future.

AIM: To evaluate the global trends in and explore hotspots of high myopia (HM) research. METHODS: This bibliometric analysis was used to reveal the publication trends in HM research field based on the Web of Science Core Collection (WoSCC). VOSviewer version 1.6.13 software was used to analyze the data and construct a knowledge map including the yearly publication number, journals, countries, international collaborations, authors, research hotspots, and intellectual base in HM. RESULTS: The search engine found 3544 peer-reviewed publications on HM between 2010 and 2019, and the yearly research output substantially elevated over the past decade. China is the top publishing country, and Sun Yat-sen University was the most active academic institution. Jonas JB is the top publishing scientist, and Investigative Ophthalmology and Visual Science (IOVS) was the most productive journal. The highest cited references mainly focused on epidemiology and management. The keywords formed 6 clusters: 1) refractive surgery; 2) etiology and clinical characteristics; 3) the mechanism of eye growth; 4) management for myopic maculopathy; 5) vitrectomy surgical treatment; 6) myopia-associated glaucoma-like optic neuropathy. CONCLUSION: The evaluation of development trends based on the data extracted from WoSCC can provide valuable information and guidance for ophthalmologists and public health researchers to improve management procedures in HM field.

Objective: Cervical cancer (CC) ranks fourth most diagnosed cancer and cancer mortality in women. Long non-coding RNAs (lncRNAs) take important roles in CC development. This study aimed to identify more and novel competing endogenous RNA (ceRNA) mechanisms of lncRNAs in CC. Materials and methods: The miRNA expression dataset GSE20592 and lncRNA/mRNA expression dataset GSE63514 were downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs), differentially expressed lncRNAs (DElncRNAs), and differentially expressed miRNAs (DEmiRNAs) between CC tumor and normal samples were identified with the criteria of adj.P.Value 2. Functional enrichment analysis was performed for DEGs. The interaction pairs among lncRNAs, miRNAs and mRNAs were predicted and the ceRNA network was then constructed. Survival analysis was performed based on the TCGA dataset. Results: Totally, 42 DEmiRNAs, 25 DElncRNAs, and 518 DEGs were identified in CC tumor samples versus normal tissues. The DEGs were associated with ‘GO:0006260: DNA replication’, ‘GO:0051301: cell division’, and ‘hsa01100:Metabolic pathways’. The ceRNA network consisted of 878 lncRNA-miRNA-mRNA pairs. Of the miRNAs, lncRNAs, and genes with the top 10 interaction degrees in the ceRNA network, the upregulated cyclin dependent kinase inhibitor 2A gene (CDKN2A) was targeted by the downregulated DEmiRNAs including hsa-miR-125b-5p and hsa-miR-125a-5p, which were targeted by the upregulated DElncRNA BBOX1-AS1. The high expression level of CDKN2A contributed to the poor overall survival of patients with CC. Conclusions: The BBOX1-AS1-hsa-miR-125b-5p/hsa-miR-125a-5p-CDKN2A ceRNA network is of great value in CC development.

Objective In this study, we aimed to investigate the potential interaction of apatinib and buspirone and underlying mechanism. Methods UPLC-MS/MS assay was applied to determine the concentrations of buspirone and its main metabolites (1-PP and 6-OH buspirone) after incubated with liver microsomes. Moreover, the connection of in vitro and in vivo was further determined. Sprague Dawley rats were randomly divided into two groups: group A (20 mg/kg buspirone) and group B (buspirone vs 40 mg/kg apatinib). Tail vein blood was collected and subjected to the UPLC-MS/MS detection. Key findings Apatinib inhibited the generations of 1-PP and 6-OH buspirone dose-dependently with IC50 of 1.76 and 2.23 μm in RLMs, and 1.51 and 1.48 μm in HLMs, respectively. There was a mixed mechanism underlying such an inhibition effect. In rat, AUC(0–t), AUC(0–∞), Tmax and Cmax of buspirone and 6-OH buspirone increased significantly while co-administering with apatinib, but Vz/F and CLz/F decreased obviously while comparing group A with group B . Conclusions Apatinib suppresses the CYP450 based metabolism of buspirone in a mixed mechanism and boosted the blood exposure of prototype drug and 6-OH buspirone dramatically. Therefore, extra caution should be taken when combining apatinib with buspirone in clinic.

To investigate the sleep quality and mental health status of healthcare professionals during the outbreak of coronavirus disease 2019 (COVID-19) in order to promote timely intervention and treatment. An Questionnaire Star of WeChat online survey was conducted at Hwamei Hospital, University of Chinese Academy of Sciences, NingBo, China. The questionnaire consisted of two parts including sociodemographic characteristics, and the Pittsburgh Sleep Quality Index (PSQI), the Generalized Anxiety Disorder (GAD-7) scale, a depression screening scale (Patient Health Questionnaire-9 [PHQ-9]) so as to investigate the sleep quality and mental health status of healthcare professionals during the outbreak of COVID-19.The data were analyzed with the t-test, χ2 test, one-way analysis of variance (ANOVA) and Pearson correlation, P

Oxidative stress following liver ischemia/reperfusion (I/R) is an important pathological mechanism responsible for liver injury. Veratric acid (VA) is a phenolic benzoic acid that has been reported to have antioxidant properties. However, whether VA has protective effects against liver I/R injury remains unclear. In the present study, a mouse liver I/R injury model was established. VA was administered intragastrically for one week before liver I/R. Biochemical indicators, histological analysis, cell apoptosis, oxidative stress, and pathway proteins were tested to evaluate the protective effects of VA on liver I/R injury. Furthermore, a mouse AML12 hepatocyte hypoxia/reoxygenation (H/R) model was used to explore the underlying mechanism. VA alleviated liver I/R injury, as manifested by decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver necrotic area, oxidative stress, and hepatocyte apoptosis. VA pretreatment increased the expression of Nrf2 and its downstream antioxidant proteins heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO-1). In addition, VA pretreatment increased AML12 cell activity and decreased oxidative stress; it also decreased the apoptosis induced by H/R. Moreover, the protective effect of VA on hepatocytes was related to the activation of the Nrf2 signaling pathway, and to increases in the Nrf2, HO-1, and NQO-1 protein expression. The inhibition of Nrf2 with ML385 offseted VA-mediated protection in AML12 cells. In conclusion, these results suggest that VA protects the liver from oxidative stress and apoptosis induced by liver I/R injury by activating the Nrf2 signaling pathway.

Pulmonary arterial hypertension (PAH) is defined as elevation of mean pulmonary arterial pressure to ≥25 mmHg within the low pressure pulmonary circulatory system. PAH is characterized by obstructive vascular remodeling, partially due to excessive pulmonary arterial smooth muscle cell (PASMC) proliferation. Puerarin is a natural flavonoid isolated from the herb Radix puerariae, which has been widely used for the treatment of cardiovascular and cerebrovascular disorders and diabetes. However, how puerarin mediates autophagy in the progression of pulmonary vascular remodeling is unclear. In this study, we explored the effects of puerarin in a hypoxic pulmonary hypertension (PH) rat model using immunohistochemistry, and morphometric analyses of right ventricle. In addition, cell counting kit 8 assay, western blotting and flow cytometry were employed to test cell proliferation in PASMCs, and then autophagy was tested with mRFP-GFP-LC3 fluorescence microscopy and Western blot. We found that puerarin could alleviate hypoxia-induced PH in rats and improved pulmonary histopathology, and also reduced the expression of autophagy markers in vivo and in vitro. Moreover, puerarin also ameliorated hypoxia-induced PASMC proliferation in an autophagy-dependent manner. Overall, these findings demonstrated that puerarin could prevent hypoxia-induced PH in rats, possibly via reducing autophagy and suppressing cell proliferation. Keywords: Puerarin, Hypoxia, Pulmonary artery hypertension, Autophagy, Proliferation

Aim Regorafenib is a tyrosine kinase inhibitor that is mainly metabolized by CYP3A4. The genetic polymorphism of CYP3A4 would contribute to differences in metabolism of regorafenib. Previously, we had discovered several novel CYP3A4 variants. However, the catalytic characteristics of these 27 CYP3A4 variants on oxidizing regorafenib have not being determined. The purpose of this study was to investigate the catalytic characteristics of 27 CYP3A4 protein variants on the oxidative metabolism of regorafenib in vitro. Method Wild-type CYP3A4.1 or other variants was incubated with 0.5-20 μmol/L regorafenib for 30 minutes. After sample processing, regorafenib-N-oxide, a primary metabolite, was detected by ultra-performance liquid chromatography-tandem mass spectrometry system. Result CYP3A4.20 had no detectable enzyme activity compared with wild-type CYP3A4.1; five variants (CYP3A4.5, .16, .19, .24, .29) exhibited similar clearance value with CYP3A4.1; four variants (CYP3A4.14, .15, .28, .31) displayed increased enzymatic activities, while remaining variants showed markedly decreased intrinsic clearance values. Conclusion This study is the first to investigate the function of 27 CYP3A4 protein variants on the metabolism of regorafenib in vitro, and it may provide some valuable information for further research in clinic.

Hepatocellular carcinoma (HCC), a type of malignant liver tumor, has a grim prognosis. As a functional protein, synaptopodin-2 (SYNPO2) has been associated with malignancy; however, the expression profile and function of SYNPO2 in HCC remains unknown. Herein, we revealed that SYNPO2 was transcriptionally downregulated in HCC tissues from both The Cancer Genome Atlas cohort and our cohort, and was also decreased at the translational level as determined by western blotting and immunohistochemical staining. Furthermore, reduced SYNPO2 expression correlated significantly with short overall survival and recurrence free survival of HCC patients. Restoring SYNPO2 expression inhibited the proliferation and aggressiveness of hepatocarcinoma cells. Mechanistically, increasing the ratio of cytoplasmic SYNPO2 to nuclear SYNPO2 was positively associated with recurrence rate in HCC patients; calcineurin (CaN) activity positively correlated with cytoplasmic SYNPO2 levels in HCC tissues; and nuclear-cytoplasmic translocation of SYNPO2 was induced by CaN to facilitate metastasis of HCC through assembly of peripheral actin bundles. In short, our findings uncover a novel role of SYNPO2 in HCC metastasis via the CaN/SYNPO2/F-actin axis, and indicate that SYNPO2 may serve as a possible prognostic marker and novel therapeutic target.

Numerous studies have illustrated the relationship between SLCO1B1 T521C polymorphism and statin-induced myopathy risk; however, this association is not consistent. Three electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched from inception to October 2017 to identify potential studies. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from different genetic models by using a random-effects model. Fourteen studies comprising 3265 myopathy patients and 7743 controls were included. The summary ORs suggested that 521CC (OR: 2.31; 95% CI: 1.15–4.63; P = 0.019), 521TC (OR: 1.34; 95% CI: 1.02–1.76; P = 0.034), and 521CC + TC (OR: 1.82; 95% CI: 1.32–2.51; P

BACKGROUND: Primary membranous nephropathy (pMN) is the most common cause of nephrotic syndrome in adults. The discovery of the 2 autoantigens, M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A), has defined pMN as an autoimmune disease. A remarkable increase in the frequency of pMN in primary glomerular disease was witnessed in China. The genetic and environmental contributors to disease susceptibility have been investigated in these patients. SUMMARY: We reviewed recent publications in genetic and environmental studies of pMN, focusing mainly on those undertaken in China. Following a genome-wide association study, the gene-gene interaction between the 2 most significant risk factors, PLA2R1 and DQA1, was validated in Chinese patients with MN. Fine mapping on human leukocyte antigen (HLA) locus found that DRB1*1501 and DRB1*0301 were risk alleles. Three amino acid residues on positions 13 and 71 of HLA-DRβ1 chain may confer the susceptibility to pMN by presenting T-cell epitopes on PLA2R. Another study found that DRB3*0202 was the most likely culprit allele for the signal at DRB1*0301. One environmental risk factor for pMN has been identified as the long-term exposure to high levels of PM(2.5) in Chinese patients with MN. Each 10 μg/m(3) increase in PM(2.5) concentration was associated with 14% higher odds for pMN in the regions with PM(2.5) above 70 μg/m(3). KEY MESSAGE: A gene-environment interaction is suspected as an underlying mechanism for the increasing trend of pMN in China.

Aim To investigate the enzymatic properties of cytochrome P450 3A4 (CYP3A4) variants and their ability to metabolize vandetanib (VNT) in vitro, and to study potential drug interactions in combination with VNT. Method Recombinant CYP3A4 cell microsomes were prepared using a Bac-to-Bac baculovirus expression system. Enzymatic reactions were carried out, and the metabolites were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Results The activities of 27 CYP3A4 variants were determined to assess the degree of VNT metabolism that occurred. Analysis indicated that there was enhanced intrinsic clearance (Vmax/Km, CLint) for eight variants (CYP3A4.2, 3, 9, 15, 16, 29, 32, and 33), while there was a significant decrease in CYP3A4.5, 7, 8, 10–14, 17–20, 23, 24, 28, 31, and 34. Compared with CYP3A4.1, no significant differences were found for CYP3A4.6 and 30. Furthermore, the relative clearances were compared between VNT and cabozantinib, which were all metabolized by CYP3A4 with the same indications. When combined with ketoconazole, which is a CYP inhibitor, obvious differences were observed in the potency of VNT between different variants, including CYP3A4.2, 15, and 18. Conclusion This comprehensive assessment of CYP3A4 variants provides significant insights into the allele-specific metabolism of VNT and drug interactions in vitro. We hope that these comprehensive data will provide references and predictions for the clinical application of VNT.

Objective The aim of our study was to evaluate and compare the differences in the clinicopathological variables and overall survival (OS) of synchronous primary cancers of the endometrium and ovary (SCEO) and endometrial cancer with ovarian metastasis (ECOM). In addition, we aimed to determine the characteristics of and effective treatments for patients with SCEO to avoid misdiagnosis and overtreatment. Materials and methods A review of medical records from January 2009 to January 2017 revealed 111 patients with coexisting ovarian and endometrial carcinoma diagnosed at the Obstetrics and Gynecology Hospital of Fudan University. Clinicopathological variables were analysed using the Chi square test and Student’s t test. The survival rate was estimated using the Kaplan-Meier method, and statistical significance was analysed using the logarithmic rank test (univariate analysis). Results There were 51 cases of SCEO and 60 cases of ECOM. The mean age at diagnosis was 53.96 years and 55.41 years, respectively. There were no differences in age, menopausal status, BMI, CA125 level or complaints between the two groups. The 5-year survival rates were 58.8 and 36.7%, respectively (P

An integrated microfluidic chip with arrayed micro channels consisted of eight repeat arrayed 6×6 cell culture chamber was designed and fabricated. The analytical microsystem combined with designed microchip, measuring device and environmental control unit was established for the cell culture and parallel cellular antioxidant activity (CAA) analysis of plant antioxidants. The microfluidic chip included a PDMS cover and a glass substrate which consisted of two hundreds and eighty-eight round cell culture micro chambers and forty-eight independent parallel array channels. Eight groups of different samples with six different concentrations could be investigated simultaneously with multimode reader in one test. HepG2 cells were successfully cultured on the microchip. Moreover, the viability percentage of the HepG2 cells exposed to these plant antioxidants solutions at different concentrations for 24 h was higher than 90%. With 2′,7′-Dichlorofluorescin diacetate (DCFH-DA) as a fluorescence probe, 2,2′-azobis(2-amidinopropane) dihydrochloride (ABAP) as the initiator of intracellular reactive oxygen species (ROS), we tested the inhibitory effect of several plant antioxidants such as quercetin, rutin and kaempferol on free radicals. The CAA units were calculated by the data measured from cellular morphology and fluorescence intensity over time. It was shown that the CAA units of quercetin, rutin and kaempferol were (71.42 ± 0.19) μM, (74.31 ± 0.36) μM and (69.92 ± 0.09) μM ( x ± s, n = 3), while the calculated IC 50 were (7.20 ± 0.06) μM, (52.06 ± 0.14) μM and 32.55±0.03 μM ( x ± s, n = 3), respectively.

OBJECTIVE The aim of this study was to determine the impact of the SLCO1B1, apolipoprotein E (ApoE), and CYP2C9 genotypes on the lipid-lowering efficacy of fluvastatin. METHODS We performed electronic searches on the PubMed, Embase, and Cochrane Library databases to identify studies published through October 2017. Studies that reported the effect estimates with 95% confidence intervals (CIs) of total cholesterol (TC), triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein were included so that the different genotype categories could be compared. Weighted mean difference (WMD) was used to summarize the effect estimates. RESULTS Six studies, involving a total of 1171 individuals, were included in the final analysis. We noted that the patient carrier SLCO1B1 521TT was associated with greater change in TC (WMD: -2.98; 95% CI: -5.12 to -0.84; P=0.006) and LDL (WMD: -5.58; 95% CI: -10.64 to -0.52; P=0.031) compared with 521TC or CC. Furthermore, the patient carrier ApoE*2/*3 showed more change in high-density lipoprotein compared with ApoE*3/*3 (WMD: 18.76; 95% CI: 8.97-28.55; P

Background The clinical outcome varies considerably in primary membranous nephropathy (pMN). Risk factors for kidney prognosis include ageing, male gender, persistent heavy proteinuria, decreased eGFR at presentation, persistent elevation of anti-PLA2R antibodies, no remission, and so on. It was controversial whether the histopathological features of pMN could predict treatment response and kidney outcome. Methods A retrospective study was conducted in 371 patients with biopsy-proven pMN. Pathological parameters included immunofluorescence staining, membranous Churg’s stages, sclerosis, crescent, focal segmental sclerosis lesion, chronic and acute tubulointerstitial injury. The fluorescence intensity was determined: 0, negative; 1, weak; 2, moderate; 3, strong; 4, glaring. Chronic tubulointerstitial injury was graded by the involved area: 0, 0–5%; 1, 6–25%; 2, 26–50%; 3, > 50%. Results We found that patients with higher intensity of C3 staining, advanced membranous stage, and more severe chronic tubulointerstitial injury presented with higher positivity rate of anti-PLA2R antibodies, higher levels of urinary protein excretion and serum creatinine, and lower level of serum albumin. Univariate Cox regression analysis showed that severe (grade = 3) chronic tubulointerstitial injury was a risk factor to the kidney outcome of ESKD (HR = 61.02, 95%CI, 7.75–480.57, P 0.05). Conclusions We found the prognostic role of chronic tubulointerstitial injury to the kidney outcome of pMN. This study highlighted the value of kidney biopsy under the widespread usage of anti-PLA2R antibodies for diagnosis and prognosis. Electronic supplementary material The online version of this article (10.1186/s12882-018-1011-5) contains supplementary material, which is available to authorized users.

Background Human leukocyte antigen (HLA) alleles are implicated in drug-induced hypersensitivity, including by nevirapine and abacavir. The purpose of this meta-analysis was to evaluate the relationship between HLA polymorphisms and hypersensitivity to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients. Methods We conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for studies that evaluated the associations of HLA polymorphisms with antiretroviral therapy-induced hypersensitivity published in April 2019. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were considered as estimates of the effect. Results The meta-analysis included 17 studies that assessed a total of 4273 patients. First, carriers of HLA-A *24 were associated with an increased risk of hypersensitivity among patients with HIV who received antiretroviral therapy (OR: 12.12; P = 0.018). Second, five SNPs of HLA-B genotypes, including *18 (OR: 1.63; P = 0.028), *35 (OR: 2.31; P = 0.002), *39 (OR: 11.85; P = 0.040), *51 (OR: 1.66; P = 0.028), and *81 (OR: 8.11; P = 0.021), were associated with an increased risk of hypersensitivity. Conversely, carriers of HLA-B *15 were associated with a reduced risk of hypersensitivity (OR: 0.43; P

Drug-drug interactions (DDIs) are thought to be associated with the inhibition of cytochrome P450 activities. The cocktail method with analysis of the metabolism of two or more probe drugs is used to determine CYP450 activities. In this study, we established a UHPLC-MS/MS method for simultaneous quantitation of four CYP450 probe drugs (phenacetin, omeprazole, metoprolol and midazolam) and their metabolites (acetaminophen, 5′-hydroxy omeprazole, α-hydroxy metoprolol and 1′-hydroxy midazolam) in rat plasma. Sample preparation by plasma protein precipitation was combined with a liquid-liquid extraction method. The separation was carried out on a ZORBAX Eclipse Plus C18 Rapid Resolution High Definition column with a gradient elution, using water containing 0.1% formic acid (A) and acetonitrile (B) in a run time of only 3.0 min. Detection was conducted with a 6420 series triple-quadrupole tandem mass spectrometer, using ESI in positive ion mode with multiple reaction monitoring (MRM). The calibration curves were linear over the concentration range 10–5000 ng/mL for phenacetin, omeprazole, metoprolol and midazolam, and 1–500 ng/mL for their metabolites. Intra- and inter-day precisions were within 15%, and the accuracies were in the range of 87–112%. The method was successfully applied to the pharmacokinetic study of probe drugs/metabolites and DDIs with 3-n-butylphthalide (NBP) after administration of a single oral dose of phenacetin, omeprazole, metoprolol and midazolam in rats.

The present study aimed to investigate the effect of clopidogrel (CLO) on pharmacokinetics of ivabradine (IVA) and its metabolite in rats and develop a reliable method to determine IVA and its metabolite N-demethyl ivabradine in serum. Healthy male SD rats were randomized to be given 0.8 mg/kg IVA or IVA combined with 8 mg/kg CLO. Blood samples were collected at 0.083, 0.16, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after administration. The serum concentrations of IVA and N-demethyl ivabradine were determined by ultra-performance liquid chromatography-mass spectrometry and pharmacokinetic parameters were calculated using DASver3.0 software. The parameters of AUC(0 - t), AUC(0 - ∞), and Cmax for IVA in the group of IVA + CLO were significantly higher than those in the group of IVA (p 0.01); the half-time (t1/2) in the IVA + CLO group was extended compared to IVA (p 0.01) and CL/F was dropped obviously (p 0.01). The decreases in AUC(0 - t), AUC(0 - ∞), and Cmax for N-demethyl ivabradine in the group of IVA + CLO was significantly compared to the group of IVA (p 0.01). CL/F was higher than IVA (p 0.01) and the t1/2 was slightly increased. In this study, we find that CLO restrains the metabolism of IVA into N-demethyl ivabradine, which may be related to its competitive inhibition effect on cytochrome P450 isoform 3A4(CYP3A4).

The epidemic of loperamide abuse and misuse in the patients for the alternative to opioids has become an increasing worldwide concern and has led to considerations about the potential for drug-drug interactions between loperamide and other combined drugs, especially inhibitors of cytochrome P450 (CYP450) enzymes, such as axitinib. This study assessed the effects of axitinib on the metabolism of loperamide and its main metabolite N-demethylated loperamide in rats and in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4*1. The concentrations of both compounds were determined by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). The exposures (AUC(0-t), AUC(0-∞) and Cmax) of loperamide and N-demethylated loperamide showed a conspicuous increase when loperamide was co-administered with axitinib. The Tmax of loperamide increased while CLz/F decreased under the influence of axitinib. In vitro, axitinib inhibited loperamide metabolism with the IC50 of 18.34 μM for RLM, 1.705 μM for HLM and 1.604 μM for CYP3A4*1, and it was confirmed as a non-competitive inhibitor in all enzymes. Taken together, the results indicated that axitinib had an obvious inhibitory impact on loperamide metabolism both in vivo and in vitro. Thus, more attention should be paid to the concurrent use of loperamide and axitinib to reduce the risk of unexpected clinical outcomes.

Islet transplantation offers hope for patients with type 1 diabetes, which is an autoimmune disease. However, islet transplant recipients must overcome two obstacles in both allograft rejection and autoimmune reaction. Alpha-1-antitrypsin (a1-proteinase inhibitor, AAT) possesses anti-inflammatory properties, reduces cytokine-mediated islet damage, and induces specific immune tolerance. In this study, an insulinoma cell line, NIT-1, was transfected with human AAT (hAAT), named NIT-hAAT, and was transplanted to the left renal subcapsular spaces of 7-week-old female non-obese diabetic (NOD) mice (n=22). Cyclophosphamide(CY) was administered to synchronize and accelerate the development of diabetes. Thus, the immunosuppressive and cytoprotective activity of hAAT in β-cell transplantation was investigated. NIT-hAAT has immunomodulatory properties, which delay the onset of autoimmune diabetes, reduce diabetes incidence, inhibit insulitis and β-cell apoptosis, and dampen transplant site inflammation. We propose that NIT-hAAT has a dual function by improving islet autoimmunity and protecting transplanted β-cells from allograft rejection. However, the low expression of hAAT in vivo results in the inability of NIT-hAAT to induce long-term specific immune tolerance and to completely block allograft rejection.

To study the effect of biological activity of Tumstatin 7 peptide on the cell proliferation and apoptosis of B16 melanoma. Tumstatin 7 peptide was synthesized and its purity is 98.4532% by high-performance liquid chromatography. The effect of 7 peptide on B16 melanoma was observed by MTT, cell growth curve, the observation of the transmission electron microscope (TEM). 7 peptide can significantly inhibit B16 melanoma cell proliferation, showing dose- and time-dependent .Its IC50 was 72.53 μg/ml.The morphology of B16 melanoma cell was obviously changed by TEM, such as karyopyknosis and apoptotic bodies. So7 peptides can inhibit the proliferation of melanoma cells and promote melanoma cells apoptosis. It will be of great potential value to melanoma treatment.

7 peptide of Tumstatin(T-7 peptide) is composed of 185-191 amino acids. To study T-7 peptide antitumor activity to human non-small-cell carcinoma(A549), T-7 peptide was designed and synthesized by amino acid synthesizer. Its purity ran up to 98.45% by HPLC and MS. The effect of T-7 peptide on A549 cell growth was observed by MTT assay, growth curve and transmission electron microscopy(TEM). T-7 peptide had the effects of suppressing A549 cell growth and promoting its apoptosis, showing dose- and time-dependent. Its IC50 was 92.84 μg/ml. TEM also revealed that A549 cell treated with T-7 peptide appeared apoptotic morphology,such as cell pyknosis and mitochondrial vacuoles formed. While T-7 peptide had little effect on human umbilical vein endothelial cells(ECV304). These researches were significant to treat human non-small-cell carcinoma in the future.

The direct anti-tumor T-7 peptide of tumstatin was obtained to study its effect on human hepatoma cells (HepG-2) and human umbilical vein endothelial cells (ECV304). T-7 peptide was synthesized and its purity was up to 98.5%. MTT assay, growth curve, transmission electron microscopy(TEM) were used to detect the proliferation inhibition and pro-apoptotic function. MTT experiments and growth curve experiments showed that the survival of human hepatoma cells (HepG-2) decreased in a time- and dose-dependent way with the concentration of T-7 peptide increased. T-7 peptide can induce apoptosis of HepG-2 significantly. Apoptosis features were observed by TEM. However, the inhibition of T-7 peptide on human umbilical vein endothelial cells (ECV304) was weaker. Experiments showed thatT-7 peptide can affect HepG-2 cells. It had a certain therapeutic effect on human hepatocellular carcinoma. T-7 peptide have little effect on ECV304 cells, which means it didn’t influence the formation of tumor angiogenesis and normal cells

As an endogenous anti-damage material in organism, Taurine (Tau) stems from food and almost resides in all animals’ cells by means of liberation，which could be found in diverse biological actions, including protection against ischemia-reperfusion injury, modulation of intracellular calcium concentration, and antioxidant, and blood pressure-lowering effects[1]. It also has an effect that inducing apoptosis in certain kinds of cells. Our results showed that Tau can degrade cell viability, mitochondrial potentials, and the expression of Procasepase-9 in PASMCs. In conclusion, Tau induces apoptosis in PASMCs through mitochondrial-dependent pathway.

Objective To investigate the mechanism of electroacupuncturein treating chronic fatigue syndrome(CFS) in term of the neuro-endocrine system by observing the regulative effect of EA on hypothalamic-pituitary-adrenal index (HPA index) and corticotropin releasing hormone mRNA (CRH mRNA) in CFS model rats.

Ovarian cancer remains the disease with the highest associated mortality rate of gynecologic malignancy due to cancer metastasis. Rearrangement of actin cytoskeleton by cytoskeleton protein plays a critical role in tumor cell metastasis. MICAL-L2, a member of MICAL family, can interact with actin-binding proteins, regulate actin cross-linking and coordinate the assembly of adherens junctions and tight junctions. However, the roles of MICAL-L2 in tumors and diseases have not been explored. In this study, we found that MICAL-L2 protein is significantly up-regulated in ovarian cancer tissues along with FIGO stage and associated with histologic subgroups of ovarian cancer. Silencing of MICAL-L2 suppressed ovarian cancer cell proliferation, migration and invasion ability. Moreover, silencing of MICAL-L2 prevented nuclear translocation of β-catenin, inhibited canonical wnt/β-catenin signaling and induced the mesenchymal-epithelial transition (MET). Taken together, our data indicated that MICAL-L2 may be an important regulator of epithelial-mesenchymal transition (EMT) in ovarian cancer cells and a new therapeutic target for interventions against ovarian cancer invasion and metastasis.

Objectives To investigate the current situation and analyze the associated factors of withdrawing or withholding life support in the intensive care unit (ICU) of our cancer center. Methods Three hundred and twenty-two cancer patients in critical status were admitted to our ICU in 2010 and 2011. They were included in the study and were classified into two groups: withdrawing or withholding life support (WWLS), and full life support (FLS). Demographic information and clinical data were collected and compared between the two groups. Factors associated with withdrawing or withholding life support were analyzed with univariate and multivariate logistic regression analysis. Results Eighty-two of the 322 cases (25.5% of all) made the decisions to withdraw or withhold life support. Emergency or critical condition at hospital admission, higher scores of Acute Physiology and Chronic Health Evaluation II (APACHE II) in 12 hours after ICU admission, financial difficulties and humanistic care requirements are important factors associated with withdrawing or withholding life support. Conclusions Withdrawing or withholding life support is not uncommon in critically ill cancer patients in China. Characteristics and associated factors of the decision-making are related to the current medical system, medical resources and traditional culture of the country.

Objective: To assess the effects of perioperative comprehensive supportive care interventions on outcome of Chinese esophageal cancer patients in a prospective study. Methods: 60 patients with primary esophageal carcinoma were randomized into an intervention group (IG, n=31) and a control group (CG, n=29). The Chinese version of symptom checklist-90 (SCL-90) was adopted to assess their psychological status. The interventions, including health education, psychological support, stress management, coping strategies and behavior training, were carried out in 3 phases (preoperative, postoperative Ⅰ and postoperative Ⅱ), and psychological effects were thereafter evaluated accordingly before surgery, and 1 week, 4 weeks and 24 weeks post-surgery. Medical costs were estimated at discharge. Survival of patients was estimated each year post-surgery. General health status and satisfaction-with-hospital were surveyed by a follow-up questionnaire 4 years post-surgery. Results: All the subjects demonstrated higher scores in the preoperative phase than the normal range of Chinese population concerning 7 psychological domains including somatization, obsessive-compulsive, depression, anxiety, hostility, phobic anxiety and paranoid ideation. Although no significant difference was observed between the two groups at admission, the scores of IG, which tended to decrease at a faster rate, were generally lower than those of CG at weeks 1, 4 and 24 post-surgery. The length of hospital stay and medical costs of IG were significantly less than those of CG and satisfaction-with-hospital was better. However, there was no significant difference in 4-year survival or health status between two groups. Conclusions: Appropriate perioperative comprehensive supportive care interventions help to improve the psychological state of Chinese patients with esophageal carcinoma, to reduce health care costs and to promote satisfaction of patients and their families with hospital.

OBJECTIVE To study the effect of taurine on apoptosis in PASMCs, and whether the death-receptor pathway act in the mechanism. METHOD Culture the PASMCs, and divided the cells into control, SD. Acridine orange(AO) assay and western-blot analysis on the expression of Bax, Bcl-2, Procaspase-3 and Fas were used to study the mechanism. RESULT A major finding of this study is that the Tau effects many apoptosis index, such as increasing the expression of Bax and Fas, decreasing the expression of Procaspase-3, and Bcl-2, accrescencing the mitochondrial depolarization, causing the nuclear shrinkage, all these datas demonstrated that Tau induced the apoptosis in pulmonary artery smooth muscle cells through mitochondrial-dependent pathway. CONCLUSION Tau induces the apoptosis in pulmonary artery smooth muscle cells through death-receptor.

Background: Recently, a simplified modified Rankin Scale (mRS) questionnaire (smRSq) showed good reliability but has not been tested for its validity by its original creators. Our study aimed to test its reliability and validity in Chinese stroke patients. Methods: Randomly chosen paired raters scored the smRSq, the conventional mRS, and the NIH Stroke Scale (NIHSS) face-to-face in 150 hospitalized stroke patients. Inter-rater reliability and concurrent validity were assessed for this translated questionnaire. Results: For inter-rater reliability of the smRSq, the overall agreement among the raters was 84%, the ĸ was 0.79 (95% CI 0.72–0.87), and the ĸw was 0.91 (95% CI 0.88–0.94). For inter-rater reliability of the mRS, the overall agreement among the raters was 81%, the ĸ was 0.75 (95% CI 0.67–0.83), and the ĸw was 0.88 (95% CI 0.84–0.92). The agreement between the mRS and smRSq was 71%, ĸ = 0.63 (95% CI 0.54–0.71), and ĸw = 0.83 (95% CI 0.79–0.88). The correlation between the NIHSS and the smRSq (concurrent validity) was moderate (Spearman’s correlation coefficient 0.70, p < 0.0001). Conclusions: Our results confirm the value of the smRSq in the assessment of stroke functional outcome in China. As this is a novel stroke tool, further validations are needed.

Aim: To investigate the potential effects of Taurine on calcium ion concentration and ATPase on cell membrane of diastole heart failure rat model. Method: Mouse models of diastole heart failure were made by the imcomplete ligation of abdominal aorta. Forty Wistar heart failure rats were divided randomly into four groups, with 10 for each group (n=10). Heart failure rats were treated according to different doses drugs as follows: Model (physiological saline 2ml), Taurine (400 mg/kg·d), Taurine (200mg/kg·d), Taurine (100 mg/kg·d) ig, for each of the four groups respectively,4 weeks after coarctation of ascending aorta operation, and 10 age matched sham operation group was taken as control (physiological saline, 2mL). After administration four weeks, Isolating single cardio myocytes by enzymatic isolation method of rat which were loaded with calcium ion sensitive fluorescent indicator Fluo-3/AM. Calcium ion concentration represented by fluorescent intensity(FI) was measured by laser scanning cofocal microscope(LSCM); ATPase activity of cell membrane was measured by ATPase kit by the method of enzymatic reaction chromatometry. Result: Compared with the normal group, the model group of rat myocardial cells calcium ion concentration markedly increased and the ATPase activity of myocardial membrane decreased significantly. (Abstract)

Human epididymis protein 4 (HE4), represented as an epididymis-specific gene and designated a WAP four-disulfide core domain protein 2 (WFDC2), is amplified in many tumors. However, little is known about its clinical significance and biological function in gastric carcinomas. We found that HE4 was more commonly observed in gastric carcinoma tissues than in normal tissues and was significantly correlated with Lauren classification, TNM stage, and tumor size by immunohistochemistry. The overall survival rate of patients with HE4 low expression was significantly higher than that of the patients with HE4 high expression. In addition, silencing of HE4 expression inhibits cell proliferation and migration and enhances cell apoptosis. Subsequent studies reveal that the Src, Akt, and Erk1/2 signaling may be involved with pro-survival and anti-apoptotic effects of the HE4 on gastric cancer cells. Taken together, this study provides new evidence on promotive effects of the HE4 on gastric cancer progression and indicates that HE4 might be a promising prognostic factor for gastric cancer diagnosis.