Renin–angiotensin system inhibition is associated with reduced risk of left atrial appendage thrombosis formation in patients with atrial fibrillation

Background: Inhibition of the renin–angiotensin axis can reduce the likelihood of atrial fibrillation (AF). However, the effects of angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on thrombogenicity in AF remain incompletely elucidated. Thisretrospective case-control study was conducted to evaluate whether the use of ACEI or ARB could reduce the incidence of left atrial appendage thrombus (LAAT) and spontaneous echocardiographic contrast (SEC) in patients with AF. Methods: A total of 199 AF patients who received both transesophageal echocardiogram (TEE) and transthoracic echocardiogram (TTE) successively on the same day from 2012 to 2016 were enrolled. Left atrial dimension, maximal left atrial volume (LAVmax), left ventricular end-diastolic dimension, left ventricular ejection fraction, and the ratio of the early transmitral flow velocity and the early mitral annular velocity (E/e’) were determined. Longitudinal LA strain was evaluated using two-dimensional speckle tracking imaging at each LA segment. Peak systolic strain was calculated by averaging total segments. LAAT, LAA emptying flow velocity (LAAeV) and SEC were evaluated by TEE. Risk factors for LAAT and usage of ACEIs or ARBs were recorded. Results: The incidence of LAAT was 27.6%. Among the patients with renin–angiotensin system (RAS) inhibitors, 20.5% were demonstrated to have LAAT, compared with 33.3% in the nonuser group (p = 0.044). LA peak systolic strain and LAAeV were significantly increased in patients with RAS inhibitors compared to the nonuser group (p = 0.002, p = 0.047, respectively). Patients with LAAT had higher CHA2DS2-VASc scores and evident SEC comparedwith those without LAAT (p = 0.000, p = 0.000, respectively). Usage of ACEIs/ARBs and antiplatelet drugs were frequent in patients with LAAT than in those without LAAT (p = 0.044, p = 0.000, respectively). Even after controlling for LAAT-related risk factors (age, body mass index, AF type, hypertension, diabetes mellitus, prior stroke or transient ischemic attack, drinking history and usage of antiplatelet drugs and LAVmax), use of RAS inhibitors remained significantly associated with a lower risk of LAAT (OR = 0.222; 95% CI 0.084–0.585, p = 0.002). Conclusions: This study shows that RAS inhibitors may be effective in reducing the risk of LAAT in patients with AF through atrial reverse remodeling

Proteasome Inhibition Augments Cigarette Smoke-Induced GM-CSF Expression in Trophoblast Cells via the Epidermal Growth Factor Receptor

Maternal cigarette smoking has adverse effects on pregnancy outcomes. The granulocyte-macrophage colony-stimulating factor (GM-CSF) is an essential cytokine for a normal pregnancy. We investigated the impact of cigarette smoke extract (CSE) on GM-CSF expression in human cytotrophoblast cells and suggested a cellular mechanism underlying the CSE-induced GM-CSF expression. An immortalized normal human trophoblast cell line (B6Tert-1) was treated with CSE. The viability and proliferation of the CSE-treated B6Tert-1 cells were evaluated, and the expression of GM-CSF in these cells was quantified at the mRNA and the protein levels by means of reverse-transcription and quantitative polymerase chain reaction (RT-qPCR); and enzyme-linked immunosorbent assay (ELISA), respectively. Human trophoblast cells treated with CSE had an increased expression of GM-CSF at both the mRNA and the protein levels. The CSE-induced GM-CSF expression was synergistically enhanced by the addition of the proteasome inhibitor MG-132, but inhibited by AG-1478, an inhibitor of the epidermal growth factor receptor (EGFR) kinase. Furthermore, CSE treatment increased the phosphorylation of the extracellular-signal regulated kinases (ERK1/2) in the trophoblast cells. The expression of other growth factors such as heparin-binding epidermal growth factor-like growth factor (HB-EGF) and vascular endothelial growth factor (VEGF) was also evaluated. Our data suggested that cigarette smoking and proteasome inhibition synergistically up-regulate GM-CSF cytokine expression by activating the EGFR signaling pathway

Expressions of B7-H4 and B7-H3 Proteins and Effect of Sorafenib on their Expressions in Different Human Hepatoma Cell Lines

Purpose: To study whether B7-H3 and B7-H4 proteins can be candidate drug targets for preventing and treating hepatoma.Methods: Western blot assay was used to study the expressions of B7-H3 and B7-H4 proteins and the effect of sorafenib on their expressions in different human hepatoma cell lines (HepG2, Hep3B, BEL- 7402, BEL-7404, BEL-7405, QGY-7701, QGY-7703, SMMC-7721, MHCC97H, MHCC97L, HCCLM3 and HCCLM6). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to study the cytotoxicity of sorafenib against different human hepatoma cell lines.Results: The expressions of B7-H3 (0.26 - 0.84 μM) and B7-H4 (0.18 - 0.78 μM) proteins in different human hepatoma cell lines were significantly (p < 0.01) up-regulated, compared with that of the normal human liver cell line (HL-7702) (0.09 and 0.08 μM). Sorafenib was cytotoxic on Hep3B, BEL-7404, MHCC97H, HCCLM3 and HCCLM6 cells with half-maximal inhibitory concentration (IC50) of 14.56, 9.14, 9.46, 17.21 and 9.29 μM, respectively. After treatment with sorafenib at concentrations of 5, 10 and 20 μM, the expressions of B7-H3 protein in MHCC97H, HCCLM3 and HCCLM6 cells and the expressions of B7-H4 protein in Hep3B, BEL-7404 and MHCC97H cells were significantly (p < 0.01) down-regulated, compared with that of the control.Conclusion: Over-expression of B7-H3 and B7-H4 proteins is common in different human hepatoma cell lines and thus, B7-H3 and B7-H4 proteins may be regarded as candidate drug targets for preventing and treating hepatoma.Keywords: Hepatoma, B7-H3, B7-H4, Sorafenib, Over-expression, Cytotoxic activity, Down-regulatio

Effects of florfenicol exposure during early life on toxicity, gut microbiota, and fecal metabolome in SD rats

Florfenicol (FLO) is a third-generation veterinary antibiotic with a high residue detection rate in food, which cause the toxicity of FLO even at low doses, receiving notable attention. The impact of FLO exposure during early life on health and gut microbiota is still unclear. Here, the effects of FLO exposure on toxicity, gut microbiota, drug resistance genes, and the fecal metabolome during early life were investigated in suckling Sprague-Dawley (SD) rats. The results showed that FLO exposure during early life significantly increased the body weight, and WBC and LY levels in the blood, induced inflammation in the liver and intestines. FLO had a dose-dependent effect on the alpha and beta diversity of the gut microbiota, increasing the ratio of Firmicutes to Bacteroides and the abundance of some pathogenic bacteria, and changing the abundance of bacteria related to energy metabolism and inflammation, also promoted the enrichment of drug resistance genes. The fecal metabolome also demonstrated the effect of FLO exposure on metabolic pathways related to energy metabolism and inflammation. In conclusion, this research shows that FLO exposure during early life can lead to excessive weight gain, an inflammatory response, gut microbiota imbalance, the enrichment of drug resistance genes, and effects on related metabolic pathways

Prostasin induces protease-dependent and independent molecular changes in the human prostate carcinoma cell line PC-3

Expression of prostasin in the PC-3 human prostate carcinoma cells inhibited in vitro invasion, but the molecular mechanisms are unknown. Wild-type human prostasin or a serine active-site mutant prostasin was expressed in the PC-3 cells. Molecular changes were measured at the mRNA and the protein levels. Cell signaling changes were evaluated by measuring phosphorylation of the extracellular signal-regulated kinases (Erk 1/2) following epidermal growth factor (EGF) treatment of the cells. Protein expression of the EGF receptor (EGFR) was differentially downregulated by the wild-type and the active-site mutant prostasin. The mRNA expression of EGFR and the transcription repressor SLUG was reduced in cells expressing wild-type prostasin but not the active-site mutant. Phosphorylation of Erk1/2 in response to EGF was greatly reduced by the wild-type prostasin but not by the active-site mutant. The mRNA expression of the urokinase-type plasminogen activator (uPA), the uPA receptor (uPAR), cyclooxygenase-2 (COX-2), and the inducible nitric oxide synthase (iNOS) was decreased by the wild-type and the active-site mutant prostasin. The mRNA or protein expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), matriptase, and E-cadherin was greatly increased by the active-site mutant prostasin. In conclusion, prostasin expression elicits both protease-dependent and independent molecular changes in the PC-3 cells. (C) 2007 Elsevier B.V. All rights reserved

Increased Risk for Entamoeba histolytica Infection and Invasive Amebiasis in HIV Seropositive Men Who Have Sex with Men in Taiwan

Entamoeba histolytica, morphologically identical to but genetically different from E. dispar and E. moshkovskii, is the causative agent of amebiasis. Recently there have been reports of increased risk for amebiasis among men who have sex with men (MSM) due to oral-anal sexual contact in several developed countries. In this longitudinal follow-up study, the incidence of amebiasis was determined among HIV-infected patients using serological and specific amebic antigen assays. DNA extracted from stool samples containing E. histolytica were analyzed by PCR, sequenced, and compared. Clinical manifestations and treatment response of invasive amebiasis in HIV-infected patients were reviewed. The results demonstrated that HIV-infected MSM were at significantly higher risk of amebiasis than patients from other risk groups. Clustering of E. histolytica isolates by sequencing analyses from geographically unrelated patients suggested person-to-person transmission. Despite immunosuppression, amebic liver abscesses and colitis responded favorably to metronidazole therapy. It is important to investigate in areas of high incidence of both amebiasis and HIV (sub-Saharan Africa) how generalizable these findings are