Bone morphogenetic protein-2 and -4 (BMP-2 and -4) mediates fraxetin-induced maturation and differentiation in human osteoblast-like cell lines

Fraxetin (7,8-dihydroxy-6-methoxy coumarin), a coumarin derivative, was investigated for its effects on differentiation of osteoblasts. By means of alkaline phosphatase (ALP) activity and osteocalcin ELISA assay, we have shown that fraxetin exhibits a significant induction of differentiation in two human osteoblast-like cell lines, MG-63 and hFOB. Alkaline phosphatase and osteocalcin are phenotypic markers for early-stage differentiated osteoblasts and terminally differentiated osteoblasts, respectively. Our results indicated that fraxetin stimulated osteoblast differentiation at various stages (from osteoprogenitors to terminally differentiated osteoblasts). Induction of differentiation by fraxetin was associated with increased bone morphogenetic protein-2 (BMP-2) and BMP-4 productions. Addition of purified BMP-2 and BMP-4 proteins did not increase the upregulation of ALP activity and osteocalcin secretion by fraxetin, whereas the BMPs antagonist noggin blocked both fraxetin and BMP-2 and BMP-4 mediated ALP activity and osteocalcin secretion enhancement, indicating that BMP-2 and BMP-4 productions are required in fraxetin-mediated osteoblast maturation and differentiation. These findings are novel and may be important in the treatment and prevention of osteoporosis.     

Impact of Renal Artery Stent-Graft Placement on Renal Function in Chronic Aortic Dissection

PurposeTo evaluate the effect of renal stent-graft placement on kidney function and size alternation in chronic aortic dissection.Materials and MethodsTwenty-five consecutive patients with chronic aortic dissection after thoracic endovascular aortic repair who underwent renal stent-graft placement between January 2015 and December 2016 were retrospectively reviewed. Forty-three patients with chronic aortic dissection who received thoracic endovascular aortic repair in the same period were reviewed as a control group for kidney volume comparison.ResultsTwenty-five stent-grafts were deployed over 25 renal arteries. Overall renal function was assessed by the slope of the regression line constructed from the plots of creatinine clearance versus time within 2 years after the procedure (–0.2810 vs –0.3146 mL/min^–1/mo^–1, P = .868), kidney volume at 12 months (129.4 ± 40.9 vs 137.0 ± 44.2 cm², P = .193) and effective renal plasma flow at 6 months (106.3 ± 46.9 vs 124.4 ± 55.5 mL/min, P = .050) and was not significantly deteriorated. Seven treated patients (87.5%) with a renal artery supplied by a false lumen had a decrease in kidney volume, as did 14 patients (56%) in the control group (P = .206). Three patients with a dissected renal artery (75%) in the stent-graft group had an increase in kidney volume compared with 1 patient (11.1%) in the control group (P = .052).ConclusionsOcclusion of the re-entry tear by a stent-graft in the renal artery remains a safe strategy to promote false lumen thrombosis. The stent-graft poses a potential risk of reducing the kidney volume in kidneys supplied by the false lumen but may provide a positive effect in kidney volume with a concomitant dissected renal artery in chronic aortic dissection.     

Bloodstream infections in hospitalized adults with dengue fever: Clinical characteristics and recommended empirical therapy

Background

Dengue is an important mosquito-borne tropical viral disease and dual infection, though rare, has been regarded as a risk factor for severe disease and mortality. However, few studies focused on bloodstream infections (BSIs) and empirical antibiotic therapy rarely addressed.

Prosthetic valve endocarditis caused by Streptobacillus moniliformis: a case of rat bite fever

We report a case of rat bite fever caused by Streptobacillus moniliformis in Taiwan. It manifested as prosthetic valve endocarditis, which was cured by cardiac valve replacement and antimicrobial therapy. The DNA sequence of the 16S rRNA gene of S. moniliformis was detected in valve specimens by PCR and nucleotide sequencing.     

Norsolorinic acid inhibits proliferation of T24 human bladder cancer cells by arresting the cell cycle at the G0/G1 phase and inducing a Fas/membrane-bound Fas ligand-mediated apoptotic pathway

1. Norsolorinic acid, isolated from Aspergillus nidulans, has been shown to have antiproliferative activity in T24 human bladder cancer cells by arresting the cell cycle at the G(0)/G(1) phase and inducing apoptosis. The aim of the present study was to investigate the antiproliferative activity of norsolorinic acid in T24 human bladder cancer cells. 2. The effects of norsolorinic acid (1, 5, 10 and 20 micromol/L) on the proliferation of T24 cells and on the distribution of cells within different phases of the cell cycle were investigated indirectly using an XTT assay and a flow cytometer, respectively. Factors affecting the cell cycle and apoptosis, including p53, p21, Fas receptor, Fas ligand (FasL) and caspase 8 activity, were examined using ELISA. 3. The results showed that norsolorinic acid inhibited proliferation of T24 cells in a dose-dependent manner, with an IC(50) of 10.5 micromol/L. The effect involved the induction of cell cycle arrest at the G(0)/G(1) phase and apoptosis. 4. These results demonstrate that G(0)/G(1) phase arrest is due to increased expression of p21 in cells treated with norsolorinic acid (10 and 20 micromol/L) for 24 h. Moreover, enhanced Fas and membrane-bound Fas ligand (mFasL) may be responsible for the apoptotic effect of norsolorinic acid. Thus, the present study reports, for the first time, that induction of p21 and the Fas/mFas ligand apoptotic system may participate in the antiproliferative action of norsolorinic acid in T24 human bladder cancer cells.     

Establishment of murine basal cell carcinoma allografts: a potential model for preclinical drug testing and for molecular analysis

Dysregulated hedgehog (HH) signaling has been found in numerous cancers, suggesting that therapeutic targeting of this pathway may be useful versus a wide range of cancers. Basal cell carcinoma (BCC) is an excellent model system for studying the influence of the HH pathway on carcinogenesis because aberrant activation of HH signaling is crucial not only for the development of but also the maintenance of BCC. Genetically engineered BCC mouse models provide one important tool for the study of the biology of human BCCs and for evaluating therapeutic interventions, as these mice produce multiple genetically defined tumors within a relatively short period of time. However, these models remain expensive and cumbersome to use for large-scale preclinical drug testing. Here we report a method for growing allografts from murine BCC tumors in NOD/SCID mice. These allografts develop faster and reproduce the histology, immunophenotypes, and response to at least one anti-BCC drug of the parental autochthonous tumors from which they arise. Therefore, the allograft model provides a practical model for (i) studying BCC carcinogenesis and (ii) initial preclinical screening for anti-HH pathway and other anti-BCC drugs.     

Tolerability of teicoplanin in 117 hospitalized adults with previous vancomycin-induced fever,rash, or neutropenia: A retrospective chart review

Background: Vancomycin has reliable antibacterial activity against many gram-positive pathogens but is associated with many adverse events. Teicoplanin, another glycopeptide, is associated with fewer adverse events, but its use in patients with previous vancomycininduced adverse reactions remains controversial.Objectives: The aims of this work were to evaluate the clinical characteristics of hospitalized patients with vancomycin-induced fever (ie, drug fever), rash, or neutropenia and to examine the tolerability of teicoplanin in these patients.Methods: This was a retrospective review of the medical charts of patients aged ≥18 years who were hospitalized between January 2002 and October 2007 at National Cheng Kung University Hospital in Tainan, Taiwan. Patients were included if they experienced drug-induced fever (ie, “drug fever”), rash, or neutropenia during vancomycin treatment. Their antimicrobial therapy was subsequently switched to teicoplanin. Clinical information and the development of drug fever, rash, or neutropenia with teicoplanin were determined from the charts.Results: Antibiotic therapy was switched to teicoplanin in 117 patients with vancomycin-induced fever alone (n = 24), rash alone (n = 77), both drug fever and rash (n = 8), or neutropenia (n = 8). The mean (SD) age of these patients was 53.1 (22.8) years, and 65 (56%) were male. The major clinical indications for vancomycin therapy among these patients were wound infections (21%), respiratory tract infections (14%), and bacteremia (13%). The dosages for vancomycin ranged from 1 g every 5 days to 1 g BID, and for teicoplanin ranged from 400 mg daily to 400 mg q72h, adjusted by the degree of renal dysfunction. Overall, 12 patients with vancomycin-induced fever (n = 2), rash (n = 6), or neutropenia (n = 4) subsequently developed teicoplanin-induced fever (n = 3), rash (n = 3), or neutropenia (n = 6). Specifically, of 8 patients with vancomycin-induced neutropenia, 4 (50%) subsequently developed neutropenia after switching to teicoplanin. Vancomycin- and teicoplanininduced neutropenia was often noted after 1 week of treatment. Among patients with vancomycin-induced fever, rash, or neutropenia, there were no differences between patients with or without teicoplanin-induced fever, rash, or neutropenia in terms of age, sex, weight, dosage or duration of vancomycin therapy, dosage of teicoplanin, or underlying disease. There was no difference in mortality rates between patients with or without teicoplanin-induced fever, rash, or neutropenia. The cause of all deaths was progression of infectious or underlying disease, unrelated to vancomycin or teicoplanin use.Conclusions: Based on this retrospective chart review of hospitalized patients with vancomycin-induced fever, rash, or neutropenia, only 10% experienced subsequent teicoplanin-induced fever, rash, or neutropenia. However, it should be noted that half of the patients with vancomycin-induced neutropenia developed teicoplanin-induced neutropenia.     

Modulation of Cytokine Expression in Human Myeloid Dendritic Cells by Environmental Endocrine-Disrupting Chemicals Involves Epigenetic Regulation

Background

Exposure to environmental endocrine-disrupting chemicals (EDCs) is often associated with dysregulated immune homeostasis, but the mechanisms of action remain unclear.

Objectives

The aim of this study was to test a hypothesis that EDCs regulate the functions of human dendritic cells, a front-line, immunoregulatory cell type in contact with the environment.

Methods

We investigated circulating myeloid dendritic cells (mDCs) from five subjects and measured their responses, with or without coculture with autologous T cells, to two common EDCs, nonylphenol (NP) and 4-octylphenol (4-OP). EDC-associated cytokine responses, signaling events, and histone modifications were examined using ELISA, Western blotting, and chromatin immunoprecipitation (ChIP) assays, respectively.

Results

In all cases, mDCs treated with NP or 4-OP demonstrated increased expression of tumor necrosis factor-α (TNF-α) but decreased baseline and lipopolysaccharide (LPS)-induced (interleukin) (IL)-10 production; the increase in TNF-α was partially reversible by an estrogen receptor (ER) antagonist. Activation of the MKK3/6-p38 signaling pathway marked the effect of NP on TNF-α expression, concomitant with enhanced levels of methyltranferase complex [mixed-lineage leukemia (MLL) and tryptophan-aspartic acid repeat domain 5 (WDR5)] in the nucleus and of trimethylated H3K4, acetylated H3, and H4 at the TNFA gene locus. Further, up-regulated TNF-α expression was significantly suppressed in NP-treated mDCs by a histone acetyltransferase inhibitor. In the presence of NP-treated mDCs, T cells showed increased levels of IL-13 but decreased expression of interferon-γ.

Conclusions

These results suggest that NP and 4-OP may have functional effects on the response of mDCs via, in part, the ER, MKK3/6-p38 MAPK signaling pathway, and histone modifications, with subsequent influence on the T-cell cytokine responses.     

Renal Function-Dependent Associations of Statins with Outcomes of Ischemic Stroke

Aim: Chronic kidney disease (CKD) is associated with unfavorable outcomes in patients with ischemic stroke. One major metabolic derangement of CKD is dyslipidemia, which can be managed by statins. This study aimed to investigate whether the association of statins with post-stroke outcomes would be affected by renal function.Methods: We evaluated the association of statin therapy at discharge with 3-month outcomes according to the estimated glomerular filtration rate (eGFR) of 50,092 patients with acute ischemic stroke from the Taiwan Stroke Registry from August 2006 to May 2016. The outcomes were mortality, functional outcome as modified Rankin Scale (mRS), and recurrent ischemic stroke at 3 months after index stroke.Results: Statin therapy at discharge was associated with lower risks of mortality (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.34 to 0.50) and unfavorable functional outcomes (mRS 3–5; aHR, 0.80; 95% CI, 0.76 to 0.84) in ischemic stroke patients. After stratification by eGFR, the lower risk of mortality associated with statins was limited to patients with an eGFR above 15 mL/min/1.73 m². Using statins at discharge was correlated with a lower risk of unfavorable functional outcomes in patients with an eGFR of 60–89 mL/min/1.73 m². Statin therapy in patients with an eGFR of 60–89 mL/min/1.73 m² may be associated with a higher risk of recurrent ischemic stroke compared with nonusers (aHR, 1.29; 95% CI, 1.07 to 1.57).Conclusions: In patients with acute ischemic stroke, the associations of statins with mortality and functional outcomes was dependent on eGFR.