Methylglyoxal down-regulates the expression of cell cycle associated genes and activates the p53 pathway in human umbilical vein endothelial cells

Abstract Although methylglyoxal (MGO) has emerged as key mediator of diabetic microvascular complications, the influence of MGO on the vascular transcriptome has not thoroughly been assessed. Since diabetes is associated with low grade inflammation causing sustained nuclear factor-kappa B (NF-κB) activation, the current study addressed 1) to what extent MGO changes the transcriptome of human umbilical vein endothelial cells (HUVECs) exposed to an inflammatory milieu, 2) what are the dominant pathways by which these changes occur and 3) to what extent is this affected by carnosine, a putative scavenger of MGO. Microarray analysis revealed that exposure of HUVECs to high MGO concentrations significantly changes gene expression, characterized by prominent down-regulation of cell cycle associated genes and up-regulation of heme oxygenase-1 (HO-1). KEGG-based pathway analysis identified six significantly enriched pathways of which the p53 pathway was the most affected. No significant enrichment of inflammatory pathways was found, yet, MGO did inhibit VCAM-1 expression in Western blot analysis. Carnosine significantly counteracted MGO-mediated changes in a subset of differentially expressed genes. Collectively, our results suggest that MGO initiates distinct transcriptional changes in cell cycle/apoptosis genes, which may explain MGO toxicity at high concentrations. MGO did not augment TNF-α induced inflammation

Assessing ischemic heart disease in patients with left bundle branch block--an emerging role for multislice computed tomography

Diagnosis of left bundle branch block (LBBB) with concomitant coronary artery disease (CAD) alters the prognosis and the therapeutic management. All common non-invasive stress tests have a limited performance to identify CAD in patients with LBBB. Thus invasive coronary angiography is often needed to confirm or defer obstructive CAD. We propose a new diagnostic algorithm in evaluation of symptomatic and asymptomatic patients with LBBB

Assessment of prostate cancer with dynamic contrast-enhanced computed tomography using an en bloc approach

OBJECTIVES The aim of this study was to assess the performance of dynamic contrast-enhanced computed tomography of the prostate in patients with biopsy-proven prostate cancer. MATERIAL AND METHODS A total of 46 male patients (median age, 65 years; range, 49-73 years) with biopsy-proven prostate cancer underwent an en bloc computed tomography perfusion (CTP) scan of the prostate before surgery. The perfusion parameters mean transit time (MTT), blood flow (BF), and blood volume (BV), as well as the microvessel density (MVD) of surgical specimens were determined. Differences in CTP parameters and MVD among postsurgical Gleason score (sGS) and postsurgical combined Gleason grade (sGG) groups were analyzed. Spearman correlation coefficients were determined between CTP parameters and presurgical biopsy-derived Gleason score (bGS), presurgical biopsy-derived combined Gleason grade (bGG), sGS, sGG, MVD, and pathological tumor stage. A linear regression analysis was carried out for exogenous variables BF, BV, MTT, bGS, and presurgical biopsy-derived combined Gleason grade and endogenous variables sGS, sGG, MVD, and T stage. A receiver operating characteristics analysis was performed to analyze the discriminating performance of CTP parameters and bGS between intermediate- and high-grade tumors. RESULTS The mean perfusion parameters within the prostate tissue were as follows: BF, 39.1 ± 13.4 mL/100 mL min; BV, 4.9 ± 2.4 mL/100 mL; and MTT, 8.9 ± 3.7 seconds. The mean MVD of the tumor tissue was 144.3 ± 55.6/mm. Computed tomography perfusion parameters and MVD were significantly higher in patients with high-grade tumors compared with those with intermediate-grade tumors (P < 0.01 for BF, BV, and MVD). Only BV and MVD were significantly different among sGS and sGG groups. Moderate correlations were found between BF and sGS (0.38) and between BV and sGS (0.43). Linear relations of BV to sGS and to sGG were found. Blood volume (area under the curve, 0.86) was superior to bGS (area under the curve, 0.75) in discriminating high-grade from intermediate-grade tumors. CONCLUSION Computed tomography perfusion parameters derived by en bloc perfusion of the prostate are higher in high-grade tumors compared with intermediate-grade tumors. Blood flow and BV correlate with the definitive Gleason score. Blood volume predicts high-grade tumors better than does the Gleason score of biopsy specimens. Further studies are needed to determine a potential role for CTP in prostate cancer patients

The effects of resveratrol, a phytoalexin derived from red wines, on chronic inflammation induced in an experimentally induced colitis model

1. Neutrophil infiltration, proinflammatory cytokines, eicosanoid generation and oxidative stress have been implicated in colitis. Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, including anti-inflammatory, antioxidant, antitumour and immunomodulatory activities. In a previous report, we documented that resveratrol decreases the degree of inflammation associated with acute experimental colonic inflammation, but its effects on chronic experimental colitis remain undetermined. 2. The aim of this research was to investigate the effects of resveratrol on the chronic colonic injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. The inflammatory response was assessed by histology and myeloperoxidase activity. Tumour necrosis factor alpha (TNF-α) production, histological and histochemical analysis of the lesions were also carried out. We determined the production of prostaglandin (PG) E(2) and D(2) in colon mucosa, as well as cyclooxygenase (COX)-1 and -2 and nuclear transcription factor NF-kappa B (NF-κB) p65 protein expression. Finally, since resveratrol has been found to modulate apoptosis, we intended to elucidate its effects on colonic mucosa under chronic inflammatory conditions. 3. Resveratrol (10 mg kg(−1) day(−1)) significantly attenuated the damage score and corrected the disturbances in morphology associated to injury. In addition, the degree of neutrophil infiltration and the levels of TNF-α were significantly ameliorated. Resveratrol did not modify PGD(2) levels but returned the decreased PGE(2) values to basal levels and also reduced COX-2 and the NF-κB p65 protein expression. Furthermore, treatment of rats with resveratrol caused a significant increase of TNBS-induced apoptosis in colonic cells. 4. In conclusion, resveratrol reduces the damage in chronic experimentally induced colitis, alleviates the oxidative events, returns PGE(2) production to basal levels and stimulates apoptosis in colonic cells

The effect of resistance training on markers of immune function and inflammation in previously sedentary women recovering from breast cancer: a randomized controlled trial

The purpose of this randomized controlled trial was to determine the effects of resistance training (RT) on markers of inflammation and immune function in breast cancer survivors. Thirty-nine breast cancer survivors were randomly assigned to a RT (n = 20) or control (n = 19) group. RT performed supervized exercise three times per week. Natural killer cell (NK) and natural killer T-cell (NKT) function, and markers of inflammation (serum TNFa, IL-6, IL-10, and CRP) were measured before and after training. Changes in NK and NKT cell function were analyzed using ANCOVA, with the change score the dependent variable, and the baseline value of the same variable the covariate. Effect sizes (ES) were calculated via partial eta-squared. We found a significant reduction, and large associated ESs, in the RT group compared to the control group for change in NK cell expression of TNF-a (p = 0.005, ES = 0.21) and NKT cell expression of TNFa (p = 0.04, ES = 0.12). No differences were observed in any serum marker. Significant improvements in all measurements of strength were found in RT compared to control (