Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5.

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

Effect of the phytotherapeutic agent Eviprostat on inflammatory changes and cytokine production in a rat model of nonbacterial prostatitis.

OBJECTIVES: To examine the effect of the phytotherapeutic agent Eviprostat on the stromal-to-epithelial (S/E) ratio, level of macrophage infiltration, expression of the macrophage inhibitory cytokine-1 (Mic1) gene, and tumor necrosis factor-alpha (TNF-α) and interleukin-8 (IL-8) concentrations in prostate tissues in a rat model of nonbacterial prostatitis (NBP). MATERIALS AND METHODS: Ten-month old Wistar rats were divided into 4 groups of 10: (1) NBP non-mixed feed (prostatitis control group); (2) NBP Eviprostat (0.1%) mixed feed (prostatitis Eviprostat group); (3) non-NBP non-mixed feed (nonprostatitis control group); and (4) non-NBP Eviprostat mixed-feed (nonprostatitis Eviprostat group). NBP was induced by castration followed by daily subcutaneous injection of 17ß-estradiol for 30 days. Ventral prostate lobes were histopathologically examined with Masson's trichrome staining or immunostaining with antimacrophage antibody. Mic1 mRNA levels were quantified by real-time reverse transcriptase polymerase chain reaction. Tissue concentrations of TNF-α and IL-8 were determined by enzyme-linked immunosorbent assay. RESULTS: Stroma was the most abundant in prostatitis control rats. The mean S/E ratio in prostatitis Eviprostat rats was significantly lower than in prostatitis control rats (P < .0001). The high levels of macrophage infiltration found in prostatitis control rats were significantly reduced in prostatitis Eviprostat rats (P < .0001). The up-regulation of the Mic1 gene observed in prostatitis control rat prostates was significantly suppressed in prostatitis Eviprostat rats (P < .0001). A marked suppression of TNF-α and IL-8 secretion was also observed in prostatitis Eviprostat rats (P < .05). CONCLUSIONS: Eviprostat significantly suppressed the S/E ratio, level of macrophage infiltration, Mic1 gene expression, and proinflammatory cytokines/chemokines in the prostate in a rat NBP model.

Low AZGP1 expression predicts for recurrence in margin-positive, localized prostate cancer.

BACKGROUND: Men with positive margins after radical prostatectomy (RP) for localized prostate cancer (PC) have a 40-50% biochemical relapse rate at 5 years. Adjuvant radiotherapy improves biochemical progression-free and overall survival in men with positive margins, but is associated with increased toxicity. There is an urgent need to identify new prognostic markers to define the group of patients who would benefit from multimodality therapy. METHODS: Nuclear ß-catenin, membranous secreted frizzled-related protein 4 (sFRP4), zinc-alpha 2-glycoprotein (AZGP1), and macrophage inhibitory cytokine-1 (MIC-1) have previously been identified as molecular markers of outcome in localized PC. From these published studies, we identified a subset of patients with positive margins. The aim of this study was to assess the association between these four molecular markers and outcome in men with margin-positive, localized PC. RESULTS: We identified 186 men with positive margins from 330 men with localized PC; 53% had preoperative PSA >10 ng/ml, 72% extraprostatic extension (EPE), 24% seminal vesicles involvement (SVI), and 57% RP Gleason score ≥ 7. AZGP1 (P = 0.009), membranous sFRP4 (P = 0.03) and MIC-1 (P = 0.04) expression predicted for biochemical relapse on univariate analysis. Only absent/low AZGP1 expression (P = 0.01) was an independent predictor of recurrence in margin-positive, localized PC when modeled with preoperative PSA (P = 0.2), EPE (P = 0.2), SVI (P = 0.4), Gleason score ≥ 7 (P = 0.5) and adjuvant treatment (P = 0.4). Furthermore, there was an association between absent/low AZGP1 expression and clinical recurrence (P = 0.007). CONCLUSIONS: AZGP1 is a potential molecular marker for biochemical relapse in men with margin-positive, localized PC. Routine assessment of this biomarker may lead to better selection of patients who will benefit from post-RP radiotherapy.