Relationship between serum levels of vascular endothelial growth factor, hepatocyte growth factor and matrix metalloproteinase-9 with biochemical markers of bone disease in multiple myeloma

Background: Multiple myeloma is characterized by accumulation of plasma cells in the bone marrow, with osteolysis and increased marrow angiogenesis. We studied molecules involved in angiogenesis (MMP-9, HGF, VEGF) in relation to disease stage, extent of bone destruction, and markers of bone turnover (Ntx and PICP). Methods: MMP-9, HGF, VEGF were measured in the serum of 42 newly diagnosed myeloma patients and 24 controls with commercial ELISA kits. Urinary levels of Ntx were measured by ELISA, and serum PICP with RIA. Extent of radiological bone disease was graded into low and high score. Stage was estimated according to the Durie-Salmon criteria. Results: HGF, VEGF and Ntx were higher in patients than controls (p < 0.001). MMP-9 and PICP did not differ between patients and controls. HGF, VEGF, MMP-9 and Ntx increased significantly with disease stage (I to III, p < 0.001) and PICP decreased significantly with advancing stage (p < 0.05). There was a positive correlation between HGF and MMP-9 (r: 0.36, p < 0.01), VEGF and MMP-9 (r: 0.38, p < 0.01), Ntx and MMP-9 (r: 0.39, p < 0.01) and an inverse correlation between PICP and MMP-9 (r: - 0.66, p < 0.0001). Conclusions: Angiogenesis and bone destruction are closely interrelated in myeloma, and cytokine levels (MMP-9, VEGF and HGF) may be useful in monitoring progression. © 2007 Elsevier B.V. All rights reserved

In prostate cancer, low adiponectin levels are not associated with insulin resistance

Purpose: Adiponectin, an adipose tissue-derived hormone with insulin-sensitizing effect, has been inversely associated with several hormonally dependent malignancies. Prostate cancer is associated with low levels of adiponectin, which have been proposed as an independent risk factor for this malignancy. Aim of this study was to examine whether hypoadiponectinaemia in prostate is associated with insulin resistance. Experimental Design: Plasma samples and covariate data in the context of a case-control study of 300 Greek men were evaluated including 75 patients with prostate cancer, 75 patients with benign prostatic hyperplasia (BPH) and 150 age-matched healthy controls. Results: Patients with prostate cancer had significantly lower plasma adiponectin levels compared with the other two groups, that is BPH patients and healthy controls (7·4 ± 5 ng/mL vs. 11·5 ± 6·4 ng/mL and 12·8 ± 8 ng/mL, respectively). On the other hand, no statistically significant differences were found between patients with prostate cancer and the other two groups for both HOMA-IR and QUICKI (P-value = 0·551). As expected, in all three groups, the levels of adiponectin correlated negatively with HOMA-IR (rho = -0·214, P-value = 0·006), QUICKI (rho = 0·214, P-value = 0·006) and insulin levels (rho = 0·942, P-value<0·001). Conclusion: In spite of what would have been expected from the relevant literature, our data suggest that the hypoadiponectinaemia in prostatic cancer does not appear to be associated with insulin resistance. © 2015 Stichting European Society for Clinical Investigation Journal Foundation

Corticotropin-releasing factor and the urocortins induce the expression of TLR4 in macrophages via activation of the transcription factors PU.1 and AP-1.

Corticotropin-releasing factor (CRF) augments LPS-induced proinflammatory cytokine production from macrophages. The aim of the present study was to determine the mechanism by which CRF and its related peptides urocortins (UCN) 1 and 2 affect LPS-induced cytokine production. We examined their role on TLR4 expression, the signal-transducing receptor of LPS. For this purpose, the murine macrophage cell line RAW 264.7 and primary murine peritoneal macrophages were used. Exposure of peritoneal macrophages and RAW 264.7 cells to CRF, UCN1, or UCN2 up-regulated TLR4 mRNA and protein levels. To study whether that effect occurred at the transcriptional level, RAW 264.7 cells were transfected with a construct containing the proximal region of the TLR4 promoter linked to the luciferase gene. CRF peptides induced activation of the TLR4 promoter, an effect abolished upon mutation of a proximal PU.1-binding consensus or upon mutation of an AP-1-binding element. Indeed, all three peptides promoted PU.1 binding to the proximal PU.1 site and increased DNA-binding activity to the AP-1 site. The effects of CRF peptides were inhibited by the CRF2 antagonist anti-sauvagine-30, but not by the CRF1 antagonist antalarmin, suggesting that CRF peptides mediated the up-regulation of TLR4 via the CRF2 receptor. Finally, CRF peptides blocked the inhibitory effect of LPS on TLR4 expression. In conclusion, our data suggest that CRF peptides play an important role on macrophage function. They augment the effect of LPS by inducing Tlr4 gene expression, through CRF2, via activation of the transcription factors PU.1 and AP-1

Effect of cefamandole, cefuroxime and cefoxitin on yeast fecal flora of surgical patients

Aim of the present study was to evaluate the effect of cefamandole, cefuroxime and cefoxitin on the level of gastrointestinal (GI) colonization by Candida albicans in humans. Twenty-eight adult patients received one of these three cephalosporins for 10 days, as treatment of infection, and were studied prospectively. Quantitative stool cultures for yeasts were performed immediately before, at the end, and 1 week after discontinuation of treatment. All three antibiotics caused an increase of the yeast concentration in the fecal flora. The increase caused by cefoxitin was the highest (2.5 log10 CFU/g of stool). Our results suggest that the cephalosporins tested cause minor increases of the colonization of the GI tract by C. albicans

Selective and differential interactions of BNN27, a novel C17-spiroepoxy steroid derivative, with TrkA receptors, regulating neuronal survival and differentiation.

Nerve growth factor (NGF) holds a pivotal role in brain development and maintenance, been also involved in the pathophysiology of neurodegenerative diseases. Here, we provide evidence that a novel C17-spiroepoxy steroid derivative, BNN27, specifically interacts with and activates the TrkA receptor of NGF, inducing phosphorylation of TrkA tyrosine residues and down-stream neuronal survival-related kinase signaling. Additionally, BNN27 potentiates the efficacy of low levels of NGF, by facilitating its binding to the TrkA receptors and differentially inducing fast return of internalized TrkA receptors into neuronal cell membranes. Furthermore, BNN27 synergizes with NGF in promoting axonal outgrowth, effectively rescues from apoptosis NGF-dependent and TrkA positive sympathetic and sensory neurons, in vitro, ex vivo and in vivo in NGF null mice. Interestingly, BNN27 does not possess the hyperalgesic properties of NGF. BNN27 represents a lead molecule for the development of neuroprotective TrkA receptor agonists, with potential therapeutic applications in neurodegenerative diseases and in brain trauma