A porous fibrous hyperelastic damage model for human periodontal ligament: Application of a microcomputerized tomography finite element model

The periodontal ligament (PDL) is a soft biological tissue that connects the tooth with the trabecular bone of the mandible. It plays a key role in load transmission and is primarily responsible for bone resorption and most common periodontal diseases. Although several numerical studies have analysed the biomechanical response of the PDL, most did not consider its porous fibrous structure, and only a few analysed damage to the PDL. This study presents an innovative numerical formulation of a porous fibrous hyperelastic damage material model for the PDL. The model considers two separate softening phenomena: fibre alignment during loading and fibre rupture. The parameters for the material model characterization were fitted using experimental data from the literature. Furthermore, the experimental tests used for characterization were computationally modelled to verify the material parameters. A finite element model of a portion of a human mandible, obtained by microcomputerized tomography, was developed, and the proposed constitutive model was implemented for the PDL. Our results confirm that damage to the PDL may occur mainly because of overpressure of the interstitial fluid, while large forces must be applied to damage the PDL fibrous network. Moreover, this study clarifies some aspects of the relationship between PDL damage and the bone remodelling process

RESVERATROL INCLUSION COMPLEX WITH β-CYCLODEXTRIN (RCD): CHARACTERIZATION AND EVALUATION OF TOXICITY IN WISTAR RATS

Objective: The aim of this study was to characterise the resveratrol inclusion complex with β-cyclodextrin (RCD) and evaluate their toxicity in wistar rats.Methods: The RCD were prepared in ultra-turrax. For characterization of the RCD were used: Fourier transform infra-red Spectroscopy, Nuclear Magnetic Resonance (NMR), Differential Scanning Calorimetry (DSC) and X-ray powder diffraction. The RCD and others 4 treatments were performed by the chronic oral administration in 35 rats during 60 ds. After the treatments they were euthanized and the serum blood were collected to analyzed some hemogram and biochemical parameters including aspartyl aminotransferase (AST); alanine aminotransferase (AST); phosphatase alkaline (ALP); total bilirubin (TB); direct bilirubin (DB); total protein (TP); total cholesterol (TC), triacylglycerol (TAG), very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), calcium, iron and phosphate using fully automated biochemistry analyzer.Results: The characterization results indicated a successful formation of the RCD. All hematological parameters analysed were within the normal values in all the groups. Furthermore, the hemogram and biochemical parameters were significantly (P>0.05) similar to the control group.Conclusion: The daily oral administration during 60 d of RCD are not harmful on blood parameters of Wistar rats. Thus, RCD can be used safely for treatment of some metabolic diseases

Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project

<p>Abstract</p> <p>Background</p> <p>Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of the <it>IL18 </it>gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes, <it>IL18R1 </it>and <it>IL18RAP</it>, with the risk of developing CVD.</p> <p>Methods</p> <p>Eleven tagging SNPs, 5 in <it>IL18R1 </it>and 6 in <it>IL18RAP</it>, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD.</p> <p>Results</p> <p>We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5 <it>IL18 </it>SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful.</p> <p>Conclusion</p> <p>Our analysis suggests that the variability of <it>IL18R1 </it>and <it>IL18RAP </it>genes are unlikely to contribute to modulate the risk of CVD.</p

Further evidence for increased macrophage migration inhibitory factor expression in prostate cancer

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine associated with prostate cancer, based on histologic evidence and circulating (serum) levels. Recent studies from another laboratory failed to document these results. This study's aims were to extend and confirm our previous data, as well as to define possible mechanisms for the discrepant results. Additional aims were to examine MIF expression, as well as the location of MIF's receptor, CD74, in human prostatic adenocarcinoma compared to matched benign prostate. METHODS: MIF amounts were determined in random serum samples remaining following routine PSA screening by ELISA. Native, denaturing and reducing polyacrylamide gels and Western blot analyses determined the MIF form in serum. Prostate tissue arrays were processed for MIF in situ hybridization and immunohistochemistry for MIF and CD74. MIF released into culture medium from normal epithelial, LNCaP and PC-3 cells was detected by Western blot analysis. RESULTS: Median serum MIF amounts were significantly elevated in prostate cancer patients (5.87 ± 3.91 ng/ml; ± interquartile range; n = 115) compared with patients with no documented diagnosis of prostate cancer (2.19 ± 2.65 ng/ml; n = 158). ELISA diluent reagents that included bovine serum albumin (BSA) significantly reduced MIF serum detection (p < 0.01). MIF mRNA was localized to prostatic epithelium in all samples, but cancer showed statistically greater MIF expression. MIF and its receptor (CD74) were localized to prostatic epithelium. Increased secreted MIF was detected in culture medium from prostate cancer cell lines (LNCaP and PC-3). CONCLUSION: Increased serum MIF was associated with prostate cancer. Diluent reagents that included BSA resulted in MIF serum immunoassay interference. In addition, significant amounts of complexed MIF (180 kDa under denaturing conditions by Western blot) found in the serum do not bind to the MIF capture antibody. Increased MIF mRNA expression was observed in prostatic adenocarcinoma compared to benign tissue from matched samples, supporting our earlier finding of increased MIF gene expression in prostate cancer

Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells

BACKGROUND: The importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established. Increased expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) has previously been associated with various types of adenocarcinoma. METHODS: MIF IHC was used to localize MIF in human bladder tissue. ELISA and Western blot analysis determined the synthesis and secretion of MIF by human bladder transitional cell carcinoma cells. The effects of MIF inhibitors (high molecular weight hyaluronate (HA), anti-MIF antibody or MIF anti-sense) on cell growth and cytokine expression were analyzed. RESULTS: Human bladder cancer cells (HT-1376) secrete detectable amounts of MIF protein. Treatment with HA, anti-MIF antibody and MIF anti-sense reduced HT-1376 cell proliferation, MIF protein secretion, MIF gene expression and secreted inflammatory cytokines. Our evidence suggests MIF interacts with the invariant chain, CD74 and the major cell surface receptor for HA, CD44. CONCLUSIONS: This study is the first to report MIF expression in the human bladder and these findings support a role for MIF in tumor cell proliferation. Since MIF participates in the inflammatory response and bladder cancer is associated with chronic inflammatory conditions, these new findings suggest that neutralizing bladder tumor MIF may serve as a novel therapeutic treatment for bladder carcinoma

Macrophage Migration Inhibitory Factor Activates Hypoxia-Inducible Factor in a p53-Dependent Manner

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Gene expression changes associated with Barrett's esophagus and Barrett's-associated adenocarcinoma cell lines after acid or bile salt exposure

<p>Abstract</p> <p>Background</p> <p>Esophageal reflux and Barrett's esophagus represent two major risk factors for the development of esophageal adenocarcinoma. Previous studies have shown that brief exposure of the Barrett's-associated adenocarcinoma cell line, SEG-1, or primary cultures of Barrett's esophageal tissues to acid or bile results in changes consistent with cell proliferation. In this study, we determined whether similar exposure to acid or bile salts results in gene expression changes that provide insights into malignant transformation.</p> <p>Methods</p> <p>Using previously published methods, Barrett's-associated esophageal adenocarcinoma cell lines and primary cultures of Barrett's esophageal tissue were exposed to short pulses of acid or bile salts followed by incubation in culture media at pH 7.4. A genome-wide assessment of gene expression was then determined for the samples using cDNA microarrays. Subsequent analysis evaluated for statistical differences in gene expression with and without treatment.</p> <p>Results</p> <p>The SEG-1 cell line showed changes in gene expression that was dependent on the length of exposure to pH 3.5. Further analysis using the Gene Ontology, however, showed that representation by genes associated with cell proliferation is not enhanced by acid exposure. The changes in gene expression also did not involve genes known to be differentially expressed in esophageal adenocarcinoma. Similar experiments using short-term primary cultures of Barrett's esophagus also did not result in detectable changes in gene expression with either acid or bile salt exposure.</p> <p>Conclusion</p> <p>Short-term exposure of esophageal adenocarcinoma SEG-1 cells or primary cultures of Barrett's esophagus does not result in gene expression changes that are consistent with enhanced cell proliferation. Thus other model systems are needed that may reflect the impact of acid and bile salt exposure on the esophagus <it>in vivo</it>.</p

Macrophage Migration Inhibitory Factor Antagonist Blocks the Development of Endometriosis In Vivo

Endometriosis, a disease of reproductive age women, is a major cause of infertility, menstrual disorders and pelvic pain. Little is known about its etiopathology, but chronic pelvic inflammation is a common feature in affected women. Beside symptomatic treatment of endometriosis-associated pain, only two main suboptimal therapeutic approaches (hormonal and invasive surgery) are generally recommended to patients and no specific targeted treatment is available. Our studies led to the detection of a marked increase in the expression of macrophage migration inhibitory factor (MIF) in the eutopic endometrium, the peripheral blood and the peritoneal fluid of women with endometriosis, and in early, vascularized and active endometriotic lesions. Herein, we developed a treatment model of endometriosis, where human endometrial tissue was first allowed to implant into the peritoneal cavity of nude mice, to assess in vivo the effect of a specific antagonist of MIF (ISO-1) on the progression of endometriosis and evaluate its efficacy as a potential therapeutic tool. Administration of ISO-1 led to a significant decline of the number, size and in situ dissemination of endometriotic lesions. We further showed that ISO-1 may act by significantly inhibiting cell adhesion, tissue remodeling, angiogenesis and inflammation as well as by altering the balance of pro- and anti-apoptotic factors. Actually, mice treatment with ISO-1 significantly reduced the expression of cell adhesion receptors αv and ß3 integrins (P<0.05), matrix metalloproteinases (MMP) 2 and 9 (P<0.05), vascular endothelial cell growth factor (VEGF) (P<0.01), interleukin 8 (IL8) (P<0.05), cyclooxygenease (COX)2 (P<0.001) and the anti-apoptotic protein Bcl2 (P<0.01), but significantly induced the expression of Bax (P<0.05), a potent pro-apoptotic protein. These data provide evidence that specific inhibition of MIF alters endometriotic tissue growth and progression in vivo and may represent a promising potential therapeutic avenue