Visfatin as a therapeutic target for rheumatoid arthritis

Introduction: The rising prevalence of musculoskeletal pathologies in developed countries has caused a dramatic impact on social welfare. Amidst these musculoskeletal pathologies is Rheumatoid arthritis (RA), a chronic systemic autoimmune disease that mostly affects the synovium. RA metabolic-associated alterations, including distorted adipokine production, enhance RA inflammatory environment. Among the altered adipokines, visfatin is particularly involved in RA inflammation and catabolism and stands out as an essential enzyme linked to critical cell features.

Areas covered: We discuss the potential mechanism supporting the contribution of visfatin to RA and the association between RA and obesity. We discuss the repurposing of cancer-tested drugs to inhibit visfatin in the context of RA. Additionally, we address the possibility of combining these drugs with current RA therapy. Finally, we explore the future of visfatin as an RA biomarker or therapeutic target.

Expert opinion: Inhibition of visfatin has become an interesting therapeutic approach for RA pathology. Such a feat has already been attained in oncology using small molecule inhibitors, which suggest that a similar course of action would be worth pursuing in the RA context. Visfatin will become an important biomarker and therapeutic target for RA.     

Analysis of tetanus toxin peptide/DR recognition by human T cell receptors reconstituted into a murine T cell hybridoma

We have previously reported that human T cell receptors (TcR) selected in the class II-restricted (HLA-DRB1*1302) response to a tetanus toxin peptide (tt830-843) frequently used the Vβ2 germ-line segment which paired with several Vα segments and that the putative CDR3 of both α and β chains showed remarkable heterogeneity. To analyze the structural basis for recognition of the tt830-843/DR complex, five of these TcR were reconstituted into a murine T cell hybridoma, 58 α^?β^?, by expressing the human α and β variable regions joined to the mouse α and β constant regions, respectively. The chimeric TcR, expressing the same Vβ germ-line segment (Vβ2), two expressing Vα21.1, twoVα17.1 and one Vα8.1 were shown to have the expected antigen specificity and DR restriction. Two lines of evidence suggested that the putative CDR3, although not conserved in these TcR, played a key role in recognition. First, two TcR with identical V germ-line segments but distinct CDR3 showed large differences in their capacity to react with the ligand. Second, interchanging the α and β chains from tt830-843/DR1302-specific TcR which differed in their CDR3 sequences invariably led to loss of recognition. We also asked whether germ-line Vα17.1 could functionally replace Vα21.1, as they appear to be related in their primary sequence. However, as in the case of CDR3 exchanges, Vα replacement abrogated TcR reactivity. Taken together, these data underline the fine interdependence of the structural components of the TcR binding site in defining a given specificity. Four of the TcR studied displaying promiscuous recognition were also tested against different DR alleles and site-directed mutants. The results of these experiments suggested that, in spite of their structural heterogeneity, anti-tt830-843 TcR may have a similar orientation with respect to the peptide/DR complex. The reconstitution system described herein should represent a valuable tool for detailed studies of human TcR specificity.     

Purification and characterization of Par o I, major allergen of Parietaria officinalis pollen.

Par o I, a major allergen of Parietaria officinalis, was purified from the pollen extract. The purified allergen was obtained by ultrafiltration, Sephadex gel filtration and DE-52 ion exchange chromatography: the purified preparation yields a single band in polyacrylamide gel isoelectric focusing (PAG-IEF), sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting, a single immunoprecipitation arc in crossed immunoelectrophoresis (CIE) and crossed radioimmunoelectrophoresis (CRIE) and a single peak in size exclusion high-performance liquid chromatography (HPLC). Par o I is a glycoprotein with a protein to carbohydrate ratio of 100:21. The molecular weight, determined by SDS-PAGE, Sephadex G-50 gel filtration and size exclusion HPLC, varied between 13.5 and 14.5 kDa according to the method employed. The isoelectric point was 4.6. The amino acid composition and the sequence of the first twelve N-terminal residues were determined. The allergenicity was assayed in vivo and in vitro. 29/29 Parietaria-allergic patients were skin positive to Par o I and possessed high level of specific serum IgE antibody as it determined by radioallergosorbent test (RAST). Par o I contained dominant epitopes for human IgE as inhibited to 85% the pollen extract RAST performed with a pool of sera of allergic patients. The RAST inhibitory activity was not abolished by deglycosylation.     

Down-regulation of nitric oxide synthase-2 and cyclooxygenase-2 pathways by p53 in squamous cell carcinoma

The goal of this study was to analyze the correlation between inducible nitric oxide synthase (iNOS) and COX-2 activities and p53 gene status in head and neck squamous cell carcinomas (HNSCCs) in vivo and in vitro. In a series of 43 HNSCCs we observed an up-regulation of both iNOS and COX-2 pathways in tumor tissues and both activities were correlated each other (rs = 0.612 and P = 0.0002). We also found that p53-mutated HNSCCs (25 cases, 58.1%) showed higher levels of iNOS activity and cGMP in comparison with wild-type p53 tumors (18 cases, 41.9%) (P = 0.0005 and P = 0.01), as well as higher iNOS immunohistochemical expression (P = 0.03). Analogously, higher PgE2 levels were documented in p53-mutated HNSCCs when compared with wild-type p53 tumors (P = 0.015) and COX-2 protein expression was higher in p53-mutated HNSCCs (P = 0.007). A431 cancer cells expressing a p53 temperature-sensitive mutant showed an approximately 1.9- and 2.6-fold decrease in spontaneous NO(2-)/NO(3-) and PgE2 synthesis at permissive temperature, respectively, when compared with the same cells at nonpermissive temperature (P 相似文献   

Effects of the sterilisation method on the wear of UHMWPE acetabular cups tested in a hip joint simulator

Ultra-high molecular-weight-polyethylene is the most commonly used bearing material in total joint replacement. Wear of polyethylene is a Serious Clinical problem that limits the longevity of orthopaedic implants. Information on degradative changes in the material properties and on the methods used for the sterilisation of polyethylene may help in the selection process of orthopaedic implants with the best wear resistance. This study was performed to investigate the effects of the sterilisation method (gamma irradiation and ethylene oxide treatment) on the wear and on the changes in physical properties of polyethylene acetabular cups. At this purpose, gamma-sterilised and ethylene oxide (EtO)-sterilised acetabular cups were tested against CoCr femoral heads in a hip joint simulator run for 5 million cycles in bovine calf serum. The crystallinity of the cups was evaluated by micro-Raman spectroscopy as a function of the inner surface position. The partial least square calibration was used to correlate the Raman spectra with the crystallinity of the polymer measured by differential scanning calorimetry. The analysis performed on soak control acetabular cups demonstrated that the gamma-sterilised cups are significantly more crystalline than the EtO-sterilised ones. The mean crystallinity values obtained for the gamma-sterilised and EtO-sterilised soak control cups were 65.0% and 63.4%, respectively. Weight loss measurements revealed that the gamma-sterilised acetabular cups exhibited a lower wear rate than that by EtO-sterilised. Thc Raman results obtained on gamma-sterilised and EtO-sterilised acetabular cups showed that the changes in surface crystallinity were mainly caused by irradiation rather than by the mechanical friction during the in vitro tests.     

Endogenous levels of mRNA for IFNs and IFN-related genes in hepatic biopsies of chronic HCV-infected and non-alcoholic steatohepatitis patients

To investigate the intra-hepatic activation of the IFN system in patients affected by chronic HCV-infection in comparison with that observed in a non-infectious liver disease such as non-alcoholic steatohepatitis, we measured the liver steady state mRNA levels of interferon-alpha, interferon-beta and interferon-gamma as well as of IFN-related genes (IFNAR-1, STAT1alpha, PKR, 2-5 AS, IRF-1, ICE and IL-18). In HCV-infected subjects, possible correlations of these parameters with viral load and liver injury were also analyzed. Twenty-four chronic untreated HCV-infected subjects and seven patients with non-alcoholic steatohepatitis were enrolled in the study. Liver biopsies were graded according to Knodell scores. Intra-hepatic mRNA levels of IFNs and related genes were assessed by semi-quantitative RT-PCR. In comparison with non-alcoholic steatohepatitis, in HCV-infected subjects IFN-alpha and -beta mRNA levels were significantly lower, whereas IFN-gamma, IFNAR-1, STAT1alpha IRF-1, and IL-18 mRNA were upregulated. Moreover, IFN-gamma mRNA steady state levels were correlated positively with those of IFNAR-1, IRF-1, and IL-18, suggesting a coordinated induction of these genes. Although plasma viral load was correlated inversely with IL-18-specific mRNA, viral load was not related to liver injury. IFN-gamma and IRF-1 mRNA levels were correlated positively with ALT, but not with the grading or staging. Conversely, IFN-alpha and -beta mRNA levels were higher in livers with lower staging scores. These findings support the hypothesis that in chronic HCV infection there is an imbalance between an upregulated IFN-gamma system and a downregulated IFN-alpha and -beta system, probably due to a mixed effect exerted by HCV-specific and inflammatory non-specific factors.     

Sodium-azide versus ProClin 300: influence on the morphology of UHMWPE particles generated in laboratory tests

Ultra-high molecular-weight polyethylene (UHMWPE) has been used in total joint replacement for the last three decades and is currently the best polymer available for this use. Nevertheless, the wear of UHMWPE remains a serious clinical problem. Polyethylene wear debris has been identified as a cause of osteolysis and a major factor reducing the life of the total hip arthroplasty. Debris generated at the articular surfaces enters the periprostethic tissue where it is phagocyted by macrophages. Studies have shown that particles in the 0.1-10microm size range are particularly important in causing adverse cellular reactions resulting in osteolysis. The morphology, size, mass, and number of wear particles produced in a hip joint simulator are influenced by the tribological conditions used during the experiment.This paper shows that the morphology of the UHMWPE particles generated in vitro is influenced by the type of lubricant used. This study compared, quantitatively and qualitatively, particles generated in vitro using bovine calf serum as lubricant with two different preservatives: sodium azide and ProClin 300. No significant difference was observed with regards to wear between the two types of lubricant used. Quantitative analysis of the wear particles showed that particles generated in serum with sodium azide were not [corrected] morphologically different from those produced in serum with ProClin 300 [corrected]     

Alumina femoral head fracture: an in vitro study

A fracture of a ceramic femoral head is reported in this study. Fractures of ceramic femoral heads are uncommon and reports on this complication are rare. After 3 million cycles, on a twelve station hip simulator that tested alumina femoral head against polyethylene acetabular cup, fracture of the ceramic ball was observed. The retrieved specimen consisted of three large ceramic fragments from the same ceramic femoral head, a polyethylene acetabular cup and a stainless steel jig. Careful and detailed examination of the removed components was made. The fracture of the ceramic ball resulted in damage to the metal taper of the jig component which was fixed into the simulator.