Collagen Oligomeric Matrix Protein Research Articles

Protective role of Oleuropein, an olive tree secoiridoid and its acyl-derivate in experimental models of rheumatic diseases

Oleuropein (OL), an olive tree secoiridoid, and its peracetylated derivate (Per-OL) have exhibited several beneficial effects reducing acute inflammatory responses on LPS-stimulated macrophages. The present study was designed to evaluate the effects of both dietary OL and Per-OL supplementations on collagen-induced arthritis (CIA) murine model. Three-weeks-old DBA-1/J male mice were fed from weaning with 0.05% (w/w) OL, 0.05% or 0.025% Per-OL. After six weeks of pre-treatment, arthritis was induced by bovine collagen type II by tail base injection (day 0) and mice received a booster injection on day 21. Mice were sacrificed 42 days after first immunization. Then, blood was recollected and paws were histological and biochemically processed. OL and Per-OL experimental diets significantly prevented histological damage and arthritic score development in RA. In addition, serum collagen oligomeric matrix protein (COMP) and metalloproteinase 3 (MMP)-3 as well as proinflammatory cytokines levels in paw homogenates (including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and interferon (IFN)-γ were significantly ameliorated in those animals fed with dietary secoiridoids. Mitogen-activated protein kinases (MAPKs) and nuclear transcription factor kappa-B (NF-κB) activations were drastically down-regulated whereas nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expressions were significantly up-regulated in those mice fed with OL and Per-OL diets. These results reveal, for the first time, the anti-inflammatory effect of a diet supplemented with OL and Per-OL in an experimental murine model of CIA, which was accompanied by a significant reduction in the pro-inflammatory markers studied (COMP, MMP-3, TNF-α, IL-1β, IL-6, IL-17 and IFN-γ). The mechanisms involved could be related to an activation of the antioxidant pathway Nrf2/HO-1 and an inhibition of MAP kinases and NF-κB signaling pathways activations. On the other hand, we studied the effects of both OL and Per-OL diets supplemented diets in a model of pristane-induced systemic lupus erythematosus (SLE) in BALB / c mice. Mice received an intraperitoneal injection of pristane or saline according to the experimental groups and were fed with experimental diets enriched with OL and Per-OL. Changes in cytokines levels and pro-inflammatory markers were evaluated by the ELISA assay. Changes in the protein expression of inducible nitric oxide synthase (iNOS), microsomal prostaglandin E synthase 1 (mPGEs-1) as well as HO-1, nuclear factor Nrf2, p38 protein kinases, C-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), signal transduction factor and activator of transcription (STAT) -3, NF-κB and inflammasome NLRP3 activation were determined using the Western Blot. Both OL and Per-OL dietary treatments significantly reduced kidney damage and reduced serum MMP-3 and renal prostaglandin E2 (PGE2) levels. Our studies indicated that OL and Per-OL enriched diets produced an increase in the expression of the antioxidant pathway Nrf2 / HO-1 which was accompanied by a decrease in the activation of the Janus kinases and signal transducer and activator of transcription (JAK / STAT), MAPKs, NF-κB and inflammasome NLRP3 proteins. In conclusion, dietary supplementation with OL and Per-OL could serve as the basis for the development of new nutritional strategies for the prevention of RA. In addition, these results also suggest that dietary supplementation with OL and Per-OL could constitute a new alternative therapeutic approach as a preventive or palliative of nephritis in the management of SLE.

A New Peracetylated Oleuropein Derivative Ameliorates Joint Inflammation and Destruction in a Murine Collagen-Induced Arthritis Model via Activation of the Nrf-2/Ho-1 Antioxidant Pathway and Suppression of MAPKs and NF-κB Activation.

Oleuropein (OL), an olive tree secoiridoid and its peracetylated derivate (Per-OL) have exhibited several beneficial effects on LPS-stimulated macrophages and murine experimental systemic lupus erythematosus (SLE). This study was designed to evaluate dietary Per-OL in comparison with OL supplementation effects on collagen-induced arthritis (CIA) murine model. Three-weeks-old DBA-1/J male mice were fed from weaning with a standard commercial diet or experimental enriched-diets in 0.05 % (w/w) OL, 0.05% and 0.025% Per-OL. After six weeks of pre-treatment, arthritis was induced by bovine collagen type II by tail base injection (day 0) and on day 21, mice received a booster injection. Mice were sacrificed 42 days after the first immunization. Both Per-OL and OL diets significantly prevented histological damage and arthritic score development, although no statistically significant differences were observed between both compounds. Also, serum collagen oligomeric matrix protein (COMP), metalloprotease (MMP)-3 and pro-inflammatory cytokines levels were ameliorated in paws from secoiridoids fed animals. Mitogen-activated protein kinases (MAPK)s and nuclear transcription factor-kappa-B (NF-κB) activations were drastically down-regulated whereas nuclear factor E2-related factor 2 (Nrf2) and heme-oxygenase-1 (HO-1) protein expressions were up-regulated in those mice fed with OL and Per-OL diets. We conclude that both Per-OL and its parent compound, OL, supplements might provide a basis for developing a new dietary strategy for the prevention of rheumatoid arthritis.

Extracellular matrix proteins as diagnostic markers of breast carcinoma.

Changes in amount and composition of extracellular matrix (ECM) are considered a hallmark of tumor development. We tested the hypothesis that abnormal production of ECM components leads to blood-released ECM molecules representing tumor circulating biomarkers. Candidate genes were selected through class comparison in two publicly available datasets and confirmed in paired normal and tumor associated fibroblasts from breast carcinoma (BC) specimens. Production and release of ECM molecules were evaluated in normal human dermal fibroblasts (NHDFs) treated with conditioned media from three BC cell lines. Plasma samples from healthy donors and from patients with malignant or benign breast disease were tested by ELISA for the presence of collagen 11a1 (COL11A1), collagen oligomeric matrix protein (COMP), and collagen 10a1 (COL10A1). Selected ECM molecules were investigated by IHC in malignant and benign specimens. In silico analysis of gene expression profiles identified 11 ECM genes significantly up-regulated in tumor versus normal tissue. Western blot analyses revealed increased levels of molecules encoded by three of these genes, COL11A1, COMP, and COL10A1, in cell lysates and supernatants of conditioned NHDFs. Class comparison and class prediction analyses of two independent series of human plasma samples identified the combination of COL11A1, COMP, and COL10A1 as potentially informative in discriminating BC patients from those with benign disease. The three molecules resulted expressed in the stroma of BC tissue samples. Our results indicate that circulating COL11A1, COMP, and COL10A1 may be useful in diagnostic assessment of suspicious breast nodules and ECM molecules could represent an avenue to biomarker identification.