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Background Resolvin D1 (RvD1), an important member of resolvins, exerts a wide spectrum of biological effects , including resolution of inflammation, tissue repair, and preservation of cell viability. The aim of the present study is to investigate the anti-arthritic potential and clarify the bone protective actions of RvD1 in vitro and in vivo. Methods RAW264.7 cells were treated with 50 ng/ml LPS for 72 h in the presence or absence of RvD1 (0–500 nM). Primary human monocytes were treated with M-CSF + RANKL for 14 days ± RvD1 (0–500 nM) with or without siRNA against RvD1 receptor FPR2. Expressions of inflammatory mediators, degrading enzymes, osteoclasts (OC) formation, and bone resorption were analyzed. The therapeutic effect of RvD1 (0–1000 ng) was carried out in murine collagen antibody-induced arthritis. Arthritis scoring, joint histology, and inflammatory and bone turnover markers were measured. Results RvD1 is not toxic and inhibits OC differentiation and activation. It decreases bone resorption, as assessed by the inhibition of TRAP and cathepsin K expression, hydroxyapatite matrix resorption, and bone loss. In addition, RvD1 reduces TNF-α, IL-1β, IFN-γ, PGE 2 , and RANK and concurrently enhances IL-10 in OC. Moreover, in arthritic mice, RvD1 alleviates clinical score, paw inflammation, and bone and joint destructions. Besides, RvD1 reduces inflammatory mediators and markedly decreases serum markers of bone and cartilage turnover. Conclusion Our results provide additional evidence that RvD1 plays a key role in preventing bone resorption and other pathophysiological changes associated with arthritis. The study highlights the clinical relevance of RvD1 as a potential compound for the treatment of inflammatory arthritis and related bone disorders.

Tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine, has been shown to play a role in the pathophysiology of rheumatoid arthritis. Silencing TNFα expression with small interfering RNA (siRNA) is a promising approach to treatment of the condition. Towards this end, our team has developed a modified chitosan (CH) nanocarrier, deploying folic acid, diethylethylamine (DEAE) and polyethylene glycol (PEG) (folate-PEG-CH-DEAE ). The gene carrier protects siRNA against nuclease destruction, its ligands facilitate siRNA uptake via cell surface receptors, and it provides improved solubility at neutral pH with transport of its load into target cells. In the present study, nanoparticles were prepared with siRNA-TNFα, DEAE, and folic acid-CH derivative. Nanoparticle size and zeta potential were verified by dynamic light scattering. Their TNFα-knockdown effects were tested in a murine collagen antibody-induced arthritis model. TNFα expression was examined along with measurements of various cartilage and bone turnover markers by performing histology and microcomputed tomography analysis. We demonstrated that folate-PEG-CH-DEAE /siRNA nanoparticles did not alter cell viability, and significantly decreased inflammation, as demonstrated by improved clinical scores and lower TNFα protein concentrations in target tissues. This siRNA nanocarrier also decreased articular cartilage destruction and bone loss. The results indicate that folate-PEG-CH-DEAE nanoparticles are a safe and effective platform for nonviral gene delivery of siRNA, and their potential clinical applications warrant further investigation.

Objective and design Resolvin D1 (RvD1), an omega-3 fatty acid derivative, has shown remarkable properties in resolving inflammation, promoting tissue repair and preserving tissue integrity. In this study, we investigated RvD1 effects on major processes involved in osteoarthritis (OA) pathophysiology. Materials and methods Human OA chondrocytes were treated with either 1 ng/ml interleukin-1β (IL-1β) or 20 μM 4-hydroxynonenal (HNE), then treated or not with increased concentrations of RvD1 (0–10 μM). RvD1 levels were measured by enzyme immunoassay in synovial fluids from experimental dog model of OA and sham operated dogs obtained from our previous study. Cell viability was evaluated by 3-(4,5-dimethyl-thiazoyl)-2,5-diphenyl-SH-tetrazolium bromide assay. Parameters related to inflammation, catabolism and apoptosis were determined by enzyme-linked immunosorbent assay, Western blotting, and quantitative polymerase chain reaction. Glutathione (GSH) was assessed by commercial kit. The activation of mitogen-activated protein kinases and nuclear factor-kappaB (NF-κB) pathways was evaluated by Western blot. Results We showed that RvD1 levels were higher in synovial fluids from OA joint compared to controls. In OA human chondrocytes, we demonstrated that RvD1 was not toxic up to 10 μM and stifled IL-1β-induced cyclooxygenase 2, prostaglandin E2, inducible nitric oxide synthase, nitric oxide, and matrix metalloproteinase-13. Our study of signalling pathways revealed that RvD1 suppressed IL-1β-induced activation of NF-κB/p65, p38/MAPK and JNK 1/2 . Moreover, RvD1 prevented HNE-induced cell apoptosis and oxidative stress, as indicated by inactivation of caspases, inhibition of lactate dehydrogenase release, and increased levels of Bcl2 and AKT, as well as GSH. Conclusion This is the first in vitro study demonstrating the beneficial effect of RvD1 in OA. That RvD1 abolishing a number of factors known to be involved in OA pathogenesis renders it a clinically valuable agent in prevention of the disease.

Diethylaminoethyl-chitosan (DEAE-CH) is a derivative with excellent potential as a delivery vector for gene therapy applications. The aim of this study is to evaluate its toxicological profile for potential future clinical applications. An endotoxin-free chitosan (CH) modified with DEAE, folic acid (FA) and polyethylene glycol (PEG) was used to complex small interfering RNA (siRNA) and form nanoparticles (DEAE -CH-PEG-FA /siRNA). Based on the guidelines from the International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), and the Nanotechnology Characterization Laboratory (NCL), we evaluated the effects of the interaction between these nanoparticles and blood components. In vitro screening assays such as hemolysis, hemagglutination, complement activation, platelet aggregation, coagulation times, cytokine production, and reactive species, such as nitric oxide (NO) and reactive oxygen species (ROS), were performed on erythrocytes, plasma, platelets, peripheral blood mononuclear cells (PBMC) and Raw 264.7 macrophages. Moreover, MTS and LDH assays on Raw 264.7 macrophages, PBMC and MG-63 cells were performed. Our results show that a targeted theoretical plasma concentration (TPC) of DEAE -CH-PEG-FA /siRNA nanoparticles falls within the guidelines' thresholds: <1% hemolysis, 2.9% platelet aggregation, no complement activation, and no effect on coagulation times. ROS and NO production levels were comparable to controls. Cytokine secretion (TNF-α, IL-6, IL-4, and IL-10) was not affected by nanoparticles except for IL-1β and IL-8. Nanoparticles showed a slight agglutination. Cell viability was >70% for TPC in all cell types, although LDH levels were statistically significant in Raw 264.7 macrophages and PBMC after 24 and 48 h of incubation. These DEAE -CH-PEG-FA /siRNA nanoparticles fulfill the existing ISO, ASTM and NCL guidelines' threshold criteria, and their low toxicity and blood biocompatibility warrant further investigation for potential clinical applications.

Background Over the years, many theories have been proposed and examined to better explain the etiology and development of osteoarthritis (OA). The characteristics of joint destruction are one of the most important aspects in disease progression. Therefore, investigating different factors and signaling pathways involved in the alteration of extracellular matrix (ECM) turnover, and the subsequent catabolic damage to cartilage holds chief importance in understanding OA development. Among these factors, reactive oxygen species (ROS) have been at the forefront of the physiological and pathophysiological OA investigation. Findings In the last decades, research studies provided an enormous volume of data supporting the involvement of ROS in OA. Most interestingly, published data regarding the effect of exogenous antioxidant therapy in OA lack conclusive results from clinical trials to back up in vitro data. Accordingly, it is rational to suggest that there are other reactive species in OA that are not taken into account. Thus, our present review is focused on our current understanding of the involvement of lipid peroxidation-derived 4-hydroxynonenal (HNE) in OA. Conclusion Our findings, like those in the literature, illustrate the central role played by HNE in the regulation of a number of factors involved in joint homeostasis. HNE could thus be considered as an attractive therapeutic target in OA.

Background: Tumor necrosis factor-alpha (TNF[alpha]), a pro-inflammatory cytokine, has been shown to play a role in the pathophysiology of rheumatoid arthritis. Silencing TNF[alpha] expression with small interfering RNA (siRNA) is a promising approach to treatment of the condition. Methods: Towards this end, our team has developed a modified chitosan (CH) nanocarrier, deploying folic acid, diethylethylamine (DEAE) and polyethylene glycol (PEG) (folate-PEG-CH-[DEAE.sub.15]). The gene carrier protects siRNA against nuclease destruction, its ligands facilitate siRNA uptake via cell surface receptors, and it provides improved solubility at neutral pH with transport of its load into target cells. In the present study, nanoparticles were prepared with siRNA-TNF[alpha], DEAE, and folic acid-CH derivative. Nanoparticle size and zeta potential were verified by dynamic light scattering. Their TNF[alpha]-knockdown effects were tested in a murine collagen antibody-induced arthritis model. TNF[alpha] expression was examined along with measurements of various cartilage and bone turnover markers by performing histology and microcomputed tomography analysis. Results: We demonstrated that folate-PEG-CH-[DEAE.sub.15]/siRNA nanoparticles did not alter cell viability, and significantly decreased inflammation, as demonstrated by improved clinical scores and lower TNF[alpha] protein concentrations in target tissues. This siRNA nanocarrier also decreased articular cartilage destruction and bone loss. Conclusion: The results indicate that folate-PEG-CH-[DEAE.sub.15] nanoparticles are a safe and effective platform for nonviral gene delivery of siRNA, and their potential clinical applications warrant further investigation. Keywords: arthritis, inflammation, siRNA, TNF[alpha], nanoparticles, chitosan