scholarly journals IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model

Cartilage ◽  
2021 ◽  
pp. 194760352110267
Author(s):  
E.M. van Helvoort ◽  
H.M. de Visser ◽  
F.P.J.G. Lafeber ◽  
K. Coeleveld ◽  
S. Versteeg ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Single Molecule ◽  
Mechanical Allodynia ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Synovial Inflammation ◽  
Interleukin 4 ◽  
Analgesic Effects ◽  
Metabolic Dysregulation ◽  
Anti Inflammatory

Objective Ideally, disease-modifying osteoarthritis (OA) drugs (DMOAD) should combine chondroprotective, anti-inflammatory, and analgesic effects in a single molecule. A fusion protein of interleukin-4 (IL-4) and IL-10 (IL4-10 FP) possesses these combined effects. In this study, the DMOAD activity of rat IL4-10 FP (rIL4-10 FP) was tested in a rat model of surgically induced OA under metabolic dysregulation. Design rIL4-10 FP was produced with HEK293F cells. Bioactivity of purified rIL4-10 FP was determined in a whole blood assay. Male Wistar rats ( n = 20) were fed a high-fat diet (HFD) to induce metabolic dysregulation. After 12 weeks, OA was induced according to the Groove model. Two weeks after OA induction, rats were randomly divided into 2 groups and treated with 10 weekly, intra-articular injections of either rIL4-10 FP ( n = 10) or phosphate buffered saline (PBS; n = 10). Possible antibody formation was evaluated using ELISA, cartilage degeneration and synovial inflammation were evaluated by histology and mechanical allodynia was evaluated using the von Frey test. Results Intra-articular injections with rIL4-10 FP significantly reduced cartilage degeneration ( P = 0.042) and decreased mechanical allodynia ( P < 0.001) compared with PBS. Only mild synovial inflammation was found (nonsignificant), limiting detection of putative anti-inflammatory effects. Multiple injections of rIL4-10 FP did not induce antibodies against rIL4-10 FP. Conclusion rIL4-10 FP showed chondroprotective and analgesic activity in a rat OA model with moderate cartilage damage, mild synovial inflammation, and pain. Future studies will need to address whether less frequent intra-articular injections, for example, with formulations with increased residence time, would also lead to DMOAD activity.

Expression of granulocyte macrophage-colony stimulating factor and its receptor in the synovium of osteoarthritis patients is negatively correlated with pain

Rheumatology ◽  
2020 ◽  
Vol 59 (11) ◽  
pp. 3452-3457 ◽  
Author(s):  
Eefje M van Helvoort ◽  
Niels Eijkelkamp ◽  
Floris P J G Lafeber ◽  
Simon C Mastbergen
Keyword(s):  
Synovial Tissue ◽  
Knee Pain ◽  
Ex Vivo ◽  
Cartilage Damage ◽  
Synovial Inflammation ◽  
Gm Csf ◽  
Knee Oa ◽  
Analgesic Effects ◽  
Womac Questionnaire ◽  
Tissue Cells

Abstract Objectives The crosstalk between the immune and nervous system in the regulation of OA pain is increasingly becoming evident. GM-CSF signals in both systems and might be a new treatment target to control OA pain. Anti GM-CSF treatment has analgesic effects in OA without affecting synovitis scores, suggesting that treatment effects are not caused by local anti-inflammatory effects. We aimed to evaluate whether expression of GM-CSF and its receptor GM-CSFrα in synovial tissue is linked to synovial inflammation and/or knee pain in knee OA patients. Methods Cartilage and synovial tissue of knee OA patients (n = 20) was collected during total knee replacement. Cartilage damage was evaluated by histology and ex vivo matrix proteoglycan turnover. Synovial inflammation was evaluated by histology and ex vivo synovial production of TNF-α, (PGE2) and nitric oxide (NO). Numbers of synovial tissue cells expressing GM-CSF or GM-CSFrα were determined by immunohistochemistry. Pain was evaluated using WOMAC questionnaire and visual analogue scale (VAS) knee pain. Results Collected cartilage and synovial tissue had a typical OA phenotype with enhanced cartilage damage and synovial inflammation. GM-CSF and GM-CSFrα expressing cells in the synovial sublining correlated negatively with knee pain. Cartilage damage and synovial inflammation did not correlate with knee pain. Conclusion Unanticipated, the negative correlation between synovial tissue cells expressing GM-CSF(r) and OA knee pain suggests that local presence of these molecules does not promote pain, and that the role of GM-CSFr in OA pain is unrelated to local inflammation. Trial registration ToetsingOnline.nl NL18274.101.07.

scholarly journals IL4-10 fusion protein has chondroprotective, anti-inflammatory and potentially analgesic effects in the treatment of osteoarthritis

2018 ◽  
Vol 26 (8) ◽  
pp. 1127-1135 ◽  
Author(s):  
C. Steen-Louws ◽  
J. Popov-Celeketic ◽  
S.C. Mastbergen ◽  
K. Coeleveld ◽  
C.E. Hack ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Analgesic Effects ◽  
Anti Inflammatory

scholarly journals A fusion protein of interleukin-4 and interleukin-10 protects against blood-induced cartilage damage in vitro and in vivo

2016 ◽  
Vol 24 ◽  
pp. S505
Author(s):  
A.E. Pulles ◽  
L.F. van Vulpen ◽  
R.E. Schutgens ◽  
M.E. van Meegeren ◽  
K. Coeleveld ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Cartilage Damage ◽  
Interleukin 10 ◽  
Interleukin 4

scholarly journals Anti-inflammatory and Analgesic Effects of Ketoprofen in Palm Oil Esters Nanoemulsion

2010 ◽  
Vol 59 (12) ◽  
pp. 667-671 ◽  
Author(s):  
Sakeena M. H. F. ◽  
Yam M. F. ◽  
Elrashid S. M. ◽  
Munavvar A. S. ◽  
Azmin M. N.
Keyword(s):  
Palm Oil ◽  
Analgesic Effects ◽  
Anti Inflammatory

scholarly journals POS0393 FIBRIN DEPOSITION IS AN ACTIVE TRIGGER OF CARTILAGE DEGENERATION IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 426.1-426
Author(s):  
T. Hügle ◽  
S. Nasi ◽  
D. Ehirchiou ◽  
P. Omoumi ◽  
A. So ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Cartilage Explants ◽  
Fibrin Deposition ◽  
Qrt Pcr ◽  
Catabolic Genes ◽  
Key Factor ◽  
Calcific Deposits

Background:Fibrin(ogen) maintains inflammation in various disorders but has never been linked to cartilage damage in rheumatoid arthritis (RA) or other forms of inflammatory arthritis.Objectives:To investigate the role of fibrin deposition on cartilage integrity in arthritis.Methods:Fibrin deposition on knee cartilage was analyzed by immunohistochemistry in RA patients and in murine adjuvant-induced arthritis (AIA). In chondrocytes, fibrinogen expression (Fgα, Fgβ, Fgγ) and procoagulant activity were evaluated by qRT-PCR and turbidimetry respectively. Fibrin-induced catabolic genes were assessed by qRT-PCR in chondrocytes. Fibrin-mediated chondro-synovial adhesion (CSA) with subsequent cartilage tears was studied in co-cultures of human RA cartilage with autologous synoviocytes, in the AIA model, and by MRI. The link between fibrin and calcification was examined in human RA cartilage stained for calcific deposits and in vitro in fibrinogen-stimulated chondrocytes.Results:Fibrin deposition on cartilage correlated with the severity of cartilage damage in human RA explants and in AIA wildtype (WT) mice, while fibrinogen deficient (Fg-/-) mice were protected. Accordingly, fibrin upregulated catabolic enzymes (Adamts5 and Mmp13) in chondrocytes. Secondly, CSA was present in fibrin-rich and damaged cartilage in AIA WT but not in Fg-/- mice. In line, autologous human synoviocytes, cultured on RA cartilage explants, adhered exclusively to fibrin-positive degraded areas. Gadolinium-enhanced MRI of human joints showed contrast-enhancement along cartilage surface in RA patients but not in controls. Finally, fibrin co-localized with calcification in human RA cartilage and triggered chondrocyte mineralization inducing pro-calcification genes (Anx5, Pit1, Pc1) and cytokine (IL-6). Although at a much lesser extent, we observed similar fibrin-mediated mechanisms in osteoarthritis (OA).Conclusion:Fibrin deposition directly impacts on cartilage integrity via induction of catabolism, mechanical stress, and calcification. Potentially, fibrin is a key factor of cartilage damage occurring in RA as a secondary consequence of inflammation.Disclosure of Interests:None declared

scholarly journals New ibuprofen derivatives with thiazolidine-4-one scaffold with improved pharmaco-toxicological profile

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ioana-Mirela Vasincu ◽  
Maria Apotrosoaei ◽  
Sandra Constantin ◽  
Maria Butnaru ◽  
Liliana Vereștiuc ◽  
...  
Keyword(s):  
Analgesic Effect ◽  
Visceral Pain ◽  
Biological Effects ◽  
Maximum Effect ◽  
Tail Flick ◽  
Paw Edema ◽  
Cell Viability Assay ◽  
Thermal Nociception ◽  
Analgesic Effects ◽  
Anti Inflammatory

Abstract Background Aryl-propionic acid derivatives with ibuprofen as representative drug are very important for therapy, being recommended especially for anti-inflammatory and analgesic effects. On other hand 1,3-thiazolidine-4-one scaffold is an important heterocycle, which is associated with different biological effects such as anti-inflammatory and analgesic, antioxidant, antiviral, antiproliferative, antimicrobial etc. The present study aimed to evaluated the toxicity degree and the anti-inflammatory and analgesic effects of new 1,3-thiazolidine-4-one derivatives of ibuprofen. Methods For evaluation the toxicity degree, cell viability assay using MTT method and acute toxicity assay on rats were applied. The carrageenan-induced paw-edema in rat was used for evaluation of the anti-inflammatory effect while for analgesic effect the tail-flick test, as thermal nociception in rats and the writhing assay, as visceral pain in mice, were used. Results The toxicological screening, in terms of cytotoxicity and toxicity degree on mice, revealed that the ibuprofen derivatives (4a-n) are non-cytotoxic at 2 μg/ml. In addition, ibuprofen derivatives reduced carrageenan-induced paw edema in rats, for most of them the maximum effect was recorded at 4 h after administration which means they have medium action latency, similar to that of ibuprofen. Moreover, for compound 4d the effect was higher than that of ibuprofen, even after 24 h of administration. The analgesic effect evaluation highlighted that 4 h showed increased pain inhibition in reference to ibuprofen in thermal (tail-flick assay) and visceral (writhing assay) nociception models. Conclusions The study revealed for ibuprofen derivatives, noted as 4 m, 4 k, 4e, 4d, a good anti-inflammatory and analgesic effect and also a safer profile compared with ibuprofen. These findings could suggest the promising potential use of them in the treatment of inflammatory pain conditions.

scholarly journals Beige adipocytes mediate the neuroprotective and anti-inflammatory effects of subcutaneous fat in obese mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
De-Huang Guo ◽  
Masaki Yamamoto ◽  
Caterina M. Hernandez ◽  
Hesam Khodadadi ◽  
Babak Baban ◽  
...  
Keyword(s):  
Subcutaneous Fat ◽  
Visceral Obesity ◽  
Interleukin 4 ◽  
Hippocampal Synaptic Plasticity ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Dietary Obesity ◽  
Anti Inflammatory ◽  
Subcutaneous Adiposity ◽  
The Relationship

AbstractVisceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not. Here, we report that beige adipocytes are indispensable for the neuroprotective and anti-inflammatory effects of subcutaneous fat. Mice lacking functional beige fat exhibit accelerated cognitive dysfunction and microglial activation with dietary obesity. Subcutaneous fat transplantation also protects against chronic obesity in wildtype mice via beige fat-dependent mechanisms. Beige adipocytes restore hippocampal synaptic plasticity following transplantation, and these effects require the anti-inflammatory cytokine interleukin-4 (IL4). After observing beige fat-mediated induction of IL4 in meningeal T-cells, we investigated the contributions of peripheral lymphocytes in donor fat. There was no sign of donor-derived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology. These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function.

scholarly journals Flunixin Meglumine Reduces Milk Isoprostane Concentrations in Holstein Dairy Cattle Suffering from Acute Coliform Mastitis

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 834
Author(s):  
Carsten C. F. Walker ◽  
Jill L. Brester ◽  
Lorraine M. Sordillo
Keyword(s):  
Medical Intervention ◽  
Systemic Involvement ◽  
Analgesic Effects ◽  
Markers Of Inflammation ◽  
Inflammatory Mediator Production ◽  
Flunixin Meglumine ◽  
Coliform Mastitis ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Oxidant Status

Dysfunctional inflammation contributes significantly to the pathogenesis of coliform mastitis and the classical pro-inflammatory enzyme cyclooxygenase-2 (COX-2) is the target of medical intervention using the non-steroidal anti-inflammatory drug (NSAID) flunixin meglumine (FM). Inhibition of COX-2 by FM can decrease concentrations of pro-inflammatory fatty acid-based mediators called eicosanoids, providing antipyretic and analgesic effects in dairy cows suffering from coliform mastitis. However, approximately 50% of naturally occurring coliform mastitis with systemic involvement results in death of the animal, even with NSAID treatment. Inadequate antioxidant potential (AOP) to neutralize reactive oxygen species (ROS) produced during excessive inflammation allows for oxidative stress (OS), contributing to tissue damage during coliform mastitis. Biomarkers of lipid peroxidation by ROS, called isoprostanes (IsoP), were used in humans and cattle to quantify the extent of OS. Blood IsoP were shown to be elevated and correlate with oxidant status during acute coliform mastitis. However, the effect of FM treatment on oxidant status and markers of OS has not been established. Blood IsoP concentrations were used to quantify systemic OS, whereas milk was used to assess local OS in the mammary gland. Results indicate that FM treatment had no effect on blood markers of inflammation but reduced the oxidant status index (OSi) by increasing blood AOP from pre- to post-FM treatment. Milk AOP significantly increased from pre- to post-FM treatment, whereas ROS decreased, resulting in a decreased OSi from pre- to post-FM treatment. The only blood IsoP concentration that was significantly different was 5-iso-iPF2α-VI, with a decreased concentration from pre- to post-FM treatment. Conversely, milk 5-iso-iPF2α-VI, 8,12-iso-iPF2α-VI, and total IsoP concentrations were decreased following FM treatment. These results indicated that administration of FM did improve systemic and local oxidant status and reduced local markers of OS. However, differential effects were observed between those animals that survived the infection and those that died, indicating that pre-existing inflammation and oxidant status greatly affect efficacy of FM and may be the key to reducing severity and mortality associated with acute coliform infections. Supplementation to improve AOP and anti-inflammatory mediator production may significantly improve efficacy of FM treatment.

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