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1.
Int J Nanomedicine ; 19: 4411-4427, 2024.
Article in English | MEDLINE | ID: mdl-38774028

ABSTRACT

Background: Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by synovial inflammation and joint destruction. Despite progress in RA therapy, it remains difficult to achieve long-term remission in RA patients. Phosphodiesterase 3B (Pde3b) is a member of the phosphohydrolyase family that are involved in many signal transduction pathways. However, its role in RA is yet to be fully addressed. Methods: Studies were conducted in arthritic DBA/1 mice, a suitable mouse strain for collagen-induced rheumatoid arthritis (CIA), to dissect the role of Pde3b in RA pathogenesis. Next, RNAi-based therapy with Pde3b siRNA-loaded liposomes was assessed in a CIA model. To study the mechanism involved, we investigated the effect of Pde3b knockdown on macrophage polarization and related signaling pathway. Results: We demonstrated that mice with CIA exhibited upregulated Pde3b expression in macrophages. Notably, intravenous administration of liposomes loaded with Pde3b siRNA promoted the macrophage anti-inflammatory program and alleviated CIA in mice, as indicated by the reduced inflammatory response, synoviocyte infiltration, and bone and cartilage erosion. Mechanistic study revealed that depletion of Pde3b increased cAMP levels, by which it enhanced PKA-CREB-C/EBPß pathway to transcribe the expression of anti-inflammatory program-related genes. Conclusion: Our results support that Pde3b is involved in the pathogenesis of RA, and Pde3b siRNA-loaded liposomes might serve as a promising therapeutic approach against RA.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Cyclic Nucleotide Phosphodiesterases, Type 3 , Genetic Therapy , Liposomes , Macrophages , Mice, Inbred DBA , RNA, Small Interfering , Animals , Liposomes/chemistry , Liposomes/administration & dosage , Cyclic Nucleotide Phosphodiesterases, Type 3/genetics , Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/therapy , Arthritis, Rheumatoid/chemically induced , Mice , Arthritis, Experimental/genetics , Arthritis, Experimental/prevention & control , Arthritis, Experimental/therapy , Macrophages/drug effects , RNA, Small Interfering/genetics , RNA, Small Interfering/administration & dosage , Genetic Therapy/methods , Male , Signal Transduction/drug effects
2.
Prostaglandins Other Lipid Mediat ; 172: 106823, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38408536

ABSTRACT

Arthritis, a prevalent inflammatory condition, is often linked to obesity as a contributing factor. This study aimed to assess the potential protective effects of purslane extract in male albino rats with induced arthritis and obesity. Fifty rats were randomly assigned to five groups: a control group, an induced arthritis-high-fat diet group, a high-dose purslane extract-supplemented group (300 mg/kg body weight) for 8 weeks, a low-dose purslane extract-supplemented group (150 mg/kg body weight) for 8 weeks, and a metformin-supplemented group. Arthritis was induced in the rats using Complete Freund's Adjuvant. Plasma biomarkers, including Total Cholesterol, Triglycerides, HDL-cholesterol, LDL-cholesterol, C Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), Rheumatoid Factor (RF), and Anti-CCP, were assessed in each group. The results revealed a significant improvement in these biomarkers in the high-dose purslane-supplemented group (300 mg/kg body weight) compared to the induced arthritis-high-fat-diet group. This suggests a potential protective role of purslane against arthritis associated with obesity, likely attributed to its lipolytic capacity and anti-inflammatory properties. These findings contribute to our understanding of the interplay between obesity, arthritis, and natural interventions, providing valuable insights for future therapeutic approaches.


Subject(s)
Arthritis, Experimental , Obesity , Plant Extracts , Animals , Obesity/metabolism , Obesity/drug therapy , Male , Rats , Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Arthritis, Experimental/prevention & control , Plant Extracts/pharmacology , Biomarkers/blood , Diet, High-Fat/adverse effects , C-Reactive Protein/metabolism
3.
Article in English | MEDLINE | ID: mdl-38064497

ABSTRACT

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial tissue inflammation, substantially impacting the quality of life of patients. The interaction between L-selectin and its glycoprotein ligands modified with 6-sulfo sialyl Lewis x (6-sulfo sLex) is known to mediate lymphocyte homing to initiate immune responses. Thus, this process could be a potential therapeutic target for RA. Herein, we explored the preventive effects of an anti-6-sulfo sLex monoclonal antibody (mAb), SF1, on collagen-induced arthritis (CIA) in DBA/1 mice. Mice were administered SF1 from day 21 postfirst immunization with type II collagen (CII), and the effects of SF1 on both clinical and histopathological disease progression evoked by the second immunization were examined. SF1 significantly suppressed clinical features and histological levels associated with arthritis severity. Enzyme-linked immunosorbent assay consistently indicated that SF1 inhibited the production of CII-specific IgG2a. Based on the reverse transcription-quantitative PCR analysis, SF1 suppressed the expression of interferon-γ, a T helper 1 cytokine, as well as that of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, in draining lymph nodes. Collectively, these results indicate that SF1, an anti-sulfated glycan mAb, could be beneficial in preventing CIA in mice and may afford as a novel agent to treat RA.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Oligosaccharides , Sialyl Lewis X Antigen/analogs & derivatives , Humans , Mice , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/prevention & control , Quality of Life , Antibodies, Monoclonal , Mice, Inbred DBA , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/prevention & control , Cytokines
4.
Nat Commun ; 14(1): 5949, 2023 09 23.
Article in English | MEDLINE | ID: mdl-37741824

ABSTRACT

Rheumatoid arthritis (RA) involves several classes of pathogenic autoantibodies, some of which react with type-II collagen (COL2) in articular cartilage. We previously described a subset of COL2 antibodies targeting the F4 epitope (ERGLKGHRGFT) that could be regulatory. Here, using phage display, we developed recombinant antibodies against this epitope and examined the underlying mechanism of action. One of these antibodies, R69-4, protected against cartilage antibody- and collagen-induced arthritis in mice, but not autoimmune disease models independent of arthritogenic autoantibodies. R69-4 was further shown to cross-react with a large range of proteins within the inflamed synovial fluid, such as the complement protein C1q. Complexed R69-4 inhibited neutrophil FCGR3 signaling, thereby impairing downstream IL-1ß secretion and neutrophil self-orchestrated recruitment. Likewise, human isotypes of R69-4 protected against arthritis with comparable efficiency. We conclude that R69-4 abrogates autoantibody-mediated arthritis mainly by hindering FCGR3 signaling, highlighting its potential clinical utility in acute RA.


Subject(s)
Arthritis, Experimental , Humans , Animals , Mice , Arthritis, Experimental/prevention & control , Neutrophils , Collagen , Autoantibodies , Epitopes
5.
Drug Deliv Transl Res ; 13(7): 1925-1935, 2023 07.
Article in English | MEDLINE | ID: mdl-36971998

ABSTRACT

Metabolic reprogramming of immune cells modulates their function and reduces the severity of autoimmune diseases. However, the long-term effects of the metabolically reprogrammed cells, specifically in the case of immune flare-ups, need to be examined. Herein, a re-induction rheumatoid arthritis (RA) mouse model was developed by injecting T-cells from RA mice into drug-treated mice to recapitulate the effects of T-cell-mediated inflammation and mimic immune flare-ups. Immune metabolic modulator paKG(PFK15 + bc2) microparticles (MPs) were shown to reduce clinical symptoms of RA in collagen-induced arthritis (CIA) mice. Upon re-induction, a significant delay in the reappearance of clinical symptoms in the paKG(PFK15 + bc2) microparticle treatment group was observed as compared to equal or higher doses of the clinically utilized U.S. Food and Drug Administration (FDA)-approved drug, Methotrexate (MTX). Furthermore, paKG(PFK15 + bc2) microparticle-treated mice were able to lower activated dendritic cells (DCs) and inflammatory T helper cell 1 (TH1) and increased activated, proliferating regulatory T-cells (Tregs) more effectively than MTX. The paKG(PFK15 + bc2) microparticles also led to a significant reduction in paw inflammation in mice as compared to MTX treatment. This study can pave the way for the development of flare-up mouse models and antigen-specific drug treatments.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Vaccines , Mice , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Methotrexate/therapeutic use , Disease Models, Animal , Inflammation/drug therapy
6.
Int J Rheum Dis ; 26(4): 718-726, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36808837

ABSTRACT

AIM: We aimed to evaluate the preventive role of the tyrosine kinase inhibitor dasatinib in an animal model of rheumatoid arthritis (RA). METHODS: DBA/1J mice were injected with bovine type II collagen to induce arthritis (collagen-induced arthritis [CIA]). There were four experimental groups of mice, namely negative control (non-CIA), vehicle-treated CIA, dasatinib-pretreated CIA, and dasatinib-treated CIA. After collagen immunization, arthritis progression in the mice was clinically scored twice weekly for 5 weeks. Flow cytometry was used to evaluate in vitro CD4+ T-cell differentiation and ex vivo mast cell/CD4+ T-cell differentiation. Osteoclast formation was evaluated using tartrate-resistant acid phosphatase (TRAP) staining and by estimating the resorption pit area. RESULTS: We found that the clinical arthritis histological scores were lower in the dasatinib pretreatment group than in the vehicle and dasatinib post-treatment groups. Flow cytometry showed that FcεR1+ cells were downregulated and regulatory T cells were upregulated in splenocytes of the dasatinib pretreatment group compared with those in the vehicle group. Additionally, there was a decline in IL-17+ CD4+ T-cell differentiation and an increase in CD4+ CD24high Foxp3+ T-cell differentiation with in vitro dasatinib treatment of human CD4+ T cells. The number of TRAP+ osteoclasts and the area of the resorption were decreased in the bone marrow cells derived from dasatinib-pretreated mice compared with those derived from vehicle group. CONCLUSION: Dasatinib protected against arthritis in an animal model of RA by regulating the differentiation of regulatory T cells and IL-17+ CD4+ T cells and inhibiting osteoclastogenesis, indicating the therapeutic potential of dasatinib in the treatment of early RA.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Humans , Animals , Cattle , Mice , Interleukin-17/therapeutic use , Dasatinib/pharmacology , Dasatinib/therapeutic use , Mice, Inbred DBA , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/prevention & control , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Arthritis, Experimental/prevention & control , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use
7.
Environ Toxicol ; 37(7): 1814-1822, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35446470

ABSTRACT

To explore the therapeutic value of lupeol on collagen-induced arthritis (CIA) in rats, a rheumatoid arthritis model. Lupeol is well known pentacyclic triterpene found in various plant sources, which possess anti-inflammatory and antioxidant actions. The current study was assessed the anti-arthritic potential of lupeol and its molecular mechanisms as compared with indomethacin (Indo) in collagen-induced arthritis CIA rats. The rats were randomly alienated into five groups: Control, CIA alone, CIA + lupeol (10 mg/kg bw), CIA + Indomethacin (3 mg/kg bw), and lupeol (10 mg/kg bw) alone. The paw volume, biochemical, hematological parameters, inflammatory enzymes, and cytokines were measured. As well protein expression of apoptotic proteins, and histopathological of ankle joint were examined. Inflammatory markers, cytokines, histological changes, paw volume, and inflammation were intensely reduced and enhanced apoptosis by lupeol. Alterations in hematological parameters, rheumatoid factor, C-reactive protein, and ceruloplasmin in arthritis were reverted by lupeol. Protein expressions of Bcl-2, and P13K/Akt signaling were declined, whereas the Bax, caspssae-3, and caspase-9 were elevated. These results highlighted that lupeol suppresses P13K/Akt signaling and has a promising anti-arthritic potential for collagen-induced rheumatic arthritis treatment. Hence lupeol would be suggested as an alternative natural source with potent anti-inflammatory and apoptotic actions for chronic inflammatory disorders.


Subject(s)
Arthritis, Experimental , Animals , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Arthritis, Experimental/prevention & control , Collagen Type II/therapeutic use , Collagen Type II/toxicity , Cytokines/metabolism , Indomethacin , Pentacyclic Triterpenes/pharmacology , Pentacyclic Triterpenes/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction
8.
Pak J Pharm Sci ; 35(1(Supplementary)): 253-257, 2022 Jan.
Article in English | MEDLINE | ID: mdl-35228185

ABSTRACT

Terbutaline have been reported to have anti-inflammatory activity. Present study aimed to check the anti-arthritic activity of terbutaline. The drug was tested using in vitro models (bovine serum albumin denaturation, egg albumin denaturation and HRBC membrane stabilization) and in vivo (formaldehyde induced arthritis). Results of bovine serum albumin denaturation assay illustrated that terbutaline inhibited 89.54±0.46% denaturation at 6400µg/ml concentration. Terbutaline resulted in dose dependent impediment of protein denaturation in egg albumin denaturation assay with 74.40±0.72% inhibition at concentration of 6400µg/ml. Terbutaline also showed protection of HRBC membrane against hypotonic stress in a dose dependent manner, with maximum 76.45±0.62% prevention at 6400µg/ml concentration. Results of formaldehyde induced arthritis model showed that paw volume was significantly declined by terbutaline with maximum percentage inhibition at 10th day of study period which implies immune inhibitory potential of terbutaline. Findings of present study concluded that terbutaline has arthritis reducing potential possible through inhibitory effects on synthesis and release of inflammatory mediators as well as limiting the formation of autoantigen. Thus, terbutaline might be the potential candidate for use in treatment of arthritis.


Subject(s)
Arthritis, Experimental/prevention & control , Sympathomimetics/pharmacology , Terbutaline/pharmacology , Animals , Arthritis, Experimental/chemically induced , Female , Formaldehyde/toxicity , Male , Ovalbumin/chemistry , Rats , Rats, Sprague-Dawley , Serum Albumin, Bovine
9.
Connect Tissue Res ; 63(6): 625-633, 2022 11.
Article in English | MEDLINE | ID: mdl-35313755

ABSTRACT

OBJECTIVE: To clarify the role of glucocerebrosidase (GBA) and Ceramide (Cer) in rheumatoid arthritis (RA). METHODS: GBA-expressing lentivirus were constructed and injected into collagen-induced arthritis (CIA) mice, and compared with CIA mice injected with empty vector. The severity of arthritis and inflammatory mediators were evaluated. Fibroblast-like synoviocytes (FLS) from RA patients were transfected with GBA-expressing lentivirus, or pretreated with C6-Cer. The migration and invasion of FLS, the production of inflammatory cytokines, and the relevant signaling pathways were assessed. RESULTS: In CIA mice, GBA markedly improved arthritis compared to that in the CIA mice, with increased content of proteoglycan and integral cartilage surfaces and tidemarks. The circulating inflammatory mediators, including interleukin (IL)-1ß, IL-6, IL-18, and matrix metalloproteinase (MMP)-1, were significantly reduced in CIA mice with GBA overexpression compared to those in CIA mice. GBA and C6-Cer treatment inhibited migration and invasion of FLS, and suppressed production of inflammatory cytokines and activation of the MAPK pathways. CONCLUSION: GBA/Cer exhibited a protective role in CIA mice and RA FLS. These results highlight the potential of targeting GBA/Cer as a therapeutic strategy in RA and warrant further investigation.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/drug therapy , Cells, Cultured , Ceramides/metabolism , Ceramides/therapeutic use , Cytokines/metabolism , Fibroblasts/metabolism , Glucosylceramidase/genetics , Glucosylceramidase/metabolism , Glucosylceramidase/therapeutic use , Inflammation Mediators/metabolism , Interleukin-18/metabolism , Interleukin-18/therapeutic use , Interleukin-6/metabolism , Mice , Proteoglycans/metabolism , Synovial Membrane/metabolism
10.
Nat Commun ; 13(1): 676, 2022 02 03.
Article in English | MEDLINE | ID: mdl-35115492

ABSTRACT

Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial fibroblasts proliferate abnormally in the presence of reactive oxygen species (ROS) and elevated lipid oxidation. Here we show, using a collagen-induced arthritis (CIA) mouse model, that imidazole ketone erastin (IKE), a ferroptosis inducer, decreases fibroblast numbers in the synovium. Data from single-cell RNA sequencing further identify two groups of fibroblasts that have distinct susceptibility to IKE-induced ferroptosis, with the ferroptosis-resistant fibroblasts associated with an increased TNF-related transcriptome. Mechanistically, TNF signaling promotes cystine uptake and biosynthesis of glutathione (GSH) to protect fibroblasts from ferroptosis. Lastly, low dose IKE together with etanercept, a TNF antagonist, induce ferroptosis in fibroblasts and attenuate arthritis progression in the CIA model. Our results thus imply that the combination of TNF inhibitors and ferroptosis inducers may serve as a potential candidate for RA therapy.


Subject(s)
Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/prevention & control , Ferroptosis/drug effects , Fibroblasts/drug effects , Imidazoles/pharmacology , Ketones/pharmacology , Piperazines/pharmacology , Tumor Necrosis Factor Inhibitors/pharmacology , Animals , Arthritis, Experimental/genetics , Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/metabolism , Cells, Cultured , Disease Models, Animal , Drug Therapy, Combination , Etanercept/pharmacology , Etanercept/therapeutic use , Fibroblasts/cytology , Fibroblasts/metabolism , Glutathione/metabolism , Humans , Imidazoles/therapeutic use , Ketones/therapeutic use , Lipid Peroxidation/drug effects , Mice , Piperazines/therapeutic use , Reactive Oxygen Species/metabolism , Synovial Membrane/cytology , Tumor Necrosis Factor Inhibitors/therapeutic use
11.
Arch Physiol Biochem ; 128(3): 679-687, 2022 Jun.
Article in English | MEDLINE | ID: mdl-31994915

ABSTRACT

MicroRNAs have been implicated in the pathogenesis of rheumatoid arthritis (RA) and their syntheses are modulated by glycogen synthase kinase-3ß (GSK-3ß). Therefore, we hypothesised that the GSK-3ß inhibitor, TDZD-8 can protect against collagen-induced arthritis (CIA) via downregulating miR155 and miR-24 expression. Rats were randomly allocated into four groups (n = 6) as follows: Control, Control + TDZD-8 (1 mg/kg), CIA, and CIA + TDZD-8. Rats were sacrificed after 6 weeks. We observed in the model group (CIA) significant (p<.05) increase in arthritis score and serum levels of RA biomarkers, which were significantly (p < .05) inhibited by TDZD-8. TDZD-8 also significantly (p<.05) inhibited CIA-induced synovial tissue levels of miR155, miR-24, and inflammation. In addition, a significant (p<.05) modulation of biomarkers of survival (Bcl-2) and apoptosis (cleaved caspase-3) by TDZD-8 was observed. Thus, TDZD-8 protects against CIA in rats for a period of 6 weeks, which is associated with the inhibition of miR155/24 and inflammation, and apoptosis augmentation.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , MicroRNAs , Thiadiazoles/pharmacology , Animals , Apoptosis , Arthritis, Experimental/genetics , Arthritis, Experimental/prevention & control , Biomarkers , Collagen Type II , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta/genetics , Inflammation , MicroRNAs/genetics , Rats , Up-Regulation
12.
Biochem Pharmacol ; 195: 114869, 2022 01.
Article in English | MEDLINE | ID: mdl-34896056

ABSTRACT

NFκB plays a key role in inflammation and skeletal disorders. Previously, we reported that pharmacological inhibition of NFκB at the level of TRAF6 suppressed RANKL, CD40L and IL1ß-induced osteoclastogenesis and attenuated cancer-induced bone disease. TNFα is also known to regulate TRAF6/NFκB signalling, however the anti-inflammatory and osteoprotective effects associated with inhibition of the TNFα/TRAF6/NFκB axis have not been investigated. Here, we show that in vitro and ex vivo exposure to the verified small-molecule inhibitor of TRAF6, 6877002 prevented TNFα-induced NFκB activation, osteoclastogenesis and calvarial osteolysis, but it had no effects on TNFα-induced apoptosis or growth inhibition in osteoblasts. Additionally, 6877002 disrupted T-cells support for osteoclast formation and synoviocyte motility, without affecting the viability of osteoblasts in the presence of T-cells derived factors. Using the collagen-induced arthritis model, we show that oral and intraperitoneal administration of 6877002 in mice reduced joint inflammation and arthritis score. Unexpectedly, no difference in trabecular and cortical bone parameters were detected between vehicle and 6877002 treated mice, indicating lack of osteoprotection by 6877002 in the arthritis model described. Using two independent rodent models of osteolysis, we confirmed that 6877002 had no effect on trabecular and cortical bone loss in both osteoporotic rats or RANKL- treated mice. In contrast, the classic anti-osteolytic alendronate offered complete osteoprotection in RANKL- treated mice. In conclusion, TRAF6 inhibitors may be of value in the management of the inflammatory component of bone disorders, but may not offer protection against local or systemic bone loss, unless combined with anti-resorptive therapy such as bisphosphonates.


Subject(s)
Anti-Inflammatory Agents/pharmacology , CD40 Antigens/antagonists & inhibitors , Osteolysis/prevention & control , TNF Receptor-Associated Factor 6/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemistry , Arthritis, Experimental/metabolism , Arthritis, Experimental/prevention & control , CD40 Antigens/metabolism , Cell Line, Tumor , Humans , Jurkat Cells , Male , Mice , Mice, Inbred C3H , Mice, Inbred DBA , Osteoblasts/cytology , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteoclasts/cytology , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteogenesis/drug effects , Osteolysis/metabolism , RAW 264.7 Cells , Rodentia/metabolism , TNF Receptor-Associated Factor 6/metabolism , Tumor Necrosis Factor-alpha/pharmacology
13.
Parasite Immunol ; 44(1-2): e12901, 2022 01.
Article in English | MEDLINE | ID: mdl-34931316

ABSTRACT

AIMS: Immunomodulatory effects of parasitic infections on the outcomes of allergic or autoimmune disorders have been addressed in many experimental studies. We examined the effects of Plasmodium yoelii 17X NL (Py) infection on collagen-induced arthritis (CIA). METHODS AND RESULTS: Male DBA/1J mice were immunized with bovine type II collagen (IIC). Py inoculation was induced at three different time points (1, 4 weeks after or 4 weeks before the immunization). Only the inoculation at 4 weeks after IIC immunization significantly inhibited arthritis development. Non-malarial anaemia induced by phenylhydrazine hydrochloride (PHZ) did not affect arthritis development. In the infected mice, anti-IIC IgG levels were transiently reduced. In addition, splenic production of pro-arthritic cytokines (IL-17 and TNF-α) and IFN-γ decreased, whereas IL-10 production increased. Flow cytometric analysis clarified that the main IL-10 producers in Py-infected mice had the CD4+ CD25- Foxp3- phenotype, presumably Tr1 cells. CONCLUSION: We demonstrated that experimental malarial infection alleviated autoimmune arthritis via immunomodulation, suggesting the importance of malaria in the hygiene hypothesis and the significance of searching for therapeutic immunomodulatory molecules from malarial parasites.


Subject(s)
Arthritis, Experimental , Malaria , Animals , Arthritis, Experimental/prevention & control , Cattle , Cytokines , Immunomodulation , Malaria/prevention & control , Male , Mice , Mice, Inbred DBA , Rodentia
14.
J Agric Food Chem ; 69(46): 13821-13830, 2021 Nov 24.
Article in English | MEDLINE | ID: mdl-34752070

ABSTRACT

Studies have revealed that a novel anti-inflammatory mediator─maresin-1 (MaR1)─can reduce the level of inflammatory factors. There is evidence that physical exercise (PE) promotes the biosynthesis of MaR1, leading to the prevention of rheumatoid arthritis (RA). Previously, we have proven that resveratrol can mitigate the formation of RA. Pterostilbene (Pte) is an analogue of resveratrol, but it is around four times more bioavailable. Hence, we hypothesize that Pte could be more effective in preventing RA, in particular, when accompanied by moderate PE. Based on this hypothesis, we explored the preventive effect of Pte combined with PE on a bovine type II collagen (BIIC)-stimulated rat RA model and its underlying molecular mechanism. Compared with the BIIC-stimulated group, the serum content of MaR1 with continuous intervention of Pte plus PE for 8 weeks was significantly increased to 46.3 pg/mL from 7.2 pg/mL in BIIC-treated alone. Besides, the variation in the relative expression levels of p-NF-κB and p-Akt was reversed with the administration of Pte plus PE. More importantly, the in vitro results confirmed that the treatment of Pte plus MaR1 inhibited proliferation and apoptosis and promoted the autophagy of the interleukin (IL)-1ß-stimulated primary rat synovial cells through the PI3K/Akt/NF-κB signal pathway. Collectively, the oral administration of Pte plus moderate PE helped to ameliorate the pathological process of RA by correcting the PI3K/Akt/NF-κB signal pathway.


Subject(s)
Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/prevention & control , NF-kappa B , Proto-Oncogene Proteins c-akt , Stilbenes/administration & dosage , Animals , Cattle , Collagen , NF-kappa B/genetics , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Physical Conditioning, Animal , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Rats , Signal Transduction
15.
PLoS Pathog ; 17(11): e1010069, 2021 11.
Article in English | MEDLINE | ID: mdl-34748611

ABSTRACT

ES-62 is the major secreted protein of the parasitic filarial nematode, Acanthocheilonema viteae. The molecule exists as a large tetramer (MW, ~240kD), which possesses immunomodulatory properties by virtue of multiple phosphorylcholine (PC) moieties attached to N-type glycans. By suppressing inflammatory immune responses, ES-62 can prevent disease development in certain mouse models of allergic and autoimmune conditions, including joint pathology in collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Such protection is associated with functional suppression of "pathogenic" hyper-responsive synovial fibroblasts (SFs), which exhibit an aggressive inflammatory and bone-damaging phenotype induced by their epigenetic rewiring in response to the inflammatory microenvironment of the arthritic joint. Critically, exposure to ES-62 in vivo induces a stably-imprinted CIA-SF phenotype that exhibits functional responses more typical of healthy, Naïve-SFs. Consistent with this, ES-62 "rewiring" of SFs away from the hyper-responsive phenotype is associated with suppression of ERK activation, STAT3 activation and miR-155 upregulation, signals widely associated with SF pathogenesis. Surprisingly however, DNA methylome analysis of Naïve-, CIA- and ES-62-CIA-SF cohorts reveals that rather than simply preventing pathogenic rewiring of SFs, ES-62 induces further changes in DNA methylation under the inflammatory conditions pertaining in the inflamed joint, including targeting genes associated with ciliogenesis, to programme a novel "resolving" CIA-SF phenotype. In addition to introducing a previously unsuspected aspect of ES-62's mechanism of action, such unique behaviour signposts the potential for developing DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA. Pertinent to these translational aspects of ES-62-behavior, small molecule analogues (SMAs) based on ES-62's active PC-moieties mimic the rewiring of SFs as well as the protection against joint disease in CIA afforded by the parasitic worm product.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/prevention & control , Epigenesis, Genetic , Fibroblasts/metabolism , Helminth Proteins/pharmacology , Inflammation/prevention & control , Synoviocytes/metabolism , Acanthocheilonema/metabolism , Animals , Arthritis, Experimental/etiology , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Cells, Cultured , DNA Methylation , Fibroblasts/drug effects , Fibroblasts/immunology , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Male , Mice , Mice, Inbred DBA , Synoviocytes/drug effects , Synoviocytes/immunology
16.
Dis Markers ; 2021: 7933453, 2021.
Article in English | MEDLINE | ID: mdl-34845417

ABSTRACT

Rheumatoid arthritis (RA) is an autoimmune disease leading to severe joint damage and disability. Fibroblast-like synoviocytes (FLSs) mostly contribute to the joint inflammation and destruction in RA through distinct mechanisms. However, little is known about newly discovered interleukin- (IL-) 36 and IL-38 involving in the pathology of RA. Here, we assessed the effect of IL-36 and IL-38 on RA-FLS function using IL-36 and IL-38 overexpression plasmids. We found that IL-36 inhibited synoviocytes proliferation while IL-38 showed an opposite influence. Furthermore, IL-36 and IL-38 significantly sequestered or accelerated RA-FLS migration and invasion capacity, respectively. Mechanically, IL-36 and IL-38 targeted autophagy for RA-FLS modulation. Using autophagy inhibitor 3-MA and inducer compound rapamycin, we found that autophagy negatively regulated the survival, migration, and invasion of synovial cells. Based on these results, IL-38 in combination with autophagy inhibitor 3-MA treatment demonstrated the strongest blockage of the above three activities of RA-FLS, and IL-38 overexpression reversed rapamycin-inhibited cell proliferation, migration, and invasion. Moreover, injection of IL-36 can improve the symptoms of RA in a rat model of RA. Taken together, we conclude that IL-38 and IL-36 target autophagy for regulating synoviocyte proliferation, migration, and invasion in RA.


Subject(s)
Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/prevention & control , Autophagy , Cell Movement , Interleukin-1/administration & dosage , Interleukins/administration & dosage , Synoviocytes/drug effects , Animals , Apoptosis , Arthritis, Experimental/etiology , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/etiology , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Cell Proliferation , Cells, Cultured , Male , Rats , Rats, Sprague-Dawley , Synoviocytes/metabolism , Synoviocytes/pathology
17.
Biomed Pharmacother ; 144: 112294, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34653764

ABSTRACT

Tolerizing DNA vaccines encoding key autoantigens are one of emerging strategies for the treatment of rheumatoid arthritis (RA). Among these vaccines, the most representative is pcDNA-CCOL2A1, an antigen-specific DNA vaccine encoding chicken type Ⅱ collagen (CCⅡ) with significant therapeutic and prophylactic efficacy in collagen-induced arthritis (CIA) rat models. We compared the in situ expression levels of CCOL2A1-mRNA and CCⅡ protein and the protective efficacies against CIA after a single dose (300 µg/kg) of this vaccine via intramuscular (IM), subcutaneous (SC) and intravenous (IV) vaccinations. The IM vaccination routes resulted in good protective efficacies in terms of decreasing CIA incidence and severity and significantly improved radiographic and histopathologic findings and scores of joints. Furthermore, IM, SC, and IV vaccinations markedly decreased serum levels of anti-type Ⅱ collagen (CⅡ) IgG antibodies, but only IM vaccination significantly reduced serum levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody. The vaccine exhibited a continuous CCOL2A1-mRNA expression in the tail and abdominal subcutaneous tissue injection sites, but no CCOL2A1-mRNA signal was observed in muscle. Strikingly, CCⅡ protein expression levels at the three injection sites were comparable with minimal variation. IM administration may be considered the preferred route for RA treatment in clinical practice.


Subject(s)
Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/prevention & control , Autoantibodies/blood , Collagen Type II/administration & dosage , Joints/drug effects , Vaccination , Vaccines, DNA/administration & dosage , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/diagnostic imaging , Arthritis, Experimental/immunology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Collagen Type II/genetics , Collagen Type II/immunology , Female , Injections, Intramuscular , Injections, Intravenous , Injections, Subcutaneous , Joints/diagnostic imaging , Joints/immunology , Joints/metabolism , Rats, Wistar , Time Factors , Vaccine Efficacy , Vaccines, DNA/genetics , Vaccines, DNA/immunology
18.
Front Immunol ; 12: 737990, 2021.
Article in English | MEDLINE | ID: mdl-34659230

ABSTRACT

Angiogenesis is a critical process in the formation of new capillaries and a key participant in rheumatoid arthritis (RA) pathogenesis. The adipokine apelin (APLN) plays critical roles in several cellular functions, including angiogenesis. We report that APLN treatment of RA synovial fibroblasts (RASFs) increased angiopoietin-1 (Ang1) expression. Ang1 antibody abolished endothelial progenitor cell (EPC) tube formation and migration in conditioned medium from APLN-treated RASFs. We also found significantly higher levels of APLN and Ang1 expression in synovial fluid from RA patients compared with those with osteoarthritis. APLN facilitated Ang1-dependent EPC angiogenesis by inhibiting miR-525-5p synthesis via phospholipase C gamma (PLCγ) and protein kinase C alpha (PKCα) signaling. Importantly, infection with APLN shRNA mitigated EPC angiogenesis, articular swelling, and cartilage erosion in ankle joints of mice with collagen-induced arthritis. APLN is therefore a novel therapeutic target for RA.


Subject(s)
Angiopoietin-1/metabolism , Apelin/metabolism , Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/metabolism , Endothelial Progenitor Cells/metabolism , Fibroblasts/metabolism , MicroRNAs/metabolism , Neovascularization, Pathologic , Synoviocytes/metabolism , 3T3 Cells , Angiopoietin-1/genetics , Animals , Apelin/genetics , Arthritis, Experimental/genetics , Arthritis, Experimental/pathology , Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/pathology , Chick Embryo , Endothelial Progenitor Cells/pathology , Fibroblasts/pathology , Humans , Mice , MicroRNAs/genetics , RNA Interference , Signal Transduction , Synoviocytes/pathology
19.
Biomarkers ; 26(8): 788-807, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34704882

ABSTRACT

CONTEXT: Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by aggressive and systematic polyarthritis. OBJECTIVE: The present study aimed to isolate and identify the phenolic constituents in Brassica oleracea L. (Brassicaceae) seeds methanolic extract and evaluates its effect against rheumatoid arthritis in rats referring to the new therapy; interleukin-1 receptor antagonist (IL-1RA). MATERIALS AND METHODS: The GC/MS profiling of the plant was determined. Arthritis induction was done using complete Freund's adjuvant. Arthritis severity was assessed by percentage of edema and arthritis index. IL-1 receptor type I gene expression, interleukin-1ß (IL-1ß), oxidative stress markers, protein content, inflammatory mediators, prostaglandin-E2 (PGE2), genetic abnormalities and the histopathological features of ankle joint were evaluated. RESULTS: For the first time twelve phenolic compounds had been isolated from the seeds extract. Treatment with extract and IL-1RA improved the tested parameters by variable degrees. CONCLUSIONS: RA is an irreversible disease, where its severity increases with the time of induction. Brassica oleracea L. seeds extract is considered as a promising anti-arthritis agent. IL-1 RA may be considered as an unusual therapeutic agent for RA disease. More studies are needed to consider the seeds extract as a nutraceutical agent and to recommend IL-1RA as a new RA drug.


Subject(s)
Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/prevention & control , Brassica/chemistry , Inflammation Mediators/metabolism , Phytochemicals/pharmacology , Receptors, Interleukin-1 Type I/antagonists & inhibitors , Seeds/chemistry , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/metabolism , Biomarkers/blood , Freund's Adjuvant , Gene Expression Regulation/drug effects , Humans , Interleukin 1 Receptor Antagonist Protein/metabolism , Interleukin-1beta/metabolism , Male , Molecular Structure , Oxidative Stress/drug effects , Phytochemicals/chemistry , Phytotherapy/methods , Plant Extracts/chemistry , Plant Extracts/pharmacology , Rats, Wistar , Receptors, Interleukin-1 Type I/genetics , Receptors, Interleukin-1 Type I/metabolism , Signal Transduction/drug effects
20.
Eur Rev Med Pharmacol Sci ; 25(17): 5402-5411, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34533814

ABSTRACT

OBJECTIVE: Chondroitin sulfate (CS) is a glycosaminoglycan with proven anti-inflammatory, anti-apoptotic, anti-oxidant properties. CS increases type II collagen and proteoglycan synthesis in human joint chondrocytes. CS can reduce the production of pro-inflammatory mediators and proteases to improve the anabolic/catabolic balance of the extracellular cartilage matrix (ECM). Due to these characteristics, it is a natural compound that is considered to be Symptomatic Slow-Acting Drugs for Osteoarthritis (SYSADOA). Microbial chondroitin sulfate (MCS) was produced from two different bacterial sources using biotechnological methods by our team. In this study, we aimed to apply microbially produced CS and bovine-derived commercial CS forms to rabbit knees with osteoarthritis experimentally and to evaluate the results. MATERIALS AND METHODS: In this study, a cruciate ligament cutting model was applied to 40 New Zealand rabbits to induce experimental osteoarthritis. Four weeks after the surgical procedure, rabbits were divided into 4 groups as control, animal-derived MCS, E coli-derived MCS and PaJC-derived MCS group. The standard rabbit diet was fed to the control group, and the other groups were additionally fed 17 mg/kg/day CS/MCS for 12 weeks. The rabbits were sacrificed at the 12th week after surgery and the preparations obtained were evaluated histopathologically. RESULTS: As a result, it was observed that regeneration tissue was statistically significant in histopathological cartilage tissue compared to the control group of CS developed from different sources given to rabbits with osteoarthritis. It was determined that among the CS groups produced from different sources, the group with the highest chondroprotective effect was MCS originating from E.coli. CONCLUSIONS: This vegan product (MCS), which we obtained as a result of our study, was produced by our team from a microbial source. According to our analysis, it has the potential to be an effective alternative therapy agent in the treatment of osteoarthritis.


Subject(s)
Arthritis, Experimental/prevention & control , Chondroitin Sulfates/pharmacology , Escherichia coli/metabolism , Osteoarthritis, Knee/prevention & control , Animals , Cattle , Chondroitin Sulfates/biosynthesis , Disease Models, Animal , Rabbits
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