Search Results (166)

Background/Objectives: Rheumatoid arthritis (RA) is a chronic, systemic, and progressive autoimmune–inflammatory disease primarily affecting small joints. Inonotus obliquus polysaccharide (IOP) is the main component of the parasitic fungus obliquus, which has anti-tumor, anti-inflammatory, and antioxidant effects. However, whether IOP has a therapeutic effect on RA is still unclear. Thus, this study aimed to reveal the effect of IOP on MH7A cells and collagen-induced arthritis (CIA) rats and to investigate the molecular mechanism of IOP in RA. Methods: In this study, network pharmacology was used to identify the key signaling pathways in IOP treatment of RA. The effect of IOP was verified in rats with CIA. We performed CCK-8, EdU, colony formation assay, cell apoptosis, cell migration and invasion, Western blot analysis, and immunofluorescence to elucidate the effect of IOP on the proliferation, apoptosis, migration and invasion of MH7A cells and revealed its modulation of the NF-κB and NLRP3 inflammasome signaling pathways. Results: IOP treatment of CIA rats significantly alleviated joint swelling, synovial tissue proliferation and erosion, and reduced the expression of inflammatory factors TNF-α, IL-6, IL-1β and IL-18. In vitro, IOP significantly inhibited the proliferation, migration, and invasion abilities of TNF-α-stimulated MH7A cells and promoted their apoptosis. Mechanistically, IOP inhibited the NF-κB and NLRP3 inflammasome activation. Conclusions: This study revealed that IOP exerts anti-RA effects by downregulating the NF-κB and NLRP3 inflammasome signaling pathways, promoting cell apoptosis, and inhibiting the expression of inflammatory cytokines, representing a promising therapeutic option for RA. Full article

Background: Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is a significant complication of RA which lacks effective treatments with high mortality. This study aimed to investigate the role of matrix metalloproteinase-7 (MMP-7) in mediating RA-ILD. Methods: Based on the database of RA-ILD patients, a bioinformatics analysis was performed. A protein–protein interaction (PPI) network focusing on MMP-7 was simulated. Pleural mesothelial cells (PMCs) were treated with RA-ILD patients’ serum or RA-ILD-related inflammatory factors, and the protein expressions of collagen-I and MMP-7 were examined. An arthritis model was established using complete Freund’s adjuvant (CFA). Changes in the weight and joints of mice were recorded, and lung tissues were evaluated by Masson staining and Sirius red stain techniques. MMP-7 inhibitor, MMP-7 siRNA and MMP shRNA lentivirus were used to inhibit MMP-7 and investigate changes in collagen-I and fibrosis in vivo and in vitro. Results: MMP-7 was found to be significantly expressed in RA-ILD lung tissue by bioinformatics analysis, and MMP-7 to maybe interact with collagen-I. In vitro experiments indicated cytokines IL-1β, IL-6 and TNF-α promoted MMP-7 and collagen-I expression in PMCs. Serum obtained from patients with RA-ILD also upregulated MMP-7 and collagen-I expression in PMCs. Inhibition of MMP-7 with MMP-7 siRNA or MMP inhibitor prevented collagen-I synthesis in PMCs. In vivo, CFA induced arthritis and subpleural lung inflammation in rats, but the MMP-7 inhibitor and MMP-7 siRNA attenuated CFA-induced lung inflammation and subpleural lung fibrosis. Conclusions: MMP-7 mediated subpleural lung inflammation as well as fibrosis in RA-ILD. It provided theoretical and experimental support for MMP-7 being a therapeutic target in RA-ILD. Full article

BYVET JOINT HEAL^TM (BJH) contains mucopolysaccharide protein, chondroitin sulfate, type II collagen, and omega-3 fatty acids, which protect and prevent osteoarthritis (OA)-associated tissue damage and degradation in dogs and cats. This study aimed to generate a novel dietary supplement and evaluate its prevention and therapeutic efficacy in an OA Sprague Dawley rat model induced using monosodium iodoacetate (MIA). Negative control, MIA-induced OA control (MIA), OA rats treated with BJH three weeks after (M+BJH3) and those treated two weeks before and three weeks after OA induction (BJH2+M+BJH3) groups were assigned. M+BJH3 and BJH2+M+BJH3 had similar mean body weight increases until 29 days. BJH2+M+BJH3 showed a significantly higher body weight than M+BJH3 and MIA on the final day. Interleukin-1β in BJH2+M+BJH3 was significantly lower than that in MIA. Tumor necrosis factor-α, aggrecan, matrix metalloproteinases13, and cyclooxygenase-2 levels in M+BJH3 and BJH2+M+BJH3 significantly differed compared to those in MIA. BJH administration before OA induction significantly decreased OA severity and functional recovery. Consuming a BJH supplement showed modifying and chondroprotective effects and significantly reduced cartilage degeneration and inflammation with no side effects. Hence, our findings demonstrate the potential of using BJH as a safe therapeutic and preventive supplement for OA and associated cartilage abnormalities. Also, 30 dogs diagnosed with OA by a veterinarian participated in the clinical trial, and BJH was provided for 8 weeks. Blood tests (CBC, serum chemistry) and joint assessment were performed before and after the feeding, and the effects of a BJH supplement were compared. BJH supplement was easy to administer, and no side effects were reported. Feeding BJH supplementation alone to dogs with arthritis had an overall positive effect on arthritis scores for 8 weeks without any other treatment, including non-steroidal drugs. Full article

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder whose precise etiology remains unclear, though growing evidence implicates gut microbiota in its pathogenesis. This study aimed to investigate the role of gut microbiota in the onset and progression of RA by employing fecal microbiota transplantation (FMT) in a collagen-induced arthritis (CIA) mouse model using DBA/1J and Aire⁻/⁻ strains. Mice received FMT from healthy donors, treatment-naïve RA patients, or treated RA patients in relapse, followed by assessment of microbiota composition via 16S rRNA sequencing, arthritis severity scoring, histological evaluations, and systemic inflammatory markers. The findings revealed distinct microbiota clustering patterns post-FMT across experimental groups, highlighting strain-specific colonization effects. Notably, genera such as Bifidobacterium and Paraprevotella correlated positively with arthritis severity in DBA/1J mice, whereas Corynebacterium, Enterorhabdus, and Odoribacter exhibited negative correlations, suggesting potential protective roles. Despite these microbial differences, minor variations in arthritis scores, paw inflammation, or systemic inflammation were observed among FMT groups. This indicates that although gut microbiota alterations are associated with RA pathogenesis, further investigation with larger cohorts and comprehensive sequencing approaches is essential to elucidate the therapeutic potential of microbiome modulation in autoimmune diseases. Full article

Lysophosphatidylinositols are degradation products of phosphatidylinositols within cell membranes and digestive metabolites of a high-fat diet in the gut. G-protein-coupled receptor 55 (GPR55) is a receptor that senses lysophosphatidylinositol and acts as an immune mediator, being primarily upregulated during immune cell activation. This study aimed to investigate the role of GPR55, using its antagonist, CID16020046, in a collagen-induced rheumatoid arthritis mouse model. It was observed that DBA-1J mice develop joint lesions characteristic of rheumatoid arthritis following immunization with bovine type II collagen. The administration of CID16020046 (1 mg/kg, intraperitoneally) alleviated rheumatoid arthritis symptoms and inflammatory responses. Histopathological analysis showed that CID16020046 reduced foot edema, proteoglycan loss, and bone erosion in the joints. CID16020046 also decreased rheumatoid-arthritis-induced serum IgG levels, as measured using enzyme-linked immunosorbent assays. The treatment reduced levels of pro-inflammatory cytokines (IL-1β and IL-6), Th1 cytokine (IFN-γ), and Th17 cytokine (IL-17A), along with matrix metalloproteinase-3 (MMP-3) and the receptor activator of nuclear factor-κB ligand (RANKL) in the feet. A significant reduction in splenomegaly was also observed, along with significant reductions in CD4⁺ T helper 1 (Th1) and Th17 cells in the spleen. Additionally, CID16020046 suppressed the differentiation of naïve T cells into CD4⁺IL-17⁺ Th17 cells. CID16020046 suppressed expression levels of inflammatory cytokine mRNAs in SW982 human synovial cells. In conclusion, blocking GPR55 alleviates collagen-induced rheumatoid arthritis symptoms by suppressing Th1 and Th17 cells in the spleen and pro-inflammatory cytokines in the joints, suggesting that GPR55 is a potential therapeutic target for autoimmune inflammatory diseases. Full article

RA is a chronic autoimmune disease characterized by synovial inflammation and joint damage, driven by autoantibodies such as ACPA, anti-CarP and RF. These autoantibodies, influenced by genetic and environmental factors, play a crucial role in RA pathogenesis through post-translational modifications like citrullination, carbamylation, and acetylation. The early detection of ACPA provides a potential window for intervention, while anti-CarP antibodies correlate with severe disease progression and RF aids in diagnosis. Translating these findings from human pathology to animal models presents significant challenges. Although the presence of adaptative immune cells (T cells) is well defined in animal models of RA, studies yield inconsistent results regarding autoantibody production and implication in the disease onset and progression, with varying detectability of ACPA, anti-CarP antibodies, and RF across different species and models. The collagen-induced arthritis (CIA) model shows PAD4 expression and citrullinated protein presence but inconsistent ACPA detection, while the K/BxN model elucidates the pathogenicity of anti-GPI autoantibodies and implicates Fcγ receptors in disease processes. Therefore, further research is needed to bridge the gap between animal models and human RA pathology. Future studies should focus on developing more representative animal models, exploring pharmacological targets and pathways that involve the interplay between anti-inflammatory and autoimmune responses, and investigating the complex interplay between genetic predisposition, environmental triggers, and autoimmune mechanisms. This approach may lead to improved early diagnostic tools, targeted therapies, and potentially preventive strategies for RA, ultimately enhancing patient outcomes and quality of life. Full article

We investigated the effects of belt electrode-skeletal muscle electrical stimulation (B-SES) on muscle atrophy in collagen-induced arthritis (CIA) rats. Twenty-eight 8-week-old male Dark Agouti rats were immunized with type II collagen and Freund’s incomplete adjuvant (day 0). From days 14 to 28, 18 rats received B-SES (50 Hz) four times only on the right hindlimb (STIM), while the contralateral left hindlimb remained unstimulated. Both hindlimbs of 10 untreated CIA rats were defined as controls (CONT). Paw volume was measured every other day. On day 28, the muscle weight, histology, and gene expression of the soleus and extensor digitorum longus (EDL) were analyzed. B-SES did not worsen paw volume throughout the experimental period. Compared with CONT, the muscle weight and fiber cross-sectional area of the soleus were higher in STIM. The expression of muscle degradation markers (atrogin-1 and MuRF-1) in the soleus and EDL was lower in the STIM group than that in the CONT group. In contrast, B-SES did not significantly affect the expression of muscle synthesis (Eif4e and p70S6K) and mitochondrial (PGC-1α) markers. B-SES prevents muscle atrophy in CIA rats by reducing muscle degradation without exacerbating arthritis, demonstrating its promising potential as an intervention for RA-induced muscle atrophy. Full article

Palbociclib, a dual CDK4/6 kinase inhibitor used for breast cancer, has been explored as a treatment option for rheumatoid arthritis (RA). Preclinical studies have reported palbociclib-induced myelosuppression, but no such effects have been observed in Cdk4 or Cdk6 single-deficient mice. Synoviocyte proliferation-associated in collagen-induced arthritis 1/serum amyloid A-like 1 (SPACIA1/SAAL1) is involved in G1 phase progression. Given that SPACIA1/SAAL1 upregulates CDK6 (but not CDK4) expression, we aimed to determine whether suppressing CDK6 expression alone could prevent synovial hyperplasia without myelosuppression. The effects of CDK6 expression on TNF-α-induced rheumatoid arthritis synovial fibroblast (RASF) proliferation and synovial hyperplasia in collagen-induced arthritis (CIA) mice were investigated by modulating the transcriptional level with a CDK6 expression inhibitor (indole-3-carbinol), CDK6 small interfering RNA (siRNA), and Cdk6-deficient mice. Indole-3-carbinol or CDK6 siRNA inhibited TNF-α-induced RASF proliferation without suppressing CDK4 expression and reduced retinoblastoma protein phosphorylation. In CIA mice, indole-3-carbinol did not cause myelosuppression, considerably delayed CIA onset and progression, and reduced arthritis severity. Cdk6-deficient mice showed similar improvements in CIA pathogenesis but had lower serum anti-type II collagen IgG levels. Notably, synovial hyperplasia was not observed in Cdk6-deficient mice. CIA-synovial hyperplasia depends on CDK6, but not CDK4, expression. Full article

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease, and it is currently incurable. Tetrandrine (TET) has an obvious curative effect with therapeutic efficacy on RA, but its use is limited due to its poor water-solubility and bioavailability. Therefore, TET-loaded nanomicelles modified with chitosan, stearic acid, and folic acid (FCST) was prepared in the study, and the pharmacokinetics and pharmacodynamics were studied. Methods: The plasma concentrations of FCST and TET were measured by the PLC-MS/MS method at different times, and the pharmacokinetic parameters were calculated. A collagen-induced arthritis (CIA) model was established with rats. On the 16th day after the first immunization, 50 rats were randomized into five groups with 10 rats in each group according to the arthritis score. The drugs were administered by intraperitoneal injection for 30 days. The swelling degree and joint score of the rats were tested during each administration. In addition, the pro-inflammatory factors IL-1β, IL-6, IL-17, and TNF-α in the serum of the rats were tested by an ELISA kit, and their joints were examined by histopathology. Results: Pharmacokinetic studies showed that the AUC_0–72h of FCST was 1.93 times that of TET. FCST demonstrated higher bioavailability compared to TET (p < 0.05). Pharmacodynamic studies demonstrated that FCST had significant anti-inflammatory effects, and its anti-inflammatory activity was stronger compared to the same dose of TET, as evidenced by measuring toe thickness and observing toe appearance. It significantly reduced the expression of IL-1, IL-6, IL-17, and TNF-α in rats with rheumatoid arthritis (p < 0.05). Conclusions: FCST can significantly improve bioavailability and has a significant therapeutic effect on rheumatoid arthritis. Full article

Background: Caryopteris mongolica Bunge (CM) shows promising potential for managing rheumatoid arthritis (RA) and digestive disorders, attributed to its rich content of bioactive compounds such as polyphenols and flavonoids. Despite its common use in herbal tea, the specific mechanisms underlying CM’s anti-inflammatory and joint-protective effects remain unclear, limiting its development as a functional food. This study investigated the effects of aqueous CM extract on RA in collagen-induced arthritis (CIA) rats and explored the underlying mechanisms. Methods: Forty-eight female Sprague-Dawley rats were randomly assigned to six groups (n = 8): normal control, CIA model, methotrexate (MTX), and CM high-, middle-, and low-dose groups. Anti-inflammatory and joint-protective effects were evaluated using biochemical and histological analyses. To elucidate the mechanisms, we applied metabolomics, network pharmacology, and transcriptomics approaches. Results: The results demonstrated that CM extract effectively suppressed synovial inflammation in CIA rats, reducing joint degradation. CM’s anti-inflammatory effects were mediated through the TNF signaling pathway, modulating glycerophospholipid and amino acid metabolism, including reduced levels of tryptophan, LysoPC, and asparagine. Molecular docking identified scutellarin and apigenin as key bioactive compounds. Additionally, immunofluorescence analysis revealed CM’s therapeutic effects via TNF signaling inhibition and suppression of M1 macrophage polarization. Conclusions: These findings highlight the therapeutic potential of CM for RA and support its development as a functional food or pharmaceutical product. Full article

The amount of sphingosine 1-phosphate (S1P) found in the synovial tissue of individuals with rheumatoid arthritis is five times greater than that in those with osteoarthritis. Our study aims to determine whether inhibiting S1P₂ can mitigate collagen-induced rheumatoid arthritis (CIA) by using an S1P₂ antagonist, JTE-013, alongside DBA-1J S1pr2 wild-type (WT) and knock-out (KO) mice. CIA causes increases in arthritis scores, foot swelling, synovial hyperplasia, pannus formation, proteoglycan depletion, cartilage damage, and bone erosion, but these effects are markedly reduced when JTE-013 is administered to S1pr2 WT mice. CIA also elevates mRNA expression levels of pro-inflammatory Th1/Th17 cytokines in the foot and spleen, which are significantly decreased by JTE-013 in S1pr2 WT mice. Additionally, CIA raises Th1/Th17 and Treg cell counts, while JTE-013 reduces these elevations in the spleens of S1pr2 WT mice. Treatment with JTE-013 or the absence of S1pr2 curtails the differentiation of naïve T cells into Th1 and Th17 cells in a dose-dependent manner. In SW982 human synovial cells, JTE-013 lowers LPS-induced increases in pro-inflammatory cytokine levels. Overall, these findings propose that blocking S1P₂ in immune and synovial cells may alleviate rheumatoid arthritis symptoms and offer a potential therapeutic approach. Full article

Campylaephora hypnaeoides (C. hypnaeoides) was extracted using fermented ethanol. The effect of fermented ethanol extract of C. hypnaeoides (FeCH) on chondrocyte viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-iphenyltetrazolium bromide assay, which showed no cytotoxicity at 2 mg/mL. FeCH pretreatment in IL-1β-stimulated chondrocytes significantly inhibited the accumulation of nitric oxide and prostaglandin E₂, which was analyzed using the ELISA assay. In addition, protein expression levels of inflammatory-related factors, such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6, tumor necrosis factor-alpha, and cartilage-degrading-related enzymes, such as matrix metalloproteinases-1, -3, and -13, and a disintegrin and metalloproteinase with thrombospondin motifs-4 and -5 were significantly decreased in IL-1β-stimulated chondrocytes pretreated with FeCH, which were analyzed using western blot analysis. In addition, as a result of analyzing the content of collagen type II (Col II) and proteoglycan through western blot analysis and alcian blue staining, FeCH pretreatment prevented the degradation of Col II and proteoglycan. It was analyzed through western blot analysis that the chondroprotective effect of FeCH may be mediated through MAPKs and NF-κB-signaling mechanisms. In an in vivo study, an osteoarthritis experimental animal model with damaged medial meniscus (DMM) was utilized and orally administered daily for 8 weeks after surgery. At the study end point, knee joints were harvested and subjected to histological analysis with safranin O staining. As a result, articular cartilage was significantly protected in the FeCH group compared to the DMM group. These results suggest FeCH as a candidate material for the development of pharmaceutical materials for the treatment or prevention of degenerative arthritis. Full article

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized primarily by the synovial infiltration of inflammatory cells. Macrophage infiltration in the joint synovium is one of the early hallmarks of RA disease activity. Cortex periplocae, which has been widely employed in traditional Chinese medicine (TCM) to alleviate RA, harbors a bioactive compound known as Periploca sepium periplosides (PePs). In this study, collagen antibody-induced arthritis (CAIA) was established in mice through the administration of collagen antibodies and lipopolysaccharide (LPS), followed by treatment with PePs. The therapeutic effects of PePs were evaluated by measuring paw thickness, clinical arthritis scores, and histological changes in joint tissues. Flow cytometry and qRT-PCR were used to assess macrophage polarization in vivo and in vitro. The findings indicate that PePs effectively attenuated CAIA by suppressing the polarization of RAW264.7 cells towards the M1 phenotype while promoting their polarization towards the M2 phenotype. These results provide valuable insights into the scientific significance of PePs as a potential therapeutic agent for RA. Full article

Cytokines play a complex and pivotal role in modulating synovitis in rheumatoid arthritis. Interleukin (IL)-37 is known for its extensive anti-inflammatory properties that set it apart from the majority of other IL-1 family members. However, IL-37a, a member of the IL-37 family, lacks research into rheumatoid arthritis. This research aims to explore the role of IL-37a in regulating T-cell homeostasis in rheumatoid arthritis using the Collagen-Induced Arthritis(CIA) model. IL-37atg mice, a genetically altered strain carrying the human IL-37a gene, were used to test the influence of this cytokine on the progression of arthritis. The results show that IL-37atg mice demonstrated a notable reduction in both the incidence and severity of arthritis relative to WT mice. The protective effect was accompanied by lower levels of cytokines in plasma and synovial tissues (such as IL-17A and IL1β) that drive the inflammatory response. The ratio of Th17/Treg decreased in the lymph nodes of IL-37atg mice. However, the knockout of IL1R8 in IL37atg mice eliminated the effects of IL-37a. Additionally, transcriptomic analysis revealed that Th17 cell differentiation is a key pathway through which IL-37a exerts its protective effects, and experiments confirmed that IL-37a suppresses Th17-polarizing in vitro. Full article

Inflammation plays an essential role in the phases of rheumatoid arthritis (RA) as the joints secrete a range of molecules that modulate the inflammatory process. While therapies based on physical properties have shown effectiveness in a range of animal experimental models, the understanding of their biological mechanisms remains unclear. The aim of this study was to investigate the immunomodulatory effects of a 0.1 terahertz (THz) wave in rheumatoid arthritis in an attempt to dissect the molecular pathways implicated. The collagen-induced rheumatoid arthritis (CIA) model joint mice were irradiated daily for 30 min over a period of 2 weeks with continuous 0.1 terahertz waves. High-throughput bulk RNA sequencing of the murine blood was performed to analyze and characterize the differences in gene expression changes between the control (Ctrl), CIA (RA), and CIA exposed to THz. Differentially expressed genes, canonical pathway analysis, gene set enrichment, and protein–protein interaction were further run on the selected DEGs. We found that terahertz exposure downregulated gene ontologies representing the “TGF-β signaling pathway”, “apoptosis”, “activation of T cell receptor signaling pathway”, and “non-canonical NF-κB signal transduction”. These observations were further confirmed by a decreased level in the expression of transcription factors Nfib and Nfatc3, and an increased level of Lsp1. In addition, the expression of Mmp8 was significantly restored. These results indicate that THz ultimately attenuates the inflammatory response of hemocytes through the T cell and NF-κB pathway, and these changes are reverberated in the blood transcriptome. In this first report of transcriptome sequencing in a model of rheumatoid arthritis exposed to terahertz waves, the downregulated DEGs were associated with anti-inflammatory effects. Full article