Search Results (99)

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

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

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

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

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by severe pain, inflammation, and joint deformity. Currently, it affects 1% of the population, with a projection to exceed 23 million cases by 2030. Despite significant advancements, non-steroidal anti-inflammatory drugs (NSAIDs), the first line of treatment, are associated with a range of adverse effects. Consequently, plant-based derivatives are being utilized as an effective alternative. This study evaluates the anti-inflammatory and safety profile of Colchicum luteum hydroethanolic extract (CLHE) in comparison to NSAIDs, with a focus on COX-2 and TNFα inhibition. Methods: CLHE potential was evaluated by phytochemical screening and in vitro bioactivity assays. Toxicity profile was conducted in Human Colon Epithelial Cells (HCEC) and Balb/c mice. Anti-inflammatory potential was explored in a collagen-induced arthritic (CIA) mice model. Bioactive compounds were identified computationally from GCMS data and subjected to docking and simulation studies against COX2 and TNFα. Results: CLHE demonstrated significant antioxidant (IC-50 = 6.78 µg/mL) and anti-inflammatory (IC-50 = 97.39 µg/mL) activity. It maintained 50% cell viability at 78.5 μg/µL in HCEC cells and exhibited no toxicity at a dose of 5000 mg/kg in mice. In the CIA model, CLHE significantly reduced paw swelling, arthritic scoring, C-reactive protein levels, and spleen indices, outperforming ibuprofen. Expression analysis confirmed the downregulation of COX-2, TNFα, and MMP-9. Histopathological analysis indicated the superior efficacy of CLHE compared to ibuprofen in reducing inflammation, synovial hyperplasia, and bone erosion. Computational studies identified compound-15 (CL15), (4-(4,7-dimethoxy-1,3-benzodioxol-5-yl)-2-oxo pyrrolidine-3-carboxylic acid), a non-toxic compound with strong binding affinities to COX-2 (−12.9 KJ/mol), and TNF-α (−5.8 KJ/mol). Conclusions: The findings suggest the potential of Colchicum luteum as a safer, anti-inflammatory, and multi-targeted alternative to NSAIDs for RA treatment. Full article

Background: In response to inflammation, the absorption of nutritional iron is restricted. Since the pathophysiological significance of the presence and uptake of iron in chronic inflammation is still unknown, we tested the effect of a low iron diet on the clinical course of arthritis in the mouse model of collagen-induced arthritis (CIA). Methods: Six- to eight-week-old male DBA/1 mice were fed either a normal (51 mg/kg) or a low iron diet (5 mg/kg) starting four weeks before the first immunization. From day 4 after the second collagen booster made on day 25, the development of arthritis was regularly monitored until the end of the experiment (day 34), using a standard clinical arthritis score. Concentrations of mouse anti-bovine and anti-mouse collagen type 2 IgG antibodies were measured by ELISA; blood cell counts were performed and mediators of inflammation, tissue matrix degradation, oxygenation and oxidative stress were measured in the mouse sera of both diet groups at the end of the experiment by bead-based multiplex assay. Fe²⁺, Fe³⁺, oxidized and reduced glutathione (GSH and GSSG) and malondialdehyde (MDA) were quantified in whole paw tissue by ELISA. Quantitative PCR was performed in the tissues for glutathione peroxidase 4 and other key regulator genes of iron metabolism and ferroptosis. We used nonparametric tests to compare cross-sectional data. Nonlinear regression models were used for longitudinal data of the arthritis scores. Results: Mice fed a low iron diet showed a significantly less severe course of arthritis compared to mice fed a normal iron diet (p < 0.001). The immune response against bovine and mouse type 2 collagen did not differ between the two diet groups. Mice fed a low iron diet exhibited significantly lower serum levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), a central regulator of inflammation and tissue matrix degradation (p < 0.05). In addition, a low iron diet led to a significant reduction in red blood cell indices, indicating restricted iron uptake and latent iron deficiency, but had no effect on hemoglobin concentrations or red blood cell counts. There were no differences between the dietary groups in Fe²⁺ or Fe³⁺ content in the paws. Based on calculation of the GSH/GSSG ratio and high MDA levels, high oxidative stress and lipid peroxidation were likewise detected in the paws of both diet groups of mice. Consequently, no differences associated with gene expression of key regulators of iron metabolism and ferroptosis could be detected between the paws of both diet groups. Conclusions: Restricted dietary iron intake alleviates immune-mediated inflammation in CIA without causing anemia. This finding suggests a promising option for dietary treatment of arthritis in inflammation. The underlying mechanism causing reduced arthritis may be linked to the complex regulatory network of TIMP-1 and appears to be independent from the local iron levels, oxidative stress and ferroptosis in the synovial tissues. Full article

The anti-inflammatory/immunomodulatory effects of Teucrium montanum L. (TM), a plant distributed in the Mediterranean region, have been insufficiently examined. The effects of the TM ethanol extract were tested in a rat collagen-induced arthritis (CIA) model of rheumatoid arthritis. LC-MS was used for the phytochemical analysis of the TM extract. Dark Agouti rats were immunized with bovine type II collagen (CII) in incomplete Freund’s adjuvant for CIA, and treated with 100 or 200 mg/kg of TM extract daily via oral administration. Clinical and histopathological evaluations and a flow cytometric analysis of the phenotypic and functional characteristics of splenocytes and draining lymph node cells were performed. The cytokines in the paw tissue culture supernatants and anti-CII antibodies in serum were determined by ELISA. The TM extract, with the dominant components verbascoside and luteolin 7-O-rutinoside, reduced the arthritic score and ankle joint inflammation in CIA rats, promoted the antioxidant profile in serum, and lowered pro-inflammatory TNF-α, IL-6 and IL-1β production. It suppressed the activation status of CD11b+ cells by lowering CD86, MHCII and TLR-4 expression, and promoted the Th17/T regulatory cell (Tregs) balance towards Tregs. A lower frequency of B cells was accompanied by a lower level of anti-CII antibodies in treated rats. These findings imply the favorable effect of TM extract on the clinical presentation of CIA, suggesting its anti-inflammatory/immunomodulatory action and potential therapeutic effect. Full article

Background: Rheumatoid arthritis (RA) tends to occur in symmetrical joints and is always accompanied by synovial hyperplasia and cartilage damage. Triptolide (TP), an extract from Tripterygium, has anti-inflammatory and immunomodulatory properties and could be used in the treatment of RA. However, its poor water solubility and the multi-system lesions caused by the use of this substance limit its clinical application. Therefore, it would be of great significance to assemble a composite nanoparticle hydrogel and apply it to a collagen-induced arthritis (CIA) mouse model to investigate the therapeutic effect and biosafety of this compound. Method: TP@HSA nanoparticles (TP@HSA NPs) were fabricated with a self-assembly method; a thermosensitive hydrogel loaded with the TP@HSA NPs (TP@HSA NP hydrogel) was prepared by using chitosan and beta- glycerophosphate (β-GP) and was then intra-articularly injected into CIA mice. The changes in joint swelling were measured with a digital caliper, and inflammation and cartilage damage were evaluated by using hematoxylin and eosin (H&E) and safranin O–fast green (SO&FG) staining, respectively. Results: TP@HSA NPs with an average diameter of 112 ± 2 nm were successfully assembled, and their encapsulation efficiency and drug loading efficiency were 47.6 ± 1.5% and 10.6 ± 3.3%, respectively. The TP@HSA NP hydrogel had a gelation temperature of 30.5 ± 0.2 °C, which allows for its injection at low temperatures and its sol–gel transformation under physiological conditions within 2 min, making it a suitable drug depot. The TP@HSA NP hydrogel was intra-articularly injected into CIA mice; it released TP locally and exerted anti-inflammatory and immunomodulatory effects, alleviating synovial inflammation and cartilage damage effectively. Conclusions: We successfully fabricated a TP@HSA NP-loaded thermosensitive hydrogel with good biosafety, which can release TP slowly for the treatment of RA. Our study provides a basis for the development of TP-based innovative preparations and has good application prospects. Full article

Background: The effects of collagen-induced arthritis (CIA), a model of systemic inflammation, on brain regional molecular markers associated with neurological disorders are uncertain. Objective: This study investigated the brain regional molecular changes in markers associated with inflammation and neuronal dysfunction in a CIA model. Methods: Fourteen male Sprague Dawley rats were divided into control (n = 5) or CIA (n = 9) groups. 10 weeks after CIA induction, brain tissue was collected. Brain regional mRNA expression of inflammatory markers (IL-1β and IL-6), apoptotic markers (BAX and Bcl2) and neurotrophic factors (BDNF, CREB and TrkB) was determined. Monoamine distribution and abundance in different brain regions were determine by mass spectrometry imaging (MSI). Results: Neuroinflammation was confirmed in the CIA group by increased IL-β mRNA expression, concurrent with an increased BAX/Bcl2 ratio. The mRNA expression of CREB was increased in the midbrain and hippocampus while BDNF was increased and TrkB was decreased across all brain regions in CIA compared to control animals. Serotonin was decreased in the midbrain and hippocampus while dopamine was decreased in the striatum of CIA rats, compared to controls. Conclusion: CIA resulted in neuroinflammation concurrent with an apoptotic state and aberrant expression of neurotrophic factors and monoamines in the brain, suggestive of neurodegeneration. Full article