Search Results (118)

Background/Objectives: Rheumatoid arthritis (RA) is an autoimmune disorder manifesting as joint destruction and synovial inflammation, with the aberrant activation of fibroblast-like synoviocytes (FLSs) functioning as a critical pathological mechanism. Liquiritigenin (LIQ), a natural flavonoid extracted from licorice root, possesses anti-inflammatory and antioxidant activities; however, its efficacy and mechanism in RA pathological models remain unclear. This study aimed to investigate the anti-RA effects of LIQ mediated through FLSs and its underlying mechanisms. Methods: Complete Freund’s adjuvant (CFA)-induced rat model and TNF-α-stimulated MH7A cell model were employed to assess the anti-RA effects and underlying mechanisms. In vivo experiments examined the effects of LIQ on RA manifestations, joint damage, and inflammatory responses in CFA-induced rats, while in vitro experiments explored its effects on aberrant activation, oxidative stress, and inflammation in TNF-α-stimulated MH7A cells. The regulatory effects of LIQ on the Nrf2/NF-κB/NLRP3 signaling pathway were validated by immunofluorescence and Western blotting in vivo and in vitro. Results: LIQ alleviated joint swelling and bone damage, reducing synovial cellular infiltration and hyperplastic changes in CFA-induced rats. Furthermore, LIQ inhibited proliferation, migration, and invasion while reducing reactive oxygen species levels in TNF-α-stimulated MH7A cells, and decreased IL-1β and IL-18 levels in rat serum and MH7A cell supernatants. Moreover, LIQ activated Nrf2 and inhibited NF-κB and NLRP3, thereby attenuating inflammatory responses and alleviating oxidative stress. Administration of the Nrf2 inhibitor ML385 partially reversed its suppressive effects on inflammatory responses and oxidative stress in vivo and in vitro. Conclusions: LIQ exerted anti-RA effects in FLSs by suppressing inflammation and aberrant activation. Its mechanism may involve modulation of the Nrf2/NF-κB/NLRP3 signaling pathway. Full article

Objective: This study aimed to investigate whether pomolic acid (PA), a predicted bioactive metabolite of the Dong botanical drug Madeng’ai (MDA), suppresses inflammatory cytokine expression by inhibiting nuclear factor-κB (NF-κB) pathway activation in a tumor necrosis factor-α (TNF-α)-induced human rheumatoid arthritis fibroblast-like synoviocyte (RA-HFLS) model. Methods: PA content in MDA from different regions and harvest years was quantified via High-Performance Liquid Chromatography (HPLC). Network analysis was employed as a hypothesis-generating tool to predict potential targets and pathways, followed by molecular docking to validate the binding affinity of PA to core targets of the NF-κB pathway, and ADMET prediction to evaluate its pharmacokinetic properties and safety profile. The RA-HFLS inflammatory model was induced by TNF-α. Cell viability and inflammatory cytokine secretion were assessed using Cell Counting Kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA). NF-κB signaling pathway activation and downstream gene expression were examined by Western blot and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. Results: HPLC analysis revealed that MDA samples from Guizhou harvested in 2019 contained the highest PA content (0.1117 mg/g). Network analysis predicted the NF-κB signaling pathway as a candidate mechanism underlying PA’s potential anti-inflammatory effects. Molecular docking showed that PA stably bound to IKKβ, p65, and IκBα, while ADMET prediction indicated favorable intestinal absorption, low drug–drug interaction risk, and good genetic safety, albeit with potential hepatotoxicity and reproductive toxicity risks. In the TNF-α-induced RA-HFLS model, PA dose-dependently inhibited abnormal cell proliferation and significantly reduced the secretion of pro-inflammatory cytokines TNF-α and interleukin-6 (IL-6). Mechanistic studies indicated that PA suppressed the activation of the NF-κB signaling pathway, thereby downregulating the mRNA expression of inflammatory genes such as IL-6, TNF-α, and interleukin-1β (IL-1β). Conclusions: PA, a bioactive metabolite of the Dong botanical drug MDA, may inhibit NF-κB signaling pathway activation, thereby downregulating TNF-α-induced inflammatory cytokine expression in RA-HFLS, demonstrating its in vitro anti-inflammatory potential. Full article

Rheumatoid arthritis (RA) treatment is severely hindered by the systemic toxicity and limited joint accumulation of conventional therapeutics. To overcome these critical clinical challenges, we engineered a biomimetic dual-targeted nanoplatform (MTX@HSA@M@HA NPs) to precisely deliver methotrexate (MTX) to inflamed synovia. The rationally designed system encapsulates MTX within human serum albumin (HSA) nanoparticles, which are subsequently cloaked in red blood cell membranes (RBCMs) for robust immune evasion and prolonged systemic circulation. To achieve active targeting, the nanoparticle surface was functionalized with hyaluronic acid (HA) to selectively bind CD44 receptors, which are heavily overexpressed on RA-driving macrophages and fibroblast-like synoviocytes (FLSs). In vitro evaluations demonstrated significantly enhanced cellular internalization by activating RAW264.7 macrophages and FLS, resulting in the potent suppression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) with minimal baseline cytotoxicity. Furthermore, comprehensive in vivo studies using a collagen-induced arthritis (CIA) murine model confirmed that MTX@HSA@M@HA NPs significantly ameliorated joint inflammation, attenuated paw swelling, and rapidly improved functional outcomes compared to free MTX. By synergizing RBCM camouflage with HA-directed active targeting, this nanoplatform maximizes localized therapeutic efficacy while minimizing systemic toxicity, thereby presenting a highly promising and translatable strategy for targeted RA treatment. Full article

Rheumatoid arthritis (RA) has traditionally been managed after the onset of clinically apparent synovitis; however, accumulating evidence indicates that disease-related immune abnormalities precede clinical diagnosis by several years. This preclinical phase is characterized by systemic autoimmunity, early musculoskeletal symptoms, and subclinical inflammation in genetically and environmentally susceptible individuals. In this review, we summarize current concepts regarding the pathogenesis, risk stratification, and therapeutic interception of preclinical RA. Particular attention is given to the mucosal origin hypothesis and to the roles of immunosenescence, peripheral helper T cells, and fibroblast-like synoviocytes in early disease evolution. Recent advances in clinical, serological, and imaging-based risk stratification have improved the identification of individuals at high risk of progression to clinical RA, and emerging intervention trials have shown that selected therapies may delay disease onset or reduce early inflammatory burden. Although complete prevention of RA has not yet been achieved, these findings support a paradigm shift from the treatment of established RA toward earlier, risk-adapted intervention before irreversible joint damage occurs. Future efforts should focus on refining predictive biomarkers, optimizing the timing and intensity of intervention, and establishing safe, individualized preventive strategies. Full article

Wuweiganlu (WGL) is a traditional formulation widely applied in the treatment of rheumatoid arthritis (RA), yet the identity of its bioactive constituents remains inadequately defined. In this study, ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and untargeted serum metabolomics were employed to characterize the active components of WGL. Fraxin was identified as a principal compound from WGL. To investigate its therapeutic mechanism in RA, a series of in silico and experimental approaches were conducted. Network pharmacology analysis and RNA sequencing identified heat shock protein family member 8 (HSPA8) as a potential molecular target of Fraxin, which was further validated by molecular docking studies. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that Fraxin exerts its effects primarily by modulating cell apoptosis through the PI3K signaling pathway. In vitro experiments demonstrated that Fraxin significantly reduced inflammatory responses and downregulated HSPA8 expression in lipopolysaccharide (LPS)-stimulated fibroblast-like synoviocytes (FLs) and macrophages. In vivo, Fraxin administration markedly reduced paw swelling, alleviated bone deformities, and improved bone volume fraction (BV/TV) in male IL1RA-deficient mice exhibiting spontaneous arthritis. Histological analysis confirmed that Fraxin attenuated joint inflammation by modulating the inflammatory microenvironment. Additionally, Fraxin inhibited synovial hyperplasia by regulating mitochondrial membrane potential collapse in FLs. Functional assays revealed that this regulation occurred via the inhibition of HSPA8/PI3K/AKT signaling axis, thereby suppressing aberrant FLS proliferation and contributing to the attenuation of RA progression. Full article

Background: Post-traumatic osteoarthritis (PTOA) lacks effective disease-modifying therapies that preserve joint structure while promoting tissue repair. This study aimed to evaluate the therapeutic efficacy and underlying mechanism of Biluo Qianyuan Formula (BLQYF), a standardized herbal formulation derived from clinical practice, as a potential disease-modifying alternative to celecoxib in a murine model of PTOA. Methods: A murine PTOA model was established and treated with BLQYF at different doses, with celecoxib serving as a pharmacological comparator. Safety was assessed by hepatic and renal toxicity analyses. Therapeutic effects were evaluated using micro-computed tomography (micro-CT) and histological staining. Network-based integrative analyses were conducted to identify key regulatory targets, followed by experimental validation in fibroblast-like synoviocytes. Results: BLQYF was well tolerated under the experimental conditions, with no detectable hepatic or renal toxicity at therapeutic doses. Micro-CT and histological analyses demonstrated that BLQYF dose-dependently mitigated subchondral bone deterioration, enhanced cartilage regeneration, and restored collagen deposition. At higher doses, BLQYF showed therapeutic efficacy comparable to celecoxib, with superior outcomes regarding cartilage reparation. Mechanistically, integrative analyses identified fibronectin 1 (FN1) as a central regulatory hub. Validation experiments confirmed that BLQYF suppressed FN1, MMP3, and TGF-β expression in fibroblast-like synoviocytes, thereby attenuating inflammation and extracellular matrix degradation. Conclusions: These findings support BLQYF as a promising disease-modifying therapeutic candidate for PTOA and highlight the fibroblast–FN1 axis as a novel pharmacological target for intervention. Full article

Background: Abnormal activation of the NRF2-cGAS-STING-NF-κB pathway can trigger an inflammatory cascade in rheumatoid arthritis (RA). Curcumin (CUR), a polyphenolic compound extracted from turmeric, possesses anti-inflammatory activity, but whether it can modulate this pathway to ameliorate RA remains unclear. This study aims to elucidate whether CUR inhibits the inflammatory response in synovial fibroblasts (MH7A) by suppressing the NRF2-cGAS-STING-NF-κB signaling cascade. Methods: An RA inflammatory model was constructed by stimulating MH7A cells with 20 ng/mL tumor necrosis factor (TNF). Groups included a control group, a model group, a methotrexate positive control group [MTX(methotrexate), 10 μmol/L], and curcumin treatment groups at varying concentrations (10–100 μmol/L). Cell viability was assessed using the CCK-8(Cell Counting Kit-8) assay. Cell migration and invasion capabilities were evaluated via scratch wound healing and Transwell assays, respectively. Apoptosis was detected by flow cytometry. mRNA and protein expression levels of NRF2(Nuclear factor erythroid 2-related factor 2), cGAS(cyclic GMP-AMP synthase), STING(stimulator of interferon genes), and NF-κB(nuclear factor kappa-light-chain-enhancer of activated B cells) were measured using qRT-PCR and Western blot, respectively. Protein localization was determined by immunofluorescence. Results: Compared to the model group (TNF-induced), the cell migration rate in the curcumin (CUR) groups was significantly decreased (p < 0.001), with a particularly marked reduction observed at a concentration of 50 μmol/L. Furthermore, as the concentration of curcumin increased, cell invasion capacity showed a significant dose-dependent decline. The apoptosis rate also significantly decreased with increasing curcumin concentrations, demonstrating a clear concentration-dependent effect. Mechanistically, curcumin treatment significantly upregulated the expression of NRF2 and inhibited the activation of its downstream cGAS-STING-NF-κB signaling pathway. Specifically, both mRNA and protein expression levels of NRF2 were markedly elevated (p < 0.001), while the mRNA and protein levels of cGAS, STING, and NF-κB were all significantly reduced (p < 0.001). Conclusions: Curcumin (CUR) can effectively inhibit the inflammatory response of synovial fibroblasts by activating the expression of NRF2 and subsequently suppressing the cGAS-STING-NF-κB signaling pathway. This study provides a new molecular mechanism target for curcumin in the treatment of RA and offers a theoretical basis for the intervention of autoimmune diseases with natural products. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by pain, persistent synovial inflammation, progressive joint destruction, and systemic immune dysregulation. Increasing evidence has revealed that the microbiota–gut–joint axis represents a crucial communication network linking intestinal dysbiosis to aberrant immune responses in RA. Among the diverse gut-derived metabolites implicated in this axis, we propose that histamine may act as a central signaling node linking microbial alterations to joint inflammation. Both host- and microbiota-derived histamine, synthesized via histidine decarboxylase (HDC), regulate immune and stromal cell activity within the joint microenvironment through histamine receptors H1R, H2R, and H4R. In addition, histamine interacts with other microbial metabolites—such as short-chain fatty acids (SCFAs) and tryptophan derivatives—forming an intricate metabolic–inflammatory network that amplifies fibroblast-like synoviocyte activation, osteoclastogenesis, and chronic inflammation. Despite accumulating evidence supporting the immunomodulatory role of histamine, the precise molecular mechanisms mediating its crosstalk with microbial and host immune pathways remain incompletely defined. This review provides a comprehensive overview of histamine-mediated regulation within the microbiota–gut–joint axis, emphasizing its interplay with other microbial metabolites and its contribution to RA pathogenesis. A deeper understanding of this histamine-centered microbiota–gut–joint axis will help elucidate its mechanistic role in immune dysregulation and may ultimately inform future strategies for restoring immune balance and preventing joint damage in RA. Full article

Background/Objectives: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase (IDUA) deficiency, leading to progressive glycosaminoglycan (GAG) accumulation and severe joint involvement. Gene editing represents a promising alternative to restore localized enzyme production. Therefore, this study aimed to evaluate the feasibility, efficacy, and safety of in situ genome editing through intra-articular administration of a nonviral CRISPR/Cas9 system to increase localized IDUA expression in an MPS I mouse model. Methods: Cationic liposomes were formulated to deliver plasmids encoding the CRISPR/Cas9 system targeted to the ROSA26 locus along with an IDUA donor sequence. In vitro assays were performed in fibroblast-like synoviocytes (FLSs) isolated from MPS I mice to assess cytotoxicity, gene editing efficiency, and IDUA activity. In vivo, MPS I mice received intra-articular injections in the knee joints, either as a single dose (short-term study) or monthly for three months (long-term study). IDUA activity, GAG levels, and genome editing efficiency were evaluated in joint tissues, synovial fluid, serum, and major organs. Results: Gene-edited FLS showed sustained IDUA activity for up to 30 days with low cytotoxicity. In vivo, intra-articular administration resulted in a significant increase in IDUA activity in joint tissue and synovial fluid without detectable systemic IDUA. Long-term treatment led to persistent joint-localized IDUA activity, significant reductions (>50%) in GAG levels, and detectable genome editing in joint DNA. Conclusions: Intra-articular delivery of CRISPR/Cas9 via cationic liposomes enables safe and effective localized genome editing, representing a promising strategy for treating joint manifestations of MPS I. Full article

Background: The body maintains homeostasis by inflammation, and arthritis is related to autoimmunity or inflammation. Angiogenesis contributes to synovitis through angiogenic factors and proteolytic enzymes, while different inflammatory arthritis conditions, such as osteoarthritis and rheumatoid arthritis, share similar cytokine networks and immune cell populations. Notably, progressive joint damage can occur despite effective systemic immunosuppression, suggesting that local stromal–immune interactions within the joint microenvironment may sustain inflammation and tissue destruction. Methods: We conducted an exploratory single-cell RNA-sequencing analysis using publicly available datasets from the NCBI GEO database, including synovial tissue and synovial fluid samples. Cell–cell communication and transcriptional regulatory networks were inferred using CellChat and SCENIC. Results: Computational analyses suggested that, in RA, macrophage-associated signaling shifts from TNF-related pathways toward SPP1-associated patterns, coinciding with transcriptional features of MMP3⁺ fibroblast-like synoviocytes (FLS). FLS–FLS interactions were associated with FGF-related signaling across disease contexts. ANGPTL-related signaling patterns differed among arthritis subtypes, with ANGPTL4 more prominent in OA and PsA and ANGPTL2 more frequently in RA-related transcriptional programs. Conclusions: These findings provide an exploratory framework for stromal–immune interactions and ANGPTL-associated signaling across inflammatory arthritis. The therapies for PsA may focus on systemic immune modulation and preservation of joint structural integrity. For OA and RA, the highlight may target ANGPTL4 and ANGPTL2 in the early and late stages of disease progression. Given the reliance on computational inference, the results warrant further experimental validation. Full article

Background/Objectives: Interleukin-17A (IL-17A) is a key pathogenic cytokine in autoimmune arthropathies. Current monoclonal antibody inhibitors targeting the IL-17/IL-17RA axis demonstrate clinical efficacy but face significant limitations, including immunogenicity, the loss of therapeutic response, and cold-chain storage. Our study evaluated oligonucleotide aptamers targeting IL-17A and its receptor as an alternative to monoclonal antibodies to suppress an IL-17A-induced inflammatory response in cell models relevant to immunoinflammatory rheumatic diseases. Methods: We examined three aptamers: 2′-F-RNA aptamers Apt21-2 and Apt3-4 specific to IL-17A and DNA aptamer RA10-6 targeting the receptor of IL-17A. Their ability to suppress IL-17A functional activity was assessed in peripheral blood mononuclear cells (PBMCs) from healthy donors and personalized fibroblast-like synoviocytes (FLSs) from patients with axial spondyloarthritis (axSpA) and rheumatoid arthritis (RA). Inhibition was measured by quantifying IL-6 and MMP-13 secretion using ELISA and flow cytometry, using secukinumab as a reference control. Results: In PBMC, all aptamers suppressed IL-17A-stimulated IL-6 secretion and cell proliferation in a concentration-dependent manner (17–200 nM), with a 65–85% efficacy, comparable to that of secukinumab. In axSpA-derived FLS, we observed time-dependent efficacy: At 4 h, all three aptamers suppressed IL-6 to the same extent as secukinumab; at 24 h, RA10-6 maintained high efficacy while Apt21-2 and Apt3-4 showed reduced activity. A combination of receptor-targeting RA10-6 with anti-IL-17A aptamers resulted in synergistic IL-6 suppression. All aptamers reduced MMP-13 to basal levels. RA-derived FLS showed diminished responses to all inhibitors. Conclusions: Aptamers demonstrate high specificity and sustained efficacy in suppressing IL-17A signaling for an in vitro model of spondyloarthritis, with superior performance over antibodies. Disease-dependent differential efficacy in RA FLS reflects heterogeneity consistent with limited clinical anti-IL-17 efficacy in RA. These findings show the strong potential of the studied aptamers as an alternative to monoclonal antibodies for IL-17-associated inflammatory arthropathies, particularly spondyloarthritis. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovitis, in which fibroblast-like synoviocytes (FLSs) serve as the primary effector cells that drive the destruction of joints. Baicalin has previously demonstrated efficacy in significantly ameliorating joint symptoms in rats with CIA. As such, this study aims to investigate its underlying molecular mechanisms and impact on the FLSs of rats with CIA through an integrated proteomics and transcriptomics analysis. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted based on two datasets; it revealed that the retrograde endocannabinoid signaling pathway—associated with susceptibility to RA—is the only one involved in both the signaling and metabolic processes modulated by baicalin. Nineteen differentially expressed proteins (DEPs) downregulated by baicalin comprise seventeen subunits of NADH dehydrogenase and two receptors, glutamate receptor 2 (GRIA2) and γ-aminobutyric acid receptor subunit alpha-5 (GABRA5). Three differential metabolites (DMs) were also affected by baicalin: γ-aminobutyric acid (GABA) and phosphatidylcholine (PC) were upregulated and phosphatidylethanolamine (PE) was downregulated. Our findings suggest that the baicalin-mediated alleviation of joint synovitis is closely related to the upregulation of GABA and PC; downregulation of GRIA2, GABRA5, and PE; and preservation of mitochondrial homeostasis within the retrograde endocannabinoid signaling pathway in FLSs. Full article

Rheumatoid arthritis (RA) is a systemic autoimmune disorder marked by chronic inflammation of small synovial joints, with frequent extra-articular involvement of the skin and eyes. Prolonged methotrexate therapy for RA is often accompanied by serious side effects. Therefore, new drugs with less toxicity and greater effectiveness need to be developed. The ginsenoside 20(R)-25-methoxyl-dammarane-3β,12β,20-triol (AD-1), purified from Panax ginseng berry, exhibits potent anti-inflammatory and anti-cancer activities. However, the pharmacological mechanism of AD-1 in RA remains unclear. This study explored the potential anti-RA effects of AD-1 using an integrative strategy that combined network pharmacology, molecular docking, molecular dynamics simulation, and in vitro pharmacological validation. Enrichment analyses of KEGG and GO terms based on network pharmacology pointed to the PI3K/Akt signaling axis as a key regulatory pathway modulated by AD-1. Molecular docking and dynamics simulations revealed that AD-1 may have a close interaction with PIK3R1 and AKT1, demonstrating a stabilizing effect. Then, after experimental verification using human rheumatoid arthritis fibroblasts (MH7A), it was found that AD-1 suppressed cell proliferation, migration, and invasion and promoted apoptosis. Subsequent analysis of the RABC databases revealed that PIK3R1 and AKT1 were upregulated in RA, while AD-1 reduces phosphorylation of PI3K and Akt. In conclusion, these findings indicate that AD-1 exerts its anti-RA action, at least in part, through modulation of the PI3K/Akt signaling pathway and induction of apoptosis in synovial cells. This study provides a basis and new strategies for the role of ginsenosides in the treatment of RA. Full article

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic joint inflammation. Its pathophysiology involves complex interactions among immune cells, leading to joint damage, primarily in the synovial membrane. MicroRNAs (miRs), single-stranded non-coding RNAs, play a critical role in regulating pathways affecting RA progression, particularly in fibroblast-like synoviocytes and peripheral blood mononuclear cells. Key pathways influenced by miRs include NF-κB, apoptosis, PI3K/AKT signaling, and cytokine production. Dysregulated miRs impact cell proliferation, survival, and inflammatory responses. This review explores not only the role of miRs in RA pathogenesis, but also highlights their potential as biomarkers for early detection and severity prediction. Moreover, therapeutic approaches targeting miRs, including mimics and inhibitors, show promise in animal models, with methods like intra-articular administration being favored due to better efficacy and reduced side effects. While early studies highlight potential pathways for RA treatment, challenges remain in translating these findings into safe and effective clinical therapies. Full article

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by a multistep pathogenesis, from the preclinical phase of autoantibody emergence to the clinical onset of synovitis and joint destruction. Cytokines play central roles throughout this progression by orchestrating immune cell activation, tissue inflammation, and bone erosion. In the preclinical phase, several cytokines, including IL-12, IL-6, IL-21 and TGF-β, promote Tfh and Tph cell differentiation, helping autoreactive B cells to produce ACPA. During the clinical phase, TNF-α, IL-6, and IL-1β drive synovitis by activating macrophages and fibroblast-like synoviocytes, while also promoting RANKL (Receptor Activator of Nuclear factor κB Ligand) expression and osteoclast differentiation. This review highlights the pathogenic role of cytokines in RA and discusses their relevance as biomarkers and therapeutic targets. A better understanding of cytokine networks may offer new opportunities for early intervention and disease prevention in RA. Full article