Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that extends beyond joint inflammation,affecting pulmonary and metabolic pathways.Interstitial lung disease(ILD)is one of its most serious extra-articul...Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that extends beyond joint inflammation,affecting pulmonary and metabolic pathways.Interstitial lung disease(ILD)is one of its most serious extra-articular complications,while type 2 diabetes mellitus(T2DM)frequently coexists with RA and may exacerbate inflammatory and fibrotic processes.This editorial discusses the study by Sutton et al,the largest population-based analysis to date exploring the link between T2DM and ILD in patients with RA,and reflects on its mechanistic and clinical implications.In a nationwide cohort of more than 120000 hospitalized RA patients,Sutton et al demonstrated that the coexistence of T2DM nearly doubles the odds of developing ILD(odds ratio=2.02;95%confidence interval:1.84-2.22),with additional increases in pulmonary hypertension,pneumothorax,and length of stay.These findings reinforce the concept of a metabolic-pulmonary-autoimmune axis,in which chronic inflammation promotes insulin resistance and metabolic dysfunction,while hyperglycaemia and advanced glycation end-products amplify oxidative stress and fibrogenesis.This reciprocal interaction may induce a self-perpetuating cycle of“metaflammation”,fibrosis,and organ damage.Conclusion:Recognizing diabetes as a silent amplifier of RA-associated ILD redefines the interface between rheumatology,pulmonology,and endocrinology.Early detection and integrated management of metabolic and pulmonary comorbidities should be prioritized,while future studies must determine whether optimizing glycemic control can attenuate pulmonary fibrosis and improve longterm outcomes.展开更多
The combination of Daphnes Cortex(DC)and Liquorice Root(LR),two traditional Chinese medicinal herbs,has shown significant therapeutic effects on rheumatoid arthritis(RA),but its synergistic mechanism of action remains...The combination of Daphnes Cortex(DC)and Liquorice Root(LR),two traditional Chinese medicinal herbs,has shown significant therapeutic effects on rheumatoid arthritis(RA),but its synergistic mechanism of action remains to be elucidated.Employing a network pharmacology and molecular docking approach,this study systematically investigated the synergistic mechanism of the herb pair DC and LR in RA treatment.Active components and their corresponding targets were retrieved from the TCMSP database and relevant literature,and RA-related targets were collected from established disease databases.A total of 73 overlapping targets between DC-LR and RA were identified,among which core targets such as AKT1,TNF,and CASP3 were highlighted.GO and KEGG enrichment analyses revealed that these targets are involved in biological processes such as oxidative stress response and cell migration,and are significantly enriched in key pathways including HIF-1,TNF,and PI3K-Akt signaling pathways.Compatibility analysis further revealed that the combination of DC and LR may enhance therapeutic effects through synergistic regulation of shared targets and complementary modulation of upstream and downstream pathway components.Molecular docking confirmed strong binding affinities between core active components and key targets.This study provides a multi-dimensional“component-target-pathway”perspective on the potential synergistic anti-RA mechanism of the DC-LR herb pair,offering a theoretical basis for further experimental validation and clinical application.展开更多
Rheumatoid arthritis(RA)patients face significant psychological challenges alongside physical symptoms,necessitating a comprehensive understanding of how psychological vulnerability and adaptation patterns evolve thro...Rheumatoid arthritis(RA)patients face significant psychological challenges alongside physical symptoms,necessitating a comprehensive understanding of how psychological vulnerability and adaptation patterns evolve throughout the disease course.This review examined 95 studies(2000-2025)from PubMed,Web of Science,and CNKI databases including longitudinal cohorts,randomized controlled trials,and mixed-methods research,to characterize the complex interplay between biological,psychological,and social factors affecting RA patients’mental health.Findings revealed three distinct vulnerability trajectories(45%persistently low,30%fluctuating improvement,25%persistently high)and four adaptation stages,with critical intervention periods occurring 3-6 months postdiagnosis and during disease flares.Multiple factors significantly influence psychological outcomes,including gender(females showing 1.8-fold increased risk),age(younger patients experiencing 42%higher vulnerability),pain intensity,inflammatory markers,and neuroendocrine dysregulation(48%showing cortisol rhythm disruption).Early psychological intervention(within 3 months of diagnosis)demonstrated robust benefits,reducing depression incidence by 42%with effects persisting 24-36 months,while different modalities showed complementary advantages:Cognitive behavioral therapy for depression(Cohen’s d=0.68),mindfulness for pain acceptance(38%improvement),and peer support for meaning reconstruction(25.6%increase).These findings underscore the importance of integrating routine psychological assessment into standard RA care,developing stage-appropriate interventions,and advancing research toward personalized biopsychosocial approaches that address the dynamic psychological dimensions of the disease.展开更多
Background:One of the first hundred traditional Chinese medicines(TCM)formulas administered in China,Qianghuo Shengshi Decoction(QSD)has a positive clinical and therapeutic impact on rheumatoid arthritis(RA).Even so,t...Background:One of the first hundred traditional Chinese medicines(TCM)formulas administered in China,Qianghuo Shengshi Decoction(QSD)has a positive clinical and therapeutic impact on rheumatoid arthritis(RA).Even so,there is still not enough knowledge on the active ingredients and possible ways that QSDs might work to treat RA.This study systematically investigated the active ingredients and mechanisms of action of QSD for treating wind-cold-dampness arthralgia type RA.Methods:UHPLC-QE-MS and network pharmacology techniques were employed to predict the potential active constituents,targets,and associated signalling pathways.Then,the therapeutic effect of QSD was examined using a wind-cold-dampness arthralgia paralytic RA rat model.Finally,the complex mechanism was comprehensively elucidated by integrating transcriptomics and network pharmacology.The above mechanisms were also verified by molecular docking,immunohistochemistry and Western blot.Results:UHPLC-QE-MS and network pharmacology analysis revealed that ferulic acid,imperatorin,magnolol,quercetin,and scopoletin could be the primary constituents in QSD responsible for its anti-RA effects.Animal experiments showed that QSD can significantly inhibit rat joint swelling degree,decrease the content of serum rheumatoid factor(RF),interleukin(IL)-1β,tumor necrosis factor-alpha(TNF-α),IL-6,and anti-citrullinated protein antibodies(ACPA),and increase the content of IL-4,IL-10 to relieve the clinical symptoms of wind-cold-dampness arthralgia type RA.The mechanistic study showed that QSD may effectively inhibit rat synovial hyperplasia via promoting autophagy and apoptosis of synovial cells by regulating the PI3K/Akt/mTOR signalling pathway.Conclusion:This study identifies key active ingredients in QSD and elucidates its potential mechanism for treating wind-cold-dampness arthralgia type RA,providing a basis for the clinical application of QSD.展开更多
Rheumatoid arthritis(RA)is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life.RA accelerates musculoskeletal aging,leading to complications such as mus...Rheumatoid arthritis(RA)is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life.RA accelerates musculoskeletal aging,leading to complications such as muscle degeneration and sarcopenia.Recent research has identified myopenia as a condition of significant muscle loss associated with illness,distinct from the muscle wasting seen in other chronic diseases like cancer cachexia or heart failure.In RA,myopenia is characterized by muscle depletion without concurrent significant fat loss,and it can affect individuals of all ages.While inflammation plays a central role,it is not the sole factor contributing to the high incidence of muscle wasting in RA.In subsequent discussions,secondary sarcopenia will be considered alongside myopenia,as both involve muscle wasting decline primarily due to disease.This review summarizes recent findings on the impact of RA-related myopenia and secondary sarcopenia on functional capacity,explores its underlying mechanisms,and discusses contemporary strategies to mitigate the process of musculoskeletal aging in RA patients.展开更多
Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly ele...Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.展开更多
Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflamm...Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.展开更多
Rheumatoid arthritis(RA)is a common chronic autoimmune disease characterized by joint pain,swelling and dysfunction[1].According to epidemiologic statistics,the incidence of RA is 1%–2%,and in severe cases,it can dev...Rheumatoid arthritis(RA)is a common chronic autoimmune disease characterized by joint pain,swelling and dysfunction[1].According to epidemiologic statistics,the incidence of RA is 1%–2%,and in severe cases,it can develop into joint deformity and disability,which brings a heavy burden to the family and society[2].However,the pathogenesis of RA is complex and involves multiple cellular interactions,which increases the difficulty of curing RA.Current therapeutic options,such as disease-modifying antirheumatic drugs,non-steroidal anti-inflammatory drugs,and biologics,still face the challenge of relapse after drug discontinuation[3,4].Therefore,the pathogenesis of RA needs to be analyzed in depth to break through the existing therapeutic bottlenecks and promote the iterative innovation of individualized diagnosis and treatment.展开更多
Background:Studies have shown that individuals who receive early treatment for rheumatoid arthritis(RA)are more likely to approach life positively,avoiding joint damage and the need for joint replacement surgery.The d...Background:Studies have shown that individuals who receive early treatment for rheumatoid arthritis(RA)are more likely to approach life positively,avoiding joint damage and the need for joint replacement surgery.The diagnosis of early rheumatoid arthritis(ERA)is crucial for effective treatment and prognosis of patients.Urine,as a diagnostic medium,offers the advantages of non-invasive diagnosis.Urinary metabolites can serve as biomarkers for diagnosis,prognosis,and risk prediction,improving specificity and accuracy.Methods:We recruited 37 ERA patients with a history of less than 3 months and a score of 6,26 osteoarthritis(OA)patients,and 30 healthy controls(HC).Urine samples were collected for 16S rRNA sequencing,and untargeted liquid chromatography-mass spectrometry(LC-MS)was used to detect metabolites.Bioinformatics approaches were employed to identify pathogenic metabolites as specific risk factors for ERA precisely.Results:2-methylnaphthalene was identified as a biomarker for ERA in urine.Prevotella,a major part of the urinary microbiome in ERA patients,exhibited a positive correlation with 2-methylnaphthalene.Notably,there were significant variations in urine metabolites among patients with ERA,OA,and HC.2-Methylnaphthalene was found to be significantly enriched in ERA.Besides,inflammatory factors were elevated in ERA patients.The research further demonstrated a positive correlation between rheumatoid factor(RF),erythrocyte sedimentation rate(ESR),and C-reactive protein(CRP)and the metabolite 2-methylnaphthalene.Conclusion:The urine metabolite 2-methylnaphthalene can be a risk factor for early urinary tract infections and may contribute to accurately screening early-risk metabolites in ERA.展开更多
Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples...Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples from patients with different pathological processes were collected, and the correlations between the subsets of FLSs and STMs and pathological processes were analyzed via flow cytometry. In vitro experimental methods such as enzyme linked immunosorbent assay (ELISA), Western blotting, Transwell assays, CCK- 8 assays and cell coculture were used to assess cell proliferation, migration and secretion of inflammatory factors. A collagen- induced arthritis mouse model was constructed to investigate the therapeutic potential of emodin in RA by flow cytometry, micro- CT and staining. Results : Unique subsets of FLSs and STMs, namely, FAPα ^(+)THY1 − FLSs, FAPα ^(+)THY1 ^(+)FLSs, and MerTK ^(pos) TREM2 ^(high) STMs, were identified in synovial tissues from RA patients. The number of MerTK ^(pos) TREM2 ^(high) STMs was negatively correlated with the degree of damage in RA, while the number of FAPα ^(+)THY1 − FLSs was positively correlated with damage. On the one hand, emodin promoted the aggregation of MerTKposTREM2high STMs. Moreover, MerTK pos TREM2 high STM- mediated secretion of exosomes was promoted, which can inhibit the secretion of pro- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs and promote the secretion of anti- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs, thereby inhibiting FAPα ^(+)THY1 − FLS proliferation and migration, improving the local immune microenvironment, and inhibiting RA damage. Conclusion : Emodin was shown to regulate the aggregation of STM subsets and exosome secretion, affecting the secretion, proliferation and migration of inflammatory factors in FLS subsets, and ultimately achieving good therapeutic efficacy in RA patients, suggesting that it has important clinical value.展开更多
Rheumatoid arthritis(RA)is a chronic autoimmune disease that affects approxi-mately 0.46%of the global population.Conventional therapeutics for RA,including disease-modifying antirheumatic drugs(DMARDs),nonsteroidal a...Rheumatoid arthritis(RA)is a chronic autoimmune disease that affects approxi-mately 0.46%of the global population.Conventional therapeutics for RA,including disease-modifying antirheumatic drugs(DMARDs),nonsteroidal anti-inflammatory drugs(NSAIDs),and corticosteroids,frequently result in unintended adverse effects.Dexamethasone(DEX)is a potent glucocorticoid used to treat RA due to its anti-inflammatory and immunosuppressive properties.Liposomal delivery of DEX,particu-larly when liposomes are surface-modified with targeting ligands like peptides or sialic acid,can improve drug efficacy by enhancing its distribution to inflamed joints and minimizing toxicity.This study investigates the potential of liposomal drug delivery systems to enhance the efficacy and targeting of DEX in the treatment of RA.Results from various studies demonstrate that liposomal DEX significantly inhibits arthritis progression in animal models,reduces joint inflammation and damage,and alleviates cartilage destruction compared to free DEX.The liposomal formulation also shows better hemocompatibility,fewer adverse effects on body weight and immune organ index,and a longer circulation time with higher bioavailability.The anti-inflammatory mechanism is associated with the downregulation of pro-inflammatory cytokines like tumor necrosis factor-α(TNF-α)and B-cell-activating factor(BAFF),which are key players in the pathogenesis of RA.Additionally,liposomal DEX can induce the expres-sion of anti-inflammatory cytokines like interleukin-10(IL-10),which has significant anti-inflammatory and immunoregulatory properties.The findings suggest that lipo-somal DEX represents a promising candidate for effective and safe RA therapy,with the potential to improve the management of this debilitating disease by providing targeted delivery and sustained release of the drug.展开更多
Objective Rheumatoid arthritis(RA)is a systemic autoimmune disease that affects the small joints of the whole body and degrades the patients’quality of life.Zhengqing Fengtongning(ZF)is a traditional Chinese medicine...Objective Rheumatoid arthritis(RA)is a systemic autoimmune disease that affects the small joints of the whole body and degrades the patients’quality of life.Zhengqing Fengtongning(ZF)is a traditional Chinese medicine preparation used to treat RA.ZF may cause liver injury.In this study,we aimed to develop a prediction model for abnormal liver function caused by ZF.Methods This retrospective study collected data from multiple centers from January 2018 to April 2023.Abnormal liver function was set as the target variable according to the alanine transaminase(ALT)level.Features were screened through univariate analysis and sequential forward selection for modeling.Ten machine learning and deep learning models were compared to find the model that most effectively predicted liver function from the available data.Results This study included 1,913 eligible patients.The LightGBM model exhibited the best performance(accuracy=0.96)out of the 10 learning models.The predictive metrics of the LightGBM model were as follows:precision=0.99,recall rate=0.97,F1_score=0.98,area under the curve(AUC)=0.98,sensitivity=0.97 and specificity=0.85 for predicting ALT<40 U/L;precision=0.60,recall rate=0.83,F1_score=0.70,AUC=0.98,sensitivity=0.83 and specificity=0.97 for predicting 40≤ALT<80 U/L;and precision=0.83,recall rate=0.63,F1_score=0.71,AUC=0.97,sensitivity=0.63 and specificity=1.00 for predicting ALT≥80 U/L.ZF-induced abnormal liver function was found to be associated with high total cholesterol and triglyceride levels,the combination of TNF-αinhibitors,JAK inhibitors,methotrexate+nonsteroidal anti-inflammatory drugs,leflunomide,smoking,older age,and females in middle-age(45-65 years old).Conclusion This study developed a model for predicting ZF-induced abnormal liver function,which may help improve the safety of integrated administration of ZF and Western medicine.展开更多
BACKGROUND This study investigates the impact of type 2 diabetes mellitus(T2DM)on the risk of interstitial lung disease(ILD)and its subtypes in patients with rheumatoid arthritis(RA).RA is often complicated by ILD.T2D...BACKGROUND This study investigates the impact of type 2 diabetes mellitus(T2DM)on the risk of interstitial lung disease(ILD)and its subtypes in patients with rheumatoid arthritis(RA).RA is often complicated by ILD.T2DM has systemic proinflam-matory effects,but its impact on RA-related ILD is unclear.This research aims to elucidate the interplay between these conditions to inform clinical management and patient care strategies.AIM To determine if RA patients with T2DM have a higher occurrence of ILD compar-ed to RA patients without T2DM.METHODS We conducted a retrospective cohort study using the 2019-2020 National Inpa-tient Sample.Adult RA patients with and without T2DM were identified via International Classification of Diseases,10th Revision(ICD-10)codes.Propensity score matching(1:1)balanced 15+confounders.Logistic regression assessed the association of T2DM with ILD(overall and by subtype)and secondary outcomes(acute respiratory distress syndrome,pneumothorax,pleural effusion,pulmonary hypertension).Missing data were excluded.ILD subtypes were included based on ICD-10 codes and case count.RESULTS Among 199380 RA inpatients,ILD was more common in those with T2DM(2.25%)vs without(1.11%).After matching(n=121046),ILD remained higher in RA+T2DM[odds ratio(OR)=2.02,95%CI:1.84-2.22,P<0.001],with an absolute risk increase of about 1.14%.T2DM was associated with higher odds of ILD subtypes including usual interstitial pneumonia(OR=3.20)and non-specific interstitial pneumonia(OR=3.50).Other subtypes showed elevated ORs;eosinophilic pneumonia showed an inverse association(OR=0.23).PAH and pneumo-thorax were also more common in RA+T2DM(OR=1.40 and 1.85,respectively).Acute respiratory distress syn-drome and pleural effusion rates did not differ by T2DM status.Rare subtype findings should be interpreted cautiously.CONCLUSION T2DM increases ILD risk in RA and is linked to higher rates of pulmonary hypertension and pneumothorax,suggesting a role in exacerbating RA-related lung complications.展开更多
Andrographolide sulfonate(AS)is a sulfonated derivative of andrographolide extracted from Andrographis paniculata(Burm.f.)Nees,and has been approved for several decades in China.The present study aimed to investigate ...Andrographolide sulfonate(AS)is a sulfonated derivative of andrographolide extracted from Andrographis paniculata(Burm.f.)Nees,and has been approved for several decades in China.The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis.Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling,improved body weights,and attenuated pathological changes in joints of rats with adjuvant-induced arthritis.Additionally,the levels of tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6),and IL-1β in the serum and ankle joints were reduced.Bioinformatics analysis,along with the spleen index and measurements of IL-17 and IL-10 levels,suggested a potential relationship between AS and Th17 cells under arthritic conditions.In vitro,AS was shown to block Th17 cell differentiation,as evidenced by the reduced percentages of CD4^(+)IL-17A^(+)T cells and decreased expression levels of RORγt,IL-17A,IL-17F,IL-21,and IL-22,without affecting the cell viability and apoptosis.This effect was attributed to the limited glycolysis,as indicated by metabolomics analysis,reduced glucose uptake,and p H measurements.Further investigation revealed that AS might bind to hexokinase2(HK2)to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase(GAPDH)or pyruvate kinase M2(PKM2),and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation.Furthermore,AS impaired the activation of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)signals in vivo and in vitro,which was abolished by the addition of lactate.In conclusion,AS significantly improved adjuvant-induced arthritis(AIA)in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.展开更多
Introduction: Among the chronic and feared complications of this disease, rheumatoid vasculitis stands out as one of the most severe, albeit rare. The most frequently affected sites by rheumatoid vasculitis are the sk...Introduction: Among the chronic and feared complications of this disease, rheumatoid vasculitis stands out as one of the most severe, albeit rare. The most frequently affected sites by rheumatoid vasculitis are the skin and the peripheral nervous system. We report a case of rheumatoid vasculitis complicating a 30-year history of untreated rheumatoid arthritis. Case Report: The patient is a 75-year-old male with a 30-year history of deforming and erosive seropositive rheumatoid arthritis. He presented with polyarthritis and digital necrosis. Physical examination revealed peripheral joint syndrome with characteristic deformities of rheumatoid arthritis. Additionally, there was well-demarcated dry gangrene affecting the first and second digits of the right hand. Laboratory findings indicated an inflammatory syndrome. Tests for antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA) to investigate other causes of vasculitis were negative. The patient received a corticosteroid bolus. After two weeks, there was a marked reduction in pain and an improvement in the general condition. The dry gangrene remained stable. Conclusion: Rheumatoid vasculitis remains a serious and chronic complication of rheumatoid arthritis, associated with significant mortality. This case highlights the crucial importance of early diagnosis and effective management of rheumatoid arthritis.展开更多
Eosinophils are multifunctional granulocytes that contribute to the initiation and modulation of inflammation.Accumulating evidence suggests that eosinophils are adaptable leukocytes that orchestrate the resolution of...Eosinophils are multifunctional granulocytes that contribute to the initiation and modulation of inflammation.Accumulating evidence suggests that eosinophils are adaptable leukocytes that orchestrate the resolution of inflammatory responses.The most prevalent chronic inflammatory illness,rheumatoid arthritis(RA),is typified by persistent synovitis thatmakes it hard for the disease to go away on its own.Interestingly,a unique subset of eosinophils known as regulatory eosinophils has been found in RA patients’synovium,especially while the disease is in remission.Pro-resolving signatures of regulatory eosinophils in the synovium are distinct from those of their lung counterparts.The most recent research on eosinophils and their function in this disease pathogenesis is compiled in this review.Based on the role of regulatory eosinophils,a new pathological model of inflammation resolution in RA is proposed,and potential therapeutic strategies aimed at enhancing the action of regulatory eosinophils in RA are proposed.展开更多
Objective To perform an in silico bioinformatics analysis to identify differentially expressed microRNAs(miRNAs)implicated in rheumatoid arthritis(RA)pathogenesis and evaluate their potential as biomarkers for assessi...Objective To perform an in silico bioinformatics analysis to identify differentially expressed microRNAs(miRNAs)implicated in rheumatoid arthritis(RA)pathogenesis and evaluate their potential as biomarkers for assessing therapeutic efficacy and monitoring acupuncture treatment.Methods miRNA microarray data(CEL and TXT formats)were acquired from human and murine RA models,with the latter undergoing acupuncture treatment.Data were normalized using the robust multi-array average(RMA)method and analyzed for differential expression.Differential expression analysis identified miRNAs through a comparative analysis of RA human tissues,acupuncture-treated murine RA models,and a bibliographic search for miRNAs implicated in RA pathogenesis and acupuncture treatment.Bioinformatics analysis was performed to identify potential target genes for each miRNA and signaling pathways via search tools for the Retrieval of Interacting Genes/Proteins(STRING)and ShinyGO.Gene-drug interaction analysis was performed through Drug-Gene Interaction Database(DGIdb)screening.Interaction networks were constructed with the Cytoscape v3.10.3 software.Results The hsa-miR-125a-5p and hsa-miR-125b-5p were identified as potential biomarkers associated with RA pathogenesis,presenting 468 and 455 target genes,respectively.These genes were enriched in 20 signaling pathways,including Janus kinasa-signal transducer and activator of transcription(JAK-STAT),mitogen-activated protein kinase(MAPK),phosphoinositide 3-kinase-protein kinase B(PI3K-Akt),and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)signaling pathway,which have been associated with RA pathogenesis and progression.Drug-gene interaction networks revealed that 22 genes were significantly associated with 58 RA treatment drugs,among which 13 genes interacted with members of the hsa-miR-125 family.Conclusion The hsa-miR-125a-5p and hsa-miR-125b-5p demonstrate critical regulatory role in RA pathogenesis by modulating signaling pathways,including JAK-STAT,MAPK,PI3K-Akt,and NF-κB.Our findings show that the hsa-miR-125a-5p and hsa-miR-125b-5p exhibit differential expression patterns in response to pharmacological intervention in various diseases,including RA management.This suggests their potential roles as biomarkers for monitoring acupuncture treatment.Although existing evidence indicates that acupuncture can modify miRNA expression profiles,rigorous validation through biological models remains essential to confirm these results.展开更多
Abnormal activation of macrophages and osteoclasts(OCs)contributes significantly to rheumatoid arthritis(RA)development by secretion of numerous inflammatory factors.Notably,these cells exhibit significant upregulatio...Abnormal activation of macrophages and osteoclasts(OCs)contributes significantly to rheumatoid arthritis(RA)development by secretion of numerous inflammatory factors.Notably,these cells exhibit significant upregulation of folate receptor proteins on their surfaces.Unfortunately,there is a current lack of safe and effective therapeutic drugs for RA.Xuetongsu(XTS),a triterpenoid compound extracted fromKadsura heteroclita Roxb Craib,has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes(RAFLS).However,its clinical application is hampered by poor targeting and short half-life.To address these drawbacks,we previously developed a nano-drug system named HRPS nanoparticles(NPs),which effectively targets RAFLS and inhibits synovial hyperplasia.However,this system overlooked the essential role of OCs in RA-related bone destruction.Therefore,we designed a novel folate-modified biomimetic Prussian blue(PB)-XTS NP(FMPX NP)for the selective delivery of XTS into inflammatory macrophages and OCs.The NP exhibits an excellent photothermal effect when assisted by laser irradiation,facilitating targeted release of XTS within inflammatory macrophages and OCs.The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs.In vivo experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times,decreased hind foot swelling from 12.10±0.49 mm to 8.24±0.09 mm in the model group,and prevented bone damage.In conclusion,this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA.FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy,providing new insights for targeted drug therapies in clinical RA treatment.展开更多
Invasive fibroblast-like synoviocytes(FLS),inflammatory macrophages and osteoclasts are the main three contributors to rheumatoid arthritis(RA)progression by promoting synovial inflammation and destructing cartilage a...Invasive fibroblast-like synoviocytes(FLS),inflammatory macrophages and osteoclasts are the main three contributors to rheumatoid arthritis(RA)progression by promoting synovial inflammation and destructing cartilage and bone.Targeting these three cell types for restoring the inflammatory homeostasis microenvironment may be a promising anti-RA strategy.Herein,we prepared a reactive oxygen species(ROS)-responsive micelles(DPTM)to co-load dexamethasone(DEX)and pristimerin(PRI)for RA therapy.This ROS-responsive system exhibits the following advantages:(1)It makes use of the“ELVIS”effect for passive delivery and targeting the ROS environment of RA-related cells to rapidly release the payload drugs DEX and PRI.(2)Compared with free drugs,DPTM showed stronger effect on the inhibition of RA-FLS proliferation and the promotion of RA-FLS apoptosis.Moreover,DPTM could significantly weaken the migration ability of RA-FLS as indicated by the results of wound healing assay and transwell assay.(3)DPTM exerted stronger cellular uptake and anti-inflammatory effect in M1 macrophages.(4)In the model studying receptor activator of nuclear factor kappa-B ligand(RANKL)-induced differentiation of bone marrow-derived macrophages(BMDMs)to osteoclasts,DPTM showed a stronger inhibitory activity on osteoclast formation as compared to free drugs.Taken together,these results highlighted the potential of DPTM for targeted RA therapy via inhibition of RA-FLS abnormal activation,macrophage polarization and osteoclastogenesis.展开更多
Systemic administration of the anti-rheumatic drug methotrexate(MTX)for a long period of time may lead to therapeutic tolerance,various adverse effects,and potential harm to the immune system.Therapeutic nano-delivery...Systemic administration of the anti-rheumatic drug methotrexate(MTX)for a long period of time may lead to therapeutic tolerance,various adverse effects,and potential harm to the immune system.Therapeutic nano-delivery carriers constructed based on biologically active phenols provide a promising approach to enhance the therapeutic effect of anti-rheumatic drugs.Caffeic acid,a natural compound with anti-inflammatory properties,holds significant potential in the treatment of diverse inflammatory conditions.In this paper,we first constructed a nano-delivery platform for MTX using caffeic acid-based polyphenol polymer Ph-CaA-OH(PCOH),and investigated the treatment of rheumatoid arthritis(RA)at low drug administration doses(2.5 mg/kg).PCOH nanoparticles(NPs)could inhibit lipopolysaccharidesstimulated macrophage inducible nitric oxide synthase(iNOS)expression and pro-inflammatory differentiation in vitro.In vivo imaging revealed the rapid accumulation and sustained presence of PCOH NPs at inflamed joints in collagen induced-arthritis(CIA)mice.Therapeutic evaluation of CIA mice demonstrated that MTX@PCOH NPs were superior to free MTX in reducing the progression of RA and decreasing the expression of multiple pro-inflammatory cytokines without significant toxic effects.By enhancing drug aggregation at inflammatory joints and capitalizing on the synergistic effects of active carriers,MTX@PCOH NPs effectively minimized the required drug dosage and mitigated toxic side effects in RA treatment.The application of PCOH NPs to RA treatment provides a new strategy for the development of safer and more effective anti-RA nanomedicines.展开更多
文摘Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that extends beyond joint inflammation,affecting pulmonary and metabolic pathways.Interstitial lung disease(ILD)is one of its most serious extra-articular complications,while type 2 diabetes mellitus(T2DM)frequently coexists with RA and may exacerbate inflammatory and fibrotic processes.This editorial discusses the study by Sutton et al,the largest population-based analysis to date exploring the link between T2DM and ILD in patients with RA,and reflects on its mechanistic and clinical implications.In a nationwide cohort of more than 120000 hospitalized RA patients,Sutton et al demonstrated that the coexistence of T2DM nearly doubles the odds of developing ILD(odds ratio=2.02;95%confidence interval:1.84-2.22),with additional increases in pulmonary hypertension,pneumothorax,and length of stay.These findings reinforce the concept of a metabolic-pulmonary-autoimmune axis,in which chronic inflammation promotes insulin resistance and metabolic dysfunction,while hyperglycaemia and advanced glycation end-products amplify oxidative stress and fibrogenesis.This reciprocal interaction may induce a self-perpetuating cycle of“metaflammation”,fibrosis,and organ damage.Conclusion:Recognizing diabetes as a silent amplifier of RA-associated ILD redefines the interface between rheumatology,pulmonology,and endocrinology.Early detection and integrated management of metabolic and pulmonary comorbidities should be prioritized,while future studies must determine whether optimizing glycemic control can attenuate pulmonary fibrosis and improve longterm outcomes.
基金supported by National Training Program of Innovation and Entrepreneurship for Undergraduates(202510163044).
文摘The combination of Daphnes Cortex(DC)and Liquorice Root(LR),two traditional Chinese medicinal herbs,has shown significant therapeutic effects on rheumatoid arthritis(RA),but its synergistic mechanism of action remains to be elucidated.Employing a network pharmacology and molecular docking approach,this study systematically investigated the synergistic mechanism of the herb pair DC and LR in RA treatment.Active components and their corresponding targets were retrieved from the TCMSP database and relevant literature,and RA-related targets were collected from established disease databases.A total of 73 overlapping targets between DC-LR and RA were identified,among which core targets such as AKT1,TNF,and CASP3 were highlighted.GO and KEGG enrichment analyses revealed that these targets are involved in biological processes such as oxidative stress response and cell migration,and are significantly enriched in key pathways including HIF-1,TNF,and PI3K-Akt signaling pathways.Compatibility analysis further revealed that the combination of DC and LR may enhance therapeutic effects through synergistic regulation of shared targets and complementary modulation of upstream and downstream pathway components.Molecular docking confirmed strong binding affinities between core active components and key targets.This study provides a multi-dimensional“component-target-pathway”perspective on the potential synergistic anti-RA mechanism of the DC-LR herb pair,offering a theoretical basis for further experimental validation and clinical application.
基金Supported by Chongqing Health Commission and Chongqing Science and Technology Bureau,No.2023MSXM182。
文摘Rheumatoid arthritis(RA)patients face significant psychological challenges alongside physical symptoms,necessitating a comprehensive understanding of how psychological vulnerability and adaptation patterns evolve throughout the disease course.This review examined 95 studies(2000-2025)from PubMed,Web of Science,and CNKI databases including longitudinal cohorts,randomized controlled trials,and mixed-methods research,to characterize the complex interplay between biological,psychological,and social factors affecting RA patients’mental health.Findings revealed three distinct vulnerability trajectories(45%persistently low,30%fluctuating improvement,25%persistently high)and four adaptation stages,with critical intervention periods occurring 3-6 months postdiagnosis and during disease flares.Multiple factors significantly influence psychological outcomes,including gender(females showing 1.8-fold increased risk),age(younger patients experiencing 42%higher vulnerability),pain intensity,inflammatory markers,and neuroendocrine dysregulation(48%showing cortisol rhythm disruption).Early psychological intervention(within 3 months of diagnosis)demonstrated robust benefits,reducing depression incidence by 42%with effects persisting 24-36 months,while different modalities showed complementary advantages:Cognitive behavioral therapy for depression(Cohen’s d=0.68),mindfulness for pain acceptance(38%improvement),and peer support for meaning reconstruction(25.6%increase).These findings underscore the importance of integrating routine psychological assessment into standard RA care,developing stage-appropriate interventions,and advancing research toward personalized biopsychosocial approaches that address the dynamic psychological dimensions of the disease.
基金the National Natural Science Foundation of China(82204935)the construction project of Zhao Feng National Old Pharmacist Inheritance Studio of State Administration of Traditional Chinese Medicine(National Traditional Chinese Medicine Education Letter[2024]255)+1 种基金the open project of the Key Laboratory of Basic and New Drug Research of Traditional Chinese Medicine in Shaanxi Province(KF202302)the project of Xi’an Municipal Bureau of Science and Technology(23YXYJ0042)for financial support.
文摘Background:One of the first hundred traditional Chinese medicines(TCM)formulas administered in China,Qianghuo Shengshi Decoction(QSD)has a positive clinical and therapeutic impact on rheumatoid arthritis(RA).Even so,there is still not enough knowledge on the active ingredients and possible ways that QSDs might work to treat RA.This study systematically investigated the active ingredients and mechanisms of action of QSD for treating wind-cold-dampness arthralgia type RA.Methods:UHPLC-QE-MS and network pharmacology techniques were employed to predict the potential active constituents,targets,and associated signalling pathways.Then,the therapeutic effect of QSD was examined using a wind-cold-dampness arthralgia paralytic RA rat model.Finally,the complex mechanism was comprehensively elucidated by integrating transcriptomics and network pharmacology.The above mechanisms were also verified by molecular docking,immunohistochemistry and Western blot.Results:UHPLC-QE-MS and network pharmacology analysis revealed that ferulic acid,imperatorin,magnolol,quercetin,and scopoletin could be the primary constituents in QSD responsible for its anti-RA effects.Animal experiments showed that QSD can significantly inhibit rat joint swelling degree,decrease the content of serum rheumatoid factor(RF),interleukin(IL)-1β,tumor necrosis factor-alpha(TNF-α),IL-6,and anti-citrullinated protein antibodies(ACPA),and increase the content of IL-4,IL-10 to relieve the clinical symptoms of wind-cold-dampness arthralgia type RA.The mechanistic study showed that QSD may effectively inhibit rat synovial hyperplasia via promoting autophagy and apoptosis of synovial cells by regulating the PI3K/Akt/mTOR signalling pathway.Conclusion:This study identifies key active ingredients in QSD and elucidates its potential mechanism for treating wind-cold-dampness arthralgia type RA,providing a basis for the clinical application of QSD.
基金supported in part by the National Natural Science Foundation of China(Grant No.82350710800,82374470,82202757)Shenzhen Medical Research Fund B2302005,and NHMRC,APP1163933.
文摘Rheumatoid arthritis(RA)is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life.RA accelerates musculoskeletal aging,leading to complications such as muscle degeneration and sarcopenia.Recent research has identified myopenia as a condition of significant muscle loss associated with illness,distinct from the muscle wasting seen in other chronic diseases like cancer cachexia or heart failure.In RA,myopenia is characterized by muscle depletion without concurrent significant fat loss,and it can affect individuals of all ages.While inflammation plays a central role,it is not the sole factor contributing to the high incidence of muscle wasting in RA.In subsequent discussions,secondary sarcopenia will be considered alongside myopenia,as both involve muscle wasting decline primarily due to disease.This review summarizes recent findings on the impact of RA-related myopenia and secondary sarcopenia on functional capacity,explores its underlying mechanisms,and discusses contemporary strategies to mitigate the process of musculoskeletal aging in RA patients.
基金supported by the National Natural Science Foundation of China(NSFC)(No.82130073,No.82372430,No.31871431,No.31821002,No.32101011,No.22177073)Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System+3 种基金Shanghai Science and Technology Committee(No.23ZR1437600,No.24410710600,No.24141901302)Shenzhen Medical Research Fund(No.B2302005)The Open Project Funding of Shanghai Key Laboratory of Orthopedics(No.KFKT202201)Biomaterials and Regenerative Medicine Institute Cooperative,Research Project,Shanghai Jiao Tong University School of Medicine(No.2022LHA01).
文摘Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.
基金the National Natural Science Foundation of China(82372412)the Social Development Project of Jiangsu Province(BE2022701)+4 种基金the Top Talent Support Program for Young and Middle-aged People of the Wuxi Health Committee(BJ2020044,BJ2020057,HB2020043)the Fundamental Research Funds of the Health and Family Planning Commission of Wuxi(M202024)the Special Program for Translational Medicine Research of the Wuxi Translational Medicine Center(2020DHYB07,2020DHYB03)the Key Special Project of Precision Medicine of the Wuxi Health Commission(J202101)peking union medical college hospital talent cultivation program(UHB50192).
文摘Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.
文摘Rheumatoid arthritis(RA)is a common chronic autoimmune disease characterized by joint pain,swelling and dysfunction[1].According to epidemiologic statistics,the incidence of RA is 1%–2%,and in severe cases,it can develop into joint deformity and disability,which brings a heavy burden to the family and society[2].However,the pathogenesis of RA is complex and involves multiple cellular interactions,which increases the difficulty of curing RA.Current therapeutic options,such as disease-modifying antirheumatic drugs,non-steroidal anti-inflammatory drugs,and biologics,still face the challenge of relapse after drug discontinuation[3,4].Therefore,the pathogenesis of RA needs to be analyzed in depth to break through the existing therapeutic bottlenecks and promote the iterative innovation of individualized diagnosis and treatment.
基金financially supported by the Natural Science Foundation of China(No.82003766)Taishan Scholars Program(NO.tsqn202211219)+1 种基金the Key Research and Development Project of Shandong Province(No.2021ZDSYS27)Shandong Province nature fund surface project(Grant No.ZR2024MH088)。
文摘Background:Studies have shown that individuals who receive early treatment for rheumatoid arthritis(RA)are more likely to approach life positively,avoiding joint damage and the need for joint replacement surgery.The diagnosis of early rheumatoid arthritis(ERA)is crucial for effective treatment and prognosis of patients.Urine,as a diagnostic medium,offers the advantages of non-invasive diagnosis.Urinary metabolites can serve as biomarkers for diagnosis,prognosis,and risk prediction,improving specificity and accuracy.Methods:We recruited 37 ERA patients with a history of less than 3 months and a score of 6,26 osteoarthritis(OA)patients,and 30 healthy controls(HC).Urine samples were collected for 16S rRNA sequencing,and untargeted liquid chromatography-mass spectrometry(LC-MS)was used to detect metabolites.Bioinformatics approaches were employed to identify pathogenic metabolites as specific risk factors for ERA precisely.Results:2-methylnaphthalene was identified as a biomarker for ERA in urine.Prevotella,a major part of the urinary microbiome in ERA patients,exhibited a positive correlation with 2-methylnaphthalene.Notably,there were significant variations in urine metabolites among patients with ERA,OA,and HC.2-Methylnaphthalene was found to be significantly enriched in ERA.Besides,inflammatory factors were elevated in ERA patients.The research further demonstrated a positive correlation between rheumatoid factor(RF),erythrocyte sedimentation rate(ESR),and C-reactive protein(CRP)and the metabolite 2-methylnaphthalene.Conclusion:The urine metabolite 2-methylnaphthalene can be a risk factor for early urinary tract infections and may contribute to accurately screening early-risk metabolites in ERA.
文摘Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples from patients with different pathological processes were collected, and the correlations between the subsets of FLSs and STMs and pathological processes were analyzed via flow cytometry. In vitro experimental methods such as enzyme linked immunosorbent assay (ELISA), Western blotting, Transwell assays, CCK- 8 assays and cell coculture were used to assess cell proliferation, migration and secretion of inflammatory factors. A collagen- induced arthritis mouse model was constructed to investigate the therapeutic potential of emodin in RA by flow cytometry, micro- CT and staining. Results : Unique subsets of FLSs and STMs, namely, FAPα ^(+)THY1 − FLSs, FAPα ^(+)THY1 ^(+)FLSs, and MerTK ^(pos) TREM2 ^(high) STMs, were identified in synovial tissues from RA patients. The number of MerTK ^(pos) TREM2 ^(high) STMs was negatively correlated with the degree of damage in RA, while the number of FAPα ^(+)THY1 − FLSs was positively correlated with damage. On the one hand, emodin promoted the aggregation of MerTKposTREM2high STMs. Moreover, MerTK pos TREM2 high STM- mediated secretion of exosomes was promoted, which can inhibit the secretion of pro- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs and promote the secretion of anti- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs, thereby inhibiting FAPα ^(+)THY1 − FLS proliferation and migration, improving the local immune microenvironment, and inhibiting RA damage. Conclusion : Emodin was shown to regulate the aggregation of STM subsets and exosome secretion, affecting the secretion, proliferation and migration of inflammatory factors in FLS subsets, and ultimately achieving good therapeutic efficacy in RA patients, suggesting that it has important clinical value.
文摘Rheumatoid arthritis(RA)is a chronic autoimmune disease that affects approxi-mately 0.46%of the global population.Conventional therapeutics for RA,including disease-modifying antirheumatic drugs(DMARDs),nonsteroidal anti-inflammatory drugs(NSAIDs),and corticosteroids,frequently result in unintended adverse effects.Dexamethasone(DEX)is a potent glucocorticoid used to treat RA due to its anti-inflammatory and immunosuppressive properties.Liposomal delivery of DEX,particu-larly when liposomes are surface-modified with targeting ligands like peptides or sialic acid,can improve drug efficacy by enhancing its distribution to inflamed joints and minimizing toxicity.This study investigates the potential of liposomal drug delivery systems to enhance the efficacy and targeting of DEX in the treatment of RA.Results from various studies demonstrate that liposomal DEX significantly inhibits arthritis progression in animal models,reduces joint inflammation and damage,and alleviates cartilage destruction compared to free DEX.The liposomal formulation also shows better hemocompatibility,fewer adverse effects on body weight and immune organ index,and a longer circulation time with higher bioavailability.The anti-inflammatory mechanism is associated with the downregulation of pro-inflammatory cytokines like tumor necrosis factor-α(TNF-α)and B-cell-activating factor(BAFF),which are key players in the pathogenesis of RA.Additionally,liposomal DEX can induce the expres-sion of anti-inflammatory cytokines like interleukin-10(IL-10),which has significant anti-inflammatory and immunoregulatory properties.The findings suggest that lipo-somal DEX represents a promising candidate for effective and safe RA therapy,with the potential to improve the management of this debilitating disease by providing targeted delivery and sustained release of the drug.
基金supported by the Budgeted Fund of Shanghai University of Traditional Chinese Medicine(Natural Science)(No.2021LK037)the Open Project of Qinghai Province Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation(No.2021-ZY-03).
文摘Objective Rheumatoid arthritis(RA)is a systemic autoimmune disease that affects the small joints of the whole body and degrades the patients’quality of life.Zhengqing Fengtongning(ZF)is a traditional Chinese medicine preparation used to treat RA.ZF may cause liver injury.In this study,we aimed to develop a prediction model for abnormal liver function caused by ZF.Methods This retrospective study collected data from multiple centers from January 2018 to April 2023.Abnormal liver function was set as the target variable according to the alanine transaminase(ALT)level.Features were screened through univariate analysis and sequential forward selection for modeling.Ten machine learning and deep learning models were compared to find the model that most effectively predicted liver function from the available data.Results This study included 1,913 eligible patients.The LightGBM model exhibited the best performance(accuracy=0.96)out of the 10 learning models.The predictive metrics of the LightGBM model were as follows:precision=0.99,recall rate=0.97,F1_score=0.98,area under the curve(AUC)=0.98,sensitivity=0.97 and specificity=0.85 for predicting ALT<40 U/L;precision=0.60,recall rate=0.83,F1_score=0.70,AUC=0.98,sensitivity=0.83 and specificity=0.97 for predicting 40≤ALT<80 U/L;and precision=0.83,recall rate=0.63,F1_score=0.71,AUC=0.97,sensitivity=0.63 and specificity=1.00 for predicting ALT≥80 U/L.ZF-induced abnormal liver function was found to be associated with high total cholesterol and triglyceride levels,the combination of TNF-αinhibitors,JAK inhibitors,methotrexate+nonsteroidal anti-inflammatory drugs,leflunomide,smoking,older age,and females in middle-age(45-65 years old).Conclusion This study developed a model for predicting ZF-induced abnormal liver function,which may help improve the safety of integrated administration of ZF and Western medicine.
文摘BACKGROUND This study investigates the impact of type 2 diabetes mellitus(T2DM)on the risk of interstitial lung disease(ILD)and its subtypes in patients with rheumatoid arthritis(RA).RA is often complicated by ILD.T2DM has systemic proinflam-matory effects,but its impact on RA-related ILD is unclear.This research aims to elucidate the interplay between these conditions to inform clinical management and patient care strategies.AIM To determine if RA patients with T2DM have a higher occurrence of ILD compar-ed to RA patients without T2DM.METHODS We conducted a retrospective cohort study using the 2019-2020 National Inpa-tient Sample.Adult RA patients with and without T2DM were identified via International Classification of Diseases,10th Revision(ICD-10)codes.Propensity score matching(1:1)balanced 15+confounders.Logistic regression assessed the association of T2DM with ILD(overall and by subtype)and secondary outcomes(acute respiratory distress syndrome,pneumothorax,pleural effusion,pulmonary hypertension).Missing data were excluded.ILD subtypes were included based on ICD-10 codes and case count.RESULTS Among 199380 RA inpatients,ILD was more common in those with T2DM(2.25%)vs without(1.11%).After matching(n=121046),ILD remained higher in RA+T2DM[odds ratio(OR)=2.02,95%CI:1.84-2.22,P<0.001],with an absolute risk increase of about 1.14%.T2DM was associated with higher odds of ILD subtypes including usual interstitial pneumonia(OR=3.20)and non-specific interstitial pneumonia(OR=3.50).Other subtypes showed elevated ORs;eosinophilic pneumonia showed an inverse association(OR=0.23).PAH and pneumo-thorax were also more common in RA+T2DM(OR=1.40 and 1.85,respectively).Acute respiratory distress syn-drome and pleural effusion rates did not differ by T2DM status.Rare subtype findings should be interpreted cautiously.CONCLUSION T2DM increases ILD risk in RA and is linked to higher rates of pulmonary hypertension and pneumothorax,suggesting a role in exacerbating RA-related lung complications.
基金supported by the project of Central Funds Guiding the Local Science and Technology Development(No.20212ZDD02010)。
文摘Andrographolide sulfonate(AS)is a sulfonated derivative of andrographolide extracted from Andrographis paniculata(Burm.f.)Nees,and has been approved for several decades in China.The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis.Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling,improved body weights,and attenuated pathological changes in joints of rats with adjuvant-induced arthritis.Additionally,the levels of tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6),and IL-1β in the serum and ankle joints were reduced.Bioinformatics analysis,along with the spleen index and measurements of IL-17 and IL-10 levels,suggested a potential relationship between AS and Th17 cells under arthritic conditions.In vitro,AS was shown to block Th17 cell differentiation,as evidenced by the reduced percentages of CD4^(+)IL-17A^(+)T cells and decreased expression levels of RORγt,IL-17A,IL-17F,IL-21,and IL-22,without affecting the cell viability and apoptosis.This effect was attributed to the limited glycolysis,as indicated by metabolomics analysis,reduced glucose uptake,and p H measurements.Further investigation revealed that AS might bind to hexokinase2(HK2)to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase(GAPDH)or pyruvate kinase M2(PKM2),and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation.Furthermore,AS impaired the activation of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)signals in vivo and in vitro,which was abolished by the addition of lactate.In conclusion,AS significantly improved adjuvant-induced arthritis(AIA)in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
文摘Introduction: Among the chronic and feared complications of this disease, rheumatoid vasculitis stands out as one of the most severe, albeit rare. The most frequently affected sites by rheumatoid vasculitis are the skin and the peripheral nervous system. We report a case of rheumatoid vasculitis complicating a 30-year history of untreated rheumatoid arthritis. Case Report: The patient is a 75-year-old male with a 30-year history of deforming and erosive seropositive rheumatoid arthritis. He presented with polyarthritis and digital necrosis. Physical examination revealed peripheral joint syndrome with characteristic deformities of rheumatoid arthritis. Additionally, there was well-demarcated dry gangrene affecting the first and second digits of the right hand. Laboratory findings indicated an inflammatory syndrome. Tests for antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA) to investigate other causes of vasculitis were negative. The patient received a corticosteroid bolus. After two weeks, there was a marked reduction in pain and an improvement in the general condition. The dry gangrene remained stable. Conclusion: Rheumatoid vasculitis remains a serious and chronic complication of rheumatoid arthritis, associated with significant mortality. This case highlights the crucial importance of early diagnosis and effective management of rheumatoid arthritis.
基金supported by NIH grants to M Bukrinsky P30 AI117970by the“Creation of Experimental Laboratories in the Natural Sciences Program”and Basic Research Program at the Higher School of Economics University.
文摘Eosinophils are multifunctional granulocytes that contribute to the initiation and modulation of inflammation.Accumulating evidence suggests that eosinophils are adaptable leukocytes that orchestrate the resolution of inflammatory responses.The most prevalent chronic inflammatory illness,rheumatoid arthritis(RA),is typified by persistent synovitis thatmakes it hard for the disease to go away on its own.Interestingly,a unique subset of eosinophils known as regulatory eosinophils has been found in RA patients’synovium,especially while the disease is in remission.Pro-resolving signatures of regulatory eosinophils in the synovium are distinct from those of their lung counterparts.The most recent research on eosinophils and their function in this disease pathogenesis is compiled in this review.Based on the role of regulatory eosinophils,a new pathological model of inflammation resolution in RA is proposed,and potential therapeutic strategies aimed at enhancing the action of regulatory eosinophils in RA are proposed.
基金Programa de Investigadores e Investigadoras of the Consejo Mexiquense de Ciencia y Tecnología(COMECYT)(EESP2024-0038)。
文摘Objective To perform an in silico bioinformatics analysis to identify differentially expressed microRNAs(miRNAs)implicated in rheumatoid arthritis(RA)pathogenesis and evaluate their potential as biomarkers for assessing therapeutic efficacy and monitoring acupuncture treatment.Methods miRNA microarray data(CEL and TXT formats)were acquired from human and murine RA models,with the latter undergoing acupuncture treatment.Data were normalized using the robust multi-array average(RMA)method and analyzed for differential expression.Differential expression analysis identified miRNAs through a comparative analysis of RA human tissues,acupuncture-treated murine RA models,and a bibliographic search for miRNAs implicated in RA pathogenesis and acupuncture treatment.Bioinformatics analysis was performed to identify potential target genes for each miRNA and signaling pathways via search tools for the Retrieval of Interacting Genes/Proteins(STRING)and ShinyGO.Gene-drug interaction analysis was performed through Drug-Gene Interaction Database(DGIdb)screening.Interaction networks were constructed with the Cytoscape v3.10.3 software.Results The hsa-miR-125a-5p and hsa-miR-125b-5p were identified as potential biomarkers associated with RA pathogenesis,presenting 468 and 455 target genes,respectively.These genes were enriched in 20 signaling pathways,including Janus kinasa-signal transducer and activator of transcription(JAK-STAT),mitogen-activated protein kinase(MAPK),phosphoinositide 3-kinase-protein kinase B(PI3K-Akt),and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)signaling pathway,which have been associated with RA pathogenesis and progression.Drug-gene interaction networks revealed that 22 genes were significantly associated with 58 RA treatment drugs,among which 13 genes interacted with members of the hsa-miR-125 family.Conclusion The hsa-miR-125a-5p and hsa-miR-125b-5p demonstrate critical regulatory role in RA pathogenesis by modulating signaling pathways,including JAK-STAT,MAPK,PI3K-Akt,and NF-κB.Our findings show that the hsa-miR-125a-5p and hsa-miR-125b-5p exhibit differential expression patterns in response to pharmacological intervention in various diseases,including RA management.This suggests their potential roles as biomarkers for monitoring acupuncture treatment.Although existing evidence indicates that acupuncture can modify miRNA expression profiles,rigorous validation through biological models remains essential to confirm these results.
基金supported by National Natural Science Foundation of China(82204766,82074122,82174078)Natural Science Foundation of Hunan province(2023JJ40490)+9 种基金Changjiang Scholars Program in Ministry Education,People’s Republic of China(T2019133)Xiaohe Sci-Tech Talents Special Funding under Hunan Provincial Sci-Tech Talents Sponsorship Program(2023TJ-X71)Science and Technology Innovation Program of Hunan Province(2024RC3201)Scientific research project of Hunan Provincial Education Department(21B0394,21A0239)Research Project of Hunan Administration of Traditional Chinese Medicine(B2023055)Changsha Outstanding Innovative Youth Training Program(kq2306021)Outstanding Youth Program of Hunan University of Chinese Medicine(202202)Postgraduate Innovation Project of Hunan University of Chinese Medicine(2024CX090)Open Foundation Project of Hunan International Joint Laboratory of Traditional Chinese Medicine(2022GJSYS02)Undergraduate Research and Innovation Foundation of Hunan University of Chinese Medicine(2023BKS097).
文摘Abnormal activation of macrophages and osteoclasts(OCs)contributes significantly to rheumatoid arthritis(RA)development by secretion of numerous inflammatory factors.Notably,these cells exhibit significant upregulation of folate receptor proteins on their surfaces.Unfortunately,there is a current lack of safe and effective therapeutic drugs for RA.Xuetongsu(XTS),a triterpenoid compound extracted fromKadsura heteroclita Roxb Craib,has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes(RAFLS).However,its clinical application is hampered by poor targeting and short half-life.To address these drawbacks,we previously developed a nano-drug system named HRPS nanoparticles(NPs),which effectively targets RAFLS and inhibits synovial hyperplasia.However,this system overlooked the essential role of OCs in RA-related bone destruction.Therefore,we designed a novel folate-modified biomimetic Prussian blue(PB)-XTS NP(FMPX NP)for the selective delivery of XTS into inflammatory macrophages and OCs.The NP exhibits an excellent photothermal effect when assisted by laser irradiation,facilitating targeted release of XTS within inflammatory macrophages and OCs.The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs.In vivo experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times,decreased hind foot swelling from 12.10±0.49 mm to 8.24±0.09 mm in the model group,and prevented bone damage.In conclusion,this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA.FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy,providing new insights for targeted drug therapies in clinical RA treatment.
基金supported by the National Natural Science Foundation of China(No.82204724)the Science and Technology Development Fund,Macao SAR(Nos.0029/2023/AFJ,005/2023/SKL)+1 种基金the Multi-Year Research Grant(MYRG)of University of Macao(Nos.MYRG2022-00203-ICMS,MYRG-GRG2023-00134-ICMS-UMDF)Macao Young Scholars Program(No.AM2022019)。
文摘Invasive fibroblast-like synoviocytes(FLS),inflammatory macrophages and osteoclasts are the main three contributors to rheumatoid arthritis(RA)progression by promoting synovial inflammation and destructing cartilage and bone.Targeting these three cell types for restoring the inflammatory homeostasis microenvironment may be a promising anti-RA strategy.Herein,we prepared a reactive oxygen species(ROS)-responsive micelles(DPTM)to co-load dexamethasone(DEX)and pristimerin(PRI)for RA therapy.This ROS-responsive system exhibits the following advantages:(1)It makes use of the“ELVIS”effect for passive delivery and targeting the ROS environment of RA-related cells to rapidly release the payload drugs DEX and PRI.(2)Compared with free drugs,DPTM showed stronger effect on the inhibition of RA-FLS proliferation and the promotion of RA-FLS apoptosis.Moreover,DPTM could significantly weaken the migration ability of RA-FLS as indicated by the results of wound healing assay and transwell assay.(3)DPTM exerted stronger cellular uptake and anti-inflammatory effect in M1 macrophages.(4)In the model studying receptor activator of nuclear factor kappa-B ligand(RANKL)-induced differentiation of bone marrow-derived macrophages(BMDMs)to osteoclasts,DPTM showed a stronger inhibitory activity on osteoclast formation as compared to free drugs.Taken together,these results highlighted the potential of DPTM for targeted RA therapy via inhibition of RA-FLS abnormal activation,macrophage polarization and osteoclastogenesis.
基金supported by the National Natural Science Foundation of China(No.52173150)the Guangzhou Science and Technology Program City University Joint Funding Project(No.2023A03J0001)to Jun Wu+6 种基金supported by the National Natural Science Foundation of China(No.52073313)Shenzhen Science and Technology Program(No.KCXFZ 202002011010232)Longhua District Science and Innovation Commission Project Grants of Shenzhen(No.10162A20221027B1FA526)to Zhong Caosupported by Shenzhen Medical Research Fund(No.A2303010)National Natural Science Foundation of China(No.82204287)Fundamental Research Funds for the Central Universities,Sun Yat-sen University(No.87000-31670001)to Yi Zhaosupported by Guangdong Basic and Applied Basic Research Foundation(No.2023A1515220126)to Xinru You。
文摘Systemic administration of the anti-rheumatic drug methotrexate(MTX)for a long period of time may lead to therapeutic tolerance,various adverse effects,and potential harm to the immune system.Therapeutic nano-delivery carriers constructed based on biologically active phenols provide a promising approach to enhance the therapeutic effect of anti-rheumatic drugs.Caffeic acid,a natural compound with anti-inflammatory properties,holds significant potential in the treatment of diverse inflammatory conditions.In this paper,we first constructed a nano-delivery platform for MTX using caffeic acid-based polyphenol polymer Ph-CaA-OH(PCOH),and investigated the treatment of rheumatoid arthritis(RA)at low drug administration doses(2.5 mg/kg).PCOH nanoparticles(NPs)could inhibit lipopolysaccharidesstimulated macrophage inducible nitric oxide synthase(iNOS)expression and pro-inflammatory differentiation in vitro.In vivo imaging revealed the rapid accumulation and sustained presence of PCOH NPs at inflamed joints in collagen induced-arthritis(CIA)mice.Therapeutic evaluation of CIA mice demonstrated that MTX@PCOH NPs were superior to free MTX in reducing the progression of RA and decreasing the expression of multiple pro-inflammatory cytokines without significant toxic effects.By enhancing drug aggregation at inflammatory joints and capitalizing on the synergistic effects of active carriers,MTX@PCOH NPs effectively minimized the required drug dosage and mitigated toxic side effects in RA treatment.The application of PCOH NPs to RA treatment provides a new strategy for the development of safer and more effective anti-RA nanomedicines.
