To investigate the clinical characteristics and prognostic significance of hypocomplementemia in patients with primary Sjögren’s disease (pSjD), with a particular focus on its association with new-onset peripheral cytopenias. This ambispective cohort study included patients with pSjD treated at the China–Japan Friendship Hospital from 2016 to 2023. Baseline features and associated factors were compared between patients with and without hypocomplementemia. Prospective analyses were performed to evaluate the association between complement levels and new-onset peripheral cytopenias using Fine–Gray competing risk models. Survival outcomes during follow-up were also assessed in patients with and without baseline hypocomplementemia. Among 1013 patients with pSjD, 52.6

Sjögren’s disease (SjD), a systemic autoimmune disease, is characterized by exocrine glandular damage and hypofunction. The molecular mechanism of SjD was still unknown. Mendelian analysis was conducted to identify the targets. Clinical characteristics of the serum protein were assessed in a cohort of SjD patients. In NOD mice, the target inhibitor was used to regulate lymphocytic infiltration and salivary secretion, and RNA-seq was conducted. Ferroptosis-related characters and salivary glandular function were evaluated in target-treated animals, as assessed by Fer-1 rescue. As the results indicated, Mendelian analysis identified LGALS9 (the gene encoding Gal9) as a key gene for SjD. In patients, clustering of CRP, ESR, IgG, and RF distinguished two patient groups with distinct Gal9 levels. Elevated Gal9 levels correlated with decreased unstimulated whole saliva flow and higher focus scores. GSE datasets showed that Gal9 is associated with the ferroptosis markers. In the NOD model, Gal9 inhibition reduced FS and IgG levels as well as decreased Th1 and Th17 infiltration. RNA-seq revealed enrichment of ferroptosis-related pathways in SjD. As a regulator of glutathione metabolism, Gal9 promotes ferroptosis through IFN-γ–dependent regulation of ACSL4 and GPX4. Meanwhile, the exacerbation of glandular injury and lipid peroxidation induced by Gal9 was abolished by ferroptosis inhibitor Fer-1. In conclusion, Gal9 promoted ferroptosis-related salivary gland dysfunction in SjD.

Ethnopharmacological relevance Zhiwang Decoction (ZWD) is a classical traditional Chinese medicine formulation with documented efficacy in alleviating the clinical manifestations of RA, yet its precise molecular mechanisms are not fully defined. Aim of the study To evaluate the anti-inflammatory and protective effects of ZWD in RA and to elucidate its potential mechanisms of action, with a focus on the role of cellular communication network factor 1 (CCN1) and macrophage polarization. Materials and methods A multi-level investigative approach was adopted, utilizing a collagen-induced arthritis (CIA) rat model, lipopolysaccharide (LPS)-activated RAW 264.7 macrophages, and human synovial tissues from RA and osteoarthritis (OA) patients. The therapeutic effects of ZWD were systematically assessed, and its mechanism was explored by analyzing CCN1 expression, macrophage M1 polarization, and the PI3K/AKT pathway. Results ZWD administration significantly attenuated arthritis severity and systemic inflammation in CIA rats. Mechanistic studies revealed that CCN1 was overexpressed in RA synovium and correlated positively with inflammatory activity. In vitro, CCN1 inhibition suppressed LPS-induced PI3K/AKT phosphorylation, inflammatory cytokine production, and M1 macrophage polarization. Notably, ZWD treatment downregulated CCN1 expression, inhibited PI3K/AKT pathway activation, and reduced inflammatory responses and M1 macrophage proportion in both animal and cellular models. Conclusion ZWD exerts anti-RA effects by mitigating inflammation and suppressing M1 macrophage polarization. These therapeutic actions are mechanistically linked to the inhibition of the CCN1-dependent PI3K/AKT pathway.

BACKGROUND:Osteoarthritis (OA) is a leading cause of chronic pain and disability worldwide, with growing evidence implicating immune dysregulation in its pathogenesis. However, the specific peripheral immune cell populations contributing causally to OA risk remain poorly characterized. METHODS:We performed a multi-stage two-sample Mendelian randomization (MR) study integrating single-cell cis-expression quantitative trait loci (cis-eQTLs) for 14 peripheral immune cell types from the OneK1K cohort with two independent OA GWAS datasets - the Million Veteran Program for discovery and the UK Biobank for replication and ICD-10-based subtype analyses. Causal inference was strengthened through Bayesian colocalization, Steiger directionality testing, and phenome-wide pleiotropy screening. Gene-level safety profiling and functional annotation were also performed. RESULTS:Among the eGene-outcome pairs tested, 13 reached false discovery rate significance in discovery. Two were replicated with concordant effect direction: MAN1A2 in CD4+ naïve and central memory T cells and SLC44A4 in NK cells. Bayesian colocalization supported a shared causal variant for MAN1A2 (PP.H4 = 0.96) and SLC44A4 (PP.H4 = 0.81). However, SLC44A4 was excluded due to extensive HLA-related pleiotropy within the major histocompatibility complex region. MAN1A2 showed concordant risk-increasing effects across all five OA subtypes, reaching significance for hip OA, polyarthrosis, and other unspecified arthrosis. Gene-level phenome-wide testing showed that genetic perturbation of MAN1A2 is not associated with detectable adverse phenotypes in population-based exome data, and functional analysis positioned MAN1A2 within N-glycan processing and endoplasmic reticulum quality control pathways. CONCLUSION:Cell-type-specific MR identifies MAN1A2 expression in CD4+ naïve T cells as a candidate therapeutic target for osteoarthritis for which genetic perturbation is not associated with detectable adverse phenotypes in population-based exome data.

To assess the impact of sex on mortality and malignancy in patients with primary Sjögren’s disease (pSD). This ambispective cohort study included 1,182 pSD patients (1,025 women and 157 men) from the China–Japan Friendship Hospital between 2014–2023 and followed through 2024. Survival outcomes were estimated via Kaplan–Meier curves, and SMRs were calculated. Independent risk factors were identified via multivariate Cox regression, followed by stepwise Cox, sex-stratified and interaction analyses. During follow-up, 125 deaths (10.6

ObjectiveTo investigate the clinical and immunological features of primary Sjögren’s disease (pSjD) patients with anti-centromere protein B (CENP-B) antibody positivity and to evaluate its prognostic significance.MethodsThis ambispective cohort study included 1,222 patients with pSjD from the China–Japan Friendship Hospital between February 2014 and February 2023, with follow-up through February 2024. Patients were categorized into anti-CENP-B positive and negative groups based on serum testing. Clinical characteristics, immunological features, and outcomes were compared between groups. A subgroup analysis compared patients with isolated CENP-B positivity to those with additional autoantibodies. Statistical analyses were conducted using SPSS 26.0 and R 4.2.3, including descriptive statistics, univariate tests, and Kaplan-Meier survival analysis.ResultsIn this study, 100 patients (8.2%) were positive for anti-CENP-B antibody, while 1,122 patients (91.8%) were negative. Compared with the negative group, positive patients were older, more often female, and have higher rates of xerostomia and Raynaud’s phenomenon, but lower frequency of dyspnea. They showed lower platelet counts, higher aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, total bilirubin, and lower estimated glomerular filtration rate, with reduced frequencies of elevated Immunoglobulin (Ig) G, but increased IgM levels and slightly lower EULAR Sjögren’s Syndrome Disease Activity Index scores. Among anti-CENP-B positive patients, those with isolated anti-CENP-B positivity had milder immunologic abnormalities than those with concomitant autoantibodies. Among patients with available LSGB data, focal lymphocytic infiltration counts were higher in the anti-CENP-B-positive group. Anti-CENP-B positivity was not significantly associated with mortality, cancer, or interstitial lung disease.ConclusionAnti-CENP-B positivity in pSjD may identify a different baseline serological and clinical profile, characterized by relatively milder immunologic abnormalities and lower disease activity. However, its prognostic and clinical significance remains uncertain and requires further validation.

In recent years, PANoptosis has garnered increasing attention for its potential to promote inflammation. Nevertheless, several issues, including resistance to conventional treatment and immune evasion, correlate with inflammation in the tumor microenvironment. Controlled by the assembly of NLRP12-, ZBP1-, AIM2-, and RIPK1-PANoptosome, the newly discovered programmed cell death PANoptosis simultaneously manifests the characteristics of apoptosis, necroptosis, and pyroptosis. This review summarizes the multifaceted characteristics and the molecule determining PANoptosis sensitivity within the microenvironment. It examines the immunomodulatory function of PANoptosis in the tumor microenvironment, including how immune cells mediate PANoptosis in tumor cells and how tumor cells leverage PANoptosis to evade immune response and promote immunosupression. The crucial role of PANoptosis in immune remodeling suggests promising therapeutic strategies for tumors, such as immunotherapy and combination therapy. The induction of PANoptosis may establish a positive feedback loop that promotes immune activation and has a potential to remodel the immunosuppressive TME. Future strategies is expected to provide new directions for more precise, personalized cancer treatment.

Primary Sjögren’s disease (pSjD) confers a markedly elevated risk for developing CVD, an important contributor to mortality in this population. This study was designed to identify factors associated with CVD in pSjD and to develop a classification model. In this cross-sectional analysis of pSjD individuals (2013–2023), multivariable logistic regression was used to identify CVD-related factors. A classification model was constructed with variable selection via LASSO regression and the Boruta algorithm. Among 734 patients with pSjD, 192 (26.2

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a context-dependent dual role in tumor immunity and immunotherapy. On one hand, it can act as an immunogenic cell death mechanism, releasing damage-associated molecular patterns that activate dendritic cells and promote T cell priming. On the other hand, ferroptosis may suppress antitumor immunity by triggering death or dysfunction in key immune cells, including T lymphocytes, dendritic cells, and macrophages. This review synthesizes current insights into the molecular determinants of ferroptosis sensitivity within the tumor microenvironment. It examines how immune cells can induce ferroptosis in cancer cells, and how tumors evolve resistance through upregulation of proteins like GPX4 and FSP1 or metabolic rewiring. The interplay between ferroptosis and immunity offers promising therapeutic avenues, such as combining ferroptosis inducers with immune checkpoint inhibitors or employing nanotechnology for targeted delivery. However, the net immunogenic outcome depends on temporal, cellular, and microenvironmental factors. Future strategies must aim to selectively induce immunogenic ferroptosis in tumors while preserving immune cell function, leveraging biomarkers and microenvironment modulation to optimize combination therapies in cancer immunotherapy.

ObjectivePrimary Sjögren’s syndrome (pSS) is a highly heterogeneous autoimmune disease. Previous studies have suggested that rheumatoid factor (RF)-positive patients appear to have a higher incidence of systemic involvement. However, the underlying mechanisms remain unclear. This study aims to elucidate the potential biological mechanisms through single-cell RNA sequencing (scRNA-seq).MethodsPeripheral blood mononuclear cells from 3 healthy controls, 6 RF-negative (RF-) pSS patients, and 6 RF-positive (RF+) pSS patients were subjected to scRNA-seq. Subsequent analyses included pathway enrichment analysis, trajectory analysis, cell-cell communication analysis, and B cell receptor (BCR) and T cell receptor (TCR) repertoire profiling. Potential differences were further validated by flow cytometry.ResultsAnalysis of B cell subsets revealed a significantly increased proportion of plasma cells in RF+ patients, and differential gene expression analysis indicated enhanced pathways related to antibody production, clonal expansion, and type I interferon activation. In T-cell subsets, the RF+ group showed a notably higher proportion of CD8+ T cells, which exhibited stronger cytotoxicity and activation of interferon signaling. In contrast, mucosal-associated invariant T (MAIT) cells demonstrated activated interferon signaling but were present at a lower proportion compared to the RF- group. Cell–cell communication analysis revealed strengthened crosstalk between B cells and T cells in the RF+ group. Pseudo-time trajectory analysis further indicated that in RF+ patients, both plasma cells and CD8+ T cells exhibited a developmental skew toward a terminally differentiated state. Additionally, both BCR and TCR repertoire analyses indicated RF+ and RF- patients exhibiting distinct patterns in clonal distribution and frequency. Flow cytometry further validated the increased proportion of CD8+ T cells and the decreased proportion of MAIT cells in the peripheral blood of RF+ pSS patients.ConclusionThe RF status in pSS patients is closely associated with specific immune cell profiles. RF+ patients exhibit more active plasma cell responses, enhanced CD8+ T-cell cytotoxicity and interferon responses, as well as heightened interferon signaling yet reduced proportion of MAIT cells. RF status serves as a key stratification marker for immune heterogeneity in pSS patients, providing new insights for understanding disease mechanisms and developing targeted therapeutic strategies.

Objective:Primary Sjögren's disease (pSjD) is a chronic systemic autoimmune disease characterized by lymphocyte infiltration of the exocrine glands. Anti-SSA (Ro) and anti-SSB (La) antibodies are diagnostic serological markers of pSjD. However, whether the coexistence of anti-SSA and anti-SSB antibodies defines an immunologically distinct subtype at the single-cell level remains unclear. Methods:From our established single-cell peripheral blood mononuclear cells (PBMCs) RNA sequencing database for pSjD, 3 healthy controls, 5 SSA+/SSB- pSjD patients, and 5 SSA+/SSB+ pSjD patients were selected. After quality control and removal of doublets using DoubletFinder, batch effects were corrected with Harmony. Unsupervised clustering was performed to identify major cell lineages. Subsequently, subpopulation clustering, differential gene expression analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis, pseudotime trajectory analysis, and cell-cell communication analysis were carried out. Flow cytometry was further used to validate the findings from the single-cell sequencing. Results:Seven major immune cell populations were identified, including T cells, B cells, monocytes/macrophages, NK cells, plasmacytoid dendritic cells (pDCs), mast cells, and platelet-megakaryocytes. Further subpopulation analysis revealed a more pronounced immune transcriptional reprogramming in the SSA+/SSB+ group compared to the SSA+/SSB- group. Specifically, cytotoxicity-related genes were upregulated in CD8+ T cells. Mucosal-associated invariant T (MAIT) cells exhibited interferon-related transcriptional program remodeling accompanied by a tissue-homing tendency. Plasma cells showed altered expression of immunoglobulin variable region genes. Monocytes/macrophages displayed changes in metabolic-related transcriptional signatures. GO/KEGG enrichment analysis, pseudotime trajectory analysis, and CellChat analysis further supported that the SSA+/SSB+ subtype possesses stronger systemic immune activation characteristics. Flow cytometry further supported altered peripheral T-cell subset distribution in SSA+/SSB+ patients, characterized by an increased proportion of CD8+ T cells and decreased proportions of CD45RA+ naïve-like T cells and MAIT cells compared with SSA+/SSB- patients. Conclusion:SSA+/SSB+ pSjD may represent a subtype with stronger systemic immune activation, which partly explains why these patients exhibit higher disease activity in clinical practice.

Galectin-9 (Gal9) is a type of animal lectin that binds terminal β-galactosides and is involved in immunoregulatory functions. Clinically, Gal9 levels are positively correlated with disease activity in systemic autoimmune diseases, and it acts as a modulator of inflammation. Gal9 regulates inflammation and T cell-mediated immune responses, and it can induce apoptosis and autophagy. Intracellularly, Gal9 regulates metabolic signaling pathways and glycosyltransferases. Extracellularly, Gal9 modulates immune polarization and promotes cell-cell interactions by binding to various receptors on immune cells. This review summarizes the multifaceted effects and underlying mechanisms of Gal9 in autoimmune diseases. Given its critical role in tissue inflammation and organ-specific damage in autoimmune diseases, we discuss the current limitations of treatment and the challenges of clinical translation.

Osteoarthritis (OA) is a common degenerative joint disease characterized by joint pain, swelling, stiffness, and limited mobility. Current treatments primarily offer partial and short-term relief, with concerns about the potential side effects. This underscores the need for safer and more effective therapeutic strategies. AMP-activated protein kinase (AMPK), a key regulator of cellular energy metabolism, plays an essential role in maintaining the homeostasis of articular cartilage, synovium, and subchondral bone. AMPK signaling has been shown to protect joint tissues from damage caused by mechanical stress and inflammatory responses. Studies suggest that modulating AMPK signaling can influence processes such as autophagy, inflammation, and oxidative stress through downstream targets, including the SIRT family and FoxO family. These mechanisms may help reduce cartilage degradation, osteophyte formation, and synovial inflammation. This review provides a systematic overview of the role of AMPK signaling in joint tissues and explores its potential as a therapeutic target for OA, with the aim of informing the development of targeted therapies that may contribute to more effective and safer management of OA symptoms.

Objective:The diverse differentiation states of mononuclear macrophages are closely associated with the pathogenesis of autoimmune diseases. This study integrates single-cell RNA sequencing data from six autoimmune diseases to characterize shared and disease-specific alterations in mononuclear macrophages, with the aim of enhancing our understanding of the immune landscape in autoimmune diseases and refining clinical treatment strategies. Methods:We collected single-cell RNA-sequencing data of autoimmune diseases including primary Sjogren's syndrome (pSS), Behçet's disease (BD), juvenile dermatomyositis (JDM), rheumatoid arthritis (RA), relapsing-remitting multiple sclerosis (RRMS), and systemic lupus erythematosus (SLE). We performed scRNA-seq analysis on 350,043 peripheral blood immune cells from autoimmune diseases patients and healthy controls, followed by validations with flow cytometry, immunohistochemical staining, and immunofluorescence. Results:Fifteen mononuclear phagocyte subpopulations were clustered from peripheral blood mononuclear cells (PBMCs), we identified a new subpopulation named CCL3+ classical monocytes (cMo) that is co-amplified in multiple autoimmune diseases (BD, JDM, pSS, RRMS, SLE). The CCL3+ cMo cells are characterized by high M1-like score, exhibiting strong inflammatory characteristics and high chemotaxis toward other monocytes. In addition, CCL3+ cMo cells upregulated antigen presentation-related signaling pathways, and the cytotoxic CD8+ T or memory CD8+ T cells were strongly perturbed by their signaling crosstalk. Conclusion:This study delineates a comprehensive landscape of mononuclear phagocyte heterogeneity in autoimmune diseases and reveals CCL3+ cMo as a commonly amplified immune subset associated with multiple autoimmune diseases. These findings highlight its potential role in disease mechanisms and nominate CCL3+ cMo as a candidate therapeutic target.

Purpose:Numerous studies have suggested that exosomes are associated with rheumatic diseases, but no bibliometric analysis has been performed. This study presents the first comprehensive bibliometric analysis aiming to evaluate the current research hotspots and to anticipate future trends. Methods:An electronic search was conducted in the Web of Science Core Collection (WOSCC) using exosome and rheumatic disease-specific terminology to identify eligible studies published from January 1, 2000 to October 19, 2024. Only English-language articles and review articles were selected for bibliometric analysis. Data analysis and visualization were conducted using CiteSpace 6.2.R3, VOSviewer 1.6.18, and the Bibliometrix R package. Results:A total of 1,251 publications with 49,374 citations were extracted from the WOSCC database. Both publication and citation frequency increased steadily. 255 different countries or regions, 4,413 institutions and 7,213 authors contributed to the field. China and the USA are the leading countries and Shanghai Jiao Tong University has a significant influence. Théry C is the most frequently co-cited researcher. Most papers are published in Frontiers in Immunology, while Stem Cell Research & Therapy has the highest citations. Research is primarily concentrated in cell biology, immunology, and experimental medicine. Exosm, mesenchymal stem cells (MSCs), autoimmunity, regeneration, and others are major areas of research in this field. Research hotspots primarily focus on the diagnostic potential and therapeutic applications of exosomes in osteoarthritis and rheumatoid arthritis. Exosomes derived from MSCs and their cargo, such as microRNAs (miRNAs), have the potential to serve as biomarkers and therapeutic vehicles in these diseases. Conclusion:This study firstly quantifies and identifies the current status and research frontiers of exosomes in RDs by using bibliometric analysis, which may provide valuable insights for researchers to navigate trends and emerging applications into the field.

Rheumatoid arthritis (RA) is a complex and highly disabling chronic autoimmune disease. As the disease progresses, patients often develop complications such as joint destruction and cardiovascular diseases, posing significant threats to human health. Celastrol, a major bioactive compound extracted from the traditional Chinese herb Tripterygium wilfordii Hook. f., exhibits potent immunomodulatory and anti-inflammatory properties. However, the specific mechanisms underlying its protective effects against bone destruction in RA remain poorly understood. To elucidate its potential therapeutic mechanisms, this study retrieved three gene expression datasets—GSE55235, GSE93777, and GSE200815—from the Gene Expression Omnibus (GEO) database. The primary molecular targets of celastrol were obtained from the HERB and TCMSP platforms. Functional mechanisms associated with these targets were explored using gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Furthermore, molecular docking, immune infiltration analysis, and single-cell RNA sequencing analysis were employed to investigate the role of key target genes. In this study, thirteen potential target genes of celastrol in RA have been identified, including ADAMTS5, AGTR1, ALOX5, CTSB, MMP3, MMP9, MYC, TNF, ITGA4, ITGB7, MMP1, MMP13, and PPARG. Among these, ALOX5 was found to significantly promote MMP3 protein expression, based on which a regulatory model with high predictive power was constructed. GSVA analysis revealed that the TNF-NFκB pathway was significantly activated in RA and exhibited a strong positive correlation with ALOX5 expression. Further experimental analysis demonstrated that knockdown of ALOX5 and its shared transcription factor with MMP2 resulted in a significant downregulation of both genes and inhibition of TNF-NFκB pathway activity. Single-cell transcriptomic analysis showed that ALOX5 was predominantly expressed in macrophages, and the AddModuleScore of celastrol-targeted genes in this cell type was significantly higher than in other cell types, suggesting that macrophages may serve as key effector cells in celastrol-mediated treatment of RA. Celastrol might attenuate RA bone destruction by inhibiting the expression of the ALOX5 gene in macrophages, thereby suppressing the activation of the NF-κB pathway and subsequently reducing the production of matrix metalloproteinases.

Background Rheumatoid factor(RF)is a common autoantibody found in patients with primary Sjögren's syndrome(pSS),but its specific role in the disease is not fully understood.Objective To explore the immune-inflammatory characteristics of pSS patients with different levels of RF.Methods This study included 262 pSS patients who visited the Department of Rheumatology of Traditional Chinese Medicine at China-Japan Friendship Hospital from December 2018 to September 2022.Patients were divided into three groups based on RF levels:negative group(RF<20 U/mL,n=137),low-titer positive group(RF:20-60 U/mL,n=47),and high-titer positive group(RF>60 U/mL,n=78).Clinical data,including general information,clinical manifestations,symptom scores,and haematological indexes,were collected and compared among groups.Results The RF positivity rate in 262 pSS patients was 47.7%(125/262),including 14 males(5.3%)and 248 females(94.7%),with a median age of 57.0(49.0,63.0)years,an average age of onset of(48.7±11.6)years,and a median disease duration of 60.0(24.0,120.0)months.There were no significant differences in gender,age,age of onset,or disease duration among the three groups(P>0.05).The top three common clinical manifestations in pSS patients were dry mouth(257 cases),dry eyes(247 cases),and fatigue(235 cases).The incidence of haematological involvement and arthritis was higher in the high-titer positive group than in the negative group(P<0.05).With the increase in RF titer,the incidence of haematological involvement(χ2trend=6.992,Ptrend=0.008)and arthritis(χ2trend=10.918,Ptrend=0.001)showed an upward trend.As RF titer increased,the proportions of pSS patients with antinuclear antibody≥1∶160(χ2trend=40.691,Ptrend<0.001),anti-SSA antibody positivity(χ2trend=26.138,Ptrend<0.001),anti-Ro52 antibody positivity(χ2trend=31.426,Ptrend<0.001),anti-SSB antibody positivity(χ2trend=23.682,Ptrend<0.001),elevated erythrocyte sedimentation rate(χ2trend=40.132,Ptrend<0.001),elevated immunoglobulin(Ig)A(χ2trend=7.508,Ptrend=0.006),elevated IgG(χ2trend=71.570,Ptrend<0.001),decreased complement 3(χ2trend=7.452,Ptrend=0.006),decreased neutrophil count(χ2trend=8.364,Ptrend=0.004),and decreased hemoglobin(χ2trend=6.390,Ptrend=0.011)all showed an upward trend.Conclusion With the increase in RF titer,the proportion of pSS patients with serum immunological abnormalities and extra-glandular involvement increases.High RF titers have predictive value for arthritis and hematologic involvement.

Objective:Total glycoside of peony (TGP) enhances methotrexate efficacy and attenuates its hepatotoxicity in rheumatoid arthritis, but the mechanisms remain unclear. This study investigates the mechanisms of TGP against methotrexate-induced liver injury through a network pharmacology-based approach. Methods:A liver injury model was established in CD-1 mice by intraperitoneal injection of 20 mg/kg methotrexate. TGP and the positive control drug silybin were used to intervene in the methotrexate-induced liver injury model in mice. Serum ALT and AST activities, liver index test and histopathology was detected to evaluate the effects of the treatment on methotrexate-induced liver injury. Additionally, network pharmacology and serum metabolomics were employed to predict the mechanisms of TGP in treating methotrexate-induced liver injury. Experimental validation was conducted by RT-PCR, ELISA and Western blot. Results:TGP effectively alleviated the liver index and pathological liver damage induced by methotrexate and reduced the liver injury markers, serum ALT and AST, showing effects comparable to those of the positive control drug silybin. Network pharmacology predicted that the key targets and key signaling pathways of TGP in treating methotrexate-induced liver injury are closely associated with inflammatory response. Furthermore, serum metabolomics and network pharmacology analysis indicated a close association between effects of TGP on methotrexate-induced liver injury and arachidonic acid pathway. Experimental validation results confirmed that the expression levels of IL-6, TNF and COX-2 in liver tissues were significantly elevated, with the activation of the PI3K/AKT, MAPK, and NFκB pathways. TGP intervention can reverse these changes to a certain extent. Conclusion:TGP treatment effectively mitigates methotrexate-induced liver injury, and its mechanism is closely associated with the inhibition of hepatic inflammatory responses.

Objective:Rheumatoid arthritis (RA) and fibromyalgia syndrome (FMS) are two common chronic pain disorders which complicate diagnosis and treatment. However, the pathological mechanisms, epidemiological characteristics, and research trends in comorbidities have not yet been systematically reviewed. Methods:Literature related to RA and FMS published between January 2015 and December 2024 was retrieved from the Web of Science (WOS) database. VOSviewer, CiteSpace, Scimago Graphica, and Excel were used to conduct co-occurrence and clustering analyses of countries, institutions, authors, journals, and keywords to evaluate research dynamics and knowledge structures. GeneCards was used to identify shared gene targets between RA and FMS, whereas Protein-Protein Interaction (PPI) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore potential comorbidity mechanisms. Results:In total, 760 articles were included in the study, with annual publication counts showing periodic fluctuations. The United States consistently ranked first in publication output and formed a highly influential collaborative network. Among the institutions, the University of Michigan and Karolinska Institute tied for first place, but the University of Michigan demonstrated a greater influence. Clinical and Experimental Rheumatology published the highest number of articles, whereas Journal of Rheumatology received the most citations. Author analysis revealed that Daniel J. Clauw published the most articles, received the most citations, and had the highest total link strength. Keyword analysis indicated that the research primarily focused on clinical studies with limited exploration of comorbidity mechanisms. GeneCards identified 216 RA and FMS overlapping genes. PPI and KEGG analyses suggested that inflammatory reactions and neuroactive ligand-receptor interactions play key roles in the mechanisms of comorbidity. Conclusion:Current research on RA-FMS comorbidity lacks depth and mechanistic insight. Future studies should explore neuroimmune regulation, central sensitization, and inflammation-pain pathways through interdisciplinary collaboration across rheumatology, neuroscience, pain medicine, and bioinformatics to establish a unified comorbidity framework.

Purpose:To identify risk factors for near-term and long-term death in patients with primary Sjogren's syndrome (pSS). Patients and Methods:This ambispective cohort study included all patients with pSS treated at China-Japan Friendship Hospital between 2013 and 2023. The time-dependent Cox regression analysis was used for statistical analysis of risk factors, with 3 months and 60 months as the cut-off time points and all-cause death as the primary endpoint. Results:Among the 1252 included patients, 138 patients had died by the end of follow-up (11.0%). Age at diagnosis, C-reactive protein (CRP) levels and total bilirubin (TBIL) were time-dependent risk factors for mortality. Within 3 months of follow-up, age > 65 years had no effect on mortality, but after 3 months of follow-up, the mortality risk in patients aged > 65 years increased over time (HR 3.97, 95% CI 2.57-6.13; HR 16.63, 95% CI 5.53-50.03). CRP >6.5 mg/L increased the risk of mortality within 3 months (HR=11.45, 95% CI 2.52-51.95), followed by 3-60 months (HR=2.94, 95% CI 1.94-4.45), but did not affect survival after 60 months of follow-up. TBIL >18.01 µmol/L increased the risk of mortality in pSS patients within 3-6 months (HR=2.30, 95% CI 1.42-3.79) but did not increase the risk of mortality in patients with pSS within 3 months of follow-up or after 60 months. Conclusion:pSS patients with a CRP level >6.5 mg/L have an 11-fold increased risk of near-term death, whereas pSS patients older than 65 years of age at diagnosis have a 16-fold increased risk of long-term death.