Genetic associations in ankylosing spondylitis: circulating proteins as drug targets and biomarkers.

Background: Ankylosing spondylitis (AS) is a complex condition with a significant genetic component. This study explored circulating proteins as potential genetic drug targets or biomarkers to prevent AS, addressing the need for innovative and safe treatments. Methods: We analyzed extensive data from protein quantitative trait loci (pQTLs) with up to 1,949 instrumental variables (IVs) and selected the top single-nucleotide polymorphism (SNP) associated with AS risk. Utilizing a two-sample Mendelian randomization (MR) approach, we assessed the causal relationships between identified proteins and AS risk. Colocalization analysis, functional enrichment, and construction of protein-protein interaction networks further supported these findings. We utilized phenome-wide MR (phenMR) analysis for broader validation and repurposing of drugs targeting these proteins. The Drug-Gene Interaction database (DGIdb) was employed to corroborate drug associations with potential therapeutic targets. Additionally, molecular docking (MD) techniques were applied to evaluate the interaction between target protein and four potential AS drugs identified from the DGIdb. Results: Our analysis identified 1,654 plasma proteins linked to AS, with 868 up-regulated and 786 down-regulated. 18 proteins (AGER, AIF1, ATF6B, C4A, CFB, CLIC1, COL11A2, ERAP1, HLA-DQA2, HSPA1L, IL23R, LILRB3, MAPK14, MICA, MICB, MPIG6B, TNXB, and VARS1) that show promise as therapeutic targets for AS or biomarkers, especially MAPK14, supported by evidence of colocalization. PhenMR analysis linked these proteins to AS and other diseases, while DGIdb analysis identified potential drugs related to MAPK14. MD analysis indicated strong binding affinities between MAPK14 and four potential AS drugs, suggesting effective target-drug interactions. Conclusion: This study underscores the utility of MR analysis in AS research for identifying biomarkers and therapeutic drug targets. The involvement of Th17 cell differentiation-related proteins in AS pathogenesis is particularly notable. Clinical validation and further investigation are essential for future applications.

Specific blood metabolite associations with Gout: a Mendelian randomization study.

OBJECTIVE: Gout, common metabolic disorders, have poorly understood links with blood metabolites. Exploring these relationships could enhance clinical prevention and treatment strategies. METHODS: We applied bidirectional two-sample Mendelian randomization (MR) analysis, using data from a genome-wide association (GWAS) study of 486 blood metabolites. Gout data was obtained from FinnGen R8 (7461 gout and 221,323 control cases). We implemented the inverse variance-weighted (IVW) method for main analytical approach. Extensive heterogeneity, pleiotropy tests, leave-one-out analysis, and reverse MR were conducted to validate the robustness of our findings. Both Bonferroni and False Discovery Rate (FDR) corrections were used to adjust for multiple comparisons, ensuring stringent validation of our results. RESULTS: Initial MR identified 31 candidate metabolites with potential genetic associations to gout. Following rigorous sensitivity analysis, 23 metabolites as potential statistical significance after final confirmation. These included metabolites enhancing gout risk such as X-11529 (OR = 1.225, 95% CI 1.112-1.350, P < 0.001), as well as others like piperine and stachydrine, which appeared to confer protective effects. The analysis was strengthened by reverse MR analysis. Additionally, an enrichment analysis was conducted, suggesting that 1-methylxanthine may be involved in the metabolic process of gout through the caffeine metabolism pathway. CONCLUSION: Identifying causal metabolites offers new insights into the mechanisms influencing gout, suggesting pathways for future research and potential therapeutic targets.

Machine learning-based identification of novel hub genes associated with oxidative stress in lupus nephritis: implications for diagnosis and therapeutic targets.

BACKGROUND: Lupus nephritis (LN) is a complication of SLE characterised by immune dysfunction and oxidative stress (OS). Limited options exist for LN. We aimed to identify LN-related OS, highlighting the need for non-invasive diagnostic and therapeutic approaches. METHODS: LN-differentially expressed genes (DEGs) were extracted from Gene Expression Omnibus datasets (GSE32591, GSE112943 and GSE104948) and Molecular Signatures Database for OS-associated DEGs (OSEGs). Functional enrichment analysis was performed for OSEGs related to LN. Weighted gene co-expression network analysis identified hub genes related to OS-LN. These hub OSEGs were refined as biomarker candidates via least absolute shrinkage and selection operator. The predictive value was validated using receiver operating characteristic (ROC) curves and nomogram for LN prognosis. We evaluated LN immune cell infiltration using single-sample gene set enrichment analysis and CIBERSORT. Additionally, gene set enrichment analysis explored the functional enrichment of hub OSEGs in LN. RESULTS: The study identified four hub genes, namely STAT1, PRODH, TXN2 and SETX, associated with OS related to LN. These genes were validated for their diagnostic potential, and their involvement in LN pathogenesis was elucidated through ROC and nomogram. Additionally, alterations in immune cell composition in LN correlated with hub OSEG expression were observed. Immunohistochemical analysis reveals that the hub gene is most correlated with activated B cells and CD8 T cells. Finally, we uncovered that the enriched pathways of OSEGs were mainly involved in the PI3K-Akt pathway and the Janus kinase-signal transducer and activator of transcription pathway. CONCLUSION: These findings contribute to advancing our understanding of the complex interplay between OS, immune dysregulation and molecular pathways in LN, laying a foundation for the identification of potential diagnostic biomarkers and therapeutic targets.

Unraveling the connection between gut microbiota and Alzheimer's disease: a two-sample Mendelian randomization analysis.

Purpose: Studies have shown a close relationship between gut microbiota (GM) and Alzheimer's disease (AD). However, the causal relationship between them remains unclear. Methods: We conducted a genome-wide association study (GWAS) using publicly available summary statistics data for GM and AD. We extracted independent genetic loci significantly associated with GM relative abundances as instrumental variables based on predefined thresholds (p < 1*e-5). The inverse variance-weighted (IVW) method was primarily used for causal relationship assessment. Additional analyses, including MR-Egger, weighted median, simple mode, and weighted mode, were performed as supplementary analyses. Results: IVW analysis revealed significant correlations between certain microbial taxa and the risk of AD. Higher abundances of Actinobacteria at the class level, phylum. Actinobacteria, class. Deltaproteobacteria, order. Desulfovibrionales, genus. Oscillospira, and genus. Ruminococcaceae UCG004 (p < 0.048) was found to be positively associated with an elevated risk of AD. However, within the genus-level taxa, Ruminococcus1 (p = 0.030) demonstrated a protective effect on lowering the risk of AD. In addition, to ensure the robustness of the findings, we employed Cochrane's Q test and leave-one-out analysis for quality assessment, while the stability and reliability of the results were validated through MR-Egger intercept test, MR-PRESSO global test, and sensitivity analysis. Conclusion: This study provided a comprehensive analysis of the causal relationship between 211 GM taxa and AD. It discerned distinct GM taxa linked to the susceptibility of AD, thereby providing novel perspectives on the genetic mechanisms governing AD via the GM. Additionally, these discoveries held promise as valuable biomarkers, enabling the identification of potential therapeutic targets and guiding forthcoming AD investigations.

Exploring the potential common denominator pathogenesis of system lupus erythematosus with COVID-19 based on comprehensive bioinformatics analysis.

Objective: Evidences show that there may be a link between SLE and COVID-19. The purpose of this study is to screen out the diagnostic biomarkers of systemic lupus erythematosus (SLE) with COVID-19 and explore the possible related mechanisms by the bioinformatics approach. Methods: SLE and COVID-19 datasets were extracted separately from the NCBI Gene Expression Omnibus (GEO) database. The limma package in R was used to obtain the differential genes (DEGs). The protein interaction network information (PPI) and core functional modules were constructed in the STRING database using Cytoscape software. The hub genes were identified by the Cytohubba plugin, and TF-gene together with TF-miRNA regulatory networks were constructed via utilizing the Networkanalyst platform. Subsequently, we generated subject operating characteristic curves (ROC) to verify the diagnostic capabilities of these hub genes to predict the risk of SLE with COVID-19 infection. Finally, a single-sample gene set enrichment (ssGSEA) algorithm was used to analyze immune cell infiltration. Results: A total of 6 common hub genes (CDC6, PLCG1, KIF15, LCK, CDC25C, and RASGRP1) were identified with high diagnostic validity. These gene functional enrichments were mainly involved in cell cycle, and inflammation-related pathways. Compared to the healthy controls, abnormal infiltration of immune cells was found in SLE and COVID-19, and the proportion of immune cells linked to the 6 hub genes. Conclusion: Our research logically identified 6 candidate hub genes that could predict SLE complicated with COVID-19. This work provides a foothold for further study of potential pathogenesis in SLE and COVID-19.

Biology of interleukin-37 and its role in autoimmune diseases (Review).

Autoimmune diseases (AIDs) are characterized by dysfunction and tissue destruction, and recent studies have shown that interleukin (IL)-37 expression is dysregulated in AIDs. Among cytokines of the IL-1 family, most are pro-inflammatory agents, and as an anti-inflammatory cytokine, IL-37 may have the potential to alleviate excessive inflammation and can be used as a ligand or transcription factor that is involved in regulating innate and adaptive immunity. IL-37 plays important roles in the development of AIDs. This review summarizes the biological characteristics and functions of IL-37 and discusses the potential of IL-37 as a therapeutic target for effective cytokine therapy and as a biomarker in AIDs.

Investigating the molecular mechanism of iguratimod act on SLE using network pharmacology and molecular docking analysis.

Objective: Iguratimod (IGU) is a novel small disease-modifying compound widely used in Asia for the treatment of rheumatic diseases. IGU is a methane sulfonanilide. We applied network pharmacology to investigate the pharmacological mechanisms of IGU act on SLE. Methods: We used PharmMapper, UniProt, and OMIM databases to screen the potential targets of IGU, and the SLE-related disease targets were predicted. Hub target genes among the intersections of the potential targets (IGU) and related genes (SLE) were validated using the PPI network generated by the String database. GO and KEGG enrichment analyses were carried out using the David online platform. Finally, the molecular docking of hub targets and their corresponding compounds were completed through AutoDock Vina and PyMOL software for visualization. Result: A total of 292 potential targets of IGU, 6501 related disease targets of SLE, and 114 cross targets were screened from the aforementioned database. Network topology analysis identified 10 hub targets, such as CASP3, AKT1, EGFR, MMP9, and IGF1. GO enrichment analysis mainly focuses on the negative regulation of the apoptotic process and signal transduction. KEGG enrichment analysis illustrated that the PI3K-AKT signaling pathway, MAPK signaling pathway, and FoxO signaling pathway might play a significant role in the pharmacological mechanisms of IGU act on SLE. Molecular docking confirmed that the IGU ligand had strong binding activity to the hub targets. Conclusion: This study based on network pharmacology and molecular docking validation preliminarily revealed the protein targets affected by IGU acting on SLE through, and explored potential therapeutic mechanism role of IGU in SLE treatment by multi pathways.

RND3 Transcriptionally Regulated by FOXM1 Inhibits the Migration and Inflammation of Synovial Fibroblasts in Rheumatoid Arthritis Through the Rho/ROCK Pathway.

Rheumatoid arthritis (RA) is a systemic immune disease. Rho family GTPase 3 (RND3) has been reported to play an important role in inflammatory diseases. In this study, the expression of RND3 in RA was analyzed by gene chips. After RND3 was overexpressed, cell counting kit-8 assay was to detect the viability of fibroblast-like synovial cells (RA-FLSs). Transwell assays were to appraise the migratory and invasive capacities of RA-FLSs. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were to estimate inflammatory response. In addition, MMP3 and MMP9 levels were also tested by ELISA analysis. After forkhead box M1 (FOXM1) was overexpressed, RND3 expression was detected by Western blot. The transcriptional relationship between FOXM1 and RND3 was predicted by HumanTFDB and JASPAR databases. Luciferase reporter and chromatin immunoprecipitation assays verified the binding ability of FOXM1 and RND3. The role of FOXM1/RND3 axis in RA was detected again by functional experiments. Western blot detected the expression of Rho/ROCK pathway-related proteins. RND3 expression was downregulated in RA. Overexpression of RND3 reduced the proliferation, migration, invasion, and inflammation of RA-FLSs. RND3 was inhibited by FOXM1 transcription, and upregulated FOXM1 reduced the inhibitory effect of RND3 overexpression on cell growth and inflammation, which might be associated with the Rho/ROCK pathway. RND3 transcriptionally regulated by FOXM1 inhibited the migration and inflammation of RA-FLSs in RA through the Rho/ROCK pathway.

Novel insight into miRNA biology and its role in the pathogenesis of systemic lupus erythematosus.

MicroRNAs(miRNAs) have emerged as key regulators that control and influence gene expression as well as multiple biological processes depending on their potential binding sites in human-protein coding genes and other unconventional patterns, including coding for peptides, activating Toll-like receptors as a ligand, and other manners. Accumulating evidence has demonstrated that microRNA expression is tightly regulated during phases of development, differentiation, and effector functions of immune cells, immunological disorders of systemic lupus erythematosus (SLE). This review outlines the biogenesis of miRNAs and their unconventional functions as well as underlying cellular and molecular mechanisms. It then summarizes our current knowledge about how the biogenesis of miRNAs is regulated. Moreover, an overview was provided concerning the role of abnormal expression of miRNAs in lupus immune cells. In particular, we will shed some light on the recent advances in the role of miRNAs and exosome-derived miRNAs in immunological and epigenetic pathways in the pathogenesis of SLE.

Understanding the Attitudes and Willingness of Adult Chinese Patients with Rheumatic Diseases Towards COVID-19 Vaccination.

Background: The SARS-CoV-2 pandemic has imposed substantial health and economic burdens on the societies. COVID-19 vaccination is the most effective method of controlling the epidemic. This study assessed the attitude, willingness, and related factors of adult patients with rheumatic diseases (RDs) in China towards COVID-19 vaccination and identified their reasons for being vaccinated. Methods:  A cross-sectional survey was administered to patients with rheumatic diseases from July 18 to August 18, 2021, using an online questionnaire. Logistic regression analysis was performed to examine the data. Results: We analyzed data drawn from 464 participants who provided valid responses. A total of 324 (69.83%) RD patients were not willing to be vaccinated, of which 76.97% believed that COVID-19 vaccination might exacerbate the diseases symptoms. Logistic regression analysis showed that a combination of experiencing systemic damage, being in the acute attack stage of the disease, and fear of the adverse impact of vaccination on rheumatism, etc., were the predominant factors affecting the intentional vaccination rate in adult patients with rheumatic diseases (p < 0.05). Conclusion: The COVID-19 intentional vaccination rate was relatively low in adult Chinese patients with RD. Public health education and the dissemination of government scientific data for patients with RD should be enhanced to increase COVID-19 vaccination rates.

Safety and immunogenicity of inactivated COVID-19 vaccination in adult rheumatic patients in South China: a prospective study.

Patients with rheumatic diseases (RD) are considered to be a high-risk population for infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The effectiveness of inactivated COVID-19 vaccinations (ICVs) was described as more effective than 95%. Despite this, no data on the immunogenicity and safety of the ICV in Han race stable RD patients in China. In this study, we sought to assess the safety and immunogenicity of the ICVs in RD patients in South China. A total of 80 adult stable RD patients were recruited. Following 14-35 days of immunization, cheiluminescence immunoassays (CLIA) were utilized to detect antibodies titers. An investigation into the relative parameters on the immunogenicity response to vaccination was carried out using logistic regression analysis. Compared to the HC group, the positive response of IgG and Nab in RD patients were lower than those in healthy control (HC) (P = .040 and P < .0001, respectively) after two doses of ICV were inoculated. The use of methotrexate (P = .016) and prednisolone (P = .018), and the level of red blood cell distribution width-C (RDW-C) (P = .035) and C-reactive protein (P = .015) were independently associated with lower rises in the magnitude of COVID-19 vaccine antibodies. No vaccine-related serious adverse reactions were observed in either group. After receiving two doses of ICVs, the production of protective antibodies in stable RD patients treated with immunosuppressive agents may decrease. It was discovered that ICVs were safe and well tolerated by RD patients.

What is the context?There are currently no accessible data on the efficacy and safety of inactivated COVID-19 vaccinations in South China RD patients who are receiving immunosuppressive medications.What is new?Inactivated COVID-19 vaccinations were immunogenic in stable RD patients in our investigation. No significant adverse reactions to the vaccination were seen in either group. No disease flares were observed in our study.What is the impact?Inactivated COVID-19 vaccinations are immunogenic and safe in stable RD patients in China, according to the findings of this study. The use of methotrexate or prednisolone, the RDW-C level, and the CRP level may all have an effect on the development of protective antibodies following vaccination.

Treatment of reactive arthritis with biological agents: a review.

The pathogenesis of reactive arthritis (ReA) has not been fully elucidated. In recent years, many researchers have confirmed that multiple cytokines are involved in the occurrence and development of ReA. Although ReA is self-limiting, it is still incurable for some patients who have no or a weak response to traditional drugs, such as non-steroidal anti-inflammatory agents, glucocorticoids and immunosuppressive agents. This is called refractory reactive arthritis. Currently, there is insufficient evidences for the treatment of refractory ReA with biological agents, though biological agents against cytokines have been developed over the past few years. This review summarizes the current development of clinical treatments of ReA with biological agents, which provides future investigations on refractory ReA with more evidence and references.

Oxidative stress-mediated mitochondrial dysfunction facilitates mesenchymal stem cell senescence in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease possessing a morbid serum microenvironment with enhanced oxidative stress. Long-term exposure to an oxidative environment usually results in cellular senescence alone with cellular dysfunction. Mesenchymal stem cells (MSCs) are a kind of stem cell possessing strong capabilities for immunoregulation, and senescent MSCs may increase inflammation and participate in AS pathogenesis. The objective of this study was to explore whether and how the oxidative serum environment of AS induces MSC senescence. Here, we found that AS serum facilitated senescence of MSCs in vitro, and articular tissues from AS patients exhibited higher expression levels of the cell cycle arrest-related proteins p53, p21 and p16. Importantly, the levels of advanced oxidative protein products (AOPPs), markers of oxidative stress, were increased in AS serum and positively correlated with the extent of MSC senescence induced by AS serum. Furthermore, MSCs cultured with AS serum showed decreased mitochondrial membrane potential and ATP production together with a reduced oxygen consumption rate. Finally, we discovered that AS serum-induced mitochondrial dysfunction resulted in elevated reactive oxygen species (ROS) in MSCs, and ROS inhibition successfully rescued MSCs from senescence. In conclusion, our data demonstrated that the oxidative serum environment of AS facilitated MSC senescence through inducing mitochondrial dysfunction and excessive ROS production. These results may help elucidate the pathogenesis of AS and provide potential targets for AS treatment.

A predicted risk score based on the expression of 16 autophagy-related genes for multiple myeloma survival.

Autophagy has an important role in the pathogenesis of plasma cell development and multiple myeloma (MM); however, the prognostic role of autophagy-related genes (ARGs) in MM remains undefined. In the present study, the expression profiles of 234 ARGs were obtained from a Gene Expression Omnibus dataset (accession GSE24080), which contains 559 samples of patients with MM analyzed with 54,675 probes. Univariate Cox regression analysis identified 55 ARGs that were significantly associated with event-free survival of MM. Furthermore, a risk score with 16 survival-associated ARGs was developed using multivariate Cox regression analysis, including ATIC, BNIP3L, CALCOCO2, DNAJB1, DNAJB9, EIF4EBP1, EVA1A, FKBP1B, FOXO1, FOXO3, GABARAP, HIF1A, NCKAP1, PRKAR1A and SUPT20H, was constructed. Using this prognostic signature, patients with MM could be separated into high- and low-risk groups with distinct clinical outcomes. The area under the curve values for the receiver operating characteristic curves were 0.740, 0.741 and 0.712 for 3, 5 and 10 years prognosis predictions, respectively. Notably, the prognostic role of this risk score could be validated with another four independent cohorts (accessions: GSE57317, GSE4581, GSE4452 and GSE4204). In conclusion, ARGs may serve vital roles in the progression of MM, and the ARGs-based prognostic model may provide novel ideas for clinical applications in MM.