Blimp1 suppressed CD4+ T cells-induced activation of fibroblast-like synoviocytes by upregulating IL-10 via the rho pathway.

BACKGROUND: B lymphocyte-induced maturation protein 1 (Blimp1) is a risk allele for rheumatoid arthritis (RA), but its functional mechanism in RA remains to be further explored. METHODS: Flow cytometry was performed to detect CD4+ T cell differentiation. ELISA was used to measure inflammatory factor secretion. Lentivirus mediated Blimp1 overexpression vector (LV-Blimp1) or short hairpin RNA (sh-Blimp1) were used to infect CD4+ T cells stimulated by anti-CD28 and anti-CD3 mAbs. RA fibroblast-like synoviocytes (FLSs) were co-cultured with CD4+ T cells or T cell conditioned medium (CD4CM), and cell proliferation, invasion, and expression of adhesion molecules and cytokines in FLSs were evaluated. Mice were injected intradermally with type II collagen to establish a collagen-induced arthritis (CIA) mouse model, and the severity of CIA was evaluated with H&E and Safranin-O staining. RESULTS: Blimp1 knockdown increased pro-inflammatory factor secretion, but downregulated IL-10 concentration in activated CD4+ T cells. Blimp1 overexpression promoted regulatory T cells (Treg) CD4+ T cell differentiation and hindered T helper 1 (Th1) and T helper 17 (Th17) CD4+ T cell differentiation. Blimp1 overexpression suppressed the expression of pro-inflammatory factors and adhesion molecules in CD4+ T cells by upregulating IL-10. Moreover, Blimp1 overexpression impeded the enhanced effect of CD4+ T cells/CD4CM on cell adhesion, inflammation, proliferation, invasion and RhoA and Rac1 activities in FLSs by upregulating IL-10. Additionally, administration with LV-Blimp1 alleviated the severity of CIA. CONCLUSION: Blimp1 restrained CD4+ T cells-induced activation of FLSs by promoting the secretion of IL-10 in CD4+ T cells via the Rho signaling pathway.

The implication of integrative multiple RNA modification-based subtypes in gastric cancer immunotherapy and prognosis.

Previous studies have focused on the impact of individual RNA modifications on tumor development. This study comprehensively investigated the effects of multiple RNA modifications, including m6A, alternative polyadenylation, pseudouridine, adenosine-to-inosine editing, and uridylation, on gastric cancer (GC). By analyzing 1,946 GC samples from eleven independent cohorts, we identified distinct clusters of RNA modification genes with varying survival rates and immunological characteristics. We assessed the chromatin activity of these RNA modification clusters through regulon enrichment analysis. A prognostic model was developed using Stepwise Regression and Random Survival Forest algorithms and validated in ten independent datasets. Notably, the low-risk group showed a more favorable prognosis and positive response to immune checkpoint blockade therapy. Single-cell RNA sequencing confirmed the abundant expression of signature genes in B cells and plasma cells. Overall, our findings shed light on the potential significance of multiple RNA modifications in GC prognosis, stemness development, and chemotherapy resistance.

Comprehensive analysis of autophagy-related clusters and individual risk model for immunotherapy response prediction in gastric cancer.

Introduction: Autophagy can be triggered by oxidative stress and is a double-edged sword involved in the progression of multiple malignancies. However, the precise roles of autophagy on immune response in gastric cancer (GC) remain clarified. Methods: We endeavor to explore the novel autophagy-related clusters and develop a multi-gene signature for predicting the prognosis and the response to immunotherapy in GC. A total of 1505 patients from eight GC cohorts were categorized into two subtypes using consensus clustering. We compare the differences between clusters by the multi-omics approach. Cox and LASSO regression models were used to construct the prognostic signature. Results: Two distinct clusters were identified. Compared with cluster 2, the patients in cluster 1 have favorable survival outcomes and lower scores for epithelial-mesenchymal transition (EMT). The two subtypes are further characterized by high heterogeneity concerning immune cell infiltration, somatic mutation pattern, and pathway activity by gene set enrichment analysis (GSEA). We obtained 21 autophagy-related differential expression genes (DEGs), in which PTK6 amplification and BCL2/CDKN2A deletion were highly prevalent. The four-gene (PEA15, HSPB8, BNIP3, and GABARAPL1) risk signature was further constructed with good predictive performance and validated in 3 independent datasets including our local Tianjin cohort. The risk score was proved to be independent prognostic factor. A prognostic nomogram showed robust validity of GC survival. The risk score was significantly associated with immune cell infiltration status, tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint molecules. Furthermore, the model was efficient for predicting the response to tumor-targeted agent and immunotherapy and verified by the IMvigor210 cohort. This model is also capable of discriminating between low and high-risk patients receiving chemotherapy. Conclusion: Altogether, our exploratory research on the landscape of autophagy-related patterns may shed light on individualized therapies and prognosis in GC.

Advances in sex disparities for cancer immunotherapy: unveiling the dilemma of Yin and Yang.

A wide sex disparity has been demonstrated in cancer incidence, tumor aggressiveness, prognosis, and treatment response of different types of cancer. The sex specificity of cancer appears to be a relevant issue in managing the disease, and studies investigating the role of sex and gender are becoming extremely urgent. Immunotherapy plays a leading role in cancer treatment, offering a new perspective on advanced malignancies. Gender has not been considered in standard cancer treatment, suggesting increasing the recognition of sex differences in cancer research and clinical management. This paper provides an overview of sex and gender disparities in cancer immunotherapy efficacy, anti-cancer immune response, predictive biomarkers, and so on. We focus on the molecular differences between male and female patients across a broad range of cancer types to arouse the attention and practice of clinicians and researchers in a sex perspective of new cancer treatment strategies.

The integrated landscape of eRNA in gastric cancer reveals distinct immune subtypes with prognostic and therapeutic relevance.

The comprehensive regulation effect of eRNA on tumor immune cell infiltration and the outcome remains obscure. We comprehensively identify the eRNA-mediated immune infiltration patterns of gastric cancer (GC) samples. We creatively proposed a random forest machine-learning (ML) algorithm to map eRNA to mRNA expression patterns. The eRNA score was constructed using principal component analysis algorithms and validated in an independent cohort. Three subtypes with distinct eRNA expression patterns were determined in GC. There were significant differences between the three subtypes in the overall survival rate, immune cell infiltration characteristics, and immunotherapy response indicators. The patients in the high eRNA score group have a higher overall survival rate and might benefit from immunotherapy. This work revealed that eRNA regulation might be a new prognostic index and might offer a potential biomarker in the response of immunotherapy. Evaluating the eRNA regulation manner of GC will contribute to guiding more effective immunotherapy strategies.

Characterization of Two Ferroptosis Subtypes With Distinct Immune Infiltration and Gender Difference in Gastric Cancer.

Background: Iron is an essential nutrient involved in the redox cycle and the formation of free radicals. The reprogramming of iron metabolism is the main link to tumor cell survival. Ferroptosis is an iron-dependent form of regulated cell death associated with cancer; the characteristics of ferroptosis in cancers are still uncertain. This study aimed to explore the application value and gender difference of ferroptosis in prognosis and immune prediction to provide clues for targeted therapy of gastric cancer. Methods: We comprehensively evaluated the ferroptosis levels of 1,404 gastric cancer samples from six independent GC cohorts based on ferroptosis-related specific genes and systematically correlated ferroptosis with immune cell infiltrating and gender characteristics. The ferroptosis score was constructed to quantify the ferroptosis levels of individual tumors using principal component analysis (PCA) algorithms. Results: We identified two distinct ferroptosis subtypes in gastric cancer, namely Subtype-A and Subtype-B. We found that male patients in Subtype-B had the worst prognosis in contrast with the other groups. Three sex hormone receptors (AR, ER, and PR) in Subtype-B tumor patients were higher than in Subtype-A tumor patients in GC, while the HER2 displayed an opposite trend. We developed a risk model termed ferroptosis score to evaluate ferroptosis levels within individual tumors. The low-ferroptosis score group was characterized by activation of immune cells and increased mutation burden, which is also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. The patients with a low-ferroptosis score showed a high microsatellite instability status (MSI-H) and had a higher response to immunotherapy. Furthermore, the patients with low-ferroptosis scores have a lower estimated IC50 in the several chemotherapy drugs, including paclitaxel, gemcitabine, and methotrexate. Conclusions: We revealed that sex hormone receptors and immune cell infiltration were markedly different between ferroptosis subtypes in GC patients. The results suggested that gender difference may be critical when the ferroptosis-related strategy is applied in GC treatment. Further, ferroptosis levels were identified with an extreme variety of prognosis and tumor immune characteristics, which might benefit GC individualized treatment.

Paeoniflorin Suppresses Rheumatoid Arthritis Development via Modulating the Circ-FAM120A/miR-671-5p/MDM4 Axis.

Paeoniflorin is an active ingredient derived from Paeonia, which has an anti-inflammatory effect. However, the potential role and basis of paeoniflorin in rheumatoid arthritis (RA) are indistinct. Cell viability, cycle distribution, migration, and invasion were evaluated via Cell Counting Kit-8 (CCK-8), flow cytometry, and transwell assays. The contents of inflammatory cytokines were examined using enzyme-linked immunosorbent assay (ELISA). RNA expression levels were determined via qRT-PCR and western blot. The targeting relationship between miR-671-5p and circ-FAM120A (hsa_circ_0003972) or murine double minute 4 (MDM4) was validated via dual-luciferase reporter assay. Paeoniflorin restrained proliferation, migration, invasion, and inflammation and accelerated cell cycle arrest in RA fibroblast-like synoviocytes (RA-FLSs). Circ-FAM120A was boosted in RA synovial tissues and RA-FLSs. Circ-FAM120A upregulation, miR-671-5p knockdown, or MDM4 augmentation reversed the repressive effect of paeoniflorin on RA-FLS progression. Moreover, paeoniflorin attenuated RA-FLS progression by regulating the circ-FAM120A/miR-671-5p/MDM4 axis. Paeoniflorin inhibited RA-FLS proliferation, mobility, and inflammation and triggered cell cycle arrest via mediating the circ-FAM120A/miR-671-5p/MDM4 pathway.

Total glucosides of paeony protects THP-1 macrophages against monosodium urate-induced inflammation via MALAT1/miR-876-5p/NLRP3 signaling cascade in gouty arthritis.

BACKGROUND: Monosodium urate (MSU)-mediated inflammatory response is a crucial inducing factor in gouty arthritis. Here, we explored the underlying mechanism of total glucosides of paeony (TGP) in MSU-induced inflammation of THP-1 macrophages in gouty arthritis. METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell viability. Enzyme-linked immunosorbent assay (ELISA) was utilized to measure the production of interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α). Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were conducted to determine RNA and protein expression. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay were used to confirm the interaction between miR-876-5p and MALAT1 or NLR family pyrin domain containing 3 (NLRP3). RESULTS: MSU-induced damage and inflammatory response in THP-1 macrophages were alleviated by the treatment of TGP in a dose-dependent manner. Overexpression of NLRP3 or MALAT1 reversed the protective effects of TGP in MSU-induced THP-1 macrophages. The binding relation between miR-876-5p and MALAT1 or NLRP3 was identified in THP-1 macrophages. MALAT1 up-regulated the expression of NLRP3 by sponging miR-876-5p in THP-1 macrophages. TGP suppressed MSU-induced inflammation in THP-1 macrophages through regulating MALAT1/miR-876-5p/NLRP3 axis. TGP suppressed MSU-induced activation of TLR4/MyD88/NF-κB pathway through regulating MALAT1/miR-876-5p/NLRP3 axis. CONCLUSION: In conclusion, TGP suppressed MSU-induced inflammation in THP-1 macrophages through regulating MALAT1/miR-876-5p/NLRP3 axis and TLR4/MyD88/NF-κB pathway, suggesting that TGP was a promising active ingredient for gouty arthritis treatment.