Macrophage extracellular traps promote tumor-like biologic behaviors of fibroblast-like synoviocytes through cGAS-mediated PI3K/Akt signaling pathway in patients with rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune disease characterized by synovium hyperplasia and bone destruction. Macrophage extracellular traps are released from macrophages under various stimuli and may generate stable autoantigen-DNA complexes, as well as aggravate autoantibody generation and autoimmune responses. We aimed to investigate the role of macrophage extracellular traps on the biologic behaviors of rheumatoid arthritis fibroblast-like synoviocytes. Synovial tissues and fibroblast-like synoviocytes were obtained from patients with rheumatoid arthritis. Extracellular traps in synovium and synovial fluids were detected by immunofluorescence, immunohistochemistry, and SYTOX Green staining. Cell viability, migration, invasion, and cytokine expression of rheumatoid arthritis fibroblast-like synoviocytes were assessed by CCK-8, wound-healing assay, Transwell assays, and quantitative real-time polymerase chain reaction, respectively. RNA sequencing analysis was performed to explore the underlying mechanism, and Western blot was used to validate the active signaling pathways. We found that extracellular trap formation was abundant in rheumatoid arthritis and positively correlated to anti-CCP. Rheumatoid arthritis fibroblast-like synoviocytes stimulated with purified macrophage extracellular traps demonstrated the obvious promotion in tumor-like biologic behaviors. The DNA sensor cGAS in rheumatoid arthritis fibroblast-like synoviocytes was activated after macrophage extracellular trap stimuli. RNA sequencing revealed that differential genes were significantly enriched in the PI3K/Akt signaling pathway, and cGAS inhibitor RU.521 effectively reversed the promotion of tumor-like biologic behaviors in macrophage extracellular trap-treated rheumatoid arthritis fibroblast-like synoviocytes and downregulated the PI3K/Akt activation. In summary, our study demonstrates that macrophage extracellular traps promote the pathogenically biological behaviors of rheumatoid arthritis fibroblast-like synoviocytes through cGAS-mediated activation of the PI3K/Akt signaling pathway. These findings provide a novel insight into the pathogenesis of rheumatoid arthritis and the mechanisms of macrophages in modulating rheumatoid arthritis fibroblast-like synoviocyte tumor-like behaviors.

Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis.

Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively correlates with RA disease severity as does lipid hyperoxidation of focal monocyte/macrophages. Further study reveals high susceptibility to iron induced ferroptosis of the anti-inflammatory macrophages M2, while pro-inflammatory M1 are less affected. Distinct glutathione peroxidase 4 (GPX4) degradation depending on p62/SQSTM1 in the two cell types make great contribution mechanically. Of note, ferroptosis inhibitor liproxstatin-1 (LPX-1) can alleviate the progression of K/BxN serum-transfer induced arthritis (STIA) mice accompanied with increasing M2 macrophages proportion. We thus propose that the heterogeneous ferroptosis susceptibility of macrophage subtypes as well as consequent inflammation and immune disorders are potential biomarkers and therapeutic targets in RA.

Fresh and Browned Lotus Root Extracts Promote Cholesterol Metabolism in FFA-Induced HepG2 Cells through Different Pathways.

Browning of fresh-cut plants is mainly attributed to the enzymatic browning of phenolic compounds induced by polyphenol oxidase (PPO), producing browning products such as anthraquinones, flavanol oxides, and glycosides, which are usually considered to be non-toxic. Could browning bring any benefits on behalf of their bioactivity? Our previous study found that browned lotus root extracts (BLREs) could reduce the cholesterol level in obese mice as fresh lotus root extracts (FLREs) did. This study aimed to compare the mechanisms of FLRE and BLRE on cholesterol metabolism and verify whether the main component's monomer regulates cholesterol metabolism like the extracts do through in vitro experiments. Extracts and monomeric compounds are applied to HepG2 cells induced by free fatty acids (FFA). Extracellular total cholesterol (TC) and triglyceride (TG) levels were also detected. In addition, RT-PCR and Western blot were used to observe cholesterol metabolism-related gene and protein expression. The in vitro results showed that BLRE and FLRE could reduce TC and TG levels in HepG2 cells. In addition, BLRE suppressed the synthesis of cholesterol. Meanwhile, FLRE promoted the synthesis of bile acid (BA) as well as the clearance and efflux of cholesterol. Furthermore, the main monomers of BLRE also decreased cholesterol synthesis, which is the same as BLRE. In addition, the main monomers of FLRE promoted the synthesis of BAs, similar to FLRE. BLRE and FLRE promote cholesterol metabolism by different pathways.

Diagnostic value of combining PI-RADS v2.1 with PSAD in clinically significant prostate cancer.

PURPOSE: To investigate the diagnostic value of the Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v2.1) for clinically significant prostate cancer (CsPCa). We also aimed to combine PI-RADS v2.1 with prostate-specific antigen (PSA) derivatives to improve the predictive value of CsPCa. METHODS: We retrospectively collected relevant data who underwent standard MRI examinations of the prostate and subjected to a prostate biopsy at Shenzhen People's hospital from November 2014 to November 2019. Included 125 cases of CsPCa and 383 cases of non-CsPCa. All cases were scored using the PI-RADS v2.1. The clinical data collected included age, PSA, free PSA/total PSA, prostate volume and PSA density (PSAD). A univariate analysis was performed to identify statistically significant indicators. Logistic regression was used to analyze the predictive value of the multi-parameter combination on CsPCa. RESULTS: Except age, the difference in all of indicators between the CsPCa group and non-CsPCa group was statistically significant. The PI-RADS score and PSAD value had the highest diagnostic value. Logistic regression analysis revealed that the PI-RADS score and PSAD value were independent predictors of CsPCa, with a regression model AUC of 0.935. CsPCa detection rates were low when the PI-RADS score ≤ 2 or the PI-RADS score = 3 and the PSAD value ≤ 0.33 ng/ml/ml. CONCLUSION: Combining the PI-RADS score and PSAD value improved the predictive performance of CsPCa. Patients with a PI-RADS score ≤ 2 or a PI-RADS score = 3 and a PSAD value ≤ 0.33 ng/ml/ml can avoid an unnecessary biopsy.

Efficacy of the Dynesys Hybrid Surgery for Patients with Multi-Segmental Lumbar Spinal Stenosis.

Objective: The efficacy of hybrid (Dynesys and fusion) surgery and the traditional transforaminal lumbar interbody fusion surgery was compared in patients with multi-segmental lumbar spinal stenosis. Methods: A total of 68 patients with multi-segmental lumbar spinal stenosis subjected to surgery were recruited between January 2013 and October 2020 in the First Affiliated Hospital of Southern University of Science and Technology. The patients were divided into a hybrid group (N = 33) and a TLIF group (N = 35) by surgery. After surgery, follow-up was conducted for 12 months. Between the two groups, the following parameters were compared: general conditions, clinical symptom scores, imaging parameters, and early complications. Results: A statistically significant difference in the duration of surgery was noted between the two groups. After 12 months of follow-up, the range of motion disappeared in the TLIF group, while 63.53% was preserved in the hybrid group with statistically significant differences. A statistically significant difference was identified in the Oswestry Disability Index one week after surgery. Nonetheless, no statistically significant differences were observed at the 12-month post-surgical follow-up. Pfirrmann grade showed a 3.03% upper adjacent segment degeneration rate in the hybrid group (1/33) at 12-month follow-up and 2.86% (1/35) in the TLIF group. Notably, no early complications (screw loosening and wound infection) were identified in the two groups. Conclusion: The Dynesys hybrid surgery combined the advantages of two systems of dynamic stabilization and rigid fusion. Besides, hybrid surgery is potentially a novel approach for the treatment of multi-segmental lumbar spinal stenosis.

Polysaccharides from soybean residue fermented by Neurospora crassa alleviate DSS-induced gut barrier damage and microbiota disturbance in mice.

Soluble polysaccharides derived from microbial fermentation of agricultural by-products were considered as potential functional ingredients, primarily having probiotic properties. Herein, soluble polysaccharides (FSRP) were isolated from soybean residue fermented by Neurospora crassa, and FSRP mainly contained rhamnose, arabinose, fucose, mannose, glucose, and galactose, according to GC-MS analysis. To further investigate the protective effect of FSRP against colitis, dextran sulfate sodium induction (DSS)-treated mice were orally gavaged with FSRP (200 mg kg-1 d-1) or inulin (400 mg kg-1 d-1, a positive control) for 7 d. The results showed that DSS-treated mice displayed symptoms of body weight loss, atrophy, and histopathological changes of colon, as well as gut barrier damage, which were recovered after FSRP supplementation (similar to inulin). Furthermore, the beneficial effects of FSRP were linked to a decreased inflammatory response and increased protein expression of E-cadherin, claudin-1 and ZO-1. Illumina-MiSeq sequencing analysis revealed that FSRP increased microbial diversity and altered community structure. Specifically, FSRP could modulate the abundance of inflammation-related bacteria (such as Tenericutes, Clostridia, and Bacilli) to ameliorate colitis symptoms. Therefore, FSRP can relieve DSS-induced colitis, which is closely associated with reduced levels of inflammatory factors, improved gut barrier function and gut microbiota homeostasis.