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Objective: Fibroblast‐like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease‐modifying antirheumatic drugs. Methods: Combining single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three patients with relapse RA and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using quantitative real‐time PCR (qPCR) and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen‐induced arthritis (CIA) model in rats. Results: Lining and sublining FLS subsets were identified using scRNA‐seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF‐κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human‐derived pannus cell culture, whereas the FGF receptor (FGFR) 1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model. Conclusion: The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue‐specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA. [ABSTRACT FROM AUTHOR]

The mechanisms underlying osteoarthritis (OA) have recently been hypothesized to involve a dysfunctional immune system. In this study, we collected synovium, synovial fluid (SF), and peripheral blood from 21 patients. Mononuclear cells were characterized using FCM. H&E staining and mIHC histological assessment of synovium were performed. Cytokine levels in the SF were measured using ELISA. We observed similar frequencies of immune cells in the synovium and SF, which were enriched in DCs. Notably, CD1c+CD163+ DC3s were expanded in the synovium and SF. Furthermore, we found that DC3s were primarily located within the ectopic lymphoid-like structure (ELLS) in close proximity to CD8+ T cells. Finally, the level of TNF-α and IL12p70 in the SF correlated with the severity of OA. These data suggest that OA is an immune system-related disease and that DC3s may play an active role in OA progression by promoting ELLS formation and inflammatory responses. [ABSTRACT FROM AUTHOR]

Considering turbulent clouds containing small heavy particles, we investigate the reverse effect of particle collision, in particular collision-&-coagulation, on particle clustering and relative motion. We perform various cases of direct numerical simulation (DNS) of coagulating particles in isotropic turbulent flow and find that, due to collision-coagulation, the radial distribution functions (RDF) fall-off dramatically at scales r ∼ d (where d is the particle diameter) to small but finite values; while the mean radial-component of particle relative velocities (MRV) increase sharply in magnitudes. Based on a previously proposed Fokker-Planck (drift-diffusion) framework, we derive a theoretical account of the relationship among particle collision-coagulation rate, RDF and MRV. The theory includes contribution from turbulent-fluctuations absent in earlier mean-field theories. We show numerically that the theory accurately account for the DNS results. We also proposed a phenomenological model for the MRV which is accurate when calibrated using 4th moments of the fluid velocities. We uncover a paradox: the unjustified accuracy of the differential version of the theory. Our result demonstrate strong coupling between RDF and MRV and implies that earlier isolated studies on either RDF or MRV have limited relevance for predicting particle collision rate. [ABSTRACT FROM AUTHOR]

Background: To anticipate the potential molecular mechanism of Astragalus membranaceus (AM) and its monomer, Calycosin, against peritoneal fibrosis (PF) and related muscle atrophy using mRNA-seq, network pharmacology, and serum pharmacochemistry. Methods: Animal tissues were examined to evaluate a CKD-PF mice model construction. mRNA sequencing was performed to find differential targets. The core target genes of AM against PF were screened through network pharmacology analysis, and CKD-PF mice models were given high- and low-dose AM to verify common genes. Serum pharmacochemistry was conducted to clarify which components of AM can enter the blood circulation, and the selected monomer was further validated through cell experiments for the effect on PF and mesothelial mesenchymal transition (MMT) of peritoneal mesothelial cells (PMCs). Results: The CKD-PF mice models were successfully constructed. A total of 31,184 genes were detected in the blank and CKD-PF groups, and 228 transcription factors had significant differences between the groups. Combined with network pharmacology analysis, a total of 228 AM-PF-related targets were identified. Androgen receptor (AR) was the remarkable transcription factor involved in regulating transforming growth factor-β1 (TGF-β1). AM may be involved in regulating the AR/TGF-β1 signaling pathway and may alleviate peritoneal dialysis-related fibrosis and muscle atrophy in CKD-PF mice. In 3% peritoneal dialysis solution-stimulated HMrSV5 cells, AR expression levels were dramatically reduced, whereas TGF-β1/p-smads expression levels were considerably increased. Conclusion: AM could ameliorate PF and related muscle atrophy via the co-target AR and modulated AR/TGF-β1 pathway. Calycosin, a monomer of AM, could partially reverse PMC MMT via the AR/TGF-β1/smads pathway. This study explored the traditional Chinese medicine theory of "same treatment for different diseases," and supplied the pharmacological evidence of "AM can treat flaccidity syndrome.", Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sheng, Sun, Huang, Yu, Meng, Shan, Dai, Wang, Shi and Sheng.)

The mechanisms underlying osteoarthritis (OA) have recently been hypothesized to involve a dysfunctional immune system. In this study, we collected synovium, synovial fluid (SF), and peripheral blood from 21 patients. Mononuclear cells were characterized using FCM. H&E staining and mIHC histological assessment of synovium were performed. Cytokine levels in the SF were measured using ELISA. We observed similar frequencies of immune cells in the synovium and SF, which were enriched in DCs. Notably, CD1c + CD163 + DC3s were expanded in the synovium and SF. Furthermore, we found that DC3s were primarily located within the ectopic lymphoid-like structure (ELLS) in close proximity to CD8 + T cells. Finally, the level of TNF- α and IL12p70 in the SF correlated with the severity of OA. These data suggest that OA is an immune system-related disease and that DC3s may play an active role in OA progression by promoting ELLS formation and inflammatory responses., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 Guowei Qiu et al.)

Brain-targeting delivery of 1,1'-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) is limited by its hydrophilic property and chemical instability. In order to solve this problem, herein, we develop a facile protocol through combining antisolvent precipitation and emulsion-solvent evaporation method to synthesize midazolam (MDZ) coated MMB4 DMS (MMB4@MDZ) nanoparticles. The as-prepared MMB4@MDZ had a MMB4 DMS nanocrystal (MMB4-NC) core and a MDZ shell. The MDZ shell prevented the MMB4-NC core from contacting the aqueous environment, and thus, guaranteed the chemical stability of MMB4 DMS. Most charmingly, the iron mimic cyclic peptide CRTIGPSVC (CRT) was modified on MMB4@MDZ surfaces to produce CRT-MMB4@MDZ which was endowed with ability to absorb transferrin (Tf)-abundant corona. Taking advantages of the Tf-abundant corona, CRT-MMB4@MDZ achieved transferrin receptor (TfR)-mediated brain-targeting delivery. With the fascinating chemical stability and brain-targeting delivery effect, CRT-MMB4@MDZ showed great clinical transform prospect as a brand-new nanomedicine. Of particular importance, this work promised not only a core-shell carrier-free nanomedicine platform for effective delivery of unstable water-soluble drug, but also a protein corona-manipulating strategy for targeting delivery.