Notoginsenoside R1 (NG-R1) Promoted Lymphatic Drainage Function to Ameliorating Rheumatoid Arthritis in TNF-Tg Mice by Suppressing NF-κB Signaling Pathway

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is primarily characterized by synovial inflammation. Our previous studies demonstrated that the lymphatic system is critical for the development and maintenance of RA disease, and sufficient lymph drainage helps to improve joint inflammation. In this study, we found that NG-R1, the main active component in the traditional Chinese medicinal herb Sanchi, activating lymphatic function can attenuate synovial inflammation. According to histopathological staining of ankle sections, NG-R1 significantly decreased the area of inflammation and reduced bone destruction of ankle joints in TNF-Tg mice. Near infrared-indocyanine green (NIR-ICG) lymphatic imaging system has shown that NG-R1 significantly improved the lymphatic drainage function. However, the molecular mechanism of its activity is not properly understood. Our in-depth study demonstrates that NG-R1 reduced the inflammatory cytokine production of lymphatic endothelial cells (LECs) stimulated by TNF-α, and the mechanism ameliorated the phosphorylation of IKKα/β and p65, and the translocation of p65 into the nucleus. In summary, this study proved that NG-R1 promoted lymphatic drainage function to ameliorating rheumatoid arthritis in TNF-Tg mice by suppressing NF-κB signaling pathway.

Persistent popliteal lymphatic muscle cell coverage defects despite amelioration of arthritis and recovery of popliteal lymphatic vessel function in TNF-Tg mice following anti-TNF therapy

“…Despite this early functional decline, 6-weeks of anti-TNF therapy restored PLV contractions 9 , but this restoration was unable to be directly attributed to LMC recovery by regional ultrastructural analysis. Similarly, immunostaining of pre-collecting synovial lymphatics from TNF-Tg mice for alpha smooth muscle actin (αSMA), a biomarker of LMC coverage, demonstrated a progressive and accelerated reduction in LMC investiture with age 23 , 24 relative to typical aging processes 25 . While unique PLV-LMC progenitors have recently been described during postnatal growth and development 26 , it remains unknown whether these precursors are capable of turnover and functional recovery following injury 27 .…”

Exploring the molecular mechanism of notoginsenoside R1 in sepsis-induced cardiomyopathy based on network pharmacology and experiments validation

“…TNF-α is a cytokine with pleiotropic effects on various cell types and has been identified is a major regulator of the inflammatory response. NG-R1 was shown to alleviate rheumatoid arthritis in TNFtg mice by inhibiting the TNF-α signaling pathway to promote lymphatic drainage function (Jiao et al, 2021). The results of our network pharmacology and molecular docking also indicated TNF-α as a key gene for NG-R1 and SIC, so we investigated the role of TNF-α in NGR1-SIC in combination with in vitro and in vivo experiments.…”

“…A pathway-target network was constructed for the top 18 KEGG pathways that were mainly enriched for the targets (Figure 5A) (Table 3), and the main pathways were found to be enriched for Lipid and atherosclerosis (hsa05417), cAMP signaling pathway (hsa04024), VEGF signaling pathway (hsa04370), inflammatory mediator regulation of TRP channels (hsa04750), exhibiting the multi-target and multi-pathway characteristics of NG-R1 against septic myocardial injury. A large body of literature suggests that septic myocardial injury is associated with inflammation (Glenn and Goldman, 1976;Honda et al, 2019;Xie et al, 2021), and NG-R1 is highly involved in anti-inflammatory regulation (Jiao et al, 2021;Li et al, 2022). Therefore, we hypothesize that the potential mechanism of NG-R1 for sepsis-induced cardiomyopathy may be the regulation of inflammation-related pathways.…”

“…The results of molecular docking revealed that NG-R1 had a low docking score with TNF-α, indicating its good binding ability. Because NG-R1 was shown to alleviate rheumatoid arthritis in TNF-Tg mice by promoting lymphatic drainage function via inhibition of the TNFα signaling pathway (Jiao et al, 2021), so we validated it in the inflammatory signaling pathway.…”

Multi-omics Analysis Identifies IgG2b Class-Switching with ALCAM-CD6 Co-Stimulation in Lymph Nodes During Advanced Inflammatory-Erosive Arthritis

“…However, with the onset of Advanced arthritis and lymphatic dysfunction, these activated macrophages stagnate within the popliteal lymphatic vessels and PLN, and mediate tissue destruction and immune cell activation (Li et al, 2013). This lymphatic stagnation is associated with LEC (Bouta et al, 2017) and lymphatic muscle cell (LMC) (Jiao et al, 2022; Kenney et al, 2020; Kenney et al, 2022c; Liang et al, 2021) apoptosis and efferocytosis by joint-draining macrophages leading to intracellular iron accumulation (Fig. 6D).…”