Astragalus membranaceus (Fisch.) Bunge root is used as herbal medicine for its immunomodulating activities in Chinese medicine. Recently, beneficial properties of A. membranaceus on allergic diseases have been proposed. Here we investigated the role of a commercial extract of A. membranaceus, standardized to 16% polysaccharides, in regulating the immune-inflammatory response in vitro and in vivo and its therapeutic application in asthma. A. membranaceus extract inhibited prostaglandin E₂ and leukotriene C₄ production in stimulated J774 and peritoneal macrophages, respectively. The extract also reduced interlukin-1β, tumor necrosis factor-α, and nitrite production, affecting inducible nitric oxide synthase expression. In vivo experiments confirmed the anti-inflammatory properties of A. membranaceus, as evident by a reduction in zymosan-induced peritoneal cellular infiltration and pro-inflammatory mediator production. The efficacy of A. membranaceus extract in modulating the immune response was confirmed in a model of allergic airway inflammation. Extracts improve lung function by inhibiting airway hyperresponsiveness, airway remodeling, and fibrosis. Its anti-asthmatic effects were further sustained by inhibition of the sensitization process, as indicated by a reduction of ovalbumin-induced IgE levels and the mounting of a Th2 immune response. In conclusion, our data demonstrate the anti-inflammatory properties of the commercial extract of A. membranaceus and its beneficial effects on asthma feature development.

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P_1-5). Increasing numbers of studies have indicated the importance of S1P₃ in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P₃ receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P₃ selective pepducin agonist) and KRX-722 (an S1P₁-selective pepducin agonist). Those selective towards S1P₃ (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.

Perturbations in DNA replication can impair fork stability, resulting in cumulative DNA replication stress. As activation of the DNA stress response elicits immunomodulatory effects, understanding the cross-talk between the epigenetic control of replication fork stability and the recruitment of immune cells may represent an actionable avenue to potentiate the sensitivity of tumors to immunotherapy. In this study, we identified DPY30, a member of the histone methyltransferase WRAD/COMPASS complex, as a replication stress–specific epigenetic modifier in pancreatic ductal adenocarcinoma (PDAC). Although other WRAD components broadly regulate transcription, DPY30 distinctively promoted H3K4me3 deposition at stressed DNA replication forks to safeguard DNA replication stability without altering global gene expression. Loss of DPY30 destabilized stalled forks causing fork degradation, chromosomal instability, and inflammation without reducing cancer cell proliferation. Consequently, T-cell infiltration induced by DPY30 deficiency promoted a tumor response to immune checkpoint blockade (ICB). In patients with PDAC, high DPY30 tumor expression was associated with poorer ICB response, underscoring the potential of DPY30 as a predictive biomarker of immunotherapy response. Together, this study redefines our understanding of a replication stress–specific epigenetic code, unveiling DPY30 as a chromatin switch essential for stressed fork stability and a potential therapeutic target. Significance: Loss of DPY30, a replication stress–specific epigenetic regulator that stabilizes stressed forks, promotes genomic instability, inflammation, and immunotherapy sensitivity, highlighting DPY30 as predictive biomarker and therapeutic target in pancreatic cancer. See related commentary by Thakur and Oberdoerffer, p. 2831