Tubuloside B, isolated from Cistanche tubulosa, a promising agent against M1 macrophage activation via synergistically targeting Mob1 and ERK1/2

• Published in: Biomedicine & pharmacotherapy 2022-09, Vol.153, p.113414-113414, Article 113414
• Main Authors: Xiao, Lingyun, Yao, Jie, Miao, Yuyang, Ou, Baoru, Wang, Jie, Huang, Yongqi, Zhou, Boping, Ge, Lanlan, Tian, Jun, Zeng, Xiaobin
• Format: Article
• Language: English
• Subjects: Cistanche tubulosa; ERK1/2; Inflammation; Macrophage M1 polarization; Mob1; Phenylethanoid glycosides
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.113414

Targeting macrophage M1 polarization is a promising strategy with fewer detrimental effects in COVID-19 curation. Phenylethanoid glycosides (PhGs) of Cistanche tubulosa are a botanical drug to possess various anti-inflammation-related functions, such as immunomodulating, hepatoprotective or neuroprotective functions, whereas their anti-inflammatory activity is rarely understood. A search into their anti-inflammatory characteristics led to the isolation of 49 PhGs along with 15 new PhGs. Their inhibitory effects against M1 polarization induced by LPS plus IFN-γ were explored in RAW264.7 macrophages. Of these PhGs, tubuloside B (Tub B) exerted substantial NO scavenging effect both in chemical- and cell-based assays, and it inhibited massive production of cytokines and chemokines. Tub B decreased ERK1/2 phosphorylation via direct binding and inhibited the MAPK signaling pathway. Tub B also directly binded to Mob1 protein, thereby increased the stability and level of Mob1 protein by inhibiting ubiquitinated degradation. Mob1 was pivotal for the anti-inflammatory activity of Tub B, and it acted independently of the canonical Hippo-YAP pathway. Moreover, ERK1/2 and Mob1 also had a synergic effect on modulating the inflammatory response. Finally, these effects of Tub B were verified in mice with LPS-induced systemic inflammatory response syndrome. Taken together, these results indicated that Tub B acted as a promising agent against M1 macrophage activation by synergistically targeting ERK1/2 and Mob1, and that it may potentially be a drug candidate to prevent/treat inflammatory diseases, especially in COVID-19. [Display omitted] •15 new and 34 known PhGs were isolated and identified from C. tubulosa.•Many isolated PhGs were able to inhibit NO production and more potent than, that of positive control Dex.•Tub B inhibited MAPK pathway through decreased ERK1/2 phosphorylation, via direct binding.•Tub B stabilized Mob1 via direct binding, and inhibited Mob1-ubiquitinated, degradation.•ERK1/2 and Mob1 also have a synergic effect on Tub B modulating M1, polarization.