Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, Southern University of Science and Technology), Shenzhen, Guangdong 518020, PR China; Department of Pathology (Longhua Branch), Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, Southern University of Science and Technology), Shenzhen, Guangdong 518020, PR China.
Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, Southern University of Science and Technology), Shenzhen, Guangdong 518020, PR China.
Biomed Pharmacother. 2022 Sep;153:113414. doi: 10.1016/j.biopha.2022.113414. Epub 2022 Jul 15.
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.
靶向巨噬细胞 M1 极化是一种有前途的策略，在 COVID-19 治疗中副作用较少。肉苁蓉苯乙醇苷（PhGs）是一种植物药，具有多种抗炎相关功能，如免疫调节、保肝或神经保护功能，但其抗炎活性鲜为人知。对其抗炎特性的研究导致分离出 49 种 PhGs 和 15 种新的 PhGs。在 RAW264.7 巨噬细胞中研究了它们对 LPS+IFN-γ诱导的 M1 极化的抑制作用。在这些 PhGs 中，tubuloside B（Tub B）在化学和细胞基础测定中均具有显著的 NO 清除作用，并抑制大量细胞因子和趋化因子的产生。Tub B 通过直接结合抑制 ERK1/2 磷酸化，并抑制 MAPK 信号通路。Tub B 还直接与 Mob1 蛋白结合，通过抑制泛素化降解增加 Mob1 蛋白的稳定性和水平。Mob1 是 Tub B 抗炎活性的关键，它独立于经典的 Hippo-YAP 通路发挥作用。此外，ERK1/2 和 Mob1 也对调节炎症反应有协同作用。最后，在 LPS 诱导的全身炎症反应综合征小鼠中验证了 Tub B 的这些作用。综上所述，这些结果表明，Tub B 通过协同靶向 ERK1/2 和 Mob1 作用于 M1 巨噬细胞激活，是一种有前途的抗炎药物候选物，可能特别适用于 COVID-19 等炎症性疾病的预防/治疗。
