Edgeworthia gardneri (Wall.) Meisn. Ethanolic Extract Attenuates Endothelial Activation and Alleviates Cardiac Ischemia-Reperfusion Injury.

Endothelial pro-inflammatory activation is pivotal in cardiac ischemia-reperfusion (I/R) injury pathophysiology. The dried flower bud of Edgeworthia gardneri (Wall.) Meisn. (EG) is a commonly utilized traditional Tibetan medicine. However, its role in regulating endothelium activation and cardiac I/R injury has not been investigated. Herein, we showed that the administration of EG ethanolic extract exhibited a potent therapeutic efficacy in ameliorating cardiac endothelial inflammation (p < 0.05) and thereby protecting against myocardial I/R injury in rats (p < 0.001). In line with the in vivo findings, the EG extract suppressed endothelial pro-inflammatory activation in vitro by downregulating the expression of pro-inflammatory mediators (p < 0.05) and diminishing monocytes' firm adhesion to endothelial cells (ECs) (p < 0.01). Mechanistically, we showed that EG extract inhibited the nuclear factor kappa-B (NF-κB), c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase (ERK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways to attenuate EC-mediated inflammation (p < 0.05). Collectively, for the first time, this study demonstrated the therapeutic potential of EG ethanolic extract in alleviating I/R-induced inflammation and the resulting cardiac injury through its inhibitory role in regulating endothelium activation.

Tiliroside Attenuates NLRP3 Inflammasome Activation in Macrophages and Protects against Acute Lung Injury in Mice.

The Nod-like receptor family PYRIN domain containing 3 (NLRP3) inflammasome is a multiprotein signaling complex that plays a pivotal role in innate immunity, and the dysregulated NLRP3 inflammasome activation is implicated in various diseases. Tiliroside is a natural flavonoid in multiple medicinal and dietary plants with known anti-inflammatory activities. However, its role in regulating NLRP3 inflammasome activation and NLRP3-related disease has not been evaluated. Herein, it was demonstrated that tiliroside is inhibitory in activating the NLRP3 inflammasome in macrophages. Mechanistically, tiliroside promotes AMP-activated protein kinase (AMPK) activation, thereby leading to ameliorated mitochondrial damage as evidenced by the reduction of mitochondrial reactive oxygen species (ROS) production and the improvement of mitochondrial membrane potential, which is accompanied by attenuated NLRP3 inflammasome activation in macrophages. Notably, tiliroside potently attenuated lipopolysaccharide (LPS)-induced acute lung injury in mice, which has been known to be NLRP3 inflammasome dependent. For the first time, this study identified that tiliroside is an NLRP3 inflammasome inhibitor and may represent a potential therapeutic agent for managing NLRP3-mediated inflammatory disease.

Edgeworthia gardneri (Wall.) Meisn. extract protects against myocardial infarction by inhibiting NF-κB-and MAPK-mediated endothelial inflammation.

Background: Experimental and clinical evidence has demonstrated a pivotal role of inflammation in the pathogenesis of ischemic heart disease, and targeting inflammation has been shown to provide clinical benefits for patients with coronary disease. Endothelial cells constitute the majority of non-cardiomyocytes in the heart. Endothelial pro-inflammatory activation is recognized as a critical component in the pathophysiology of cardiovascular disease. The dried flowers of Edgeworthia gardneri (Wall.) Meisn. (EG) have been widely used as Tibetan folk medicine to ameliorate a range of metabolic disorders, such as diabetes mellitus, hyperlipidemia, hypertension, and obesity. However, its role in modulating endothelial inflammation and ischemic heart disease has not been evaluated. Methods and results: Herein, using a preclinical rat model of coronary artery ligation-induced myocardial infarction (MI), we demonstrated that systemic administration of EG extract (EEEG) attenuated ischemic cardiac injury. EEEG reduced myocardial infarct size, improved cardiac function, and ameliorated adverse cardiac remodeling. Moreover, the cardioprotective effects of EEEG were associated with decreased MI-induced myocardial inflammation. Consistent with the anti-inflammatory role of EEEG in vivo, EEEG attenuated TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) activation and monocyte-endothelial cell firm adhesion in vitro. Mechanistically, our data showed that EEEG's mode of action suppresses the activation of NF-κB, ERK, and p38 MAPK signaling pathways in ECs. Importantly, we demonstrated that EEEG inhibits endothelial inflammation in an NF-κB- and p38 MAPK-dependent manner using pharmacological inhibitors. Conclusion: Collectively, this study identified EG as a potential therapeutic agent in attenuating endothelial inflammation and managing ischemic cardiovascular disease.