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High‐altitude cardiac injury (HACI) is one of the common tissue injuries caused by high‐altitude hypoxia that may be life threatening. Notoginsenoside R1 (NG‐R1), a major saponin of Panax notoginseng, exerts anti‐oxidative, anti‐inflammatory, and anti‐apoptosis effects, protecting the myocardium from hypoxic injury. This study aimed to investigate the protective effect and molecular mechanism of NG‐R1 against HACI. We simulated a 6000 m environment for 48 h in a hypobaric chamber to create a HACI rat model. Rats were pretreated with NG‐R1 (50, 100 mg/kg) or dexamethasone (4 mg/kg) for 3 days and then placed in the chamber for 48 h. The effect of NG‐R1 was evaluated by changes in Electrocardiogram parameters, histopathology, cardiac biomarkers, oxidative stress and inflammatory indicators, key protein expression, and immunofluorescence. U0126 was used to verify whether the anti‐apoptotic effect of NG‐R1 was related to the activation of ERK pathway. Pretreatment with NG‐R1 can improve abnormal cardiac electrical conduction and alleviate high‐altitude‐induced tachycardia. Similar to dexamethasone, NG‐R1 can improve pathological damage, reduce the levels of cardiac injury biomarkers, oxidative stress, and inflammatory indicators, and down‐regulate the expression of hypoxia‐related proteins HIF‐1α and VEGF. In addition, NG‐R1 reduced cardiomyocyte apoptosis by down‐regulating the expression of apoptotic proteins Bax, cleaved caspase 3, cleaved caspase 9, and cleaved PARP1 and up‐regulating the expression of anti‐apoptotic protein Bcl‐2 through activating the ERK1/2‐P90RSK‐Bad pathway. In conclusion, NG‐R1 prevented HACI and suppressed apoptosis via activation of the ERK1/2‐P90RSK‐Bad pathway, indicating that NG‐R1 has therapeutic potential to treat HACI. [ABSTRACT FROM AUTHOR]

Inflammation and oxidative stress caused by fine particulate matter (PM2.5) increase the incidence and mortality rates of respiratory disorders. Rosavin is the main chemical component of Rhodiola plants, which exerts anti-oxidative and antiinflammatory effects. In this research, the potential therapeutic effect of rosavin was investigated by the PM2.5-induced lung injury rat model. Rats were instilled with PM2.5 (7.5 mg/kg) suspension intratracheally, while rosavin (50 mg/kg, 100 mg/kg) was delivered by intraperitoneal injection before the PM2.5 injection. It was observed that rosavin could prevent lung injury caused by PM2.5. PM2.5 showed obvious ferroptosis-related ultrastructural alterations, which were significantly corrected by rosavin. The pretreatment with rosavin downregulated the levels of tissue iron, malondialdehyde, and 4-hydroxynonenal, and increased the levels of glutathione. The expression of nuclear factor E2-related factor 2 (Nrf2) was upregulated by rosavin, together with other ferroptosis-related proteins. RSL3, a specific ferroptosis agonist, reversed the beneficial impact of rosavin. The network pharmacology approach predicted the activation of rosavin on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. LY294002, a potent PI3K inhibitor, decreased the upregulation of Nrf2 induced by rosavin. In conclusion, rosavin prevented lung injury induced by PM2.5 stimulation and suppressed ferroptosis via upregulating PI3K/Akt/Nrf2 signaling pathway., (© 2022 John Wiley & Sons Ltd.)