Intensive Care Unit, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Department of Cardiology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 312500, China.
Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Int Immunopharmacol. 2024 Jan 5;126:111241. doi: 10.1016/j.intimp.2023.111241. Epub 2023 Nov 18.
Sepsis is a systemic inflammatory syndrome that can lead to multiple organ dysfunction and life-threatening complications. Sepsis-induced myocardial dysfunction (SIMD) has been confirmed to be present in half of patients with septic shock, increasing their mortality rate to 70-90%. The pathogenesis of SIMD is complex, and no specific clinical treatment has yet been developed. Caloric restriction mimetics (CRM), compounds that simulate the biochemical and functional properties of CR, can improve cardiovascular injury by activating autophagy. This study investigated the effect of a new type of CRM which can induce hypoxia, the SGLT nonspecific inhibitor phlorizin on SIMD.
In vivo, phlorizin was administered at 1 mg/kg/day intragastrically for 28 days. In vitro, AC16 was treated with 120 μM phlorizin for 48 h. Echocardiography was used to assess cardiac function. Myocardial injury markers were detected in serum and cell supernatant. Western blotting was employed to detect changed proteins associated with apoptosis and autophagy. Immunofluorescence, immunohistochemistry, co-immunoprecipitation, molecular docking, and other methods were also used to illustrate cellular changes.
In vivo, phlorizin significantly improved the survival rate and cardiac function after sepsis injury, reduced markers of myocardial injury, inhibited myocardial apoptosis and oxidative stress, and promoted autophagy. In vitro, phlorizin alleviated the apoptosis of AC16, as well as inhibited oxidative stress and apoptotic enzyme activity. Phlorizin acts on autophagy at multiple sites through low energy (activation of AMPK) and hypoxia (release of Beclin-1 by Hif-1α/Bnip3 axis), promoting the formation and degradation of autophagosomes.
We indicated for the first time that phlorizin could inhibit glucose uptake via GLUT-1 and conforms to the metabolic characteristics of CRM, it can induce the hypoxic transcriptional paradigm. In addition, it inhibits apoptosis and improves SIMD by promoting autophagy generation and unobstructing autophagy flux. Moreover, it affects autophagy by releasing Beclin-1 through the Hif-1α/Bnip3 axis.
败血症是一种全身炎症综合征，可导致多器官功能障碍和危及生命的并发症。已证实败血症性心肌功能障碍（SIMD）存在于半数感染性休克患者中，使死亡率增加至 70-90%。SIMD 的发病机制复杂，目前尚无特定的临床治疗方法。热量限制模拟物（CRM）是一种模拟 CR 的生化和功能特性的化合物，可以通过激活自噬来改善心血管损伤。本研究探讨了一种新型 CRM，即能诱导缺氧的非特异性 SGLT 抑制剂根皮苷对 SIMD 的影响。
体内，根皮苷以 1mg/kg/天的剂量经胃内给药 28 天。体外，AC16 用 120μM 根皮苷处理 48 小时。采用超声心动图评估心功能。检测血清和细胞上清液中心肌损伤标志物。采用 Western blot 检测与细胞凋亡和自噬相关的蛋白变化。还采用免疫荧光、免疫组化、免疫共沉淀、分子对接等方法阐明细胞变化。
体内，根皮苷显著提高败血症损伤后的存活率和心功能，降低心肌损伤标志物，抑制心肌细胞凋亡和氧化应激，促进自噬。体外，根皮苷缓解 AC16 的凋亡，抑制氧化应激和凋亡酶活性。根皮苷通过低能量（激活 AMPK）和缺氧（Hif-1α/Bnip3 轴释放 Beclin-1）作用于自噬的多个部位，促进自噬体的形成和降解。
我们首次表明，根皮苷可以通过 GLUT-1 抑制葡萄糖摄取，并符合 CRM 的代谢特征，它可以诱导缺氧转录范式。此外，它通过促进自噬的产生和畅通自噬流来抑制凋亡并改善 SIMD。此外，它通过 Hif-1α/Bnip3 轴释放 Beclin-1 影响自噬。
