DOS in Biochemistry, University of Mysore, Manasagangotri, Mysuru 570 006, India.
DOS in Biochemistry, University of Mysore, Manasagangotri, Mysuru 570 006, India; Department of Internal Medicine, Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada.
Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2303-2316. doi: 10.1016/j.bbadis.2019.05.009. Epub 2019 May 16.
Reactive oxygen species (ROS) are capable of inducing cell death or apoptosis. Recently, we demonstrated that lipid-ROS can mediate ferroptosis and activation of human platelets. Ferroptosis is an intracellular iron-mediated cell death, distinct from classical apoptosis and necrosis, which is mediated through the accumulation of ROS, lipid peroxides and depletion of cellular GSH. Lately, we demonstrated that hemoglobin degradation product hemin induces ferroptosis in platelets via ROS and lipid peroxidation. In this study, we demonstrate that hemin-induced ferroptosis in platelets is mediated through ROS-driven proteasome activity and inflammasome activation, which were mitigated by Melatonin (MLT). Although inflammasome activation is linked with pyroptosis, it is still not clear whether ferroptosis is associated with inflammasome activation. Our study for the first time demonstrates an association of platelet activation/ferroptosis with proteasome activity and inflammasome activation. Although, high-throughput screening has recognized ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) as potent ferroptosis inhibitors, having an endogenous antioxidant such as MLT as ferroptosis inhibitor is of high interest. MLT is a well-known chronobiotic hormone that regulates the circadian rhythms in vertebrates. It also exhibits potent antioxidant and ROS quenching capabilities. MLT can regulate fundamental cellular functions by exhibiting cytoprotective, oncostatic, antiaging, anti-venom, and immunomodulatory activities. The ROS scavenging capacity of MLT is key for its cytoprotective and anti-apoptotic properties. Considering the anti-ferroptotic and anti-apoptotic potentials of MLT, it could be a promising clinical application to treat hemolytic, thrombotic and thrombocytopenic conditions. Therefore, we propose MLT as a pharmacological and therapeutic agent to inhibit ferroptosis and platelet activation.
活性氧（ROS）能够诱导细胞死亡或凋亡。最近，我们证明脂质 ROS 可以介导铁死亡和人血小板的激活。铁死亡是一种细胞内铁介导的细胞死亡，与经典的凋亡和坏死不同，它是通过 ROS、脂质过氧化物的积累和细胞 GSH 的耗竭来介导的。最近，我们证明血红蛋白降解产物血红素通过 ROS 和脂质过氧化诱导血小板中的铁死亡。在这项研究中，我们证明血红素诱导的血小板铁死亡是通过 ROS 驱动的蛋白酶体活性和炎症小体激活介导的，而褪黑素（MLT）可以减轻这种作用。虽然炎症小体的激活与细胞焦亡有关，但铁死亡是否与炎症小体的激活有关尚不清楚。我们的研究首次证明了血小板激活/铁死亡与蛋白酶体活性和炎症小体激活之间的关联。虽然高通量筛选已经识别出 ferrostatin-1（Fer-1）和 liproxstatin-1（Lip-1）作为有效的铁死亡抑制剂，但具有内源性抗氧化剂如 MLT 作为铁死亡抑制剂具有很高的研究价值。褪黑素是一种调节脊椎动物昼夜节律的著名生物钟激素。它还具有强大的抗氧化和 ROS 清除能力。褪黑素通过表现出细胞保护、抗肿瘤、抗衰老、抗毒液和免疫调节作用来调节基本的细胞功能。褪黑素的 ROS 清除能力是其细胞保护和抗凋亡特性的关键。考虑到 MLT 的抗铁死亡和抗凋亡潜力，它可能是治疗溶血性、血栓性和血小板减少性疾病的有前途的临床应用。因此，我们提出 MLT 作为一种药理学和治疗剂来抑制铁死亡和血小板激活。
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