HMGB1 release by H2O2-induced hepatocytes is regulated through calcium overload and 58-F interference

Abstract

HMGB1 is passively released by injured or dying cells and aggravates inflammatory processes. The release of HMGB1 and calcium overload have each been reported to be important mediators of H2O2-induced injury. However, a potential connection between these two processes remains to be elucidated. In the present study, we employed H2O2-induced hepatocytes to investigate how calcium overload takes place during cellular injury and how the extracellular release of HMGB1 is regulated by this overload. In addition, we investigated the use of 58-F, a flavanone extracted from Ophiopogon japonicus, as a potential therapeutic drug. We show that the PLCγ1–IP3R–SOC signalling pathway participates in the H2O2-induced disturbance of calcium homoeostasis and leads to calcium overload in hepatocytes. After a rise in intracellular calcium, two calcium-dependent enzymes, PKCα and CaMKIV, are activated and translocated from the cytoplasm to the nucleus to modify HMGB1 phosphorylation. In turn, this promotes HMGB1 translocation from the nucleus to the cytoplasm and subsequent extracellular release. 58-F effectively rescued the hepatocytes by suppressing the PLCγ1–IP3R–SOC signalling pathway and decreasing the calcium concentration in cells, thus reducing HMGB1 release.

Antiproliferative Activity and Induction of Apoptosis in Human Melanoma Cells by Houttuynia cordata Thunb Extract

“…HMGB1 is overexpressed in melanoma relative to levels in normal skin and nevi (21). Hydrogen peroxide (H 2 O 2 ) is a key contributor to cellular oxidative stress and is involved in a wide variety of pathological processes (28). After incubation with 0.125 and 0.25 mM H 2 O 2 , the levels of HMGB1 in the media increased to ~14 and 31 ng/ml, respectively ( Figure 3A), and HMGB1 significantly decreased after exposure to 50 -100 μg/ml HCT extract ( Figure 3B).…”

High Mobility Group Box 1 in Human Cancer

“…Several mechanisms may contribute to the pathogenesis of HMGB1-associated tumor promotion, most prominent among which is an indirect mechanism linked to perpetuation of chronic inflammation of both infective and noninfective origin [ 50 ]. In these settings, the activation of vascular endothelium [ 112 , 113 , 114 ], platelets [ 115 ], tissue macrophages [ 43 , 116 ] and possibly parenchymal cells [ 117 ] at sites of tissue injury results in both the active and passive release of HMGB1 from these cells. Platelets, although anucleate cells, represent a major source of HMGB1 that is acquired from megakaryocytes during thrombopoiesis and is located in the cytosol of these cells, as well as in platelet vesicles, as the unmodified protein or its encoding mRNA [ 115 , 118 ].…”

Downregulation of Lysosomal Acid Ceramidase Mediates HMGB1-Induced Migration and Proliferation of Mouse Coronary Arterial Myocytes

“…High-mobility group box 1 protein (HMGB1) was originally identified as a ubiquitous non-histone DNA-binding nuclear protein and cytosolic protein produced by almost all types of injured or necrotic cells such as mouse smooth muscle cells (SMCs) (Kim et al, 2018;Wang et al, 2018;Li et al, 2019), endothelial cells (Jiang and Steinle, 2018;Xie et al, 2018;Ma et al, 2019), hepatocytes (Zhao et al, 2017;Zhang et al, 2019), and macrophage cells (Dragomir et al, 2011;Irie et al, 2017;Elfeky et al, 2018). HMGB1 serves as an important inflammatory mediator involved in the pathogenesis of inflammatory diseases such as sepsis (Stevens et al, 2017), rheumatoid arthritis (Park et al, 2015), atherosclerosis (Andrassy et al, 2012), and aneurysm (Kohno et al, 2011(Kohno et al, , 2012Ousaka et al, 2017).…”