Piezo1 as a potential player in intracranial hemorrhage: from perspectives on biomechanics and hematoma metabolism.

Intracranial hemorrhage (ICH) causes numerous neurological deficits and deaths worldwide each year, leaving a significant health burden on the public. The pathophysiology of ICH is complicated, and involves both primary and secondary injury. Hematoma, as the prime pathology of ICH, undergoes metabolism and triggers biochemical and biomechanical alterations in the brain, leading to secondary injury. Past endeavors mainly aimed at biochemical-initiated mechanisms for causing secondary injury have made limited progress in recent years, although ICH itself is also highly biomechanics-related. The discovery of the mechanical-activated cation channel Piezo1 provides a new avenue to further explore underlying mechanisms of secondary injury. The current article reviews the structure and gating mechanisms of Piezo1, its roles in the physiology/pathophysiology of neurons, astrocytes, microglia, and bone-marrow-derived macrophages, and especially its roles in erythrocytic turnover and iron metabolism, revealing a potential interplay between the biomechanics and biochemistry of hematoma in ICH. Collectively, these advances provide deeper insights into the secondary injury of ICH and lay the foundations for future research.

2-Methoxyestradiol synergizes with Erlotinib to suppress hepatocellular carcinoma by disrupting the PLAGL2-EGFR-HIF-1/2α signaling loop.

Erlotinib, an EGFR tyrosine kinase inhibitor has been introduced into cancer chemotherapy. However, the therapeutic effects of erlotinib in hepatocellular carcinoma (HCC) remain vaguely understood. Our previous study found that a hypoxia-mediated PLAGL2-EGFR-HIF-1/2α signaling loop in HCC decreased response to erlotinib. The current study has demonstrated that the combination of erlotinib and 2ME2 exerted synergistic antitumor effects against HCC. Further investigation showed that erlotinib increased the expression level of EGFR, HIF-2α, and PLAGL2, which contributes to the insensitivity of hypoxic HCC cells to erlotinib. The simultaneous exposure to 2ME2 effectively inhibited the expression level of EGFR, HIF-2α, and PLAGL2 that was induced by erlotinib. This contributes to the synergistic effect of the two therapeutic agents. Furthermore, the combination of erlotinib and 2ME2 induced apoptosis and inhibited the stemness of hypoxic HCC cells. Our findings potentially explain the mechanism of HCC insensitivity to erlotinib and provide a new strategy of combining EGFR and HIF1/2α inhibitors for HCC treatment.