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Extracellular histones have been determined as important mediators of sepsis, which induce excessive inflammatory responses in macrophages and impair innate immunity. Magnesium (Mg 2+ ), one of the essential nutrients of the human body, contributes to the proper regulation of immune function. However, no reports indicate whether extracellular histones affect survival and bacterial phagocytosis in macrophages and whether Mg 2+ is protective against histone-induced macrophage damage. Our clinical data revealed a negative correlation between circulating histone and monocyte levels in septic patients, and in vitro experiments confirmed that histones induced mitochondria-associated apoptosis and defective bacterial phagocytosis in macrophages. Interestingly, our clinical data also indicated an association between lower serum Mg 2+ levels and reduced monocyte levels in septic patients. Moreover, in vitro experiments demonstrated that Mg 2+ attenuated histone-induced apoptosis and defective bacterial phagocytosis in macrophages through the PLC/IP3R/STIM-mediated calcium signaling pathway. Importantly, further animal experiments proved that Mg 2+ significantly improved survival and attenuated histone-mediated lung injury and macrophage damage in histone-stimulated mice. Additionally, in a cecal ligation and puncture (CLP) + histone-induced injury mouse model, Mg 2+ inhibited histone-mediated apoptosis and defective phagocytosis in macrophages and further reduced bacterial load. Overall, these results suggest that Mg 2+ supplementation may be a promising treatment for extracellular histone-mediated macrophage damage in sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

[Display omitted] • GPER decreased in gastric cancer with highly proven clinical relevance. • There was no difference between males and females in GPER expression. • GPER regulated the stability of the microenvironment in gastric cancer. • GPER governed GSE-1 cell apoptosis by activating of NF-κB/ROS/Apoptosis pathway. Gastric cancer (GC) is with high mortality and morbidity. The GC morbidity of males is twice as high as that of females. G-protein estrogen receptor (GPER) bears on this phenomenon. Networks and experiments assessed the GPER expression in different validity and content. The evidence-based practice involved accessing the clinical relevance of GPER by UALCAN and Kaplan-Meier plotter. Enrichment analyses contributed to guide further experimental validations. Activation of the NF-κB/ROS/Apoptosis pathway was analyzed by WB, immunofluorescence (IF), microplate reader and flow cytometry. TISIDB and TIMER identified the immune infiltration investigations, with credibility boosted by the Kaplan-Meier plotter. The appraisers revealed that GPER significantly decreased in GC at both gene and protein levels with highly approved prognosis value (P < 0.05). GPER was a significant fate determinant governing the inner part of gastric glands. NF-κB pathway and the following ROS in gastric cells were activated after MNU stimulation (20 μM, 24 h), and the GPER antagonist G15 strengthened the effect of MNU. Furthermore, GPER expression positively correlated with immune cells and various immune markers in GC patients, with highly approved clinical relevance. For example, type-2 helper cells enriched GC patients had a lower survival rate in the GPER-high expression group (P < 0.05). We demonstrated that GPER governs the GC progression by activating the NF-κB/ROS/Apoptosis pathway in gastric cells and regulating the immune environment around them. [ABSTRACT FROM AUTHOR]