Hormesis, an adaptive response, occurs when exposure to low doses of a stressor potentially induces a stimulatory effect, while higher doses may inhibit it. This phenomenon is widely observed across various organisms and stressors, significantly advancing our understanding and inspiring further exploration of the beneficial effects of toxins at doses both below and beyond traditional thresholds. This has profound implications for promoting biological regulation at the cellular level and enhancing adaptability throughout the biosphere. Therefore, conducting bibliometric analysis in this field is crucial for accurately analyzing and summarizing its current research status. The results of the bibliometric analysis reveal a steady increase in the number of publications in this field over the years. The United States emerges as the leading country in both publication and citation numbers, with the journal Dose–Response publishing the highest number of papers in this area. Calabrese E.J. is a prominent person with significant contributions and influence among authors. Through keyword co-occurrence and trend analysis, current hotspots in this field are identified, primarily focusing on the relationship between hormesis, oxidative stress, and aging. Analysis of highly cited references predicts that future research trends may center around the relationship between hormesis and stress at different doses, as well as exploring the mechanisms and applications of hormesis. In conclusion, this review aims to visually represent hormesis-related research through bibliometric methods, uncovering emerging patterns and areas of focus within the field. It provides a summary of the current research status and forecasts trends in hormesis-related research.

Background: Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol (Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory diseases. This study aimed to investigate the pharmacological activity and molecular mechanism of Cel in models of endotoxemia and sepsis. Methods: We evaluated the anti-inflammatory efficacy of Cel against endotoxemia and sepsis in mice and macrophage cultures treated with lipopolysaccharide (LPS). We screened for potential protein targets of Cel using activity-based protein profiling (ABPP). Potential targets were validated using biophysical methods such as cellular thermal shift assays (CETSA) and surface plasmon resonance (SPR). Residues involved in Cel binding to target proteins were identified through point mutagenesis, and the functional effects of such binding were explored through gene knockdown. Results: Cel protected mice from lethal endotoxemia and improved their survival with sepsis, and it significantly decreased the levels of pro-inflammatory cytokines in mice and macrophages treated with LPS ( P < 0.05). Cel bound to Cys424 of pyruvate kinase M2 (PKM2), inhibiting the enzyme and thereby suppressing aerobic glycolysis (Warburg effect). Cel also bound to Cys106 in high mobility group box 1 (HMGB1) protein, reducing the secretion of inflammatory cytokine interleukin (IL)-1β. Cel bound to the Cys residues in lactate dehydrogenase A (LDHA). Conclusion: Cel inhibits inflammation and the Warburg effect in sepsis via targeting PKM2 and HMGB1 protein.

Background: Neutrophil extracellular traps (NETs) are specialized structures formed by neutrophils that were initially found to be important in killing pathogenic bacteria during infection. With the development of related research, the relationship between NETs and diseases such as sepsis, cancer, and systemic lupus erythematosus has received close attention. However, there is a lack of reports that comprehensively and objectively present the current status of NETs-related studies. Therefore, this study aims to visually analyze the current status and trends of NETs-related research by means of bibliometrics and knowledge mapping.Methods: NETs-related articles and reviews were retrieved using the Web of Science core collection subject search, and bibliometric analysis was performed in Excel 365, CiteSpace, VOSviewer, and Bibliometrix (R-Tool of R-Studio).Results: A total of 4866 publications from 2004 to 2022 were included in the bibliometric analysis. The number of publications shows an increasing trend from year to year. Collaborative network analysis shows that the United States and Germany are the most influential countries in this field, with the highest number of publications and citations. The journal with the most publications is Frontiers in Immunology. Brinkmann Volker is an authoritative author in this field, and his publication “Neutrophil extracellular traps kill bacteria” is the most frequently cited. The literature and keyword analysis shows that the relationship between NETs and diseases (hematological diseases, sepsis, cancer, etc.) and cell death (apoptosis, necroptosis, pyroptosis, etc.) is a popular research topic. Currently, NETs and SARS-CoV-2-related studies are at the forefront of the field.Conclusion: This study is the first to visualize the research in NETs-related fields using bibliometric methods, revealing the trends and frontiers of NETs research. This study will provide valuable references for scholars to find research focus questions and partners.

Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/β, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.

Histone methylation is an important epigenetic mechanism that plays an essential role in regulating gene expression in mammalian cells. To understand its influence on inflammation, methylation of H3K4, H3K9, H3K36, H3K79, and H4K20, the most common histones methylated in the inflammatory response was analyzed in murine RAW264.7 cells and bone marrow-derived macrophages (BMDMs) upon lipopolysaccharide (LPS) stimulation. LPS stimulation resulted in enhanced methylation at H3K4 and H3K9 in both RAW264.7 and BMDMs. To further confirm whether LPS-stimulated H3K4me2 and H3K9me2 were responsible for subsequent proinflammatory cytokine expression, the recruitment of H3K4me2 and H3K9me2 at the promoters of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) was assessed. H3K4me2, but not H3K9me2, was enriched at the promoters of both IL-6 and TNF-α. Furthermore, LPS-stimulated gene expression and release of IL-6 and TNF-α were markedly suppressed in macrophages by MTA, a specific inhibitor of H3K4 methylation. These results demonstrate that histone methylation, in particular H3K4me2, plays a critical role in the regulation of LPS-induced expression and release of IL-6 and TNF-α.