{'fraction_non_alphanumeric': 0.034375, 'fraction_numerical': 0.013888888888888888, 'mean_word_length': 6.11358024691358, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Anti‐inflammatory Effects of Zerumbone on Chronic Inflammation Models in Differentiated Human THP‐1 Monocytes Induced by Lipopolysaccharide

Inflammation plays a key role in the pathogenesis of various human diseases, such as cancer, chronic asthma, rheumatoid arthritis, and psoriasis. In analyses of pathogen‐associated molecular patterns (PAMPs), at least four families of mammalian innate immune receptors, known as pattern recognition receptors (PRPs), have been identified, including toll‐like receptor (TLR). TLR plays a critical role in triggering immune responses by sensing conserved microbial‐derived macromolecules. Lipopolysaccharide (LPS), a product of gram‐negative bacteria, stimulates the TLR4 complex, particularly in macrophages and dendritic cells. LPS plays a vital role not only in leading inflammatory processes but also in stimulating the production of inflammatory mediators. For these reasons, LPS‐activated THP‐1 macrophages have been used as in vitro models for evaluating anti‐inflammatory effects. Zerumbone is the main component of the tropical plant Zingiber zerumbet Smith and has been reported to exert anti‐inflammatory, anti‐ulcer, and anti‐hyperglycemic effects. However, the specific mechanisms through which zerumbone exerts these anti‐inflammatory effects in the context of LPS‐induced inflammation in differentiated human THP‐1 monocytes is not fully understood. THP‐1 cells were differentiated into macrophages by phorbol 12‐myristate 13‐acetate (PMA, 1 μM) for 48 h. Differentiated THP‐1 cells were cultured with or without zerumbone (1–10 μM) for 48 h and then treated with 500 ng/mL LPS 6 h prior to harvesting. In this study, we found that zerumbone suppressed the secretion of pro‐inflammatory markers (cyclooxygenase‐2, interleukin‐6, and tumor necrosis factor‐α) and expression of nuclear factor‐κB in LPS‐stimulated THP‐1 macrophages. Histone deacetylases (HDACs) remove the acetyl group from lysine residues within a range of proteins, including transcription factors and histones. Thus, we examined HDAC3 and SIRT1 activity in differentiated THP‐1 cells. Although LPS treatment reduced or induced HDAC3 expression, zerumbone increased SIRT1 and suppressed HDAC3, as demonstrating using enzyme‐linked immunosorbent assay, real‐time polymerase chain reaction, western blotting, and immunofluorescence analysis. H3K9ac, which is regulated by histone acetylating enzymes, has an open chromatin structure that activates gene expression. The expression of H3K9ac was decreased following LPS stimulation plus zerumbone treatment. Zerumbone treatment significantly inhibited Toll‐like receptor 2/4 protein and mRNA expression and MyD88 gene expression under LPS‐induced THP‐1 macrophages. Thus, based on the results of this study, zerumbone may be a promising candidate for the treatment and prevention of chronic inflammatory diseases.