Molecular Mechanism of 5,6-Dihydroxyflavone in Suppressing LPS-Induced Inflammation and Oxidative Stress

• Published in: International journal of molecular sciences Vol. 25; no. 19; p. 10694
• Main Authors: Cao, Yujia, Tan, Yee-Joo, Huang, Dejian
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.10.2024; MDPI
• Subjects: 5,6-dihydroxyflavone; Animals; anti-inflammation; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Antioxidants; Bioflavonoids; Care and treatment; Cytokines; Development and progression; Flavones; Flavones - chemistry; Flavones - pharmacology; Flavonoids; Flavonoids - chemistry; Flavonoids - pharmacology; Health aspects; Heme Oxygenase-1 - metabolism; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Janus Kinase 2 - metabolism; Kinases; Lipopolysaccharides; Macrophages - drug effects; Macrophages - metabolism; Mice; NF-kappa B - metabolism; Nitric oxide; Nitric Oxide - metabolism; Oxidative stress; Oxidative Stress - drug effects; Phosphorylation; Physiological aspects; Proteins; RAW 264.7 Cells; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; signaling pathway; STAT3 Transcription Factor - metabolism; Toll-Like Receptor 4 - metabolism; Tumor necrosis factor-TNF; Singapore; signaling pathway; anti-inflammation; flavonoids; 5,6-dihydroxyflavone; oxidative stress
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms251910694

5,6-dihydroxyflavone (5,6-DHF), a flavonoid that possesses potential anti-inflammatory and antioxidant activities owing to its special catechol motif on the A ring. However, its function and mechanism of action against inflammation and cellular oxidative stress have not been elucidated. In the current study, 5,6-DHF was observed inhibiting lipopolysaccharide (LPS)-induced nitric oxide (NO) and cytoplasmic reactive oxygen species (ROS) production with the IC of 11.55 ± 0.64 μM and 0.8310 ± 0.633 μM in murine macrophages, respectively. Meanwhile, 5,6-DHF suppressed the overexpression of pro-inflammatory mediators such as proteins and cytokines and eradicated the accumulation of mitochondrial ROS (mtROS). The blockage of the activation of cell surface toll-like receptor 4 (TLR4), impediment of the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 from the mitogen-activated protein kinases (MAPK) pathway, Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) from the JAK-STAT pathway, and p65 from nuclear factor-κB (NF-κB) pathways were involved in the process of 5,6-DHF suppressing inflammation. Furthermore, 5,6-DHF acted as a cellular ROS scavenger and heme-oxygenase 1 (HO-1) inducer in relieving cellular oxidative stress. Importantly, 5,6-DHF exerted more potent anti-inflammatory activity than its close structural relatives, such as baicalein and chrysin. Overall, our findings pave the road for further research on 5,6-DHF in animal models.