Berberine Suppresses Colonic Inflammation in Dextran Sulfate Sodium–Induced Murine Colitis Through Inhibition of Cytosolic Phospholipase A2 Activity

Abstract

Ulcerative colitis (UC) causes chronic inflammation and damage to the colonic mucosal layer. Recent studies have reported significant changes in phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) in UC patients and oral administration of PC has considerable therapeutic effects against UC, suggesting the metabolism of phosphatidylcholine may be involved in the UC development. Our previous work has demonstrated that berberine effectively suppresses inflammation and protects colonic mucosa injury in DSS-induced colitic mice. However, whether the therapeutic effects of berberine are attributed to its action on the PC metabolism remains unknown. In the present study, we have shown that berberine significantly reduces the lysophosphatidylcholine (LPC) levels in the sera of DSS-induced experimental colitis mice and LPS-stimulated macrophage RAW 264.7 cells. The cytosolic phospholipase A2a (PLA2G4A), an enzyme for hydrolyzing PC to LPC, was found to be up-regulated in the colon tissue of experimental colitis mice and inflamed macrophage RAW 264.7 cells. We then demonstrated berberine inhibits the phosphorylation of cytosolic phospholipase A2a (PLA2G4A) in the colon tissue of experimental colitis mice and inflamed macrophage RAW 264.7 cells. Subsequently, we revealed berberine suppressed the expression of pro-inflammatory factors including TNF-alpha and IL-6 through regulating PLA2G4A dysfunction in macrophage RAW 264.7 cells. Mechanistically, we found that berberine directly binds to PLA2G4A and inhibits MAPK/JNK signaling pathway to inhibit PLA2G4A activity in inflammatory status. Therefore, we concluded that berberine inhibits colonic PLA2G4A activity to ameliorate colonic inflammation in experimental colitic mice, suggesting modulation of the PC metabolism via PLA2G4A might be beneficial for establishing new therapies strategy for UC.

P2Y1R Ligation Suppresses Th17 Cell Differentiation and Alleviates Colonic Inflammation in an AMPK-Dependent Manner

“…Western blot analysis were performed as our previously described ( 18 ). Used antibodies were listed as below: primary antibodies against p-AMPK (BS5003, Bioworld Technology, 1:1000), AMPK (BS1009, Bioworld Technology, 1:1000), RORγt (ab207082, abcam, 1:1000), GAPDH (2118S, Cell Signaling Technology, 1:1000) and anti-Rabbit IgG (7074S, Cell Signaling Technology, 1:2000).…”

Biomarkers of Metabolomics in Inflammatory Bowel Disease and Damp-Heat Syndrome: A Preliminary Study

“…We infer that damp-heat syndrome may exacerbate the in ammatory response of IBD patients through LPCs. A previous report indicated that damp-heat syndrome was closely related to proin ammatory cytokines and typical medication to clear damp-heat would signi cantly reduce the LPC [43,44]. We suppose that LPCs might have the potential to become diagnostic biomarkers when the sample size increases in the future.…”

Current Advances in Coptidis Rhizoma for Gastrointestinal and Other Cancers

“…Cytosolic phospholipase A2a (PLA2G4A), an enzyme that hydrolyzes phosphatidylcholine to lysophosphatidylcholine, decreases in a colitis mouse model and in the inflammatory response of RAW 264.7 macrophages. Berberine binds to PLA2G4A directly and inhibits PLA2G4A activity by suppressing the MAPK/JNK signaling pathway to ameliorate colon inflammation ( Zhai et al, 2020 ).…”

“…In MKN-45-related gastric cancer, which harbors wild type p53, epiberberine shows great potential in inhibiting cell growth by inducing ROS, mitochondrial apoptosis and cell cycle arrest in vitro and inhibiting tumor growth in vivo via the p53/Bax pathway, and also inhibiting cell growth in the human gastric cancer (HGC-27) cells, which harbors mutated p53 ( Zhai et al, 2020 ). Lysine-specific demethylase 1 (LSD1) is considered a critical target in many cancer treatments ( Fiskus et al, 2014 ; Hong et al, 2018 ; Hu et al, 2019 ).…”