Kaempferol Inhibits Hepatic Stellate Cell Activation by Regulating miR-26b-5p/Jag1 Axis and Notch Pathway

Abstract

Kaempferol, a natural flavonoid molecule, has demonstrated anti-inflammatory, antimicrobial and antioxidant activities. Recent studies have shown the beneficial effects of kaempferol on liver fibrosis. Notch pathway has been reported to be involved in the aberrant activation of hepatic stellate cells (HSCs). However, whether Notch pathway plays a key role in the anti-fibrotic effects of kaempferol is largely unknown. In this study, kaempferol significantly suppressed liver fibrosis in CCl4 mice, with reduced collagen deposition as well as restored liver function. In vitro, kaempferol enhanced the suppression of HSC activation, with a decrease in α-SMA as well as collagen level. It was found that Notch pathway played an important role in kaempferol-reduced the activation of HSCs. Jag1, a ligand of Notch pathway, was obviously inhibited by kaempferol. Overexpression of Jag1 effectively abolished kaempferol-induced HSC inactivation. Furthermore, Jag1 was demonstrated as a target of microRNA-26b-5p (miR-26b-5p). Interestingly, miR-26b-5p inhibitor prevented HSC activation inhibition caused by kaempferol. Further studies indicated that kaempferol inhibited Notch pathway via miR-26b-5p and Jag1, leading to HSC inactivation. Collectively, we demonstrate that kaempferol could inhibit HSC activation, at least in part, via miR-26b-5p-mediated Jag1 axis and Notch pathway. Kaempferol may serve as a promising drug in the application of treating liver fibrosis.

Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl4-induced liver fibrosis in mice

“…Similarly, many bioactive chemicals ameliorate LF via suppressing HSC activation. 19,26,[31][32][33] Phenomena above suggest that restraining HSC activation is a feasible strategy for combating LF. Based on previously published literatures, the concentration of EGT applied in cultured cells is around 10 μM, 34 while the dosage of EGT used in mice via gavage is around 15 mg kg −1 .…”

Exploration and validation of a novel signature of seven necroptosis-related genes to improve the clinical outcome of hepatocellular carcinoma

“…Immunohistochemistry was performed as previously described [ 19 ]. Briefly, the tissues were immersed in 4% formalin for fixation, and then the formalin-fixed tissue was degreased and rehydrated.…”

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

“…On closer inspection, kaempferol inhibited the Notch pathway through miR-26b-5p and Jag1, bringing about HSCs inactivation. Altogether, kaempferol can inactivate HSC, at any rate partly, through the miR-26b-5p-mediated Jag1 axis as well as the Notch pathway [195] .…”

“…Malvidin Inducing HSCs apoptosis via the endoplasmic reticulum stress pathway and mitochondrial pathway [192] Pelargonidin Suppressing the ROS-NLRP3-IL-1 β axis via activating the Nrf2 pathway [193] Isoliquiritigenin Alleviates LF through caveolin-1-mediated hepatic stellate cells ferroptosis [194] Kaempferol Regulating miR-26b-5p/Jag1 axis and Notch pathway [195] Dihydroartemisinin [128,196,197] Hesperidin Inhibiting NF-κB/IL-1β/IL-10 and TGFβ/Smad2/3/CTGF signaling pathways [198] Carvacrol Inhibiting TRPM7 and modulating the MAPK signal [199] Small Ellagic Acid Regulates inflammatory mediators to inhibit TGF-β-mediated HSC activation [223] Sulforaphane Through the Nrf2-mediated antioxidant response and acetaldehyde metabolization with inhibition of the LPS/TLR4 signaling pathway [224] Tanshinone IIA Intervening TGFβ/ Smad signaling pathway [225] Protocatechuic acid [265] Byakangelicin [266] Quercetin [267] Gooseberry anthocyanins [268] Naringin (NIN) [268] Germacrone [269] Small-molecule natural products…”