(–)-Catechin-7-O-β-d-Apiofuranoside Inhibits Hepatic Stellate Cell Activation by Suppressing the STAT3 Signaling Pathway

Abstract

Hepatic fibrosis is characterized by the abnormal deposition of extracellular matrix (ECM) proteins. During hepatic fibrogenesis, hepatic stellate cell (HSC) activation followed by chronic injuries is considered a key event in fibrogenesis, and activated HSCs are known to comprise approximately 90% of ECM-producing myofibroblasts. Here, we demonstrated that (-)-catechin-7-O-β-d-apiofuranoside (C7A) significantly inhibited HSC activation via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. This is the first study to show the hepatic protective effects of C7A with possible mechanisms in vitro and in vivo. In our bioactivity screening, we figured out that the EtOH extract of Ulmus davidiana var. japonica root barks, which have been used as a Korean traditional medicine, inhibited collagen synthesis in HSCs. Four catechins isolated from the EtOAc fraction of the EtOH extract were compared with each other in terms of reduction in collagen, which is considered as a marker of hepatic protective effects, and C7A showed the strongest inhibitory effects on HSC activation in protein and qPCR analyses. As a possible mechanism, we investigated the effects of C7A on the STAT3 signaling pathway, which is known to activate HSCs. We found that C7A inhibited phosphorylation of STAT3 and translocation of STAT3 to nucleus. C7A also inhibited expressions of MMP-2 and MMP-9, which are downstream genes of STAT3 signaling. Anti-fibrotic effects of C7A were evaluated in a thioacetamide (TAA)-induced liver fibrosis model, which indicated that C7A significantly inhibited ECM deposition through inhibiting STAT3 signaling. C7A decreased serum levels of aspartate amino transferase and alanine transaminase, which were markedly increased by TAA injection. Moreover, ECM-associated proteins and mRNA expression were strongly suppressed by C7A. Our study provides the experimental evidence that C7A has inhibitory effects on HSC activation after live injury and has preventive and therapeutic potentials for the management of hepatic fibrosis.

Probiotics counteract the expression of hepatic profibrotic genes via the attenuation of TGF-β/SMAD signaling and autophagy in hepatic stellate cells

“…brevis , reduced the level of collagen deposition in LX-2 cells. Park et al [ 21 ] reported that TGF-β stimulation upregulated the levels of pro-fibrogenic makers, such as α-SMA, fibronectin, MMP2, MMP-9, TIMP1, and TIMP2 in LX-2 cells. Similar results were found with TGF-β in that a treatment increased the mRNA levels of the profibrogenic markers in HSCs.…”

“…Because HSCs is a potent therapeutic target in the pathogenesis of LF, several studies have used HSCs to examine the mechanisms linked to the inhibition and activation of HSCs. For example, a recent study reported that the treatment of LX-2 cells with TGF-β increased the level of collagen, α-SMA, fibronectin, CTGF, MMP2, MMP-9, TIMP1, and TIMP2 via the suppression of STAT3 phosphorylation [ 21 ]. Therefore, in this study, a human HSCs (LX-2) was used to evaluate the anti-fibrogenic effects of probiotic strains against TGF-β and study the molecular mechanisms behind the immunomodulatory and anti-fibrogenic activity of the selected probiotic strains.…”

Ulmus parvifolia Jacq. Exhibits Antiobesity Properties and Potentially Induces Browning of White Adipose Tissue

“…Catechin has been know for antiobesity properties, explaining its possible contribution in the efficacy of UP in curbing obesity [ 44 ]. Catechin-7- O - β -D-apiofuranoside prevents hepatic fibrogenesis by inhibiting stellate cell activation [ 45 ]. GCMS analysis was carried out to identify the nonpolar constituents of UP.…”

Ulmus parvifolia Modulates Platelet Functions and Inhibits Thrombus Formation by Regulating Integrin αIIbβ3 and cAMP Signaling

“…Catechins are polyphenolic phytochemicals exhibiting several biological activities in the human body, potentially in the treatment and prevention of cardiovascular ailments through modulation of blood lipid metabolism, cardioprotective effects including vascular endothelium protection and stabilizing blood pressure (Shaterzadeh-Yazdi et al, 2017), while another study has also summarized the beneficial effects of catechins on cardiovascular system (Braicu et al, 2013). Most of the Ulmus species are reported to possess pharmacological properties including antiplatelet effects; due to their polyphenolic contents such as catechin, epicatechin, catechin-7-O-b-D -apiofuranoside, and catechin-7-O-b-D -xylopyranoside (Jung et al, 2010;Yang et al, 2013;Park et al, 2020). Among these catechins, catechin-7-O-b-D -apiofuranoside has been also known for its anti-oxidant, antiinflammatory and anti-fibrotic properties (MinHee et al, 2003;Jung et al, 2010;Kwon et al, 2011;Park et al, 2020).…”

“…Most of the Ulmus species are reported to possess pharmacological properties including antiplatelet effects; due to their polyphenolic contents such as catechin, epicatechin, catechin-7-O-b-D -apiofuranoside, and catechin-7-O-b-D -xylopyranoside (Jung et al, 2010;Yang et al, 2013;Park et al, 2020). Among these catechins, catechin-7-O-b-D -apiofuranoside has been also known for its anti-oxidant, antiinflammatory and anti-fibrotic properties (MinHee et al, 2003;Jung et al, 2010;Kwon et al, 2011;Park et al, 2020). Previous studies have shown that catechins inhibit platelet activity by regulating calcium mobilization (Kang et al, 2001), impeding several signaling kinases including ERK and p38 MAPK (Lill et al, 2003), increasing cAMP levels, and enhancing VASP ser157 phosphorylation in platelets (Ok et al, 2012); they also inhibit ERK, JNK, p38 MAPK , and Akt activation in vascular smooth muscles and endothelial cells.…”