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BY 4.0 license Open Access Published by De Gruyter Open Access October 28, 2022

Cynarin inhibits PDGF-BB-induced proliferation and activation in hepatic stellate cells through PPARγ

  • Yong Ding , Congcong Tao , Qian Chen , Lulu Chen , Xianwen Hu , Mingyu Li , Shicong Wang EMAIL logo and Fuquan Jiang EMAIL logo
From the journal Open Chemistry

Abstract

Cynarin, a caffeoylquinic acid compound that was mainly extracted from Cynara scolymus L., displays various activities such as antioxidant, antibacterial, choleretic, and hepatoprotective functions. However, the target of cynarin and the mechanism of its hepatoprotective effect are still unclear. To find cynarin’s target, we performed molecular docking analysis, fluorescence-based ligand-binding assay, and reporter gene system assay. Our results indicated that cynarin was a partial agonist of peroxisome proliferator-activated receptor gamma (PPARγ). Further studies showed that cynarin significantly inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and activation of rat CFSC-8G hepatic stellate cells (HSCs). Our results also revealed that cynarin inhibited PDGF-BB-induced extracellular regulated protein kinase (ERK) and v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation in HSCs. In addition, this inhibition effect was PPARγ dependent since the knockdown of PPARγ significantly attenuated the effects of cynarin on PDGF-BB-induced p-ERK, p-AKT, and α-smooth muscle actin (α-SMA) expressions. Therefore, this study suggests that cynarin is a promising antifibrotic lead compound that inhibits the activation of HSCs, and it works by targeting PPARγ.

1 Introduction

Hepatic stellate cells (HSCs), a type of mesenchymal cells in the liver, play a key role in the development and progression of hepatic fibrosis, which is not only the result of chronic liver damage but also an important predictor of poor outcomes of liver disease [1,2,3]. Under physiological conditions, HSCs are quiescent. However, during liver injury, quiescent stellate cells are activated and then transdifferentiate into myofibroblast-like cells expressing α-smooth muscle actin (α-SMA) [1,4,5]. Many pathways involve in the HSC proliferation and activation. Among these pathways, many of them are receptor dependent, which are triggered by autocrine or paracrine activation of mitotic growth factors such as platelet-derived growth factor (PDGF) [6,7]. Therefore, suppression of the proliferation and activation of HSCs by inhibiting mitogen signals such as PDGF is a feasible strategy to develop anti-hepatic fibrosis drugs.

Peroxisome proliferator-activated receptor gamma (PPARγ), an important member of the nuclear receptor family, has diverse functions and plays important roles in various physiological and pathological processes including cell proliferation, differentiation, and apoptosis [8,9,10]. Upon ligand stimulation, PPARγ binds to retinoid X receptor αlpha (RXRα) to form a heterodimer, which binds to the PPAR response element to regulate the transcription of target genes [11]. Interestingly, the expression and activity of PPARγ were significantly reduced during HSC activation [12,13]. Moreover, studies have been reported that activation of PPARγ inhibited PDGF-induced HSC activation [14]. Taken together, these studies suggested that inhibition of HSC activation by targeting PPARγ is a promising approach, and identifying PPARγ small molecule activator is a good way to go.

Cynarin (1,3-dicaffeoylquinic acid), a natural polyphenolic compound extracted mainly from Cynara scolymus L., has broad biological activities, including antioxidant, antiviral, immunomodulatory, and vasodilator functions [15,16,17,18,19]. It has been reported that cynarin has protective effects on liver damage caused by CCl4 [20], cyclophosphamide [21], or alcohol [22]. However, the detailed mechanism, especially the role of cynarin in HSCs, remains unclear. In the present study, we identified cynarin as a novel PPARγ-selective partial agonist for the first time and demonstrated that it inhibits PDGF-BB-induced HSC proliferation and activation.

2 Materials and methods

2.1 Cell culture

CFSC-8G and HEK-293T cell lines were purchased from Stem Cell Bank, Chinese Academy of Sciences (Shanghai, China). Cells were cultured at 37°C in DMEM (Gibco Thermo Fisher, USA) supplemented with 10% fetal bovine serum (Gibco Thermo Fisher, USA) and 1% penicillin/streptomycin (NCM Biotech, Suzhou, China).

2.2 Western Blot

Western blot was performed as described. Cells were lysed in radio immunoprecipitation assay buffer (150 mM sodium chloride, 1.0% Triton X-100, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, 50 mM Tris, pH 7.6) with protease and phosphatase inhibitors. Cells were lysed at 13000 rpm at 4°C for 10 min and then degenerated with loading buffer thoroughly. Then, the mixture lysis was heated at 100°C for 7 min and loaded into 8 or 10% Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by transfer to polyvinylidene fluoride membrane (GE Healthcare, Buckinghamshire, UK). The membranes were incubated with appropriate primary antibodies such as α-SMA (sc-53142, Santa Cruz Biotechnology, USA), β-actin (3,700 s, Cell Signaling Technology, Danvers, MA, USA), α-Tubulin (AC012, Abclone, Wuhan, China), PPARγ (A19676, Abclone, Wuhan, China), glyceraldehyde-3-phosphate dehydrogenase (sc-365062, Santa Cruz Biotechnology, USA), AKT (4,691 s, Cell Signaling Technology, Danvers, MA, USA), Phospho-AKT (Ser473) (4,060 s, Cell Signaling Technology, Danvers, MA, USA), extracellular regulated protein kinase (ERK) (5,013 s, Cell Signaling Technology, Danvers, MA, USA), and p-ERK (4,370 s, Cell Signaling Technology, Danvers, MA, USA) in tris buffer solution and tween (TBST) for 1 h, washed twice, and then probed with horseradish peroxide-linked conjugated secondary antibodies such as anti-rabbit IgG, horseradish peroxidase (HRP)-linked antibody (111-035-003, Jackson, USA) or anti-mouse IgG, HRP-linked antibody (115-035-003, Jackson, USA) for 1 h at room temperature. After three washes with TBST, immunoreactive products were visualized using the ECL system (K-12045-D50, APGBio, Hongkong, China).

2.3 Cell viability assay

The cells were inoculated in 96-well plates and treated with a specific concentration gradient, then detected with the medium containing 10% Cell Counting Kit-8 (HY-K0301, MCE, USA), and incubated for 2 h. The value was read at 450 nm.

2.4 Immunofluorescence

Cells were planted on 8 mm × 8 mm glass coverslips (NEST, Wuxi, China) and treated according to the corresponding design. After treatments, cells were fixed with 4% (w/v) paraformaldehyde (Sigma, St Louis, USA) at room temperature for 15 min and blocked with 5 mg/mL bovine serum albumin in tris buffer solution for 1 h at room temperature. Then, cells were incubated with primary antibody α-SMA (A1011, Abclone, Wuhan, China) (1:200) at 4°C overnight and then incubated with Alexa Fluor secondary antibody (FITC-488, 111-545-003, Jackson, USA) for 1 h at room temperature. Finally, coverslips were covered with DAPI Fluoromount-G (Yeasen Biotech, Shanghai, China) for 10 min, and the images were taken under the confocal laser scanning microscope system (Leica TCS SP8) or LSM-510 confocal laser scanning microscope system.

2.5 Dual luciferase reporter assay

HEK-293T cells were plated in 48-well plates and then transiently co-transfected with the luciferase reporter plasmid pG5, pBind-PPARγ-ligand-binding domain (LBD), or pBind-RXRα-LBD. 24 h after transfection, the medium was replaced by medium containing cynarin (HY-N0359, MCE, USA) and 0.2 μM 9-cis-RA (T19169, TargetMol, USA) or 1 μM rosiglitazone (ROS) (HY-17386, MCE, USA). After 24 h, cells were lysed by NP40 lysis buffer, and the lysate was analyzed by Dual-Luciferase Reporter Kit (11402ES60, Yeasen Biotech, Shanghai, China).

2.6 Fluorescence titration assay

The fluorescence titration assay was performed as described [23]. PPARγ-LBD protein was serially titrated with cynarin or the classical antagonist of PPARγ, T0070907 (HY-13202, MCE, USA), and the titration amount was 1 μL each time. Allow the mixture to stand for 3 min to equilibrate before acquiring fluorescence emission spectra from 280 to 450 nM under excitation at 270 nM. The PPARγ-LBD protein concentration in the cuvette was 1 µM, and the volume was 3 mL. The stock solution of cynarin and T0070907 was 3 mM. The cynarin or T0070907 was then added to the cuvette drop by drop, 1 μL each time, and the fluorescence spectrum was recorded for each titration. The compound concentration was taken as the abscissa, and the change of the spectral signal after each titration was taken as the ordinate. The Kd value was calculated by the following equation using Origin software.

y = C ( x + P + K d ) / C sqrt ( ( x + P + K d ) 2 4 P x ) / 2 ,

where y represents the change in fluorescence intensity after each titration, x represents the compound concentration, P represents the protein concentration, and C is the constant unit that measures the signal change (ΔF) per change of complex (ligand–protein) concentration (molar signal coefficient).

2.7 The binding mode of cynarin to PPARγ

To determine the binding mode of cynarin to PPARγ, we used Glide to perform molecular docking protocols with SP and XP precision. In addition, MM-GBSA (the molecular mechanics with generalized Born and surface area) binding energies were calculated with prime (supplied with Maestro), which can be expected to agree reasonably well with experimental binding affinity. GScore (docking score of Glide) is expressed in kcal/mol−1 unit, which consists of van der Waals energy, Coulomb energy, Lipophilic, Hydrogen-bonding, and rewards term [24]. The referenced crystal structure of PPARγ was downloaded from PDB (ID:2PRG) and preprocessed using Protein Preparation Wizard, a module of Maestro, with default parameters. A grid box that was defined at the centroid of co-crystal ligand ROS was generated with a side length of 20 Å for molecular docking. The redock research was performed before molecular docking, and results indicated that protocols both of SP and XP precision are good enough to predict the correct binding poses of ROS with the root mean square deviation (RMSD) lower than 2.0 Å.

2.8 Statistical analysis

Data are expressed as mean ± standard deviation. Statistical comparisons were made using one-way analysis of variance, followed by Tukey’s test. Statistical significance was defined as p-value <0.05.

3 Results and discussion

3.1 Cynarin binds to PPARγ as a selective partial agonist

We performed a virtual screening of an in-house compound library using Glide (provided by Maestro) and found that cynarin (Figure 1a) is a potential PPARγ ligand with a better docking score. To determine the binding mode of cynarin to PPARγ, we performed further molecular docking studies using Glide for the ROS [25,26], a classic agonist of PPARγ and cynarin (Figure 1b). We then performed fluorescence-based ligand-binding assay to confirm their physical binding. The result showed that T0070907 [27], a confirmed PPARγ antagonist, bound to PPARγ-LBD in a dose-dependent manner, and the Kd value is 1.873 μmol/L (Figure 1c and d). Similarly, cynarin bound to PPARγ-LBD with a Kd value of 9.9665 μmol/L (Figure 1e and f). Taken together, these results suggested that cynarin can directly bind to PPARγ.

Figure 1 
                  Cynarin binds to PPARγ. (a) Molecular structure of cynarin. (b) Interactions of ROS and cynarin, respectively, with the PPARγ ligand-binding pocket. (c and d) Fluorescence titration assay of T0070907 binding to PPARγ-LBD. (e and f) Fluorescence titration assay of cynarin binding to PPARγ-LBD.
Figure 1

Cynarin binds to PPARγ. (a) Molecular structure of cynarin. (b) Interactions of ROS and cynarin, respectively, with the PPARγ ligand-binding pocket. (c and d) Fluorescence titration assay of T0070907 binding to PPARγ-LBD. (e and f) Fluorescence titration assay of cynarin binding to PPARγ-LBD.

Then, we used the chimeric Gal4-DBD-PPARγ-LBD (pBind-PPARγ-LBD) reporter gene system to examine the effect of cynarin on PPARγ transcriptional activation. The results showed that the reporter gene of pBind-PPARγ-LBD was slightly activated by the treatment with cynarin alone compared to the PPARγ full agonist ROS, which significantly increased reporter activity. Interestingly, when combined with the classic PPARγ agonist ROS, cynarin instead inhibited ROS-induced PPARγ transcriptional activation (Figure 2a). Based on the aforementioned results, and the definition of a partial agonist, that is, a ligand binds to the agonist recognition site but elicits a lower response at the receptor than that of a full agonist, we then consider cynarin to be a partial agonist of PPARγ. Under the same treatment conditions, cynarin alone or even in combination with the RXRα agonist 9-cis-RA had no significant effect on the pBind-RXRα-LBD reporter gene (Figure 2b), suggesting that cynarin has a certain selectivity for PPARγ.

Figure 2 
                  Cynarin is a selective partial agonist of PPARγ. (a) The effect of cynarin on PPARγ transcriptional activity. (b) The effect of cynarin on RXRα transcriptional activity. *p < 0.05 vs vehicle group, **p < 0.01 vs vehicle group, #
                     p < 0.05 vs ROS group, ##
                     p < 0.01 vs ROS group, ###
                     p < 0.001 vs ROS group, n = 3.
Figure 2

Cynarin is a selective partial agonist of PPARγ. (a) The effect of cynarin on PPARγ transcriptional activity. (b) The effect of cynarin on RXRα transcriptional activity. *p < 0.05 vs vehicle group, **p < 0.01 vs vehicle group, # p < 0.05 vs ROS group, ## p < 0.01 vs ROS group, ### p < 0.001 vs ROS group, n = 3.

It is well known that clinically used PPARγ full agonists like ROS have many unwanted side effects, such as weight gain, fluid retention, and lowering of blood pressure, which limit their widespread use [28]. Fortunately, several partial agonists such as INT131, MCC-555, DRF-2593, Metaglidasen, and Halofenate have been reported to show good activity compared to full agonists of PPARγ, while avoiding the side effects of full agonists [29,30]. Therefore, PPARγ partial agonists are considered to have a better development potential because they avoid side effects such as lipid accumulation and weight gain caused by PPARγ full agonists. It can be seen that cynarin, as a novel partial agonist of PPARγ, deserves further development and research.

3.2 Cynarin inhibits HSC proliferation and activation induced by PDGF-BB

Given that PPARγ is a key regulator of HSC activation [12,26,31], we examined the effect of cynarin on CFSC-8B HSC proliferation and activation induced by PDGF-BB, an important activator of HSCs. First, we performed a cell counting kit 8 assay to examine the effect of cynarin on HSC proliferation. The results showed that cynarin could significantly inhibit PDGF-BB-induced HSC proliferation in a dose-dependent manner, but had no significant effect on quiescent HSCs (Figure 3a and b). We then examined the effect of cynarin on the expression of α-SMA, a marker of HSC activation [1,6], by western blot assay. The results showed that cynarin could significantly inhibit the expression of α-SMA induced by PDGF-BB in a dose- and time-dependent manner (Figure 3c–f). Furthermore, our immunofluorescence staining showed that the expression of α-SMA was dramatically decreased in the presence of cynarin (Figure 3g). Taken together, these results indicated that cynarin has a significant inhibitory effect on HSC proliferation and activation.

Figure 3 
                  Cynarin inhibits PDGF-BB-induced HSC proliferation and activation. (a) The effect of cynarin on quiescent HSC proliferation. (b) The effect of cynarin on PDGF-BB-induced HSC proliferation. (c–g) Inhibitory effect of cynarin on α-SMA expression induced by PDGF-BB (10 ng/mL) as indicated. ***p < 0.001 vs vehicle group, #
                     p < 0.05 vs PDGF-BB group, ##
                     p < 0.01 vs PDGF-BB group, ###
                     p < 0.001 vs PDGF-BB group, n = 3.
Figure 3

Cynarin inhibits PDGF-BB-induced HSC proliferation and activation. (a) The effect of cynarin on quiescent HSC proliferation. (b) The effect of cynarin on PDGF-BB-induced HSC proliferation. (c–g) Inhibitory effect of cynarin on α-SMA expression induced by PDGF-BB (10 ng/mL) as indicated. ***p < 0.001 vs vehicle group, # p < 0.05 vs PDGF-BB group, ## p < 0.01 vs PDGF-BB group, ### p < 0.001 vs PDGF-BB group, n = 3.

3.3 Cynarin inhibits PDGF-induced downstream signaling pathways

A large number of studies reported that the downstream signal modulator such as AKT and ERK mediated by PDGF-BB played important roles in HSC activation [6,32,33,34]. To assess the effect of cynarin on PDGF-BB-mediated downstream signaling pathways, we examined the expression levels of p-AKT/AKT and p-ERK/ERK in CFSC-8B cells. The results showed that the expression levels of p-AKT and p-ERK were significantly increased in CFSC-8B HSC cells treated with PDGF-BB for 20 min. However, cynarin dose dependently reduced their levels in PDGF-BB-activated CFSC-8B HSC cells (Figure 4a–c). The result, i.e., Cynarin inhibits p-ERK and p-AKT expression induced by PDGF-BB in CFSC-8B HSC cells, was further validated under conditions with a series of treatment times (5, 10, 15, 20, and 30 min) for PDGF-BB (Figure 4d and e). Given the promoting role of ERK and AKT signaling pathways in stellate cell proliferation and activation [34], these results suggested that cynarin inhibits stellate cell activation likely through suppressing ERK and AKT signaling pathways.

Figure 4 
                  Cynarin inhibits PDGF-BB-induced expression of p-AKT and p-ERK. (a–c) Cynarin dose dependently inhibits the expression of p-ERK and p-AKT induced by PDGF-BB. (d) Cynarin inhibits the expression of p-ERK induced by PDGF-BB (10 ng/mL) as indicated. (e) Cynarin inhibits the expression of p-AKT induced by PDGF-BB (10 ng/mL) as indicated. ***p < 0.001 vs vehicle group, #
                     p < 0.05 vs PDGF-BB group, ##
                     p < 0.01 vs PDGF-BB group, n = 3.
Figure 4

Cynarin inhibits PDGF-BB-induced expression of p-AKT and p-ERK. (a–c) Cynarin dose dependently inhibits the expression of p-ERK and p-AKT induced by PDGF-BB. (d) Cynarin inhibits the expression of p-ERK induced by PDGF-BB (10 ng/mL) as indicated. (e) Cynarin inhibits the expression of p-AKT induced by PDGF-BB (10 ng/mL) as indicated. ***p < 0.001 vs vehicle group, # p < 0.05 vs PDGF-BB group, ## p < 0.01 vs PDGF-BB group, n = 3.

3.4 Cynarin inhibits HSC activation dependent on PPARγ

To investigate whether the inhibition of HSC activation by cynarin is dependent on PPARγ, we then investigated the effect of cynarin on α-SMA expression in CFSC-8B HSC cells by using PPARγ siRNA. The results showed that the PPARγ siRNA significantly knockdown the PPARγ protein level in CFSC-8B cells, and knockdown of PPARγ abolished the inhibitory effect of cynarin on PDGF-BB-induced α-SMA expression (Figure 5a and b). We further examined the effect of PPARγ on the inhibition of p-ERK and p-AKT expression by cynarin. The results showed that knockdown of PPARγ attenuated the inhibitory effect of cynarin on PDGF-BB-induced p-ERK and p-AKT expression (Figure 5c–e). Taken together, these results suggest that cynarin inhibited HSC activation largely dependent on PPARγ.

Figure 5 
                  The inhibition of HSC activation by cynarin is dependent on PPARγ. (a and b) Knockdown of PPARγ abolished the inhibitory effect of cynarin on PDGF-BB-induced α-SMA expression. (c–e) Knockdown of PPARγ abolished the inhibitory effect of cynarin on PDGF-BB-induced p-ERK and p-AKT expression. #
                     p < 0.05 vs PDGF-BB group, ###
                     p < 0.001 vs PDGF-BB group, n = 3.
Figure 5

The inhibition of HSC activation by cynarin is dependent on PPARγ. (a and b) Knockdown of PPARγ abolished the inhibitory effect of cynarin on PDGF-BB-induced α-SMA expression. (c–e) Knockdown of PPARγ abolished the inhibitory effect of cynarin on PDGF-BB-induced p-ERK and p-AKT expression. # p < 0.05 vs PDGF-BB group, ### p < 0.001 vs PDGF-BB group, n = 3.

Numerous studies have shown that PPARγ is a key factor regulating HSC activation, which is a central event in the initiation and progression of liver fibrosis [1,3,31,35]. Activation of PPARγ inhibits HSC proliferation and activation [36]. These molecular mechanistic studies suggest that PPARγ is a promising drug target for antifibrotic chemotherapy. A large number of animal studies have shown that upregulation of PPARγ expression or administration of PPARγ ligands has good therapeutic prospects for liver fibrosis caused by various etiologies [31,37]. Partial agonists of PPARγ are considered to have better development value because they avoid side effects such as lipid accumulation and weight gain caused by full PPARγ agonists [30]. As a novel partial agonist of PPARγ, cynarin can significantly inhibit HSC activation in a PPARγ-dependent manner (Figure 6) and will be a potential antifibrotic lead with good efficacy and minimal side effects, although it still needs to be validated in experimental animal models.

Figure 6 
            The schematic diagram of cynarin inhibiting PDGF-induced HSC activation via PPARγ. Cynarin, as a novel PPARγ partial agonist, activates PPARγ to inhibit PDGF-BB-induced phosphorylation of ERK and AKT, thereby inhibiting HSC proliferation and activation.
Figure 6

The schematic diagram of cynarin inhibiting PDGF-induced HSC activation via PPARγ. Cynarin, as a novel PPARγ partial agonist, activates PPARγ to inhibit PDGF-BB-induced phosphorylation of ERK and AKT, thereby inhibiting HSC proliferation and activation.

4 Conclusion

We identified a novel selective partial agonist of PPARγ, cynarin, which can inhibit HSC activation in a PPARγ-dependent manner. These results will provide a potential lead for the treatment of liver fibrosis.


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Acknowledgments

This research was funded by grants from the National Natural Science Foundation of China (81772993 and 31960073) and Natural Science Foundation of Fujian Province of China (2019J01145). We are grateful to Dingyu Xu and Shan Jiang for their technical help.

  1. Author contributions: Fuquan Jiang: conceptualization, formal analysis, funding acquisition, project administration, resources, supervision, and writing–review and editing; Shicong Wang: conceptualization, formal analysis, funding acquisition, resources, and writing–review and editing; Yong Ding: formal analysis, funding acquisition, investigation, project administration, validation, and writing– original draft; Congcong Tao: data curation, formal analysis, investigation, project administration, validation, visualization, and writing–original draft; Qian Chen: investigation and methodology; Lulu Chen: investigation and methodology; Xianwen Hu: methodology; and Mingyu Li: formal analysis, software, and writing–review and editing.

  2. Conflict of interest: The authors state no conflict of interest.

  3. Ethical approval: The conducted research was not related to either human or animal use.

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Received: 2022-05-10
Revised: 2022-06-13
Accepted: 2022-07-09
Published Online: 2022-10-28

© 2022 Yong Ding et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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