Ferulate, an Active Component of Wheat Germ, Ameliorates Oxidative Stress-Induced PTK/PTP Imbalance and PP2A Inactivation
Toxicological Research 2018;34:333−341
Published online October 15, 2018;  https://doi.org/10.5487/TR.2018.34.4.333
© 2018 Korean Society of Toxicology.

Eun Mi Koh1,†, Eun Kyeong Lee1,†, Chi Hun Song1, Jeongah Song2, Hae Young Chung3, Chang Hoon Chae4, and Kyung Jin Jung1,5

1Bioanalytical and Immunoanalytical Research Group, Korea Institute of Toxicology, Daejeon, Korea, 2Animal Model Research Center, Korea Institute of Toxicology, Jeonbuk, Korea, 3Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Korea, 4Celldi, 2-212 Jeonbuk TechnoPark, Wanju, Korea, 5Department of Human and Environmental Toxicology, Korea University of Science and Technology (UST), Daejeon, Korea
Kyung Jin Jung, Bioanalytical and Immunoanalytical Research Group, Analytical Research Center, Korea Institute of Toxicology, 141 Gajungro, Yuseong-gu, Daejeon 34114, Korea. E-mail: jungk@kitox.re.kr
Received: August 25, 2017; Revised: June 4, 2018; Accepted: July 4, 2018
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Ferulate is a phenolic compound abundant in wheat germ and bran and has been investigated for its beneficial activities. The aim of the present study is to evaluate the efficacy of ferulate against the oxidative stress-induced imbalance of protein tyrosine kinases (PTKs), protein tyrosine phosphatases (PTPs), and serine/threonine protein phosphatase 2A (PP2A), in connection with our previous finding that oxidative stress-induced imbalance of PTKs and PTPs is linked with proinflammatory nuclear factor-kappa B (NF-κB) activation. To test the effects of ferulate on this process, we utilized two oxidative stress-induced inflammatory models. First, YPEN-1 cells were pretreated with ferulate for 1 hr prior to the administration of 2,2′-Azobis(2-methylpropionamidine) dihydrochloride (AAPH). Second, 20-month-old Sprague-Dawley rats were fed ferulate for 10 days. After ferulate treatment, the activities of PTKs, PTPs, and PP2A were measured because these proteins either directly or indirectly promote NF-κB activation. Our results revealed that in YPEN-1 cells, ferulate effectively suppressed AAPH-induced increases in reactive oxygen species (ROS) and NF-κB activity, as well as AAPH-induced PTK activation. Furthermore, ferulate also inhibited AAPH-induced PTP and PP2A inactivation. In the aged kidney model, ferulate suppressed aging-induced activation of PTKs and ameliorated aging-induced inactivation of PTPs and PP2A. Thus, herein we demonstrated that ferulate could modulate PTK/PTP balance against oxidative stress-induced inactivation of PTPs and PP2A, which is closely linked with NF-κB activation. Based on these results, the ability of ferulate to modulate oxidative stress-related inflammatory processes is established, which suggests that this compound could act as a novel therapeutic agent.

Keywords : Ferulate, Wheat germ, Oxidative stress, PTK, PTP, PP2A
INTRODUCTION

Ferulate (4-hydroxy-3-methoxycinnamic acid) is a well-known phytochemical that has been widely used in maintaining good health and nutrition (1) and has been reported to exert beneficial effects, such as lowering blood glucose levels, diminishing cerebral ischemic injury, and promoting anti-tumor activity (24). Other reports have shown that ferulate has the potential ability to treat various abnormal conditions, including cancer, arthritis, and aging (57).

Research continues to investigate ferulate and acquire additional evidence of its powerful activities. Ferulate has been shown to reduce LPS-induced TNF-α and IL-1β expression (8), modulate IL-6 expression (9), and attenuate the inflammatory release of NALP3 (10). These promising outcomes of ferulate originate from its strong antioxidant activity, which was shown to affect the regulation of nuclear factor-kappa B (NF-κB) (11).

During inflammation, NF-κB plays a critical role in regulating proinflammatory gene expression (12). NF-κB is an inducible dimeric transcription factor that is comprised of Rel family proteins that bind a consensus sequence motif and is found in all cell types (13). NF-κB activation is involved in a wide variety of gene expression patterns in response to infection, inflammation, inflammatory disease, cancer, and senescence (14). It is also a well-established redox-sensitive transcription factor that is tightly regulated by redox changes (15). Reactive oxygen species (ROS) interact with the cysteine residues of redox-sensitive signaling molecules, such as transcription factors, protein tyrosine phosphatases, and protein kinases; thus, oxidation of thiol groups on these residues can lead to modifications of the target proteins’ biological activities, signaling capacities, immune responses, and additional cell live/dead paradigms (16).

As a part of redox biology, cellular signaling is involved in redox-regulated control of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Moreover, balancing the activation and inhibition of the reversible oxidation of the active sites on these proteins has emerged as a critical sensor of the redox state (17). Reversible tyrosine phosphorylation of proteins is a key regulatory mechanism in eukaryotic physiology that is catalyzed by kinases and phosphatases (18). Accumulating evidence from cell and animal models has demonstrated PTP oxidation in models of common diseases, such as cancer, metabolic/cardiovascular disease, immune dysfunction, and age-related diseases (18,19). Moreover, the activation status of the PTK Src as well as that of the transcription factor NF-κB are decisive criteria for the onset of cancer (20). Thus, NF-κB and the expression of its downstream effector genes are also affected by the imbalance of PTKs and PTPs, which was deemed to be the cause of numerous diseases in humans (16,21).

In addition to limiting tyrosine phosphorylation and dephosphorylation, PTKs and PTPs affect serine/threonine phosphorylation by modulating the activities of serine/threonine protein phosphatases (PP) (22). In the PP family, serine/threonine protein phosphatase 2A (PP2A) has been reported to be closely linked with NF-κB activation; thus, PP2A is now considered a potential therapeutic target of inflammatory diseases and cancer (23). Some reports have provided evidence that inhibition of pan-tyrosine phosphatase activity by orthovanadate translates to inhibition of PP2A, which would result in the upregulation of cellular physiological responses and proinflammatory genes via NF-κB activation (20,22).

Based on these reports, ferulate could be a promising agent for treating NF-κB-related diseases. Despite the status of ferulate as a therapeutic agent against inflammatory diseases, cancer, and aging, the effects of ferulate on the regulation of NF-κB remain unclear. Therefore, we conducted the present study to elucidate the anti-inflammatory effect (if any) of ferulate using a rat endothelial cell line and aged rat kidneys.

MATERIALS AND METHODS

Materials

2,2′-Azobis(2-methylpropionamidine) dihydrochloride (AAPH), a bicinchoninic acid (BCA) protein assay kit, and the BCA protein reagent were purchased from Sigma-Aldrich (St. Louis, MO, USA). 2′,7′-Dichlorodihydrofluorescein diacetate (H2DCFDA) was purchased from Molecular Probes (Eugene, OR, USA). Fetal bovine serum (FBS) and penicillin-streptomycin were purchased from Gibco (New York, NY, USA). The Lipofectamine 2000 transfection reagent and an Antibody Beacon™ Tyrosine Kinase Assay kit were purchased from Invitrogen (Carlsbad, CA, USA). A ONE-Glo™ Luciferase Assay System was obtained from Promega (Madison, WI, USA). Primary antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). The anti-rabbit IgG-horseradish peroxidase-conjugated antibody was purchased from Cell Signaling Biotechnology (Beverly, MA, USA). 3,6-Fluorescein diphosphate (FDP) and a RediPlate™ 96 EnzChek® Serine/Threonine Phosphatase Assay kit were acquired from ThermoFisher Scientific (Waltham, MA, USA). An enhanced chemiluminescence (ECL) kit was purchased from Pierce Biotechnology (Rockford, IL, USA).

Animals

Young (7-month-old) and old (20-month-old) male Sprague-Dawley (SD) rats raised in specific pathogen-free conditions were obtained from Samtako (Osan, Korea). Animals were individually housed in polycarbonate cages with wood chip bedding, maintained in a climate-controlled room (temperature: 24°C, relative humidity: 55 ± 5%) with a 12-hr light/dark cycle, and given feed and tap water ad libitum (AL). The old rats were divided into 3 groups (n = 4 per group), such that the mean body weight of the groups was identical. Rats in the control group were provided a diet AL with the following composition: 21% soybean protein, 15% sucrose, 43.65% dextrin, 10% corn oil, 0.15% α-methionine, 0.2% choline chloride, 5% salt mix, 2% vitamin mix, and 3% Solka-Floc. Ferulate supplementation was carried out by mixing ferulate at a daily dose of 3 or 6 mg/kg of body weight into the chow. The respective diets were fed to the rats for 10 days. The animal protocol used in this study was reviewed and approved by the Institutional Animal Care and Use Committee at Pusan National University (PNU-IACUC, Approval Number: PNU-2014-0601).

Cell culture

YPEN-1 cells (rat prostate endothelial cells) were obtained from the ATCC (American Type Culture Collection, Manassas, VA, USA). The cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 2 mM L-glutamine, antibiotics (100 U/mL penicillin and 100 μg/mL streptomycin), and 10% heat-inactivated FBS and incubated at 37°C in a humidified atmosphere containing 5% CO2.

Measurement of intracellular ROS

YPEN-1 cells were seeded into a clear-bottom 96-well plate for tissue culture. After they were incubated overnight, the medium was replaced, and the cells were incubated for 1 hr in the presence or absence of ferulate. Afterwards, all cells were administered 400 μg/mL AAPH for 3 hr. The medium was then replaced with fresh serum-free medium. In addition, 12.5 μM H2DCFDA was added and incubated with the cells for 30 min. The fluorescence intensity was measured every 10 min for 40 min using the bottom read mode of a SpectraMax M3 (Molecular Devices, Sunnyvale, CA, USA) with excitation and emission wavelengths of 485 and 535 nm, respectively.

Luciferase reporter assay

The pNF-κB-Luc vector was purchased from Clontech Laboratories (Mountain View, CA, USA). A mixture of 0.02 μg of plasmid and Lipofectamine 2000 at a 1:1 ratio was prepared, added to each well of a 96-well plate (1 × 104 cells/well), and incubated for 36 hr. After replacing the media, ferulate and AAPH were added to the cells for 8 hr. Then the luciferase assay was performed at which point reagents from the ONE-Glo Luciferase Assay System were added to the plate according to the manufacturer’s instructions. Then the luciferase activity was measured using luminometric analysis on a SpectraMax M3 microplate reader (Molecular Devices).

PTK activity

Protein tyrosine kinase activity in the tissue homogenate and cell lysates was assayed by using the Antibody Beacon™ Tyrosine Kinase Assay kit according to the manufacturer’s instructions. To detect tyrosine kinase activity, samples were prepared in 1× kinase buffer (100 mM Tris-HCl, 20 mM MgCl2, 2 mM EGTA, 2 mM DTT, and 0.02% Brij 35; pH 7.5) and mixed with the Antibody Beacon detection complex plus substrate in a 96-well microplate. The ATP reagent was then added to the plate and continuously incubated at the reaction temperature. The fluorescence was measured at multiple time points on a GENios (TECAN, Schweiz AG, Mannedorf, Switzerland) with the excitation and emission wavelengths set at 485 and 535 nm, respectively.

PTP activity

To detect tyrosine kinase activity, samples were prepared in PTP assay buffer (50 mM Tris-HCl, 2 mM EGTA, 5 mM DTT, and 100 μM CaCl2; pH 6.3) and mixed with a 100 μM solution of 3,6-fluorescein diphosphate (FDP, a fluorogenic substrate that is highly sensitive to PTP activity) in a 96-well microplate. The plate was incubated at room temperature for 5 min, and then the fluorescence was measured at multiple time points on a GENios with the excitation and emission wavelengths set at 485 and 535 nm, respectively.

PP activity

PP activity was measured by using the RediPlate 96 EnzChek Serine/Threonine Phosphatase Assay Kit (ThermoFisher Scientific) according to the manufacturer’s protocol. To detect the PP activity, samples were prepared in PP assay buffer (100mM Tris-HCl, 2 mM EGTA, 5 mM DTT, and 200 μM CaCl2; pH 6.0) and mixed with 100 μM of 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP, a fluorogenic substrate sensitive to PP) in the 96-well microplate. The plate was incubated at room temperature for 5 min, and then fluorescence was measured at multiple time points on a GENios with excitation and emission wavelengths of 360 and 460 nm, respectively.

Tissue homogenates and cell lysates

To prepare Western blot samples, one gram of kidney was homogenized in 5 mL of homogenate buffer (100 mM Tris, 20 mM β-glycerophosphate, 20 mM NaF, 2 mM sodium orthovanadate, 1 mM EDTA, 0.5 mM PMSF, 1 μM pepstatin, and 80 mg/L trypsin inhibitor; pH 7.4) and centrifuged at 900 × g for 15 min at 4°C. The supernatants were then recentrifuged at 12,000 × g for 15 min at 4°C to yield a pelleted mitochondrial fraction and postmitochondrial supernatant fraction; the latter was used as the cytosolic fraction. For the cell lysates, cells were collected, centrifuged, and rinsed once with PBS. The collected cell pellets were resuspended by using a nuclear and cytoplasmic extraction reagent kit (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions. Then protein quantification of the tissue homogenates and cell lysates was determined using the BCA protein assay according to the manufacturer’s instructions.

Western blot analysis

Homogenized samples were boiled for 5 min with 2× sample buffer (0.125 M Tris-HCl, 4% SDS, 10% 2-mercaptoethanol, and 0.2% bromophenol blue; pH 6.8). Equivalent amounts of protein from each sample were separated on 10% acrylamide gels by using SDS-PAGE and transferred to a PVDF membrane at 15 V for 20 min in a semi-dry transfer system. The membrane was immediately placed into blocking buffer (1% bovine serum albumin in 10 mM Tris, 100 mM NaCl, and 0.1% Tween 20; pH 7.5) and incubated at room temperature for 1 hr. The membrane was then treated with specific primary antibodies for 2 hr at 25°C followed by the addition of a horseradish peroxidase-conjugated anti-goat antibody (Cell Signaling Technology, Danvers, MA, USA) diluted 1:10000 in Tris-buffered saline/Tween 20 (TBS/T) and another incubation at 25°C for 1 hr. Antibody labeling was detected using enhanced chemiluminescence (Thermo Fisher Scientific) according to the manufacturer’s instructions. Pre-stained protein markers were used to determine molecular weight.

Statistical analysis

One representative western blot from the replicates is shown in the figures; however, we analyzed the relative optical intensity of each corresponding band from three separate experiments. For all other assays, the results are expressed as the mean ± SD from three separate experiments. The statistical significance of differences among the groups was determined by one-factor ANOVA followed by the protected Fisher’s LSD post hoc test. Values of p < 0.05 were considered statistically significant.

Figures
Fig. 1. Schematic diagram of the effect of PTK/PTP imbalance that causes NF-κB activation. Increases in ROS result in changes in the PTK/PTP balance, which promotes inflammatory processes in inflammatory disease and aging models. Furthermore, ROS consequently inactivate PP2A by phosphorylating Tyr307. These alterations lead to NF-κB activation via NIK/IKKalpha/beta and MAPKs and contribute to the development of molecular inflammation during aging.
Fig. 2. Effect of ferulate on AAPH-induced intracellular ROS generation and NF-κB promoter binding activity. (A) To detect the level of ROS, the relative fluorescence was measured by H2DCFDA probes. YPEN-1 cells were treated with 31, 63, 125, or 250 μM ferulate for 1 hr and then incubated with either PBS (vehicle) or 400 μg/mL AAPH. (B) To confirm the inhibitory effect of ferulate on AAPH-induced NF-κB activation, a NF-κB-dependent luciferase reporter gene assay was performed. YPEN-1 cells were transiently transfected with a plasmid containing the NF-κB binding motif. After the cells were transfected, they were treated with ferulate and AAPH at the designated concentrations for 8 hr, and the luciferase activity was then measured. The results were analyzed using one-way ANOVA: **p< 0.01, ***p< 0.001 vs. vehicle-treated group; #p< 0.05, ##p<0.01, ###p< 0.001 vs. AAPH-treated group.
Fig. 3. Effect of ferulate on AAPH-induced PTK/PTP activities. Cells were treated with 125 or 250 μM ferulate for 1 hr, followed by treatment with AAPH for 3 hr. (A) PTK and (B) PTP activity was measured to determine (C) the PTK/PTP ratio in AAPH-treated YPEN-1 cells. Each value is presented as the mean ± SD. The results were analyzed using one-way ANOVA: *p < 0.05, **p < 0.01 vs. vehicle-treated group; #p<0.05, ##p< 0.01 vs. AAPH-treated group.
Fig. 4. Effect of ferulate on total PP activity in AAPH-treated YPEN-1 cells. (A) Cell lysates were prepared to measure total PP activity by using a RediPlate 96 EnzChek Serine/Threonine Phosphatase Assay Kit (ThermoFisher Scientific). (B) The levels of phospho-PP2Ac (Tyr307) and total-PP2Ac were detected by western blotting. One representative result from three independent experiments is shown here. β-Actin was used as the loading control. The results were analyzed using one-way ANOVA: ***p < 0.001 vs. vehicle-treated group. ###p<0.001 vs. AAPH-treated group.
Fig. 5. Reversible effects of ferulate on PTK/PTP activity in the kidneys of aged rats. Kidney homogenates were prepared to detect the PTK (A) and PTP (B) activity, which were then used to determine the PTK/PTP ratio (C) in the kidneys of aged rats. Each value is presented as the mean ± SD (n=4). The results were analyzed using one-way ANOVA: ***p < 0.001 vs young (Y, 7-month-old) rats; ##p< 0.01, ###p< 0.001 vs. untreated aged (O, 20-month-old) rats.
Fig. 6. Reversible effects of ferulate on age-related decreases of total PP activity in the kidneys of aged rats. (A) Kidney homogenates were prepared to measure total PP activity by using a RediPlate 96 EnzChek Serine/Threonine Phosphatase Assay Kit (ThermoFisher Scientific). (B) The levels of phospho-PP2Ac (Tyr307) and total-PP2Ac were detected by western blotting. A representative blot from three independent experiments is shown. β-Actin was used as a loading control. The results were analyzed using one-way ANOVA: ***p < 0.001 vs. young (Y, 7-month-old) rats; #p < 0.05, ###p < 0.001 vs. untreated aged (O, 20-month-old) rats.
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