Modified Gegen Qinlian Decoction Ameliorates DSS-Induced Ulcerative Colitis in Mice by Inhibiting Ferroptosis via Nrf2/GPX4 Pathway

Huang, Jinke; Zhang, Jiaqi; Liu, Zhihong; Ma, Jing; Wang, Fengyun; Tang, Xudong

doi:https://doi.org/10.1155/2024/6802701

Journal of Food Quality

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Abstract Introduction Materials and Methods Results Discussion Conclusion Abbreviations Data Availability Ethical Approval Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2024 | Article ID 6802701 | https://doi.org/10.1155/2024/6802701

Modified Gegen Qinlian Decoction Ameliorates DSS-Induced Ulcerative Colitis in Mice by Inhibiting Ferroptosis via Nrf2/GPX4 Pathway

Jinke Huang,¹Jiaqi Zhang,¹Zhihong Liu,¹Jing Ma,¹Fengyun Wang,¹and Xudong Tang¹

Academic Editor: Muhammad Babar Khawar

Received13 Nov 2023

Revised16 Jan 2024

Accepted22 Jan 2024

Published07 Feb 2024

Abstract

Objective. Ferroptosis, a form of programmed cell death, is considered a novel target for the treatment of ulcerative colitis (UC). The aim of this study was to explore whether modified Gegen Qinlian decoction (MGQD) ameliorates UC in mice via mediating ferroptosis. Methods. Mice with dextran sulfate sodium- (DSS-) induced colitis were administered with MGQD for seven days. Subsequently, iron, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) were measured. ELISA and immunohistochemistry were used to evaluate the levels of proinflammatory cytokines and tight junction proteins, respectively. Transmission electron microscopy was used to reveal mitochondrial morphology. Western blot and qRT-PCR analyses were used to assess the expression levels of the proteins of Nrf2/GPX4 pathway. The docking affinity of MGQD and Nrf2 was assessed using AutoDock Vina 1.1.2. Results. Ferroptosis was identified in mice with UC, as demonstrated by mitochondrial disruption, MDA and ROS production, iron overload, decrease in GSH level, and abnormal expression of core marker proteins of ferroptosis. After MGQD treatment, these characteristic changes of ferroptosis were significantly reversed, along with concomitant activation of the Nrf2/GPX4 pathway. Furthermore, molecular docking analysis revealed that MGQD had a high affinity for Nrf2. Conclusion. MGQD may ameliorate UC by inhibiting ferroptosis via the activation of Nrf2/GPX4 pathway. This study provided new insights into the application of MGQD complementary therapy for UC.

1. Introduction

Ulcerative colitis (UC) is a common inflammatory bowel disease [1]. The incidence of UC has been increasing continuously worldwide, imposing a significant economic burden on society [2]. The etiology of UC remains poorly understood, although environmental factors, genetics, immune responses, and intestinal microflora have been implicated as causative factors for UC [1]. Currently, the therapies for UC are focused on controlling the active inflammatory response and regulating intestinal immune balance, and commonly used drugs include 5-aminosalicylic acid drugs, immunosuppressants, and steroids [3, 4]. However, the long-term use of these drugs poses the challenges of significant adverse events and drug resistance [5, 6]. Therefore, it is urgent to develop potent medications for UC.

Ferroptosis is a newly discovered type of programmed cell death caused by oxidative stress and high reactive oxygen species (ROS) production [7]. The death of epithelial cells in UC has recently been linked to ferroptosis, and inhibition of ferroptosis has been demonstrated to be beneficial for UC [8, 9]. Nrf2 is a transcription factor involved in the resistance to endogenous oxidative stress. Genes located downstream of Nrf2 play roles in key regulatory functions in iron metabolism (FTH1, FTL, SLC40A1, MT1G, and FECH), ROS accumulation (GPX4, HO-1, and NQO1), and GSH production (GSR, GCLC, GSS, and SLC7A11). Thus, activation of Nrf2/GPX4 pathway is a classical strategy to inhibit ferroptosis [10, 11].

Gegen Qinlian decoction (GQD) is a well-known Chinese herbal formula beneficial for UC [12]. Our previous study reported that modified GQD (MGQD) is efficacious in alleviating UC in mice [13–15]. Intestinal epithelial cell death can promote the pathological progression of UC by altering the integrity of the intestinal barrier [16]. Therefore, in this study, we aimed to further investigate the mechanism underlying the therapeutic action of MGQD in UC via ferroptosis regulation.

2. Materials and Methods

2.1. Decoction Preparation

The composition of MGQD is as follows: Coptidis Rhizoma (9 g), Radix Puerariae (24 g), Zingiberis Rhizoma (9 g), Scutellariae Radix (9 g), Talcum (9 g), and Liquorice (6 g). MGQD was provided by the pharmacy of Xiyuan Hospital of China Academy of Chinese Medical Sciences. MGQD extracts were prepared as per the standard for preparing the decoction of Chinese herbal medicines. The production process was as follows. The herbs were soaked in distilled water (1 : 8, w/v) for 1 h. Talcum was boiled in distilled water for 30 min before adding the rest of the herbs for 1.5 h and then filtered. The residue was combined with six times the amount of distilled water and boiled for 1 h, followed by filtration. The two filtrates were mixed, and crude drug of concentrations 0.5, 1, and 2 g/mL was prepared.

2.2. Animal Experimental Protocol

C57BL/6J mice (weighing 18–22 g) provided by SPF Biotech (Beijing, China) were randomly allocated into six groups: control, dextran sulfate sodium (DSS), medium-dose MGQD (GM), low-dose MGQD (GL), high-dose MGQD (GH), and ferroprostatin-1 (Fer-1; a ferroptosis inhibitor) (n = 10/group). Except the control group, other five groups received 3% (w/v) DSS diluted in drinking water for 7 days to induce acute experimental UC. At the same time, the GL, GM, and GH groups orally received 5, 10, and 20 mg/kg MGQD once per day for 7 consecutive days. The MGQD dose used here was calculated based on the clinical dose of raw materials. For the Fer-1 group, every other day from the day before DSS induction, the ferroptosis inhibitor Fer-1 (HY-100579, MedChemExpress, USA) was administered intraperitoneally to mice. The control and DSS groups intragastrically received the same dosages of distilled water. On day 8, all mice were sacrificed under anesthesia using ether, and the length of the colon was measured. The detailed experimental procedure is presented in Figure 1(a).

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2.3. Histological Analysis

For hematoxylin and eosin (H&E) staining, colon samples were embedded in paraffin, fixed in 4% paraformaldehyde, and cut into 5 m thick blocks. Based on previously established standards, a blinded assessment of the colitis activity was performed using the sections stained with H&E [13–15].

2.4. Transmission Electron Microscopy

Fresh colorectal tissue samples of mice were fixed in glutaraldehyde. The samples were dehydrated using various concentrations of ethanol, followed by washing multiple times with phosphate buffer saline. The samples were dehydrated, thinly sliced, and inserted into the resin. The sections were stained with 0.5% lead citrate and 4% uranyl acetate, and images were captured using transmission electron microscopy.

2.5. Measurement of the Levels of Proinflammatory Cytokines

The levels of IFN-γ, IL-6, IL-1β, and TNF-α in colonic tissues of mice with UC were determined using respective ELISA kits as per the manufacturer’s instructions (Ruixin Biotechnology Co., Ltd., Quanzhou, China).

2.6. Immunohistochemistry

Tight junction protein concentration in colonic tissues of mice with UC was measured using immunohistochemistry. The slices were incubated with ZO-1 (1 : 100; Affinity Biosciences; AF5145), occludin (1 : 200; Proteintech; 28674-1-AP), claudin-1 (1 : 200; Proteintech; 28674-1-AP), and 4HNE (1 : 1000; Bio-Techne; MAB3249) antibodies overnight at 4°C, followed by incubation with the secondary antibody (1 : 200; Servicebio; GB23303). The images of stained samples were taken using a light microscope (Olympus BX41, Shanghai, China). The mean optical density value was used to analyze and represent staining intensity.

2.7. Western Blot Analysis

Proteins from the colon tissue samples were extracted and separated as per their molecular weights using 10% SDS-PAGE. The membrane was incubated with the primary antibodies for Nrf2 (1 : 3000, Proteintech, 16396-1-ap), GPX4 (1 : 3000, Proteintech, GB113091), FTH1 (1 : 3000, Proteintech, GB112933), ACSL4 (1 : 3000, Servicebio, GB113871), SLC7A11 (1 : 3000, Proteintech, 26864-1-ap), and GAPDH (1 : 5000, Servicebio, GB15002) overnight at 4°C. Furthermore, the membrane was incubated with HRP-labeled rabbit or mouse IgG secondary antibodies (1 : 5000, Servicebio, GB23303 and GB25301) for 2 h at room temperature. The protein signals were visualized using ECL solution (P0018, Beyotime).

2.8. Measurement of Iron Content and Levels of GSH, MDA, and ROS

After extraction of protein samples from the colonic tissues, the levels of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and iron were measured using respective kits as per the manufacturer’s instructions (Ruixin Biotechnology Co., Ltd., Quanzhou, China).

2.9. RT-qPCR Analysis

Total RNA was extracted from the colon tissue and used to synthesize cDNA using reverse transcription. RT-qPCR was performed using the CFX96 real-time PCR detection system (Bio-Rad, USA). GAPDH was used as the internal control. The relative expression levels of target genes were determined using 2^−ΔΔCT method. The primer sequences are given in Table 1.

2.10. Macromolecular Docking

Baicalin, puerarin, palmatine chloride, wogonin, and berberine chloride were identified as the main components of MGQD in our previous study via high-performance liquid chromatography system [13]. In this study, the molecular docking of the components of MGQD and Nrf2 was performed using AutoDock Vina 1.1.2. The structure of component was obtained using the PubChem database. Energy minimization of the components and conversion of their 2D structures into 3D chemical structures were performed using ChemBio3D 13.0 software. The crystal structure of the Nrf2 domain was used as the receptor model, and the 3D structure was obtained using PDB database.

2.11. Statistical Analysis

All continuous data were expressed as mean ± standard deviation. Before analysis, normality and variance homogeneity tests were performed for each set of data to be compared. For comparisons of more than two groups, one-way or two-way analysis of variance was performed, with Bonferroni’s or Dunnett’s multiple-comparisons test for normally distributed data or the Mann–Whitney test for nonnormally distributed data. Unless otherwise stated, was considered significant. Statistical analyses were performed using SPSS 26.0 and GraphPad Prism version 9 software.

3. Results

3.1. MGQD Attenuated UC in Mice

On day 4 of the experiments, weight of the mice with UC was significantly lower (Figure 1(b)) and the disease activity index (DAI) was significantly higher (Figure 1(c)), compared with mice in the control group. Similarly, the length of the colon was significantly shorter in mice with UC (Figure 1(d)). In addition, mice with DSS-induced UC exhibited mortality rate of 30%. After MGQD treatment, the mortality rate of mice with UC was reduced, particularly the survival rate of mice in the GH group significantly improved to 90% (Figure 1(e)).

Pathological results revealed that the mice in the control group had clear crypt structure and intact colonic mucosa, whereas the colonic histopathological damage was obvious in the mice with UC with extensive infiltration of inflammatory cells, crypt structure, and severe disorganization of the mucosa (Figures 1(f) and 1(g)). Surprisingly, all the aforementioned alterations in mice with UC were reversed by MGQD and Fer-1 treatment, and the most significant improvement in clinical symptoms in the mice with UC was observed at a dose of 20 g/kg MGQD (Figures 1(b)–1(g)).

3.2. MGQD Suppressed Proinflammation in Mice with UC

High levels of IFN-γ, IL-1β, IL-6, and TNF-α were observed in the colonic tissues of mice with UC compared with the control mice (Figures 2(a)–2(d)). Surprisingly, the levels of these proinflammatory cytokines were dramatically reduced in colonic tissues after MGQD and Fer-1 treatments (Figures 2(a)–2(d)).

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3.3. MGQD Enhanced the Intestinal Barrier Function of Mice with UC

UC is pathologically characterized by inflammation of the intestinal mucosa and disruption of intestinal barrier function [1]. Continued deterioration of ferroptosis will lead to disruption of intestinal barrier function, which is characterized by suppression of the expression of tight junction proteins [8, 16]. Tight junction proteins such as claudin-1, ZO-1, and occludin were therefore detected by immunohistochemistry in this study, and results suggested that the expression of claudin-1, ZO-1, and occludin was suppressed in the colonic tissues of mice with UC compared with the control mice (Figures 3(a)–3(f)). Interestingly, mice treated with MGQD exhibited an increased expression of claudin-1, ZO-1, and occludin in a dose-dependent manner (Figures 3(a)–3(f)). Furthermore, the expressions of these proteins were comparable in the Fer-1 and GH groups (Figures 3(a)–3(f)).

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3.4. MGQD Inhibited Ferroptosis in Mice with UC

Transmission electron microscopic results revealed that the colonic tissues of mice with UC exhibited reduced mitochondrial size, membrane density, and cristae and apparent rupture of the outer membranes compared with the control. Interestingly, the mitochondria in the MGQD and Fer-1 groups were relatively normal, and the cristae were clear (Figure 4).

Furthermore, elevated levels of Fe²⁺, ROS, and MDA and decreased levels of GSH and Fe³⁺ were observed in mice with UC (Figures 5(a)–5(e)). Interestingly, these abnormal results were considerably reversed by MGQD and Fer-1 treatments (Figures 5(a)–5(e)). In addition, 4HNE expression was higher in colonic tissues of mice with UC but was inhibited by MGQD and Fer-1 treatments (Figure 6).

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Western blot analysis (Figure 7) revealed that SCL7A11 and FTH1 were downregulated, whereas ACSL4 was upregulated in the colonic tissues of mice with UC compared with the control group. However, after MGQD treatment, all these changes were reversed. Notably, ferroptosis was inhibited to the highest level when the dose of MGQD was 20 mg/kg.

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3.5. MGQD Activated the Nrf2/GPX4 Pathway in the Colonic Tissues of Mice with UC

Western blot and RT-qPCR analyses revealed that protein and mRNA levels of Nrf2 and GPX4 were significantly reduced in the colonic tissues of mice with UC compared with the control group (Figure 8). Interestingly, mice with UC who received MGQD exhibited a dose-dependent increase in Nrf2 and GPX4 expression levels (Figure 8). Furthermore, the levels of genes located downstream of Nrf2, namely, SCL7A11 and FTH1, were notably increased after MGQD treatment.

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3.6. Molecular Docking of MGQD and Nrf2

In molecular docking, the lower the energy needed for the ligand to bind to the receptor to form a conformation, the more stable the structure was. Our results (Table 2 and Figure 9) revealed that the binding energies of MGQD and Nrf2 were less than −5 kcal/mol, and at least one hydrogen bond was formed between them. This indicated that the main components of MGQD could stably bind to Nrf2, and MGQD may affect UC through the Nrf2 pathway.

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4. Discussion

Traditional Chinese herbal medicines have been popular in these years for many diseases [17, 18]. As complementary and alternative therapies, traditional Chinese herbal medicines are considered promising adjuvant treatment options for colitis [19]. GQD is a well-known Chinese herbal formula beneficial for UC [12]. GQD has been reported to alleviate UC by modulating immune responses, inhibiting oxidative stress, promoting intestinal mucosal barrier repair, and regulating gut microbes [20–22]. As a modified herbal compound of GQD, MGQD has likewise been found to alleviate UC by modulating immunity, inhibiting oxidative stress, and regulating gut microbes [13–15]. Accumulating evidence suggested that epithelial cell injury is associated with ferroptosis in UC, and targeted inhibition of ferroptosis can help to promote repair of the intestinal mucosal barrier [22, 23]. Therefore, we aimed to explore whether MGQD can ameliorate UC via targeting the inhibition of ferroptosis through the establishment of an experimental mouse model with UC.

After 7 days of UC induction using DSS, mice in the DSS group developed characteristic symptoms of colitis, including blood in the stool, loose stools, weight loss, and shortening of the colon. In addition, pathological findings revealed an inflammatory infiltrate and mucosal damage in the colonic tissues of mice with UC, which corresponded to an increase in a large number of inflammatory cytokines and suppression of tight junction proteins. These results demonstrated that an experimental mouse model of UC had been successfully established. More importantly, the core characteristics of ferroptosis, such as lipid peroxidation accumulation, iron deposition, reduction in GPX4 activity and GSH level, and morphological changes in the mitochondria, were observed in the intestine of mice with UC. When the mice with UC were administered with Fer-1, a ferroptosis inhibitor, these core characteristics of ferroptosis were reversed and were accompanied by improvements in colitis symptoms, such as blood in stool, loose stools, weight loss, shortened colon, and inflammatory infiltration. The intestinal barrier breaks down as a result of intestinal epithelial cell death [24]. Interestingly, the levels of tight junction proteins were significantly restored after protecting the intestinal epithelium of mice with UC by inhibiting ferroptosis. These findings suggested that ferroptosis is associated with intestinal mucosal barrier breakdown in UC, and targeted inhibition of ferroptosis can help in alleviating colitis.

In this study, mice with UC treated with MGQD exhibited increased body weight, longer colon length, decreased DAI score, and improved pathology score, which is consistent with our previous findings [13–15]. More importantly, similar to Fer-1, the core characteristics of ferroptosis exhibited by mice with UC, such as lipid peroxide accumulation, iron deposition, reduced GSH levels, and mitochondrial morphological changes, were significantly reversed after treatment with MGQD. This suggested that MGQD inhibits ferroptosis in mice with UC. In addition, MGQD helped to promote the repair of the colonic mucosal barrier as the levels of tight junction proteins in the colonic tissues of mice with UC were restored after MGQD treatment.

Ferroptosis is characterized by iron overload and lipid accumulation [25]. The Nrf2 pathway is well known for its role in antioxidant defense [26, 27]. Notably, GPX4 is an established Nrf2 transcriptional target [28]. Therefore, activation of the Nrf2/GPX4 pathway is considered critical for the inhibition of ferroptosis [10, 11]. In this study, the Nrf2/GPX4 pathway was significantly inhibited in mice with UC, and the expression of the downstream genes of Nrf2, including SCL7A11 and FTH1, was inhibited. When the Nrf2/GPX4 pathway is inhibited, indicators of lipid peroxidation including ACSL4 and 4HNE are significantly activated. Surprisingly, the Nrf2/GPX4 pathway and its downstream genes were activated in the colonic tissues of mice with UC after treatment with MGQD. In addition, the levels of ACSL4 and 4HNE, which are generally used as biomarkers of ferroptosis, were decreased in mice treated with MGQD. Additionally, the results of molecular docking revealed that Nrf2 could be stably bound to the components of MGQD. These findings suggested that MGQD inhibits ferroptosis via the Nrf2/GPX4 pathway to alleviate UC (Figure 10).

Limitations should be acknowledged. First, molecular docking was carried out based on the results of animal experiments, and the results obtained by the molecular docking method were not validated by in vitro experiments, and further exploration of the effects of the components of MGQD on the Nrf2 pathway on the basis of the UC model is still necessary in the future. Second, ferroptosis belongs to one of the forms of programmed cell death, and further studies to explore whether MGQD can regulate other forms of programmed cell death to alleviate UC are also necessary in the future.

5. Conclusion

In conclusion, our study demonstrated that ferroptosis is involved in DSS-induced UC in mice, and MGQD may exert anticolitis effect by inhibiting ferroptosis through the activation of the Nrf2/GPX4 pathway. These findings provided novel insights into the application of MGQD to ameliorate UC.

Abbreviations

UC:	Ulcerative colitis
GQD:	Gegen Qinlian decoction
MGQD:	Modified Gegen Qinlian decoction
DSS:	Dextran sulfate sodium
GM:	Medium-dose MGQD
GL:	Low-dose MGQD
GH:	High-dose MGQD
Fer-1:	Ferroprostatin-1
MDA:	Malondialdehyde
GSH:	Glutathione
ROS:	Reactive oxygen species
H&E:	Hematoxylin and eosin
DAI:	Disease activity index
MOD:	Mean optical density.

Data Availability

The datasets generated for this study are available upon request to the corresponding author.

Ethical Approval

This work was approved by the Animal Ethics Committee of Xiyuan Hospital of China Academy of Chinese Medical Sciences (Approval No. 2019XLC003-2).

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Authors’ Contributions

Jinke Huang designed the research, analyzed the data, and wrote the paper. Jinke Huang, Zhihong Liu, Jiaqi Zhang, Jing Ma, and Fengyun Wang performed the experiments. Xudong Tang contributed to review and editing.

Acknowledgments

We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript. This work was supported by the National Natural Science Foundation of China (Nos. 82341233 and 81830118), China Academy of Chinese Medical Sciences Innovation Fund (No. CI2021A01012), China Academy of Chinese Medical Sciences Excellent Young Talent Cultivation Fund (No. ZZ15-YQ-002), and Administration of Traditional Chinese Medicine Digestive Refractory Disease Inheritance and Innovation Team Project (No. ZYYCXTD-C-202010).

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Copyright © 2024 Jinke Huang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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