Abstract
Ulcerative colitis (UC) is a chronic disease characterized by mucosal and submucosal inflammation, which has a low cure rate and is prone to relapse, due to the immune imbalance of the body. Inhibition of inflammation‐related pathways can delay the progression of UC. Toll‐like receptor 4 (TLR4) pathway is considered to be one of the important signaling pathways involved in colon inflammation. Eriodictyol (EDT) is a natural flavonoid widely distributed in foodborne plants. EDT plays an important role in the regulation of inflammation and related signaling pathways. However, whether EDT plays a role in UC remains unknown. Herein, we established a TNBS induced animal model of enteritis in Wistar rats. Our data confirmed the establishment of TNBS induced animal model of enteritis and the administration Eriodictyol in Wistar rats. EDT treatment alleviated TNBS‐induced intestinal tissue injury in rats. We further found that EDT reduced MPO expression and regulated the cytokine parameters in TNBS‐induced intestinal tissues of rats. The levels of TNF‐α, IL‐1β, IL‐6, IL‐10, IL‐2, and IL‐12 were also affected by the treatment of EDT. EDT also affected SOD, CAT, GSH‐Px, and MDA level in rats with colitis. Moreover, EDT regulated TNBS‐induced TLR4/NF‐κB pathway activation, therefore inhibiting the progression of UC. Our results suggest that EDT could be a potential therapeutic agent for UC.
Keywords: eriodictyol, NF‐κB, TNBS, toll‐like receptor 4, ulcerative colitis
1. INTRODUCTION
Ulcerative colitis (UC) is a chronic disease characterized by mucosal and submucosal inflammation, confined to the colon, and accompanied by crypts and crypts abscesses. 1 UC has a low cure rate and is prone to relapse, which is caused by the immune imbalance of the body and is closely related to the incidence of colon cancer. 2 Amino salicylic acid preparations and glucocorticoids are often used in the first‐line treatment of UC, but the effect remains to be improved. 3 , 4 Previous study indicates that the dysregulation of the intrinsic and adaptive immune responses of the intestinal mucosa driven by symbiotic bacteria in the host with genetic susceptibility plays a key role in the pathogenesis of UC. 5 Under chronic inflammatory conditions, a decrease in the synthesis and secretion of pro‐inflammatory mediators is beneficial. 6 Notably, inhibition of inflammation‐related pathways can delay the progression of UC.
Toll‐like receptor 4 (TLR4) pathway is considered to be one of the important signaling pathways involved in colon inflammation. 7 TLR4 is a key receptor for intestinal innate immune synesthesia and is consistently overexpressed in IBD. 7 , 8 During inflammation, TLR4, as one of the innate immune receptors, is activated by recognition of PAMPs in the gut, conformation changes and dimerization, and then is recruited to the aptamer, leading to NF‐κB activation. 9 Activated NF‐κB leads to the production of a variety of pro‐inflammatory and inflammatory mediators, including ICAM‐1, McP‐1, COX‐2, TNF‐α, and IL‐1, which are essential for the inflammatory response. 10 A large number of studies have also demonstrated that colitis is associated with excessive activation of the TLR4/NF‐κB signaling pathway. 11
Eriodictyol (EDT, IUPAC name (2S)‐2‐(3,4‐dihydroxyphenyl)‐5,7‐dihydroxy‐2,3‐dihydrochromen‐4‐one) is a natural flavonoid widely distributed in foodborne plants. 12 It has been reported that EDT can protect endothelial cells from oxidative stress‐induced cell death by regulating ERK/Nrf2/ dependent heme oxygenase‐1 expression. 13 It also alleviates LPS‐induced acute lung injury through antioxidant and anti‐inflammatory activity 14 ; Studies have also suggested that EDT alleviates cisplatin‐induced kidney injury by inhibiting oxidative stress and inflammation. 15 EDT inhibited the TLR4 and NF‐κB pathways in mouse BV2 microglia, and alleviated lPS‐induced neuroinflammation. 16 However, whether EDT plays a role in UC remains unknown.
In this study, we established an animal model of enteritis in Wistar rats and found that EDT alleviated TNBS‐induced intestinal tissue injury in rats. EDT reduced MPO expression and inflammatory response in TNBS‐induced intestinal tissues of rats, and further regulated the activation of TLR4/NF‐κB pathway induced by TNBS. Our results suggest that EDT could be a potential therapeutic agent for UC.
2. MATERIALS AND METHODS
2.1. TNBS‐induced colitis in rats and EDT administration
For TNBS‐induced colitis, male Wistar rats were fasting for 24 h with free access to water, and then were anesthetized with ether (SLAC Animal Laboratories, Shanghai, China). Then, TNBS (100 mg/kg dissolved in 0.25 ml 50% ethanol) and equal volume of 50% ethanol saline solution were slowly given with flexible catheter into the colons of rats in different groups.
Rats obtained from SLAC (Shanghai, China) were randomly divided into five groups (six rats in each group): (1) Control, (2) TNBS, (3) TNBS+ EDT 5 mg/kg, (4) TNBS+EDT 20 mg/kg, and (5) TNBS+ EDT 50 mg/kg. Eriodictyol dissolved in 5% Tween 80, 20% polyethylene glycol and 75% saline was orally administered to the animals by intragastric intubation. All experiments in this study were conducted in accordance with the guidelines of the Medical Ethics Committee of The Second Affiliated Hospital of Harbin Medical University (Approval no.sydw2020‐005).
The EDT were administered from day 1 to 7 in TNBS‐induced bowel disease. Rat weight were monitored each day. At the end of the week, rats were executed, colons were collected, photographed and subjected to HE staining.
2.2. HE staining
The colon tissue slices were deparaffinized with xylene and rehydrated through a graded alcohol series. After the slices were washed and dried, they were incubated with hematoxylin for 4 min, and then a 1% HCl alcohol solution was added for 10 s before rinsing with water. Slices were washed for 25 min and then incubated with 0.5% eosin Y, and cleared in xylenes before mounting.
2.3. Assessment of histological score and macroscopic scores
The colons were fixed, dehydrated, embedded in paraffin, sliced into 4 μm sections, and stained with hematoxylin and eosin (HE). Colonic sections were examined by histopathologists, who were blinded to the treatment, and the results were used for evidence of inflammation. Histological damage was quantified as combination score of inflammatory cell infiltration (score 0–3) and mucosal damage (score 0–3) following a previously described method (need reference). Severity of inflammation was graded as described below.
Briefly, for the score of inflammatory cell infiltration: 0 was considered as rare inflammatory cells in the lamina propria; 1 was considered as increased inflammatory cells; 2 was assessed as inflammatory cells stretching into the submucosa; and a score of 3 was given for transmural extension of the inflammatory cell infiltration. For epithelial damage, 0 was considered as absence of mucosal damage; 1 was considered as scattered focal lymphoepithelial lesions; 2 was assessed as mucosal erosion/ulceration; and 3 was scored for extensive mucosal damage and extension through deeper structures of the bowel wall. The score of inflammatory cell infiltration and mucosal damage were added from 0 (no changes) to 6 (extensive cell infiltration and tissue damage).
2.4. Immunohistochemistry for MPO level
The colon tissue slices were blocked with goat serum for 1 h at room temperature and then incubated with antibodies against MPO (ab9535, Abcam, Cambridge, UK). After washing for 3 times, the slides were incubated with HRP conjugated secondary antibodies at 37 °C for 1 h. Finally, immune complexes were visualized by incubating with diaminobenzidine for 10 min and counterstained with hematoxylin.
2.5. Enzyme‐linkedimmunosorbentassay
Supernatants from rats serum were analyzed by ELISA for TNF‐α, IL‐1β, IL‐6, IL‐10, IL‐2, and IL‐12, according to manufacturer's instructions (Dakewei, Beijing, China). Briefly, Standards and samples were pipetted into the wells. After removing unbound solutions, biotin‐conjugated specific antibodies were added to the wells. After washing, avidin conjugated Horseradish Peroxidase (HRP) is added to the wells. Following a wash to remove any unbound avidin‐enzyme reagent, substrate solution was added to the wells and color develops. The color development was stopped, and the intensity of the color is measured.
2.6. Assessment of antioxidant activity
The levels of SOD, CAT, GSH‐Px, and the concentration of MDA in rats were assessed by the detection kits of Nanjing Jiancheng Bio‐engineering Institute (Jiangsu, China) in accordance with the manufacturer's instructions.
2.7. Western blotting assay
The total proteins were collected with RIPA lysis buffer and separated by SDS‐PAGE. After transferred onto PVDF membrane, membranes were blocked and subsequently incubated using the specific antibodies against β‐actin (ab8226, Abcam), TLR4 (ab22048), p‐IkBa (ab133462), IkBa (ab32518), p‐p65 (ab194726), and p65 antibody (ab16502) purchased from Abcam (Cambridge, UK). Then the membranes were subjected to HRP‐conjugated secondary antibodies for 1 h. After washing, signals were visualized by an ECL kit.
2.8. Statistical analysis
Data are displayed as mean ± SD. The data was analyzed by GraphPad Prism (ver.5.04). A two‐tailed Student t‐test for unpaired examinations or a one‐way ANOVA for multiple comparisons were performed for statistical analyses. p value <0.05 was considered statistically significant.
3. RESULTS
3.1. Eriodictyol treatment alleviates TNBS‐induced colitis in rats
TNBS‐induced bowel disease model was established to evaluate the therapeutic effect of EDT. The molecular structure of EDT was shown in Figure 1A. Rectal administration of TNBS induced severe weight loss in rats. As shown in Figure 1B, TNBS treatment dramatically decreased rat weight and EDT treatment alleviated this effect in a dose and time‐dependent manner. For the first 4 days, the difference was small, but the body weight was significantly changed in different groups over time. Histological analysis showed that the colon tissues of TNBS‐induced rats presented marked crypt destruction, mucosal ulceration, and significant inflammatory cell infiltration. The histological lesions in EDT treated rats were weakened as indicated by HE staininng of colon tissues (Figure 1C,D). EDT significantly reduced histological score as measured by combination score of inflammatory cell infiltration and mucosal damage in TNBS‐induced bowel disease (Figure 1D). Thus, we assumed that EDT could alleviate TNBS‐induced bowel disease in rats.
FIGURE 1.
EDT adminstration alleviates TNBS‐induced colitis in rats. A, The chemical formula of EDT. B, Rat weight change in TNBS and TNBS with EDT assumption group. C, D, The histological changes and the scores of colons in control, TNBS, TNBS+EDT 5 mg/kg, TNBS+EDT 20 mg/kg, TNBS+EDT 50 mg/kg groups. Data were presented as means ± SD (n = 6 in each group). TNBS versus control group, *p < 0.05, **p < 0.01. TNBS+EDT (5, 20, and 50 mg/kg) versus TNBS group, ## p < 0.01
3.2. Eriodictyol reduces MPO level induced by TNBS in colons
The degree of inflammatory cell infiltration can be assessed by detecting MPO level. Colonic MPO activity was linearly correlated with neutrophil infiltration in inflamed colons. 17 TNBS‐induced model exhibited increased MPO level in the colonic tissues compared to control as assessed by commercial kits. And EDT treatment significantly decreased MPO level in rats with TNBS‐induced colitis, as detected by Immunnohistochemistry (Figure 2). These results verified that EDT attenuated TNBS‐induced high MPO level in colons.
FIGURE 2.
EDT reduces MPO level induced by TNBS in colons. MPO expression level in control, TNBS, TNBS+EDT 5 mg/kg, TNBS+EDT 20 mg/kg, TNBS+EDT 50 mg/kg groups were assessed by IHC and MPO positive cell number was analyzed. Three independent experiments were performed. Data were presented as means ± SD TNBS versus control group, **p < 0.01. TNBS+EDT (5, 20, and 50 mg/kg) versus TNBS group, ## p < 0.01
3.3. Eriodictyol regulates the cytokine parameters in the colons of rats with TNBS‐induced colitis
IL‐6, IL‐1β, and TNF‐α secreted by macrophages are key pro‐inflammatory cytokines responsible for the inflammation of colonic mucosa and destruction of mucosal barrier. 18 As shown in Figure 3, TNBS could significantly elevate the production of IL‐6, IL‐1β, IL‐12, IL‐2, and TNF‐α, and decrease the secretion of IL‐10. However, EDT supplementation dramatically reduced TNF‐α, IL‐6, IL‐1β, IL‐2, and IL‐12 level in rat with TNBS stimulation. In addition, IL‐10 level was inhibited by TNBS induction in rats, while EDT treatment significantly enhanced IL‐10 level in TNBS induced rats (Figure 3). Taken together, EDT decreased IL‐6, IL‐1β, TNF‐α, IL‐2, and IL‐12 levels and elevated IL‐10 level in colons of rats with TNBS‐induced colitis.
FIGURE 3.
EDT regulates the cytokine parameters in rat's colons with TNBS‐induced colitis. IL‐6, IL‐1β, TNF‐α, IL‐2, IL‐10, and IL‐12 level in control, TNBS, TNBS+EDT 5 mg/kg, TNBS+EDT 20 mg/kg, and TNBS+EDT 50 mg/kg groups was detected by ELISA assay. Three independent experiments were performed. Data were presented as means ± SD TNBS versus control group, **p < 0.01. TNBS+EDT (5, 20, and 50 mg/kg) versus TNBS group, ## p < 0.01
3.4. Eriodictyol affects SOD, CAT, GSH‐Px, and MDA level in rats with colitis
To examine the antioxidant effect of EDT, the level of SOD, CAT, GSH‐Px, and MDA were detected in five groups. Compared with Control group, SOD, CAT, and GSH‐Px in TNBS‐induced group were significantly decreased, whereas MDA was markedly enhanced in the TNBS group (Figure 4). EDT treatment dramatically restored antioxidant capacity, as exhibited by the increase in SOD, CAT, and GSH‐Px levels and decrease in MDA content (Figure 4). These data suggested EDT treatment exerted an antioxidant effect in rats with TNBS induction.
FIGURE 4.
EDT affects SOD, CAT, GSH‐Px, and MDA level in rats with colitis. SOD, CAT, GSH‐Px, and MDA level in rats in control, TNBS, TNBS+EDT 5 mg/kg, TNBS+EDT 20 mg/kg, TNBS+EDT 50 mg/kg groups were detected with respective ELISA kit. Three independent experiments were performed. Data were presented as means ± SD TNBS versus control group, **p < 0.01. TNBS+EDT (5, 20, and 50 mg/kg) versus TNBS group, ## p < 0.01
3.5. Eriodictyol regulates TNBS‐induced TLR4/NF‐κB siganaling pathway
TLR4/NF‐κB signaling pathway is activated during the occurrence and development of colitis. We sought to evaluate the potential effect of EDT on TLR4/NF‐κB signaling pathway. As previously reported, TNBS effectively activated TLR4/NF‐κB signaling pathway as illustrated by increased TLR4, p‐IκBa, and p‐p65 and reduced IκBa. However, EDT challenge significantly reduced the phosphorylated level of p65 and IκBα and increased IκBα level in the colon of TNBS‐colitis rats in a dose‐dependent manner (Figure 5).
FIGURE 5.
EDT regulates TNBS induced TLR4/NF‐κB siganaling pathway. Immunoblot assay was performed and the protein levels of TLR4, IκBa, p‐IκBa, p65, and p‐p65 in control, TNBS, TNBS+EDT 5 mg/kg, TNBS+EDT 20 mg/kg, and TNBS+EDT 50 mg/kg groups were detected. Three independent experiments were performed. Data were presented as means ± SD TNBS versus control group, **p < 0.01. TNBS+EDT (5, 20, and 50 mg/kg) versus TNBS group, ## p < 0.01
4. DISCUSSION
Ulcerative colitis tends to be malignant and often poses a serious threat to patients. 19 The incidence rate is highest in Europe and North America, and has been rising year by year in Asia and other places in recent years. The exact etiology and pathogenesis of UC are still unclear, and the possible pathogenic factors include environmental microorganisms, immunity and genetic factors. 20 Since UC is prone to relapse, the existing therapeutic drugs for UC are difficult to meet clinical needs, and more effective therapeutic drugs for UC are still needed to be developed. 21 In this study, we developed a TNBS‐induced colitis rat model, and found that EDT could obviously attenuated TNBS‐induced colitis. We therefore thought that EDT could serve as a promising therapeutic drug for the treatment of UC.
Eriodictyol is widely distributed in fruits and vegetables. 22 It has multiple physiological functions, such as antioxidant, neuroprotection, anti‐inflammatory, analgesic, and improving diabetes and diabetic complications. 22 It has been found that EDT can effectively protect keratinocytes from UV induced death by inhibiting the cleavage of pro‐caspase‐3 or pro‐caspase‐9 and the release of cytochrome c. 23 Additionally, EDT can suppress Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis. 24 In view of its important physiological role in inflammation, we speculate that it has a unique effect in combating UC. Our experimental results also confirmed the significant effect of EDT on the symptoms of UC rats.
In this study, we also noticed that EDT attenuated rat colitis through repressing TLR4/NF‐kB signaling pathway. This signaling pathway plays an important role in inflammation related diseases. 11 For an example, Bupropion ameliorated acetic acid‐induced colitis through TLR4/NF‐kB pathway. 7 In addition, Maresin 1 alleviated dextran sulfate sodium‐induced UC via TLR4/NF‐kB pathway. 8 Similarly, we found that EDT improved UC by targeting this pathway, further confirming that TLR4/NF‐kB axis was important in the progression and pathogenesis of inflammation related diseases, such as UC. However, the precise effects of EDT on UC in vitro and in vivo and the potential regulatory mechanisms still need further study.
Notably, in inflammation, EDT also improves the symptoms of related diseases through a variety of different regulatory ways. 25 EDT has been reported to protect retinal ganglion cells (RGCs) from high glucose‐induced oxidative stress via the activation of Nrf2/HO‐1 pathway. 26 Another study indicated that EDT mitigated atopic dermatitis through the inhibition of IL‐4 and the upregulation of serum immunoglobulin E. 27 Also, EDT activated the sirtuin 1 (Sirt1) pathway which suppressed the downstream translocation of NF‐κB signaling, which was similar with our study. 28 In addition to these studies, EDT also affected multiple signaling pathways. For example, it moderated the inflammation of macrophages via phosphorylation of p38 MAPK, ERK1/2, and c‐Jun N‐terminal kinase (JNK). 25 , 29 Next, we plan to investigate the effects of EDT on other pathways in the TNBS‐induced colitis model.
IKK activation can inhibit a variety of downstream effectors, such as McP‐1, MMP‐2,CTGF, etc., which can further lead to a variety of biological effects. 30 For example, in the process of liver fibrosis, the activation of IKK‐beta regulates the process of liver fibrosis through this pathway. 31 Our study found that IKK inhibited the function of downstream effectors in a similar way in TNBS.
EDT downregulates the levels of inflammatory cytokines, such as IL‐1, IL‐6, IL‐8, and TNF‐induced by LPS in human monocyte leukemia cell line THP‐1 cells. In LPS‐induced acute lung injury in mice, EDT plays an anti‐inflammatory role by activating the Nrf2/HO‐1 pathway. 32 Similarly, in mouse kidney injury model, EDT can further play an anti‐inflammatory role by activating Nrf2 and inhibiting NF‐κB activation. 28 These studies, together with our findings, confirmed that EDT had critical effects on inflammatory via targeting Nrf‐2.
In summary, we established a TNBS‐induced colitis model and revealed the effects of EDT on UC progression. Our data confirmed that EDT alleviated intestinal tissue injury in rat model and suppressed MPO expression and inflammatory response in rat intestinal tissues. We further found that EDT regulated the activation of TNBS‐induced TLR4/NF‐κB pathway, thus inhibiting the progression of UC. Therefore, EDT can be used as a promising drug for the treatment of UC.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Hu L‐H, Liu J‐Y, Yin J‐B. Eriodictyol attenuates TNBS‐induced ulcerative colitis through repressing TLR4/NF‐kB signaling pathway in rats. Kaohsiung J Med Sci. 2021;37:812–818. 10.1002/kjm2.12400
Funding information Basic scientific research operating expenses of Heilongjiang Provincial Institutions of higher learning in 2018, Grant/Award Number: 2018‐KYYWF‐0500; Scientific Research Project of Heilongjiang Provincial Health and Family Planning Commission in 2018, Grant/Award Number: 2018194
REFERENCES
- 1. Jentzer A, Veyrard P, Roblin X, Saint‐Sardos P, Rochereau N, Paul S, et al. Cytomegalovirus and inflammatory bowel diseases (IBD) with a special focus on the link with ulcerative colitis (UC). Microorganisms. 2020;8:1078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Nascimento RPD, Machado A, Galvez J, Cazarin CBB, Marostica Junior MR. Ulcerative colitis: gut microbiota, immunopathogenesis and application of natural products in animal models. Life Sci. 2020;258:118129. [DOI] [PubMed] [Google Scholar]
- 3. Yang X, Geng J, Meng H. Glucocorticoid receptor modulates dendritic cell function in ulcerative colitis. Histol Histopathol. 2020;35:1379–89. [DOI] [PubMed] [Google Scholar]
- 4. Tan M, Ye J, Zhou Z, Ke X, Yu X, Huang K. Fatty acid metabolism in immune cells: a bioinformatics analysis of genes involved in ulcerative colitis. DNA Cell Biol. 2020;39:1573–82. [DOI] [PubMed] [Google Scholar]
- 5. Dal Buono A, Roda G, Argollo M, Paridaens K, PeyrinBiroulet L, Danese S. Treat to target in mild to moderate ulcerative colitis: evidence to support this strategy. Curr Drug Targets. 2021;22:117–25. [DOI] [PubMed] [Google Scholar]
- 6. Barberio B, Zingone F, D'Inca R, Rovigo L, Bertani L, Bodini G, et al. Infliximab originator, infliximab biosimilar, and adalimumab are more effective in Crohn's disease than ulcerative colitis: a real‐life cohort study. Clin Transl Gastroenterol. 2020;11:e00177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Rashidian A, Dejban P, Karami Fard K, Abdollahi A, Chamanara M, Dehpour A, et al. Bupropion ameliorates acetic acid‐induced colitis in rat: the involvement of the TLR4/NF‐kB signaling pathway. Inflammation. 2020;43:1999–2009. [DOI] [PubMed] [Google Scholar]
- 8. Qiu S, Li P, Zhao H, Li X. Maresin 1 alleviates dextran sulfate sodium‐induced ulcerative colitis by regulating NRF2 and TLR4/NF‐kB signaling pathway. Int Immunopharmacol. 2020;78:106018. [DOI] [PubMed] [Google Scholar]
- 9. Liu H, Xiong J, He T, Xiao T, Li Y, Yu Y, et al. High uric acid‐induced epithelial‐mesenchymal transition of renal tubular epithelial cells via the TLR4/NF‐kB signaling pathway. Am J Nephrol. 2017;46:333–42. [DOI] [PubMed] [Google Scholar]
- 10. Chen Z, Dong WH, Wu Q, Wang J. Two‐layer regulation of TRAF6 mediated by both TLR4/NF‐kB signaling and miR‐589‐5p increases proinflammatory cytokines in the pathology of severe acute pancreatitis. Am J Transl Res. 2020;12:2379–95. [PMC free article] [PubMed] [Google Scholar]
- 11. Rashidian A, Muhammadnejad A, Dehpour AR, Mehr SE, Akhavan MM, Shirkoohi R, et al. Atorvastatin attenuates TNBS‐induced rat colitis: the involvement of the TLR4/NF‐kB signaling pathway. Inflammopharmacology. 2016;24:109–18. [DOI] [PubMed] [Google Scholar]
- 12. Islam A, Islam MS, Rahman MK, Uddin MN, Akanda MR. The pharmacological and biological roles of eriodictyol. Arch Pharm Res. 2020;43:582–92. [DOI] [PubMed] [Google Scholar]
- 13. Xie G, Meng X, Wang F, Bao Y, Huo J. Eriodictyol attenuates arsenic trioxide‐induced liver injury by activation of Nrf2. Oncotarget. 2017;8:68668–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. He P, Yan S, Zheng J, Gao Y, Zhang S, Liu Z, et al. Eriodictyol attenuates LPS‐induced neuroinflammation, amyloidogenesis, and cognitive impairments via the inhibition of NF‐kappaB in male C57BL/6J mice and BV2 microglial cells. J Agric Food Chem. 2018;66:10205–14. [DOI] [PubMed] [Google Scholar]
- 15. Hu Q, Zhang DD, Wang L, Lou H, Ren D. Eriodictyol‐7‐O‐glucoside, a novel Nrf2 activator, confers protection against cisplatin‐induced toxicity. Food Chem Toxicol. 2012;50:1927–32. [DOI] [PubMed] [Google Scholar]
- 16. Bai J, Wang Y, Zhu X, Shi J. Eriodictyol inhibits high glucose‐induced extracellular matrix accumulation, oxidative stress, and inflammation in human glomerular mesangial cells. Phytother Res. 2019;33:2775–82. [DOI] [PubMed] [Google Scholar]
- 17. Jayaraj P, Narasimhulu CA, Maiseyeu A, Durairaj R, Rao S, Rajagopalan S, et al. Methoxyphenol derivatives as reversible inhibitors of myeloperoxidase as potential antiatherosclerotic agents. Future Med Chem. 2020;12:95–110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Zhu XM, Shi YZ, Cheng M, Wang DF, Fan JF. Serum IL‐6, IL‐23 profile and Treg/Th17 peripheral cell populations in pediatric patients with inflammatory bowel disease. Pharmazie. 2017;72:283–7. [DOI] [PubMed] [Google Scholar]
- 19. Hu LH, Fan YJ, Li Q, Guan JM, Qu B, Pei FH, et al. Bortezomib protects against dextran sulfate sodiuminduced ulcerative colitis in mice. Mol Med Rep. 2017;15:4093–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Clement E, Dang J, Laffin M, Wang H. Incidence of venous thromboembolism following Proctectomy is greater in ulcerative colitis than in malignancy or Crohn's disease. J Gastrointest Surg. 2020;24:2664–6. [DOI] [PubMed] [Google Scholar]
- 21. Modesto I. Inhibitors of the Janus kinases: a new oral treatment option for ulcerative colitis. J Clin Gastroenterol. 2020;54:911. [DOI] [PubMed] [Google Scholar]
- 22. Kwon EY, Choi MS. Dietary eriodictyol alleviates adiposity, hepatic steatosis, insulin resistance, and inflammation in diet‐induced obese mice. Int J Mol Sci. 2019;20:1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Rajan VK, Ahamed TKS, Muraleedharan K. Data on the UV filtering and radical scavenging capacity of the bitter masking flavanone Eriodictyol. Data Brief. 2018;20:981–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Yang T, Li X, Yu J, Deng X, Shen PX, Jiang YB, et al. Eriodictyol suppresses Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis. Food Funct. 2020;11:6875–88. [DOI] [PubMed] [Google Scholar]
- 25. Lei Z, Ouyang L, Gong Y, Wang Z, Yu B. Effect of eriodictyol on collagen‐induced arthritis in rats by Akt/HIF‐1alpha pathway. Drug Des Devel Ther. 2020;14:1633–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Lee SE, Yang H, Son GW, Park HR, Park CS, Jin YH, et al. Eriodictyol protects endothelial cells against oxidative stress‐induced cell death through modulating ERK/Nrf2/ARE‐dependent heme oxygenase‐1 expression. Int J Mol Sci. 2015;16:14526–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Lou H, Jing X, Ren D, Wei X, Zhang X. Eriodictyol protects against H(2)O(2)‐induced neuron‐like PC12 cell death through activation of Nrf2/ARE signaling pathway. Neurochem Int. 2012;61:251–7. [DOI] [PubMed] [Google Scholar]
- 28. Li CZ, Jin HH, Sun HX, Zhang ZZ, Zheng JX, Li SH, et al. Eriodictyol attenuates cisplatin‐induced kidney injury by inhibiting oxidative stress and inflammation. Eur J Pharmacol. 2016;772:124–30. [DOI] [PubMed] [Google Scholar]
- 29. Li H, Li C, Shen T, Zhao L, Ren D. R‐eriodictyol and S‐eriodictyol exhibited comparable effect against H2O2‐induced oxidative stress in EA.hy926 cells. Drug Discov Ther. 2014;8:218–24. [DOI] [PubMed] [Google Scholar]
- 30. Patil KR, Mohapatra P, Patel HM, Goyal SN, Ojha S, Kundu CN, et al. Pentacyclic triterpenoids inhibit IKKbeta mediated activation of NF‐kappaB pathway: in silico and in vitro evidences. PLoS One. 2015;10:e0125709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Sunami Y, Leithauser F, Gul S, Fiedler K, Guldiken N, Espenlaub S, et al. Hepatic activation of IKK/NFkappaB signaling induces liver fibrosis via macrophage‐mediated chronic inflammation. Hepatology. 2012;56:1117–28. [DOI] [PubMed] [Google Scholar]
- 32. Zhu GF, Guo HJ, Huang Y, Wu CT, Zhang XF. Eriodictyol, a plant flavonoid, attenuates LPS‐induced acute lung injury through its antioxidative and anti‐inflammatory activity. Exp Ther Med. 2015;10:2259–66. [DOI] [PMC free article] [PubMed] [Google Scholar]