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Zhang Y, Jin X, Xia H, Wu X, Chen W, Zhuang M, Tang S. β-Sitosterol Ameliorates Ulcerative Colitis Through Modulation of the AMPK/MLCK Anti-Inflammatory Pathway. J Biochem Mol Toxicol 2025; 39:e70287. [PMID: 40400313 DOI: 10.1002/jbt.70287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 03/21/2025] [Accepted: 04/25/2025] [Indexed: 05/23/2025]
Abstract
Ulcerative colitis (UC), a common inflammatory bowel disease, has become increasingly prevalent worldwide, posing significant health challenges. This study explored the anti-inflammatory effects of β-sitosterol on UC and its underlying molecular mechanisms. Using a dextran sulfate sodium (DSS)-induced colitis model in male C57BL/6 mice, the therapeutic potential of β-sitosterol at low (2 mg/kg) and high (6 mg/kg) doses was compared with sulfasalazine (300 mg/kg) as a positive control. Disease progression was assessed through Disease Activity Index (DAI) scores, histological analysis, and inflammatory marker expression. β-sitosterol significantly ameliorated colonic inflammation, demonstrated by lower DAI scores, improved histological architecture, and reduced levels of inflammatory mediators, including NO, MPO, IL-6, and iNOS, while upregulating the anti-inflammatory cytokine IL-10. Mechanistically, β-sitosterol promoted AMP-activated protein kinase (AMPK) expression and suppressed myosin light chain kinase (MLCK) expression. These findings were validated in vitro using LPS-stimulated Caco-2 cells, where β-sitosterol decreased inflammatory marker levels and modulated AMPK/MLCK signaling. Notably, the use of Compound C, an AMPK inhibitor, reversed these effects by suppressing AMPK activity and restoring MLCK expression, confirming that the anti-inflammatory actions of β-sitosterol are AMPK-dependent. In conclusion, this study highlights the therapeutic potential of β-sitosterol in UC through modulation of the AMPK/MLCK signaling pathway. These findings not only deepen our understanding of β-sitosterol's anti-inflammatory properties but also suggest its potential in developing novel AMPK-targeted therapies for inflammatory bowel disease management.
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Affiliation(s)
- Yuansen Zhang
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, Zhejiang, China
| | - Xiaosheng Jin
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, Zhejiang, China
| | - Huanhuan Xia
- Department of Pharmacy, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, Zhejiang, China
| | - Xiaoqiu Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, Zhejiang, China
| | - Wenjun Chen
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, Zhejiang, China
| | - Mengxiao Zhuang
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, Zhejiang, China
| | - Sensen Tang
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, Zhejiang, China
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Esaki M, Ihara Y, Tominaga N, Takedomi H, Tsuruoka N, Akutagawa T, Yukimoto T, Kawasaki K, Umeno J, Torisu T, Sakata Y. Predictive factors of the clinical efficacy of ustekinumab in patients with refractory Crohn's disease: tertiary centers experience in Japan. Int J Colorectal Dis 2023; 38:57. [PMID: 36856849 DOI: 10.1007/s00384-023-04359-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2023] [Indexed: 03/02/2023]
Abstract
PURPOSE Therapeutic efficacy of ustekinumab in the real-world data is limited in patients with refractory Crohn's disease (CD). In addition, factors predictive of better therapeutic efficacy of ustekinumab remains unsolved in CD. We aimed to evaluate therapeutic efficacy of ustekinumab in patients with refractory CD and to identify the factors associated with the efficacy of ustekinumab. METHODS We retrospectively analyzed the clinical data of 72 patients treated with ustekinumab for refractory CD. Therapeutic efficacy was assessed at weeks 8, 26, 52, and 104 on the basis of dual remission, defined as the combination of Crohn's Disease Activity Index < 150 and CRP < 0.3 mg/dL, and factors predictive of the induction and maintenance of dual remission were investigated. The cumulative continuation rates and safety of ustekinumab were assessed. RESULTS The dual remission rates at weeks 8, 26, 52, and 104 were 31.9%, 37.9%, 47.5%, and 42.6%, respectively. A short disease duration (≤ 2 years) and higher baseline serum albumin levels (≥ 3.1 g/dL) were positively associated with dual remission at weeks 8 and 52. Meanwhile, higher serum CRP levels (≥ 1.19 mg/dL) were negatively associated with dual remission at week 8. The cumulative ustekinumab continuation rate was favorable, and no severe adverse events were found. CONCLUSION A short disease duration and higher baseline serum albumin levels might be predictive of favorable therapeutic efficacy of ustekinumab in refractory CD. Induction efficacy appears to be lower in patients with higher serum CRP levels.
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Affiliation(s)
- Motohiro Esaki
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan.
| | - Yutaro Ihara
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoyuki Tominaga
- Department of Gastroenterology, Saga Medical Center Koseikan, Saga, Japan
| | - Hironobu Takedomi
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan
| | - Nanae Tsuruoka
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan
| | - Takashi Akutagawa
- Department of Endoscopic Diagnostics and Therapeutics, Saga University Hospital, Saga, Japan
| | - Takahiro Yukimoto
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan
| | - Keisuke Kawasaki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takehiro Torisu
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuhisa Sakata
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan
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Mohajeri S, Moayedi S, Mohajeri S, Yadegar A, Haririan I. Targeting pathophysiological changes using biomaterials-based drug delivery systems: A key to managing inflammatory bowel disease. Front Pharmacol 2022; 13:1045575. [PMID: 36438794 PMCID: PMC9685402 DOI: 10.3389/fphar.2022.1045575] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/27/2022] [Indexed: 08/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a gastrointestinal disorder, affecting about several million people worldwide. Current treatments fail to adequately control some clinical symptoms in IBD patients, which can adversely impact the patient's quality of life. Hence, the development of new treatments for IBD is needed. Due to their unique properties such as biocompatibility and sustained release of a drug, biomaterials-based drug delivery systems can be regarded as promising candidates for IBD treatment. It is noteworthy that considering the pathophysiological changes occurred in the gastrointestinal tract of IBD patients, especially changes in pH, surface charge, the concentration of reactive oxygen species, and the expression of some biomolecules at the inflamed colon, can help in the rational design of biomaterials-based drug delivery systems for efficient management of IBD. Here, we discuss about targeting these pathophysiological changes using biomaterials-based drug delivery systems, which can provide important clues to establish a strategic roadmap for future studies.
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Affiliation(s)
- Sahar Mohajeri
- Department of Pharmaceutical Biomaterials, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Moayedi
- Department of Pharmaceutical Biomaterials, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Shabnam Mohajeri
- Faculty of Food Science and Technology, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ismaeil Haririan
- Department of Pharmaceutical Biomaterials, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Dybska E, Nowak JK, Banaszkiewicz A, Szaflarska-Popławska A, Kierkuś J, Kwiecień J, Grzybowska-Chlebowczyk U, Walkowiak J. Methylation of RUNX3 Promoter 2 in the Whole Blood of Children with Ulcerative Colitis. Genes (Basel) 2022; 13:genes13091568. [PMID: 36140736 PMCID: PMC9498668 DOI: 10.3390/genes13091568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/22/2022] [Accepted: 08/30/2022] [Indexed: 12/03/2022] Open
Abstract
Ulcerative colitis (UC) results from a complex interplay between the environment, gut microbiota, host genetics, and immunity. Runt-related transcription factor 3 (RUNX3) regulates Th1/Th2 balance and, thus, the synthesis of cytokines and inflammation. We aimed to analyze the dependence of RUNX3 promoter 2 (P2) methylation level on: age, sex, body mass index (BMI), C-reactive protein (CRP), serum albumin, disease duration, Pediatric Ulcerative Colitis Activity Index (PUCAI), the Paris classification, and exposure to medications. This multicenter, cross-sectional study recruited hospitalized children with UC. Methylation of RUNX3 P2 was measured with methylation-sensitive restriction enzymes in the whole blood DNA. Sixty-four children were enrolled, with a mean age of 14.5 ± 2.8 years. Half of them were female (51.6%), and the average BMI Z-score was −0.44 ± 1.14. The mean methylation of RUNX3 P2 was 54.1 ± 13.3%. The methylation level of RUNX3 P2 did not correlate with age, sex, nutritional status, CRP, albumin, PUCAI, or the extent of colitis (Paris E1–E4). RUNX3 P2 methylation did not differ between patients recruited within two and a half months of diagnosis and children who had UC for at least a year. Current or past exposure to biologics, immunosuppressants, or steroids was not associated with RUNX3 P2 methylation. Methylation of RUNX3 promoter 2 in whole blood DNA does not seem to be associated with the characteristics of UC in children.
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Affiliation(s)
- Emilia Dybska
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Jan Krzysztof Nowak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Aleksandra Banaszkiewicz
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Anna Szaflarska-Popławska
- Department of Pediatric Endoscopy and Gastrointestinal Function Testing, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Jarosław Kierkuś
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
| | - Jarosław Kwiecień
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland
| | - Urszula Grzybowska-Chlebowczyk
- Department of Pediatrics, Faculty of Medical Sciences, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
| | - Jarosław Walkowiak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
- Correspondence:
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Li S, Jin Y, Fu W, Cox AD, Lee D, Reddivari L. Intermittent antibiotic treatment accelerated the development of colitis in IL-10 knockout mice. Biomed Pharmacother 2022; 146:112486. [PMID: 34891113 DOI: 10.1016/j.biopha.2021.112486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/22/2021] [Accepted: 11/30/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND AND AIMS Many epidemiological studies suggest an association between antibiotic exposure and the development of inflammatory bowel disease [IBD]. However, the majority of these studies are observational and still the question remains, "Does the specific antibiotic administration regimen play a role in the development of colitis?" This study aimed to compare the possible effects of continuous and intermittent antibiotic exposure on the development of colitis using a colitis-susceptible IL-10 knockout [IL-10-/-] mouse model. METHODS IL-10-/- mice [C57BL/6] were randomly assigned to a non-antibiotic group, continuous antibiotic group and intermittent antibiotic group, and observed for 30 weeks. The antibiotic cocktail was given via the drinking water. The differential response to antibiotics was assessed. RESULTS Intermittent antibiotic treatment resulted in severe colitis with early disease onset in IL-10-/- mice. Higher unit colon weight and spleen weight were observed in intermittent antibiotic-treated mice but not in the continuous antibiotic group. Moreover, intermittent antibiotic treatment aggravated epithelial damage and colonic inflammation, mucosal barrier dysfunction and colonic allergic sensitization in IL-10-/- mice, whereas continuous antibiotic treatment ameliorated these symptoms. Male IL-10-/- mice with intermittent antibiotic exposure were more susceptible to colonic inflammation and allergic response than females. CONCLUSIONS In summary, intermittent antibiotic exposure accelerated the development of severe colitis more than continuous antibiotic exposure in IL-10-/- male mice. In addition to the colonic damage and impaired barrier function, stimulation of allergic response may play a role in accelerating the development of colitis in genetically susceptible mice.
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Affiliation(s)
- Shiyu Li
- Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA
| | - Yusong Jin
- College of Chemistry, Chemical Engineering and Resource Utilization, Northeast Forestry University, Harbin 150040, China; Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China
| | - Wenyi Fu
- Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA
| | - Abigail D Cox
- College of Veterinary Medicine, Purdue University, 625 Harrison Street West Lafayette, IN 47907, USA
| | - Dale Lee
- Seattle Children's Hospital, University of Washington, Seattle, WA 98105, USA
| | - Lavanya Reddivari
- Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA.
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Swedik S, Madola A, Levine A. IL-17C in human mucosal immunity: More than just a middle child. Cytokine 2021; 146:155641. [PMID: 34293699 DOI: 10.1016/j.cyto.2021.155641] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 02/07/2023]
Abstract
Interleukin-17C (IL-17C) is an understudied member of the IL-17 family of cytokines. Its synthesis is induced by both cytokines and pathogenic stimuli in a variety of cell types, most often expressed at mucosal and barrier surfaces. IL-17C expression is dysregulated in a variety of autoinflammatory and autoimmune diseases including inflammatory bowel disease, psoriasis, and atopic dermatitis, yet it is protective against bacterial infections of the gut, skin, and lungs. In this review we highlight studies on IL-17C regulation and its function at human mucosal surfaces. Understanding the relationship between IL-17C and autoinflammatory and autoimmune diseases of the mucosa and defining the beneficial and pathogenic functions of the cytokine in inflammatory responses are the first steps in determining the potential for IL-17C as a therapeutic target.
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Affiliation(s)
- Stephanie Swedik
- Department of Molecular Biology and Microbiology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, United States
| | - Abson Madola
- Department of Biology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, United States
| | - Alan Levine
- Department of Molecular Biology and Microbiology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, United States; Departments of Pathology, Pharmacology, Medicine, and Pediatrics, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, United States.
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Qiu F, Zhang Z, Yang L, Li R, Ma Y. Combined effect of vitamin C and vitamin D 3 on intestinal epithelial barrier by regulating Notch signaling pathway. Nutr Metab (Lond) 2021; 18:49. [PMID: 33964955 PMCID: PMC8105975 DOI: 10.1186/s12986-021-00576-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 04/26/2021] [Indexed: 12/13/2022] Open
Abstract
Background Tight junction proteins play crucial roles in maintaining the intestinal mucosal barrier. Although previous studies have shown that Notch signaling is closely related to tight junction proteins, the mechanism remains unclear. This study was performed to investigate whether vitamin C combined with vitamin D3 affects intestinal mucosal barrier stability via the Notch signaling pathway. Methods Intestinal epithelial barrier and notch signaling pathway were studied using guinea pig and SW480 cells. The guinea pigs were randomized into four groups (n = 6 in each group): control group (C, 200 IU/kg d VD3 + 100 mg/kg d VC), low VC group (LVC, 200 IU/kg d VD3 + 10 mg/kg d VC), medium VC group (MVC, 200 IU/kg d VD3 + 100 mg/kg d VC), and high VC group (HVC, 200 IU/kg d VD3 + 200 mg/kg d VC). Except for the control group, the other three groups were freely drinked with 2% dextran sodium sulfate solution for 4 days. And the control group was free to drink distilled water. The following cell groups were used: control group (SW480 cells without intervention); LPS group (100 ng/mL LPS); VD3 group (0.1 μmol/L VD3); VC + VD3 group (0.1, 1, 5, 10 μmol/mL VC + 0.1 μmol/L VD3). Results Electron microscopy analysis revealed that both low and high doses of vitamin C combined with vitamin D3 maintained dextran sodium sulfate-induced ulcerative colitis in the guinea pig intestinal epithelium tight junction. Compared with the control group, the expression level of ZO-1 mRNA in the colon tissue of the high-dose vitamin C group was significantly increased. In SW480 cell experiments, compared with the control group, cell migration and repair following treatment with different concentrations of vitamin C combined with vitamin D3 were significantly improved and the protein expression of Notch-1 was increased, whereas the protein expression of claudin-2 was significantly decreased. Thus, our results demonstrate that an appropriate amount of vitamin C combined with vitamin D3 can regulate the expression of claudin-2 by regulating Notch-1, relieve destruction of the intestinal mucosal barrier, and promote the repair of damage to the cell mucosal barrier. Conclusions We found that vitamin C combined with vitamin D3 protected against dextran sodium sulfate-induced ulcerative colitis in the guinea pig intestinal mucosa.
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Affiliation(s)
- Fubin Qiu
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China.
| | - Zehui Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China
| | - Linxue Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China
| | - Rui Li
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China
| | - Ying Ma
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, China
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Vitale S, Strisciuglio C. The potential use of gene expression profile to identify useful biomarkers for the diagnosis and the treatment of pediatric inflammatory bowel diseases. Pediatr Res 2020; 87:805-806. [PMID: 31896123 DOI: 10.1038/s41390-019-0732-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 10/07/2019] [Accepted: 11/06/2019] [Indexed: 11/09/2022]
Affiliation(s)
- Serena Vitale
- Institute of Biochemistry and Cell Biology-National Research Council (IBBC-CNR), Naples, Italy.,Collaboration with Italian Foundation for the Celiac Disease-FC and Italian Society for the Celiac Disease-AIC, Naples, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
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Li X, Lee EJ, Gawel DR, Lilja S, Schäfer S, Zhang H, Benson M. Meta-Analysis of Expression Profiling Data Indicates Need for Combinatorial Biomarkers in Pediatric Ulcerative Colitis. J Immunol Res 2020; 2020:8279619. [PMID: 32411805 PMCID: PMC7204128 DOI: 10.1155/2020/8279619] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/02/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Unbiased studies using different genome-wide methods have identified a great number of candidate biomarkers for diagnosis and treatment response in pediatric ulcerative colitis (UC). However, clinical translation has been proven difficult. Here, we hypothesized that one reason could be differences between inflammatory responses in an inflamed gut and in peripheral blood cells. METHODS We performed meta-analysis of gene expression microarray data from intestinal biopsies and whole blood cells (WBC) from pediatric patients with UC and healthy controls in order to identify overlapping pathways, predicted upstream regulators, and potential biomarkers. RESULTS Analyses of profiling datasets from colonic biopsies showed good agreement between different studies regarding pathways and predicted upstream regulators. The most activated predicted upstream regulators included TNF, which is known to have a key pathogenic and therapeutic role in pediatric UC. Despite this, the expression levels of TNF were increased in neither colonic biopsies nor WBC. A potential explanation was increased expression of TNFR2, one of the membrane-bound receptors of TNF in the inflamed colon. Further analyses showed a similar pattern of complex relations between the expression levels of the regulators and their receptors. We also found limited overlap between pathways and predicted upstream regulators in colonic biopsies and WBC. An extended search including all differentially expressed genes that overlapped between colonic biopsies and WBC only resulted in identification of three potential biomarkers involved in the regulation of intestinal inflammation. However, two had been previously proposed in adult inflammatory bowel diseases (IBD), namely, MMP9 and PROK2. CONCLUSIONS Our findings indicate that biomarker identification in pediatric UC is complicated by the involvement of multiple pathways, each of which includes many different types of genes in the blood or inflamed intestine. Therefore, further studies for identification of combinatorial biomarkers are warranted. Our study may provide candidate biomarkers for such studies.
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Affiliation(s)
- Xinxiu Li
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Eun Jung Lee
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Danuta R. Gawel
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Sandra Lilja
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Samuel Schäfer
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Huan Zhang
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
- Crown Princess Victoria Children's Hospital, Linköping University Hospital, Sweden
| | - Mikael Benson
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
- Crown Princess Victoria Children's Hospital, Linköping University Hospital, Sweden
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