Effect of MicroRNA145 on the multidrug resistance gene of ulcerative colitis in rats
Introduction
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD). It is a unique gastrointestinal disease characterized by diffuse inflammation of the intestinal mucosa and recurrence disease processes. UC affects mainly the rectum and sigmoid colon, but also may involve the entire colon and distal ileum [[1], [2], [3]]. At present, the pathogenesis of UC is not very clear and may be related to the interaction of genetic factors, environmental factors, intestinal flora, immune or psychological factors [[4], [5], [6], [7]]. The incidence of UC in China has increased about 3.08 times in the last 10 years [8,9]. Multidrug resistance gene (MDR1a) is the only P-gp gene expressed in mouse intestinal epithelial cells and intestinal lymphocytes. Also, a rat model of IBD in MDR1a has been established. The MDR1a gene sequences of humans and rats are highly homologous. MDR1a protein exists in the cell membrane and intracellular organelles, and ABC family members perform different functions according to the cellular conditions [10]. Apical cell membranes are mainly located at the epithelial and endothelial interfaces in the intestines, testes, kidneys, liver, brain, and placenta [11] and serve as a barrier that affects the exogenous substrates absorption, distribution, excretion, and toxicological effects, which has a potential impact on inflammation and carcinogenesis [12]. Some nuclear receptors may be involved in the transcriptional regulation of ABC transporters [13]. In addition, MDR1a has experienced several modifications after translation [14], and these modifications have been reported to affect the stability and/or substrate transport characteristics of MDR1a [15]. The polymorphism of the MDR1a gene can lead to differences in drug sensitivity and disease susceptibility among individuals. The polymorphism of synonymous C3435T leads to the change in protein folding due to ribosomal stagnation resulting from the impaired interaction between tRNA and chaperone proteins, contributing to the folding process on the ribosome [16], leading to the changes in transport function [17]. A recent meta-analysis found that C3435T polymorphism (rs1045642) in ABCB1 was associated with the risk of UC, but not Crohn's disease (CD) [18].
P-glycoprotein (P-gp) is an ATP-dependent drug transporter encoded by the ABCB1 gene, which is distributed mainly on the apical membrane or the cell membrane of the lumen. P-gp is responsible for a wide range of structurally different metabolites and cytotoxic chemicals expelled into the extracellular space and may play a role in drug–drug interactions [19]. In Ueda' study, P-gp is a 170-kDa membrane protein encoded by the MDR1/ABCB1 gene in human. Rodents have two genes, Mdr1a/Abcb1a and Mdr1b/Abcb1b, which encode the P-gp enzyme. Recently, in vitro studies have shown that P-gp function is related to the lipid membrane bilayer, which regulates substrate interactions, ATP hydrolysis, and drug transport [20]. P-gp represents the mostly investigated ATP-dependent efflux transporter pump among exogenous substances (including metabolites, toxins, and drugs) [21]. Elevated P-gp expression has been shown in peripheral blood lymphocytes of patients with IBD who have failed in the glucocorticoid therapy [22]. P-gp is a multi-specific effective carrier that can regulate the pharmacokinetics of various drugs. Studies have shown that P-gp expression in the large and small intestines increases after hepatic ischemia/reperfusion (I/R) injury in rats. IBD is also reduced by intestinal mucosa ischemia and hypoxia, indicating that the regulatory mechanism of P-gp on UC needs further exploration [23].
MiRNAs play a key role in autoimmune and inflammatory diseases, especially in IBD. The newly discovered data suggested that specific miRNAs inhibiting functional targets played a key role in regulating the pathogenesis of IBD [25]. MiRNAs have been found to be involved in the regulation of the nuclear transcription factor NF-κB pathway (e.g., miR-146a, miR-146b, miR-122, miR-132, and miR-126), intestinal epithelial barrier function (e.g., miR-21, miR-150, and miR-200b), and autophagic function (e.g., miR-30c, miR-130a, miR-06b, miR-93, and miR-196) [24]. NF-κB is considered to be an important regulators of the immune system and inflammatory diseases.
Section snippets
Materials and methods
All experiments were performed according to the ethical guidelines set out in the Guide for the Care and Use of Laboratory Animals and with approval of the “Ethics Committee of the First Affiliated Hospital of Henan University of Science and Technology and the Institutional Review Board of Henan University of Science and Technology (HUST).”, and followed the guidelines of the Committee for Research and Ethical issues of the International Association for the Study of Pain [26]. All experiments
Establishment of the animal model of UC rats
The rats in the control group had normal daily feeding and drinking water, normal activities, alert reaction, glossy fur, good growth and development, and body mass increased to different degrees. The model, the low-dose mesalazine treatment, the high-dose mesalazine treatment, and the glucocorticoid treatment groups all showed lazy movements, yellow hair color, decreased food and water intake, decreased weight gain, watery stools, and perianal dampness on the fourth day after drinking 4.0% DSS
Discussion
The incidence of UC has increased in recent years with the changes of people's living and diet, and the onset age of patients is decreasing, which may be related to the unhealthy living habits and lack of exercise in young people nowadays. Clinically, UC has a low cure rate and easily repeat, and the canceration rate is on the rise. On the mechanism, the pathogenesis of UC is still unknown, which may be related to the environment, heredity, autoimmunity, and intestinal flora factors. Besides,
Conclusion
- 1.
MiR-145 has a protective effect on the colorectal mucous membrane, and its down-regulated expression may affect the expression and function of MDR1a and P-gp, and promote the development of UC.
- 2.
The down-regulation of MiR-145 plays an important role in the drug sensitivity reduction of 5-ASA and glucocorticoids in the treatment of UC. MiR-145 may have the potential of biomarkers and therapeutic targets, and may be applied in the diagnosis of disease, prediction of drug sensitivity, treatment and
CRediT authorship contribution statement
Conception and design: Y. Chen, P. Wang, L.M. Zhang, Y. J. Zhang. Analysis and interpretation of data: Y. Chen, P. Wang, L. M. Zhang, Y.J. Zhang. Drafting of the article: Y. Chen, L. M. Zhang, Y.J. Zhang. Critical revision of the article for important intellectual content: Y. Chen, P. Wang, L. M. Zhang, S. Q. Yuan, S. A. Lu, and Y. J. Zhang. Final approval of the article: Y. Chen, P. Wang, L.M. Zhang, S.Q. Yuan, S. A. Lu, and Y.J. Zhang. Statistical expertise: P. Wang, L. M. Zhang, Y. J. Zhang.
Declaration of competing interest
All authors have no conflict of interest.
Acknowledgements
This study was supported by Scientific Research Fund of Henan Provincial Science and Technology Department (No. 182102310302).
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These authors contributed equally to this article.