Abstract
Background: Irritable bowel syndrome (IBS) is a known brain-gut disorder. Currently, the molecular and cellular mechanisms of IBS remain unclear. Atractylenolide‐I (ATL-I) is a majorly bioactive component extracted from Rhizoma Atractylodes Macrocephalae.
Methods: Studies have revealed that ATL-I functioned as an anti-tumor drug in various cancers. However, the effects and molecular mechanisms of ATL-I on the pathological processes of colonic mucosal epithelial cells (CMECs) during IBS remain unclear. This study reports ATL-I effectively alleviated the oxidative stress-induced colonic mucosal epithelial cell dysfunction. In colonic mucosal tissues from IBS patients, we detected upregulated miR-34a-5p and suppressed glucose metabolism enzyme expressions. Under H2O2 treatment which mimics in vitro oxidative stress, miR-34a-5p was induced and glucose metabolism was inhibited in the colon mucosal epithelial cell line, NCM460. Meanwhile, ATL-I treatment effectively overcame the oxidative stress-induced miR-34a- 5p expression and glucose metabolism in NCM460 cells.
Result: By bioinformatics analysis, Western blot and luciferase assay, we illustrated that miR-34a-5p directly targeted the 3’UTR region of glucose metabolism key enzyme, lactate dehydrogenase-A (LDHA) in colonic mucosal epithelial cells. Rescue experiments validated that miR-34a-5p inhibited glucose metabolism by targeting LDHA. Finally, we demonstrated that ATL-I treatment reversed the miR-34a-5p-inhibited glucose metabolism and -exacerbated colonic mucosal epithelial cell dysfunction under oxidative stress by modulating the miR-34a-5p-LDHA pathway.
Conclusion: Summarily, our study reports the roles and mechanisms of ATL-I in the oxidative stress-induced colonic mucosal epithelial cell dysfunction during IBS through regulating the miR-34a-5p-LDHA-glucose metabolism axis.
Keywords: Irritable bowel syndrome, atractylenolide‐I, colonic mucosal epithelial cell, miR-34a-5p, glucose metabolism, lactate dehydrogenase-A.
[http://dx.doi.org/10.1016/S0140-6736(20)31548-8] [PMID: 33049223]
[http://dx.doi.org/10.1016/j.pop.2017.07.009] [PMID: 29132527]
[http://dx.doi.org/10.1097/MED.0000000000000523] [PMID: 31789724]
[http://dx.doi.org/10.1002/kjm2.12154] [PMID: 31782606]
[http://dx.doi.org/10.1016/j.cell.2020.08.007] [PMID: 32916129]
[http://dx.doi.org/10.1038/s41586-019-0992-y] [PMID: 30814735]
[http://dx.doi.org/10.1016/j.jep.2018.08.023] [PMID: 30130541]
[http://dx.doi.org/10.3389/fphar.2021.674340] [PMID: 34335248]
[http://dx.doi.org/10.3389/fphar.2020.598939] [PMID: 33363472]
[http://dx.doi.org/10.12659/MSM.902886] [PMID: 28141785]
[http://dx.doi.org/10.1016/j.ejphar.2015.08.022] [PMID: 26297303]
[http://dx.doi.org/10.1016/j.jep.2018.09.015] [PMID: 30218812]
[http://dx.doi.org/10.3892/mmr.2021.12331] [PMID: 34368880]
[http://dx.doi.org/10.1211/jpp.62.03.0014] [PMID: 20487223]
[http://dx.doi.org/10.3390/ijms21217893] [PMID: 33114313]
[http://dx.doi.org/10.3390/ijms21155353] [PMID: 32731413]
[http://dx.doi.org/10.1016/j.biopha.2020.111099] [PMID: 33338745]
[http://dx.doi.org/10.3390/ijms18091907] [PMID: 28878141]
[http://dx.doi.org/10.5056/jnm16044] [PMID: 27032543]
[http://dx.doi.org/10.3389/fpsyt.2020.00805] [PMID: 32922317]
[http://dx.doi.org/10.3390/ijms19010278] [PMID: 29342124]
[http://dx.doi.org/10.1002/ctm2.139] [PMID: 32898324]
[http://dx.doi.org/10.14670/HH-11-839] [PMID: 27824216]
[http://dx.doi.org/10.1113/JP272208] [PMID: 27121603]
[http://dx.doi.org/10.1038/srep21735] [PMID: 26902416]
[http://dx.doi.org/10.3233/CBM-201621] [PMID: 33074217]