Abstract
BackgroundCerebral ischemia and reperfusion injury (CIRI) affects bodily function by causing irreversible damage to brain cells. The diverse pathophysiological course factors hinder the research work to go deeper. Long noncoding RNA taurine-upregulated gene 1 (TUG1) has been reported to be related to CIRI. This study explored the undefined regulatory pathway of TUG1 in CIRI.MethodsQuantitative real-time polymerase chain reaction was applied to test the expression of TUG1, microRNA (miR)-493-3p and miR-410-3p. The viability and apoptosis of oxygen and glucose deprivation/reoxygen (OGD/R) model cells were evaluated by cell counting kit-8 and flow cytometry assay, respectively. The determination of inflammatory factors of interleukin-6, interleukin-1β and tumor necrosis factor-α was presented by enzyme-linked immunosorbent assay. The oxidative stress was performed by measuring the generation of malondialdehyde, reactive oxygen species and the activity of superoxide dismutase. Cytotoxicity was presented by measuring the generation of lactate dehydrogenase. Western blot assay was devoted to assessing the level of apoptosis-related factors (cleaved-caspase-3 and cleaved-caspase-9) and the protein level of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathway-related factors in neuro-2a cells treated by OGD/R. Besides, online database starBase was applied to predict the potential binding sites of TUG1 to miR-493-3p and miR-410-3p, which was further confirmed by the dual-luciferase reporter system.ResultsThe expression of TUG1 was upregulated, while miR-493-3p or miR-410-3p was downregulated in the serum of CIRI and OGD/R model cells. Meanwhile, knockdown of TUG1 eliminated the suppression in proliferation, the promotion in apoptosis, inflammation and oxidative stress, as well as the cytotoxicity in OGD/R model cells. Interestingly, the inhibition of miR-493-3p or miR-410-3p allayed the above effects. In addition, TUG1 harbored miR-493-3p or miR-410-3p and negatively regulated their expression. Finally, the TUG1 activated JNK and p38 MAPK pathways by sponging miR-493-3p/miR-410-3p.ConclusionTUG1 motivated the development of CIRI by sponging miR-493-3p/miR-410-3p to activate JNK and p38 pathways. The novel role of TUG1 in CIRI may contribute to the advancement of CIRI treatment.
Highlights
Cerebral ischemia and reperfusion injury (CIRI) affects bodily function by causing irreversible damage to brain cells
The production of IL-6, IL-1β and TNF-α in N2a cells treated by oxygen and glucose deprivation/reoxygen (OGD/R) was measured by Enzyme-linked immunosorbent assay (ELISA) kits (Beyotime)
Attention to this study was focused on the functional role of taurine-upregulated gene 1 (TUG1) in apoptosis, inflammation, oxidative stress and protein kinases, which were accompanied by CIRI
Summary
Cerebral ischemia and reperfusion injury (CIRI) affects bodily function by causing irreversible damage to brain cells. The production of oxidative stress products, including reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA), lactate dehydrogenase (LDH), increased sharply, and the proinflammatory neutrophils (e.g., interleukin-6 [IL-6], interleukin-1β [IL-1β] and tumor necrosis factor-α [TNFα]) aggravated the ischemic injury by infiltrating into the ischemic tissues [7,8]. LncRNA CAMK2Dassociated transcript 1 protected against CIRI by Ca2+/ calmodulin-dependent protein kinase II-δ/nuclear factor kappa-B signal pathway [12]. These studies highlighted the crucial role of lncRNAs that might serve as a biomarker in CIRI. TUG1 could promote colon cancer progression via regulating miR-26a5p/matrix metalloproteinases-14/p38 mitogen-activated protein kinase (p38 MAPK)/heat shock protein 27 pathway [18]. We wondered if TUG1 exerted its function in CIRI by sponging miRNAs to regulate the activity of JNK/p38 MAPK pathway
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