Tinnitus could be associated with neuronal hyperactivity in the auditory center. As a neuronal activity marker, immediate-early gene (IEG) expression is considered part of a general neuronal response to natural stimuli. Some IEGs, especially the activity-dependent cytoskeletal protein (Arc) and the early growth response gene-1 (Egr-1), appear to be highly correlated with sensory-evoked neuronal activity. We hypothesize, therefore, an increase of Arc and Egr-1 will be observed in a tinnitus model. In our study, we used the gap prepulse inhibition of acoustic startle (GPIAS) paradigm to confirm that salicylate induces tinnitus-like behavior in rats. However, expression of the Arc gene and Egr-1 gene were decreased in the inferior colliculus (IC) and auditory cortex (AC), in contradiction of our hypothesis. Expression of N-methyl D-aspartate receptor subunit 2B (NR2B) was increased and all of these changes returned to normal 14 days after treatment with salicylate ceased. These data revealed long-time administration of salicylate induced tinnitus markedly but reversibly and caused neural plasticity changes in the IC and the AC. Decreased expression of Arc and Egr-1 might be involved with instability of synaptic plasticity in tinnitus.

Aspirin (salicylate), as a common drug that is frequently used for long-term treatment in a clinical setting, has the potential to cause reversible tinnitus. However, few reports have examined the inflammatory cytokines expression and alteration of synaptic ultrastructure in the cochlear nucleus (CN) in a rat model of tinnitus. The tinnitus-like behavior of rats were detected by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. We investigated the expression levels of the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), N-methyl D-aspartate receptor subunit 2A (NR2A) mRNA and protein in the CN and compared synapses ultrastructure in the CN of tinnitus rats with normal ones. GPIAS showed that rats with long-term administration of salicylate were experiencing tinnitus, and the mRNA and protein expression levels of TNF-α and NR2A were up-regulated in chronic treatment groups, and they returned to baseline 14 days after cessation of treatment. Furthermore, compared to normal rats, repetitive salicylate-treated rats showed a greater number of presynaptic vesicles, thicker and longer postsynaptic densities, increased synaptic interface curvature. These data revealed that chronic salicylate administration markedly, but reversibly, induces tinnitus possibly via augmentation of the expression of TNF-α and NR2A and cause changes in synaptic ultrastructure in the CN. Long-term administration of salicylate causes neural plasticity changes at the CN level.

2018) Loss of miR-16 contributes to tumor progression by activation of tousled-like kinase 1 in oral squamous cell carcinoma, Cell Cycle, 17:18, 2284-2295, ABSTRACT A different expression signature of miRNA in oral squamous cell carcinoma (OSCC) has been validated. as one of the distinctly dysregulated miRNAs in OSCC, its functional role in progression of OSCC remains not fully clear. Herein, miR-16 expression was significantly lower in OSCC tissues compared to that in adjacent normal tissues (n = 131). A lower level of miR-16 was found to be associated with poor prognosis on a cohort of 131 patients with OSCC, and on an extensive public data (457) from TCGA database. Additionally, expression of TLK1 was significantly higher in OSCC tissues compared to that in adjacent normal tissues, which is negatively correlated with miR-16 expression in OSCC. Bioinformatics analyses exhibited that TLK1 is a potential downstream effector of miR-16 by directly targeting the 3′-untranslated regions (3′-UTR) of mRNA. Forced expression of miR-16 in OSCC cell lines inhibits cell proliferation in vitro, and tumor growth in vivo by inhibition of TLK1. Mechanistically, downregulation of TLK1 by miR-16 enhances higher level of DNA damage leading to a significant increase of G 2 /M arrest in SCC9 cells. And, overexpression of TLK1 substantially reduces DNA damage and G 2 /M arrest by activation of TLK1-dependent cell cycle checkpoint response. To conclude, miR-16 is downregulated in OSCC and serves as tumor suppressor in OSCC progression by targeting TLK1, which has potential to be the novel therapeutic targets and diagnostic biomarkers for OSCC. ARTICLE HISTORY

Background: Drug resistance to chemotherapeutic drugs or targeted medicines is an obstacle encountered in the treatment of non-small-cell lung cancer (NSCLC). However, the mechanisms of competing endogenous RNA (ceRNA) on the drug resistance in NSCLC are rarely reported. In this paper, the comprehensive expression profiles of lncRNAs and mRNAs in drug-resistant NSCLC cells were obtained by RNA sequencing. Methods: The dysregulated lncRNAs, miRNAs and mRNAs in drug-resistant NSCLC cell lines were identified by RNA-sequencing and bioinformatics methods. Results: A total of 39 dysregulated lncRNAs and 650 dysregulated mRNAs were identified between drug-resistant NSCLC cell lines and their parental cell lines. Additionally, 33 lncRNA-miRNA-mRNA pathways in the ceRNA network in drug-resistant NSCLC were constructed through bioinformatics methods and ceRNA regulatory rules. These comprised 12 dysregulated lncRNAs, five dysregulated miRNAs, and eight dysregulated mRNAs. In addition, lncRNA ATP2B1/miR-222-5p/TAB2 and lncRNA HUWE1/miR-222-5p/TAB2 were identified as potential ceRNA networks involved in drug resistance to NSCLC. Conclusions: The current study provides a promising therapeutic strategy against the lncRNA-miRNA-mRNA ceRNA regulatory network for NSCLC treatment and deepens our comprehension of the ceRNA regulatory mechanisms related to drug resistance to NSCLC.