microRNA-33a (miR-33a) belongs to the miR-33 family that is implicated in the progression of various types of cancers. Aberrant expression of miR-33a has been detected in several human cancers, and has been shown to regulate the migration and invasion as well as proliferation and apoptosis of tumor cells. However, the clinical significance and precise mechanisms underlying the dysfunction of miR-33a in glioma have not been well investigated in previous studies. In this study, overexpression of miR-33a was observed in clinical glioma specimens and cell lines. Clinicopathological detection revealed that miR-33a highly expressing patients showed large tumor sized and advanced World Health Organization (WHO) grade as well as reduced overall survival. Furthermore, the results of in vitro experiments confirmed that loss of miR-33a resulted in reduced proliferation and enhanced apoptosis in U251 cells, while miR-33a restoration showed opposite effects in U87 cells. Further studies indicated that miR-33a knockdown restrained tumor growth of glioma in vivo. miR-33a negatively regulated the expression of sirtuin 6 (SIRT6) at both mRNA and protein levels via targeting the 3'UTR of SIRT6 mRNA. SIRT6 was underexpressed and inversely correlated with miR-33a expression in the glioma tissues. Mechanistically, SIRT6 overexpression increased the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) while it reduced cell survival under H2O2 treatment. In addition, SIRT6 restoration led to apoptosis with alterative expression of Bax, Bcl-2, cleaved caspase-8, and inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway in glioma. Thus, our studies demonstrated that the deregulation of miR-33a may promote tumor development in human glioma by regulating the expression of its target gene, SIRT6.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share specific molecular mechanisms, and agents with proven efficacy in one may be useful against the other. The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has similar properties to GLP-1 and is currently in clinical use for T2DM treatment. Thus, this study was designed to characterize the effects of exendin-4 on the impairment of learning and memory induced by amyloid protein (Aβ) and its probable molecular underlying mechanisms. The results showed that (1) intracerebroventricular (i.c.v.) injection of Aβ1-42 resulted in a significant decline of spatial learning and memory of rats in water maze tests; (2) pretreatment with exendin-4 effectively and dose-dependently protected against the Aβ1-42-induced impairment of spatial learning and memory; (3) exendin-4 treatment significantly decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl2 in Aβ1-42-induced Alzheimer's rats. The vision and swimming speed of the rats among all groups in the visible platform tests did not show any difference. These findings indicate that systemic pretreatment with exendin-4 can effectively prevent the behavioral impairment induced by neurotoxic Aβ1-42, and the underlying protective mechanism of exendin-4 may be involved in the Bcl2, Bax and caspase-3 pathways. Thus, the application of exendin-4 or the activation of its signaling pathways may be a promising strategy to ameliorate the degenerative processes observed in AD.

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Background: Homer is a family of post synaptic density proteins functionally and physically attached to target proteins at proline-rich sequences. Reducing Homer1b/c expression has been shown in previous studies to be protective against excitotoxic insults, implicating Homer1b/c in the physiological regulation of aberrant neuronal excitability. Methods: To test the efficacy of a Homer1b/c reducing therapy for disorders with a detrimental hyperexcitability profile in mice, we used small interfere RNA (siRNA) to decrease endogenous Homer1b/c expression in mouse hippocampus. The baseline motor and cognitive behavior was measured by sensorimotor tests, Morris water maze and elevated plus maze tasks. The anti-epileptic effects of Homer1b/c knockdown were determined in two chemically induced seizure models induced by Picrotoxin (PTX) or pentylenetetrazole (PTZ) administration. Results: The results of sensorimotor tests, Morris water maze and elevated plus maze tasks showed that Homer1b/c reduction had no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced Homerb/c protein had less severe seizures than control mice. Total Homer1b/c protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of Homer1b/c. In addition, the phosphorylation of mammalian target of rapamycin (mTOR) and its target protein S6 was significantly inhibited in Homer1b/c down-regulated mice. Homer1b/c knockdown-induced inhibition of mTOR pathway was partially ablated by the metabotropic glutamate receptor 5 (mGluR5) agonist CHPG. Conclusion: Our results demonstrate that endogenous Homer1b/c is integral for regulating neuronal hyperexcitability in adult animals and suggest that reduction of Homer1b/c could protect against chemically induced seizures through inhibition mTOR pathway.