Characteristic MicroRNA Expression Induced by δ-Opioid Receptor Activation in the Rat Liver Under Prolonged Hypoxia

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The delta-opioid receptor (DOR) is one of three classic opioid receptors in the opioid system. It was traditionally thought to be primarily involved in modulating the transmission of messages along pain signaling pathway. Although there were scattered studies on its other neural functions, inconsistent results and contradicting conclusions were found in past literatures, especially in terms of DOR’s role in a hypoxic/ischemic brain. Taking inspiration from the finding that the turtle brain exhibits a higher DOR density and greater tolerance to hypoxic/ischemic insult than the mammalian brain, we clarified DOR’s specific role in the brain against hypoxic/ischemic injury and reconciled previous controversies in this aspect. Our serial studies have strongly demonstrated that DOR is a unique neuroprotector against hypoxic/ischemic injury in the brain, which has been well confirmed in current research. Moreover, mechanistic studies have shown that during acute phases of hypoxic/ischemic stress, DOR protects the neurons mainly by the stabilization of ionic homeostasis, inhibition of excitatory transmitter release, and attenuation of disrupted neuronal transmission. During prolonged hypoxia/ischemia, however, DOR neuroprotection involves a variety of signaling pathways. More recently, our data suggest that DOR may display its neuroprotective role via the BDNF-TrkB pathway. This review concisely summarizes the progress in this field.

Section: Opioid Receptors and Endogenous Opioidsmentioning

confidence: 99%

Neuroprotection Against Hypoxic/Ischemic Injury: δ-Opioid Receptors and BDNF-TrkB Pathway

Sheng¹,

Huang²,

Ren³

et al. 2018

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“…Mature miR-184, which contains 22 nucleotides, exhibits expression patterns specific to tissue and developmental stages [12]. It has been extensively reported that miR-184 activity participates in the control of a wide range of biological functions and processes such as changes in response to DOR activation in the Rat Liver Under Prolonged Hypoxia [13]. MiR-184 has been extensively explored in various cancers.…”

Section: Introductionmentioning

confidence: 99%

miR-184 Inhibits Tumor Invasion, Migration and Metastasis in Nasopharyngeal Carcinoma by Targeting Notch2

Zhu¹,

Jiang

et al. 2018

Background/Aims: A recent study found that dysregulated microRNA-184 (miR-184) is involved in the proliferation and survival of nasopharyngeal carcinoma (NPC). This study aimed to evaluate the detailed mechanisms of invasion, migration and metastasis of NPC cells. Methods: Quantitative reverse-transcription PCR (qRT-PCR) and Western blot were used to confirm the expression levels of miR-184 and Notch2. NPC cell invasion and migration were subsequently examined using in vitro cell invasion and wound-healing assays, respectively. MicroRNA (miRNA) target gene prediction databases and dual-luciferase reporter assay were adopted to validate the target genes of miR-184. Results: MiR-184 was downregulated in the NPC cell lines. The miR-184 inhibitor increased the number of invading NPC cells, whereas miR-184 mimics inhibited the invasive ability of such cells. The protein level of E-cadherin decreased, whereas those of N-cadherin and vimentin increased in the anti-miR-184 group. This result showed that miR-184 inhibited NPC cell invasion and metastasis by regulating EMT progression. MiRNA target gene prediction databases indicated the potential of Notch2 as a direct target gene of miR-184. Such a notion was then validated by results of dual-luciferase reporter assay. Notably, shRNANotch2 restrained the EMT and partially abrogated the inhibitory effects of miR-184 on EMT progression in NPC cells. Conclusion: MiR-184 functions as a tumour-suppressive miRNA targeting Notch2 and inhibits the invasion, migration and metastasis of NPC.

“…For example, the paradoxical trend towards increase in glycogen content after IH, despite inhibition of AKT/GSK-3β, may implicate hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1 [33]. Third, in addition to JNK, changes in other stress/hypoxia-inducible pathways including Sestrins, oxidative stress, as well as microRNA profiles should be considered in interpreting the metabolic consequences of IH in liver cells [34][35][36].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner

Gu¹,

Yi²,

Feng³

et al. 2018

Background/Aims: Obstructive sleep apnea is associated with diabetes and insulin resistance, but the underlying mechanisms remain unclear. The purpose of the current study was to determine the molecular effects of intermittent hypoxia (IH) on hepatic insulin signaling and glucose homeostasis, and whether c-Jun NH₂-terminal-kinase (JNK) contributed to metabolic responses to IH in liver cells. Methods: The human HepG₂ cells and rat FAO cells were exposed to 10, 30, 120, 240 or 360 cycles of IH (1% O₂ for 60 s followed by 21% O₂ for 60s, 7.5 cycles per hour) or normoxia as a control. In a subgroup, we exposed cells to 360 cycles of IH with the JNK inhibitor SP600125. After IH exposure, cell glycogen content and glucose output were measured using colorimetric assay kits. Canonical insulin signaling and gluconeogenic genes were measured by western blot and quantitative polymerase chain reaction. Results: IH decreased insulin-stimulated protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β) phosphorylation in a time-dependent manner, while inhibiting forkhead box protein O1 (FOXO1) expression and phosphoenolpyruvate carboxykinase (PEPCK) transcription independent of insulin signaling. JNK inhibitor SP600125 partially restored AKT/ GSK-3β phosphorylation and glycogen synthesis, but did not affect other IH-induced glucose metabolic changes. Conclusion: IH in vitro impaired insulin signal transduction in liver cells as assessed by inhibited AKT/GSK-3β phosphorylation via JNK activation. IH inhibited FOXO1 and gluconeogenesis in an insulin-independent manner.