The IRF2/CENP-N/AKT signaling axis promotes proliferation, cell cycling and apoptosis resistance in nasopharyngeal carcinoma cells by increasing aerobic glycolysis.

BACKGROUND: Centromere protein N (CENP-N) has been reported to be highly expressed in malignancies, but its role and mechanism in nasopharyngeal carcinoma (NPC) are unknown. METHODS: Abnormal CENP-N expression from NPC microarrays of GEO database was analyzed. CENP-N expression level was confirmed in NPC tissues and cell lines. Stable CENP-N knockdown and overexpression NPC cell lines were established, and transcriptome sequencing after CENP-N knockdown was performed. In vitro and in vivo experiments were performed to test the impact of CENP-N knockdown in NPC cells. ChIP and dual luciferase reporter assays were used to verify the combination of IRF2 and CENP-N. Western blot analysis, cellular immunofluorescence, immunoprecipitation and GST pulldown assays were used to verify the combination of CENP-N and AKT. RESULTS: CENP-N was confirmed to be aberrantly highly expressed in NPC tissues and cell lines and to be associated with high 18F-FDG uptake in cancer nests and poor patient prognosis. Transcriptome sequencing after CENP-N knockdown revealed that genes with altered expression were enriched in pathways related to glucose metabolism, cell cycle regulation. CENP-N knockdown inhibited glucose metabolism, cell proliferation, cell cycling and promoted apoptosis. IRF2 is a transcription factor for CENP-N and directly promotes CENP-N expression in NPC cells. CENP-N affects the glucose metabolism, proliferation, cell cycling and apoptosis of NPC cells in vitro and in vivo through the AKT pathway. CENP-N formed a complex with AKT in NPC cells. Both an AKT inhibitor (MK-2206) and a LDHA inhibitor (GSK2837808A) blocked the effect of CENP-N overexpression on NPC cells by promoting aerobic glycolysis, proliferation, cell cycling and apoptosis resistance. CONCLUSIONS: The IRF2/CENP-N/AKT axis promotes malignant biological behaviors in NPC cells by increasing aerobic glycolysis, and the IRF2/CENP-N/AKT signaling axis is expected to be a new target for NPC therapy.

Melanin-based nanomaterials: The promising nanoplatforms for cancer diagnosis and therapy.

Melanin-based nanoplatforms are biocompatible nanomaterials with a variety of unique physicochemical properties such as strong photothermal conversion ability, excellent drug binding capacity, strong metal chelation capacity, high chemical reactivity and versatile adhesion ability. These innate talents not only make melanin-based nanoplatforms be an inborn theranostic nanoagent for photoacoustic imaging-guided photothermal therapy of cancers, but also enable them to be conveniently transferred into cancer-targeting drug delivery systems and multimodality imaging nanoprobes. Due to the intriguing properties, melanin-based nanoplatforms have attracted much attention in investigations of cancer diagnosis and therapy. This review provides an overview of recent research advances in applications of melanin-based nanoplatforms in the fields of cancer diagnosis and therapy including cancer photothermal therapy, anticancer drug delivery, cancer-specific multimodal imaging and theranostics, etc. The remaining challenges and prospects of melanin-based nanoplatforms in biomedical applications are discussed at the end of this review.

BpV(pic) confers neuroprotection by inhibiting M1 microglial polarization and MCP-1 expression in rat traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of motor and cognitive impairment in young adults. It is associated with high mortality rates and very few effective treatment options. Bisperoxovanadium (pyridine-2-carboxyl) [bpV(pic)] is an commercially available inhibitor of Phosphatase and tensin homolog (PTEN). Previous studies have shown that bpV(pic) has protective effects in central nervous system. However, the role of bpV(pic) in TBI is unclear. In this study we aimed to investigate the neuroprotective role of bpV(pic) in rat TBI model. We found that injection of bpV(pic) significantly reduces brain edema and neurological dysfunction after TBI and this is mediated by AKT pathway. TBI is known to promote the M1 pro-inflammatory phenotype of microglial polarization and this effect is inhibited by bpV(pic) treatment which, instead promotes M2 microglial polarization in vivo and in vitro. We also found evidence of bpV(pic)-regulated neuroinflammation mediated by AKT activation and NF-κB p65 inhibition. BpV(pic) treatment also suppressed microglia in the peri-TBI region. MCP-1 is known to recruit monocytes and macrophages to promote inflammation, we show that bpV(pic) can inhibit TBI-induced up-regulation of MCP-1 via the AKT/NF-κB p65 signaling pathway. Taken together, our findings demonstrate that bpV(pic) plays a neuroprotective role in rat TBI, which may be achieved by inhibiting M1 microglia polarization and MCP-1 expression by modulating AKT/NF-κB p65 signaling pathway.

Glycine Exhibits Neuroprotective Effects in Ischemic Stroke in Rats through the Inhibition of M1 Microglial Polarization via the NF-κB p65/Hif-1α Signaling Pathway.

Glycine is a simple nonessential amino acid known to have neuroprotective properties. Treatment with glycine results in reduced infarct volume of the brain, neurologic function scores, and neuronal and microglial death in ischemic stroke injury. Neuroinflammation has been considered a major contributor to cerebral ischemia-induced brain damage. However, the role of glycine in neuroinflammation following ischemic stroke is unclear. The present study aimed to determine whether neuroinflammation is involved in the neuroprotective effects of glycine in cerebral ischemia injury. Ischemic stroke promotes M1 microglial polarization. Interestingly, we found that the injection of glycine in rats after injury can inhibit ischemia-induced inflammation and promote M2 microglial polarization in vivo (Sprague-Dawley rats) and in vitro (cortical microglia and BV-2 cells). We show that glycine suppresses Hif-1α by inhibiting the upregulation of NF-κB p65 after ischemia-reperfusion injury, resulting in the inhibition of proinflammatory activity. The activation of AKT mediates the inhibition of NF-κB p65/Hif-1α signaling by glycine. Moreover, we confirm that glycine-regulated AKT activation is mediated by the inhibition of PTEN in a PTEN depletion cell line, U251 cells. Glycine modulates microglial polarization after ischemic stroke, which indirectly inhibits ischemia-induced neuronal death and functional recovery. Taken together, our findings provide a new understanding of glycine in neuroprotection by inhibiting M1 microglial polarization and promoting anti-inflammation by suppressing NF-κB p65/Hif-1α signaling.

Effects of dietary phytoestrogens on core body temperature during the estrous cycle and pregnancy.

Phytoestrogens have received increased investigative attention due to their potential protective effects in connection to age-related diseases and hormone-dependent cancers. Phytoestrogens appear to be an effective treatment during perimenopause where symptoms, such as hot flashes are reduced. However, little is known about the influence of phytoestrogens on core body temperature during various hormonal conditions. This study examined the effects of dietary phytoestrogens on core body temperature during estrous cycles or pregnancy by feeding Long-Evans rats either a diet rich in phytoestrogens (Phyto-600) versus a diet relatively low in phytoestrogens (Phyto-free). Independent of treatments, body temperature was highest at proestrus and declined during estrus and diestrus. Moreover, the consumption of the Phyto-600 diet moderately decreased body temperature during proestrus, estrus and diestrus versus Phyto-free-fed animals. During pregnancy, independent of treatments, core body temperature decreased as a function of increasing gestational length. Phyto-600-fed rats displayed significantly decreased body temperatures (by approximately 0.5 degrees C) from gestation days 6 to 19, compared to Phyto-free values. The results from this study indicate that consumption of dietary phytoestrogens alters the neuroendocrine mechanism of core body temperature regulation that may help explain, in part, the beneficial effects of phytoestrogens for hot flashes.

Stress (hypothalamic-pituitary-adrenal axis) and pain response in male rats exposed lifelong to high vs. low phytoestrogen diets.

Estrogens exhibit complex but beneficial effects on brain structure, function and behavior. Soy-derived dietary phytoestrogens protect against hormone-dependent and age-related diseases, due to their estrogen-like hormonal actions. However, the effects of phytoestrogens on brain and behavior are relatively unknown. This study examined the influence of exposing male Long-Evans rats (lifelong) to either a phytoestrogen-rich (Phyto-600) or a phytoestrogen-free (Phyto-free) diet on body weights, behavioral pain thresholds, the hypothalamic-pituitary-adrenal (HPA) hormonal stress response, hippocampal glucocorticoid receptor and brain neural cell adhesion molecules (NCAM) and synaptophysin levels using standard behavioral and biochemical techniques. Body weights were significantly decreased in Phyto-600 fed animals compared to Phyto-free values. There were no significant changes in behavioral pain thresholds, circulating corticosterone concentrations (after acute immobilization stress) or NCAM and synaptophysin levels in various brain regions by the diet treatments. However, Phyto-600 fed males displayed significantly higher plasma adrenocorticotrophin (ACTH) (post-stress) and hippocampal glucocorticoid receptor levels vs. Phyto-free values. These data suggest that (1) body weights are significantly reduced by soy-derived phytoestrogens, (2) behavioral pain thresholds (via heat stimuli) are not influenced by dietary phytoestrogens, but (3) these estrogenic molecules in the hippocampus enhance glucocorticoid receptor abundance and alter the negative feedback of stress hormones towards a female-like pattern of higher ACTH release after activation of the HPA stress axis. This study is the first to show that lifelong consumption of dietary phytoestrogens alters the HPA stress response in male rats.