Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • The B class scavenger receptor CD

    2019-07-24

    The B class scavenger receptor CD36 acts as a fibrillar Aβ receptor [40]. In our studies, acute OAB-14 treatment caused a remarkable increase in CD36 expression on the surface of microglia, which might be the main reason why microglia remove fibrillar Aβ. CD36-positive microglia are M2 microglia [41], providing further validation for the hypothesis that OAB-14 promotes the conversion of microglia from the M1 to M2 phenotype. Aβ overaccumulation in the AD Imatinib (STI571) may trigger neuronal loss and synaptic degeneration. APP/PS1 mice displayed a loss of synaptic proteins. OAB-14 increased the number of NeuN-positive cells and the levels of the NeuN protein, and attenuated the decrease in the levels of the synapse-related proteins SYP, GAP43, and PSD95 in APP/PS1 mice, suggesting that OAB-14 improves synaptic plasticity and ameliorates synapse and neuronal loss. Among the numerous neurotrophic factors, BDNF is the most widely distributed factor in the central nervous system. BDNF binds to its specific receptor TrkB, inducing the phosphorylation of the TrkB receptor. Activated receptors trigger the MEK/ERK and PI3K/AKT pathways, increasing the expression of synapse-related proteins [42,43]. Thus, we asked how OAB-14 affected the expression synapse-associated proteins. Notably, bexarotene was recently shown to exert neuroprotective effects and improve behaviours by activating the nuclear receptor Nurr1 and BDNF [44]. BDNF-TrkB signalling increased PSD95 expression [45]. In the present study, acute OAB-14 treatment indeed activated the BDNF/TrkB pathway, followed by the PI3K/AKT and Raf/MEK/ERK pathways to enhance synaptic plasticity. The strong neuroprotective effects of OAB-14 are likely mediated by its dual function in increasing the clearance of Aβ deposits and enhancing neurotrophin function. ApoE3 was recently shown to increase the acetylation of histone H3 (Ac-H3) and then upregulate BDNF expression, whereas ApoE4 increases the expression of histone deacetylases, thereby reducing BDNF expression. Furthermore, ApoE3 also blocks ApoE4-mediated downregulation of BDNF [46]. Our results confirmed that OAB-14 increased ApoE3 expression, elevated the levels of acetylated H3, and subsequently increased BDNF expression. Additionally, OAB-14 also decreased ApoE4 expression and reduced its inhibitory effects on BDNF expression. ApoE3 activates the Aβ-degradation enzyme neprilysin [32]. ApoE3 not only inhibits GSK-3β activity by activating the PI3K/PKB pathway but also upregulates PSD95 and SYP to stimulate synaptogenesis. ApoE4 exerts the opposite effects. Moreover, ApoE interacts with its receptor LRP1 to exert an anti-inflammatory effect [47]. Thus, according to these reports, we propose the bold hypothesis that the ultimate mechanism by which OAB-14 improves cognitive impairments in APP/PS1 mice may be due to the increase of ApoE expression in the brain, particularly the expression of ApoE3. However, this hypothesis requires further validation in follow-up experiments.
    Conclusion
    Conflicts of interest statement
    Transparency document
    Introduction Gastric cancer (GC) is the fourth most common cancer and the second highest cause of cancer-related death worldwide, especially in East Asia [1,2]. Despite improvements in multidisciplinary treatment strategies, patient prognosis remains poor. Metastasis is the main cause of mortality in GC patients before or after curative surgery, and it severely threatens the survival of the patients [3]. Therefore, it is of great importance to identify new genes that are involved in the progression of GC metastasis and present a predictive value for prognosis. Recently, we performed a gene profiling analysis of samples from GC patients, and the abnormal expression of the gene KIF14 was identified. Kinesins are ATP-dependent molecular motors that carry cargo along microtubules. They are classified into 14 distinct families, with varying structural and functional characteristics [4]. KIF14 is a member of the kinesin‑3 superfamily and is located on chromosome 1q32.1 [5]. The KIF14 protein has a C-terminal motor domain, a citron kinase binding region and an N-terminal extension for the binding of PRC1 [6], and it plays an essential role in the mitotic spindle formation, midbody formation, cell cytokinesis and chromosome segregation. The deletion of KIF14 increases the level of p27Kip1 and induces cytokinesis failure in hepatocellular carcinoma cells [7,8]. KIF14 is widely accepted to play a role in tumorigenesis as a chromokinesin. The overexpression of KIF14 may lead to rapid and error-prone mitosis, which induces aneuploidy during tumorigenesis [9]. Its high expression is involved in the progression of many types of malignant tumors. The increased expression of KIF14 is identified in retinoblastoma, breast cancer, and lung cancer, which provides evidence that KIF14 may be an oncogene in the progression of multiple cancers [[9], [10], [11]]. Recently, KIF14 was reported to be overexpressed in medulloblastoma and associated with unfavorable progression-free survival and overall survival; moreover, the downregulation of KIF14 suppresses tumor proliferation and induces apoptosis [12]. KIF14 is also reported to induce anchorage-independent growth in the ovarian cancer cell line SKOV3 [13] and indicates a poor prognosis in patients with epithelial ovarian cancer. Moreover, it is strongly correlated with invasion and migration and is reported to be a predictor of grade and outcome of breast cancer [14]. In adult synovial sarcomas, enhanced KIF14 expression is strongly associated with metastasis [15]. Importantly, the deletion of KIF14 in breast cancer cells leads to increased cell spreading, altered focal adhesion dynamics, and the inhibition of cell migration and invasion [5]. In gastric cancer, Tong et al. recently reported that KIF14 was upregulated in a GC dataset [16]. However, the biological role and the underlying molecular mechanism of KIF14 in GC is still not known.