Fine particulate matter leads to reproductive impairment in male rats by overexpressing phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway

Ketamine is a widely used anesthetic in pediatric clinical practice. Previous studies have demonstrated that ketamine induces neurotoxicity and has a modulatory effect on the cells of the immune system. Here, we evaluated the potential protective effect and underlying mechanisms of natural phenolic compound curcumin against ketamine-induced toxicity in rat thymocytes. Rat thymocytes were exposed to 100 µM ketamine alone or combined with increasing concentrations of curcumin (0.3, 1, and 3 μM) for 24 hours. Cell viability was analyzed with CCK-8 assay kit. Apoptosis was analyzed using flow cytometry and propidium iodide as well as Z-VAD-FMK and Z-LEHD-FMK inhibitors. Reactive oxygen species (ROS) production and mitochondrial membrane potential [MMP] were measured by flow cytometry. Colorimetric assay with DEVD-pNA substrate was used for assessing caspase-3 activity. Involvement of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was tested with Wortmannin inhibitor. Ketamine induced toxicity in cells, increased the number of hypodiploid cells, caspase-3 activity and ROS production, and inhibited the MMP. Co-incubation of higher concentrations of curcumin (1 and 3 μM) with ketamine markedly decreased cytotoxicity, apoptosis rate, caspase-3 activity, and ROS production in rat thymocytes, and increased the MMP. Application of Z-VAD-FMK (a pan caspase inhibitor) or Z-LEHD-FMK (caspase-9 inhibitor) with ketamine effectively attenuated the ketamine-induced apoptosis in rat thymocytes. Administration of Wortmannin (a PI3K inhibitor) with curcumin and ketamine significantly decreased the protective effect of curcumin on rat thymocytes. Our results indicate that ketamine-induced toxicity in rat thymocytes mainly occurs through the mitochondria-mediated apoptotic pathway and that the PI3K/Akt signaling pathway is involved in the anti-apoptotic effect of curcumin.

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Berberine Exerts Anti-cancer Activity by Modulating Adenosine Monophosphate-Activated Protein Kinase (AMPK) and the Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) Signaling Pathways

Current Pharmaceutical Design ◽

10.2174/1381612826666200928155728 ◽

2020 ◽

Vol 26 ◽

Author(s):

Jin Huang ◽

Wei Feng ◽

Shanshan Li ◽

Huiling Tang ◽

Siru Qin ◽

...

Keyword(s):

Protein Kinase ◽

Signaling Pathways ◽

Protein Kinase B ◽

Scientific Evidence ◽

Adenosine Monophosphate ◽

Akt Signaling ◽

Phosphatidylinositol 3 Kinase ◽

Pubmed Database ◽

Anti Cancer ◽

Phosphatidylinositol 3

Background: The antagonistic relationship between adenosine monophosphate-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling play a vital role in cancer development. The anti-cancer effects of berberine have been reported as a main component of the traditional Chinese medicine Rhizoma coptidis, although the roles of these signaling pathways in these effects have not been systematically reviewed. Methods: We searched the PubMed database for studies with keywords including [“berberine”] and [“tumor” or “cancer”] and [“AMPK”] or [“AKT”] published between January 2010 and July 2020, to elucidate the roles of the AMPK and PI3K/AKT pathways and their upstream and downstream targets in the anti-cancer effects of berberine. Results: The anti-cancer effects of berberine include inhibition of cancer cell proliferation, promotion of apoptosis and autophagy in cancer cells, and prevention of metastasis and angiogenesis. The mechanism of these effects involves multiple cell kinases and signaling pathways, including activation of AMPK and forkhead box transcription factor O3a (FOXO3a), accumulation of reactive oxygen species (ROS), and inhibition of the activity of PI3K/AKT, rapamycin (mTOR) and nuclear factor-κB (NF-κB). Most of these mechanisms converge on regulation of the balance of AMPK and PI3K/AKT signaling by berberine. Conclusion: This evidence supports the possibility that berberine is a promising anti-cancer natural product, with pharmaceutical potential in inhibiting cancer growth, metastasis and angiogenesis via multiple pathways, particularly by regulating the balance of AMPK and PI3K/AKT signaling. However, systematic preclinical studies are still required to provide scientific evidence for further clinical studies.

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Nuclear Factor-κB Activating Protein Plays an Oncogenic Role in Neuroblastoma Tumorigenesis and Recurrence Through the Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.622793 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jun Liu ◽

Mingyu Zhang ◽

Ying Kan ◽

Wei Wang ◽

Jie Liu ◽

...

Keyword(s):

Signaling Pathway ◽

Protein Kinase B ◽

Nuclear Factor Κb ◽

Akt Signaling ◽

Nuclear Factor ◽

Akt Signaling Pathway ◽

Phosphatidylinositol 3 Kinase ◽

Recurrence Group ◽

Chromosome 11Q Deletion ◽

11Q Deletion

Nuclear factor-κB activating protein (NKAP) is a conserved nuclear protein that acts as an oncogene in various cancers and is associated with a poor prognosis. This study aimed to investigate the role of NKAP in neuroblastoma (NB) progression and recurrence. We compared NKAP gene expression between 89 recurrence and 134 non-recurrence patients with NB by utilizing the ArrayExpress database. The relationship between NKAP expression and clinicopathological features was evaluated by correlation analysis. We knocked down NKAP expression in NB1 and SK-N-SH cells by small interfering RNA transfection to verify its role in tumor proliferation, apoptosis, and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. NKAP gene expression in NB tissues was significantly overexpressed in the recurrence group compared with the non-recurrence group, and NKAP was enriched in the PI3K/AKT pathway. Correlation analysis revealed NKAP expression was correlated with chromosome 11q deletion in patients with NB. Knockdown of NKAP expression significantly inhibited the proliferation and promoted the apoptosis of NB1 and SK-N-SH cells. Moreover, we found that small interfering NKAP significantly reduced p-PI3K and p-AKT expression. NKAP knockdown played an oncogenic role in NB by inhibiting PI3K/AKT signaling pathway activations both in vitro and in vivo. Our research revealed that NKAP mediates NB cells by inhibited proliferation and promoted apoptosis through activating the PI3K/AKT signaling pathways, and the expression of NKAP may act as a novel biomarker for predicting recurrence and chromosome 11q deletion in patients with NB.

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