Bergaptol inhibits glioma cell proliferation and induces apoptosis via STAT3/Bcl-2 pathway.

Glioblastoma (GBM) is the most common primary malignant brain tumour and lacks therapeutic options with significant effects. The aberrant activation of STAT3 is a critical factor in glioma progression via activating multiple signalling pathways that promote glioma. Among them, the antiapoptotic gene Bcl-2 could be upregulated by p-STAT3, which is an important reason for the continuous proliferation of glioma. We previously reported that bergaptol, a natural furanocoumarin widely found in citrus products, exerts antineuroinflammatory effects by inhibiting the overactivation of STAT3. Here, we aimed to evaluate whether bergaptol could promote glioma apoptosis by inhibiting the STAT3/Bcl-2 pathway. This study found that bergaptol inhibited the proliferation and migration of GBM cell lines (U87 and A172) and promoted apoptosis in vitro. We also found that bergaptol significantly inhibited the STAT3/Bcl-2 pathway in GBM cells. U87 cells were implanted intracranially into nude mice to establish a glioma model, and glioma-bearing mice were treated with bergaptol (40 mg/kg). Bergaptol treatment significantly inhibited glioma growth and prolonged the glioma-bearing mice's survival time. In addition, bergaptol administration also significantly inhibited the STAT3/Bcl-2 pathway of tumour tissue in vivo. Overall, we found that bergaptol could effectively play an antiglioma role by inhibiting STAT3/Bcl-2 pathway, suggesting the potential efficacy of bergaptol in treating glioma.

Abnormal phosphorylation of protein tyrosine in neurodegenerative diseases.

Neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis, are chronic disorders of the CNS that are characterized by progressive neuronal dysfunction. These diseases have diverse clinical and pathological features and their pathogenetic mechanisms are not yet fully understood. Currently, widely accepted hypotheses include the accumulation of misfolded proteins, oxidative stress from reactive oxygen species, mitochondrial dysfunction, DNA damage, neurotrophin dysfunction, and neuroinflammatory processes. In the CNS of patients with neurodegenerative diseases, a variety of abnormally phosphorylated proteins play important roles in pathological processes such as neuroinflammation and intracellular accumulation of ß-amyloid plaques and tau. In recent years, the roles of abnormal tyrosine phosphorylation of intracellular signaling molecules regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) in neurodegenerative diseases have attracted increasing attention. Here, we summarize the roles of signaling pathways related to protein tyrosine phosphorylation in the pathogenesis of neurodegenerative diseases and the progress of therapeutic studies targeting PTKs and PTPs that provide theoretical support for future studies on therapeutic strategies for these devastating and important neurodegenerative diseases.

Bergaptol Alleviates LPS-Induced Neuroinflammation, Neurological Damage and Cognitive Impairment via Regulating the JAK2/STAT3/p65 Pathway.

Purpose: Neuroinflammation is considered a critical pathological process in various central nervous system (CNS) diseases and is closely related to neuronal death and dysfunction. Bergaptol is a natural 5-hydroxyfurocoumarin found in lemon, bergamot and other plants. Some studies have confirmed its anti-cancer, anti-inflammatory and anti-atherogenic functions, indicating that it may have significant medicinal value. In this study, we investigated the potential effect of Bergaptol in vitro and in vivo neuroinflammatory models. Methods: Mice were injected with LPS (40 µg/kg) into the hippocampal CA1 region and then injected intraperitoneally with Bergaptol (10, 20 and 40 mg/kg) once a day for two weeks. In addition, to verify the effect of Bergaptol on BV2 cells, Bergaptol with different concentrations (5, 10 and 20 µg/mL) was firstly incubated for 1 hour, then LPS with a concentration of 1 µg/mL was added and incubated for 23 hours. Results: Bergaptol treatment significantly improved the cognitive impairment induced by LPS. In addition, Bergaptol significantly inhibited the reduction of dendritic spines and the mRNA level of inflammatory factors (TNF-α, IL-6 and IL-1ß) in hippocampal induced by LPS. In vitro, Bergaptol inhibited the production of TNF-α, IL-6 and IL-1ß from LPS-treated BV-2 cells. In addition, Bergaptol treatment significantly reduced the phosphorylation levels of JAK2, STAT3 and p65 in LPS-stimulated BV-2 cells. Conclusion: In conclusion, our results suggest that Bergaptol alleviates LPS-induced neuroinflammation, neurological damage and cognitive impairment by regulating the JAK2/STAT3/P65 pathway, suggesting that Bergaptol is a promising neuroprotective agent.

PHLDA1 promotes sevoflurane-induced pyroptosis of neuronal cells in developing rats through TRAF6-mediated activation of Rac1.

Sevoflurane anesthesia induces neurocognitive impairment and pyroptosis in the developing brain. Pleckstrin homology-like domain, family A, member 1 (PHLDA1) was involved in neuronal apoptosis, oxidative stress and inflammation during ischemic stroke. The role of PHLDA1 in sevoflurane-induced pyroptosis in developing rats was investigated. Firstly, neonatal rats at day 7 was exposed to 2.0% sevoflurane for 6 h to induce neurotoxicity. Pathological analysis showed that sevoflurane anesthesia induced hippocampal injury and reduced the number of neurons. The expression of PHLDA1 was elevated in hippocampus of sevoflurane-treated rats. Secondly, sevoflurane anesthesia-treated neonatal rats were injected with adeno-associated virus serotype (AAV) to mediate knockdown of PHLDA1. Injection with AAV-shPHLDA1 ameliorated sevoflurane-induced hippocampal injury and neurocognitive impairment in rats. Moreover, knockdown of PHLDA1 increased the number of neurons in sevoflurane-treated rats. Silence of PHLDA1 suppressed neuronal apoptosis, and inhibited pyroptosis in sevoflurane-treated rats. Thirdly, PHLDA1 was also elevated in sevoflurane-treated primary neuronal cells. Loss of PHLDA1 also enhanced cell viability and suppressed pyroptosis of sevoflurane-treated primary neuronal cells. Lastly, silence of PHLDA1 reduced protein expression of TRAF6 and p-Rac1 in sevoflurane-treated rats and neuronal cells. Over-expression of TRAF6 attenuated PHLDA1 silence-induced increase of cell viability and decreased pyroptosis in neuronal cells. In conclusion, loss of PHLDA1 protected against sevoflurane-induced pyroptosis in developing rats through inhibition of TRAF6-mediated activation of Rac1.

Downregulation of Williams syndrome transcription factor (WSTF) suppresses glioblastoma cell growth and invasion by inhibiting PI3K/AKT signal pathway.

Williams syndrome transcription factor (WSTF) participates in diverse cellular processes, including tumor cell proliferation and migration. However, the function of WSTF in glioblastoma (GBM) remains unknown. Data from the Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) datasets showed that WSTF was up-regulated in GBM tissues. Moreover, WSTF was also increased in the GBM cells. pcDNA-mediated over-expression of WSTF contributed to cell proliferation and invasion of GBM cells, while GBM cell proliferation and invasion were suppressed by shRNA-mediated silencing of WSTF. Additionally, GBM cell apoptosis was reduced by over-expression of WSTF accompanied by decrease in Bax and cleaved caspase-3, while promoted by silencing of WSTF with increase in Bax and cleaved caspase-3. Protein expression of AKT phosphorylation was enhanced by WSTF over-expression while reduced by WSTF silencing. Inhibitor of phosphatidylinositol 3 kinase attenuated WSTF over-expression-induced increase in GBM cell proliferation and invasion. In conclusion, WSTF contributed to GBM cell growth and invasion through activation of PI3K/AKT pathway.