Neuroprotective Effects of New Protein Kinase C Activator TPPB Against Aβ25–35 Induced Neurotoxicity in PC12 Cells

Alzheimer's disease (AD) is pathologically characterized by presence of senile plaques in the hippocampus, which are composed mainly of extracellular deposition of a polypeptide known as the beta amyloid, the Aβ. It has been demonstrated on numerous occasions that it was the deposition and aggregation of this Aβ peptide that cause neuronal dysfunction and even finally, the dementia. Lowering the deposition of Aβ or decreasing its neurotoxicity has long been one of the purposes of AD therapy. In previous study, we reported that protein kinase C (PKC) activator TPPB could regulate APP processing by increasing α-secretase activity. In this study we further investigated the potential neuroprotective effect of TPPB against Aβ(25-35)-induced neurotoxicity in PC12 cells. The results indicated that TPPB at concentration of 1?μM could antagonize Aβ(25-35) induced cell damage as evidenced by MTT assays, LDH release and by morphological changes. Furthermore, the neuroprotection in cell viability can be blocked by inhibitors of PKC, Akt and MAPK. The experiment also indicated that TPPB could increase the phosphorylation of Akt, PKC, MARCKS and MAPK, which were inhibited by Aβ(25-35) treatment. Finally, TPPB inhibited the activation of caspase-3 induced by Aβ(25-35). Taken together, the experiment here implies that TPPB has a role against Aβ(25-35)-induced neurotoxicity in PC12 cells and may suggest its therapeutic potential in AD.     

Genistein Inhibits Aβ25–35 –Induced Neurotoxicity in PC12 Cells via PKC Signaling Pathway

Protein kinase C (PKC) signaling pathway is recognized as an important molecular mechanism of Alzheimer??s disease (AD) in the regulation of neuronal plasticity and survival. Genistein, the most active molecule of soy isoflavones, exerts neuroprotective roles in AD. However, the detailed mechanism has not been fully understood yet. The present study aimed to investigate whether the neuroprotective effects of genistein against amyloid ?? (A??)-induced toxicity in cultured rat pheochromocytoma (PC12) cells is involved in PKC signaling pathway. PC12 cells were pretreated with genistein for 2?h following incubation with A??_25?C35 for additional 24?h. Cell viability was assessed by MTT. Hoechst33342/PI staining was applied to determine the apoptotic cells. PKC activity, intracellular calcium level and caspase-3 activity were analyzed by assay kits. The results showed that pretreatment with genistein significantly increased cell viability and PKC activity, decreased the levels of intracellular calcium, attenuated Hoechst/PI staining and blocked caspase-3 activity in A??_25?C35-treated PC12 cells. Pretreatment of Myr, a general PKC inhibitor, significantly attenuated the neuroprotective effect of genistein against A??_25?C35-treated PC12 cells. The present study indicates that PKC signaling pathway is involved in the neuroprotective action of genistein against A??_25?C35-induced toxicity in PC12 cells.     

Protective Effect of 1-Methylated β-Carbolines Against 3-Morpholinosydnonimine-Induced Mitochondrial Damage and Cell Viability Loss in PC12 Cells

The present study investigated the effect of 1-methylated beta-carbolines (harmaline, harmalol and harmine) on change in the mitochondrial membrane permeability and cell death due to reactive nitrogen species in differentiated PC12 cells. beta-Carbolines, caspase inhibitors (z-LEHD.fmk and z-DQMD.fmk) and antioxidants (N-acetylcysteine, dithiothreitol, melatonin, carboxy-PTIO and uric acid) depressed cell viability loss due to 3-morpholinosydnonimine (SIN-1) in PC12 cells. beta-Carbolines inhibited the nuclear damage, the decrease in mitochondrial transmembrane potential, the cytochrome c release, the formation of reactive oxygen species and the depletion of GSH caused by SIN-1 in PC12 cells. beta-Carbolines decreased the SIN-1-induced formations of 3-nitrotyrosine, malondialdehyde and carbonyls in PC12 cells. The results show that 1-methylated beta-carbolines attenuate SIN-1-induced mitochondrial damage. This results in the inhibition of caspase-9 and -3 and apoptotic cell death in PC12 cells by suppressing the toxic actions of reactive oxygen and nitrogen species, including the GSH depletion.     

Magnesium Lithospermate B Protects Neurons Against Amyloid β (1–42)-Induced Neurotoxicity Through the NF-κB Pathway

Neurochemical Research - Magnesium lithospermate B (MLB) is one of the major bioactive components of Radix Salviae miltiorrhizae, a Chinese traditional herbal medicine colloquially known as Dan...     

β-Asarone Exerts Antioxidative Effects on H2O2-Stimulated PC12 Cells by Activating Nrf2/HO-1 Pathway

Neurochemical Research - Oxidative stress-mediated neuron damage is considered an important contributor to the pathogenesis and development of neurodegenerative diseases. Although β-asarone is...     

Enhanced Expression of Integrin αvβ3 Induced by TGF-β Is Required for the Enhancing Effect of Fibroblast Growth Factor 1 (FGF1) in TGF-β-Induced Epithelial-Mesenchymal Transition (EMT) in Mammary Epithelial Cells

Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer metastasis, and is regulated by growth factors such as transforming growth factor β (TGF-β) and fibroblast growth factors (FGF) secreted from the stromal and tumor cells. However, the role of growth factors in EMT has not been fully established. Several integrins are upregulated by TGF-β1 during EMT. Integrins are involved in growth factor signaling through integrin-growth factor receptor crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and the interaction was required for FGF1 functions such as cell proliferation and migration. We studied the role of αvβ3 induced by TGF-β on TGF-β-induced EMT. Here, we describe that FGF1 augmented EMT induced by TGF-β1 in MCF10A and MCF12A mammary epithelial cells. TGF-β1 markedly amplified integrin αvβ3 and FGFR1 (but not FGFR2). We studied if the enhancing effect of FGF1 on TGF-β1-induced EMT requires enhanced levels of both integrin αvβ3 expression and FGFR1. Knockdown of β3 suppressed the enhancement by FGF1 of TGF-β1-induced EMT in MCF10A cells. Antagonists to FGFR suppressed the enhancing effect of FGF1 on EMT. Integrin-binding defective FGF1 mutant did not augment TGF-β1-induced EMT in MCF10A cells. These findings suggest that enhanced integrin αvβ3 expression in addition to enhanced FGFR1 expression is critical for FGF1 to augment TGF-β1-induced EMT in mammary epithelial cells.