Signaling Pathways Involved in Manganese-Induced Neurotoxicity.

Manganese (Mn) is an essential trace element, but insufficient or excessive bodily amounts can induce neurotoxicity. Mn can directly increase neuronal insulin and activate insulin-like growth factor (IGF) receptors. As an important cofactor, Mn regulates signaling pathways involved in various enzymes. The IGF signaling pathway plays a protective role in the neurotoxicity of Mn, reducing apoptosis in neurons and motor deficits by regulating its downstream protein kinase B (Akt), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR). In recent years, some new mechanisms related to neuroinflammation have been shown to also play an important role in Mn-induced neurotoxicity. For example, DNA-sensing receptor cyclic GMP-AMP synthase (cCAS) and its downstream signal efficient interferon gene stimulator (STING), NOD-like receptor family pyrin domain containing 3(NLRP3)-pro-caspase1, cleaves to the active form capase1 (CASP1), nuclear factor κB (NF-κB), sirtuin (SIRT), and Janus kinase (JAK) and signal transducers and activators of the transcription (STAT) signaling pathway. Moreover, autophagy, as an important downstream protein degradation pathway, determines the fate of neurons and is regulated by these upstream signals. Interestingly, the role of autophagy in Mn-induced neurotoxicity is bidirectional. This review summarizes the molecular signaling pathways of Mn-induced neurotoxicity, providing insight for further understanding of the mechanisms of Mn.

Triclosan induces PC12 cells injury is accompanied by inhibition of AKT/mTOR and activation of p38 pathway.

Triclosan (TCS) has been widely used as a disinfectant and antiseptic in multiple consumer and healthcare products due to its clinical effectiveness against various bacteria, fungi and protozoa. Recently, several studies have reported the adverse effects of TCS on various nerve cells, arousing concerns about its potential neurotoxicity. The present study aimed to investigate the neurotoxicity of TCS in rat pheochromocytoma PC12 cells. After differentiation, the stabilized PC12 cells were treated with 1, 10, 50 µM TCS for 12 h. At the end of the treatment, the generation of reactive oxygen species (ROS), protein expression of apoptotic-related genes, AMPK-AKT/mTOR, as well as p38 in PC12 cells were determined. The concentrations were chosen based on the results of cell viability and lactic dehydrogenase (LDH) assays in response to TCS treatment (ranging from 0.001 to 100 µM) for varied time periods. The results showed that TCS is cytotoxic to PC12 cells, causing decreased cell viability accompanied by increased LDH release. TCS treatment at 10 and 50 µM for 12 h increased the mRNA and protein expression of the pro-apoptotic gene Bax, while Bcl-2 levels remained unchanged. Moreover, an increase in the generation of reactive oxygen species (ROS) was found in TCS-treated PC12 cells at the concentrations of 1 and 10 µM. Pretreatment with 100 µM N-acetyl cysteine (NAC- ROS scavenger) for 1 h normalized the ROS generations in TCS-treated PC12 cells. Additionally, the suppression of the phosphorylation of Akt and mTOR was observed in TCS-treated PC12 cells at 10 and 50 µM for 12 h, concomitant with the activation of p38 MAPK pathway at 50 µM TCS. However, there were no effects of TCS on the phosphorylation of AMPK in these cells. Taken together, these results suggest that TCS may cause adverse effects and oxidative stress in PC12 cells accompanied by inhibition of Akt/mTOR and activation of p38.