Cadmium induces mitochondrial dysfunction via SIRT1 suppression-mediated oxidative stress in neuronal cells.

Cadmium is a widespread environmental contaminant and its neurotoxicity has raised serious concerns. Mitochondrial dysfunction is a key event in Cd-induced nervous system disease; however, the exact molecular mechanism involved has not been fully elucidated. Increasing evidences have shown that Sirtuin 1 (SIRT1) is the key target protein impaired in Cd-induced mitochondrial dysfunction. In this study, the role of SIRT1 in Cd-induced mitochondrial dysfunction and cell death and the underlying mechanisms were evaluated in vitro using PC12 cells and primary rat cerebral cortical neurons. The results showed that Cd exposure caused cell death by inhibiting SIRT1 expression, thus inducing oxidative stress and mitochondrial dysfunction in vitro. However, inhibition of oxidative stress by the antioxidant puerarin alleviated Cd-induced mitochondrial dysfunction. Furthermore, activation of SIRT1 using the agonist Srt1720 significantly abolished Cd-induced oxidative stress and mitochondrial dysfunction and ultimately alleviated Cd-induced neuronal cell death. Collectively, our data indicate that Cd induced mitochondrial dysfunction via SIRT1 suppression-mediated oxidative stress, leading to the death of PC12 cells and primary rat cerebral cortical neurons. These findings suggest a novel mechanism for Cd-induced neurotoxicity.

Puerarin alleviates cadmium-induced mitochondrial mass decrease by inhibiting PINK1-Parkin and Nix-mediated mitophagy in rat cortical neurons.

Cadmium (Cd) has well-known central nervous system toxicity, and mitochondria are direct targets of Cd-induced neuronal toxicity. However, how Cd induces mitochondrial mass decrease in terms of its neurotoxic effects remains unknown. Puerarin, an isoflavone extracted from kudzu root, can cross the blood-brain barrier and exert protective effects in nervous system disease. The purpose of the study was to determine the mechanism of Cd-induced mitochondrial mass decrease and the protective role of puerarin in rat cortical neurons. The results indicated that Cd induced mitochondrial mass decrease by activating mitophagy mediated by the PTEN-induced putative kinase protein 1 (PINK1)-E3 ubiquitin ligase (Parkin) and Nip3-like protein X (Nix) pathways in rat cortical neurons. Puerarin improved the Cd-induced decrease in mitochondrial membrane potential (MMP) in vitro, and blocked PINK1-Parkin and Nix-mediated mitophagy, inhibiting Cd-induced mitochondrial mass decrease in rat cortical neurons in vitro and in vivo. In summary, our data clearly indicated that puerarin protects rat cortical neurons against Cd-induced neurotoxicity by ameliorating mitochondrial damage, inhibiting mitophagy-mediated mitochondrial mass decrease. Puerarin appears to have great potential as a neuroprotective agent.

Puerarin alleviates cadmium-induced rat neurocyte injury by alleviating Nrf2-mediated oxidative stress and inhibiting mitochondrial unfolded protein response.

Cadmium (Cd) is a highly neurotoxic environmental pollutant. Puerarin (Pur) is a natural antioxidant isolated from Kudzu root that exhibits a powerful neuroprotective effect. Herein, we illustrated the mechanism underlying the protective effect of Pur on Cd-induced rat neurocyte injury in an in vivo rat model as well as in vitro using PC12 cells and primary rat cerebral cortical neurons. First, the results showed that Pur alleviated Cd-induced cerebral cortical pathological damage and decreased the viability of neurocytes. Furthermore, Cd activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which plays a negative role in Cd-induced rat neurocyte injury. In addition, Pur alleviated Cd-induced oxidative stress by enhancing antioxidant defense, reducing reactive oxygen species (ROS) accumulation and lipid peroxidation, and inhibiting activation of the Nrf2 signaling pathway in rat neurocytes. Moreover, Pur inhibited the Cd-induced mitochondrial unfolded protein response (UPRmt) in rat neurocytes. Overall, Pur alleviated Cd-induced rat neurocyte injury by alleviating Nrf2-mediated oxidative stress and inhibiting UPRmt.

Induction of mitochondrial apoptosis pathway mediated through caspase-8 and c-Jun N-terminal kinase by cadmium-activated Fas in rat cortical neurons.

Cadmium (Cd) is a toxic metal and an environmental pollutant and can cause neurotoxicity by inducing apoptosis. Fas (CD95/Apo-1) is a cell-surface receptor that triggers apoptosis upon ligand binding, mediated through the mitochondrial apoptotic pathway. However, the role and regulatory mechanism of Fas in Cd-induced neuronal apoptosis remain understudied. Here, we demonstrate that activation of caspase-8 and the c-Jun N-terminal kinase (JNK) pathway are mechanisms underlying Cd-induced Fas-mediated activation of the mitochondrial apoptotic pathway in rat cerebral cortical neurons. In vitro, Cd induced apoptosis in primary cortical neurons by activating caspase-8, JNK, and the mitochondrial apoptotic pathway. Fas knockdown enhanced cell viability in the presence of Cd and inhibited apoptosis by blocking Cd-activated Fas, caspase-8, and JNK. Fas knockdown also inhibited the decrease of mitochondrial membrane potential, cleavage of caspase-9/3 and poly (ADP-ribose) polymerase 1, and impaired nuclear translocation of apoptosis-inducing factor and endonuclease G. In vivo, Fas knockdown alleviated Cd-induced neuronal injury and inhibited apoptosis, activation of caspase-8, JNK, and mitochondrial apoptotic pathways in rat cerebral cortical neurons. In summary, our results demonstrate that Cd-activated Fas relays apoptotic signals from the cell surface to the mitochondria via caspase-8 and JNK activation in rat cerebral cortical neurons, leading to aggravation of the neuronal injury.

The role of striking and struck vehicles in side crashes between vehicles: Bayesian bivariate probit analysis in China.

OBJECTIVE: Side crashes between vehicles which usually lead to high casualties and property loss, rank first among total crashes in China. This paper aims to identify the factors associated with injury severity of side crashes at intersections and to provide suggestions for developing countermeasures to mitigate the levels of injuries. METHOD: In order to investigate the role of striking and struck vehicles in side crashes simultaneously, bivariate probit model was proposed and Bayesian approach was employed to evaluate the model, compared to the corresponding univariate probit model. DATA: Crash data from Beijing, China for the period 2009-2012 were used to carry out the statistical analysis. Based on the investigation with vehicles and data analysis on events, 130 intersection side crash cases were selected to form a specific dataset. Then, the influence of human, vehicles, roadway and environmental variables on crash severity was examined by means of bivariate probit regression within Bayesian framework. RESULTS: The effects of the factors on striking vehicle drivers and struck vehicle drivers were considered separately and simultaneously to find more targeted conclusions. The statistical analysis revealed vehicle type, lane number, no non-motorized lane and speeding have the corresponding influence on the injury severity of striking vehicles, while time of day and vehicle type of struck vehicles increased the likelihood of being injured. CONCLUSIONS: From the results it can be concluded that there indeed exists correlation between striking and struck vehicles in side crashes, although the correlation is not so strong. Importantly, Bayesian bivariate probit model can address the role of striking and struck vehicles in side crashes simultaneously and can accommodate the correlation clearly, which extends the range of univariate probit analysis. The general and empirical countermeasures are presented to improve the safety at intersections.