Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation.

Shank3, a key molecule related to the development and deterioration of autism, has recently been found to downregulate in the murine brain after ischemia/reperfusion (I/R). Despite this discovery, however, its effects on neuronal injury and the mechanism underlying the effects remain to be clarified. To address this, in this study, based on genetically modified mice models, we revealed that the expression of Shank3 showed a time-dependent change in murine hippocampal neurons after I/R, and that conditional knockout (cko) of Shank3 in neurons resulted in aggravated neuronal injuries. The protective effects of Shank3 against oxidative stress and inflammation after I/R were achieved through direct binding STIM1 and subsequent proteasome-mediated degradation of STIM1. The STIM1 downregulation induced the phosphorylation of downstream Nrf2 Ser40, which subsequently translocated to the nucleus, and further increased the expression of antioxidant genes such as NQO1 and HO-1 in HT22 cells. In vivo, the study has further confirmed that double knockout of Shank3 and Stim1 alleviated oxidative stress and inflammation after I/R in Shank3cko mice. In conclusion, the present study has demonstrated that Shank3 interacts with STIM1 and inhibits post-I/R neuronal oxidative stress and inflammatory response via the Nrf2 pathway. This interaction can potentially contribute to the development of a promising method for I/R treatment.

Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice.

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness. Autophagy plays a critical role in ischemic brain injury, but its role in hypobaric hypoxia (HH) remains unknown. Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain, and is partially responsible for HH-induced oxidative stress, neuronal loss, and brain damage. The autophagic agonist rapamycin only promotes the initiation of autophagy. By proteome analysis, a screen showed that protein dynamin2 (DNM2) potentially regulates autophagic flux. Overexpression of DNM2 significantly increased the formation of autolysosomes, thus maintaining autophagic flux in combination with rapamycin. Furthermore, the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure. These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

Acidic condition accelerates cation release from purple rock in Southwestern China.

In spite of the fact that rock weathering performs an essential task in the evolution of the Earth's surface, the quantitative assessment between pH and rates of chemical weathering remain unclear. This study aims to characterize the chemical weathering rate of purple rocks and then develops a model to calculate the release rates of cations (K+, Na+, Ca2+ and Mg2+) under various pH conditions. Two types of purple rock were sampled from the Shaximiao Group (J2s) and Penglaizhen Group (J3p), and a series of laboratory experiments were performed by soaking the purple rocks in solutions with pHs from 2.5 to 7.0, over 24 treatment cycles. The results showed that the release rates of cations apparently increased as the pH decreased. The release of Ca2+ was the dominant process of chemical weathering in J3p under various pH treatments, while K+ and Na+ were remarkably high in J2s (with the exception of the pH 2.5 treatment). Quantitative analysis revealed that the rate of cation release was significantly related to the H+ concentration (p < 0.001) and the air temperature (p < 0.001). The relationship between cation release and acidity was found to be an exponential function. Our results suggested that solution acidity serves as an important driving force for cation release rates from purple rocks and that environmental acidification would enhance rock weathering.