Astaxanthin inhibits homocysteine­induced endothelial cell dysfunction via the regulation of the reactive oxygen species­dependent VEGF­VEGFR2­FAK signaling pathway.

Increased plasma levels of homocysteine (Hcy) can cause severe damage to vascular endothelial cells. Hcy­induced endothelial cell dysfunction contributes to the occurrence and development of human cerebrovascular diseases (CVDs). Our previous studies have revealed that astaxanthin (ATX) exhibits novel cardioprotective activity against Hcy­induced cardiotoxicity in vitro and in vivo. However, the protective effect and mechanism of ATX against Hcy­induced endothelial cell dysfunction requires further investigation. In the present study, treatment of human umbilical vascular endothelial cells (HUVECs) with Hcy inhibited the migration, invasive and tube formation potentials of these cells in a dose­dependent manner. Hcy treatment further induced a time­dependent increase in the production of reactive oxygen species (ROS), and downregulated the expression of vascular endothelial growth factor (VEGF), phosphorylated (p)­Tyr­VEGF receptor 2 (VEGFR2) and p­Tyr397­focal adhesion kinase (FAK). On the contrary, ATX pre­treatment significantly inhibited Hcy­induced cytotoxicity and increased HUVEC migration, invasion and tube formation following Hcy treatment. The mechanism of action may involve the effective inhibition of Hcy­induced ROS generation and the recovery of FAK phosphorylation. Collectively, our findings suggested that ATX could inhibit Hcy­induced endothelial dysfunction by suppressing Hcy­induced activation of the VEGF­VEGFR2­FAK signaling axis, which indicates the novel therapeutic potential of ATX in treating Hcy­mediated CVD.

Correction to: Reversal of homocysteine-induced neurotoxicity in rat hippocampal neurons by astaxanthin: evidences for mitochondrial dysfunction and signaling crosstalk.

[This corrects the article DOI: 10.1038/s41420-018-0114-x.].

Reversal of homocysteine-induced neurotoxicity in rat hippocampal neurons by astaxanthin: evidences for mitochondrial dysfunction and signaling crosstalk.

Elevated plasma level of homocysteine (Hcy) represents an independent risk for neurological diseases, and induction of oxidative damage is considered as one of the most important pathomechanisms. Astaxanthin (ATX) exhibits strong antioxidant activity in kinds of experimental models. However, the potential of ATX against Hcy-induced neurotoxicity has not been well explored yet. Herein, the neuroprotective effect of ATX against Hcy-induced neurotoxicity in rat hippocampal neurons was examined, and the underlying mechanism was evaluated. The results showed that ATX pre-treatment completely reversed Hcy-induced neurotoxicity through inhibiting cell apoptosis in rat primary hippocampal neurons. The mechanical investigation revealed that ATX effectively blocked Hcy-induced mitochondrial dysfunction by regulating Bcl-2 family and opening of mitochondrial permeability transition pore (MPTP). ATX pre-treatment also attenuated Hcy-induced oxidative damage via inhibiting the release of intracellular reactive oxide species (ROS) and superoxide anion through regulating MPTP opening. Moreover, normalization of MAPKs and PI3K/AKT pathways also contributed to ATX-mediated protective effects. Taken together, these results above suggested that ATX has the potential to reverse Hcy-induced neurotoxicity and apoptosis by inhibiting mitochondrial dysfunction, ROS-mediated oxidative damage and regulation of MAKPs and AKT pathways, which validated the strategy of using ATX could be a highly effective way in combating Hcy-mediated neurological disorders.

Selenocysteine antagonizes oxygen glucose deprivation-induced damage to hippocampal neurons.

Designing and/or searching for novel antioxidants against oxygen glucose deprivation (OGD)-induced oxidative damage represents an effective strategy for the treatment of human ischemic stroke. Selenium is an essential trace element, which is beneficial in the chemoprevention and chemotherapy of cerebral ischemic stroke. The underlying mechanisms for its therapeutic effects, however, are not well documented. Selenocysteine (SeC) is a selenium-containing amino acid with neuroprotective potential. Studies have shown that SeC can reduce irradiation-induced DNA apoptosis by reducing DNA damage. In this study, the in vitro protective potential and mechanism of action of SeC against OGD-induced apoptosis and neurotoxicity were evaluated in HT22 mouse hippocampal neurons. We cultured HT22 cells in a glucose-free medium containing 2 mM Na2S4O2, which formed an OGD environment, for 90 minutes. Findings from MTT, flow cytometry and TUNEL staining showed obvious cytotoxicity and apoptosis in HT22 cells in the OGD condition. The activation of Caspase-7 and Caspase-9 further revealed that OGD-induced apoptosis of HT22 cells was mainly achieved by triggering a mitochondrial-mediated pathway. Moreover, the OGD condition also induced serious DNA damage through the accumulation of reactive oxygen species and superoxide anions. However, SeC pre-treatment for 6 hours effectively inhibited OGD-induced cytotoxicity and apoptosis in HT22 cells by inhibiting reactive oxygen species-mediated oxidative damage. Our findings provide evidence that SeC has the potential to suppress OGD-induced oxidative damage and apoptosis in hippocampal neurons.

Function of Znf804a in neuronal migration, proliferation and differentiation during mice brain development / 中国心理卫生杂志

Objective:To explore the function of Znf804a during brain development by using mouse model.Methods:The shRNA of Znf804a (shZnf804a) and control (pSUPER) plasmids were introduced into ventricular zone of ICR (Institute of Cancer Research) mice at E14.5 (three mice in each group) by using in utero electroporation.The speed of migration was evaluated by comparing the proportions of neuron in cortical plate (CP) zone.The proliferation speed was evaluated by comparing the diameters of neurospheres formed by neuron progenitor cells.The differentiation speed was evaluated by comparing the proportions of Nestin staining positive cells in neuron progenitor cells.Results:The proportion of neurons in CP zone was lower in shZnf804a group than in controls(11.8％ vs.75.4％,P ＜ 0.001).The diameter of neurospheres formed by neuron progenitor cells was bigger in shZnf804a group than in controls (295μm vs.172μm,P ＜0.01).The proportion of Nest in staining positive cells in neuron progenitor cells was larger in shZnf804a group than in controls (31.5％ vs.9.6％,P ＜0.01).Conclusion:It suggests that the migration speed of neurons in shZnf804a is lower than that in controls,the proliferation speed is higher than that in controls,and the differentiation speed is lower than that in controls.These results indicate that Znf804a may play an important role in the development of mouse brain.