Inhibition of PI3K/Akt/mTOR signaling by NDRG2 contributes to neuronal apoptosis and autophagy in ischemic stroke.

BACKGROUND: Astrocytic N-myc downstream-regulated gene 2 (NDRG2), a differentiation- and stress-associated molecule, has been involved in the cause of ischemic stroke (IS). However, its downstream effector in IS remains unclear. This study aimed to characterize expression of NDRG2 in IS patients and rats and to investigate the underlying mechanism. METHODS: The protein expression of NDRG2 and mammalian target of the rapamycin (mTOR) and the extent of mTOR phosphorylation in plasma of IS patients were detected by ELISA. An oxygen-glucose deprivation model was established in mouse neuronal cells CATH.a, followed by cell counting kit-8, flow cytometry, TUNEL, and western blot assays to examine cell viability, apoptosis and autophagy. Finally, the effect of NDRG2-mediated phosphatidylinositol 3-kinase/protein kinase-B/mTOR (PI3K/AKT/mTOR) pathway on neuronal apoptosis and autophagy was verified in rats treated with middle cerebral artery occlusion. RESULTS: NDRG2 was highly expressed in the plasma of IS patients, while the extent of mTOR phosphorylation was reduced in IS patients. NDRG2 blocked the PI3K/Akt/mTOR signaling through dephosphorylation. Depletion of NDRG2 suppressed apoptosis and autophagy in CATH.a cells, which was reversed by a dual inhibitor of PI3K and mTOR, BEZ235. In vivo experiments confirmed that NDRG2 promoted neuronal apoptosis and autophagy by dephosphorylating and blocking the PI3K/Akt/mTOR signaling. CONCLUSION: The present study has shown that NDRG2 impairs the PI3K/Akt/mTOR pathway via dephosphorylation to promote neuronal apoptosis and autophagy in IS. These findings provide potential targets for future clinical therapies for IS.

Micro-structure and morphology of tailings sand under different oxidation and acidification degree.

The tailings pond is a dangerous source of man-made debris flow with high potential energy. The oxidative acidification of tailings may cause the instability of the pond and induce serious safety accidents. The influence of oxidation and acidification degree on macro mechanical properties of tailings is discussed from the aspects of mineral composition and microstructure. The results show that as the degree of oxidation and acidification of tailings sand increases, the overall structural performance and load-bearing capacity decrease, and its cohesion (c) and internal friction angle (φ) show a decreasing trend. In fact, the engineering properties of tailings with different oxidation and acidification degrees are dominated by the physicochemical composition and structural characteristics. On the one hand, as the degree of oxidation increases, acidic substance will neutralize with CaCO3 and CaMg(CO3)2, resulting in the loss of cemented substance and the decrease of cementation force between tailing sand particles as well as the gradual destruction of the integrity of tailing sand. On the other hand, the increase of oxidation and acidification degree of tailing sand leads to a gradual reduction of outline (2D) fractal dimension and gray surface (3D) fractal dimension of surface laminated structure as well as the obvious reduction of laminated structure and its roughness of tailings sand.

Changes and significance of serum CXCL-16, GDF-15, PLA-2 levels in patients with cerebral infarction.

OBJECTIVE: To explore the changes and significance of serum CXC chemokine ligand 16 (CXCL-16), growth differentiation factor 15 (GDF-15) and lipoprotein-related phospholipase A2 (PLA-2) levels in patients with cerebral infarction. METHODS: A total of 87 patients with cerebral infarction between August 2019 and May 2020 in our hospital were selected as the disease group, and 50 healthy patients were selected as the healthy control group. Enzyme-linked immunosorbent assay was used to detect serum CXCL-16, GDF-15, PLA-2 expression levels in all subjects. A comprehensive evaluation was made in terms of changes of various indicator levels in patients while the changes of CXCL-16, GDF-15, PLA-2 in patients with cerebral infarction after effective treatment were monitored. RESULTS: Compared with the healthy group, the expression levels of serum CXCL-16, GDF-15 and PLA-2 in the disease group were up-regulated (P < 0.001). Patients with cerebral infarction were divided into subgroups according to the National Institutes of Health Neurological Impairment Score (NIHSS). The expression levels of serum CXCL-16, GDF-15 and PLA-2 in patients with cerebral infarction increased with the increase of the impairment score (P < 0.001). The areas of the patient's cerebral infarction were calculated according to the Pullicino formula. The expression levels of serum CXCL-16, GDF-15 and PLA-2 in patients with cerebral infarction increased with the enlargement of the infarct area, and the difference between the groups was statistically significant (P < 0.001). The expression levels of serum CXCL-16, GDF-15 and PLA-2 in patients with cerebral infarction when discharged from the hospital after treatment were significantly lower than those before treatment (P < 0.001). The AUC areas of serum CXCL-16, GDF-15 and PLA-2 indicators in predicting the therapeutic effect of cerebral infarction were 0.821, 0.883, and 0.711, respectively. CONCLUSION: Serum CXCL-16, GDF-15, PLA-2 in patients with cerebral infarction were all highly expressed and changed with the disease severity, which can be used as reliable indicators for monitoring the incidence, severity, and prognosis of cerebral infarction.

The Neuroprotective Mechanism of Low-Frequency rTMS on Nigral Dopaminergic Neurons of Parkinson's Disease Model Mice.

Background. Parkinson's disease is a neurodegenerative disease in elder people, pathophysiologic basis of which is the severe deficiency of dopamine in the striatum. The purpose of the present study was to evaluate the neuroprotective effect of low-frequency rTMS on Parkinson's disease in model mice. Methods. The effects of low-frequency rTMS on the motor function, cortex excitability, neurochemistry, and neurohistopathology of MPTP-induced Parkinson's disease mice were investigated through behavioral detection, electrophysiologic technique, high performance liquid chromatography-electrochemical detection, immunohistochemical staining, and western blot. Results. Low-frequency rTMS could improve the motor coordination impairment of Parkinson's disease mice: the resting motor threshold significantly decreased in the Parkinson's disease mice; the degeneration of nigral dopaminergic neuron and the expression of tyrosine hydroxylase were significantly improved by low-frequency rTMS; moreover, the expressions of brain derived neurotrophic factor and glial cell line derived neurotrophic factor were also improved by low-frequency rTMS. Conclusions. Low-frequency rTMS had a neuroprotective effect on the nigral dopaminergic neuron which might be due to the improved expressions of brain derived neurotrophic factor and glial cell line-derived neurotrophic factor. The present study provided a theoretical basis for the application of low-frequency rTMS in the clinical treatment and recovery of Parkinson's disease.

Edaravone protects neurons in the rat substantia nigra against 6-hydroxydopamine-induced oxidative stress damage.

To investigate the mechanism of the neuroprotective effect of edaravone in substantia nigra (SN) of the 6-OHDA-induced rat model of Parkinson's disease. Animal model of Parkinson's disease was induced in male Sprague-Dawley rats by injecting 6-OHDA into the left medial forebrain bundle. Subsequently, rats were intraperitoneally injected with 0.3, 1, or 3 mg/kg of edaravone for 14 days or with 3 mg/kg edaravone for 14 days followed by 14 days of no treatment. We evaluated the effect of edaravone on the rotational and normal behavior of the rats, and on the number of tyrosine hydroxylase (TH)-positive cells, the amount of Nissl bodies, and the levels of glutathione (GSH), and malondialdehyde (MDA) in the SN. Edaravone treatment at 3 mg/kg significantly reduced apomorphine-induced rotational behavior (P < 0.01), improved the spontaneous behavior, prevented the decrease in the levels of TH-positive cells, Nissl bodies and GSH, and inhibited the increase in the levels of MDA (P < 0.05) in SN of rats with 6-OHDA-induced PD. Edaravone exerted a long-term neuroprotective effects in 6-OHDA-induced PD animal model by attenuating changes in the levels of GSH and MDA in SN, caused by oxidative stress. Edaravone prevented 6-OHDA-induced behavioral changes and de-pigmentation of SN that results from the loss of dopaminergic neurons.