Astroglial N-myc downstream-regulated gene 2 protects the brain from cerebral edema induced by stroke.

Brain edema is a grave complication of brain ischemia and is the main cause of herniation and death. Although astrocytic swelling is the main contributor to cytotoxic edema, the molecular mechanism involved in this process remains elusive. N-myc downstream-regulated gene 2 (NDRG2), a well-studied tumor suppressor gene, is mainly expressed in astrocytes in mammalian brains. Here, we found that NDRG2 deficiency leads to worsened cerebral edema, imbalanced Na+ transfer, and astrocyte swelling after ischemia. We also found that NDRG2 deletion in astrocytes dramatically changed the expression and distribution of aquaporin-4 and Na+ -K+ -ATPase ß1, which are strongly associated with cell polarity, in the ischemic brain. Brain edema and astrocyte swelling were significantly alleviated by rescuing the expression of astrocytic Na+ -K+ -ATPase ß1 in NDRG2-knockout mouse brains. In addition, the upregulation of astrocytic NDRG2 by lentiviral constructs notably attenuated brain edema, astrocytic swelling, and blood-brain barrier destruction. Our results indicate a particular role of NDRG2 in maintaining astrocytic polarization to facilitate Na+ and water transfer balance and to protect the brain from ischemic edema. These findings provide insight into NDRG2 as a therapeutic target in cerebral edema.

A portable continuous blood purification machine for emergency rescue in disasters.

BACKGROUND: Continuous renal replacement therapy plays an important role in emergency rescue. Currently, no continuous renal replacement therapy machine can be used under unstable conditions as the fluid flow of these machines is controlled electronically. A novel machine that can provide emergency continuous renal replacement therapy in disaster rescue is therefore needed. METHODS: Based on a volumetric metering method, a prototype portable continuous blood purifier based on a volumetric metering method was developed. Basic performance tests, special environmental tests, animal experiments and clinical use of the novel machine were completed to test and verify its performance under unstable conditions. RESULTS: All tests completed showed that the machine met the requirements of the national industry standards with a size reduced to approximately one half of the Baxter Aquarius machine. The clearance of harmful substances by the machine described here was equal to that of the Baxter Aquarius machine and was adequate for clinical purposes. CONCLUSIONS: The novel prototype performed well in all situations tested and can aid rescue work on disaster sites.

Estimation of the Rural Dog Population Within a Mega-City: An Example in Jiading District, Shanghai.

Rural dog populations have long been recognized to be inadequately managed in terms of disease control and prevention. In this study we consider dog management in rural Shanghai and its implications for rabies control in the entire metropolitan area of Shanghai. The prerequisite to improve rabies vaccination coverage in rural Shanghai depends on a proper enumeration of the total rural dog population. In this study we selected one of the nine administrative districts in Shanghai (Jiading), within which there are 7 towns and 2 industrial zones (township-level division) that contain agricultural areas. A total of 9 villages (rabies model villages) were chosen from each township-level division in Jiading, and an additional 3 non-model villages were also included in the study. A household questionnaire survey was implemented in all 12 villages recruited. In 3 of the model villages and the 3 non-model villages chosen as a comparison, two methods of enumeration-a sight-resight survey and a household census survey-were implemented. Results from the household survey in these 6 villages showed that among the total 1,560 owned dogs, 80.4% were Chinese Garden Dogs, 69.1% were aged 1 to 3 years, 49.2% were homebred, and 88.3% were kept for the purpose of guarding the house. However, only 3.7% of the owned dogs were desexed. There was a higher proportion of chained or confined dogs in model compared to non-model villages. The model villages had an absolute rabies vaccination coverage of 100% among its owned dog population and a smaller number of stray dogs. It was also identified that the two enumeration methods yielded similar counts (P = 0.12), particularly within smaller villages. From the questionnaire survey implemented within all 12 villages and based on the average human-to-dog ratio, the total rural dog population of Jiading district was estimated to be 24,058. This study generated information on the general demographics of the rural dog population in Jiading, and demonstrates an approach to the study of rural dog populations within the context of a megacity. In such a context, rural dog populations need to be considered as a critical component of animal and public health.

N-myc downstream-regulated gene 2 deficiency aggravates memory impairment in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic degenerative disease of the central nervous system and the most common dementia type in elderly people. N-myc downstream-regulated gene 2 (NDRG2), a cell stress response gene, is primarily expressed in astrocytes in mammalian brains. The hippocampal protein levels of NDRG2 in AD patients were significantly higher than those in healthy peers. However, whether the increase in NDRG2 is involved in the development of AD or is an endogenous protective response initiated by stress remains unknown. Here, we investigated the roles of NDRG2 in the development of memory impairment in AD using mouse models established by amyloid ß injection or crossing of APP/PS1 mice. We found that NDRG2 deficiency worsened the memory impairment in AD mice. In addition, NDRG2 deletion induced downregulation of the proteasome functional subunit PSMB6 in AD mice. These findings suggest that NDRG2 is an endogenous neuroprotectant that participates in the pathological course of waste-clearing impairment and memory damage in AD. NDRG2 may be a therapeutic target for the intervention of AD memory degradation.

Glycogenolysis Is Crucial for Astrocytic Glycogen Accumulation and Brain Damage after Reperfusion in Ischemic Stroke.

Astrocytic glycogen is an important energy reserve in the brain and is believed to supply fuel during energy crisis. However, the pattern of glycogen metabolism in ischemic stroke and its potential therapeutic impact on neurological outcomes are still unknown. Here, we found extensive brain glycogen accumulation after reperfusion in ischemic stroke patients and primates. Glycogenolytic dysfunction in astrocytes is responsible for glycogen accumulation, caused by inactivation of the protein kinase A (PKA)-glycogen phosphorylase kinase (PhK)-glycogen phosphorylase (GP) cascade accompanied by the activation of glycogen synthase kinase-3ß (GSK3ß). Genetic or pharmacological augmentation of astrocytic GP could promote astrocyte and neuron survival and improve neurological behaviors. In addition, we found that insulin exerted a neuroprotective effect, at least in part by rescuing the PKA-PhK-GP cascade to maintain homeostasis of glycogen metabolism during reperfusion. Together, our findings suggest a promising intervention for undesirable outcomes in ischemic stroke.

Estrogen regulates the expression of Ndrg2 in astrocytes.

N-myc downstream-regulated gene 2 (Ndrg2) is a newly identified molecule that is mainly expressed in astrocytes within the central nervous system (CNS) and is involved in the proliferation and activation of astrocytes. 17ß-estradiol (E2) is one of the most important circulating hormones, and in the CNS, astrocytes are a target and potential mediator of the action of E2. Our most recent study found that DPN, an estrogen receptor (ER) ß-specific agonist, activated the Ndrg2 promoter and elevated endogenous NDRG2 protein expression in MCF7, HSG and T-47D cells. However, whether E2 regulates Ndrg2 expression in astrocytes remains unknown. Here, we conducted both in vivo and in vitro experiments and found that ERß co-localized with NDRG2 in astrocytes. Furthermore, in primary cultured astrocytes, we demonstrated that E2 up-regulated Ndrg2 mRNA and protein expression in a dose- and time-dependent manner and that the ERß agonist DPN but not the ERα agonist PPT up-regulated Ndrg2 expression. In vivo, we found that in the hippocampus of adult ovariectomized (OVX) female mice, Ndrg2 mRNA and protein expression were significantly decreased compared with those in normal adult female mice. After the OVX mice received continuous subcutaneous injections of 50µg/kg E2, 100µg/kg E2 or the ERß agonist DPN for 10 days, the Ndrg2 expression significantly increased compared with that of the OVX mice. Our results indicate that E2 may affect astrocytes by regulating Ndrg2 expression.