Edaravone protects against oxygen-glucose-serum deprivation/restoration-induced apoptosis in spinal cord astrocytes by inhibiting integrated stress response

We previously found that oxygen-glucose-serum deprivation/restoration（OGSD/R） induces apoptosis of spinal cord astrocytes, possibly via caspase-12 and the integrated stress response, which involves protein kinase R-like endoplasmic reticulum kinase（PERK）, eukaryotic initiation factor 2-alpha（eIF2α） and activating transcription factor 4（ATF4）. We hypothesized that edaravone, a low molecular weight, lipophilic free radical scavenger, would reduce OGSD/R-induced apoptosis of spinal cord astrocytes. To test this, we established primary cultures of rat astrocytes, and exposed them to 8 hours/6 hours of OGSD/R with or without edaravone（0.1, 1, 10, 100 μM） treatment. We found that 100 μM of edaravone significantly suppressed astrocyte apoptosis and inhibited the release of reactive oxygen species. It also inhibited the activation of caspase-12 and caspase-3, and reduced the expression of homologous CCAAT/enhancer binding protein, phosphorylated（p）-PERK, p-eIF2α, and ATF4. These results point to a new use of an established drug in the prevention of OGSD/R-mediated spinal cord astrocyte apoptosis via the integrated stress response.

Intraneuronal tau aggregation induces the integrated stress response in astrocytes

Progressive aggregation of tau protein in neurons is associated with neurodegeneration in tauopathies.Cell non-autonomous disease mechanisms in astrocytes may be important drivers of the disease process but remain largely elusive.Here,we studied cell type-specific responses to intraneuronal tau aggregation prior to neurodegeneration.To this end,we developed a fully human co-culture model of seed-independent intraneuronal tau pathology,which shows no neuron and synapse loss.Using high-content microscopy,we show that intraneuronal tau aggregation induces oxidative stress accompanied by activation of the integrated stress response specifically in astrocytes.This requires the direct co-culture with neurons and is not related to neurodegeneration or extracellular tau levels.Tau-directed antisense therapy reduced intraneuronal tau levels and aggregation and prevented the cell non-autonomous responses in astrocytes.These data identify the astrocytic integrated stress response as a novel disease mechanism activated by intraneuronal tau aggregation.In addition,our data provide the first evidence for the efficacy of tau-directed antisense therapy to target cell autonomous and cell non-autonomous disease pathways in a fully human model of tau pathology.

Understanding Plant Development and Stress Responses through Integrative Approaches

As the name reflects, integrative plant biology is the core topic of JIPB. In the past few years JIPB has been pursuing the development of this area, to assist the scientific community to bring together all possible research tools to understand plant growth, development and stress responses in micro- and macro-scales. As part of these efforts, JIPB and Yantai University organized the 1st International Symposium on Integrative Plant Biology in the seaside town of Yantai during August 10-12, 2009 （Figure 1） The symposium was co-sponsored by Botanical Society of China, Chinese Society for Cell Biology, Genetics Society of China, and Chinese Society for Plant Physiology.

Homeostatic responses to amino acid insufficiency

This article provides a brief overview describing how two key signaling pathways, namely the integrated stress response and the mammalian target of rapamycin complex 1, work together to facilitate cellular adaptation to dietary amino acid insufficiency. A deeper understanding of these mechanisms is leading to identification of novel targets which aid in disease treatments, improve stress recovery and increase health span through slowed aging and enhanced metabolic fitness.

Alternate day fasting aggravates atherosclerosis through the suppression of hepatic ATF3 in Apoe^(-/-)mice

Atherosclerosis is the major contributor to cardiovascular mortality worldwide.Alternate day fasting(ADF)has gained growing attention due to its metabolic benefits.However,the effects of ADF on atherosclerotic plaque formation remain inconsistent and controversial in atherosclerotic animal models.The present study was designed to investigate the effects of ADF on atherosclerosis in apolipoprotein E-deficient(Apoe^(-/-))mice.Eleven-week-old male Apoe^(-/-)mice fed with Western diet(WD)were randomly grouped into ad libitum(AL)group and ADF group,and ADF aggravated both the early and advanced atherosclerotic lesion formation,which might be due to the disturbed cholesterol profiles caused by ADF intervention.ADF significantly altered cholesterol metabolism pathways and down-regulated integrated stress response(ISR)in the liver.The hepatic expression of activating transcription factor 3(ATF3)was suppressed in mice treated with ADF and hepatocyte-specific overexpression of Aft3 attenuated the effects of ADF on atherosclerotic plaque formation in Apoe^(-/-)mice.Moreover,the expression of ATF3 could be regulated by Krüppel-like factor 6(KLF6)and both the expressions of ATF3 and KLF6 were regulated by hepatic cellular ISR pathway.In conclusion,ADF aggravates atherosclerosis progression in Apoe^(-/-)mice fed on WD.ADF inhibits the hepatic ISR signaling pathway and decreases the expression of KLF6,subsequently inhibiting ATF3 expression.The suppressed ATF3 expression in the liver mediates the deteriorated effects of ADF on atherosclerosis in Apoe^(-/-)mice.The findings suggest the potentially harmful effects when ADF intervention is applied to the population at high risk of atherosclerosis.

Mitochondrial complex Ⅰ as a therapeutic target for Alzheimer’s disease

Alzheimer’s disease(AD),the most prominent form of dementia in the elderly,has no cure.Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials.Novel therapeutic targets and strategies are urgently needed.Emerging data suggest that in response to environmental stress,mitochondria initiate an integrated stress response(ISR)shown to be beneficial for healthy aging and neuroprotection.Here,we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR.Specifically,partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions,including AD,with several small molecules being tested in clinical trials.We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach.Since this strategy has also been shown to enhance health and life span,the development of safe and efficacious complex Ⅰ inhibitors could promote healthy aging,delaying the onset of age-related neurodegenerative diseases.