Oxidative stress induction of DJ-1 protein in reactive astrocytes scavenges free radicals and reduces cell injury

Astrocytes, one of the predominant types of glial cells, function as both supportive and metabolic cells for the brain. Under cerebral ischemia/reperfusion-induced oxidative conditions, astrocytes accumulate and activate in the ischemic region. DJ-1 has recently been shown to be a sensor of oxidative stress in living cells. However, the function of astrocytic DJ-1 is still unknown. In the present study, to clarify the effect of astrocytic DJ-1 protein under massive oxidative insult, we used a focal ischemic rat model that had been subjected to middle cerebral artery occlusion (MCAO) and reperfusion. We then investigated changes in the distribution of DJ-1 in astrocytes, DJ-1 release from cultured astrocytes, and the effects of recombinant DJ-1 protein on hydrogen peroxide (H2O2)-induced death in normal and DJ-1-knockdown SH-SY5Y cells and on in vitro scavenging of hydroxyl radicals (•OH) by electron spin resonance spectrometry. At 24 h after 2-h MCAO and reperfusion, an infarct lesion was markedly observed using magnetic resonance imaging and 2,3,5-triphenyltetrazolium chloride staining. In addition, reactive astrocytes enhanced DJ-1 expression in the penumbral zone of the ischemic core and that DJ-1 protein was extracellularly released from astrocytes by H2O2 in in vitro primary cultures. Although DJ-1-knockdown SH-SY5Y cells were markedly vulnerable to oxidative stress, treatment with glutathione S-transferase-tagged recombinant human DJ-1 protein (GST-DJ-1) significantly inhibited H2O2-induced cell death. In addition, GST-DJ-1 protein directly scavenged •OH. These results suggest that oxidative stress induces the release of astrocytic DJ-1 protein, which may contribute to astrocyte-mediated neuroprotection

Domesticating Vigna stipulacea: Chromosome-Level genome assembly reveals VsPSAT1 as a candidate gene decreasing hard-seededness

To increase food production under the challenges presented by global climate change, the concept of de novo domestication—utilizing stress-tolerant wild species as new crops—has recently gained considerable attention. We had previously identified mutants with desired domestication traits in a mutagenized population of the legume Vigna stipulacea Kuntze (minni payaru) as a pilot for de novo domestication. Given that there are multiple stress-tolerant wild legume species, it is important to establish efficient domestication processes using reverse genetics and identify the genes responsible for domestication traits. In this study, we identified VsPSAT1 as the candidate gene responsible for decreased hard-seededness, using a Vigna stipulacea isi2 mutant that takes up water from the lens groove. Scanning electron microscopy and computed tomography revealed that the isi2 mutant has lesser honeycomb-like wax sealing the lens groove than the wild-type, and takes up water from the lens groove. We also identified the pleiotropic effects of the isi2 mutant: accelerating leaf senescence, increasing seed size, and decreasing numbers of seeds per pod. While doing so, we produced a V. stipulacea whole-genome assembly of 441 Mbp in 11 chromosomes and 30,963 annotated protein-coding sequences. This study highlights the importance of wild legumes, especially those of the genus Vigna with pre-existing tolerance to biotic and abiotic stresses, for global food security during climate change

Prediction of recurrence after chemoradiotherapy

We retrospectively assessed whether magnetic resonance imaging (MRI) radiomics combined with clinical parameters can improve the predictability of out-of-field recurrence (OFR) of cervical cancer after chemoradiotherapy. The data set was collected from 204 patients with stage IIB (FIGO: International Federation of Gynecology and Obstetrics 2008) cervical cancer who underwent chemoradiotherapy at 14 Japanese institutes. Of these, 180 patients were finally included for analysis. OFR-free survival was calculated using the Kaplan–Meier method, and the statistical significance of clinicopathological parameters for the OFR-free survival was evaluated using the log-rank test and Cox proportional-hazards model. Prediction of OFR from the analysis of diffusion-weighted images (DWI) and T2-weighted images of pretreatment MRI was done using the least absolute shrinkage and selection operator (LASSO) model for engineering image feature extraction. The accuracy of prediction was evaluated by 5-fold cross-validation of the receiver operating characteristic (ROC) analysis. Para-aortic lymph node metastasis (p = 0.003) was a significant prognostic factor in univariate and multivariate analyses. ROC analysis showed an area under the curve (AUC) of 0.709 in predicting OFR using the pretreatment status of para-aortic lymph node metastasis, 0.667 using the LASSO model for DWIs and 0.602 using T2 weighted images. The AUC improved to 0.734 upon combining the pretreatment status of para-aortic lymph node metastasis with that from the LASSO model for DWIs. Combining MRI radiomics with clinical parameters improved the accuracy of predicting OFR after chemoradiotherapy for locally advanced cervical cancer

Oxidative Neurodegeneration Is Prevented by UCP0045037, an Allosteric Modulator for the Reduced Form of DJ-1, a Wild-Type of Familial Parkinson’s Disease-Linked PARK7

Although a loss-of-function mutation has been identified in familial Parkinson’s disease PARK7, the wild-type of DJ-1 is known to act as an oxidative stress sensor in neuronal cells. Recently, we identified UCP0045037 as a compound that bound to the reduced form of DJ-1 by in silico virtual screening. In this study, we determined the neuroprotective effects of UCP0045037 against focal cerebral ischemia-induced neurodegeneration in rats. Hydrogen peroxide-induced cell death was significantly inhibited by UCP0045037 in both rat mesencephalic dopaminergic neurons and human normal SH-SY5Y cells. In contrast, DJ-1-knockdown SH-SY5Y cells lost the protective activity of UCP0045037. These results suggest that UCP0045037 interacts with endogenous DJ-1 and produces a neuroprotective response

Prefoldin Plays a Role as a Clearance Factor in Preventing Proteasome Inhibitor-induced Protein Aggregation

Prefoldin is a molecular chaperone composed of six subunits, PFD1-6, and prevents misfolding of newly synthesized nascent polypeptides. Although it is predicted that prefoldin, like other chaperones, modulates protein aggregation, the precise function of prefoldin against protein aggregation under physiological conditions has never been elucidated. In this study, we first established an anti-prefoldin monoclonal antibody that recognizes the prefoldin complex but not its subunits. Using this antibody, it was found that prefoldin was localized in the cytoplasm with dots in co-localization with polyubiquitinated proteins and that the number and strength of dots were increased in cells that had been treated with lactacystin, a proteasome inhibitor, and thapsigargin, an inducer of endoplasmic reticulum stress. Knockdown of prefoldin increased the level of SDS-insoluble ubiquitinated protein and reduced cell viability in lactacystin and thapsigargin-treated cells. Opposite results were obtained in prefoldin-overexpressed cells. It has been reported that mice harboring a missense mutation L110R of MM-1 alpha/PFD5 exhibit neurodegeneration in the cerebellum. Although the prefoldin complex containing L110R MM-1 alpha was properly formed in vitro and in cells derived from L110R MM-1 alpha mice, the levels of ubiquitinated proteins and cytotoxicity were higher in L110R MM-1 alpha cells than in wild-type cells under normal conditions and were increased by lactacystin and thapsigargin treatment, and growth of L110R MM-1 alpha cells was attenuated. Furthermore, the polyubiquitinated protein aggregation level was increased in the brains of L110R MM-1 alpha mice. These results suggest that prefoldin plays a role in quality control against protein aggregation and that dysfunction of prefoldin is one of the causes of neurodegenerative diseases

Preferential orientation of anisotropic polythiophene rods toward macroscopic chain ordering

International audienceThe orientation of polymer chains plays an important role in governing the mechanical, optical, and electronic properties of polymeric materials. Here, we report on the fabrication of anisotropic polythiophene particles with controlled lengths using a metal–organic framework template, in which the alignment of the polymer chains was retained without a host support. The formation of the rod-shaped particles with long length allowed for the facile preferential orientation of the polymer particles, and consequently resulted in the macroscopic chain alignment of unprocessable polythiophene