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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,225 records · Page 68
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 expression in both in vivo and in vitro Parkinson's disease models

The abnormality of nuclear receptor-related protein 1 (Nurr1) in expression and function can contribute to neurodegeneration of dopaminergic neurons and occurrence of Parkinson's disease (PD). However, its related mechanism in PD is still unknown. In this study, we found that Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. CCL2 promoted apoptosis and secretion of TNF-α and IL-1β in SH-SY5Y cells and inhibited cell viability while knockdown of CCL2 exerted the opposite effects. Nurr1 overexpression inhibited apoptosis, the release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells, which was markedly promoted by CCL2 antibody and dramatically reversed by CCL2. Nurr1 overexpression negatively regulated CCL2 expression in vivo and in vitro. Furthermore, Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits and played neuroprotective and anti-inflammatory roles in MPTP-induced PD mice by down-regulating CCL2 in vivo. In conclusion, Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 in both in vivo and in vitro PD models, contributing to developing mechanism-based and neuroprotective strategies against PD. - Highlights: • Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. • Nurr1 overexpression inhibited apoptosis, release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells. • CCL2 reversed the effect of Nurr1 overexpression on apoptosis, inflammatory cytokines secretion and viability. • Nurr1 overexpression negatively regulated CCL2 expression in vivo and in vitro. • Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

In vitro effects of the anti-Alzheimer drug memantine on the human erythrocyte membrane and molecular models

Memantine is a NMDA antagonist receptor clinically used for treating Alzheimer's disease. NMDA receptors are present in the human neurons and erythrocyte membranes. The aim of the present study was to investigate the effects of memantine on human erythrocytes. With this purpose, the drug was developed to in vitro interact with human red cells and bilayers built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE). The latter represent lipids respectively present in both outer and inner monolayers of the red cell membrane. Results obtained by scanning electron microscopy (SEM) showed that memantine changed the normal biconcave shape of red cells to cup-shaped stomatocytes. According to the bilayer-couple hypothesis the drug intercalated into the inner monolayer of the erythrocyte membrane. Experimental results obtained by X-ray diffraction on multibilayers of DMPC and DMPE, and by differential scanning calorimetry on multilamellar vesicles indicated that memantine preferentially interacted with DMPC in a concentration-dependent manner. Thus, it can be concluded that in the low therapeutic plasma concentration of circa 1 μM memantine is located in NMDA receptor channel without affecting the erythrocyte shape. However, at higher concentrations, once the receptors became saturated excess of memantine molecules (20 μM) would interact with phosphoinositide lipids present in the inner monolayer of the erythrocyte membrane inducing the formation of stomatocytes. However, 40–50 μM memantine was required to interact with isolated phosphatidylcholine bilayers. - Highlights: • The interaction of memantine with human erythrocytes and lipid bilayers were assessed. • Memantine induced morphological changes to human erythrocytes. • Memantine interacted with classes of phospholipids present in the erythrocyte membrane. • Results support the hypothesis that memantine interacts with NMDA receptors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Activation of Nrf2 attenuates carbonyl stress induced by methylglyoxal in human neuroblastoma cells: Increase in GSH levels is a critical event for the detoxification mechanism

The present study focused on the methylglyoxal (MG) detoxification mechanism in neuroblastoma cells. The involvement of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway as a defense response against the formation of MG-modified proteins, which is well-known evidence of carbonyl stress, was also examined. We found that MG treatment resulted in accumulation of modified proteins bearing the structure of advanced glycation end products (AGEs) derived from MG in SH-SY5Y cells. This accumulation was suppressed by activation of the Nrf2 pathway prior to MG exposure via pre-treatment with an Nrf2 activator, carnosic acid and CDDO-Im, confirming the involvement of the Nrf2 pathway in MG detoxification. Although pre-treatment with the Nrf2 activator did not affect mRNA levels of GLO1, AKR1B1, and AKR7A2, the expressions of GCL and xCT mRNA, involved in GSH synthesis, were induced prior to increase in GSH levels. Furthermore, we demonstrated that a GSH synthesis inhibitor eliminated the MG detoxification effect derived from pretreatment with the Nrf2 activator. These results indicated that increase in GSH levels, induced by pre-treatment with carnosic acid, promoted the formation of the GLO1 substrate, hemithioacetal, thereby accelerating MG metabolism via the glyoxalase system and suppressing its toxicity. It was, therefore, determined that promotion of GSH synthesis via the Nrf2/Keap1pathway is important in the MG detoxification mechanism against neuronal MG-induced carbonyl stress, and Nrf2 activators contribute to reduction in the accumulation and toxic expression of carbonyl proteins. - Highlights: • Nrf2 activator prevents methylglyoxal-induced cytotoxicity and protein modifications. • MG treatment resulted in accumulation of modified proteins bearing the structure of CEL and MG-H1. • The promotion of GSH synthesis by activation of Nrf2 is a key response to MG detoxification.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Necdin modulates osteogenic cell differentiation by regulating Dlx5 and MAGE-D1

Osteoblasts originate from mesenchymal stem cells that also differentiate into adipocytes, myoblasts, chondrocytes and fibroblasts. Osteogenic differentiation involves diverse regulatory proteins, including transcription and growth factors. Neurally differentiated embryonal carcinoma-derived protein (Necdin) has been identified as a key regulator of cell differentiation in various tissues, including neuronal, adipose, and muscular tissues; although its role in bone tissue remains to be established. Here, we investigated the potential involvement of Necdin in osteogenic differentiation. Our experiments revealed high expression of Necdin during osteoblast differentiation. Moreover, both transient and stable expression of Necdin induced osteoblast-specific markers in an osteogenic cell line through formation of a complex with melanoma-associated antigen D1 (MAGE-D1) and distal-less Homeobox 5 (Dlx5) and Runx2 promoter activation. Necdin expression was further associated with suppression of both cell proliferation and death in osteoblasts. Our results suggest that Necdin plays roles in cellular differentiation, proliferation and death in bone tissue. - Highlights: • Necdin is highly expressed during osteoblast differentiation. • Necdin induces expression of osteoblast-specific markers in osteogenic cells. • Necdin forms complex with MAGE-D1 and Dlx5, and induces Runx2 promoter activation. • Necdin plays important roles in osteoblastic differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Structure of an unconventional SH3 domain from the postsynaptic density protein Shank3 at ultrahigh resolution

The Shank family comprises three large multi-domain proteins playing central roles as protein scaffolds in the neuronal postsynaptic density. The Shank proteins are closely linked to neuropsychiatric diseases, such as autism spectrum disorders. One characteristic domain in the Shank family is the SH3 domain, assumed to play a role in protein-protein interactions; however, no specific ligand binding to any Shank SH3 domain has been described. We solved the crystal structure of the SH3 domain from Shank3 at sub-atomic resolution. While the structure presents the canonical SH3 domain fold, the binding site for proline-rich peptides is not conserved. In line with this, no binding of Pro-rich sequences by the Shank3 SH3 domain was observed. Sequence comparisons indicate that all Shank isoforms have similarly lost the classical Pro-rich peptide binding site from the SH3 domain. Whether the corresponding site in the Shank SH3 domains has evolved to bind a non-poly-Pro target sequence is currently not known. Our work provides an intriguing example of the evolution of a well-characterized protein-protein interaction domain within the context of multi-domain protein scaffolds, allowing the conservation of structural features, but losing canonical functional sites. The data are further discussed in light of known mutations in the SH3 domain or its vicinity in the different Shank isoforms. - Highlights: • The SH3 domain from Shank3 was studied at sub-atomic resolution. • The Shank family has lost the canonical peptide-binding site of the SH3 domain. • The Shank SH3 domain may have lost or altered canonical SH3 domain functions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Identification of novel ALK2 inhibitors and their effect on cancer cells

Bone morphogenetic protein 9 (BMP9), a member of the TGF-β superfamily, is considered a regulator of glucose homeostasis as well as a neuronal differentiation factor. BMP9 induces phosphorylation of Smad1/5 through activin receptor-like kinase 1 and 2 (ALK1 and ALK2). Recently, many studies have shown that BMP9 contributes to tumorigenesis, and aberrant ALK2 expression is involved in many diseases. To investigate the role of BMP9-ALK2 signaling in cancer cells, we used TF-1 cells that require granulocyte-macrophage colony-stimulating factor (GM-CSF) for cell proliferation. BMP9 promoted the proliferation of TF-1 cells in media lacking GM-CSF. TF-1 cells overexpressing ALK2 resulted in the autophosphorylation of Smad1/5, leading to consequent increase in cell growth. Through high-throughput screening (HTS), we found two ALK2-specific inhibitors, KRC203 and KRC360, with IC{sub 50} values of 0.9 nM and 0.3 nM. These compounds were more potent and specific for the inhibition of ALK2 when compared to LDN193189. In cell-based assays, these compounds effectively inhibited the proliferation and migration of cancer cells induced by ALK2 and BMP9. Therefore, we propose that our compounds are promising candidates for the treatment of cancer or diseases with abnormal ALK2 or BMP9 signaling. - Highlights: • BMP9 signaling promoted the proliferation of cancer cells via Smad1/5 pathway. • Overexpressing ALK2, a BMP9 receptors, promoted the proliferation of cancer cells. • KRC203 and KRC360 that we found through high-throughput screening showed high specific inhibition against ALK2. • Our compounds inhibited specificity BMP9 signaling and inhibited the migration of hepatocellular carcinoma. • Our compounds also effectively inhibited the proliferation of cancer cells by BMP9 and ALK2 signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

TLR7 deficiency contributes to attenuated diabetic retinopathy via inhibition of inflammatory response

Diabetic retinopathy (DR) is a major microvascular complication of diabetes, resulting in neuronal dysfunction, retinal vascular leakage, and apoptosis within the retina. Innate immunity plays an important role in the pathogenesis of type 2 diabetes (T2D) and related complications. The toll-like receptors (TLRs), central to innate immunity, are essential participants in the progression and pathogenesis of the disease and its complications. In the study, streptozotocin (STZ) was combined with whole-body hypoxia for quicker induction of early-stage diabetic retinopathy (DR) in the wild type (WT) and TLR7-knockout (KO) C57BL/6 mice. The effects of TLR7 were also investigated in fructose-treated retinal pigment epithelial (RPE) cells. In the retinas of WT/DR mice, abnormal a-wave and b-wave activity, hyperfluorescence, and reduced retinal thickness were observed. DR development was associated with enhanced TLR7 expression, whose deletion dramatically reduced VEGF expression levels. And the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-18 and IL-12, was highly reduced by TLR7-deficiency in DR mice. Consistently, WT/DR mice exhibited higher phosphorylation of IκB kinase α (IKKα), inhibitor of NF-κB α (IκBα) and nuclear factor κB (NF-κB), which were found to be down-regulated in KO/DR mice. Similarly, DR-induced mitogen-activated protein kinases (MAPKs) activation was blocked by TLR7-knockout. In vitro, fructose incubation-triggered inflammation was reversed by TLR7 knockdown, accompanied with inactivated NF-κB and MAPKs pathways. And reduced reactive oxygen species (ROS) generation was observed in TLR7-knockdown cells with fructose treatment. Together, inhibiting TLR7 suppressed diabetic retinopathy by reducing inflammation and suggested a potential application in clinics. - Highlights: • TLR7 deletion restrains abnormal amplitude of ERG recordings in dark-adapted C57BL/6 mice. • TLR7 deficiency attenuates retinal damage in diabetic retinopathy model. • TLR7 deletion reduces the release of pro-inflammatory cytokines. • TLR7 suppression alleviates inflammatory response in retinal pigment epithelial (RPE) cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The BET/BRD inhibitor JQ1 attenuates diabetes-induced cognitive impairment in rats by targeting Nox4-Nrf2 redox imbalance

Highlights: • The BET/BRD inhibitor JQ1 treatment improves cognitive performance in diabetic rats. • JQ1 treatment alleviated oxidative stress and inflammation in the hippocampus of diabetic rats. • JQ1 treatment restored Nox4-Nrf2 redox balance in the hippocampus of diabetic rats. • JQ1 treatment suppressed apoptosis in the hippocampus of diabetic rats and high glucose induced apoptosis in PC12 cells. Diabetes-induced oxidative damage is believed to play an important role in the development of cognitive dysfunction. In this study, the involvement of the Nox4-Nrf2 redox imbalance was investigated. STZ-induced diabetic rats exhibited obvious oxidative stress and apoptosis in the hippocampus assessed by augmentation of lipid peroxidation, positive TUNEL staining, elevated ratio of Bax/Bcl-2 and increased caspase 3 activity. Furthermore, hyperglycemia markedly increased Nox4 activity and reduced the activation of Nrf2 by suppressing its up-stream regulatory Akt as well as down-stream target HO-1. Significant improvement of cognitive performance was observed after treatment with the BET/BRD inhibitor JQ1, accompanied by decreased oxidative stress, neuroinflammation and apoptosis in the hippocampus. JQ1 treatment also improved changes in the neuronal cell morphology as well as increased the expression of p-AKT, Nrf2 and HO-1. Our results provide evidence indicating that JQ1 treatment could modulate Nox4-Nrf2 redox imbalance in the hippocampus and may be a promising agent for diabetes-associated cognitive dysfunction.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Transcriptional regulation of acetoacetyl-CoA synthetase by Sp1 in neuroblastoma cells

Highlights: • The core promoter of AACS is located in a region with 110 bps upstream from the TSS. • Sp1 interacts with an Sp1 binding site in the promoter region of AACS. • Overexpression of Sp1 upregulates AACS mRNA levels. • Knockdown of AACS results in downregulation of HDAC9. Acetoacetyl-CoA synthetase (AACS) is the enzyme responsible for cholesterol and fatty acid synthesis in the cytosol. We have previously shown that AACS has an important role in normal neuronal development and that knockdown of SREBP-2, which orchestrates cholesterol synthesis, resulted in the downregulation of AACS mRNA levels. In this study, we investigated the transcriptional mechanism of AACS in Neuro-2a, neuroblastoma cells. Luciferase assay showed that the minimal core promoter of the mouse AACS gene is located in a region with 110 bps upstream from the transcription start site. Mutagenesis studies showed that the Sp1 binding site was crucial for AACS promoter activity. ChIP assay and DNA affinity precipitation assay showed that Sp1 binds to the Sp1 binding site on the promoter region of AACS. Moreover, overexpression of Sp1 increased AACS mRNA levels. Knockdown of AACS resulted in a decrease in histone deacetylase 9, associated with gene silencing. These results suggest that Sp1 regulates gene expression of AACS in Neuro-2a cells and ketone body utilization affects the balance of histone acetylation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The SCF ubiquitin ligase Slimb controls Nerfin-1 turnover in Drosophila

Highlights: • Slimb associates with Nerfin-1 and promotes Nerfin-1 turnover. • The C-terminal half of Nerfin-1 is required for Slimb-binding and Slimb-mediated degradation by UPS. • Slimb regulates Nerfin-1 activity in vivo. The C2H2 type zinc-finger transcription factor Nerfin-1 expresses dominantly in Drosophila nervous system and plays an important role in early axon guidance decisions and preventing neurons dedifferentiation. Recently, increasing reports indicated that INSM1 (homologue to nerfin-1 in mammals) is a useful marker for prognosis of neuroendocrine tumors. The dynamic expression of Nerfin-1 is regulated post-transcriptionally by multiple microRNAs; however, its post-translational regulation is still unclear. Here we showed that the protein turnover of Nerfin-1 is regulated by Slimb, the substrate adaptor of SCF{sup Slimb} ubiquitin ligase complex. Mechanistically, Slimb associates with Nerfin-1 and promotes it ubiquitination and degradation in Drosophila S2R{sup +} cells. Furthermore, we determined that the C-terminal half of Nerfin-1 (Nerfin-1{sup CT}) is required for its binding to Slimb. Genetic epistasis assays showed that Slimb misexpression antagonizes, while knock-down enhances the activity of Nerfin-1{sup CT} in Drosophila eyes. Our data revealed a new link to understand the underlying mechanism for Nerfin-1 turnover in post-translational level, and provided useful insights in animal development and disease treatment by manipulating the activity of Slimb and Nerfin-1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Cell membrane dynamics induction using optogenetic tools

Highlights: • Actin-based cell membrane movements play important roles in various cellular functions. • Recently, we developed a brand-new optogenetic tool, called the Magnet system. • This tool enabled us to spatiotemporally induce the change in cell membrane dynamics. • In this review, we summarized recent advances in optogenetic tools and our Magnet system. Structures arising from actin-based cell membrane movements, including ruffles, lamellipodia, and filopodia, play important roles in a broad spectrum of cellular functions, such as cell motility, axon guidance in neurons, wound healing, and micropinocytosis. Previous studies investigating these cell membrane dynamics often relied on pharmacological inhibition, RNA interference, and constitutive active/dominant negative protein expression systems. However, such studies did not allow the modulation of protein activity at specific regions of cells, tissues, and organs in animals with high spatial and temporal precision. Recently, optogenetic tools for inducing cell membrane dynamics have been developed which address several disadvantages of previous techniques. In a recent study, we developed a powerful optogenetic tool, called the Magnet system, to change cell membrane dynamics through Tiam1 and PIP3 signal transductions with high spatial and temporal resolution. In this review, we summarize recent advances in optogenetic tools that allow us to induce actin-regulated cell membrane dynamics and unique membrane ruffles that we discovered using our Magnet system.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Rbfox family proteins make the homo- and hetero-oligomeric complexes

Rbfox family of proteins that consists of Rbfox1, Rbfox2, and Rbfox3 in mammals regulates alternative pre-mRNA splicing in various tissues via direct binding to their RNA binding element. Although many studies have indicated the splicing activity of each member of the Rbfox family, the interactions of Rbfox family proteins are largely unknown. Here, we have investigated interactions among Rbfox family proteins. Co-immunoprecipitation (Co-IP) and GST-pull down assays confirmed that Rbfox proteins form homo and hetero complexes. Moreover, in vivo crosslinking using disuccinimidyl suberate treatment indicated that the Rbfox proteins form a dimer which then assembles with other proteins to form a large multiprotein complex. Duolink in situ proximity ligation (PLA) assay revealed that neuron specific Rbfox3 protein interacts with other Rbfox family proteins. This study is the first to provide an evidence that Rbfox family proteins form homo- and hetero-oligomeric complexes in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Collagen VI suppresses fibronectin-induced enteric neural crest cell migration by downregulation of focal adhesion proteins

Highlights: • We identified 1355 differentially expressed genes in intestine during development. • The identified differentially expressed genes were enriched extracellular proteins. • Collagen VI reduced fibronectin-induced enteric neural crest cell migration. • Collagen VI promoted the down regulation of fibronectin-induced p130{sup Cas} proteins. The enteric nervous system (ENS) is a network of neurons and glia that are derived from enteric neural crest cells (ENCCs) and essential for regulating peristaltic activity of the colon. ENCCs migrate along the gastrointestinal tract to form the ENS, and disruption of ENCC motility leads to ENS disorders, such as Hirschsprung's disease. Previous ENCC-transplant experiments show that ENCCs can invade into isolated mouse intestines by age E13.5, but not after E15.5. We hypothesized that altered age-specific micro-environments in the intestine are responsible for ENCC invasion/migration. Here, we compared gene expression in the intestine between at E11.5 and E15.5 and identified 1355 differentially expressed transcripts. Among these, we found that genes encoding extracellular matrix (ECM) proteins were enriched. Notably, collagen VI (ColVI) family members were upregulated in the E15.5 mouse intestine at the mRNA and protein levels, whereas fibronectin (FN) was downregulated; however, both proteins showed colocalization at E15.5. To understand the mechanisms of ColVI and FN in ENCC migration, we examined neurosphere or individual ENCC-adherence capabilities toward the ECM. ColVI suppressed FN-induced ENCC spreading/migration, whereas ColVI induced morphologically narrow ENCC spreading and weak stress-fiber formation as compared with those with FN. Additionally, in ENCCs cultured on plates containing ColVI, the expression and phosphorylation of p130{sup Cas}, a members of focal adhesion complexes, was reduced. These data indicated an inhibitory role of ColVI in ENCC migration and suggested that ColVI suppression in the intestine might represent a novel therapeutic strategy for aganglionic colonic diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Short-term exposure to dim light at night disrupts rhythmic behaviors and causes neurodegeneration in fly models of tauopathy and Alzheimer's disease

Highlights: • Dim light disturbs circadian rhythm and sleep behaviors. • Internal clock is maintained in Drosophila model of tauopathy Alzheimer's disease. • Short-term disturbance of circadian rhythm by dim light increases formation of phosphorylated Tau in AD model flies. • Dim light exposure at night promotes neurodegeneration in AD model flies. The accumulation and aggregation of phosphorylated tau proteins in the brain are the hallmarks for the onset of Alzheimer's disease (AD). In addition, disruptions in circadian rhythms (CRs) with altered sleep-wake cycles, dysregulation of locomotion, and increased memory defects have been reported in patients with AD. Drosophila flies that have an overexpression of human tau protein in neurons exhibit most of the symptoms of human patients with AD, including locomotion defects and neurodegeneration. Using the fly model for tauopathy/AD, we investigated the effects of an exposure to dim light at night on AD symptoms. We used a light intensity of 10 lux, which is considered the lower limit of light pollution in many countries. After the tauopathy flies were exposed to the dim light at night for 3 days, the flies showed disrupted CRs, altered sleep-wake cycles due to increased pTau proteins and neurodegeneration, in the brains of the AD flies. The results indicate that the nighttime exposure of tauopathy/AD model Drosophila flies to dim light disrupted CR and sleep-wake behavior and promoted neurodegeneration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Mitochondrial dynamics and protective effects of a mitochondrial division inhibitor, Mdivi-1, in lipopolysaccharide-induced brain damage

Highlights: • Mdivi-1 ameliorated brain damage in a lipopolysaccharide-induced sepsis model. • Drp1 was up-regulated, while p-Drp1 and OPA1 were down-regulated in hippocampus. • The protective effect of Mdivi-1 could be associated with its inhibition of Drp1 and its activation of p-Drp1 and OPA1. Sepsis is one of the most common reasons for mortality in Intensive Care Units. As a common but severe neurological complication, sepsis associated encephalopathy (SAE) has always been ignored and there is no generally accepted treatment. In this study, we demonstrated that Mdivi-1 ameliorated brain damage assessed by Nissl staining. Furthermore, Mdivi-1 reduced TUNEL-positive cells in hippocampus, and inhibited S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) release into plasma. Biochemical analysis also showed that Mdivi-1 protected hippocampus from oxidative stresses. Western blot analysis revealed that Mdivi-1, as a Drp1 inhibitor, inhibited LPS induced dynamin-related GTPase (Drp1) increase. Interestingly, it can also attenuate LPS induced optic atrophy 1 (OPA1) and phosphorylated Drp1 (p-Drp1) decrease. Thus Mdivi-1 protected rats from SAE, and this protective effect could be associated with its inhibition of Drp1 and its activation of p-Drp1 and OPA1. Mitochondrial dynamics may be a potential pharmacological therapeutic target for treating SAE.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Zika virus infected primary microglia impairs NPCs proliferation and differentiation

Highlights: • ZIKV infects primary microglia and induce inflammatory response. • ZIKV infected microglia decreases NPCs proliferation. • ZIKV infected microglia promote astrogenesis at the expense of neurogenesis. • Cytokines secreted by ZIKV infected microglia decrease neurogenesis. Zika virus (ZIKV) can lead to severe birth defects especially microcephaly in newborns by infecting human neural progenitors and impairing brain development. However, as the resident immune cells in the brain, the role of microglia in the ZIKV pathology is not clearly defined. To understand the interplay between immune response and neural cells, we investigate the interaction between microglia and NPCs during ZIKV infection. Our results demonstrate that primary microglia infected with ZIKV induces an inflammatory response similar to that in human, producing high level of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1β) and inducible nitric oxide synthase (iNOS). Furthermore, conditional medium (CM) of ZIKV infected microglia showed inhibitory effects on cell proliferation and neuronal differentiation of neural precursor cells (NPCs) derived from E14 mice brain. Blocking cytokines in the CM remarkably improved neurogenesis and decreased astrocytic differentiation of NPCs. Together, our results suggest that microglia mediated neuroinflammation plays an important role in neuropathogenesis during ZIKV infection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effects of PQ's cytotoxicity on secretory vesicles in astroglia: Expression alternation of secretogranin II and its potential interaction with intracellular factors

Highlights: • PQ upregulated SCG2 expression and altered its subcellular location in astroglia. • SCG2 knockdown dysregulated GS and IL-6 expressions on RNA and protein levels. • SCG2-positive LDCVs were partially involved in trafficking of IL-6 but not GS. • SCG2 may contribute to PQ toxicology by regulating neurotransmitters and cytokines. It has been extensively characterized that paraquat (PQ) selectively targets to the substantia nigra and exerts neurotoxic actions on dopaminergic neurons. However, a little knowledge is available about astroglia in PQ exposure, especially its complex secretory machinery. To explore this point, we built up a PQ-induced model in cultural U118 astrocyte. Since the granin family is considered as a master regulator of cargo sorting and large dense core vesicles (LDCVs) biogenesis in the regulated secretory pathway of nervous and neuroendocrine cells, the current study focused on one member, secretogranin II (SCG2) and investigated its alternation and potential relationship with other astrocyte-derived factors under PQ insult. We found that PQ upregulated SCG2 expression on both RNA and protein levels and stimulated the mRNA expression of neurotrophic factors, cytokines and glutamine synthetase (GS) simultaneously. RNAi knockdown of SCG2 did not rescue the cell cycle arrest induced by PQ but affected expressions of IL-6 and GS on mRNA and protein levels. Further studies on subcellular location showed that SCG2-positive secretory granules were partially colocalized with IL-6 but not GS in PQ exposure astrocyte. Taken together, our findings indicate that the expression alternation of SCG2 under astroglial activation by PQ may be necessary compensation for cargo sorting and LDCV biogenesis. The involvement of the IL-6 and GS suggests that the SCG2 may potentially regulate inflammatory factors and excitatory neurotransmitter to the cytotoxicity of PQ on astroglia.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Leucokinin signaling regulates hunger–driven reduction of behavioral responses to noxious heat in Drosophila

Highlights: • Hunger has a significant impact on sensory systems or brain functions in Drosophila. • It remains unclarified whether hunger affects behavioral responses to heat stimuli. • Food deprivation reduced the responses to noxious heat in wild-type flies. • Leucokinin signaling was essential for the reduction of responses to noxious heat. In the fruitfly Drosophila melanogaster, hunger has a significant impact on its sensory systems and brain functions, and consequently modifies related behaviors. However, it remains unclarified whether hunger affects nociceptive behavioral responses to heat stimuli. In this study, we show that food deprivation reduces responses to noxious heat in wild–type flies. We further identified that the neuropeptide Leucokinin (Lk) and its receptor (Lkr) are essential for the reduction of responses to noxious heat. Temporal silencing of Lk–expressing neurons and a knockout mutation of Lkr generated using the CRISPR/Cas9 system inhibited the reduction of responses to noxious heat. Thus, our results reveal that hunger induces reduction of responses to noxious heat through the Lk/Lkr signaling pathway in Drosophila.

60 APPLIED LIFE SCIENCES↗