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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 1,207 records · Page 67
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

Ulinastatin suppresses lipopolysaccharide induced neuro-inflammation through the downregulation of nuclear factor-κB in SD rat hippocampal astrocyte

Astrocyte activation plays a pivotal role in neuroinflammation, which contributes to neuronal damage, so the inhibition of astrocyte activation may alleviate the progression of neurodegeneration. Recent studies have proved that urinary trypsin inhibitor ulinastatin could inhibit NF-kB activation. In our study, the inhibitory effects of ulinastatin on the production of pro-inflammatory mediators were investigated in lipopolysaccharide (LPS)-reduced primary astrocyte. Our results showed that ulinastatin significantly inhibited LPS-induced astrogliosis, which is measured by MTT and BrdU. Ulinastatin decreased the production of pro-inflammatory cytokines, such as TNF-α, IL-6, IL-1β, it significantly decreased both the mRNA and the protein levels of these pro-inflammatory cytokines and also increased the protein levels of IκB-α binded to NF-κB, which blocked NF-κB translocation to the nucleus and prevented its activity. Our results suggest that ulinastatin is able to inhibit neuroinflammation by interfering with NF-κB signaling. The study provides direct evidence of potential therapy methods of ulinastatin for the treatment of neuroinflammatory diseases. - Highlights: • The anti-inflammatory effect of UTI on hippocampal astrocyte. • UTI showed protective effect on neuroinflammation by the downregulation of NF-κB. • UTI led to expression of cytokines decreased in concentration and time dependence.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling

Calcineurin (CaN) over-activation constrains synaptic plasticity and memory formation. Upon CaN activation, NFAT imports into the nucleus and guides its downstream genes, which also affect neuronal and synaptic function. Aberrant CaN/NFAT signaling involves in neurotoxicity and cognitive impairment in neurological disorders such as Alzheimer's disease, but its role in postoperative cognitive dysfunction (POCD) remains uninvestigated. Inhaled anesthetic isoflurane facilitates the development of POCD, and the present study investigated the role of CaN/NFAT signaling in isoflurane induced cognitive impairment of aged rats, and the therapeutic effects of CaN inhibitor cyclosporine A (CsA). The results indicated that hippocampal CaN activity increased and peaked at 6 h after isoflurane exposure, and NFAT, especially NFATc4, imported into the nucleus following CaN activation. Furthermore, phamacological inhibition of CaN by CsA markedly attenuated isoflurane induced aberrant CaN/NFATc4 signaling in the hippocampus, and rescued relevant spatial learning and memory impairment of aged rats. Overall, the study suggests hippocampal CaN/NFAT signaling as the upstream mechanism of isoflurane induced cognitive impairment, and provides potential therapeutic target and possible treatment methods for POCD. - Highlights: • Isoflurane induces hippocampal calcineurin activation. • Isoflurane induces hippocampal NFAT, especially NFATc4, nuclear import. • Cyclosporine A attenuates isoflurane induced aberrant calcineurin/NFAT signaling. • Cyclosporine A rescues isoflurane induced cognitive impairment. • Calcineurin/NFAT signaling is the upstream mechanism of isoflurane induced synaptic dysfunction and cognitive impairment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

Myelin-forming glial cells undergo dynamic morphological changes in order to produce mature myelin sheaths with multiple layers. In the central nervous system (CNS), oligodendrocytes differentiate to insulate neuronal axons with myelin sheaths. Myelin sheaths play a key role in homeostasis of the nervous system, but their related disorders lead not only to dismyelination and repeated demyelination but also to severe neuropathies. Hereditary hypomyelinating leukodystrophies (HLDs) are a group of such diseases affecting oligodendrocytes and are often caused by missense mutations of the respective responsible genes. Despite increasing identification of gene mutations through advanced nucleotide sequencing technology, studies on the relationships between gene mutations and their effects on cellular and subcellular aberrance have not followed at the same rapid pace. In this study, we report that an HLD4-associated (Asp-29-to-Gly) mutant of mitochondrial heat shock 60-kDa protein 1 (HSPD1) causes short-length morphologies and increases the numbers of mitochondria due to their aberrant fission and fusion cycles. In experiments using a fluorescent dye probe, this mutation decreases the mitochondrial membrane potential. Also, mitochondria accumulate in perinuclear regions. HLD4-associated HSPD1 mutant blunts mitochondrial dynamics, probably resulting in oligodendrocyte malfunction. This study constitutes a first finding concerning the relationship between disease-associated HSPD1 mutation and mitochondrial dynamics, which may be similar to the relationship between another disease-associated HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics. - Highlights: • The HLD4 mutant of HSPD1 decreases mitochondrial fission frequency. • The HLD4 mutant decreases mitochondrial fusion frequency. • Mitochondria harboring the HLD4 mutant exhibit slow motility. • The HLD4 mutant of HSPD1 decreases mitochondrial membrane potential. • HLD4-related diseases may be due to decreased mitochondrial dynamics.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Expression of REST4 in human gliomas in vivo and influence of pioglitazone on REST in vitro

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) has an irreplaceable role during the differentiation of neurons. REST has multiple splice variants which link to various types of cancer. Previous work had highlighted the role of REST in glioma, where the expression of REST is enhanced. But whether alternative splicing of REST is expressed in glioma has not been described. Here, we show that a specific isoform REST4 is expressed in glioma specimens, and will influence the mRNA level of REST in vivo. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have a role of antineoplastic in various tumor cells, which including glioma cells. Moreover, study indicated that PPARγ agonist pioglitazone can promote alternative splicing of REST pre-mRNA. In this study, we selected pioglitazone as a tool drug to explore whether the role of pioglitazone in anti-glioma is mediated by regulating REST expression or promoting alternative splicing of REST in glioma cells. Results show that pioglitazone can inhibit proliferation and induce apoptosis of glioma cell in vitro, which may be mediated by down-regulating REST mRNA level but not by inducing alternative splicing of REST pre-mRNA. Our study firstly reports the expression of REST4 in glioma tissue samples. And we recommend that pioglitazone, which can reduce the expression level of REST, represents a promising drug for therapy of glioma. - Highlights: • A specific isoform REST4 is expressed in glioma specimens in vivo. • REST4 will influence the mRNA level of REST in vivo. • Pioglitazone can inhibit proliferation and induce apoptosis of glioma cells. • The role of pioglitazone in anti-glioma may be mediated by down-regulating REST.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SG2NA enhances cancer cell survival by stabilizing DJ-1 and thus activating Akt

SG2NA in association with striatin and zinedin forms a striatin family of WD-40 repeat proteins. This family of proteins functions as scaffold in different signal transduction pathways. They also act as a regulatory subunit of protein phosphatase 2A. We have shown that SG2NA which evolved first in the metazoan evolution among the striatin family members expresses different isoforms generated out of alternative splicing. We have also shown that SG2NA protects cells from oxidative stress by recruiting DJ-1 and Akt to mitochondria and membrane in the post-mitotic neuronal cells. DJ-1 is both cancer and Parkinson's disease related protein. In the present study we have shown that SG2NA protects DJ-1 from proteasomal degradation in cancer cells. Hence, downregulation of SG2NA reduces DJ-1/Akt colocalization in cancer cells resulting in the reduction of anchorage dependent and independent growth. Thus SG2NA enhances cancer cell survival. Reactive oxygen species enhances SG2NA, DJ-1 and Akt trimerization. Removal of the reactive oxygen species by N-acetyl-cysteine thus reduces cancer cell growth. - Highlights: • Reactive oxygen species (ROS) play potential role in cancer cell proliferation. • It enhances the association between DJ-1 and Akt mediated by SG2NA. • In cancer cells SG2NA stabilizes DJ-1 by inhibiting it from proteosomal degradation. • DJ-1 then activates Akt and cancer cells get their property of enhanced proliferation by sustained activation of Akt. • Further study on this field could lead to new target for cancer therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function

Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase{sup −/−} mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase{sup −/−} mice showed many hyperreflective spots and staining for the retinal microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase{sup −/−} mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. - Highlights: • aSMase-deficient mice show impaired retinal function and reactive microgliosis. • aSMase-deficient microglia express pro-inflammatory transcripts. • aSMase-deficient microglia proliferate and have increased cell body size. • In vivo imaging shows hyperreflective spots in the fundus of aSMase-deficient mice. • aSMase-deficient microglia accumulate sphingolipid-rich intracellular deposits.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Sox2 promotes survival of satellite glial cells in vitro

Sox2 is a transcriptional factor expressed in neural stem cells. It is known that Sox2 regulates cell differentiation, proliferation and survival of the neural stem cells. Our previous study showed that Sox2 is expressed in all satellite glial cells of the adult rat dorsal root ganglion. In this study, to examine the role of Sox2 in satellite glial cells, we establish a satellite glial cell-enriched culture system. Our culture method succeeded in harvesting satellite glial cells with the somata of neurons in the dorsal root ganglion. Using this culture system, Sox2 was downregulated by siRNA against Sox2. The knockdown of Sox2 downregulated ErbB2 and ErbB3 mRNA at 2 and 4 days after siRNA treatment. MAPK phosphorylation, downstream of ErbB, was also inhibited by Sox2 knockdown. Because ErbB2 and ErbB3 are receptors that support the survival of glial cells in the peripheral nervous system, apoptotic cells were also counted. TUNEL-positive cells increased at 5 days after siRNA treatment. These results suggest that Sox2 promotes satellite glial cell survival through the MAPK pathway via ErbB receptors. - Highlights: • We established satellite glial cell culture system. • Function of Sox2 in satellite glial cell was examined using siRNA. • Sox2 knockdown downregulated expression level of ErbB2 and ErbB3 mRNA. • Sox2 knockdown increased apoptotic satellite glial cell. • Sox2 promotes satellite glial cell survival through ErbB signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Cu(II) promotes amyloid pore formation

The aggregation of α-synuclein is associated with dopamine neuron death in Parkinson's disease. There is controversy in the field over the question of which species of the aggregates, fibrils or protofibrils, are toxic. Moreover, compelling evidence suggested the exposure to heavy metals to be a risk of PD. Nevertheless, the mechanism of metal ions in promoting PD remains unclear. In this research, we investigated the structural basis of Cu(II) induced aggregation of α-synuclein. Using transmission electron microscopy experiments, Cu(II) was found to promote in vitro aggregation of α-synuclein by facilitating annular protofibril formation rather than fibril formation. Furthermore, neuroprotective baicalein disaggregated annular protofibrils accompanied by considerable decrease of β-sheet content. These results strongly support the hypothesis that annular protofibrils are the toxic species, rather than fibrils, thereby inspiring us to search novel therapeutic strategies for the suppression of the toxic annular protofibril formation. - Highlights: • Cu(II) promoted the annular protofibril formation of α-synuclein in vitro. • Cu(II) postponed the in vitro fibrillization of α-synuclein. • Neuroprotective baicalein disaggregated annular protofibrils.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway

Methamphetamine (MA) is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to MA causes psychosis and increases the risk of Parkinson's disease. Lithium (Li) is a known mood stabilizer and has neuroprotective effects. Previous studies suggest that MA exposure decreases the phosphorylation of Akt/GSK3β pathway in vivo, whereas Li facilitates the phosphorylation of Akt/GSK3β pathway. Moreover, GSK3β and mTOR are implicated in the locomotor sensitization induced by psychostimulants and mTOR plays a critical role in MA induced toxicity. However, the effect of MA on Akt/GSK3β/mTOR pathway has not been fully investigated in vitro. Here, we found that MA exposure significantly dephosphorylated Akt/GSK3β/mTOR pathway in PC12 cells. In addition, Li remarkably attenuated the dephosphorylation effect of MA exposure on Akt/GSK3β/mTOR pathway. Furthermore, Li showed obvious protective effects against MA toxicity and LY294002 (Akt inhibitor) suppressed the protective effects of Li. Together, MA exposure dephosphorylates Akt/GSK3β/mTOR pathway in vitro, while lithium protects against MA-induced neurotoxicity via phosphorylation of Akt/GSK3β/mTOR pathway. - Highlights: • Lithium protects against methamphetamine-induced neurotoxicity in vitro. • Methamphetamine exposure dephosphorylates Akt/GSK3β/mTOR pathway. • Lithium attenuates methamphetamine-induced toxicity via phosphorylating Akt/GSK3β/mTOR pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein

Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation. - Highlights: • Edaravone reduces oxLDL-induced monocyte adhesion to HUVECs. • Edaravone attenuates oxLDL-induced expression of MCP-1, VCAM-1, and ICAM-1. • Edaravone reduces NF-κB transcriptional activity and p65 nuclear translocation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

The pro-resolving lipid mediator Maresin 1 protects against cerebral ischemia/reperfusion injury by attenuating the pro-inflammatory response

Inflammation plays a crucial role in acute ischemic stroke pathogenesis. Macrophage-derived Maresin 1 (MaR1) is a newly uncovered mediator with potent anti-inflammatory abilities. Here, we investigated the effect of MaR1 on acute inflammation and neuroprotection in a mouse brain ischemia reperfusion (I/R) model. Male C57 mice were subjected to 1-h middle cerebral artery occlusion (MCAO) and reperfusion. By the methods of 2,3,5-triphenyltetrazolium chloride, haematoxylin and eosin or Fluoro-Jade B staining, neurological deficits scoring, ELISA detection, immunofluorescence assay and western blot analysis, we found that intracerebroventricular injection of MaR1 significantly reduced the infarct volume and neurological defects, essentially protected the brain tissue and neurons from injury, alleviated pro-inflammatory reactions and NF-κB p65 activation and nuclear translocation. Taken together, our results suggest that MaR1 significantly protects against I/R injury probably by inhibiting pro-inflammatory reactions. - Highlights: • MaR1 significantly protects against ischemia reperfusion injury. • MaR1 inhibits pro-inflammatory cytokines and chemokines and reducing glial activation and neutrophil infiltration. • These effects at least partially occurred via suppression of the NF-κB p65 signalling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

The protein inhibitor of nNOS (PIN/DLC1/LC8) binding does not inhibit the NADPH-dependent heme reduction in nNOS, a key step in NO synthesis

The neuronal nitric oxide synthase (nNOS) is an essential enzyme involved in the synthesis of nitric oxide (NO), a potent neurotransmitter. Although previous studies have indicated that the dynein light chain 1 (DLC1) binding to nNOS could inhibit the NO synthesis, the claim is challenged by contradicting reports. Thus, the mechanism of nNOS regulation remained unclear. nNOS has a heme-bearing, Cytochrome P450 core, and the functional enzyme is a dimer. The electron flow from NADPH to Flavin, and finally to the heme of the paired nNOS subunit within a dimer, is facilitated upon calmodulin (CaM) binding. Here, we show that DLC1 binding to nNOS-CaM complex does not affect the electron transport from the reductase to the oxygenase domain. Therefore, it cannot inhibit the rate of NADPH-dependent heme reduction in nNOS, which results in L-Arginine oxidation. Also, the NO release activity does not decrease with increasing DLC1 concentration in the reaction mix, which further confirmed that DLC1 does not inhibit nNOS activity. These findings suggest that the DLC1 binding may have other implications for the nNOS function in the cell. - Highlights: • The effect of interaction of nNOS with DLC1 has been debatable with contradicting reports in literature. • Purified DLC1 has no effect on electron transport between reductase and oxygenase domain of purified nNOS-CaM. • The NO release activity of nNOS was not altered by DLC1, supporting that DLC1 does not inhibit the enzyme. • These findings suggest that the DLC1 binding may have other implications for the nNOS function in the cell.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Expanded polyglutamine embedded in the endoplasmic reticulum causes membrane distortion and coincides with Bax insertion

The endoplasmic reticulum (ER) is important in various cellular functions, such as secretary and membrane protein biosynthesis, lipid synthesis, and calcium storage. ER stress, including membrane distortion, is associated with many diseases such as Huntington's disease. In particular, nuclear envelope distortion is related to neuronal cell death associated with polyglutamine. However, the mechanism by which polyglutamine causes ER membrane distortion remains unclear. We used electron microscopy, fluorescence protease protection assay, and alkaline treatment to analyze the localization of polyglutamine in cells. We characterized polyglutamine embedded in the ER membrane and noted an effect on morphology, including the dilation of ER luminal space and elongation of ER-mitochondria contact sites, in addition to the distortion of the nuclear envelope. The polyglutamine embedded in the ER membrane was observed at the same time as Bax insertion. These results demonstrated that the ER membrane may be a target of polyglutamine, which triggers cell death through Bax. -- Highlights: •We characterized polyglutamine embedded in the ER membrane. •The polyglutamine embedded in the ER membrane was observed at the same time as Bax insertion. •The ER membrane may be a target of polyglutamine, which triggers cell death.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers

Psychoactive pharmaceuticals have been found as teratogens at clinical dosage during pregnancy. These pharmaceuticals have also been detected in minute (ppb) concentrations in drinking water in the US, and are environmental contaminants that may be complicit in triggering neurological disorders in genetically susceptible individuals. Previous studies have determined that psychoactive pharmaceuticals (fluoxetine, venlafaxine and carbamazepine) at environmentally relevant concentrations enriched sets of genes regulating development and function of the nervous system in fathead minnows. Altered gene sets were also associated with potential neurological disorders, including autism spectrum disorders (ASD). Subsequent in vitro studies indicated that psychoactive pharmaceuticals altered ASD-associated synaptic protein expression and gene expression in human neuronal cells. However, it is unknown if environmentally relevant concentrations of these pharmaceuticals are able to cross biological barriers from mother to fetus, thus potentially posing risks to nervous system development. The main objective of this study was to test whether psychoactive pharmaceuticals (fluoxetine, venlafaxine, and carbamazepine) administered through the drinking water at environmental concentrations to pregnant mice could reach the brain of the developing embryo by crossing intestinal and placental barriers. We addressed this question by adding {sup 2}H-isotope labeled pharmaceuticals to the drinking water of female mice for 20 days (10 pre-and 10 post–conception days), and quantifying {sup 2}H-isotope enrichment signals in the dam liver and brain of developing embryos using isotope ratio mass spectrometry. Significant levels of {sup 2}H enrichment was detected in the brain of embryos and livers of carbamazepine-treated mice but not in those of control dams, or for fluoxetine or venlafaxine application. These results provide the first evidence that carbamazepine in drinking water and at typical environmental concentrations is transmitted from mother to embryo. Our results, combined with previous evidence that carbamazepine may be associated with ASD in infants, warrant the closer examination of psychoactive pharmaceuticals in drinking water and their potential association with neurodevelopmental disorders.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone

Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Pioglitazone prevents tau oligomerization

Tau aggregation and amyloid β protein (Aβ) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activation modulates Aβ production. To test whether the PPARγ agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3β, a major tau kinase, associated with activation of Akt. In addition, PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high molecular-weight (120 kDa), oligomeric tau species in Tris Insoluble, sarkosyl-soluble fractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our current results support the idea that PPARγ agonists may be useful therapeutic agents for AD. - Highlights: • PPARγ agonist pioglitazone decreased tau oligomerization. • The mechanism lies on the reduction of phosphorylated tau and caspase cleaved tau. • Pioglitazone inactivated GSK3β and caspase3. • Tau decrease was reversed by the PPAR γ antagonist GW9662.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Dixdc1 targets CyclinD1 and p21 via PI3K pathway activation to promote Schwann cell proliferation after sciatic nerve crush

Dixdc1 (DIX domain containing-1), the mammalian homolog of Ccd1 (Coiled-coil-Dishevelled-Axin1), is a protein containing a coiled-coil domain and a Dishevelled-Axin (DIX) domain. As a novel component of the Wnt pathway, Dixdc1 has been reported to be able to promote neural progenitor proliferation and neuronal differentiation via Wnt/β-catenin signaling. But there still remains something unknown about Dixdc1 distribution and functions in the lesion and regeneration of the peripheral nervous system (PNS), so we tried to investigate dynamic changes of Dixdc1 expression in a rat sciatic nerve crush (SNC) model in this study. First of all, we detected SNC-induced increased levels of Dixdc1 in Schwann cells and interestingly identified parallel expression of PCNA (proliferation cell nuclear antigen) with Dixdc1. Besides, we observed up-regulated Dixdc1 during the process of TNF-α-induced Schwann cell proliferation. Also, we discovered that Dixdc1 could promote G1-S phase transition accompanied with the up-regulation of CyclinD1 and down-regulation of p21. More importantly, enhanced effects of Dixdc1 on cell proliferation were confirmed to be associated with PI3K activation. Not only blocking of the PI3K but Dixdc1 knockdown led to significantly decreased ability for proliferation, as well as down-regulation of CyclinD1 and up-regulation of p21. In summary, these data demonstrated that Dixdc1 might participate in Schwann cell proliferation by targeting CyclinD1 and p21 at least partially through the PI3K/AKT activation. - Highlights: • The dynamic changes and location of Dixdc1 after sciatic nerve crush. • Dixdc1 was associated with Schwann cell proliferation. • Dixdc1 promoted Schwann cell proliferation partly via PI3K/AKT pathway.

36 MATERIALS SCIENCE↗
DOE OSTI2017

Injury-stimulated Sonic hedgehog expression in microglia contributes to neuroinflammatory response in the MPTP model of Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder in which dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) region are selectively destroyed. Sonic hedgehog (Shh) has been well known to play a key role in a variety of processes such as embryogenesis, cell proliferation and protection, and tissue repair during inflammation. However, the evidences for the innate role of Shh in adult brain injury are presently lacking and studies have been needed to unveil the importance of Shh in the process of neurodegeneration. Here, we investigated the role of Shh in the pathologic progress of Parkinson's disease in MPTP-induced animal model system. Interestingly, we observed that Shh expression was gradually increased in MPTP affected SNpc region. Activated microglia exclusively expressed SHH in vivo and we could recapitulate Shh induction in activated cultured primary microglia cells. Using the SHH responsive Cre-loxP binary genetic reporter transgenic mouse system, we also found that most of the cell types except for oligodendrocyte in the SNpc region reacted to the SHH by MPTP injection. Taken together, activated microglia induced Shh expression and most neural cells except oligodendrocyte responded to microglia-derived SHH in MPTP-treated SN. These results suggest that SHH in activated microglia by MPTP-injection might be involved in the innate processes of recovery from neurotoxin induced injury in the PD animal model system. - Highlights: • Sonic hedgehog (Shh) was induced by MPTP neurotoxin at the Substantia Nigra (SN) in vivo. • Activated microglia are major cell type for SHH expression in vivo and in vitro. • Different types of cells in the brain, except oligodendrocyte, respond to microglia-derived SHH in SN region.

60 APPLIED LIFE SCIENCES↗