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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 1,045 records · Page 58
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Full-length RPB1 is required in two-step shoot regeneration

Highlights: • Mutations in RPB1 result in defects in callus formation in Arabidopsis. • Auxin gradient formation is disturbed in RPB1 mutants. • The frequency of shoot regeneration upon SIM is repressed in RPB1 mutants. • The cytokinin response receded during shoot regeneration. Regeneration is a complicated progress in plants and animals. Most multicellular organisms can regenerate new tissue when wounded, and plants excel most animals in their ability to regenerate whole new growth module from adult tissues. Regeneration in Arabidopsis includes two steps. Firstly, the explants from differentiated plant tissues such as roots or hypocotyls are induced to generate callus, then the shoots regenerate upon the callus. The phytohormone auxin and cytokinin play important parts in this process. And genes related to auxin and cytokinin siganls involved in the regeneration have been studied widely. As we reported before, in Arabidopsis the full-length CTD of RNA Polymerase II's largest subunit RPB1 is necessary in keeping normal cell cycling and maintaining stem cell niches. Here, we report that the mutants of card1s have significant defects in the regeneration progress both in the induction of callus and the formation of shoot. All the results further proved the importance of intact RPB1 from a distinctive perspective.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Glycine confers neuroprotection through PTEN/AKT signal pathway in experimental intracerebral hemorrhage

Highlights: • Glycine attenuated brain injuries after rats ICH. • Glycine down-regulated PTEN in rats ICH. • The neuroprotective effect of glycine was mediated through PTEN/Akt signal pathway in experimental rat ICH. Glycine has been shown to protect against ischemic stroke through various mechanisms. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) which antagonize Akt-dependent cell survival has been linked to neuronal damage. However, whether glycine has a neuroprotective property in intracerebral hemorrhage (ICH) was unknown. This study aimed to determine the protective effect of glycine in rats ICH. Adult male Sprague-Dawley (SD) rats were subjected to left striatum infusion of autologous blood. ICH animals received glycine (0.2–3 mg/kg, icv) at 1 h after ICH with or without pre-injection of Akt Inhibitor IV (100 μM, 2 μl, icv) 0.5 h prior to glycine treatment. Our results showed that in the perihematomal area PTEN was up-regulated in the early stage after ICH. However, glycine treatment decreased PTEN protein level and increased the phosphorylation level of AKT (p-AKT) in the perihematomal area. With the administration of glycine, neuronal death was significantly reduced and Evans blue leakage was alleviated as well as the brain edema after ICH. Moreover, hematoma volume was decreased and neurobehavioral outcome was improved. Nevertheless, Akt Inhibitor IV abolished the neuroprotective effects of glycine after ICH. Together, our findings demonstrate, for the first time, the protective role of glycine on ICH rats, and suggest that the neuroprotective effect of glycine was mediated through PTEN/Akt signal pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The endogenous agonist, β-alanine, activates glycine receptors in rat spinal dorsal neurons

Highlights: • Activation of glycine receptors by β-alanine in substantia gelatinosa neurons. • β-alanine opens Cl{sup −} channels on postsynaptic substantia gelatinosa neurons. • β-alanine acts as a inhibitory neurotransmitter in sunstantia gelatinosa neurons. • β-alanine may be involved in antinociception. β-alanine is a structural analog of glycine and γ-aminobutyric acid (GABA) and is thought to be involved in the modulation of nociceptive information at the spinal cord. However, it is not known whether β-alanine exerts its effect in substantia gelatinosa (SG) neurons of the spinal dorsal horn, where glycine and GABA play an important role in regulating nociceptive transmission from the periphery. Here, we investigated the effects of β-alanine on inhibitory synaptic transmission in adult rat SG neurons using whole-cell patch-clamp. β-alanine dose-dependently induced outward currents in SG neurons. Current-voltage plots revealed a reversal potential at approximately −70 mV, which was close to the equilibrium potential of Cl{sup −}. Pharmacological analysis revealed that β-alanine activates glycine receptors, but not GABA{sub A} receptors. These results suggest that β-alanine hyperpolarizes the membrane potential of SG neurons by activating Cl{sup −} channels through glycine receptors. Our findings raise the possibility that β-alanine may modulate pain sensation through glycine receptors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

SPG6 supports development of acute myeloid leukemia by regulating BMPR2-Smad-Bcl-2/Bcl-xl signaling

Highlights: • Up-regulated expression of SPG6 correlated with poor survival of AML patients. • Knockdown expression of SPG6 suppresses growth and promotes apoptosis of AML cells. • SPG6 regulates BMPR2-Smad-Bcl-2/Bcl-xl signaling in AML cells. Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. To effectively treat AML, new molecular targets and therapeutic approaches must be identified. In silico analysis of several available databases of AML patients showed that the expression of Spastic Paraplegia 6 Protein (SPG6) significantly inversely correlates with the overall survival of AML patients. To determine whether SPG6 supports AML development, we employed an shRNA-encoding lentivirus system to inhibit SPG6 expression in human AML cells including NB4 and MV4-11 cells. Knockdown expression of SPG6 resulted in decreased cell growth and elevated apoptosis of these leukemia cells. Notably, the SPG6 deficiency resulted in higher BMPR2 expression indicating that BMPR2 signaling contributes to AML pathogenesis. Furthermore, SPG6 deficiency promoted phosphorylation of Smad1/5/9 and decreased transcription of Bcl-2 and Bcl-xl. Our study suggests that SPG6 contributes to AML pathogenesis, and suggests that inhibition of SPG6 may be novel strategy for treating human AML.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hypomyelination and cognitive impairment in mice lacking CD133 (Prominin-1)

The CD133 antigen, also known as prominin-1, is a glycoprotein that specifically localizes to plasma membrane protrusions. The precise function of CD133 remains unknown, but it is expressed in various progenitor cells including those derived from the neural and hematopoietic system, as well as different tissues. In the adult mouse brain, CD133 is highly expressed in white matter. Here, we performed immunohistochemical staining and electron microscopy to demonstrate that mice lacking CD133 (CD133{sup −/−}) exhibit decreased myelin in the corpus callosum, the largest white matter tract in the brain. Hypomyelination in CD133{sup −/−} mice was associated with fewer oligodendrocyte progenitor cells and mature oligodendrocytes. Behavioral analyses revealed that significantly impaired object recognition memory and altered Y-maze performance by CD133{sup −/−} mice compared with wild-type mice, suggesting perturbed cognitive performance. These results suggest that CD133 regulates myelination and understanding the underlying molecular mechanisms may guide the development of novel therapeutic strategies for diseases characterized by myelin deficiency.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Small GTPase R-Ras participates in neural tube formation in zebrafish embryonic spinal cord

Ras related (R-Ras), a small GTPase, is involved in the maintenance of apico-basal polarity in neuroepithelial cells of the zebrafish hindbrain, axonal collapse in cultured murine hippocampal neurons, and maturation of blood vessels in adult mice. However, the role of R-Ras in neural tube formation remains unknown. Using antisense morpholino oligonucleotides (AMOs), we found that in the spinal cord of zebrafish embryos, the lumen was formed bilaterally in rras morphants, whereas it was formed at the midline in control embryos. As AMO can cause off-target effects, we generated rras mutant zebrafish lines using CRISPR/Cas9 technology. Although these rras mutant embryos did not have a bilateral lumen in the spinal cord, the following findings suggest that the phenotype is unlikely due to an off-target effect of rras AMO: 1) The rras morphant phenotype was rescued by an injection of AMO-resistant rras mRNA, and 2) a bilaterally segregated spinal cord was not observed in rras mutant embryos injected with rras AMO. The results suggest that the function of other ras family genes may be redundant in rras mutants. Previous research reported a bilaterally formed lumen in the spinal cord of zebrafish embryos with a mutation in a planar cell polarity (PCP) gene, van gogh-like 2 (vangl2). In the present study, in cultured cells, R-Ras was co-immunoprecipitated with Vangl2 but not with another PCP regulator, Pricke1. Interestingly, the interaction between R-Ras and Vangl2 was stronger in guanine-nucleotide free point mutants of R-Ras than in wild-type or constitutively active (GTP-bound) forms of R-Ras. R-Ras may regulate neural tube formation in cooperation with Vangl2 in the developing zebrafish spinal cord.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Dietary mung bean protein reduces high-fat diet-induced weight gain by modulating host bile acid metabolism in a gut microbiota-dependent manner

Highlights: • Mung bean protein intake reduces high fat diet-induced weight gain, fat accumulation, and hepatic steatosis. . • Mung bean protein intake increases plasma GLP-1 and intestinal secondary bile acids. • The anti-obesity effects occur via a mechanism that depends on the gut microbiota. The 8-globulin-rich mung bean protein (MPI) suppresses hepatic lipogenesis in rodent models and reduces fasting plasma glucose and insulin levels in obese adults. However, its effects on mitigating high fat diet (HFD)-induced obesity and the mechanism underlying these effects remain to be elucidated. Herein, we examined the metabolic phenotype, intestinal bile acid (BA) pool, and gut microbiota of conventionally raised (CONV-R) male C57BL/6 mice and germ-free (GF) mice that were randomized to receive either regular HFD or HFD containing mung bean protein isolate (MPI) instead of the dairy protein present in regular HFD. MPI intake significantly reduced HFD-induced weight gain and adipose tissue accumulation, and attenuated hepatic steatosis. Enhancement in the secretion of intestinal glucagon-like peptide-1 (GLP-1) and an enlarged cecal and fecal BA pool of dramatically elevated secondary/primary BA ratio were observed in mice that had consumed MPI. These effects were abolished in GF mice, indicating that the effects were dependent upon the presence of the microbiota. As revealed by 16S rRNA gene sequence analysis, MPI intake also elicited dramatic changes in the gut microbiome, such as an expansion of taxa belonging to the phylum Bacteroidetes along with a reduced abundance of the Firmicutes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Reno-protective effects of TAK-242 on acute kidney injury in a rat model

Highlights: • Acute kidney inschemia/reperfusion (I/R) injury is characterized by an abrupt loss of kidney function. • TAK-242 is a selective inhibitor of the Toll-like receptor 4, which may cause kidney damage via aldosterone-induced pathway. • Administration of TAK-242 may act as a reno-protective agent in reducing overall kidney damage following ischemia/reperfusion injury. • IL-18, MDA and NGAL are useful biomarkers of kidney damage following ischemia/reperfusion injury . Acute kidney inschemia/reperfusion (I/R) injury is characterized by an abrupt loss of kidney function, resulting in the retention of urea and other nitrogenous waste products and in the dysregulation of extracellular volume and electrolytes. Despite the advances in therapeutic techniques, the mortality and morbidity of patients remain high and have not appreciably improved. This study aims to evaluate the potential protective effect of TAK-242 on renal ischemia/reperfusion injury using an animal model. Thirty-five adult male Sprague-dawely rats (weighing 200–300), were assigned randomly into the following experimental groups (n = 7 in each group), Control (I/R), Sham (negative control), TAK-242 (5 mg/kg body weight), TAK-242 (10 mg/kg body weight) and Vehicle (DMSO). Rats were exposed to a 30 min of ischemia then 3 h of reperfusion. At the end of reperfusion phase, rats were sacrificed then plasma, serum and tissue samples were obtained to measure markers of kidney oxidative stress and inflammation. Plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), and tissue levels of interleukin-18 (IL-18) and malondialdehyde (MDA) were significantly lower in TAK-242 pretreated groups than the vehicle group and the control group (p < 0.05). Furthermore; serum levels of urea and creatinine were significantly lower in the TAK-242 pretreated groups as compared to the control group (p < 0.05). We conclude that administration of TAK-242 can be useful preventive method in attenuating the degree of acute kidney injury during ischemic reperfusion process as shown by a significant reduction of urinary inflammatory markers as well as significant reduction of urea and creatinine levels.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Mitoflash lights single mitochondrial dynamics events in mature cardiomyocytes

Mitochondria, the powerhouse of eukaryotic cells, are highly dynamic organelle. Mitochondrial fission, fusion, kissing and contraction have been reported over and over again in non-static cells, such as fibroblast, with tubular mitochondrial networks. Even though the fluorescence propagation among mitochondria of mature cardiomyocytes had been captured using mitochondrial matrix targeted photoactivatable GFP (PAGFP) or MitoDendra proteins, there are no direct evidence that single real time mitochondrial dynamics events exist in mature cardiomyocytes with ball-like mitochondria. Here we first time revealed the visualizable single mitochondrial dynamics events in adult mature cardiomyocytes by the mitochondrial flash (mitoflash). We found fission, fusion, contraction and kissing were accompanied by a mitoflash event. Metabolism could increase mitochondrial contraction. Fusion and Kissing mediated inter-mitochondrial communication with higher frequency than fission. These results demonstrate that mitochondria of static mature cardiomyocytes are undergoing the rare, but real dynamics change.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

mir-127-3p inhibits the proliferation of myocytes by targeting KMT5a

MicroRNAs are a class of highly conserved ∼20 nucleotides non-coding RNAs that post-transcriptionally regulate gene expression. Many miRNAs were studied in the development of skeletal muscle, such as miR-1, miR-206, and miR-133. In our previous study, miR-127-3p was found highly expressed in porcine fetal skeletal muscle, whereas the detailed functions of miR-127-3p in muscle development is still unclear. In this study, we detected that miR-127-3p also highly expressed in skeletal muscle, cardiac muscle of adult mice and proliferative C2C12 cell lines. Overexpression of miR-127-3p almost has no effects on differentiation of C2C12 cell lines. However, miR-127-3p significantly inhibited the cell proliferation of C2C12 cells. Moreover, we identified KMT5a as a target gene that was down-regulated in both mRNA and protein level when miR-127-3p mimics were introduced. Furthermore, KMT5a overexpression in miR-127-3p treated cells rescued the influence of miR-127-3p on C2C12 proliferation. In brief, our data reveals that miR-127-3p regulates the proliferation of myocytes through KMT5a.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Induction of the mitochondrial NDUFA4L2 protein by HIF-1a regulates heart regeneration by promoting the survival of cardiac stem cell

The adult mammalian heart doesn't regenerate after cardiomyocyte injury, which was mainly caused by the severe and persistent effects of cardiomyopathy. Recently, some studies reported that the mammalian heart can regenerate under low oxygen environment. However, the mechanism that the mammalian heart can regenerate remains unknown. Here, we used cardiac stem cells (CSCs) to be planted in serum-free medium under hypoxia environment to understand the mechanism of HIF1α/NDUFA4L2 in the regulation of hypoxia-alleviated apoptosis. Our results revealed that hypoxia can alleviated CSCs apoptosis. Hypoxia inhibited the level of cleaved-caspase3 and stimulated the expression of stabilized HIF-1α. DMOG promotes the survival of CSCs and the protein expression of NDUFA4L2. 2-ME repressed the survival of CSCs and the protein expression of NDUFA4L2. CHIP assay showed that HIF-1α regulated the survival of CSCs by augmenting the combination of HIF-1α and NDUFA4L2's HRE. Knockdown of NDUFA4L2 reversed the role of hypoxia in the survival of CSCs. Taken together, hypoxia promotes the viability of CSCs in serum-free medium by HIF-1α/NDUFA4L2 signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Tankyrase regulates apoptosis by activating JNK signaling in Drosophila

Highlights: • Ectopic expression of DTNKS induces wing and eye defects. • DTNKS positively regulates cell apoptosis. • DTNKS regulates apoptosis by controlling JNK signaling activity. Programmed cell death (PCD), or apoptosis, plays essential roles in various cellular and developmental processes, and dysregulation of apoptosis causes many diseases. Thus, regulation of apoptotic process is very important. Drosophila tankyrase (DTNKS) is an evolutionarily conserved protein with poly(ADP-ribose) polymerase activity. In mammalian cells, tankyrases (TNKSs) have been reported to regulate cell death. To determine whether DTNKS plays function in inducing apoptosis in in vivo development, we used Drosophila as a model system and generated transgenic flies expressing DTNKS. We show that ectopic expression of DTNKS promotes caspase-dependent apoptosis and knockdown of DTNKS by RNAi dramatically alleviates apoptotic defect caused by ectopic expression of pro-apoptotic protein hid or rpr in the adult eye. Moreover, our result shows that ectopic expression of DTNKS triggers the activation of c-Jun N-terminal kinase (JNK) signaling, which is required for DTNKS-mediated apoptosis. Taken together, our finding identifies the role of DTNKS in regulating apoptosis by activating JNK signaling in Drosophila.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Vaccine based on antibody-dependent cell-mediated cytotoxicity epitope on the H1N1 influenza virus increases mortality in vaccinated mice

Antibody-dependent cell-mediated cytotoxicity bridges humoral immunity and cellular immunity. Thus vaccine candidates which can elicit both broadly neutralizing antibodies and potent antibody-dependent cell-mediated cytotoxicity (ADCC) are recommended. Previously, a panel of functional epitopes that can elicit ADCC effects is isolated and characterized on the H1N1 Influenza Virus. Based on these identified epitopes, an epitope vaccine against H1N1 infection has been designed. The serum of vaccine immunized mice show potent ADCC activities in comparison with vector control group and HA ecto domain vaccinated group. However, the release of IL-6 and TNFα is higher in lung of epitope vaccine immunized mice. The viral load is also higher in epitope vaccine immunized mice. In addition, the epitope vaccine immunized mice showed lower survive rate than both empty vector immunized mice and HA ectodomain immunized mice. Passive transfer of serum from epitope vaccine immunized mice to healthy adult mice can decrease the survival rate of recipients after viral challenge. Our data suggested that ADCC epitope based vaccine has a mortality promoting effect rather than protective effect after H1N1 viral challenge. This result provides indications in future vaccine design with a consideration of balancing humoral immune response and cellular immune response.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Microglia support neural stem cell maintenance and growth

Increasing evidence suggests that disease-associated microglia play a protective role in neurodegenerative diseases. Microglia are known to polarize into two reciprocate forms in response to external cues - inflammatory M1 state and anti-inflammatory M2 state. These cells perform key functions in the development of the brain, such as circuit refinement, neurogenesis, and neuronal growth. In this study, we analyzed the secretion effect of microglia on neural stem/progenitor cell (NSPC) proliferation and differentiation. We cultured adult mouse-derived NSPCs in a conditioned medium from BV2 immortalized microglia without growth factors and evaluated their differentiation. When cultivated with BV2-derived soluble factors in the presence of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), NSPCs were able to maintain Nestin expression and showed increased proliferation compared with those cells cultivated with bFGF and EGF only. Moreover, conditioned media from M2-polarized primary microglia, stimulated by IL-10/IL-13, showed supportive effect on NSPC proliferation. These data suggest that microglia support neural stem cell proliferation through secreting neuro-nutritious soluble factors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Valproic acid promotes the neuronal differentiation of spiral ganglion neural stem cells with robust axonal growth

Highlights: • Hearing loss occurs with loss of both hair cells and spiral ganglion neurons (SGNs). • SGN-neural stem cells (NSCs) may be a source of SGN regeneration. • Valproic acid (VPA) induces neural differentiation of SGNs and inhibits their proliferation. • VPA-treated SGN-NSCs show longer neurite outgrowths than those cultured without bFGF. • The effects of VPA are related to Wnt/β-catenin signaling activation. Hearing loss occurs with the loss of hair cells of the cochlea and subsequent degeneration of spiral ganglion neurons (SGNs). Regeneration of SGNs is a potentially promising therapeutic approach to hearing loss in addition to the use of a cochlear implant (CI), because this device stimulates SGNs directly to restore hearing bypassing the missing hair cells. The presence of SGN-neural stem cells (NSCs) has been reported in adult human and mice. These cells have the potential to become SGNs and thus represent a cellular foundation for regeneration therapies for hearing loss. Valproic acid (VPA) has been shown to influence the neural differentiation of NSCs through multiple signaling pathways involving glycogen synthase kinase3β (GSK3β). Our present study therefore aimed to modulate the neural differentiation potential of SGN-NSCs by treatment with VPA. We here report that a clinically relevant concentration of 1 mM VPA induced the differentiation of basic fibroblast growth factor (bFGF)-treated P1- and P14-SGN-NSCs into neuronal and glial cells, confirmed by neuronal marker (Tuj1 and MAP2) and glial cell marker (GFAP and S100β) detection. VPA-treated cells also promoted much longer neurite outgrowth compared to differentiated cells cultured without bFGF. The effects of VPA on the regulation of differentiation may be related to the activation of the Wnt/β-catenin signaling pathway, but not the inhibition of histone deacetylases (HDACs). We propose that VPA has the potential to convert SGN-NSCs into SGNs and thereby restore hearing when combined with a CI.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Decreased expression of LATS1 correlates with astrogliosis after spinal cord injury

Large tumor suppressor kinase 1 (LATS1) is a serine/threonine kinase of the AGC kinase family in mammals and involved in various biological processes, it is a key regulator of cell cycle progression. However, the role of LATS1 in central nervous system trauma is still unknown. In present study, we performed an acute spinal cord injury (SCI) model in adult rats and investigated the dynamic changes of LATS1 expression in the spinal cord. We found that LATS1 protein levels were significantly decreased at day 1 after injury. Meanwhile, double immunofluorescence staining showed these changes were striking in astrocytes, which were largely proliferated after SCI. In vitro, LATS1 overexpression inhibited astrocyte proliferation. Conversely, LATS1 depletion by siRNA promoted cell proliferation in primary astrocyte. Moreover, LATS1 overexpression reduced cyclin D1 expression and increased the expression of p27{sup kip1}. In addition, LATS1 overexpression also promoted yes-associated protein 1 (YAP) phosphorylation. Our data suggested that LATS1 might play an important role in spinal cord injury and suppress astrogliosis through regulating the expression of cyclin D1, p27{sup kip1} and p-YAP.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Disproportionately high levels of HGF induce the degradation of the c-met receptor through the proteasomal degradation pathway

Highlights: • HGF-mediated cell migration increased as concentration of HGF increased, but declined beyond a certain point. • The c-met receptor was degraded when unnecessarily large amounts of HGF were present. • Excessive amounts of HGF attenuated downstream signaling even if cells were re-treated with optimal amounts of HGF. • Excessive amounts of HGF diverted c-met toward the proteasomal degradation pathway through phosphorylation of Tyr 1003. Hepatocyte growth factor (HGF) receptor is a member of the receptor tyrosine kinases (RTKs) and has been reported to perform diverse functions in various cell types during both the developmental and adult stages. Among different roles, HGF is best known for its angiogenic effects of inducing the migration of endothelial cells. Because angiogenesis is one of the prerequisite steps for tumor metastasis, HGF-dependent cell migration has to be tightly controlled. However, the underlying mechanisms regulating the optimum level of HGF/c-met signaling have been poorly understood. In this study, we tested whether the migration of endothelial cells is regulated by a negative feedback mechanism under disproportionately large amounts of HGF. Data from endothelial cell migration assays showed that HGF activity increased as its concentration increased, but declined beyond a certain point. Under limiting conditions, amounts of phosphorylated Erk and Akt surged, reaching a plateau in which the enhanced level was more or less maintained. The c-met receptor was degraded when unnecessarily large amounts of HGF were present. Under these conditions, HGF could no longer activate downstream signaling pathways even if cells were re-treated with optimal amounts of HGF. Excessive doses of HGF increased the phosphorylation of tyrosine residue 1003 involved in the ubiquitination of c-met, and phosphorylated c-met was diverted toward the proteasomal degradation pathway. Taken together, HGF/c-met signaling is tightly regulated by a negative feedback loop through an ubiquitin-proteasomal degradation pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Cyclophilin 1 (Cyp1) mutation ameliorates oxidative stress-induced defects in a Drosophila DJ-1 null mutant

Highlights: • Drosophila Cyp1 mutant exhibits no significant defects in mitochondria. • Cyp1 mutant shows decreased lipid peroxidation. • Cyp1 inhibition increases fly survival under oxidative stress. • Cyp1 mutation ameliorates oxidative stress-induced defects in a DJ-1 mutant model. Drosophila cyclophilin 1 (Cyp1) is a structural and functional homolog of mammalian cyclophilin D (CypD), a unique mitochondrial cyclophilin (Cyp) that regulates the inner mitochondrial membrane permeability transition and cell survival under cellular stresses such as oxidative damage. In this study, we generated and characterized a Drosophila Cyp1 mutant. Cyp1 mutant flies successfully developed into adults and showed no significant defects in mitochondrial morphology, function, and content. However, oxidative damage significantly decreased in Cyp1 mutant flies, and inhibition of Cyp1 expression substantially increased the survival under various oxidative stress paradigms. Moreover, Cyp1 mutation successfully ameliorated survival rates, locomotor activity, and dopaminergic neuron quantity in a Drosophila DJ-1 mutant under oxidative stress, further confirming the protective role of Cyp1 mutation against oxidative stress. In conclusion, these results suggest Cyp1 and its human homolog CypD as putative molecular targets for the treatment of DJ-1 deficiency-associated diseases, including Parkinson's disease.

60 APPLIED LIFE SCIENCES↗