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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 667 records · Page 37
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Quantitative phosphoproteomics reveals GTBP-1 regulating C.elegans lifespan at different environmental temperatures

Highlights: • Comprehensive quantitative phosphoproteomics study of C.elegans during aging under different temperatures. • Phosphoproteomics analysis identified important proteins and signaling pathways. • The kinases CK2, MAPK and CAMK2 might play important roles in aging. • Functional experiments confirm that GTBP-1 could regulate C.elegans lifespan. • An important resource for future studies of protein phosphorylation in C.elegans. Temperature is one of the primary environmental factors that affect aging, in which protein phosphorylation is an important regulator. Currently, the understanding of phosphorylation events in regulatory networks during aging has remained rather limited. Herein, the phosphoproteomes of C.elegans of different age groups cultured at 20 °C (natural aging) and 25 °C (accelerated aging) were analyzed. Through using the iTRAQ-labeled phosphoproteomics method, 2375 phosphoproteins and 9063 phosphosites were identified. Volcano plots illustrated that 208 proteins during natural aging and 130 proteins during accelerated aging, were significantly changed. Gene ontology and pathway analysis revealed that these proteins were mainly involved in translation, development, metabolisms, and animal behavior processes. Moreover, our results uncovered those kinases CK2, MAPK and CAMK2 might play important roles in aging regulation. Functional experiments confirm that the candidated phosphoprotein GTBP-1 could regulate C.elegans lifespan at 20 °C or 25 °C and is more resistant to heat and oxidative stresses. In summary, our results provided an important resource for future studies of protein phosphorylation in worms. Data are available via ProteomeXchange with identifier PXD009661.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA SBF2-AS1 promotes hepatocellular carcinoma progression through regulation of miR-140-5p-TGFBR1 pathway

Highlights: • LncRNA SBF2-AS1 was overexpressed in HCC tissues and cell lines. • Up-regulation of lncRNA SBF2-AS1 was associated with poor clinical features and prognosis in HCC patients. • Knockdown of lncRNA SBF2-AS1 suppressed HCC progression by regulation of miR-140-5p-TGFBR1 pathway. A growing number of studies has suggested that long non-coding RNAs (lncRNAs) exert essential roles in the development and progression of hepatocellular carcinoma (HCC). However, the roles of lncRNA and its molecular mechanism in HCC are largely unknown. In the present study, the functions and molecular mechanisms of a novel lncRNA, SET-binding factor 2 (SBF2) antisense RNA1 (SBF2-AS1), were investigated in HCC tissues and cell lines. We found that the expression levels of SBF2-AS1 were significantly up-regulated in HCC tissues and correlated with poor prognosis. SBF2-AS1 knockdown could inhibit the proliferation of HCC cells and attenuate the development of HCC tumor in vivo. Moreover, wound healing and Transwell assays revealed that down-regulation of SBF2-AS1 suppressed the migration and invasion of HCC cells by modulating epithelial-mesenchymal transition (EMT) ability. Mechanistically, we observed that SBF2-AS1 served as a competing endogenous RNA (ceRNA) of miR-140–5p. Subsequently, transforming growth factor beta receptor 1 (TGFBR1) was certified as a direct target of miR-140–5p and enforcing SBF2-AS1 expression elevated TGFBR1 expression in HCC. Taken together, our study suggested that SBF2-AS1 modulated TGFBR1 through sponging miR-140–5p in HCC development and progression indicating that SBF2-AS1 might be further chosen as a potential anticancer therapeutic target and a promising prognostic biomarker for HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ERα is a negative regulator of PD-L1 gene transcription in breast cancer

Highlights: • PD-L1 mRNA level is much lower in ERα-positive breast cancer cell lines. • E2 treatment inhibits PD-L1 gene transcription in ERα-positive MCF7 cells. • Ectopic expression of ERα down-regulates PD-L1 gene expression in ERα-negative MDA-MB-231 cells. • ERα expression is negatively correlated with PD-L1 expression in ERα-positive breast cancer. The programmed death-ligand 1 (PD-L1) expression by tumors results in potent antitumor immune suppression through binding to programmed death-1 (PD-1) on T cells and subsequent inhibition of T cells activity. Although recent pathological studies have shown that PD-L1 is actively expressed in certain ERα-negative breast cancer, little is known about whether ER signaling regulates PD-L1 gene expression. Here, we investigated the relationship between ERα and PD-L1 in breast cancer. Analysis of Comprehensive Cell Line Encyclopedia (CCLE) data showed that the average mRNA level of PD-L1 in ERα-positive breast cancer cell lines was significantly lower than that in ERα-negative breast cancer cell lines. E2 treatment inhibited PD-L1 mRNA expression in hormone-depleted ERα-positive MCF7 cells. Moreover, ectopic expression of ERα in triple-negative MDA-MB-231 cells reduced PD-L1 mRNA and protein expression. Consistently, analysis of The Cancer Genome Atlas (TCGA) data revealed an inverse correlation between ERα and PD-L1 expression in ERα-positive breast cancer. Taken together, our results identify ERα as a negative regulator of PD-L1 gene transcription in breast cancer cells, suggesting that ERα loss-of-function may facilitate the immune evasion of breast cancer cells via up-regulation of PD-L1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TORC1 signaling regulates DNA replication via DNA replication protein levels

Highlights: • TORC1 protein kinase reduced the levels of proteins critical for DNA replication initiation and retarded DNA replication. • TORC1 inactivation promoted Mcm3 degradation in a manner dependent on Skp1–Cullin–F-box (SCF)-Grr1 and proteasome. • TORC1-downstream factors PP2A-Cdc55 protein phosphatase and protein kinase A regulated Mcm3 degradation. Accurate DNA replication is at the heart of faithful genome transmission in dividing cells. DNA replication is strictly controlled by various factors. However, how environmental stresses such as nutrient starvation impact on these factors and DNA replication is largely unknown. Here we show that DNA replication is regulated by target of rapamycin complex 1 (TORC1) protein kinase, which is a central regulator of cell growth and proliferation in response to nutrients. TORC1 inactivation reduced the levels of various proteins critical for DNA replication initiation, such as Mcm3, Orc3, Cdt1, and Sld2, and retarded DNA replication. TORC1 inactivation promoted proteasome-mediated Mcm3 degradation. Skp1–Cullin–F-box (SCF)-Grr1 and PEST motif mediated Mcm3 degradation. TORC1-downstream factors PP2A-Cdc55 protein phosphatase and protein kinase A regulated Mcm3 degradation. This study showed that TORC1 signaling modulates DNA replication to coordinate cell growth and genome replication in response to nutrient availability.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

DDX21 promotes gastric cancer proliferation by regulating cell cycle

Highlights: • DDX21 is highly expressed in gastric cancer tissues and cell lines. • Overexpressed DDX21 regulates cancer cell growth and tumorigenesis. • DDX21 promotes gastric cancer cell proliferation via regulating Cyclin D1/CDK2. DEAD (Asp-Glu-Ala-Asp) cassette helicase 21 (DDX21) is an ATP-dependent RNA helicase that is overexpressed in various malignancies. There is increasing evidence that DDX21 is involved in carcinogenesis and cancer progression by promoting cell proliferation. However, the functional role of DDX21 in gastric cancer is largely unknown. In this study, we observed that DDX21 was significantly up-regulated in gastric cancer tissues compared to paired adjacent normal tissues. The expression of DDX21 was closely related to the pathological stage of gastric cancer. In vitro and in vivo studies had shown that knockdown of DDX21 inhibited gastric cancer cell proliferation, colony formation, G1/S cell cycle transition and xenograft growth, while ectopic expression of DDX21 promoted these cell functions. Mechanically, DDX21 induced gastric cancer cell growth by up-regulating levels of Cyclin D1 and CDK2. Taken together, these results revealed a novel role for DDX21 in the proliferation of gastric cancer cells via the Cyclin D1 and CDK2 pathways. Therefore, DDX21 can be used as a therapeutic target for gastric cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CDK phosphorylation regulates Mcm3 degradation in budding yeast

Highlights: • CDK generates phosphodegron in Mcm3. • CDK represses SCF-mediated Mcm3 degradation by exclusion of the MCM complex from the nucleus. • Mcm3 degradation in the nucleus could be a compensatory backup system to protect against unscheduled DNA replication. Accurate regulation of activity and level of the MCM complex is critical for precise DNA replication and genome transmission. Cyclin-dependent kinase (CDK) negatively regulates nuclear localization of the MCM complex via phosphorylation of the Mcm3 subunit. More recently, we found that Mcm3 is degraded via the Skp1–Cullin–F-box (SCF)–proteasome axis in budding yeast. However, how Mcm3 degradation is regulated is largely unknown. Here, we show that CDK represses Mcm3 degradation. Phosphorylated Mcm3 was excluded from the nucleus, where SCF is predominantly located, although CDK-mediated phosphorylation itself generated a phosphodegron of Mcm3, stimulating the degradation of Mcm3 resident in the nucleus. Thus, CDK negatively regulated nuclear MCM levels by exclusion from the nucleus and degradation in the nucleus via Mcm3 phosphorylation. We will discuss the physiological importance of Mcm3 degradation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

SpWRKY6 acts as a positive regulator during tomato resistance to Phytophthora infestans infection

Highlights: • SpWRKY6 acts as a positive regulator of tomato resistance to P. infestans infection. • Over-expressing SpWRKY6 tomato increased resistance to P. infestans by scavenging reactive oxygen species. • SpWRKY6-mediated tomato resistance to P. infestans through regulating the expression level of PR genes. WRKY transcription factors have been widely known to play key regulatory roles in plant disease resistance. In our previous study, characteristics of SpWRKY6 and its role in response to biotic and abiotic stress was studied. To further investigate the function of SpWRKY6 in tomato resistance to Phytophthora infestans (P. infestans), we studied the effects of loss and gain of function of SpWRKY6. Inhibition of SpWRKY6 mRNA accumulation in tomato leaves, using virus-induced gene silencing (VIGS), greatly reduced SpWRKY6 mRNA levels, and compromised tomato resistance to P. infestans. In contrast, overexpressing- SpWRKY6 tomato plants showed enhanced resistance to P. infestans, accompanied by decreased number of necrotic cells, lesion sizes and disease index. Furthermore, after P. infestans infection, the expression levels of pathogenesis related (PR) genes in transgenic tomato plants overexpressed SpWRKY6 were significantly higher than those in wild type plants, while the number of necrotic cells and the reactive oxygen species (ROS) accumulation were fewer and lower. Taken together, these results indicating that SpWRKY6 acts as a positive regulator of tomato resistance to P. infestans infection through regulating the ROS level and the expression level of PR genes along with alleviating cell membrane injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

AURKA contributes to the progression of oral squamous cell carcinoma (OSCC) through modulating epithelial-to-mesenchymal transition (EMT) and apoptosis via the regulation of ROS

Highlights: • AURKA knockdown inhibited the proliferation and ETM in OSCC cell lines. • Silencing AURKA induced apoptosis and ROS in OSCC cell lines. • AURKA knockdown inhibited tumor growth in vivo. Oral squamous cell carcinoma (OSCC) is known as one of the most common cancer influencing the head and neck region. However, the molecular mechanisms revealing OSCC progression is largely unclear. Aurora kinase A (AURKA) is a serine-threonine kinase that functions in mitotic spindle formation and chromosome segregation, and is associated with the progression of human cancers. But its role in regulating OSCC development has not yet been investigated. In the study, we found that AURKA expression was up-regulated in OSCC cell lines and tumor specimens from patients. OSCC patients with high expression of AURKA exhibited a significant decreased overall survival rate. In vitro, AURKA knockdown markedly reduced the proliferation, migration and invasion of OSCC cells using cell counting kit-8 (CCK-8), EdU, colony formation and transwell analysis. EMT was suppressed by AURKA silence, as evidenced by the up-regulated expression of E-cadherin and down-regulated Vimentin in OSCC cells. In addition, apoptosis was markedly induced by AURKA inhibition through promoting the expression of cleaved Caspase-3 and poly (ADP)-ribose polymerase (PARP). Reactive oxygen species (ROS) production was also markedly enhanced in AURKA-knockdown OSCC cells. Importantly, we found that repressing ROS generation using its scavenger of n-acetylcysteine (NAC) significantly abolished AURKA silence-induced apoptosis, accompanied with restored proliferation and EMT. In vivo, AURKA knockdown notably inhibited tumor growth. Therefore, knockdown of AURKA suppressed cell proliferation, migration and invasion, and also induced apoptosis and ROS generation in OSCC possibly via the production of ROS, demonstrating that AURKA inhibition might represent a novel therapeutic target for the prevention of OSCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Retinoic acid modulates iron metabolism imbalance in anemia of inflammation induced by LPS via reversely regulating hepcidin and ferroportin expression

Highlights: • Anemia of inflammation (AI) model was induced by lipopolysaccharide in mouse. • Retinoic acid (RA) increases RBC, Hb, HCT, MCV, MCHC and EPO in AI model. • RA inhibits inflammation in AI model by decreasing TNF-α, IL-18 and IL-1β contents. • RA modulates iron metabolism imbalance in AI model. • RA reversely regulates hepcidin and ferroportin expression in AI model. The present study was designed to investigate the effect of retinoic acid (RA) on anemia of inflammation (AI) induced by lipopolysaccharide (LPS) and explore the potential mechanisms. BALB/c mice were randomly assigned into four groups: control group; LPS (10 mg/kg) group, LPS + RA (3 mg/kg) and LPS + RA (15 mg/kg) groups. Red blood cell count (RBC), hemoglobulin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin contentration (MCHC), erythropoietin (EPO) and iron content in both serum and liver tissue were measured. The AI model induced by LPS was successfully established represented by the decreases in RBC, Hb, HCT, MCV, MCHC and EPO for anemia indicators and by the increases in TNF-α, IL-18 and IL-1β contents for inflammation indicators. However, supplementation of RA increased the levels of anemia indicators and decreased the content of inflammation indicators. In addition, RA increased the content of iron in serum, while decreased its content in liver tissue. Furthermore, RA down-regulated the protein expression of hepcidin, toll-like receptor 4 (TLR4) and p-p65 in liver tissue, while up-regulated that of ferroportin. RA modulates iron metabolism imbalance in AI induced by LPS via reversely regulating hepcidin and ferroportin expression, which might be mediated by TLT-4/NFκB signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

What are the Impacts on the HVAC System when it Provides Frequency Regulation? – A Comprehensive Case Study with a Multi-Zone Variable Air Volume (VAV) System

Heating, ventilation, and air-conditioning (HVAC) systems in commercial buildings have proven to be a great asset for providing secondary frequency regulation (FR) service to the power grid. However, how the provision of FR service affects the HVAC system Quality of Service (QOS) is still largely unknown. In particular, there exists a controversy regarding the energy efficiency impact. This paper investigates how a HVAC system performance and its associated controls are impacted during and after the FR service. For the assessment, we developed a dynamic Modelica-based medium office building model as a virtual testbed with the Air Handling Unit (AHU) fans providing the FR service. Different regulation capacities (demand levels) and standard test signals under various load profiles in the U.S. are considered. The results show that FR has little or no impact on the HVAC operation and occupant thermal comfort while the building is providing the service if an appropriate regulation capacity is pre-determined. However, if the regulation capacity is overestimated, the quality of the FR service provided by the HVAC system and the HVAC energy efficiency will be affected due to the equipment operating constraints. In addition, the AHU supply air temperature fluctuates, and the controller cannot maintain the desired setpoint as the FR magnitude is increased. After the FR service time, the system takes a certain period to return to normal operation. The recovery period extends with the increase in the FR magnitude. For this case study, there exists a control conflict between the FR control and the existing HVAC control (from ASHRAE Guideline 36-2018) during high load conditions, causing the fan speed to saturate. The fan power consumption could increase significantly; up to 77% increase compared to the baseline was observed. This case study demonstrates that the HVAC system controls need to be enhanced and adapted to minimize the interaction between the FR controller and the indoor environmental controls in order to preserve the HVAC system QOS while (during and after) providing satisfactory FR service.

Lu, Xing↗
DOE OSTI2016

Single-walled carbon nanotubes disturbed the immune and metabolic regulation function 13-weeks after a single intratracheal instillation

Due to their unique physicochemical properties, the potential health effects of single-walled carbon nanotubes (SWCNTs) have attracted continuous attention together with their extensive application. In this study, we aimed to identify local and systemic health effects following pulmonary persistence of SWCNTs. As expected, SWCNTs remained in the lung for 13 weeks after a single intratracheal instillation (50, 100, and 200 μg/kg). In the lung, the total number of cells and the percentages of lymphocytes and neutrophils significantly increased at 200 μg/kg compared to the control, and the Th1-polarized immune response was induced accompanying enhanced expression of tissue damage-related genes and increased release of chemokines. Additionally, SWCNTs enhanced the expression of antigen presentation-related proteins on the surface of antigen-presenting cells, however, maturation of dendritic cells was inhibited by their persistence. As compared to the control, a significant increase in the percentage of neutrophils and a remarkable decrease of BUN and potassium level were observed in the blood of mice treated with the highest dose. This was accompanied by the down-regulation of the expression of antigen presentation-related proteins on splenocytes. Moreover, protein and glucose metabolism were disturbed with an up-regulation of fatty acid β-oxidation. Taken together, we conclude that SWCNTs may induce adverse health effects by disturbing immune and metabolic regulation functions in the body. Therefore, careful application of SWCNTs is necessary for the enforcement of safety in nano-industries. - Highlights: • We evaluated local and systemic health effects following persistence of SWCNTs. • SWCNTs remained in the lung for 13 weeks after a single intratracheal instillation. • Th1-polarized immune response was induced in the lung. • The expression of antigen presentation-related proteins was altered. • Immune and metabolic regulation function were disturbed.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

Challenges for tree officers to enhance the provision of regulating ecosystem services from urban forests

Urbanisation and a changing climate are leading to more frequent and severe flood, heat and air pollution episodes in Britain's cities. Interest in nature-based solutions to these urban problems is growing, with urban forests potentially able to provide a range of regulating ecosystem services such as stormwater attenuation, heat amelioration and air purification. The extent to which these benefits are realized is largely dependent on urban forest management objectives, the availability of funding, and the understanding of ecosystem service concepts within local governments, the primary delivery agents of urban forests. This study aims to establish the extent to which British local authorities actively manage their urban forests for regulating ecosystem services, and identify which resources local authorities most need in order to enhance provision of ecosystem services by Britain's urban forests. Interviews were carried out with staff responsible for tree management decisions in fifteen major local authorities from across Britain, selected on the basis of their urban nature and high population density. Local authorities have a reactive approach to urban forest management, driven by human health and safety concerns and complaints about tree disservices. There is relatively little focus on ensuring provision of regulating ecosystem services, despite awareness by tree officers of the key role that urban forests can play in alleviating chronic air pollution, flood risk and urban heat anomalies. However, this is expected to become a greater focus in future provided that existing constraints – lack of understanding of ecosystem services amongst key stakeholders, limited political support, funding constraints – can be overcome. Our findings suggest that the adoption of a proactive urban forest strategy, underpinned by quantified and valued urban forest-based ecosystem services provision data, and innovative private sector funding mechanisms, can facilitate a change to a proactive, ecosystem services approach to urban forest management. - Highlights: • British urban forests are managed reactively, in response to risks and complaints. • Tree officers are aware of urban forests’ delivery of regulating ecosystem services. • Limited funding and lack of political support are obstacles to a proactive approach. • Awareness raising via ecosystem service valuation and strategic planning is needed. • Research into a public-private urban forest funding model would be beneficial.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Site-Specific Phosphorylation of Ikaros Induced by Low-Dose Ionizing Radiation Regulates Cell Cycle Progression of B Lymphoblast Through CK2 and AKT Activation

Purpose: To determine how low-dose ionizing radiation (LDIR) regulates B lympho-proliferation and its molecular mechanism related with Ikaros, transcription factor. Methods and Materials: Splenocytes and IM-9 cells were uniformly irradiated with various doses of a {sup 137}Cs γ-source, and cell proliferation was analyzed. To determine the LDIR-specific phosphorylation of Ikaros, immunoprecipitation and Western blot analysis were performed. To investigate the physiologic function of LDIR-mediatied Ikaros phosphorylation, Ikaros mutants at phosphorylation sites were generated, and cell cycle analysis was performed. Results: First, we found that LDIR enhances B lymphoblast proliferation in an Ikaros-dependent manner. Moreover, we found that LDIR elevates the phosphorylation level of Ikaros protein. Interestingly, we showed that CK2 and AKT are involved in LDIR-induced Ikaros phosphorylation and capable of regulating DNA binding activity of Ikaros via specific phosphorylation. Finally, we identified LDIR-specific Ikaros phosphorylation sites at S391/S393 and showed that the Ikaros phosphorylations at these sites control Ikaros's ability to regulate G1/S cell cycle progression. Conclusion: Low-dose ionizing radiation specifically phosphorylates Ikaros protein at Ser 391/393 residues to regulate cell cycle progression in B lymphoblast.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Direct regulation of p190RhoGEF by activated Rho and Rac GTPases

Rho family GTPases regulate a wide range of cellular processes. This includes cellular dynamics where three subfamilies, Rho, Rac, and Cdc42, are known to regulate cell shape and migration though coordinate action. Activation of Rho proteins largely depends on Rho Guanine nucleotide Exchange Factors (RhoGEFs) through a catalytic Dbl homology (DH) domain linked to a pleckstrin homology (PH) domain that subserves various functions. The PH domains from Lbc RhoGEFs, which specifically activate RhoA, have been shown to bind to activated RhoA. Here, p190RhoGEF is shown to also bind Rac1·GTP. Crystal structures reveal that activated Rac1 and RhoA use their effector-binding surfaces to associate with the same hydrophobic surface on the PH domain. Additionally, both activated RhoA and Rac1 can stimulate exchange of nucleotide on RhoA by localization of p190RhoGEF to its substrate, RhoA·GDP, in vitro. The binding of activated RhoA provides a mechanism for positive feedback regulation as previously proposed for the family of Lbc RhoGEFs. In contrast, the novel interaction between activated Rac1 and p190RhoGEF reveals a potential mechanism for cross-talk regulation where Rac can directly effect stimulation of RhoA. The greater capacity of Rac1 to stimulate p190RhoGEF among the Lbc RhoGEFs suggests functional specialization.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

A regional comparison of sub-daily flow variability in regulated and unregulated rivers in the United States

Regulating rivers for hydropower or other purposes can dramatically alter river flow patterns, including creating substantial changes in flow over short, minutes-to-hours-long timespans known as sub-daily flow variability (SDFV). The impacts of flexible hydropower production on flow and aquatic organisms are increasingly documented in research. However, the degree to which flow alteration relates to different hydropower operational modes in distinct geographical regions and seasons is not well understood. This study offers a methodology for regional- and species-appropriate evaluations of potential impacts of flow on fish based on sub-daily flow characteristics of hydropower operational modes. We analyzed 15-min discharge data between 2018 and 2021 from 69 USGS stream gages to compare SDFV in hydropeaking, run-of-river, and unregulated systems in the US Southeast and Pacific Northwest. Regulated systems exhibited significant SDFV downstream from hydropower facilities relative to unregulated systems, but specific impacts differed between regions. Regulated systems in the Southeast were characterized by high flow coefficients of variation and ratios (hydropeaking only) and extended durations of daily upramping flow phases. Regulated systems in the Pacific Northwest were characterized by many short flow phases per day and large portions of the day spent upramping. Pacific Northwest unregulated systems displayed the strongest seasonal flow patterns while Southeastern hydropeaking systems displayed the greatest SDFV. Given that SDFV impacts multiple dimensions of fish ecology, region-specific sub-daily flow signatures have important implications for understanding and mitigating potential community-, species-, and age-specific effects on fish in different parts of the country.

Fish↗
DOE OSTI2011

ICAM-1 and AMPK regulate cell detachment and apoptosis by N-methyl-N Prime -nitro-N-nitrosoguanidine, a widely spread environmental chemical, in human hormone-refractory prostate cancers

Poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, plays a crucial role in the regulation of DNA repair. PARP-1 hyperactivation causes DNA damage and cell death. The underlying mechanism is complicated and is through diverse pathways. The understanding of responsible signaling pathways may offer implications for effective therapies. After concentration-response determination of N-Methyl-N Prime -Nitro-N-Nitrosoguanidine (MNNG, a PARP-1 activating agent and an environmental mutagen) in human hormone-refractory prostate cancers, the data showed that concentrations below 5 {mu}M did not change cell survival but cause a time-dependent up-regulation of intracellular adhesion molecule-1 (ICAM-1) in mRNA, total protein and cell surface levels. Detection of phosphorylation and degradation of I{kappa}B-{alpha} and nuclear translocation of NF-{kappa}B showed that MNNG induced the activation of NF-{kappa}B that was responsible for the ICAM-1 up-regulation since PDTC (a NF-{kappa}B inhibitor) significantly abolished this effect. However, higher concentrations (e.g., 10 {mu}M) of MNNG induced a 61% detachment of the cells which were apoptosis associated with the activation of AMP-activated protein kinase (AMPK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Further identification showed that both AMPK and JNK other than p38 MAPK functionally contributed to cell death. The remaining 39% attached cells were survival associated with high ICAM-1 expression. In conclusion, the data suggest that NF-{kappa}B-dependent up-regulation of ICAM-1 plays a key role on cell attachment and survival; whereas, activation of AMPK and JNK participates in cytotoxic signaling pathways in detached cells caused by PARP-1 activation. Highlights: Black-Right-Pointing-Pointer Low level of DNA damage helps cell attachment and survival via ICAM-1 upregulation. Black-Right-Pointing-Pointer High level of DNA damage causes AMPK- and JNK-involved cell detachment and death. Black-Right-Pointing-Pointer The study provides an anticancer approach targeting PARP-1 and DNA damage response.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

JBP485 improves gentamicin-induced acute renal failure by regulating the expression and function of Oat1 and Oat3 in rats

We investigated the effects of JBP485 (an anti-inflammatory dipeptide and a substrate of OAT) on regulation of the expression and function of renal Oat1 and Oat3, which can accelerate the excretion of accumulated uremic toxins (e.g. indoxyl sulfate) in the kidney to improve gentamicin-induced ARF in rats. JBP485 caused a significant decrease in the accumulation of endogenous substances (creatinine, blood urea nitrogen and indoxyl sulfate) in vivo, an increase in the excretion of exogenous compounds (lisinopril and inulin) into urine, and up-regulation of the expressions of renal Oat1 and Oat3 in the kidney tissues and slices via substrate induction. To determine the effect of JBP485 on the accelerated excretion of uremic toxins mediated by Oat1 and Oat3, the mRNA and protein expression levels of renal basolateral Oats were assessed by quantitative real-time PCR, western blot, immunohistochemical analysis and an immunofluorescence method. Gentamicin down-regulated the expression of Oats mRNA and protein in rat kidney, and these effects were reversed after administration of JBP485. In addition, JBP485 caused a significant decrease in MPO and MDA levels in the kidney, and improved the pathological condition of rat kidney. These results indicated that JBP485 improved acute renal failure by increasing the expression and function of Oat1 and Oat3, and by decreasing overoxidation of the kidney in gentamicin-induced ARF rats. - Highlights: • JBP485 could up-regulate function and expression of Oat1 and Oat3 in kidney. • Effects of JBP485 on ARF are mediated by stimulating excretion of uremic toxins. • JBP485 protected against gentamicin-induced ARF by decreasing MPO and MDA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Keap1 redox-dependent regulation of doxorubicin-induced oxidative stress response in cardiac myoblasts

Doxorubicin (DOX) is a widely prescribed treatment for a broad scope of cancers, but clinical utility is limited by the cumulative, dose-dependent cardiomyopathy that occurs with repeated administration. DOX-induced cardiotoxicity is associated with the production of reactive oxygen species (ROS) and oxidation of lipids, DNA and proteins. A major cellular defense mechanism against such oxidative stress is activation of the Keap1/Nrf2-antioxidant response element (ARE) signaling pathway, which transcriptionally regulates expression of antioxidant genes such as Nqo1 and Gstp1. In the present study, we address the hypothesis that an initial event associated with DOX-induced oxidative stress is activation of the Keap1/Nrf2-dependent expression of antioxidant genes and that this is regulated through drug-induced changes in redox status of the Keap1 protein. Incubation of H9c2 rat cardiac myoblasts with DOX resulted in a time- and dose-dependent decrease in non-protein sulfhydryl groups. Associated with this was a near 2-fold increase in Nrf2 protein content and enhanced transcription of several of the Nrf2-regulated down-stream genes, including Gstp1, Ugt1a1, and Nqo1; the expression of Nfe2l2 (Nrf2) itself was unaltered. Furthermore, both the redox status and the total amount of Keap1 protein were significantly decreased by DOX, with the loss of Keap1 being due to both inhibited gene expression and increased autophagic, but not proteasomal, degradation. These findings identify the Keap1/Nrf2 pathway as a potentially important initial response to acute DOX-induced oxidative injury, with the primary regulatory events being the oxidation and autophagic degradation of the redox sensor Keap1 protein. - Highlights: • DOX caused a ∼2-fold increase in Nrf2 protein content. • DOX enhanced transcription of several Nrf2-regulated down-stream genes. • Redox status and total amount of Keap1 protein were significantly decreased by DOX. • Loss of Keap1 protein was due to inhibited gene expression and increased autophagy. • Keap1/Nrf2 pathway is an important initial response to DOX-induced oxidative injury.

60 APPLIED LIFE SCIENCES↗