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At least 1,009 records · Page 56
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

Adrenomedullin attenuates interleukin-1β-induced inflammation and apoptosis in rat Leydig cells via inhibition of NF-κB signaling pathway

The aim of this paper is to investigate the protective effects of adrenomedullin (ADM) on interleukin-1β (IL-1β)-induced inflammation and apoptosis in rat Leydig cells and its underlying molecular mechanisms. Leydig cells were isolated from adult Sprague–Dawley rats. The cell culture was established by adding ADM 2 h prior to 24 h treatment with IL-1β-induced cytotoxicity. We detected cell viability and concentrations of testosterone, reactive oxygen species (ROS), malondialdehyde (MDA), and reduced glutathione (GSH). Gene expression levels were measured for inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2). Concentrations were detected for nitric oxide (NO) and prostaglandin E2 (PGE2). Apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Levels of gene expression and protein were detected for Bcl-2, Bax, caspase-3, and poly adenosine diphosphate-ribose polymerase (PARP). Protein levels were measured for nuclear factor kappa B (NF-κB) p65 and IκBα. ADM reduced IL-1β-induced cytotoxicity. ADM pretreatment significantly increased testosterone concentrations and decreased ROS, MDA, and GSH concentrations. ADM pretreatment inhibited IL-1β-induced inflammation in Leydig cells by decreasing the gene expression levels of iNOS and COX-2, as well as the concentrations of NO and PGE2. ADM pretreatment further decreased the number of TUNEL-positive stained Leydig cells, as confirmed by the increase in gene expression and protein levels of Bcl-2 and the decrease of Bax, caspase-3, and PARP levels. Moreover, ADM pretreatment inhibited NF-κB p65 phosphorylation and IκBα phosphorylation and degradation. ADM has potential anti-inflammatory and anti-apoptotic properties in IL-1β-induced rat Leydig cells, which might be related to NF-κB signaling pathway. - Highlights: • ADM attenuates IL-1β-induced oxidative stress in rat Leydig cells. • ADM attenuates IL-1β-induced uncontrolled inflammation in rat Leydig cells. • ADM inhibits IL-1β-induced apoptosis in rat Leydig cells. • ADM effects on rat Leydig cells via inhibition of NF-κB signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Role of human amnion-derived mesenchymal stem cells in promoting osteogenic differentiation by influencing p38 MAPK signaling in lipopolysaccharide -induced human bone marrow mesenchymal stem cells

Periodontitis is a chronic inflammatory disease induced by bacterial pathogens, which not only affect connective tissue attachments but also cause alveolar bone loss. In this study, we investigated the anti-inflammatory effects of Human amnion-derived mesenchymal stem cells (HAMSCs) on human bone marrow mesenchymal stem cells (HBMSCs) under lipopolysaccharide (LPS)-induced inflammatory conditions. Proliferation levels were measured by flow cytometry and immunofluorescence staining of 5-ethynyl-2′-deoxyuridine (EdU). Osteoblastic differentiation and mineralization were investigated using chromogenic alkaline phosphatase activity (ALP) activity substrate assays, Alizarin red S staining, and RT-PCR analysis of HBMSCs osteogenic marker expression. Oxidative stress induced by LPS was investigated by assaying reactive oxygen species (ROS) level and superoxide dismutase (SOD) activity. Here, we demonstrated that HAMSCs increased the proliferation, osteoblastic differentiation, and SOD activity of LPS-induced HBMSCs, and down-regulated the ROS level. Moreover, our results suggested that the activation of p38 MAPK signal transduction pathway is essential for reversing the LPS-induced bone-destructive processes. SB203580, a selective inhibitor of p38 MAPK signaling, significantly suppressed the anti-inflammatory effects in HAMSCs. In conclusion, HAMSCs show a strong potential in treating inflammation-induced bone loss by influencing p38 MAPK signaling. - Highlights: • LPS inhibites osteogenic differentiation in HBMSCs via suppression of p38 MAPK signaling pathway. • HAMSCs promote LPS-induced HBMSCs osteogenic differentiation through p38 MAPK signaling pathway. • HAMSCs reverse LPS-induced oxidative stress in LPS-induced HBMSCs through p38 MAPK signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

SIRT3 mediates mitofusin 2 ubiquitination and degradation to suppress ischemia reperfusion-induced acute kidney injury

Ischemia reperfusion-induced acute kidney injury (IR-induced AKI) is a life-threatening disease with many complications. Mitofusin 2 (Mfn2) ubiquitination is related to AKI. But the underlying molecular mechanisms remain unknown. This study aimed to probe the mechanism of Mfn2 ubiquitination in IR-induced AKI development. In IR-induced AKI mouse models, orbital blood and urine were collected for assessing kidney function. The kidney injury, ultrastructure of mitochondria, and histopathology in mice were evaluated after injection of G5, an ubiquitination inhibitor. Oxygen glucose deprivation/reoxygenation (OGD/R) models were established in HK-2 cells, and the mitochondria were extracted. Cell viability, apoptosis, oxidative stress, inflammatory reaction, mitochondrial membrane potential, and ATP production were measured. Mfn2 ubiquitination in mouse and cell models was evaluated. si-SIRT3 and pcDNA3.1-SIRT3 were transfected into cell models. Consequently, kidney function in mice was impaired by IR-induced AKI. Mfn2 ubiquitination and degradation promoted IR-induced AKI. OGD/R induced renal tubular epithelial cell injury and disrupted mitochondrial dynamics and functions through promoting Mfn2 ubiquitination. SIRT3 knockdown led to Mfn2 ubiquitination by binding to UBC; while its overexpression alleviated tubular epithelial cell injury. Briefly, SIRT3 mediates Mfn2 ubiquitination to relieve IR-induced AKI. This investigation may offer new insights for the treatment of IR-induced AKI injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Caffeic acid attenuates irradiation-induced hematopoietic stem cell apoptosis through inhibiting mitochondrial damage

Highlights: • IR-induced mitochondrial damage accelerates HSC apoptosis. • CA attenuates mitochondrial damage and apoptosis of HSCs induced by IR. • CA protects against BM hematopoietic failure in mice after IR exposure. Hematopoietic stem cells (HSCs) are sensitive to ionizing radiation (IR) damage, and its injury is the primary cause of bone marrow (BM) hematopoietic failure and even death after exposure to a certain dose of IR. However, the underlying mechanisms remain incompletely understood. Here we show that mitochondrial oxidative damage, which is characterized by mitochondrial reactive oxygen species overproduction, mitochondrial membrane potential reduction and mitochondrial permeability transition pore opening, is rapidly induced in both human and mouse HSCs and directly accelerates HSC apoptosis after IR exposure. Mechanistically, 5-lipoxygenase (5-LOX) is induced by IR exposure and contributes to IR-induced mitochondrial oxidative damage through inducing lipid peroxidation. Intriguingly, a natural antioxidant, caffeic acid (CA), can attenuate IR-induced HSC apoptosis through suppressing 5-LOX-mediated mitochondrial oxidative damage, thus protecting against BM hematopoietic failure after IR exposure. These findings uncover a critical role for mitochondria in IR-induced HSC injury and highlight the therapeutic potential of CA in BM hematopoietic failure induced by IR.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

KrF- and ArF-excimer-laser-induced absorption in silica glasses produced by melting synthetic silica powder

KrF- and ArF-excimer-laser-induced absorption of silica glasses produced by electric melting and flame fusion of synthetic silica powder were investigated. The growth of KrF-laser-induced absorption was more gradual than that of ArF-laser-induced absorption. Induced absorption spectra exhibited a peak at about 5.8 eV, of which the position and width differed slightly among samples and laser species. Widths of ArF-laser-induced absorption spectra were wider than those of KrF-laser-induced spectra. KrF-laser-induced absorption is reproducible by two Gaussian absorption bands peaking at 5.80 eV with full width at half maximum (FWHM) of 0.62 eV and at 6.50 eV with FWHM of 0.74 eV. For reproduction of ArF-laser-induced absorption, Gaussian bands at 5.41 eV with FWHM of 0.62 eV was necessary in addition to components used for reproducing KrF-laser-induced absorption. Based on the discussion of the change of defect structures evaluated from change of absorption components, we proposed that the precursor of the 5.8-eV band ascribed to E Prime center ({identical_to}Si{center_dot}) is {identical_to}Si-H HO-Si{identical_to} structures formed by the reaction between strained Si-O-Si bonds and interstitial H{sub 2} molecules during the irradiation.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2018

Real-space analysis of radiation-induced specific changes with independent component analysis

A method of analysis is presented that allows for the separation of specific radiation-induced changes into distinct components in real space. The method relies on independent component analysis (ICA) and can be effectively applied to electron density maps and other types of maps, provided that they can be represented as sets of numbers on a grid. Here, for glucose isomerase crystals, ICA was used in a proof-of-concept analysis to separate temperature-dependent and temperature-independent components of specific radiation-induced changes for data sets acquired from multiple crystals across multiple temperatures. ICA identified two components, with the temperature-independent component being responsible for the majority of specific radiation-induced changes at temperatures below 130 K. The patterns of specific temperature-independent radiation-induced changes suggest a contribution from the tunnelling of electron holes as a possible explanation. In the second case, where a group of 22 data sets was collected on a single thaumatin crystal, ICA was used in another type of analysis to separate specific radiation-induced effects happening on different exposure-level scales. Here, ICA identified two components of specific radiation-induced changes that likely result from radiation-induced chemical reactions progressing with different rates at different locations in the structure. In addition, ICA unexpectedly identified the radiation-damage state corresponding to reduced disulfide bridges rather than the zero-dose extrapolated state as the highest contrast structure. The application of ICA to the analysis of specific radiation-induced changes in real space and the data pre-processing for ICA that relies on singular value decomposition, which was used previously in data space to validate a two-component physical model of X-ray radiation-induced changes, are discussed in detail. This work lays a foundation for a better understanding of protein-specific radiation chemistries and provides a framework for analysing effects of specific radiation damage in crystallographic and cryo-EM experiments.

Borek, Dominika (ORCID:0000000243216253)↗
DOE OSTI2021

Recommended Practices for Managing Induced Seismicity Risk Associated with Geologic Carbon Storage

The geologic storage of carbon dioxide (CO 2 ) is one method to help reduce or eliminate atmospheric CO 2 emissions. The sequestered CO 2 is originally captured from the atmosphere or from a stationary industrial source and subsequently injected into a deep subsurface porous rock formation. To facilitate the successful deployment of field scale carbon storage projects, the U.S. Department of Energy (DOE) is developing tools and protocols for defensible, science-based frameworks to quantify and mitigate risks associated with the long-term storage of CO 2 . This protocol specifically addresses the risk of induced seismicity due to injection in a geologic carbon storage (GCS) site. This integrated and risk-based protocol is a product of the U.S. DOE Fossil Energy’s National Risk Assessment Partnership (NRAP), a multi-year collaborative research effort of Los Alamos National Laboratory (LANL), Lawrence Berkeley National Laboratory (LBNL), Lawrence Livermore National Laboratory (LLNL), National Energy Technology Laboratory (NETL), and Pacific Northwest National Laboratory (PNNL). These recommended practices describe a set of 7 steps to evaluate, manage, communicate, and mitigate the risk of induced seismicity at GCS sites. The base methodology of the recommended practices follows a framework similar to the Protocol for Addressing Induced Seismicity Associated with Enhanced Geothermal Systems (Majer et al., 2012), developed for the Geothermal Technology Office of the U.S. DOE. These recommended practices present a framework to systematically assess the induced seismicity risk and quantify the associated uncertainties. These recommendations are based on current research and are sufficiently general to allow for modification and application to a variety of different types of sites. The substance of the recommended practices contained herein includes both technical and non-technical issues, and covers all operational stages of the GCS project lifecycle. They start at the preliminary risk assessment phase, continue through site assessment and characterization, include best practice communication and seismic monitoring plan methodologies, discuss the evaluation and mitigation of seismic hazard and risk, and closes with an exploration of operational management plans, which conclude when the induced seismicity risk abates back to background level. The focus of these recommendations is on actively managing the risks associated with induced seismicity by developing an actionable risk management plan that starts at the project proposal stage and continues through site closure through an iterative assessment and improvement process. The audience of this document is expected to include all interested stakeholders (e.g., operators, project developers, regulators, and the general public) and is expressly written to be accessible to this broad range of partners. This document is intended to disseminate knowledge gained through recent advances in the science of induced seismicity hazard and risk assessments, to provide updates based on recent experience gained by similar corollary injection-induced seismicity cases, and most importantly to establish a uniform framework to carry out a successful induced seismicity risk management plan for carbon storage projects in the future. These recommendations do not directly address any domestic or international regulations or standards. A complementary NRAP report makes recommendations for the assessment and management of environmental subsurface risks associated with unwanted fluid migration at GCS sites (Thomas et al., 2021) and should be referred to in order to address those additional GCS site risks.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Recommended Practices for Managing Induced Seismicity Risk Associated with Geologic Carbon Storage

The geologic storage of carbon dioxide (CO 2 ) is one method to help reduce or eliminate atmospheric CO 2 emissions. The sequestered CO 2 is originally captured from the atmosphere or from a stationary industrial source and subsequently injected into a deep subsurface porous rock formation. To facilitate the successful deployment of field scale carbon storage projects, the U.S. Department of Energy (DOE) is developing tools and protocols for defensible, science-based frameworks to quantify and mitigate risks associated with the long-term storage of CO 2 . This protocol specifically addresses the risk of induced seismicity due to injection in a geologic carbon storage (GCS) site. This integrated and risk-based protocol is a product of the U.S. DOE Fossil Energy’s National Risk Assessment Partnership (NRAP), a multi-year collaborative research effort of Los Alamos National Laboratory (LANL), Lawrence Berkeley National Laboratory (LBNL), Lawrence Livermore National Laboratory (LLNL), National Energy Technology Laboratory (NETL), and Pacific Northwest National Laboratory (PNNL). These recommended practices describe a set of 7 steps to evaluate, manage, communicate, and mitigate the risk of induced seismicity at GCS sites. The base methodology of the recommended practices follows a framework similar to the $\textit{Protocol for Addressing Induced Seismicity Associated with Enhanced Geothermal Systems}$ (Majer et al., 2012), developed for the Geothermal Technology Office of the U.S. DOE. These recommended practices present a framework to systematically assess the induced seismicity risk and quantify the associated uncertainties. These recommendations are based on current research and are sufficiently general to allow for modification and application to a variety of different types of sites. The substance of the recommended practices contained herein includes both technical and non-technical issues, and covers all operational stages of the GCS project lifecycle. They start at the preliminary risk assessment phase, continue through site assessment and characterization, include best practice communication and seismic monitoring plan methodologies, discuss the evaluation and mitigation of seismic hazard and risk, and closes with an exploration of operational management plans, which conclude when the induced seismicity risk abates back to background level. The focus of these recommendations is on actively managing the risks associated with induced seismicity by developing an actionable risk management plan that starts at the project proposal stage and continues through site closure through an iterative assessment and improvement process. The audience of this document is expected to include all interested stakeholders (e.g., operators, project developers, regulators, and the general public) and is expressly written to be accessible to this broad range of partners. This document is intended to disseminate knowledge gained through recent advances in the science of induced seismicity hazard and risk assessments, to provide updates based on recent experience gained by similar corollary injection-induced seismicity cases, and most importantly to establish a uniform framework to carry out a successful induced seismicity risk management plan for carbon storage projects in the future. These recommendations do not directly address any domestic or international regulations or standards. A complementary NRAP report makes recommendations for the assessment and management of environmental subsurface risks associated with unwanted fluid migration at GCS sites (Thomas et al., 2021) and should be referred to in order to address those additional GCS site risks

58 GEOSCIENCES↗
NASA NTRS1997

Modulation of Radiation-Induced Apoptosis by Thiolamines

Exposure to the thiolamine radioprotector N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) induced apoptosis in the mouse TB8-3 hybridoma after 60-minute (LD(sub50) = 4.5mM) or during a 20-hour (LD(sub50) = 0.15 mM) exposure. In contrast, a 20-hour exposure to 17 mM L-cysteine or 10 mM cysteamine was required to induce 50 percent apoptosis within 20 hours. Apoptosis was not induced by either a 60-minute or 20-hour exposure to 10 mM of the thiazolidime prodrugs ribose-cysteine (RibCys) or ribose-cysteamine (RibCyst). Thiolamine-induced apoptosis appeared to be a p53-independent process since it was induced by WR-1065 exposure in human HL60 cells. Exposure to WR-1065 (4mM for 15 minutes) or cysteine (10mM for 60 minutes) before and during irradiation protected cells against the induction of both DNA double-strand breaks and apoptosis, while exposure to RibCys (10 mM for 3 hours) did not. Treatment with either WR-1065, cysteine, RibCys or RibCyst for 60 minutes beginning 60 minutes after irradiation did not affect the level of radiation-induced apoptosis. In contrast, treatment with either cysteine, cysteamine or RibCys for 20 hours beginning 60 minutes after irradiation enhanced radiation-induced apoptosis. Similar experiments could not be conducted with WR-1065 because of its extreme toxicity. Our results indicate that thiolamine enhancement of radiation-induced apoptosis is not involved in their previously reported capacity to reduce radiation-induced mutations.

Warters, R. L.↗
NASA NTRS2011

Water Flow Testing and Unsteady Pressure Analysis of a Two-Bladed Liquid Oxidizer Pump Inducer

The unsteady fluid dynamic performance of a cavitating two-bladed oxidizer turbopump inducer was characterized through sub-scale water flow testing. While testing a novel inlet duct design that included a cavitation suppression groove, unusual high-frequency pressure oscillations were observed. With potential implications for inducer blade loads, these high-frequency components were analyzed extensively in order to understand their origins and impacts to blade loading. Water flow testing provides a technique to determine pump performance without the costs and hazards associated with handling cryogenic propellants. Water has a similar density and Reynolds number to liquid oxygen. In a 70%-scale water flow test, the inducer-only pump performance was evaluated. Over a range of flow rates, the pump inlet pressure was gradually reduced, causing the flow to cavitate near the pump inducer. A nominal, smooth inducer inlet was tested, followed by an inlet duct with a circumferential groove designed to suppress cavitation. A subsequent 52%-scale water flow test in another facility evaluated the combined inducer-impeller pump performance. With the nominal inlet design, the inducer showed traditional cavitation and surge characteristics. Significant bearing loads were created by large side loads on the inducer during synchronous cavitation. The grooved inlet successfully mitigated these loads by greatly reducing synchronous cavitation, however high-frequency pressure oscillations were observed over a range of frequencies. Analytical signal processing techniques showed these oscillations to be created by a rotating, multi-celled train of pressure pulses, and subsequent CFD analysis suggested that such pulses could be created by the interaction of rotating inducer blades with fluid trapped in a cavitation suppression groove. Despite their relatively low amplitude, these high-frequency pressure oscillations posed a design concern due to their sensitivity to flow conditions and test scale. The amplitude and frequency of oscillations varied considerably over the pump s operating space, making it difficult to predict blade loads.

Schwarz, Jordan B.↗
NASA NTRS2011

Fluctuating Pressure Environments and Hydrodynamic Radial Force Mitigation for a Two Blade Unshrouded Inducer

Fluctuating pressure data from water flow testing of an unshrouded two blade inducer revealed a cavitation induced oscillation with the potential to induce a radial load on the turbopump shaft in addition to other more traditionally analyzed radial loads. Subsequent water flow testing of the inducer with a rotating force measurement system confirmed that the cavitation induced oscillation did impart a radial load to the inducer. After quantifying the load in a baseline configuration, two inducer shroud treatments were selected and tested to reduce the cavitation induced load. The first treatment was to increase the tip clearance, and the second was to introduce a circumferential groove near the inducer leading edge. Increasing the clearance resulted in a small decrease in radial load along with some steady performance degradation. The groove greatly reduced the hydrodynamic load with little to no steady performance loss. The groove did however generate some new, relatively high frequency, spatially complex oscillations to the flow environment.

Mulder, Andrew↗
NASA NTRS2011

Fluctuating Pressure Environments and Hydrodynamic Radial Force Mitigation for a Two Blade Unshrouded Inducer

Fluctuating pressure data from water flow testing of an unshrouded two blade inducer revealed a cavitation induced oscillation with the potential to induce a radial load on the turbopump shaft in addition to other more traditionally analyzed radial loads. Subsequent water flow testing of the inducer with a rotating force measurement system confirmed that the cavitation induced oscillation did impart a radial load to the inducer. After quantifying the load in a baseline configuration, two inducer shroud treatments were selected and tested to reduce the cavitation induced load. The first treatment was to increase the tip clearance, and the second was to introduce a circumferential groove near the inducer leading edge. Increasing the clearance resulted in a small load decrease along with some steady performance degradation. The groove greatly reduced the hydrodynamic load with little to no steady performance loss. The groove did however generate some new, relatively high frequency, spatially complex oscillations to the environment.

Mulder, Andrew↗
DOE OSTI2018

Natural time and nowcasting induced seismicity at the Groningen gas field in the Netherlands

The Groningen gas field in the Netherlands has a significant level of induced seismicity; this seismicity is attributed to fluid withdrawal not fluid injection. This is one of the most productive gas fields in Europe. Production began in 1963 and the first induced earthquake occurred in 1991. Increasing levels of seismicity led to the installation of a sensitive seismic network in 1995 with a minimum magnitude completeness of $M$ ≥ 1.5. The largest induced earthquake was a magnitude 3.6 in 2012, which caused thousands of damage claims and led to a reduction in gas production in 2014 January. In our work, we show that the induced earthquakes satisfy Gutenberg–Richter (GR) frequency–magnitude statistics over the range 1.5 ≤ $M$ ≤ 3.0. We utilize truncated GR scaling to introduce a possible maximum earthquake with $M$ = 3.85. We also demonstrate an almost complete absence of aftershocks following the largest induced earthquakes. To quantify the temporal evolution of the induced seismicity, we perform our nowcasting method. Nowcasting uses the catalogue of seismicity in the region. Two earthquake magnitudes are selected, one large say $M_λ$ ≥ 2.5, and one small say $M_σ$ ≥ 1.5. The method utilizes the number of small earthquakes that occur between pairs of large earthquakes. A major advantage of nowcasting is that it relies on ‘natural time’, earthquake counts, between events rather than clock time. Thus, the results are applicable to induced seismicity that varies in time. We count the rate of occurrence of small induced earthquakes to nowcast the probability of occurrence of larger earthquakes.

58 GEOSCIENCES↗
DOE OSTI2018

Structural and Magnetic Properties of Thermal- and Deformation-Induced Martensite in an Fe-27%Ni-4%Mn-1%Zn Alloy

Deformation- and thermal-induced martensite properties were examined according to existing martensite morphology and magnetic properties for same prior austenite homogenization conditions in Fe-27%Ni-4%Mn-1%Zn alloy. Scanning electron microscope (SEM) and vibrating sample magnetometer (VSM) characterization techniques were employed for the investigation. Scanning electron microscope observations showed that while martensite formation in the austenite phase of alloy exhibited a lath morphology by thermal effect, elongated deformation-induced martensite morphology exists after deformation. The Curie temperatures were detected at about 201 K for thermal-induced martensite and at about 226 K for deformation-induced martensite from VSM measurements. The magnetic saturation values were determined as about 21 emu g{sup −1} for thermal-induced martensite and 23 emu g{sup −1} for deformation-induced martensite. We found that magnetic saturation increased with deformation effect. On the other hand, VSM offered the soft ferromagnetic characteristic with coersive values of 36 Oe for thermal-induced martensite and the soft ferromagnetic characteristic with 47 Oe for deformation-induced martensite. The changes in the magnetic properties resulting from the thermal and deformation affect were clearly determined. Deformation caused magnetic stabilization in Fe-27%Ni-4%Mn-1%Zn alloy.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2012

SIRT1 overexpression decreases cisplatin-induced acetylation of NF-{kappa}B p65 subunit and cytotoxicity in renal proximal tubule cells

Highlights: Black-Right-Pointing-Pointer Cisplatin increases acetylation of NF-{kappa}B p65 subunit in HK2 cells. Black-Right-Pointing-Pointer SIRT1 overexpression decreases cisplatin-induced p65 acetylation and -cytotoxicity. Black-Right-Pointing-Pointer Resveratrol decreased cisplatin-induced cell viability through deacetylation of p65. -- Abstract: As the increased acetylation of p65 is linked to nuclear factor-{kappa}B (NF-{kappa}B) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-{kappa}B p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-{kappa}B during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-{kappa}B p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-{kappa}B through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Celastrol inhibits TGF-β1-induced epithelial–mesenchymal transition by inhibiting Snail and regulating E-cadherin expression

Highlights: •We investigated the effects of celastrol on TGF-β1-induced EMT in epithelial cells. •Celastrol regulates TGF-β1-induced morphological changes and E-cadherin expression. •Celastrol inhibits TGF-β1-induced Snail expression. •Celastrol strongly suppresses TGF-β1-induced invasion in MDCK and A549 cells. -- Abstract: The epithelial–mesenchymal transition (EMT) is a pivotal event in the invasive and metastatic potentials of cancer progression. Celastrol inhibits the proliferation of a variety of tumor cells including leukemia, glioma, prostate, and breast cancer; however, the possible role of celastrol in the EMT is unclear. We investigated the effect of celastrol on the EMT. Transforming growth factor-beta 1 (TGF-β1) induced EMT-like morphologic changes and upregulation of Snail expression. The downregulation of E-cadherin expression and upregulation of Snail in Madin–Darby Canine Kidney (MDCK) and A549 cell lines show that TGF-β1-mediated the EMT in epithelial cells; however, celastrol markedly inhibited TGF-β1-induced morphologic changes, Snail upregulation, and E-cadherin expression. Migration and invasion assays revealed that celastrol completely inhibited TGF-β1-mediated cellular migration in both cell lines. These findings indicate that celastrol downregulates Snail expression, thereby inhibiting TGF-β1-induced EMT in MDCK and A549 cells. Thus, our findings provide new evidence that celastrol suppresses lung cancer invasion and migration by inhibiting TGF-β1-induced EMT.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Nanosecond pulsed electric fields induce poly(ADP-ribose) formation and non-apoptotic cell death in HeLa S3 cells

Highlights: •Nanosecond pulsed electric field (nsPEF) is a new and unique means for life sciences. •Apoptosis was induced by nsPEF exposure in Jurkat cells. •No signs of apoptosis were detected in HeLa S3 cells exposed to nsPEFs. •Formation of poly(ADP-ribose) was induced in nsPEF-exposed HeLa S3 cells. •Two distinct modes of cell death were activated by nsPEF in a cell-dependent manner. -- Abstract: Nanosecond pulsed electric fields (nsPEFs) have recently gained attention as effective cancer therapy owing to their potency for cell death induction. Previous studies have shown that apoptosis is a predominant mode of nsPEF-induced cell death in several cell lines, such as Jurkat cells. In this study, we analyzed molecular mechanisms for cell death induced by nsPEFs. When nsPEFs were applied to Jurkat cells, apoptosis was readily induced. Next, we used HeLa S3 cells and analyzed apoptotic events. Contrary to our expectation, nsPEF-exposed HeLa S3 cells exhibited no molecular signs of apoptosis execution. Instead, nsPEFs induced the formation of poly(ADP-ribose) (PAR), a hallmark of necrosis. PAR formation occurred concurrently with a decrease in cell viability, supporting implications of nsPEF-induced PAR formation for cell death. Necrotic PAR formation is known to be catalyzed by poly(ADP-ribose) polymerase-1 (PARP-1), and PARP-1 in apoptotic cells is inactivated by caspase-mediated proteolysis. Consistently, we observed intact and cleaved forms of PARP-1 in nsPEF-exposed and UV-irradiated cells, respectively. Taken together, nsPEFs induce two distinct modes of cell death in a cell type-specific manner, and HeLa S3 cells show PAR-associated non-apoptotic cell death in response to nsPEFs.

60 APPLIED LIFE SCIENCES↗