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At least 163 records · Page 9
All sourcesNASA NTRSDOE OSTI
NASA NTRS2000

Simulated Microgravity Reduces TNF-Alpha Activity, Suppresses Glucose Uptake and Enhances Arginine Flux in Pancreatic Islets of Langerhans

The present studies were designed to determine effects of microgravity upon lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha (TNF - alpha) activity and indices of insulin and fuel homeostasis of pancreatic islets of Langerhans. Islets (1726+/-117,150 u IEU) from Wistar Furth rats were treated as: 1) HARV (High Aspect Ratio Vessel cell culture) , 2) HARV plus LPS 3) static culture, 4) static culture plus LPS TNF-alpha (L929 cytotoxicity assay) was significantly increased in LPS-induced HARV and static cultures, yet the increase was more pronounced in the static culture group (p<0.05). A decrease in insulin concentration was demonstrated in the LPS stimulated HARV culture (p<0.05). We observed a greater glucose concentration and increased disappearance of arginine in islets cultured in HARVs. While nitrogenous compound analysis indicated a ubiquitous reliance upon glutamine in all experimental groups, arginine was converted to ornithine at a two-fold greater rate in the islets cultured in the HARV microgravity paradigm (p<0.05). These studies demonstrate alterations in LPS induced TNF-alpha production of pancreatic islets of Langerhans, favoring a lesser TNF activity in the HARV paradigm. These alterations in fuel homeostasis may be promulgated by gravity averaged cell culture methods or by three dimensional cell assembly.

Tobin, Brian W.↗
NASA NTRS1990

Photomorphogenesis and photoassimilation in soybean and sorghum grown under broad spectrum or blue-deficient light sources

The role of blue light in plant growth and development was investigated in soybean (Glycine max [L.] Merr. cv Williams) and sorghum (Sorghum bicolor [L.] Moench. cv Rio) grown under equal photosynthetic photon fluxes (approximately 500 micromoles per square meter per second) from broad spectrum daylight fluorescent or blue-deficient, narrow-band (589 nanometers) low pressure sodium (LPS) lamps. Between 14 and 18 days after sowing, it was possible to relate adaptations in photosynthesis and leaf growth to dry matter accumulation. Soybean development under LPS light was similar in several respects to that of shaded plants, consistent with an important role for blue light photoreceptors in regulation of growth response to irradiance. Thus, soybeans from LPS conditions partitioned relatively more growth to leaves and maintained higher average leaf area ratios (mean LAR) that compensated lower net assimilation rates (mean NAR). Relative growth rates were therefore comparable to plants from daylight fluorescent lamps. Reductions in mean NAR were matched by lower rates of net photosynthesis (A) on an area basis in the major photosynthetic source (first trifoliolate) leaf. Lower A in soybean resulted from reduced leaf dry matter per unit leaf area, but lower A under LPS conditions in sorghum correlated with leaf chlorosis and reduced total nitrogen (not observed in soybean). In spite of a lower A, mean NAR was larger in sorghum from LPS conditions, resulting in significantly greater relative growth rates (mean LAR was approximately equal for both light conditions). Leaf starch accumulation rate was higher for both species and starch content at the end of the dark period was elevated two- and three-fold for sorghum and soybean, respectively, under LPS conditions. Possible relations between starch accumulation, leaf export, and plant growth in response to spectral quality were considered.

NASA Discipline Life Support Systems↗
NASA NTRS2001

Altered TNF-Alpha, Glucose, Insulin and Amino Acids in Islets Langerhans Cultured in a Microgravity Model System

The present studies were designed to determine effects of a microgravity model system upon lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha (TNF-alpha) activity and indices of insulin and fuel homeostasis of pancreatic islets of Langerhans. Islets (1726+/-1 17,150 u IEU) from Wistar Furth rats were treated as: 1) HARV (High Aspect Ratio Vessel cell culture) , 2) HARV plus LPS, 3) static culture, 4) static culture plus LPS. TNF-alpha (L929 cytotoxicity assay) was significantly increased in LPS-induced HARV and static cultures, yet the increase was more pronounced in the static culture group (p<0.05). A decrease in insulin concentration was demonstrated in the LPS stimulated HARV culture (p<0.05). We observed a greater glucose concentration and increased disappearance of arginine in islets cultured in HARVs. While nitrogenous compound analysis indicated a ubiquitous reliance upon glutamine in all experimental groups, arginine was converted to ornithine at a two-fold greater rate in the islets cultured in the HARV microgravity model system (p<0.05). These studies demonstrate alterations in LPS induced TNF-alpha production of pancreatic islets of Langerhans, favoring a lesser TNF activity in the HARV. These alterations in fuel homeostasis may be promulgated by gravity averaged cell culture methods or by three dimensional cell assembly.

Tobin, Brian W.↗
NASA NTRS2010

Triggered-Lightning Interaction with a Lightning Protective System: Current Distribution and Electromagnetic Environment

A new comprehensive lightning instrumentation system has been designed for Launch Complex 39B (LC3913) at the Kennedy Space Center, Florida. This new instrumentation system includes the synchronized recording of six high-speed video cameras; currents through the nine downconductors of the new lightning protection system for LC3913; four dH/dt, 3-axis measurement stations; and five dE/dt stations composed of two antennas each. A 20:1 scaled down model of the new Lightning Protection System (LPS) of LC39B was built at the International Center for Lightning Research and Testing, Camp Blanding, FL. This scaled down lightning protection system was instrumented with the transient recorders, digitizers, and sensors to be used in the final instrumentation installation at LC3913. The instrumentation used at the ICLRT is also a scaled-down instrumentation of the LC39B instrumentation. The scaled-down LPS was subjected to seven direct lightning strikes and six (four triggered and two natural nearby flashes) in 2010. The following measurements were acquired at the ICLRT: currents through the nine downconductors; two dl-/dt, 3-axis stations, one at the center of the LPS (underneath the catenary wires), and another 40 meters south from the center of the LPS; ten dE/dt stations, nine of them on the perimeter of the LPS and one at the center of the LPS (underneath the catenary wire system); and the incident current. Data from representative events are presented and analyzed in this paper.

Mata, C. T.↗
NASA NTRS2012

Summary of 2011 Direct and Nearby Lightning Strikes to Launch Complex 39B, Kennedy Space Center, Florida

A Lightning Protection System (LPS) was designed and built at Launch Complex 39B (LC39B), at the Kennedy Space Center (KSC), Florida in 2009. This LPS was instrumented with comprehensive meteorological and lightning data acquisition systems that were deployed from late 2010 until mid 2011. The first direct strikes to the LPS were recorded in March of 2011, when a limited number of sensors had been activated. The lightning instrumentation system detected a total of 70 nearby strokes and 19 direct strokes to the LPS, 2 of the 19 direct strokes to the LPS had two simultaneous ground attachment points (in both instances one channel terminated on the LPS and the other on the nearby ground). Additionally, there are more unaccounted nearby strokes seen on video records for which limited data was acquired either due to the distance of the stroke or the settings of the data acquisition system. Instrumentation deployment chronological milestones, a summary of lightning strikes (direct and nearby), high speed video frames, downconductor currents, and dH/dt and dE/dt typical waveforms for direct and nearby strokes are presented.

Mata, C.T.↗
DOE OSTI2010

Super-resolution microscopy reveals protein spatial reorganization in early innate immune responses.

Over the past decade optical approaches were introduced that effectively break the diffraction barrier. Of particular note were introductions of Stimulated Emission/Depletion (STED) microscopy, Photo-Activated Localization Microscopy (PALM), and the closely related Stochastic Optical Reconstruction Microscopy (STORM). STORM represents an attractive method for researchers, as it does not require highly specialized optical setups, can be implemented using commercially available dyes, and is more easily amenable to multicolor imaging. We implemented a simultaneous dual-color, direct-STORM imaging system through the use of an objective-based TIRF microscope and filter-based image splitter. This system allows for excitation and detection of two fluorophors simultaneously, via projection of each fluorophor's signal onto separate regions of a detector. We imaged the sub-resolution organization of the TLR4 receptor, a key mediator of innate immune response, after challenge with lipopolysaccharide (LPS), a bacteria-specific antigen. While distinct forms of LPS have evolved among various bacteria, only some LPS variations (such as that derived from E. coli) typically result in significant cellular immune response. Others (such as from the plague bacteria Y. pestis) do not, despite affinity to TLR4. We will show that challenge with LPS antigens produces a statistically significant increase in TLR4 receptor clusters on the cell membrane, presumably due to recruitment of receptors to lipid rafts. These changes, however, are only detectable below the diffraction limit and are not evident using conventional imaging methods. Furthermore, we will compare the spatiotemporal behavior of TLR4 receptors in response to different LPS chemotypes in order to elucidate possible routes by which pathogens such as Y. pestis are able to circumvent the innate immune system. Finally, we will exploit the dual-color STORM capabilities to simultaneously image LPS and TLR4 receptors in the cellular membrane at resolutions at or below 40nm.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Near-Surface Layer Perforations as Precursors to Fracture in Accumulative Roll Bonding of a Multilayered Metal Composite

We use micro-computed tomography (µ-CT) to characterize the sizes, shapes, and locations of layer perforation (LP) defects in laminates of copper (Cu) and tantalum (Ta) processed by accumulative roll bonding (ARB). One—termed Cu/Ta—was processed from an initial stacking of seven alternating Cu and Ta sheets, with the exterior sheets being Cu. In the other—termed Ta/Cu—the exterior sheets are Ta. Cu/Ta remained intact during processing and exhibits an approximately uniform spatial distribution of LPs. By contrast, Ta/Cu fractured by longitudinal splitting. LPs in this latter sample are concentrated near the sample surfaces. Moreover, their density increases with decreasing distance to the fracture surface. Furthermore, these findings show that materials undergoing ARB may remain intact, despite profuse formation of LPs, provided that the LPs are uniformly distributed. However, a non-uniform distribution of LPs is correlated with longitudinal splitting.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Laser pre-sintering for denudation reduction in the laser powder bed fusion additive manufacturing of Ti-6Al-4V alloy

As a fundamentally different process for creation of complex parts, laser powder bed fusion (LPBF) additive manufacturing exhibits complex behavior at the melt pool that has a direct influence on the macroscopic properties of the final material. Powder denudation, a previously studied deleterious phenomenon, is the displacement of powder due to entrainment in a jet of rapidly vaporized metal created by the process laser. To minimize the effect of denudation and inspired by methods in adjacent fields, a laser pre-sintering (LPS) method was studied in an effort to reduce denudation. LPS was found to be most effective in the 1–4 J/mm3 volumetric energy density processing regimes, minimizing the common experimentally observed problems with the LPBF process. Scanning electron microscopy of the LPS-treated powder bed revealed insight into the accelerating effect morphological irregularities along the powder particle surface have in the pre-sintering process. To further understand the process, an estimation of the sintered neck sizes necessary to eliminate denudation in LPS is made, qualitatively affirming the low energy densities needed to prevent denudation. Here, the results presented in this work represent an initial step towards understanding and implementing LPS as a quality-enhancing step in LPBF.

36 MATERIALS SCIENCE↗
DOE OSTI2011

PARP-1 regulates the expression of caspase-11

Highlights: {yields} Knockdown of PARP-1 suppresses the LPS-induced expression of caspase-11. {yields} Knockdown of PARP-1 suppresses the caspase-11 promoter activity following LPS stimulation. {yields} PARP-1 is recruited to the caspase-11 promoter region containing NF-{kappa}B-binding sites following LPS stimulation. {yields} PARP-1 inhibitors cannot suppress the caspase-11 induction. {yields} PARP-1 does not suppress IFN-{gamma}-induced expression of caspase-11. -- Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) is a multifunctional enzyme that regulates DNA repair, cell death and transcription of inflammatory proteins. In the present study, we present evidence that PARP-1 regulates the expression of caspase-11 following lipopolysaccharide (LPS) stimulation. Knockdown of PARP-1 suppressed the LPS-induced expression of caspase-11 at both mRNA and protein levels as well as caspase-11 promoter activity. Importantly, PARP-1 was recruited to the caspase-11 promoter region containing predicted nuclear factor (NF)-{kappa}B-binding sites when examined by chromatin immunoprecipitation assay. However, knockdown of PARP-1 did not suppress the expression of caspase-11 induced by interferon-{gamma} that activates signal transducer and activator of transcription 1 but not NF-{kappa}B. PARP-1 enzymatic activity was not required for the caspase-11 upregulation since pharmacological inhibitors of PARP-1 did not suppress the induction of caspase-11. Our results suggest that PARP-1, as a transcriptional cofactor for NF-{kappa}B, regulates the induction of caspase-11 at a transcriptional level.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

CPEB1 modulates lipopolysaccharide-mediated iNOS induction in rat primary astrocytes

Highlights: {yields} Expression and phosphorylation of CPEB1 is increased by LPS stimulation in rat primary astrocytes. {yields} JNK regulates expression and phosphorylation of CPEB1 in reactive astrocytes. {yields} Down-regulation of CPEB1 using siRNA inhibits oxidative stress and iNOS induction by LPS stimulation. {yields} CPEB1 may play an important role in regulating inflammatory responses in reactive astrocytes induced by LPS. -- Abstract: Upon CNS damage, astrocytes undergo a series of biological changes including increased proliferation, production of inflammatory mediators and morphological changes, in a response collectively called reactive gliosis. This process is an essential part of the brains response to injury, yet much is unknown about the molecular mechanism(s) that induce these changes. In this study, we investigated the role of cytoplasmic polyadenylation element binding protein 1 (CPEB1) in the regulation of inflammatory responses in a model of reactive gliosis, lipopolysaccharide-stimulated astrocytes. CPEB1 is an mRNA-binding protein recently shown to be expressed in astrocytes that may play a role in astrocytes migration. After LPS stimulation, the expression and phosphorylation of CPEB1 was increased in rat primary astrocytes in a JNK-dependent process. siRNA-induced knockdown of CPEB1 expression inhibited the LPS-induced up-regulation of iNOS as well as NO and ROS production, a hallmark of immunological activation of astrocytes. The results from the study suggest that CPEB1 is actively involved in the regulation of inflammatory responses in astrocytes, which might provide new insights into the regulatory mechanism after brain injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Endotoxin-induced basal respiration alterations of renal HK-2 cells: A sign of pathologic metabolism down-regulation

Highlights: Black-Right-Pointing-Pointer A HK-2 cells model of inflammation-induced acute kidney injury. Black-Right-Pointing-Pointer Two oximetry methods: high resolution respirometry and ESR spectroscopy. Black-Right-Pointing-Pointer Oxygen consumption rates of renal cells decrease when treated with LPS. Black-Right-Pointing-Pointer Cells do not recover normal respiration when the LPS treatment is removed. Black-Right-Pointing-Pointer This basal respiration alteration is a sign of pathologic metabolism down-regulation. -- Abstract: To study the mechanism of oxygen regulation in inflammation-induced acute kidney injury, we investigate the effects of a bacterial endotoxin (lipopolysaccharide, LPS) on the basal respiration of proximal tubular epithelial cells (HK-2) both by high-resolution respirometry and electron spin resonance spectroscopy. These two complementary methods have shown that HK-2 cells exhibit a decreased oxygen consumption rate when treated with LPS. Surprisingly, this cellular respiration alteration persists even after the stress factor was removed. We suggested that this irreversible decrease in renal oxygen consumption after LPS challenge is related to a pathologic metabolic down-regulation such as a lack of oxygen utilization by cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Lipopolysaccharide induces multinuclear cell from RAW264.7 line with increased phagocytosis activity

Highlights: Black-Right-Pointing-Pointer LPS induces multinuclear cells from murine macrophage-derived RAW264.7 cells. Black-Right-Pointing-Pointer The multinuclear cells are formed through cell-cell fusion in the presence of Ca{sup 2+}. Black-Right-Pointing-Pointer The multinuclear cells do not express osteoclast-specific enzymes. Black-Right-Pointing-Pointer They internalized more and larger beads than mononuclear cells and osteoclasts. -- Abstract: Lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, induces strong proinflammatory responses, including the release of cytokines and nitric oxide from macrophage. In this study, we found that a murine macrophage-derived line, RAW264.7, became multinuclear through cell-cell fusion after incubation with highly purified LPS or synthetic lipid A in the presence of Ca{sup 2+}. The same cell line is known to differentiate into multinuclear osteoclast, which expresses a specific proton pumping ATPase together with osteoclast markers on stimulation by the extracellular domain of receptor activator of nuclear factor {kappa}B ligand (Toyomura, T., Murata, Y., Yamamoto, A., Oka, T., Sun-Wada, G.-H., Wada, Y. and Futai, M., 2003). The LPS-induced multinuclear cells did not express osteoclast-specific enzymes including tartrate-resistant acid phosphatase and cathepsin K. During multinuclear cell formation, the cells internalized more and larger polystyrene beads (diameter 6-15 {mu}m) than mononuclear cells and osteoclasts. The internalized beads were located in lysosome-marker positive organelles, which were probably phagolysosomes. The LPS-induced multinuclear cell could be a good model system to study phagocytosis of large foreign bodies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Carbachol ameliorates lipopolysaccharide-induced intestinal epithelial tight junction damage by down-regulating NF-{kappa}{beta} and myosin light-chain kinase pathways

Highlights: Black-Right-Pointing-Pointer Carbachol reduced the lipopolysaccharide-induced intestinal barrier breakdown. Black-Right-Pointing-Pointer Carbachol ameliorated the lipopolysaccharide-induced ileal tight junction damage. Black-Right-Pointing-Pointer Carbachol prevented the LPS-induced NF-{kappa}{beta} and myosin light-chain kinase activation. Black-Right-Pointing-Pointer Carbachol exerted its beneficial effects in an {alpha}7 nicotinic receptor-dependent manner. -- Abstract: Carbachol is a cholinergic agonist that protects the intestines after trauma or burn injury. The present study determines the beneficial effects of carbachol and the mechanisms by which it ameliorates the lipopolysaccharide (LPS)-induced intestinal barrier breakdown. Rats were injected intraperitoneally with 10 mg/kg LPS. Results showed that the gut barrier permeability was reduced, the ultrastructural disruption of tight junctions (TJs) was prevented, the redistribution of zonula occludens-1 and claudin-2 proteins was partially reversed, and the nuclear factor-kappa beta (NF-{kappa}{beta}) and myosin light-chain kinase (MLCK) activation in the intestinal epithelium were suppressed after carbachol administration in LPS-exposed rats. Pretreatment with the {alpha}7 nicotinic acetylcholine receptor ({alpha}7nAchR) antagonist {alpha}-bungarotoxin blocked the protective action of carbachol. These results suggested that carbachol treatment can protect LPS-induced intestinal barrier dysfunction. Carbachol exerts its beneficial effect on the amelioration of the TJ damage by inhibiting the NF-{kappa}{beta} and MLCK pathways in an {alpha}7nAchR-dependent manner.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Basal and inducible anti-inflammatory epoxygenase activity in endothelial cells

Highlights: • We examined epoxygenase product formation and regulation in endothelial cells. • The epoxygenase CYP2J2 is an LPS (TLR-4) inducible enzyme in endothelial cells. • The endothelial cell line EA.Hy926 synthesises epoxygenase products. • Inhibition of endothelial epoxygenases increases TNFα secretion. • Soluble epoxide hydrolase inhibitors reduce inflammation-induced TNFα and NFκB. - Abstract: The roles of CYP lipid-metabolizing pathways in endothelial cells are poorly understood. Human endothelial cells expressed CYP2J2 and soluble epoxide hydrolase (sEH) mRNA and protein. The TLR-4 agonist LPS (1 μg/ml; 24 h) induced CYP2J2 but not sEH mRNA and protein. LC–MS/MS analysis of the stable commonly used human endothelial cell line EA.Hy926 showed active epoxygenase and epoxide hydrolase activity: with arachidonic acid (stable epoxide products 5,6-DHET, and 14,15-DHET), linoleic acid (9,10-EPOME and 12,13-EPOME and their stable epoxide hydrolase products 9,10-DHOME and 12,13-DHOME), docosahexaenoic acid (stable epoxide hydrolase product 19,20-DiHDPA) and eicosapentaenoic acid (stable epoxide hydrolase product 17,18-DHET) being formed. Inhibition of epoxygenases using either SKF525A or MS-PPOH induced TNFα release, but did not affect LPS, IL-1β, or phorbol-12-myristate-13-acetate (PMA)-induced TNFα release. In contrast, inhibition of soluble epoxide hydrolase by AUDA or TPPU inhibited basal, LPS, IL-1β and PMA induced TNFα release, and LPS-induced NFκB p65 nuclear translocation. In conclusion, human endothelial cells contain a TLR-4 regulated epoxygenase CYP2J2 and metabolize linoleic acid > eicosapentaenoic acid > arachidonic acid > docosahexaenoic acid to products with anti-inflammatory activity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Sodium butyrate attenuates soybean oil-based lipid emulsion-induced increase in intestinal permeability of lipopolysaccharide by modulation of P-glycoprotein in Caco-2 cells

Down-regulation of intestinal P-glycoprotein (P-gp) by soybean oil-based lipid emulsion (SOLE) may cause elevated intestinal permeability of lipopolysaccharide (LPS) in patients with total parenteral nutrition, but the appropriate preventative treatment is currently limited. Recently, sodium butyrate (NaBut) has been demonstrated to regulate the expression of P-gp. Therefore, this study aimed to address whether treatment with NaBut could attenuate SOLE-induced increase in intestinal permeability of LPS by modulation of P-gp in vitro. Caco-2 cells were exposed to SOLE with or without NaBut. SOLE-induced down-regulation of P-gp was significantly attenuated by co-incubation with NaBut. Nuclear recruitment of FOXO 3a in response to NaBut was involved in P-gp regulation. Transport studies revealed that SOLE-induced increase in permeability of LPS was significantly attenuated by co-incubation with NaBut. Collectively, our results suggested that NaBut may be a potentially useful medication to prevent SOLE-induced increase in intestinal permeability of LPS. - Highlights: • Caco-2 cells were used as models for studying parenteral nutrition in vitro. • NaBut restored SOLE-induced down-regulation of P-gp in Caco-2 cells. • Regulation of P-gp by NaBut was mediated via nuclear recruitment of FOXO 3a. • NaBut modulated the permeability of LPS by P-gp function, not barrier function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The down-regulation of cardiac contractile proteins underlies myocardial depression during sepsis and is mitigated by carbon monoxide

Highlights: • Cardiac dysfunction was associated with LPS-administered rat hearts. • Levels of myosin and actin were decreased in the hearts. • CORM mitigated these decreases as well as myocardial depression. The aim of this study is to investigate the mechanism underling cardiac dysfunction during sepsis, as well as the possible amelioration of this dysfunction by exogenous carbon monoxide (CO) administration. For this purpose, rats (six-week-old, male, Sprague-Dawley) were administered LPS (15 mg/kg body weight, i.p. 6 h) and/or CORM (30 mg/kg, i.p.). The decreased left ventricular ejection fraction (EF) observed in LPS group rats was recovered in the LSP + CORM group, confirming the protective role of CO against sepsis-induced myocardial depression. Proteomic as well as immunoblot analysis showed that the levels of myosin heavy and light chains (MHC and MLC) as well as α-cardiac actin (ACTC) were decreased in the LPS group, and these decreases were mitigated in the LSP + CORM group, suggesting that the amounts of major contractile proteins are decreased in depressed myocardium. Not only LPS-induced inflammatory cytokine (TNFα and IL-1β) production but also the decrease in myofilament proteins was mitigated by CORM. These results confirm the protective action of exogenously administered CO against myocardial depression during sepsis, and reveal a novel mechanism underling cardiac dysfunction during sepsis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Deficiency of unc-51 like kinase 1 (Ulk1) protects against mice traumatic brain injury (TBI) by suppression of p38 and JNK pathway

Highlights: • Ulk1-KO mice show reduced inflammation and apoptosis in hippocampus after TBI. • Ulk1-KO mice alleviate glial cells activation and autophagy in hippocampus of mice with TBI. • Ulk1 inhibition reduces inflammatory response, apoptosis and autophagy in LPS-stimulated astrocytes (AST) via p38/JNK pathway. Unc-51 like autophagy activating kinase 1 (Ulk1) is a serine/threonine kinase that plays a key role in regulating autophagy processes. We attempted to investigate the effects of Ulk1 on traumatic brain injury (TBI) progression by using wild type (WT) mice and Ulk1-knockout (KO) mice suffered with or not TBI. The results were verified using LPS-treated primary astrocyte (AST). Here, Ulk1 was over-expressed in hippocampus of WT mice after TBI, as well as in lipopolysaccharide (LPS)-stimulated AST. Ulk1-deletion improved cognitive ability and hippocampus histological changes in TBI mice. Nissl and neuronal nuclei (NeuN) staining indicated that Ulk1-deletion increased the number of surviving neurons in hippocampus of TBI mice. Ulk1-ablation alleviated neuroinflammation, as evidenced by the reduced expression of hippocampus pro-inflammatory cytokines in TBI mice. TBI-induced apoptosis was also ameliorated by Ulk1-ablation, as proved by the reduced number of TUNEL-staining cells, and cleaved Caspase-3 and poly (ADP-ribose) polymerase (PARP) expressions. Moreover, Ulk1-knockout suppressed TBI-stimulated activation of astrocytes and microglia cells. Additionally, hippocampus autophagy induced by TBI was attenuated by Ulk1-knockout. Further, TBI-activated p38/c-Jun N-terminal Kinase (JNK) pathway was repressed by Ulk1-deletion in hippocampus of mice. The findings above were confirmed in LPS-stimulated AST with or without Ulk1 siRNA transfection. Intriguingly, pre-treatment of p38 or JNK activator markedly abolished the anti-inflammation, anti-apoptosis and anti-autophagy effects of Ulk1-knockdown on LPS-incubated AST. In conclusion, our results demonstrated that Ulk1 might be a potential target for developing therapeutic strategy against TBI in future.

60 APPLIED LIFE SCIENCES↗