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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 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Structural basis of BAK activation in mitochondrial apoptosis initiation

BCL-2 proteins regulate mitochondrial poration in apoptosis initiation. How the pore-forming BCL-2 Effector BAK is activated remains incompletely understood mechanistically. Here we investigate autoactivation and direct activation by BH3-only proteins, which cooperate to lower BAK threshold in membrane poration and apoptosis initiation. We define in trans BAK autoactivation as the asymmetric “BH3-in-groove” triggering of dormant BAK by active BAK. BAK autoactivation is mechanistically similar to direct activation. The structure of autoactivated BAK BH3-BAK complex reveals the conformational changes leading to helix α1 destabilization, which is a hallmark of BAK activation. Helix α1 is destabilized and restabilized in structures of BAK engaged by rationally designed, high-affinity activating and inactivating BID-like BH3 ligands, respectively. Altogether our data support the long-standing hit-and-run mechanism of BAK activation by transient binding of BH3-only proteins, demonstrating that BH3-induced structural changes are more important in BAK activation than BH3 ligand affinity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif

Apolipoprotein L1 (ApoL1) is a circulating innate immunity protein protecting against trypanosome infection. However, two ApoL1 coding variants are associated with a highly increased risk of chronic kidney disease. Here we present X-ray and NMR structures of the N-terminal domain (NTD) of ApoL1 and of its closest relative ApoL2. In both proteins, four of the five NTD helices form a four-helix core structure which is different from the classical four-helix bundle and from the pore-forming domain of colicin A. The reactivity with a conformation-specific antibody and structural models predict that this four-helix motif is also present in the NTDs of ApoL3 and ApoL4, suggesting related functions within the small ApoL family. The long helix 5 of ApoL1 is conformationally flexible and contains the BH3-like region. This BH3-like α-helix resembles true BH3 domains only in sequence and structure but not in function, since it does not bind to the pro-survival members of the Bcl-2 family, suggesting a Bcl-2-independent role in cytotoxicity. These findings should expedite a more comprehensive structural and functional understanding of the ApoL immune protein family.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Lignin monomer conversion into biolubricant base oils

Despite progress in the depolymerization of lignin, only a few studies convert the obtained monomers to value-added products. Here we introduce a strategy to synthesize branched benzene lubricant (BBL) and branched cyclic lubricant (BCL) base oils from lignin-derived monomers and aldehyde. We perform carbon–carbon coupling via Brønsted acid-catalyzed hydroxyalkylation/alkylation (HAA) then hydrodeoxygenation (HDO). Optimum HAA reaction conditions achieve up to 90% guaiacol conversion and an HAA product containing 76% BBL and 24% enal condensation product over a P-SiO 2 catalyst. Subsequent HDO of HAA products over an Ir-ReO x /SiO 2 catalyst produces a lubricant-ranged mixture of BCL (C 24 ) up to yield (82%) and small fractions of dodecyl cyclohexane and C 10 and C 15 carbons alkanes. The kinematic viscosity, viscosity index, and Noack volatility of these base oils are comparable to commercial petroleum-derived poly α-olefin Group IV and refrigerant base oils. In conclusion, this approach provides a sustainable pathway for replacing petroleum-derived base oils.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Deep level study of chlorine-based dry etched β-Ga 2 O 3

Chlorine-based gases are used for the reactive ion etching (RIE) of β-Ga 2 O 3 . However, the effects of Cl-plasma on the electronic properties of β-Ga 2 O 3 are not known. In order to shed light on this topic, we carried out an experimental and theoretical study on β-Ga 2 O 3 epilayers treated with Cl 2 /Ar or BCl 3 /Ar plasma. We found four traps in the 0.2–0.8 eV energy range below the conduction band edge (EC). Two of these, located at E C -0.24 eV and E C -0.28 eV, arise only when the epilayers are treated with BCl 3 /Ar. While the involvement of Cl in their microscopic structure is not discarded, the possibility that these two levels might have an intrinsic nature seems more plausible. Our findings might explain the reported effects on the Schottky barrier diodes of β-Ga 2 O 3 when RIE is employed during processing.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Iterative optimization yields Mcl-1–targeting stapled peptides with selective cytotoxicity to Mcl-1–dependent cancer cells

Bcl-2 family proteins regulate apoptosis, and aberrant interactions of overexpressed antiapoptotic family members such as Mcl-1 promote cell transformation, cancer survival, and resistance to chemotherapy. Discovering potent and selective Mcl-1 inhibitors that can relieve apoptotic blockades is thus a high priority for cancer research. An attractive strategy for disabling Mcl-1 involves using designer peptides to competitively engage its binding groove, mimicking the structural mechanism of action of native sensitizer BH3-only proteins. We transformed Mcl-1–binding peptides into α-helical, cell-penetrating constructs that are selectively cytotoxic to Mcl-1–dependent cancer cells. Critical to the design of effective inhibitors was our introduction of an all-hydrocarbon cross-link or “staple” that stabilizes α-helical structure, increases target binding affinity, and independently confers binding specificity for Mcl-1 over related Bcl-2 family paralogs. Two crystal structures of complexes at 1.4 Å and 1.9 Å resolution demonstrate how the hydrophobic staple induces an unanticipated structural rearrangement in Mcl-1 upon binding. Systematic sampling of staple location and iterative optimization of peptide sequence in accordance with established design principles provided peptides that target intracellular Mcl-1. Here, this work provides proof of concept for the development of potent, selective, and cell-permeable stapled peptides for therapeutic targeting of Mcl-1 in cancer, applying a design and validation workflow applicable to a host of challenging biomedical targets.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Ultrathin Boron Growth onto Nanodiamond Surfaces via Electrophilic Boron Precursors

Diamond as a templating substrate is largely unexplored, and the unique properties of diamond, including its large bandgap, thermal conductance, and lack of cytotoxicity, makes it versatile in emergent technologies in medicine and quantum sensing. Surface termination of an inert diamond substrate and its chemical reactivity are key in generating new bonds for nucleation and growth of an overlayer material. Oxidized high-pressure high temperature (HPHT) nanodiamonds (NDs) are largely terminated by alcohols that act as nucleophiles to initiate covalent bond formation when an electrophilic reactant is available. In this work, we demonstrate a templated synthesis of ultrathin boron on ND surfaces using trigonal boron compounds. Boron trichloride (BCl 3 ), boron tribromide (BBr 3 ), and borane (BH 3 ) were found to react with ND substrates at room temperature in inert conditions. BBr 3 and BCl 3 were highly reactive with the diamond surface, and sheet-like structures were produced and verified with electron microscopy. Surface-sensitive spectroscopies were used to probe the molecular and atomic structure of the ND constructs’ surface, and quantification showed the boron shell was less than 1 nm thick after 1–24 h reactions. Observation of the reaction supports a self-terminating mechanism, similar to atomic layer deposition growth, and is likely due to the quenching of alcohols on the diamond surface. X-ray absorption spectroscopy revealed that boron-termination generated midgap electronic states that were originally predicted by density functional theory (DFT) several years ago. DFT also predicted a negative electron surface, which has yet to be confirmed experimentally here. The boron-diamond nanostructures were found to aggregate in dichloromethane and were dispersed in various solvents and characterized with dynamic light scattering for future cell imaging or cancer therapy applications using boron neutron capture therapy (BNCT). The unique templating mechanism based on nucleophilic alcohols and electrophilic trigonal precursors allows for covalent bond formation and will be of interest to researchers using diamond for quantum sensing, additive manufacturing, BNCT, and potentially as an electron emitter.

36 MATERIALS SCIENCE↗
NASA NTRS1974

Development of strain gages for use to 1311 K (1900 F)

A high temperature electric resistance strain gage system was developed and evaluated to 1366 K (2000 F) for periods of at least one hour. Wire fabricated from a special high temperature strain gage alloy (BCL-3), was used to fabricate the gages. Various joining techniques (NASA butt welding, pulse arc, plasma needle arc, and dc parallel gap welding) were investigated for joining gage filaments to each other, gage filaments to lead-tab ribbons, and lead-tab ribbons to lead wires. The effectiveness of a clad-wire concept as a means of minimizing apparent strain of BCL-3 strain gages was investigated by sputtering platinum coatings of varying thicknesses on wire samples and establishing the optimum coating thickness--in terms of minimum resistivity changes with temperature. Finally, the moisture-proofing effectiveness of barrier coatings subjected to elevated temperatures was studied, and one commercial barrier coating (BLH Barrier H Waterproofing) was evaluated.

Lemcoe, M. M.↗
NASA NTRS1992

High temperature strain gage technology for hypersonic aircraft development applications

An experimental evaluation of Pd 13 percent Cr and of BCL-3 alloy wire strain gages was conducted on IN100 and Cu 0.15 percent Zr alloy substrates. Testing included apparent strain, drift, gage factor, and creep. Maximum test temperature was 1144 K (1600 F). The PdCr gages incorporated Pt temperature compensation elements. The PdCr gages were found to have good resistance stability below 866 K (1100 F). The BCL 3 gages were found to have good resistance stability above 800 K (981 F), but high drift around 700 K (800 F).

Anderson, W. L.↗
DOE OSTI2018

Neuroprotection of rhGLP‐1 in diabetic rats with cerebral ischemia/reperfusion injury via regulation of oxidative stress, EAAT2, and apoptosis

Preclinical Research & Development The purpose of the present study is to evaluate the neuroprotective effect of recombinant human glucagon‐like peptide‐1 (rhGLP‐1) as well as to explore corresponding mechanisms in diabetic rats with cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion (MCAO). Diabetes mellitus was induced by intraperitoneal injection of streptozotocin. The rats were pretreated with rhGLP‐1 (20 μg/kg intraperitoneally, thrice a day) for 14 days. Thereafter, the rats were subjected to MCAO 90 min/reperfusion 24 hr. At 2 and 24 hr of reperfusion, the rats were assessed for neurological deficits and subsequently executed for the evaluation of cerebral infarct volume, oxidative stress parameters, and the expression of excitatory amino acid transporter 2 (EAAT2) and apoptotic markers. Results indicate that rhGLP‐1 significantly ameliorated neurological deficits and reduced cerebral infarct volume in diabetic MCAO rats. In addition, oxidative stress parameters in ischemic penumbra were significantly alleviated in rhGLP‐1‐pretreated diabetic MCAO rats. rhGLP‐1 significantly upregulated the ratio of Bcl‐2/Bax and EAAT2 expression and downregulated cleaved caspase‐3 expression in ischemic penumbra of diabetic MCAO rats. Our results suggest that rhGLP‐1 could significantly ameliorate neurological deficits and reduce cerebral infarct volume in diabetic MCAO rats, which may be due to the inhibition of oxidative stress and apoptosis and the promotion of EAAT2 expression.

Fang, Yi↗
DOE OSTI2019

Effect of magnesium on reducing the UV‐induced oxidative damage in marrow mesenchymal stem cells

Abstract Oxidative stress could cause damage to lipids, proteins and DNA, which is induced by the imbalance between the production of reactive oxygen species (ROS) and the biological system ability to counteract or detoxify their harmful effects. The oxidative stress damage significantly contributes to a number of diseases. Magnesium (Mg) is endowed with a novel function of removing excess ROS by releasing H 2 during the degradation. In this study, in order to explore the property of anti‐oxidative damage of Mg metal, rat bone marrow mesenchymal stem cells (MSCs) oxidative damaged by ultraviolet (UV) radiation was employed to co‐culture with Mg metal. The effect of Mg metal on the response of antioxidant enzymes and mitochondria in MSCs was studied. We found that Mg metal could reduce the cellular oxidative stress damage and elevate the activities of antioxidant enzymes to maintain redox homeostasis. In addition, Mg metal could reduce the risk of UV‐induced cell apoptosis by increasing the ratio of Bcl‐2/Bax, elevating the mitochondrial membrane potential and blocking the release of cytochrome c. This finding showed Mg metal might have the potential for treating diseases caused by oxidative stress damage. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1253–1263, 2019.

Chen, Yangmei↗
DOE OSTI2019

Zearalenone induces apoptosis of rat Sertoli cells through Fas‐Fas ligand and mitochondrial pathway

Abstract Zearalenone (ZEA) is an estrogen‐like toxin produced by Fusarium that is widely found in cereals worldwide. In recent years, ZEA has been found to cause reproductive dysfunction in male animals, but the underlying mechanism remains unclear. This study examined the apoptosis of rat Sertoli cells induced by different concentrations (0, 5, 10, and 20 μmol/L) of ZEA via Fas‐Fas ligand and mitochondrial signaling pathway in vitro. Apoptosis rate was detected by flow cytometry. The mitochondrial membrane potential was detected by immunofluorescence assay and flow cytometry. Western Blot and qRT‐PCR were used to identify the signaling pathway. The results revealed that ZEA induced apoptosis of rat Sertoli cells, significantly reduced the transcription and expression of the anti‐apoptotic protein Bcl‐2, increased the transcription and expression of pro‐apoptotic proteins Bax and tBID, and Fas, FasL, FADD, and caspase‐8. ZEA also increased the activation of caspase‐8 and caspase‐9, and promoted the release of cytochrome C from mitochondria to cytoplasm. Moreover, addition of caspase‐8 inhibitor Z‐IETD‐FMK led to significant decrease in the mitochondrial membrane potential and apoptosis rate of the ZEA + Z‐IETD‐FMK group as compared to the ZEA treatment group. The release of cytochrome C from mitochondria to cytoplasm and the activation of caspase‐9 and caspase‐3 were significantly decreased in the ZEA + Z‐IETD‐FMK group. These results suggested that ZEA can induce apoptosis of rat Sertoli cells, activate the Fas‐Fas ligand signaling pathway and participate in the regulation of mitochondrial apoptosis pathway.

Cai, Guodong↗
DOE OSTI2019

Dioscin-6’-O-acetate impairs migration of lung cancer cells through attenuations of MMP-2 and MMP-9 via NF-κB suppression

More than 90% of the cancer-associated mortality is attributed to its metastasis. Numerous studies demonstrated that natural steroidal saponins from plants had the capacity to inhibit lung cancer metastasis. Dioscin-6’-O-acetate (DA) was a novel steroidal saponin first obtained from the rhizomes of Dioscorea althaeoides R. Knuth. Our previous study indicated that it suppressed lung cancer cell proliferation via inducing cell-cycle arrest and enhancing caspase-dependent apoptosis. Until now, there were still no reports on its anti-migration activity. In the present study, we further verified the anti-proliferation and apoptosis-inducing effects and investigated the anti-migration effects of DA on human NSCLC (NCI-H460, NCI-H1299, NCI-H520) and SCLC (NCI-H446) cells for the first time. To clarify the possible mechanisms, western blot and/or RT-PCR analysis were used. The results revealed that DA treatment increased the levels of caspase 3, 8, 9, and Bax and markedly decreased the expression of bcl-2, PCNA, MMP-2, MMP-9, and NF-κB. Docking study indicated that DA presented strong affinity with the key metastasis-related proteins, such as MMP-2, MMP-9, and NF-κB. We proposed that DA might suppress lung cancer proliferation by downregulating PCNA, induce lung cancer apoptosis via activation of caspase-dependent apoptosis pathways, and inhibit lung cancer migration possibly by targeting MMP-2/9 through NF-κB signaling suppression. The findings would provide the foundation for the clinical use of DA in future.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

N{sup 2}-Methylaurantiamide acetate: a new dipeptide from Mimusops elengi L. flowers

Mimusops elengi L. belonging to the Sapotaceae family is used in various folk systems of medicine in South and Southeast Asia. This study aims to identify the potential constituents responsible for anticancer activity of M. elengi flowers. The EtOAc fraction of M. elengi flowers methanolic extract possessed cytotoxicity and gave an intensive apoptotic response on human leukemia HL-60 cells. A new dipeptide N{sup 2}-methylaurantiamide acetate was isolated from the fraction along with two peptide derivatives and four phenolic compounds. Among the peptide constituents, N{sup 2}-methylaurantiamide acetate showed significant inhibition of cell proliferation and possible induction of apoptotic cell death. Molecular docking analysis demonstrated that N{sup 2}-methylaurantiamide acetate could fit tightly into the BH3-binding groove of anti-apoptotic protein Bcl-2. Our results provide further compelling evidence and enhance the ethnopharmacological value of M. elengi.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Lappaconitine sulfate induces apoptosis in human colon cancer HT-29 cells and down-regulates PI3K/AKT/GSK3β signaling pathway

Lappaconitine (LA), a diterpenoid alkaloid extracted from the roots of Aconitum sinomontanum Nakai, possesses strong central analgesic, local anesthetic, antifebric and anti-inflflammatory effect. Lappaconitine hydrobromide (LH) is used clinically to treat analgesia, but its clinical application is limited because of its poor solubility in water. Studies have suggested that lappaconitine sulfate (LS) is a promising pain reliever, and this particular form not only has readily water soluble, but also exhibits anti-cancer effects. However, the mechanism of LS anti-cancer activity is poorly understood. The aim of this study was intended to investigate the role of LS in apoptosis of human colon cancer HT-29 cells and explore the potential molecular mechanism. Cell proliferation was detected by CCK-8 assay and EdU proliferation assay. Cell morphological change was expressed by Hoechst 33258 staining assay. Expression of apoptosis related proteins were detected by western blot. The effect of LS on cell cycle was detected by flow cytometry. Experimental results showed that LS exhibited anti-proliferative activity and induced apoptosis in HT-29 cells in a dose-dependent manner. LS increased the expression of p53, Bax, cleaved-PARP, cleaved-caspase-3/7/9, and inhibited Bcl-2 expression. LS affected cyclin D1 and p21 expression and induced cell cycle arrest in G0/G1 phase. Additionally, LY294002 signifificantly abrogated the activation of p-PI3K, p-Akt and p-GSK3β. To summarize, these results demonstrated that LS was able to prevent cell proliferation probably via PI3K/Akt/GSK3β signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Oxidative stress induced apoptosis mediated anticancer activity of Rhus typhina fruits extract in human colon cancer

The present work was tested the anti-proliferation activity of Rhus typhina fruits extract (RTFE) in HEK293 and HT-29 cells, and studied their underlying mechanisms through the analysis of oxidative stress and apoptosis-related genes expressions by flow cytometer and RT-qPCR. In addition, the bioactive constituents were identified from RTFE by chromatography and NMR analysis. Among the various type of the fractions from the RTFE, the ethyl acetate fraction (EAF) was showed the potent anti proliferation effect in HT-29 cells. Thus EAF was selected for the further extensive analysis. Cytotoxcity and RT-qPCR results revealed that the treatment of EAF significantly inhibit the growth of the HT-29 cells by the up regulating of Bax and down regulation of Bcl-2, Survivn, AIF and SOD-2 gene expressions in time and dose dependent manner. Followed by sub G1 accumulation and the G0/G1 phase arrest, ROS production, and mitochondrial transmembrane potential (ΔΨm). Finally, the active anti-proliferations agents such as luteolin and luteolin-7-O-glucuronide were identified from EAF by NMR. This work suggests that EAF could be a functional food to treat the chronic diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Zunyimycin C inhibits the proliferation of lung cancer cells by inducing apoptosis through an AKT-related mechanism

Objective: Zunyimycin C is a novel halogenated type II polyketide derived from the fermentation product of the Streptomyces species with notable antibiotic activity. However, it is still unclear whether zunyimycin C could inhibit the activity of cancer cells. In this study, human lung adenocarcinoma cell line A549, the large-cell lung cancer cell line NCI-H460 and the non-small-cell lung cancer cell line NCI-H1299 were employed to determine the in vitro anticancer properties of zunyimycin C and underlying molecular mechanisms. Materials and methods: The cellular viability and proliferative properties of lung cancer cells were investigated using the Cell Counting Kit-8 and colony formation assay, respectively. The mRNA expression of apoptotic genes related to lung cancer was studied using reverse-transcription polymerase chain reaction. The apoptotic ratio was measured through flow cytometry. The protein expression was visualized via western blotting using specific antibodies. Results: Zunyimycin C could inhibit cell proliferation and induce apoptosis in a dose-dependent manner. The expression levels of apoptosis-related proteins (i.e., BAX, cleaved-caspase-3, and cleaved-caspase-9) were increased compared with the control group. However, the levels of Bcl-2 and phosphorylated AKT were decreased by administration by zunyimycin C. Conclusions: Collectively, these results implied that zunyimycin C could inhibit cell proliferation and induce apoptosis via AKT phosphorylation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines

The sphingolipid ceramide is a pro apoptotic molecule of ceramide metabolic pathway and is hydrolyzed to proliferative metabolite, sphingosine 1 phosphate by the action of acid ceramidase. Being upregulated in the tumors of breast, acid ceramidase acts as a potential target for breast cancer therapy. We aimed at targeting this enzyme with a small molecule acid ceramidase inhibitor, Ceranib 2 in human breast cancer cell lines MCF 7 and MDA MB 231. Ceranib 2 effectively inhibited the growth of both the cell lines in dose and time dependant manner. Morphological apoptotic hallmarks such as chromatin condensation, fragmented chromatin were observed in AO/EtBr staining. Moreover, ladder pattern of fragmented DNA observed in DNA gel electrophoresis proved the apoptotic activity of Ceranib 2 in breast cancer cell lines. The apoptotic events were associated with significant increase in the expression of pro-apoptotic genes (Bad, Bax and Bid) and down regulation of anti-apoptotic gene (Bcl 2). Interestingly, increase in sub G1 population of cell cycle phase analysis and elevated Annexin V positive cells after Ceranib 2 treatment substantiated its apoptotic activity in MCF 7 and MDA MB 231 cell lines. Thus, we report Ceranib 2 as a potent therapeutic agent against both ER{sup +} and ER{sup −} breast cancer cell lines. - Highlights: • Acid Ceramidase inhibitor, Ceranib 2 induced apoptosis in Breast cancer cell lines (MCF 7 and MDA MB 231 cell lines). • Apoptosis is mediated by DNA fragmentation and cell cycle arrest. • Ceranib 2 upregulated the expression of pro-apoptotic genes and down regulated anti-apoptotic gene expression. • More potent compared to the standard drug Tamoxifen.

60 APPLIED LIFE SCIENCES↗