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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 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
NASA NTRS2000

A calcium-dependent protein kinase can inhibit a calmodulin-stimulated Ca2+ pump (ACA2) located in the endoplasmic reticulum of Arabidopsis

The magnitude and duration of a cytosolic Ca(2+) release can potentially be altered by changing the rate of Ca(2+) efflux. In plant cells, Ca(2+) efflux from the cytoplasm is mediated by H(+)/Ca(2+)-antiporters and two types of Ca(2+)-ATPases. ACA2 was recently identified as a calmodulin-regulated Ca(2+)-pump located in the endoplasmic reticulum. Here, we show that phosphorylation of its N-terminal regulatory domain by a Ca(2+)-dependent protein kinase (CDPK isoform CPK1), inhibits both basal activity ( approximately 10%) and calmodulin stimulation ( approximately 75%), as shown by Ca(2+)-transport assays with recombinant enzyme expressed in yeast. A CDPK phosphorylation site was mapped to Ser(45) near a calmodulin binding site, using a fusion protein containing the N-terminal domain as an in vitro substrate for a recombinant CPK1. In a full-length enzyme, an Ala substitution for Ser(45) (S45/A) completely blocked the observed CDPK inhibition of both basal and calmodulin-stimulated activities. An Asp substitution (S45/D) mimicked phosphoinhibition, indicating that a negative charge at this position is sufficient to account for phosphoinhibition. Interestingly, prior binding of calmodulin blocked phosphorylation. This suggests that, once ACA2 binds calmodulin, its activation state becomes resistant to phosphoinhibition. These results support the hypothesis that ACA2 activity is regulated as the balance between the initial kinetics of calmodulin stimulation and CDPK inhibition, providing an example in plants for a potential point of crosstalk between two different Ca(2+)-signaling pathways.

NASA Discipline Plant Biology↗
NASA NTRS1999

Potassium uptake supporting plant growth in the absence of AKT1 channel activity: Inhibition by ammonium and stimulation by sodium

A transferred-DNA insertion mutant of Arabidopsis that lacks AKT1 inward-rectifying K+ channel activity in root cells was obtained previously by a reverse-genetic strategy, enabling a dissection of the K+-uptake apparatus of the root into AKT1 and non-AKT1 components. Membrane potential measurements in root cells demonstrated that the AKT1 component of the wild-type K+ permeability was between 55 and 63% when external [K+] was between 10 and 1,000 microM, and NH4+ was absent. NH4+ specifically inhibited the non-AKT1 component, apparently by competing for K+ binding sites on the transporter(s). This inhibition by NH4+ had significant consequences for akt1 plants: K+ permeability, 86Rb+ fluxes into roots, seed germination, and seedling growth rate of the mutant were each similarly inhibited by NH4+. Wild-type plants were much more resistant to NH4+. Thus, AKT1 channels conduct the K+ influx necessary for the growth of Arabidopsis embryos and seedlings in conditions that block the non-AKT1 mechanism. In contrast to the effects of NH4+, Na+ and H+ significantly stimulated the non-AKT1 portion of the K+ permeability. Stimulation of akt1 growth rate by Na+, a predicted consequence of the previous result, was observed when external [K+] was 10 microM. Collectively, these results indicate that the AKT1 channel is an important component of the K+ uptake apparatus supporting growth, even in the "high-affinity" range of K+ concentrations. In the absence of AKT1 channel activity, an NH4+-sensitive, Na+/H+-stimulated mechanism can suffice.

Non-NASA Center↗
NASA NTRS1999

A large blood pressure-raising effect of nitric oxide synthase inhibition in humans

In experimental animals, systemic administration of nitric oxide synthase (NOS) inhibitors causes large increases in blood pressure that are in part sympathetically mediated. The aim of this study was to determine the extent to which these conclusions can be extrapolated to humans. In healthy normotensive humans, we measured blood pressure in response to two NOS inhibitors, NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), the latter of which recently became available for use in humans. The major new findings are 3-fold. First, L-NAME produced robust increases in blood pressure that were more than 2 times larger than those previously reported in humans with L-NMMA and approximated those seen in experimental animals. L-NAME (4 mg/kg) raised mean arterial pressure by 24+/-2 mm Hg (n=27, P<0.001), whereas in subjects who received both inhibitors, a 12-fold higher dose of L-NMMA (50 mg/kg) raised mean arterial pressure by 15+/-2 mm Hg (n=4, P<0.05 vs L-NAME). Second, the L-NAME-induced increases in blood pressure were caused specifically by NOS inhibition because they were reversed by L-arginine (200 mg/kg, n=12) but not D-arginine (200 mg/kg, n=6) and because NG-nitro-D-arginine methyl ester (4 mg/kg, n=5) had no effect on blood pressure. Third, in humans, there is an important sympathetic component to the blood pressure-raising effect of NOS inhibition. alpha-Adrenergic blockade with phentolamine (0.2 mg/kg, n=9) attenuated the L-NAME-induced increase in blood pressure by 40% (P<0.05). From these data, we conclude that pharmacological inhibition of NOS causes large increases in blood pressure that are in part sympathetically mediated in humans as well as experimental animals.

Non-NASA Center↗
DOE OSTI2020

High molecular weight polysaccharide that binds and inhibits virus

This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods of inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further includes methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

Konowalchuk, Thomas W.↗
DOE OSTI2023

High molecular weight polysaccharide that binds and inhibits virus

This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods of inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further includes methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

Konowalchuk, Thomas W.↗
DOE OSTI2020

Regulated lithium ionic flux through well-aligned channels for lithium dendrite inhibition in solid-state batteries

The utilization of solid electrolyte (SE) to suppress lithium (Li) dendrites is promising but still far from satisfactory due to the inhomogeneous Li plating/stripping. In this paper, we demonstrated a novel strategy to inhibit Li dendrites via regulating Li-ion flux in SE by using vertically aligned channels. The ion-insulating walls facilitated uniform distribution of Li-ion flux through the channels, leading to a homogeneous Li deposition, thus alleviating Li dendrite formation. As a result, symmetric cells with this SE exhibited excellent long-term stability (1000 h) against Li metal. In addition, Li4Ti5O12 (LTO)/Li cell with the developed SE achieved good battery performance over 100 cycles. The mechanism for dendrite suppression was further investigated by phase-field simulation. This work provides a novel strategy by manipulating uniform Li-ion flux to fabricate SE to inhibit Li dendrites and facilitates the development of high-performance rechargeable Li batteries.

25 ENERGY STORAGE↗
DOE OSTI2022

n-Butanol or isobutanol as a value-added fuel additive to inhibit microbial degradation of stored gasoline

Biofouling of gasoline can occur during fuel storage caused by bacteria and fungi that form a biofilm at a fuel/water interface and that produce organic acids and sulfides. Fuel additives are applied to gasoline to prevent biofouling but are relatively expensive, are not always effective against biofilms, and do not contribute to the combustibility of gasoline. Bio-isobutanol is an approved, certified advanced biofuel and is added up to 16% ( v/v ) in gasoline blends “iBut16”; n-butanol blends are currently under review. Microorganisms are inhibited by n-butanol or isobutanol when the aqueous concentration reaches >2-3% (w/ v ). We determined that n-butanol partitions into the aqueous phase of a model gasoline/water system reaching concentrations of 42 g/L and up to 48 g/L from gasoline blends at 10% and 24% ( v/v ), respectively. Likewise, isobutanol blended in gasoline at 10% and 24% ( v/v ) partitioned into an aqueous phase at 45 g/L and 53 g/L, respectively. Several bacterial and fungal strains that originate from fuel storage tanks, or are known to be solvent tolerant, were evaluated for their potential growth in a range of n- and isobutanol concentrations. Growth rates for all strains tested were reduced by 40–100% relative to untreated controls in n- and isobutanol concentrations of 1.5 and 2.0% ( v/v ). No observable growth occurred for any of the microorganisms in solvent concentrations at 3.0% ( v/v ). T amphiphilic and chaotropic properties of n- or isobutanol help them inhibit microbial growth and could serve as effective biocides during fuel storage as well as being valuable fuel additives.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

TWIST2 inhibits EMT and induces oxidative stress in lung cancer cells by regulating the FGF21-mediated AMPK/mTOR pathway

Twist related protein 2 (TWIST2) plays an important role in bone development, tumorigenesis, tumour progression and epithelial mesenchymal transition (EMT). At present, there are few reports about the role of TWIST2 in lung cancer, which need to be further explored. Therefore, the purpose of this study is to explore the role and molecular mechanism of TWIST2 in the occurrence and development of lung cancer. The expression of TWIST2 in tissues of patients and cell lines was measured using RT-qPCR and western blotting. MTT and CCK8 assays were used to detect cell proliferation and viability. Western blotting was used to measure the expression of EMT-related proteins, including E-cadherin, N-cadherin, Vimentin and Slug. The results revealed that TWIST2 is lowly expressed in the tissues of lung cancer patients and cell lines. Further studies found that overexpression of TWIST2 significantly induced apoptosis and promoted the expression of E-cadherin, as well as inhibiting the expression of N-cadherin, Vimentin and Slug. More importantly, TWIST2 induced oxidative stress in lung cancer cells. In addition, TWIST2 regulated the FGF21 and AMPK/mTOR signalling pathway, which is involved in the molecular mechanism of the gene in lung cancer cells. We suggest that the mechanism of TWIST2 inhibition of the progression of lung cancer is by regulating the FGF21-mediated AMPK/mTOR signalling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Downregulation of miR-892b inhibits the progression of osteoarthritis via targeting cyclin D1 and cyclin D2

Highlights: • miR-892b antagomir reversed IL-1β-induced chondrocyte growth inhibition. • miR-892b directly targeted cyclin D1 and cyclin D2. • miR-892b antagomir inhibited the symptom of osteoarthritis in vivo. Osteoarthritis (OA) is an orthopedic inflammatory disease which can cause functional disability and chronic pain. MiRNAs are known to play important roles in OA. To identify the targets for the treatment of OA, bioinformatics analysis was performed to explore differentially expressed miRNAs between OA and normal samples.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Targeting HSPA8 inhibits proliferation via downregulating BCR-ABL and enhances chemosensitivity in imatinib-resistant chronic myeloid leukemia cells

The resistance to tyrosine kinase inhibitors is currently a major problem for chronic myeloid leukemia (CML) treatment and HSPA8 is highly expressed and a hallmark of poor prognosis in several human cancers. However, its role in imatinib-resistant CML (IR-CML) cells remains undetermined. Here, we determined HSPA8 was overexpressed in IR-CML cells and associated with imatinib resistance. HSPA8 ablation could downregulate BCR-ABL/STAT5 and BCR-ABL/AKT signaling pathways, dramatically induce proliferation inhibition, autophagy, G0/G1 phase cell cycle arrest but not apoptosis in IR-CML cells. Significantly, HSPA8 ablation enhanced the antitumor activity of imatinib via promoting apoptosis in vitro and vivo. These findings unraveled that HSPA8 ablation inhibits proliferation via downregulating BCR-ABL and enhances chemosensitivity of imatinib in IR-CML cells, which investigate the role and molecular mechanism of HSPA8 in IR-CML cells and suggest that HSPA8 may be a potential target for IR-CML treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Tetramethylpyrazine inhibits neutrophil extracellular traps formation and alleviates hepatic ischemia/reperfusion injury in rat liver transplantation

Hepatic ischemia/reperfusion injury (IRI) is an adverse effect for liver transplantation which is characterized by immune response mediated inflammation. Recent studies report that neutrophil extracellular traps (NETs) are implicated in hepatic IRI. The aim of this study was to explore the mechanism of action of tetramethylpyrazine (TMP), the main chemical composition of Ligusticum chuanxiong in treatment of ischemic related diseases. Data showed that hepatic IRI increases the leak of alanine aminotransferase (ALT) and aspartate transaminase (AST), and stimulates formation of NETs. Extracellular DNA/NETs assay, hematoxylin-eosin (HE) staining, immunofluorescence assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and Western blot assay, showed that TMP significantly reduces formation of NETs and alleviates hepatic IRI. Moreover, TMP and Diphenyleneiodonium (DPI) suppressed ROS production in neutrophils. In addition, analysis showed that activation of NADPH oxidase plays a role in formation of NETs triggered by hepatic IRI. Notably, TMP inhibited formation of NETs though inhibition of NADPH oxidase. Additionally, Combination treatment using TMP and DPI was more effective compared with monotherapy of either of the two drugs. These findings show that combination therapy using TMP and DPI is a promising method for treatment hepatic IRI.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

PPARα agonist exerts protective effects in podocyte injury via inhibition of the ANGPTL3 pathway

Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exert protective effects on podocytes, whereas angiopoietin-like 3 (ANGPTL3) has been shown to exert significant pathogenic effects on these cells. This study aimed to investigate the link between the protective effects of PPARα activation and the pathogenic effects of ANGPTL3 in podocytes. Both PPARα and ANGPTL3 were expressed in cultured podocytes. PPARα mRNA and protein levels decreased whereas ANGPTL3 mRNA and protein levels increased in a time-dependent manner in podocytes treated with puromycin aminonucleoside (PAN). Gemfibrozil, a pharmacological agonist of PPARα, increased PPARα levels and activity in podocytes. The drug also decreased ANGPTL3 levels by potentially weakening ANGPTL3 promoter activity in both normal and PAN-treated podocytes. Furthermore, gemfibrozil significantly decreased PAN-induced apoptosis and F-actin rearrangement. Primary podocytes from Angptl3-knockout mice were cultured. There was no significant difference between Angptl3{sup −/−} podocytes treated with or without gemfibrozil in the lamellipodia numbers after PAN treatment. The results suggested that the protective effects of gemfibrozil on podocytes were not exerted following knockout of the Angptl3 gene. This study identified a novel mechanism of the PPARα agonist gemfibrozil that exerts its protective effects by inhibiting PAN-induced apoptosis and cytoskeleton rearrangements through inhibition of ANGPTL3 expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Ice Recrystallization Inhibition Activity of Soy Protein Hydrolysates

Identifying and developing ice recrystallization inhibitors from sustainable food proteins such as soy protein isolate (SPI) can lead to practical applications in both pharmaceutical and food industries. Here, the objective of this study was to investigate the ice recrystallization inhibition (IRI) activity of SPI hydrolysates, and this was achieved by using an IRI activity-guided fractionation approach and relating IRI activity to interfacial molecular activity measured by vibrational sum frequency generation (VSFG). In addition, the impact of molecular weight (MW) and enzyme specificity was analyzed using three different proteases (Alcalase, trypsin, and pancreatin) and varying hydrolysis times. Using preparative chromatography, hydrolysates from each enzyme treatment were fractionated into five different MW fractions (F1–F5), which were then characterized by high-performance liquid chromatography (HPLC). All SPI hydrolysates had IRI activity, resulting in a 57–29% ice crystal diameter reduction when compared to native SPI. The F1 fraction (of 4–14 kDa) was most effective among all tested hydrolysates, while the lower MW peptide fractions lacked activity. One sample (SPI-ALC 20-F1) had a 52% reduction of ice crystal size at a lower concentration of 2% compared to the typical 4% used. SFG showed a difference in H-bonding and hydrophobic interactions of the molecules on the water/air interface, which may be linked to IRI activity. This study demonstrates for the first time the ability of SPI hydrolysates to inhibit ice crystal growth and the potential application of SFG to study molecular interaction at the interface that may help illustrate the mechanism of action.

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

Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Inhibition of Amyloid β-Induced Lipid Membrane Permeation and Amyloid β Aggregation by K162

Alzheimer's disease (AD) is characterized by progressive neurodegeneration associated with amyloid β (Aβ) peptide aggregation. The aggregation of Aβ monomers (AβMs) leads to the formation of Aβ oligomers (AβOs), the neurotoxic Aβ form, capable of permeating the cell membrane. Here, we investigated the effect of a fluorene-based active drug candidate, named K162, on both Aβ aggregation and AβO toxicity toward the bilayer lipid membrane (BLM). Electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM), and molecular dynamics (MD) were employed to show that K162 inhibits AβOs-induced BLM permeation, thus preserving BLM integrity. In the presence of K162, only shallow defects on the BLM surface were formed. Apparently, K162 modifies Aβ aggregation by bypassing the formation of toxic AβOs, and only nontoxic AβMs, dimers (AβDs), and fibrils (AβFs) are produced. Unlike other Aβ toxicity inhibitors, K162 preserves neurologically beneficial AβMs. This unique K162 inhibition mechanism provides an alternative AD therapeutic strategy that could be explored in the future.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Targeting Mycobacterium tuberculosis Persistence through Inhibition of the Trehalose Catalytic Shift

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple antibiotics, an extremely challenging regimen necessitated by Mtb’s ability to form drug-tolerant persister cells. Mtb persister formation is dependent on the trehalose catalytic shift, a stress-responsive metabolic remodeling mechanism in which the disaccharide trehalose is liberated from cell surface glycolipids and repurposed as an internal carbon source to meet energy and redox demands. Here, using a biofilm-persister model, metabolomics, and cryo-electron microscopy (EM), we found that azidodeoxy- and aminodeoxy-d-trehalose analogues block the Mtb trehalose catalytic shift through inhibition of trehalose synthase TreS (Rv0126), which catalyzes the isomerization of trehalose to maltose. Out of a focused eight-member compound panel constructed by chemoenzymatic synthesis, the natural product 2-trehalosamine exhibited the highest potency and significantly potentiated first- and second-line TB drugs in broth culture and macrophage infection assays. We also report the first structure of TreS bound to a substrate analogue inhibitor, obtained via cryo-EM, which revealed conformational changes likely essential for catalysis and inhibitor binding that can potentially be exploited for future therapeutic development. Our results demonstrate that inhibition of the trehalose catalytic shift is a viable strategy to target Mtb persisters and advance trehalose analogues as tools and potential adjunctive therapeutics for investigating and targeting mycobacterial persistence.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Substitution of distal and active site residues reduces product inhibition of E1 from Acidothermus Cellulolyticus

Abstract Cellulases are largely afflicted by inhibition from their reaction products, especially at high-substrate loading, which represents a major challenge for biomass processing. This challenge was overcome for endoglucanase 1 (E1) from Acidothermus cellulolyticus by identifying a large conformational change involving distal residues upon binding cellobiose. Having introduced alanine substitutions at each of these residues, we identified several mutations that reduced cellobiose inhibition of E1, including W212A, W213A, Q247A, W249A and F250A. One of the mutations (W212A) resulted in a 47-fold decrease in binding affinity of cellobiose as well as a 5-fold increase in the kcat. The mutation further increased E1 activity on Avicel and dilute-acid treated corn stover and enhanced its productivity at high-substrate loadings. These findings were corroborated by funnel metadynamics, which showed that the W212A substitution led to reduced affinity for cellobiose in the +1 and +2 binding sites due to rearrangement of key cellobiose-binding residues.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

4'-Deoxypyridoxine disrupts vitamin B 6 homeostasis in Escherichia coli K12 through combined inhibition of cumulative B 6 uptake and PLP-dependent enzyme activity

Pyridoxal 5'-phosphate (PLP) is the active form of vitamin B 6 and a cofactor for many essential metabolic processes such as amino acid biosynthesis and one carbon metabolism. 4’-deoxypyridoxine (4dPN) is a long known B 6 antimetabolite but its mechanism of action was not totally clear. By exploring different conditions in which PLP metabolism is affected in the model organism Escherichia coli K12, we showed that 4dPN cannot be used as a source of vitamin B 6 as previously claimed and that it is toxic in several conditions where vitamin B 6 homeostasis is affected, such as in a B 6 auxotroph or in a mutant lacking the recently discovered PLP homeostasis gene, yggS . In addition, we found that 4dPN sensitivity is likely the result of multiple modes of toxicity, including inhibition of PLP-dependent enzyme activity by 4’-deoxypyridoxine phosphate (4dPNP) and inhibition of cumulative pyridoxine (PN) uptake. These toxicities are largely dependent on the phosphorylation of 4dPN by pyridoxal kinase (PdxK).

59 BASIC BIOLOGICAL SCIENCES↗