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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 793 records · Page 44
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Mouse model of chorea-acanthocytosis exhibits male infertility caused by impaired sperm motility as a result of ultrastructural morphological abnormalities in the mitochondrial sheath in the sperm midpiece

Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis caused by loss-of-function mutations in the Vacuolar Protein Sorting 13 Homolog A (VPS13A) gene, which encodes chorein. We previously produced a ChAc-model mouse with a homozygous deletion of exons 60–61 in Vps13a, which corresponded to the human disease mutation. We found that male ChAc-model mice exhibited complete infertility as a result of severely diminished sperm motility. Immunocytochemical study revealed that chorein-like immunoreactivity is abundant only in the midpiece, mitochondria-rich region, of the sperm of wild type mice. They showed no significant differences from wild types in terms of the adenosine 5′-triphosphate (ATP) concentration of their sperm, sperm count, or sexual activity. Electron microscopy revealed abnormal ultrastructural morphology of the mitochondria in the midpiece of sperm from ChAc-model mice. These results suggest that chorein is essential in mouse sperm for the maintenance of ultrastructural mitochondrial morphology and sperm motility.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Polymorphisms of ABCG2 and its impact on clinical relevance

Human ABCG2 is one of the most important ATP-binding cassette (ABC) transporters. This protein functions as a xenobiotic transporter of large, hydrophobic, positively or negatively charged molecules, a wide variety anticancer drugs, fluorescent dyes, and different toxic compounds found in normal food. SNPs in ABCG2 may affect absorption and distribution of these substrates, altering the accumulation, effectiveness and toxicity of compounds or drugs in large populations. Its transport properties have been implicated clinically and ABCG2 expression is linked with different disease states. We reviewed the SNPs of ABCG2 in clinical relevance about gout, acute myeloid leukemia, solid tumors, and other diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Global regulatory function of the low oxygen-induced transcriptional regulator LoiA in Salmonella Typhimurium revealed by RNA sequencing

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major intestinal pathogen that can infect both humans and a variety of animals. LoiA, a novel virulence-regulating protein encoded in Salmonella pathogenicity island (SPI)-14, has been shown to be induced under low oxygen conditions and contribute to S. Typhimurium invasion into intestinal epithetical cells by activating the SPI-1 invasion genes. However, the global regulatory network of LoiA remains unknown. Here, we used high-throughput RNA sequencing (RNA-seq) technology to investigate the regulatory function of LoiA in S. Typhimurium under low oxygen conditions. A total of 1250 genes were differentially expressed between the loiA mutant and the wild-type strain; 413 genes were up-regulated and 837 were down-regulated. SPI-1 gene expression was down-regulated in the loiA mutant, consistent with previous results. SPI-2 gene expression was not affected by deletion of loiA; the expression of most genes involved in flagellar basal body and hook biosynthesis was up-regulated in the loiA mutant, while the expression of genes associated with flagellin, motility, and chemotaxis was down-regulated; the expression of lon, encoding an ATP-dependent protease, was up-regulated in the mutant. This study indicates that LoiA regulates a variety of virulence-associated genes in S. Typhimurium. The negative regulation of Lon protease by LoiA indicates that LoiA can regulates several virulence-associated genes in S. Typhimurium via the Lon protease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

DDX5 promotes hepatocellular carcinoma tumorigenesis via Akt signaling pathway

The DEAD-box-protein DDX5 is an ATP-dependent RNA helicase and also acts as co-activator that contributes to progression and metastasis of various tumours. However, its expression as well as prognostic roles of DDX5 in hepatocellular carcinoma (HCC) remain elusive. In this study, we investigated clinical significance and biological functions of DDX5 in HCC. Our results suggested that DDX5 showed overexpression at both transcriptional and translational levels in HCC tissues compared with adjacent normal tissues. Moreover, DDX5 expression was demonstrated to be correlated with tumor size (p p = 0.013), M stage (p = 0.006), tumor differentiation (p p = 0.001). Simultaneously, high DDX5 expression was found to be significantly correlated to worse outcome including Disease free survival (DFS) (p = 0.016) and overall survival (OS) (p = 0.032) according to Kaplan-Meier survival analysis. In vitro studies, it suggested that knockdown of DDX5 suppressed HCC cells migration, invasion and epithelial -to- mesenchymal transition (EMT) process. Depletion of DDX5 could promote HCC cells growth. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that PI3K/Akt signaling pathway obtained the highest enrichment. Furthermore, we found that knockdown of DDX5 decreased Akt as well as p-Akt (S473) expressions. Collectively, these findings suggested that DDX5 facilitated HCC cells growth via Akt signaling pathway. DDX5 played a crucial role in HCC proliferation and tumorigenesis and may be a novel prognostic marker and potential therapeutic target for HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

E3317 promotes cholesterol efflux in macrophage cells via enhancing ABCA1 expression

Highlights: • E3317 was first found as an ABCA1 upregulator in an ABCA1 transcriptional activity assay. • E3317 increased ABCA1 mRNA and protein expression in both L02 and RAW264.7 cells. • E3317 promoted cholesterol efflux and reduced cellular lipid accumulation in RAW264.7 macrophages dependent on ABCA1. • E3317 upregulated ABCA1 expression through activating PPARγ. • Y327 and F363 are the key PPARγ binding epitopes of E3317. Reverse cholesterol transport (RCT) plays an important role in cholesterol and lipid metabolism. Regulating the activities of key transporters and receptors in RCT, such as ATP-binding cassette transporter A1 (ABCA1), helps to prevent atherosclerotic cardiovascular disease. In this study, we used an ABCA1 promoter luciferase reporter assay to screen 20,000 compounds for ABCA1 upregulators. Compound E3317 (N-(6-butylbenzo[d]thiazol-2(3H)-ylidene)-3-(N-(2-cyanoethyl)sulfamoyl)benzamide)) was identified as a positive hit with an EC{sub 50} value of 0.2 μM in ABCA1p-LUC HepG2 cells. Thus, we hypothesized that E3317 might have cholesterol- and lipid metabolism-regulating effects through ABCA1 upregulation. E3317 significantly increased ABCA1 mRNA and protein expression in hepatic L02 cells and RAW264.7 macrophages. E3317 promoted cholesterol efflux to apolipoprotein A-I in RAW264.7 macrophages and significantly decreased lipid accumulation in oxidized low-density lipoprotein-induced murine RAW264.7 macrophages. Further studies using ABCA1 siRNA showed that the promotion of cholesterol efflux and decrease of lipid accumulation by E3317 depended on ABCA1 expression. Mechanistic studies indicated that E3317 regulated ABCA1 expression via activating nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays an important role in the regulation of glucose homeostasis and lipid metabolism. The structure of E3317 was docked in the ligand-binding domain of PPARγ (PBD code: 4EMA) to find the key binding amino acids. Site mutation assays confirmed that Y327 and F363 were the key PPARγ binding epitopes of E3317. Our results revealed that E3317 upregulates ABCA1 expression and thereby promotes cholesterol efflux. E3317 may regulate ABCA1 expression through PPARγ. Our findings provide a new compound, E3317, which may have beneficial cardiovascular effects.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Crystal structure of GSK3β in complex with the flavonoid, morin

GSK3β is a key kinase that plays a role in cellular signaling pathways. In Alzheimer's disease (AD), GSK3β has been implicated in hyperphosphorylation of tau proteins in the neuron, which is a hallmark of AD. Morin, a flavonoid that is abundant in nature, was found as an inhibitor of GSK3β that can reduce tau pathology in vivo and in vitro. In this study, we determined the crystal structure of GSK3β in complex with morin. The structure revealed that morin inhibits GSK3β by binding to the ATP binding pocket. Our findings augment the potential of morin as a functional food to help prevent AD, as well as to provide structural information to develop new therapeutics based on the morin skeleton.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Ropivacaine impairs mitochondrial biogenesis by reducing PGC-1α

Highlights: • Ropivacaine inhibits the expressions of PGC-1α, NRF-1, and TFAM in M17 cells. • Ropivacaine impairs mitochondrial biogenesis and causes mitochondrial malfunction. • Ropivacaine-induced reduction of PGC-1α requires the inactivation of CREB. • PGC-1α rescues Ropivacaine-caused impairment of mitochondrial biogenesis. Ropivacaine is one of the commonly used local anesthetics in medical and dental care. However, preclinical and observational studies indicate that ropivacaine could have substantial side effects including neurotoxicity, which has raised concern regarding the safety of this drug. In the present study, we investigated the effects of clinically relevant doses of ropivacaine on mitochondrial biogenesis and function in neuronal cells. Our data indicate that exposure to ropivacaine leads to reduced expression of the major mitochondrial regulator PGC-1α and its downstream transcription factors NRF1 and TFAM. Ropivacaine treatment induces impairment of mitochondrial biogenesis by reducing mitochondrial mass, the ratio of mtDNA to nDNA (mtDNA/nDNA), cytochrome C oxidase activity, and COX-1 expression. Additionally, treatment with ropivacaine causes “loss of mitochondrial function” by impairing the mitochondrial respiratory rate and ATP production. Mechanistically, the reduction of PGC-1α caused by ropivacaine exposure requires inactivation of CREB, while re-introduction of PGC-1α completely rescues ropivacaine-induced mitochondrial abnormalities. In summary, our results provide supporting evidence that mitochondrial impairment is a key event in ropivacaine-mediated neurotoxicity, and the reduction of PGC-1α and its downstream signals are likely the molecular mechanism behind its cellular toxicity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effect of Acyl Activating Enzyme (AAE) 3 on the growth and development of Medicago truncatula

The Acyl-Activating Enzyme (AAE) 3 gene encodes an oxalyl-CoA synthetase that catalyzes the conversion of oxalate to oxalyl-CoA in a CoA and ATP-dependent manner. Although the biochemical activity of AAE3 has been established, its biological role in plant growth and development remains unclear. To advance our understanding of the role of AAE3 in plant growth and development, we report here the characterization of two Medicago truncatula AAE3 (Mtaae3) mutants. Characterization of a Mtaae3 RNAi mutant revealed an accumulation of calcium oxalate crystals and increased seed permeability. These phenotypes were also exhibited in the Arabidopsis aae3 (Ataae3) mutants. Unlike the Ataae3 mutants, the Mtaae3 RNAi mutant did not show a reduction in vegetative growth, decreased seed germination, or increased seed calcium concentration. In an effort to clarify these phenotypic differences, a Mtaae3 Tnt1 mutant was identified and characterized. This Mtaae3 Tnt1 mutant displayed reduced vegetative growth, decreased seed germination, and increased seed calcium concentration as well as an accumulation of calcium oxalate crystals and increased seed permeability as found in Ataae3. Overall, the results presented here show the importance of AAE3 in the growth and development of plants. In addition, this study highlights the ability to separate specific growth and development phenotypes based on the level of AAE3 gene expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Co3O4 nanoparticles at sublethal concentrations inhibit cell growth by impairing mitochondrial function

Highlights: • Co{sub 3}O{sub 4} nanoparticles (NPs) severely inhibit cell growth at the sublethal concentrations. • Cell death and ROS accumulation are not involved in the toxicity of Co{sub 3}O{sub 4} NPs. • Co{sub 3}O{sub 4} NPs cause remarkable down-regulation of the mitochondrial genes. • Co{sub 3}O{sub 4} NPs severely impair the mitochondrial function. Co{sub 3}O{sub 4} nanoparticles (NPs) are one kind of the important nanomaterials that have the application potential in catalyst, electrochromic devices, sensors, etc. However, their biological effect remains to be detailed. In this study, we investigated the effect of the as-synthesized Co{sub 3}O{sub 4} NPs (15–30 nm) on the growth of mammalian cells, and found that the NPs severely inhibited cell growth at the sublethal concentrations from 12.5 to 200 mg/L. Interestingly, the NPs did not cause obvious cell death and ROS accumulation, indicating that their inhibitory effect was not attributed to both apoptosis- or necrosis-related cell death and ROS accumulation. Transcription profiling analysis revealed that the NPs caused remarkable down regulation of the genes involved in mitochondrial functions. Transmission electron microscopy (TEM) and biochemical analysis further showed that the NPs might interact with the mitochondria, impairing the mitochondrial membrane potential (MMP) and ATP production. This study uncovers a mitochondrial respiratory chain-related and ROS-independent toxicity mechanism of Co{sub 3}O{sub 4} NPs in eukaryotic cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Cyclic stretch increases mitochondrial biogenesis in a cardiac cell line

Unlike stable and immobile cell line conditions, animal hearts contract and relax to pump blood throughout the body. Mitochondria play an essential role by producing biological energy molecules to maintain heart function. In this study, we assessed the effect of heart mimetic cyclic stretch on mitochondria in a cardiac cell line. To mimic the geometric and biomechanical conditions surrounding cells in vivo, cyclic stretching was performed on HL-1 murine cardiomyocytes seeded onto an elastic micropatterned substrate (10% elongation, 0.5 Hz, 4 h/day). Cell viability, semi-quantitative Q-PCR, and western blot analyses were performed in non-stimulated control and cyclic stretch stimulated HL-1 cell lines. Cyclic stretch significantly increased the expression of mitochondria biogenesis-related genes (TUFM, TFAM, ERRα, and PGC1-α) and mitochondria oxidative phosphorylation-related genes (PHB1 and CYTB). Western blot analysis confirmed that cyclic stretch increased protein levels of mitochondria biogenesis-related proteins (TFAM, and ERRα) and oxidative phosphorylation-related proteins (NDUFS1, UQCRC, and PHB1). Consequently, cyclic stretch increased mitochondrial mass and ATP production in treated cells. Our results suggest that cyclic stretch transcriptionally enhanced mitochondria biogenesis and oxidative phosphorylation without detrimental effects in a cultured cardiac cell line.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

DDX21 promotes gastric cancer proliferation by regulating cell cycle

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

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Identification of a rare homozygous c.790C>T variation in the TFB2M gene in Korean patients with autism spectrum disorder

Highlights: • TFB2M have been known to critical in mitochondrial DNA gene expression. • We identified a variation of TFB2M gene sequence in Korean autism patients. • The variation caused increased mitochondrial DNA gene expression. • Increased mitochondrial biogenesis resulted in ROS production and damaged cells. • Structural changes of variant TFB2M seems to delay unloading of DNA from TFB2M. Mitochondrial dysfunction and subsequent enhanced oxidative stress is implicated in the pathogenesis of autism spectrum disorder (ASD). Mitochondrial transcription factor B2 (TFB2M) is an essential protein in mitochondrial gene expression. No reports have described TFB2M mutations and variations involved in any human diseases. We identified a rare homozygous c.790C>T (His264Tyr) variation in TFB2M gene in two Korean siblings with ASD by whole-exome sequencing. The roles of the TFB2M variation in the pathogenesis of ASD were investigated. Patient fibroblasts revealed increased transcription of mitochondrial genes and mitochondrial function in terms of ATP, membrane potential, oxygen consumption, and reactive oxygen species (ROS). Overexpression of the TFB2M variant in primary-cultured fibroblasts demonstrated significantly increased transcription of mitochondrial genes and mitochondrial function compared with overexpression of wild-type TFB2M. Molecular dynamics simulation of the TFB2M variant protein suggested an increase in the rigidity of the hinge region, which may cause alterations in loading and/or unloading of TFB2M on target DNA. Our results suggest that augmentation of mitochondrial gene expression and subsequent enhancement of mitochondrial function may be associated with the pathogenesis of ASD in Korean patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Crystal structure of the 65-kilodalton amino-terminal fragment of DNA topoisomerase I from the gram-positive model organism Streptococcus mutans

Here, we report the first structure of topoisomerase I determined from the gram-positive bacterium, S. mutans. Bacterial topoisomerase I is an ATP-independent type 1A topoisomerase that uses the inherent torsional strain within hyper-negatively supercoiled DNA as an energy source for its critical function of DNA relaxation. Interest in the enzyme has gained momentum as it has proven to be essential in various bacterial organisms. In order to aid in further biochemical characterization, the apo 65-kDa amino-terminal fragment of DNA topoisomerase I from the gram-positive model organism Streptococcus mutans was crystalized and a three-dimensional structure was determined to 2.06 Å resolution via x-ray crystallography. The overall structure illustrates the four classic major domains that create the traditional topoisomerase I “lock” formation comprised of a sizable toroidal aperture atop what is considered to be a highly dynamic body. A catalytic tyrosine residue resides at the interface between two domains and is known to form a 5’ phosphotyrosine DNA-enzyme intermediate during transient single-stranded cleavage required for enzymatic relaxation of hyper negative DNA supercoils. Surrounding the catalytic tyrosine residue is the remainder of the highly conserved active site. Within 5 Å from the catalytic center, only one dissimilar residue is observed between topoisomerase I from S. mutans and the gram-negative model organism E. coli. Immediately adjacent to the conserved active site, however, S. mutans topoisomerase I displays a somewhat unique nine residue loop extension not present in any bacterial topoisomerase I structures previously determined other than that of an extremophile.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

A dynamic thermal algal growth model for pilot-scale open-channel raceways

Here this study describes the makeup of and results from a simulation consisting of a lumped thermal model integrated with a dynamic algae growth model to simulate the microalgae productivity of an open-channel raceway cultivation system. The thermal model considers the dynamic effects of weather, light absorption, convective heat transfer, radiation heat transfer, conductive heat transfer, thermal capacitance, and water control strategies. The dynamic algae growth model solves a set of ordinary differential equations consisting of growth functions dependent on incident radiation, temperature, nutrient availability, basal metabolism, and losses due to dark- and photo-respiration. Relative errors in the predicted ash-free dry weight of Nannochloropsis oceanica are 12.5%, -6.1%, and 4.4% for three separate replicates of cultivation cycles (~4.2 m 2 ) performed at AzCATI during the ATP 3 Unified Field Studies in Fall, Spring, and Summer. This research demonstrates that thermal modeling is an essential contributor to the validation of microalgae growth models.

09 BIOMASS FUELS↗
DOE OSTI2016

Multiple CaMKII Binding Modes to the Actin Cytoskeleton Revealed by Single-Molecule Imaging

Localization of the Ca2þ/calmodulin-dependent protein kinase II (CaMKII) to dendritic spine synapses is determined in part by the actin cytoskeleton. We determined binding of GFP-tagged CaMKII to tag-RFP-labeled actin cytoskeleton within live cells using total internal reflection fluorescence microscopy and single-molecule tracking. Stepwise photobleaching showed that CaMKII formed oligomeric complexes. Photoactivation experiments demonstrated that diffusion out of the evanescent field determined the track lifetimes. Latrunculin treatment triggered a coupled loss of actin stress fibers and the colocalized, long-lived CaMKII tracks. The CaMKIIa (a) isoform, which was previously thought to lack F-actin interactions, also showed binding, but this was threefold weaker than that observed for CaMKIIb (b). The bE0 splice variant bound more weakly than a, showing that binding by b depends critically on the interdomain linker. The mutations bT287D and aT286D, which mimic autophosphorylation states, also abolished F-actin binding. Autophosphorylation triggers autonomous CaMKII activity, but does not impair GluN2B binding, another important synaptic protein interaction of CaMKII. The CaMKII inhibitor tatCN21 or CaMKII mutations that inhibit GluN2B association by blocking binding of ATP (bK43R and aK42M) or Ca2þ/calmodulin (bA303R) had no effect on the interaction with F-actin. These results provide the first rationale for the reduced synaptic spine localization of the aT286D mutant, indicating that transient F-actin binding contributes to the synaptic localization of the CaMKIIa isoform. The track lifetime distributions had a stretched exponential form consistent with a heterogeneously diffusing population. This heterogeneity suggests that CaMKII adopts different F-actin binding modes, which is most easily rationalized by multiple subunit contacts between the CaMKII dodecamer and the F-actin cytoskeleton that stabilize the initial weak (micromolar) monovalent interaction.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Lattice light-sheet microscopy allows for super-resolution imaging of receptors in leaf tissue

Plant leaf tissues are difficult to image via fluorescent microscopy, largely due to the presence of chlorophyll and other pigments that provide large background fluorescence. An advantage of Lattice Light-Sheet microscopy is its use of Bessel beams that illuminate a thin focal region of interest for microscopy, allowing for the excitation of fluorescent molecules within this region without surrounding chlorophyll-like objects outside of the region of interest. Here, we apply STORM Super-resolution techniques to observe Receptor-Like Kinases in Arabidopsis thaliana leaf cells. By applying this technique with the Lattice Light-Sheet, we can localize immune response proteins in sub-100 nm length scales and reconstruct three-dimensional locations of proteins within individual leaf cells. Using this technique, we observed the effect of the elicitors ATP and flg22, where we observed a significant degree of internalization of cognate receptors P2K1 and FLS2. We were also able to similarly observe differences in colocalization due to stimulation with these elicitors, where we observe proteins on the membrane becoming less colocalized as a result of stimulation, suggesting an immune response mechanism involving receptors internalizing via pathways distinct to the receptor. Further, these data show the Lattice Light-Sheet’s capabilities for imaging tissue with problematic background fluorescence that otherwise makes super-resolution fluorescence microscopy difficult.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-$α$ Inhibition for Cancer and Autoimmune Disease

Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF-α antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNF-α-mediated signaling. In this paper, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNF-α stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-α-induced cell death, with general implications for cancer and autoimmune disease treatment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors

Epidermal growth factor receptor (EGFR, also known as HER1) and HER2, prominent members of receptor tyrosine kinase (RTK) superfamily, have been reported as diagnostic or prognostic markers in tumor progression. Based on the importance of molecular hybridization of pyrazoline and thiazole scaffolds in the discovery of potent anticancer agents, new thiazolyl-pyrazoline derivatives (3a-v) were synthesized and screened for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and A375 human melanoma cell lines. 1-(4-(4-Fluorophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3c),1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3f) and 1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3q) were found as the most potent anticancer agents against A549 and MCF-7 cell lines compared to erlotinib. Compound 3q also showed moderate cytotoxic activity against A375 cell line. Moreover, these compounds exert a cancer cell–selective action against Jurkat cell line posing no toxicity on peripheral blood mononuclear cells (PBMCs). In order to enlighten the mechanism of action underlying anticancer activity, compounds 3c, 3f and 3q were investigated for their apoptotic effects on A549 and MCF-7 cell lines and inhibitory potencies against eight different RTKs including EGFR and HER2 compared to erlotinib. The results indicated that compounds 3f and 3q induced apoptosis in both cell lines and showed significant EGFR inhibitory activity with IC50 values of 4.34 ± 0.66 μM and 4.71 ± 0.84 μM, respectively when compared with erlotinib (IC 50 = 0.05 ± 0.01 μM). Besides, compound 3f also inhibited HER2 notably with an IC 50 value of 2.28 ± 0.53 μM making it a dual EGFR and HER2 inhibitor. Molecular docking studies, which were conducted to support the in vitro assays, pointed out that compound 3f showed high affinity into the ATP binding sites of EGFR and HER2.

60 APPLIED LIFE SCIENCES↗