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Results for “cytotoxicity”

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 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Overexpression and surface localization of HPRT in prostate cancer provides a potential target for cancer specific antibody mediated cellular cytotoxicity

Highlights: • HPRT is heterogeneously expressed in prostate cancer cells, with surface HPRT being expressed in a p53-dependent fashion. • HPRT is localized to the surface of DU145 prostate cancer cells and is targeted specifically to induce anti-tumor efficacy. • Reductions in p53 expression correspond to reductions in HPRT internal and surface expression within mutant p53 cell lines. We chose to evaluate Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) as a possible biomarker for prostate cancer due to its involvement in nucleotide synthesis and cell cycle progression. We utilized two prostate cancer cell lines (PC3 and DU145) along with patient tissue and knockdowns to evaluate overall HPRT expression. The surface localization of HPRT was determined utilizing flow cytometry, confocal microscopy, and scanning electron microscopy followed by ADCC to evaluate targeting potential. We found significant upregulation of HPRT within malignant samples with approximately 47% of patients had elevated levels of HPRT compared to normal controls. We also observed a significant association between HPRT and the plasma membrane of DU145 cells (p = 0.0004), but found no presence on PC3 cells (p = 0.14). This was confirmed with scanning electron microscopy and confocal microscopy. ADCC experiments were performed to determine whether HPRT could be used as a target antigen for selective cell-mediated killing. We found that DU145 cells treated with HPRT antibodies had a significantly higher incidence of cell death than both isotype treated samples and PC3 cells treated with the same concentrations of HPRT antibody. Finally, we determined that p53 had a significant impact on HPRT expression both internally and on the surface of cancer cells. These results suggest HPRT as a possible biomarker target for the treatment of patients with prostate cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Correction to “Self-Assembly of Accumulated Sphingolipids into Cytotoxic Fibrils in Globoid Cell Leukodystrophy and Their Inhibition by Small Molecules in Vitro”

Dr. Laor Bar-Yosef was significantly involved in the introduction and use of the Raman microspectroscopy part of this project. She was a major contributor to the novel conceptual use of this technology for detecting and monitoring sphingolipids in vitro and in cells. As expected from her deep involvement, Dr. Laor Bar-Yosef took part in analyzing the corresponding results.

Kumar, Sourav [Tel Aviv University (Israel)] (ORCI↗
DOE OSTI2020

Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides

The use of non-standard toxicity models is a hurdle in the early development of antimicrobial peptides towards clinical applications. Herein we report an extensive in vitro and in vivo toxicity study of a library of 24 peptide-based antimicrobials with narrow spectrum activity towards veterinary pathogens. The haemolytic activity of the compounds was evaluated against four different species and the relative sensitivity against the compounds was highest for canine erythrocytes, intermediate for rat and human cells and lowest for bovine cells. Selected peptides were additionally evaluated against HeLa, HaCaT and HepG2 cells which showed increased stability towards the peptides. Therapeutic indexes of 50–500 suggest significant cellular selectivity in comparison to bacterial cells. Three peptides were administered to rats in intravenous acute dose toxicity studies up to 2– 8 × MIC. None of the injected compounds induced any systemic toxic effects in vivo at the concentrations employed illustrating that the correlation between the different assays is not obvious. This work sheds light on the in vitro and in vivo toxicity of this class of promising compounds and provides insights into the relationship between the different toxicity models often employed in different manners to evaluate the toxicity of novel bioactive compounds in general.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Vibrio MARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy

Vibrio vulnificus causes life-threatening wound and gastrointestinal infections, mediated primarily by the production of a Multifunctional-Autoprocessing Repeats-In-Toxin (MARTX) toxin. The most commonly present MARTX effector domain, the Makes Caterpillars Floppy-like (MCF) toxin, is a cysteine protease stimulated by host adenosine diphosphate (ADP) ribosylation factors (ARFs) to autoprocess. Here, we show processed MCF then binds and cleaves host Ra s-related proteins in b rain (Rab) guanosine triphosphatases within their C-terminal tails resulting in Rab degradation. We demonstrate MCF binds Rabs at the same interface occupied by ARFs. Moreover, we show MCF preferentially binds to ARF1 prior to autoprocessing and is active to cleave Rabs only subsequent to autoprocessing. We then use structure prediction algorithms to demonstrate that structural composition, rather than sequence, determines Rab target specificity. We further determine a crystal structure of aMCF as a swapped dimer, revealing an alternative conformation we suggest represents the open, activated state of MCF with reorganized active site residues. The cleavage of Rabs results in Rab1B dispersal within cells and loss of Rab1B density in the intestinal tissue of infected mice. Collectively, our work describes an extracellular bacterial mechanism whereby MCF is activated by ARFs and subsequently induces the degradation of another small host guanosine triphosphatase (GTPase), Rabs, to drive organelle damage, cell death, and promote pathogenesis of these rapidly fatal infections.

Science & Technology - Other Topics↗
DOE OSTI2023

A symbiotic bacterium of Antarctic fish reveals environmental adaptability mechanisms and biosynthetic potential towards antibacterial and cytotoxic activities

Antarctic microbes are important agents for evolutionary adaptation and natural resource of bioactive compounds, harboring the particular metabolic pathways to biosynthesize natural products. However, not much is known on symbiotic microbiomes of fish in the Antarctic zone. In the present study, the culture method and whole-genome sequencing were performed. Natural product analyses were carried out to determine the biosynthetic potential. We report the isolation and identification of a symbiotic bacterium Serratia myotis L7-1, that is highly adaptive and resides within Antarctic fish, Trematomus bernacchii . As revealed by genomic analyses, Antarctic strain S. myotis L7-1 possesses carbohydrate-active enzymes (CAZymes), biosynthetic gene clusters (BGCs), stress response genes, antibiotic resistant genes (ARGs), and a complete type IV secretion system which could facilitate competition and colonization in the extreme Antarctic environment. The identification of microbiome gene clusters indicates the biosynthetic potential of bioactive compounds. Based on bioactivity-guided fractionation, serranticin was purified and identified as the bioactive compound, showing significant antibacterial and antitumor activity. The serranticin gene cluster was identified and located on the chrome. Furthermore, the multidrug resistance and strong bacterial antagonism contribute competitive advantages in ecological niches. Our results highlight the existence of a symbiotic bacterium in Antarctic fish largely represented by bioactive natural products and the adaptability to survive in the fish living in Antarctic oceans.

Xiao, Yu↗
DOE OSTI2020

PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response

Theranostics are emerging as a pillar of cancer therapy that enable the use of single molecule constructs for diagnostic and therapeutic application. As poly adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) is overexpressed in various cancer types, and is localized to the nucleus, PARP-1 can be safely targeted with Auger emitters to induce DNA damage in tumors. Here, we investigated a radioiodinated PARP inhibitor, [125I]KX1, and show drug target specific DNA damage and subsequent killing of BRCA1 and non-BRCA mutant ovarian cancer cells at sub-pharmacological concentrations several orders of magnitude lower than traditional PARP inhibitors. Furthermore, we demonstrated that viable tumor tissue from ovarian cancer patients can be used to screen tumor radiosensitivity ex-vivo, enabling the direct assessment of therapeutic efficacy. Finally, we showed tumors can be imaged by single-photon computed tomography (SPECT) with PARP theranostic, [123I]KX1, in a human ovarian cancer xenograft mouse model. These data support the utility of PARP-1 targeted radiopharmaceutical therapy as a theranostic option for PARP-1 overexpressing ovarian cancers.

BRCA1↗
NASA NTRS2003

Exposure to Carbon Nanotube Material: Assessment of Nanotube Cytotoxicity Using Human Keratinocyte Cells

Carbon nanotubes are new members of carbon allotropes similar to fullerenes and graphite. Because of their unique electrical, mechanical, and thermal properties, carbon nanotubes are important for novel applications in the electronics, aerospace, and computer industries. Exposure to graphite and carbon materials has been associated with increased incidence of skin diseases, such as carbon fiber dermatitis, hyperkeratosis, and naevi. We investigated adverse effects of single-wall carbon nanotubes (SWCNT) using a cell culture of immortalized human epidermal keratinocytes (HaCaT). After 18 h of exposure of HaCaT to SWCNT, oxidative stress and cellular toxicity were indicated by formation of free radicals, accumulation of peroxidative products, antioxidant depletion, and loss of cell viability. Exposure to SWCNT also resulted in ultrastructural and morphological changes in cultured skin cells. These data indicate that dermal exposure to unrefined SWCNT may lead to dermal toxicity due to accelerated oxidative stress in the skin of exposed workers.

Keratinocytes/drug effects↗
NASA NTRS1993

Three distinct cell phenotypes of induced-TNF cytotoxicity and their relationship to apoptosis

We have identified three distinct cell phenotypes with respect to the conditions under which cells became susceptible to TNF-mediated lysis. These conditions include: 1) treatment with the protein synthesis inhibitor, cycloheximide; 2) contact with activated macrophages, and 3) infection with vaccinia virus. Whereas vaccinia virus-infected 3T3 cells became sensitive to soluble TNF, F5b cells required contact with activated macrophages. We showed that the "macrophage-resistant" F5m cells did not become sensitive to TNF or to killing by activated macrophages after infection with vaccinia virus. Therefore, vaccinia infection does not sensitize all cells to TNF. We also determined the pathways of lysis for cells after sensitization. Whereas 3T3, LM929, and F5b cells were killed by the process of necrosis, F5m cells lysis was characterized by the release of low mol wt DNA fragments (apoptosis).

Non-NASA Center↗