Verification Of Two Novel Phytochemical Inducers Of Phase Ii Metabolic Enzyme NQOI In Human Lung Cells

2011 ◽  
Author(s):  
Simon D. Spivack ◽  
Gaby Marquardt ◽  
Xianglin Tan
Keyword(s):  
Phase Ii ◽  
Human Lung ◽  
Metabolic Enzyme ◽  
Lung Cells ◽  
Human Lung Cells

scholarly journals Candidate Dietary Phytochemicals Modulate Expression of Phase II Enzymes GSTP1 and NQO1 in Human Lung Cells

2010 ◽  
Vol 140 (8) ◽  
pp. 1404-1410 ◽  
Author(s):  
Xiang-Lin Tan ◽  
Miao Shi ◽  
Hui Tang ◽  
Weiguo Han ◽  
Simon D. Spivack
Keyword(s):  
Phase Ii ◽  
Human Lung ◽  
Lung Cells ◽  
Phase Ii Enzymes ◽  
Human Lung Cells ◽  
Dietary Phytochemicals

scholarly journals Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells

2021 ◽  
Author(s):  
Ruidong Li ◽  
Albert Liclican ◽  
Yili Xu ◽  
Jared Pitts ◽  
Congrong Niu ◽  
...  
Keyword(s):  
Enzyme Inhibitors ◽  
Human Lung ◽  
Bioinformatic Analysis ◽  
Metabolic Enzyme ◽  
Nucleoside Triphosphate ◽  
Target Cells ◽  
Lung Cells ◽  
Human Lung Tissue ◽  
Key Enzymes ◽  
Human Lung Cells

Remdesivir (RDV; GS-5734; Veklury®), the first FDA-approved antiviral to treat COVID-19, is a single diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV is taken up in the target cells and metabolized in multiple steps to form the active nucleoside triphosphate (TP) (GS-443902), which in turn acts as a potent and selective inhibitor of multiple viral RNA polymerases. In this report, we profiled the key enzymes involved in the RDV metabolic pathway with multiple parallel approaches: (1) bioinformatic analysis of nucleoside/tide metabolic enzyme mRNA expression using public human tissue and lung single-cell RNAseq datasets; (2) protein and mRNA quantification of enzymes in human lung tissue and primary lung cells; (3) biochemical studies on the catalytic rate of key enzymes; (4) effects of specific enzyme inhibitors on the GS-443902 formation; and (5) the effects of these inhibitors on RDV antiviral activity against SARS-CoV-2 in cell culture. Our data collectively demonstrated that carboxylesterase 1 (CES1) and cathepsin A (CatA) are enzymes involved in hydrolyzing RDV to its alanine intermediate Met X, which is further hydrolyzed to the monophosphate form by histidine triad nucleotide-binding protein 1 (HINT1). The monophosphate is then consecutively phosphorylated to diphosphate and triphosphate by cellular phosphotransferases. Our data support the hypothesis that the unique properties of RDV prodrug not only allow lung-specific accumulation critical for the treatment of respiratory viral infection such as COVID-19, they also enable efficient intracellular metabolism of RDV and its Met X to monophosphate and successive phosphorylation to form the active TP in disease-relevant cells.

scholarly journals RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells

2021 ◽  
Author(s):  
Taisho Yamada ◽  
Seiichi Sato ◽  
Yuki Sotoyama ◽  
Yasuko Orba ◽  
Hirofumi Sawa ◽  
...  
Keyword(s):  
Human Lung ◽  
Lung Cells ◽  
Human Lung Cells

scholarly journals Polyphosphate Reverses the Toxicity of the Quasi-Enzyme Bleomycin on Alveolar Endothelial Lung Cells In Vitro

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 750
Author(s):  
Werner E. G. Müller ◽  
Meik Neufurth ◽  
Shunfeng Wang ◽  
Heinz C. Schröder ◽  
Xiaohong Wang
Keyword(s):  
Dna Damage ◽  
Human Lung ◽  
Dna Integrity ◽  
Lung Cells ◽  
Antitumor Antibiotic ◽  
Cell Toxicity ◽  
Inorganic Polyphosphate ◽  
Human Lung Cells ◽  
Anti Cancer

The anti-cancer antitumor antibiotic bleomycin(s) (BLM) induces athyminic sites in DNA after its activation, a process that results in strand splitting. Here, using A549 human lung cells or BEAS-2B cells lunc cells, we show that the cell toxicity of BLM can be suppressed by addition of inorganic polyphosphate (polyP), a physiological polymer that accumulates and is released from platelets. BLM at a concentration of 20 µg ml−1 causes a decrease in cell viability (by ~70%), accompanied by an increased DNA damage and chromatin expansion (by amazingly 6-fold). Importantly, the BLM-caused effects on cell growth and DNA integrity are substantially suppressed by polyP. In parallel, the enlargement of the nuclei/chromatin in BLM-treated cells (diameter, 20–25 µm) is normalized to ~12 µm after co-incubation of the cells with BLM and polyP. A sequential application of the drugs (BLM for 3 days, followed by an exposure to polyP) does not cause this normalization. During co-incubation of BLM with polyP the gene for the BLM hydrolase is upregulated. It is concluded that by upregulating this enzyme polyP prevents the toxic side effects of BLM. These data might also contribute to an application of BLM in COVID-19 patients, since polyP inhibits binding of SARS-CoV-2 to cellular ACE2.

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