Publications by authors named "Paul Meister"

7 Publications

  • Page 1 of 1

Antagonizing binding of cell cycle and apoptosis regulatory protein 1 (CARP-1) to the NEMO/IKKγ protein enhances the anticancer effect of chemotherapy.

J Biol Chem 2020 03 4;295(11):3532-3552. Epub 2020 Feb 4.

John D. Dingell Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Department of Oncology, Wayne State University, Detroit, Michigan 48201. Electronic address:

NF-κB is a pro-inflammatory transcription factor that critically regulates immune responses and other distinct cellular pathways. However, many NF-κB-mediated pathways for cell survival and apoptosis signaling in cancer remain to be elucidated. Cell cycle and apoptosis regulatory protein 1 (CARP-1 or CCAR1) is a perinuclear phosphoprotein that regulates signaling induced by anticancer chemotherapy and growth factors. Although previous studies have reported that CARP-1 is a part of the NF-κB proteome, regulation of NF-κB signaling by CARP-1 and the molecular mechanism(s) involved are unclear. Here, we report that CARP-1 directly binds the NF-κB-activating kinase IκB kinase subunit γ (NEMO or NF-κB essential modulator) and regulates the chemotherapy-activated canonical NF-κB pathway. Importantly, blockade of NEMO-CARP-1 binding diminished NF-κB activation, indicated by reduced phosphorylation of its subunit p65/RelA by the chemotherapeutic agent adriamycin (ADR), but not NF-κB activation induced by tumor necrosis factor α (TNFα), interleukin (IL)-1β, or epidermal growth factor. High-throughput screening of a chemical library yielded a small molecule inhibitor of NEMO-CARP-1 binding, termed selective NF-κB inhibitor 1 (SNI)-1). We noted that SNI-1 enhances chemotherapy-dependent growth inhibition of a variety of cancer cells, including human triple-negative breast cancer (TNBC) and patient-derived TNBC cells , and attenuates chemotherapy-induced secretion of the pro-inflammatory cytokines TNFα, IL-1β, and IL-8. SNI-1 also enhanced ADR or cisplatin inhibition of murine TNBC tumors and reduced systemic levels of pro-inflammatory cytokines. We conclude that inhibition of NEMO-CARP-1 binding enhances responses of cancer cells to chemotherapy.
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http://dx.doi.org/10.1074/jbc.RA119.009898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076213PMC
March 2020

Multiscale Computational Study on the Catalytic Mechanism of the Nonmetallo Amidase Maleamate Amidohydrolase (NicF).

J Phys Chem A 2019 Sep 3;123(36):7710-7719. Epub 2019 Sep 3.

Department of Chemistry and Biochemistry , University of Windsor , Windsor , Ontario N9B 3P4 , Canada.

Maleamate amidohydrolase (NicF) is a key enzyme in vitamin B metabolism that catalyzes the hydrolysis of maleamate to produce maleic acid and ammonia. Unlike most members from the amidohydrolase superfamily it does not require a metal ion. Here, we use multiscale computational enzymology to investigate the catalytic mechanism, substrate binding, oxyanion hole, and roles of key active site residues of NicF from . In particular, molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM) and QTAIM methods have been applied. The mechanism of the NicF-catalyzed reaction proceeds by a nucleophilic addition-elimination sequence involving the formation of a thioester enzyme intermediate ( in stage 1) followed by hydrolysis of the thioester bond to form the products (stage 2). Consequently, the formation of in stage 1 is the rate-limiting step with a barrier of 88.8 kJ·mol relative to the reactant complex, . Comparisons with related metal-dependent enzymes, particularly the zinc-dependent nicotinamidase from (SpNic), have also been made to further illustrate unique features of the present mechanism. Along with -NH- donor groups of the oxyanion hole (i.e., HN-Thr146, HN-Cys150), the active site β-hydroxyl of threonine (HO-βThr146) is concluded to play a role in stabilizing the carbonyl oxygen of maleamate during the mechanism.
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http://dx.doi.org/10.1021/acs.jpca.9b05914DOI Listing
September 2019

The K(9-ethylguanine) quadruplex is more stable to unimolecular dissociation than the K(9-ethylguanine) quadruplex in the gas phase: a BIRD, energy resolved SORI-CID, IRMPD spectroscopic, and computational study.

Phys Chem Chem Phys 2019 Jul;21(28):15319-15326

Department of Chemistry, Memorial University of Newfoundland, St. John's, NL, Canada.

A combination of experimental trapped-ion mass spectrometric studies and computational chemistry has been used in the present work to assess the intrinsic properties of the potassiated 9-ethylguanine (9eG) self-assembled quadruplex, K2(9eG)122+, in the gas phase. Infrared multiple photon dissociation (IRMPD) spectroscopy in the N-H/C-H stretching region (2700-3800 cm-1) revealed that this G-quadruplex is a sandwich-type structure with two G-tetrads sandwiching each of the two K+, very similar to the structure determined previously for the K(9eG)8+ complexes. The stability of K2(9eG)122+ toward unimolecular dissociation and its binding energy were examined using energy-resolved sustained off-resonance collision induced dissociation (SORI-CID) and blackbody infrared radiative dissociation (BIRD) kinetics experiments. SORI-CID experiments showed that the self-assembled K2(9eG)122+ complex undergoes charge separation forming K(9eG)8+ and K(9eG)4+ compared to K(9eG)8+ which loses neutral 9eG. More interestingly, K2(9eG)122+ is more stable toward unimolecular dissociation activated by SORI-CID than the K(9eG)8+ complex. Temperature dependent BIRD kinetics for K2(9eG)122+ were consistent with energy-resolved SORI-CID results showing K2(9eG)122+ to have an activation energy of 225 ± 15 kJ mol-1, approximately 50 kJ mol-1 greater than that determined for K(9eG)8+. The extra stability of K2(9eG)122+ is apparently not thermodynamic stability, but most likely due to an energy barrier for dissociation.
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http://dx.doi.org/10.1039/c9cp01651aDOI Listing
July 2019

A H2AX⁻CARP-1 Interaction Regulates Apoptosis Signaling Following DNA Damage.

Cancers (Basel) 2019 Feb 14;11(2). Epub 2019 Feb 14.

John D. Dingell Veterans Administration Medical Center, Detroit, MI 48201, USA.

Cell Cycle and Apoptosis Regulatory Protein (CARP-1/CCAR1) is a peri-nuclear phosphoprotein that regulates apoptosis via chemotherapeutic Adriamycin (doxorubicin) and a novel class of CARP-1 functional mimetic (CFM) compounds. Although Adriamycin causes DNA damage, data from Comet assays revealed that CFM-4.16 also induced DNA damage. Phosphorylation of histone 2AX (γH2AX) protein is involved in regulating DNA damage repair and apoptosis signaling. Adriamycin or CFM-4.16 treatments inhibited cell growth and caused elevated CARP-1 and γH2AX in human breast (HBC) and cervical cancer (HeLa) cells. In fact, a robust nuclear or peri-nuclear co-localization of CARP-1 and γH2AX occurred in cells undergoing apoptosis. Knock-down of CARP-1 diminished γH2AX, their co-localization, and apoptosis in CFM-4.16- or Adriamycin-treated cells. We found that CARP-1 directly binds with H2AX, and H2AX interacted with CARP-1, but not CARP-1 (Δ600⁻652) mutant. Moreover, cells expressing CARP-1 (Δ600⁻652) mutant were resistant to apoptosis, and had diminished levels of γH2AX, when compared with cells expressing wild-type CARP-1. Mutagenesis studies revealed that H2AX residues 1⁻35 harbored a CARP-1-binding epitope, while CARP-1 amino acids 636⁻650 contained an H2AX-interacting epitope. Surface plasmon resonance studies revealed that CARP-1 (636⁻650) peptide bound with H2AX (1⁻35) peptide with a dissociation constant (K) of 127 nM. Cells expressing enhanced GFP (EGFP)-tagged H2AX (1⁻35) peptide or EGFP-tagged CARP-1 (636⁻650) peptide were resistant to inhibition by Adriamycin or CFM-4.16. Treatment of cells with transactivator of transcription (TAT)-tagged CARP-1 (636⁻650) peptide resulted in a moderate, statistically significant abrogation of Adriamycin-induced growth inhibition of cancer cells. Our studies provide evidence for requirement of CARP-1 interaction with H2AX in apoptosis signaling by Adriamycin and CFM compounds.
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http://dx.doi.org/10.3390/cancers11020221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406907PMC
February 2019

An Assessment of Computational Methods for Calculating Accurate Structures and Energies of Bio-Relevant Polysulfur/Selenium-Containing Compounds.

Molecules 2018 Dec 14;23(12). Epub 2018 Dec 14.

Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada.

The heavier chalcogens sulfur and selenium are important in organic and inorganic chemistry, and the role of such chalcogens in biological systems has recently gained more attention. Sulfur and, to a lesser extent selenium, are involved in diverse reactions from redox signaling to antioxidant activity and are considered essential nutrients. We investigated the ability of the DFT functionals (B3LYP, B3PW91, ωB97XD, M06-2X, and M08-HX) relative to electron correlation methods MP2 and QCISD to produce reliable and accurate structures as well as thermochemical data for sulfur/selenium-containing systems. Bond lengths, proton affinities (PA), gas phase basicities (GPB), chalcogen⁻chalcogen bond dissociation enthalpies (BDE), and the hydrogen affinities (HA) of thiyl/selenyl radicals were evaluated for a range of small polysulfur/selenium compounds and cysteine per/polysulfide. The S⁻S bond length was found to be the most sensitive to basis set choice, while the geometry of selenium-containing compounds was less sensitive to basis set. In mixed chalcogens species of sulfur and selenium, the location of the sulfur atom affects the S⁻Se bond length as it can hold more negative charge. PA, GPB, BDE, and HA of selenium systems were all lower, indicating more acidity and more stability of radicals. Extending the sulfur chain in cysteine results in a decrease of BDE and HA, but these plateau at a certain point (199 kJ mol and 295 kJ mol), and PA and GPB are also decreased relative to the thiol, indicating that the polysulfur species exist as thiolates in a biological system. In general, it was found that ωB97XD/6-311G(2d,p) gave the most reasonable structures and thermochemistry relative to benchmark calculations. However, nuances in performance are observed and discussed.
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http://dx.doi.org/10.3390/molecules23123323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320821PMC
December 2018

Anodic Behavior of the Aluminum Current Collector in Imide-Based Electrolytes: Influence of Solvent, Operating Temperature, and Native Oxide-Layer Thickness.

ChemSusChem 2017 02 27;10(4):804-814. Epub 2017 Jan 27.

University of Münster, MEET Battery Research Center, Institute of Physical Chemistry, Corrensstraße 46, 48149, Münster, Germany.

The inability of imide salts to form a sufficiently effective passivation layer on aluminum current collectors is one of the main obstacles that limit their broad application in electrochemical energy-storage systems. However, under certain circumstances, the use of electrolytes with imide electrolyte salts in combination with the aluminum current collector is possible. In this contribution, the stability of the aluminum current collector in electrolytes containing either lithium bis(trifluoromethanesulfonyl) imide (LiTFSI) or lithium fluorosulfonyl-(trifluoromethanesulfonyl) imide (LiFTFSI) as conductive salt was investigated by electrochemical techniques, that is, cyclic voltammetry (CV) and chronocoulometry (CC) in either room-temperature ionic liquids or in ethyl methyl sulfone. In particular, the influence of the solvent, operating temperature, and thickness of the native oxide layer of aluminum on the pit formation at the aluminum current collector surface was studied by means of scanning electron microscopy. In general, a more pronounced aluminum dissolution and pit formation was found at elevated temperatures as well as in solvents with a high dielectric constant. An enhanced thickness of the native aluminum oxide layer increases the oxidative stability versus dissolution. Furthermore, we found a different reaction rate depending on dwell time at the upper cut-off potential for aluminum dissolution in TFSI- and FTFSI-based electrolytes during the CC measurements; the use of LiFTFSI facilitated the dissolution of aluminum compared to LiTFSI. Overall, the mechanism of anodic aluminum dissolution is based on: i) the attack of the Al O surface by acidic species and ii) the dissolution of bare aluminum into the electrolyte, which, in turn, is influenced by the electrolyte's dielectric constant.
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http://dx.doi.org/10.1002/cssc.201601636DOI Listing
February 2017

Investigation of PF6(-) and TFSI(-) anion intercalation into graphitized carbon blacks and its influence on high voltage lithium ion batteries.

Phys Chem Chem Phys 2014 Dec 22;16(46):25306-13. Epub 2014 Oct 22.

MEET Battery Research Center, Institute of Physical Chemistry, University of Muenster, Corrensstraße 46, 48149 Muenster, Germany.

Graphitized carbon blacks have shown a more promising electrochemical performance than the non-treated ones when being applied in small amounts as conductive additives in composite cathode electrodes for lithium ion batteries, due to the absence of surface functional groups which contribute to detrimental side-reactions with the electrolyte. Here, we report that at high potentials of >4.5 V vs. Li/Li(+), graphitic structures in carbon black can provide host sites for the partially reversible intercalation of electrolyte salt anions. This process is in analogy to the charge reaction of graphite positive electrodes in dual-ion cells. A standard furnace carbon black with small graphitic structural units, as well as slightly and highly graphitized carbon blacks, were characterized and analyzed with regard to anion intercalation. A LiPF6 containing organic solvent based electrolyte as well as a state-of-the-art ionic liquid based electrolyte composed of LiTFSI in PYR14TFSI were applied. The intercalation of both PF6(-) and TFSI(-) could be confirmed by cyclic voltammetry in electrodes made of carbon blacks. When exposed to high potentials, carbon blacks experienced strong activation in the 1st cycle, which promotes the perception for anion intercalation, and thus increases the anion intercalation capacity in the following cycles. The specific capacity from anion intercalation was evaluated by constant current charge-discharge cycling. The obtained capacity was proportional to the graphitization degree. As anion intercalation might be accompanied by decomposition reactions of the electrolyte, e.g., by co-intercalation of solvent molecules, it could induce the decomposition of the electrolyte inside the carbon and thus degradation of the carbon black graphitic structure. In order to avoid side reactions from surface groups and from anion intercalation, the thermal treatment of carbon blacks must be optimized.
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http://dx.doi.org/10.1039/c4cp04113eDOI Listing
December 2014
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