- |||||||||| Compound C inhibits metabolic programming of ovarian cancer (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_1221;
However, it significantly decreased the ratio of mitochondrial oxygen consumption rate to glycolytic proton efflux rate (mitoOCR/glycoPER), indicating a direct inhibitory effect of Compound C on mitochondrial electron transport chain and a bioenergetic shift from oxidative phosphorylation towards glycolysis. These results demonstrate for the first time, the direct inhibitory effect of Compound C on mitochondrial function as a novel mechanism of inhibition of the malignant phenotype of ovarian cancer cells.
- |||||||||| [VIRTUAL] Tyrosine Kinase Inhibitors (TKIs) Targeting Syk and BTK Signaling Differentially Affect PI3K Organization and Inhibit Platelet Function (Virtual Meeting Room 6) - May 14, 2020 - Abstract #ISTH2020ISTH_1389;
Aims: Determine the effects of 12 Syk and BTK inhibitors (Bay 61-3606, R406/fostamatinib, entospletinib, TAK-659, ibrutinib, acalabrutinib, ONO-4059/tirabrutinib, AVL-292/spebrutinib, CG' 806, BMS-935, BMS-986, fenebrutinib) on platelet functional responses. Clinically utilized TKIs targeting Syk and BTK inhibit platelet functional responses and differentially alter PI3K signaling and organization.
- |||||||||| Journal: Reversible dimerization of cytochrome c oxidase regulates mitochondrial respiration. (Pubmed Central) - May 9, 2020
Increased intracellular calcium, as a consequence of stress, dephosphorylates and monomerises CytOx, whereas cAMP rephosphorylates and dimerises it. Only dimeric CytOx exhibits an "allosteric ATP-inhibition" which inhibits respiration at high cellular ATP/ADP-ratios and could prevent oxygen radical formation and the generation of diseases.
- |||||||||| Journal: Structure of F-ATPase from the obligate anaerobe Fusobacterium nucleatum. (Pubmed Central) - Apr 30, 2020
The β-subunits in all three enzymes are in the conventional 'open' state, and in the case of C. thermarum and M. smegmatis, they are occupied by an ADP and phosphate (or sulfate), but in F. nucleatum, the occupancy by ADP appears to be partial. It is likely that the hydrolytic activity of the F. nucleatum enzyme is regulated by the concentration of ADP, as in mitochondria.
- |||||||||| Journal: Dodecameric structure of a small Heat Shock Protein from Mycobacterium marinum M. (Pubmed Central) - Apr 22, 2020
Hydrophobic and hydrogen bond interactions stabilise the peptide at this interface and provide important insights into the mode of sHSP-substrate interaction. Further, it was observed that in the presence of ATP, the protein undergoes conformational changes leading to a reduction in its molecular chaperoning activity.
- |||||||||| Journal: Pharmacological evaluation of dotinurad, a selective urate reabsorption inhibitor. (Pubmed Central) - Apr 22, 2020
Dotinurad had no effect on urate secretion transporters in vivo, whereas benzbromarone, lesinurad, probenecid, and febuxostat increased the plasma concentrations of probe substrates...Dotinurad had no effect on these urate secretion transporters in vivo, whereas the other uricosuric agents increased the plasma concentrations of the probe substrates. These results suggested dotinurad as a potent and selective urate reabsorption inhibitor (SURI), is characterized by increased efficacy with decreasing plasma urate levels compared to the other uricosuric agents studied.
- |||||||||| Journal: Metabolic requirements of Besnoitia besnoiti tachyzoite-triggered NETosis. (Pubmed Central) - Apr 12, 2020
Moreover, a significant reduction of tachyzoite-induced NET formation was also achieved by treatments with oligomycin A (inhibitor of ATP synthase) and NF449 (purinergic receptor P2X antagonist) thereby suggesting a pivotal role of ATP availability for tachyzoite-mediated NETosis. In summary, the current data provide first evidence on carbohydrate-related metabolic pathways and energy supply to be involved in B. besnoiti tachyzoite-induced NETosis.
- |||||||||| Journal: Structure of a bacterial ATP synthase. (Pubmed Central) - Apr 5, 2020
The architecture of the membrane region shows how the simple bacterial ATP synthase is able to perform the same core functions as the equivalent, but more complicated, mitochondrial complex. The structures reveal the path of transmembrane proton translocation and provide a model for understanding decades of biochemical analysis interrogating the roles of specific residues in the enzyme.
- |||||||||| bleomycin / Generic mfg., BMS
Journal: The regulation of skin fibrosis in systemic sclerosis by extracellular ATP via P2Y purinergic receptor. (Pubmed Central) - Apr 4, 2020 These results suggest that vasculopathy-induced hypoxia and oxidative stress might enhance ATP release in the dermis in SSc, and extracellular ATP-induced phosphorylation of p38 via P2Y receptor might enhance IL-6 and collagen type I production in SSc fibroblasts. P2Y receptor antagonists therapy could be a treatment for skin sclerosis in patients with SSc.
- |||||||||| Journal: Extrinsic conditions influence the self-association and structure of IF, the regulatory protein of mitochondrial ATP synthase. (Pubmed Central) - Mar 29, 2020
Therefore, we investigated the influence of pH and salt-types on the self-association of bovine IF and the folding of its unfolded region. We identified the equilibrium between dimers and tetramers as a potential central factor in the in vivo modulation of the inhibitory activity and suggest that the intrinsically disordered region makes its inhibitory potency exquisitely sensitive and responsive to physiological changes that influence the capability of mitochondria to make ATP.
- |||||||||| Journal: Novel approach for quantification of endoplasmic reticulum Ca transport. (Pubmed Central) - Mar 18, 2020
After ventricular myocyte isolation, the same methodology used in HEK293 cells was applied to study endogenous SERCA2a. In conclusion, this new approach can be used as a sensitive screening tool to study effect of different drugs, post-translational modifications and mutations on SERCA function.
- |||||||||| Journal: Reversal Effect of ALK Inhibitor NVP-TAE684 on ABCG2-Overexpressing Cancer Cells. (Pubmed Central) - Mar 17, 2020
Molecular in silico analysis showed that NVP-TAE684 interacts with the substrate binding sites of the ABCG2 transporter. Taken together, our study indicates that NVP-TAE684 could reduce the resistance of MDR cells to chemotherapeutic agents, which provides a promising strategy to overcome MDR.
- |||||||||| chloroquine phosphate / Generic mfg.
Chloroquine Is a Potent Pulmonary Vasodilator and Attenuates Hypoxia-Induced Pulmonary Hypertension (PENNSYLVANIA CONVENTION CENTER, Hall D-E (200 Level), Area D) - Mar 15, 2020 - Abstract #ATS2020ATS_7262; Chloroquine is a potent vasodilator of PA and a potential blocker of VDCC, store-operated Ca2+ channels and receptor-operated Ca2+ channels in PASMCs. The therapeutic potential of chloroquine on pulmonary hypertension is likely due to the combination of its vasodilative, anti-proliferative and anti-autophagic effects.
- |||||||||| Journal: Locally-Induced CaMKII Translocation Requires Nucleotide Binding. (Pubmed Central) - Mar 3, 2020
However, expression of the catalytically dead K42M mutation that prevents ATP-binding to CaMKII, significantly inhibited locally-induced translocation. Thus, CaMKII translocation following brief, local glutamate application requires nucleotide binding, providing support for future research into the molecular mechanisms of this distinct form of CaMKII translocation.
- |||||||||| Nexletol (bempedoic acid) / Esperion Therap
Journal: Bempedoic acid: effects on lipoprotein metabolism and atherosclerosis. (Pubmed Central) - Feb 24, 2020 The LDL-C-lowering and attenuated atherosclerosis in animal models and reduced LDL-C in hypercholesterolemic patients has validated ACLY inhibition as a therapeutic strategy. Positive results from phase 3 long-term cardiovascular outcome trials in high-risk patients are required for bempedoic acid to be approved for prevention of atherosclerosis.
- |||||||||| Journal: Marie-Joelle Virolle. (Pubmed Central) - Feb 21, 2020
Type II antibiotics inhibit respiration through different strategies, to reduce ATP generation in conditions of low phosphate availability. Lastly, Type III antibiotics that are known to inhibit ATP consuming anabolic processes contribute to ATP saving in conditions of phosphate starvation.
- |||||||||| Preclinical, Journal: Rhein inhibits ATP-triggered inflammatory responses in rheumatoid rat fibroblast-like synoviocytes. (Pubmed Central) - Feb 15, 2020
Both rhein and BBG attenuated these inflammatory gene expressions enhanced by ATP. Above data together suggested a potential anti-arthritic role of rhein by inhibiting ATP-induced [Ca] increase, ROS production and inflammatory gene expression targeting P2X in CIA rat synoviocytes, which will provide a novel insight in the therapy of RA.
- |||||||||| Journal: Migration of Small Ribosomal Subunits on the 5' Untranslated Regions of Capped Messenger RNA. (Pubmed Central) - Feb 14, 2020
Impeding scanning through the 5'UTR in this system with elevated magnesium and AMP-PNP (similar to the toeprinting conditions), we visualised assemblies consisting of several SSUs together with one full ribosome by electron microscopy, suggesting direct detection of scanning intermediates. Collectively, our data provide additional biochemical, molecular and physical evidence to underpin the scanning model of translation initiation in eukaryotes.
- |||||||||| Journal: Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca. (Pubmed Central) - Feb 1, 2020
Furthermore, the ATP level in the ER is readily depleted by oxidative phosphorylation (OxPhos) inhibitors and that ER protein misfolding increases ATP uptake from mitochondria into the ER. These findings suggest that ATP usage in the ER may increase mitochondrial OxPhos while decreasing glycolysis, i.e., an 'anti-Warburg' effect.
- |||||||||| Journal: Modeling Host-Pathogen Interaction to Elucidate the Metabolic Drug Response of Intracellular Mycobacterium tuberculosis. (Pubmed Central) - Jan 28, 2020
Notably, the effect of eight could be recreated and two major profiles of the metabolic state were predicted. The profiles of the metabolic states of Mtb affected by the drugs BTZ043, cycloserine and its derivative terizidone, ethambutol, ethionamide, propionamide, and isoniazid were very similar, while TMC207 is predicted to have quite a different effect on metabolism as it inhibits ATP synthase and therefore indirectly interferes with a multitude of metabolic pathways.
- |||||||||| Journal: ATP-binding affinity of the ε subunit of thermophilic F-ATPase under label-free conditions. (Pubmed Central) - Jan 16, 2020
In this report, to determine the affinity for ATP under label-free conditions, we have measured the competitive displacement of 2'(3')-O-N'-methylaniloyl-aminoadenosine-5'-triphosphate (Mant-ATP), a fluorescent analog of ATP, by ATP. The dissociation constant for ATP of wild-type ε subunit of TF at 25 °C was determined to be 0.29 μM, which is one order of magnitude higher affinity than previously reported values.
- |||||||||| Journal: GLI1-inducible glucuronidation targets a broad spectrum of drugs. (Pubmed Central) - Dec 20, 2019
Here, we demonstrate that GLI1 imparts resistance to ∼40 compounds, including FDA-approved drugs with disparate chemotypes ( e.g., methotrexate and venetoclax)...Further, we demonstrate that resistant cells are more sensitive to ATP inhibitors suggesting an Achilles' heel which could be exploited in future. In all, we identify GLI1-inducible glucuronidation as a broad-spectrum multi-drug resistance pathway.
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