Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We sought to know whether hypertonic (7%) saline (HTS) attenuates brain injury by improving cerebral perfusion pressure (CPP) and down-modulating acute inflammatory responses in experimental bacterial meningitis in the newborn piglet. Twenty-five newborn piglets were assorted into three groups: 6 in the control group (C), 10 in the meningitis group (M), and 9 in the meningitis with HTS infusion group (H). Meningitis was induced by intracisternal injection of 10(8) colony forming units of Escherichia coli in 100 microL of saline. 10 mL/kg of HTS was given intravenously as a bolus 6 hr after induction of meningitis, thereafter the infusion rate was adjusted to maintain the serum sodium level between 150 and 160 mEq/L. HTS significantly attenuated meningitis-induced brain cell membrane disintegration and dysfunction, as indicated by increased lipid peroxidation products and decreased Na+, K+-ATPase activity in the cerebral cortex in M. HTS significantly attenuated acute inflammatory markers such as increased intracranial pressure, elevated lactate level and pleocytosis in the cerebrospinal fluid observed in M. Reduced CPP observed in M was also significantly improved with HTS infusion. These findings implicate some attenuation of the meningitis-induced alterations in cerebral cortical cell membrane structure and function with HTS, possibly by improving CPP and attenuating acute inflammatory responses.
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PMID:Effects of hypertonic (7%) saline on brain injury in experimental Escherichia coli meningitis. 1622 65

In this study we describe a simplified, HTS-capable functional assay for the multidrug resistance (MDR) transporter P-glycoprotein (P-gp) based on its substrate Hoechst 33342. The physicochemical properties of Hoechst 33342 and the enormous milieu dependency of its fluorescence intensity allowed performing the assay in a homogeneous manner. This new assay served as an effective tool to estimate the potency of 10 well recognized P-gp substrates and modulators. Further, the potency of these compounds was also estimated in the calcein AM assay. The Hoechst 33342 and calcein AM assays yielded significantly comparable results for all compounds tested. Principal component analysis (PCA) applied to literature data on inhibition of P-gp activity and our results obtained in the Hoechst 33342 and calcein AM assay indicated similarity of compared functional transport assays. However, no correlation could be detected between these functional assays and the ATPase activity assay.
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PMID:New functional assay of P-glycoprotein activity using Hoechst 33342. 1789 94

Human Na+, K+ ATPase, an ATP-driven ion transporter, is an emerging drug target for heart-related conditions. Three types of assays including purified enzyme, radiotracer flux, and cold Rb+ flux have been used to determine the activity of this transporter. As an alternative to primary cardiomyocytes, mouse embryonic stem cells-derived cardiomyocytes with functional expression of essential cardiac ion channels were used in the present studies. The results on its pharmacology with digitoxin and ouabain, the 2 well-known cardioglycosides, imply that these cardiomyocytes can be used as a predictive model for the identification of modulators of Na+, K+ ATPase in HTS format.
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PMID:Validation of a Rb+ uptake assay for the mouse embryonic stem cell-derived cardiomyocytes Na+, K+ ATPase. 2015 37

Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.
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PMID:Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships. 2324 11

To discover more potent p97 inhibitors, we carried out a structure-activity relationship study of the quinazoline scaffold previously identified from our HTS campaigns. Two improved inhibitors, ML240 and ML241, inhibit p97 ATPase with IC(50) values of 100 nM. Both compounds inhibited degradation of a p97-dependent but not a p97-independent proteasome substrate in a dual-reporter cell line. They also impaired the endoplasmic-reticulum-associated degradation (ERAD) pathway. Unexpectedly, ML240 potently stimulated accumulation of LC3-II within minutes, inhibited cancer cell growth, and rapidly mobilized the executioner caspases 3 and 7, whereas ML241 did not. The behavior of ML240 suggests that disruption of the protein homeostasis function of p97 leads to more rapid activation of apoptosis than is observed with a proteasome inhibitor. Further characterization revealed that ML240 has broad antiproliferative activity toward the NCI-60 panel of cancer cell lines, but slightly lower activity toward normal cells. ML240 also synergizes with the proteasome inhibitor MG132 to kill multiple colon cancer cell lines. Meanwhile, both probes have low off-target activity toward a panel of protein kinases and central nervous system targets. Our results nominate ML240 as a promising starting point for the development of a novel agent for the chemotherapy of cancer, and provide a rationale for developing pathway-specific p97 inhibitors.
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PMID:Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase. 2331 25

Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.
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PMID:Discovery of 2-(cyclohexylmethylamino)pyrimidines as a new class of reversible valosine containing protein inhibitors. 2547 26