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Histone deacetylase inhibitor enhances recovery after AKI.
Cianciolo Cosentino C, Skrypnyk NI, Brilli LL, Chiba T, Novitskaya T, Woods C, West J, Korotchenko VN, McDermott L, Day BW, Davidson AJ, Harris RC, de Caestecker MP, Hukriede NA
(2013) J Am Soc Nephrol 24: 943-53
MeSH Terms: Acute Kidney Injury, Animals, Disease Models, Animal, Fibrosis, Gentamicins, Histone Deacetylase 1, Histone Deacetylase Inhibitors, Ischemia, Kidney, Male, Mice, Mice, Inbred BALB C, Phenylbutyrates, Protein Synthesis Inhibitors, Recovery of Function, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 10, 2014
At present, there are no effective therapies to ameliorate injury, accelerate recovery, or prevent postinjury fibrosis after AKI. Here, we sought to identify candidate compounds that accelerate recovery after AKI by screening for small molecules that increase proliferation of renal progenitor cells in zebrafish embryos. One compound identified from this screen was the histone deacetylase inhibitor methyl-4-(phenylthio)butanoate, which we subsequently administered to zebrafish larvae and mice 24-48 hours after inducing AKI. In zebrafish, treatment with the compound increased larval survival and proliferation of renal tubular epithelial cells. In mice, treatment accelerated recovery, reduced postinjury tubular atrophy and interstitial fibrosis, and increased the regenerative capacity of actively cycling renal tubular cells by decreasing the number of cells in G2/M arrest. These data suggest that accelerating recovery may be a viable approach to treating AKI and provide proof of concept that a screen in zebrafish embryos can identify therapeutic candidates for kidney injury.
2 Communities
2 Members
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17 MeSH Terms
Discovery of a series of 2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K(v)7.2 (KCNQ2) channel pharmacology: identification of (S)-2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide (ML252) as a potent, brain penetrant K(v)7.2 channel inhibitor.
Cheung YY, Yu H, Xu K, Zou B, Wu M, McManus OB, Li M, Lindsley CW, Hopkins CR
(2012) J Med Chem 55: 6975-9
MeSH Terms: Animals, Brain, Databases, Factual, High-Throughput Screening Assays, Humans, KCNQ2 Potassium Channel, Microsomes, Liver, Permeability, Phenylbutyrates, Potassium Channel Blockers, Pyrrolidines, Rats, Small Molecule Libraries, Stereoisomerism, Structure-Activity Relationship
Show Abstract · Added March 7, 2014
A potent and selective inhibitor of KCNQ2, (S)-5 (ML252, IC(50) = 69 nM), was discovered after a high-throughput screen of the MLPCN library was performed. SAR studies revealed a small structural change (ethyl group to hydrogen) caused a functional shift from antagonist to agonist activity (37, EC(50) = 170 nM), suggesting an interaction at a critical site for controlling gating of KCNQ2 channels.
1 Communities
1 Members
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15 MeSH Terms
ERp29 regulates DeltaF508 and wild-type cystic fibrosis transmembrane conductance regulator (CFTR) trafficking to the plasma membrane in cystic fibrosis (CF) and non-CF epithelial cells.
Suaud L, Miller K, Alvey L, Yan W, Robay A, Kebler C, Kreindler JL, Guttentag S, Hubbard MJ, Rubenstein RC
(2011) J Biol Chem 286: 21239-53
MeSH Terms: Animals, Biotinylation, Cell Membrane, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Electrophysiology, Endoplasmic Reticulum, Epithelial Cells, Heat-Shock Proteins, Humans, Ions, Oocytes, Phenylbutyrates, Protein Transport, Xenopus
Show Abstract · Added January 20, 2015
Sodium 4-phenylbutyrate (4PBA) improves the intracellular trafficking of ΔF508-CFTR in cystic fibrosis (CF) epithelial cells. The underlying mechanism is uncertain, but 4PBA modulates the expression of some cytosolic molecular chaperones. To identify other 4PBA-regulated proteins that might regulate ΔF508-CFTR trafficking, we performed a differential display RT-PCR screen on IB3-1 CF bronchiolar epithelial cells exposed to 4PBA. One transcript up-regulated by 4PBA encoded ERp29, a luminal resident of the endoplasmic reticulum (ER) thought to be a novel molecular chaperone. We tested the hypothesis that ERp29 is a 4PBA-regulated ER chaperone that influences ΔF508-CFTR trafficking. ERp29 mRNA and protein expression was significantly increased (∼1.5-fold) in 4PBA-treated IB3-1 cells. In Xenopus oocytes, ERp29 overexpression increased the functional expression of both wild-type and ΔF508-CFTR over 3-fold and increased wild-type cystic fibrosis transmembrane conductance regulator (CFTR) plasma membrane expression. In CFBE41o- WT-CFTR cells, expression of and short circuit currents mediated by CFTR decreased upon depletion of ERp29 as did maturation of newly synthesized CFTR. In IB3-1 cells, ΔF508-CFTR co-immunoprecipitated with endogenous ERp29, and overexpression of ERp29 led to increased ΔF508-CFTR expression at the plasma membrane. These data suggest that ERp29 is a 4PBA-regulated ER chaperone that regulates WT-CFTR biogenesis and can promote ΔF508-CFTR trafficking in CF epithelial cells.
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15 MeSH Terms
Impact of a glycogen phosphorylase inhibitor and metformin on basal and glucagon-stimulated hepatic glucose flux in conscious dogs.
Torres TP, Sasaki N, Donahue EP, Lacy B, Printz RL, Cherrington AD, Treadway JL, Shiota M
(2011) J Pharmacol Exp Ther 337: 610-20
MeSH Terms: Animals, Blood Glucose, Dogs, Enzyme Inhibitors, Fasting, Fatty Acids, Nonesterified, Female, Glucagon, Gluconeogenesis, Glucose, Glucose-6-Phosphatase, Glycerol, Glycogen Phosphorylase, Liver Form, Hematocrit, Hypoglycemic Agents, Indoles, Insulin, Lactic Acid, Liver, Liver Glycogen, Male, Metformin, Phenylbutyrates
Show Abstract · Added December 5, 2013
The effects of a glycogen phosphorylase inhibitor (GPI) and metformin (MT) on hepatic glucose fluxes (μmol · kg(-1) · min(-1)) in the presence of basal and 4-fold basal levels of plasma glucagon were investigated in 18-h fasted conscious dogs. Compared with the vehicle treatment, GPI infusion suppressed net hepatic glucose output (NHGO) completely (-3.8 ± 1.3 versus 9.9 ± 2.8) despite increased glucose 6-phosphate (G-6-P) neogenesis from gluconeogenic precursors (8.1 ± 1.1 versus 5.5 ± 1.1). MT infusion did not alter those parameters. In response to a 4-fold rise in plasma glucagon levels, in the vehicle group, plasma glucose levels were increased 2-fold, and NHGO was increased (43.9 ± 5.7 at 10 min and 22.7 ± 3.4 at steady state) without altering G-6-P neogenesis (3.7 ± 1.5 and 5.5 ± 0.5, respectively). In the GPI group, there was no increase in NHGO due to decreased glucose-6-phosphatase flux associated with reduced G-6-P concentration. A lower G-6-P concentration was the result of increased net glycogenesis without altering G-6-P neogenesis. In the MT group, the increment in NHGO (22.2 ± 4.4 at 10 min and 12.1 ± 3.6 at steady state) was approximately half of that of the vehicle group. The lesser NHGO was associated with reduced glucose-6-phosphatase flux but a rise in G-6-P concentration and only a small incorporation of plasma glucose into glycogen. In conclusion, the inhibition of glycogen phosphorylase a activity decreases basal and glucagon-induced NHGO via redirecting glucose 6-phosphate flux from glucose toward glycogen, and MT decreases glucagon-induced NHGO by inhibiting glucose-6-phosphatase flux and thereby reducing glycogen breakdown.
1 Communities
2 Members
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23 MeSH Terms
The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure.
da-Silva WS, Ribich S, Arrojo e Drigo R, Castillo M, Patti ME, Bianco AC
(2011) FEBS Lett 585: 539-44
MeSH Terms: Adipocytes, Brown, Animals, Cell Line, Cells, Cultured, Dietary Fats, Energy Metabolism, Gene Expression Regulation, Gene Knockout Techniques, Glucose Intolerance, Humans, Iodide Peroxidase, Lipid Metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxygen Consumption, Phenylbutyrates, RNA, Messenger, Taurochenodeoxycholic Acid, Triiodothyronine
Show Abstract · Added April 14, 2021
Exposure of cell lines endogenously expressing the thyroid hormone activating enzyme type 2 deiodinase (D2) to the chemical chaperones tauroursodeoxycholic acid (TUDCA) or 4-phenylbutiric acid (4-PBA) increases D2 expression, activity and T3 production. In brown adipocytes, TUDCA or 4-PBA induced T3-dependent genes and oxygen consumption (∼2-fold), an effect partially lost in D2 knockout cells. In wild type, but not in D2 knockout mice, administration of TUDCA lowered the respiratory quotient, doubled brown adipose tissue D2 activity and normalized the glucose intolerance associated with high fat feeding. Thus, D2 plays a critical role in the metabolic effects of chemical chaperones.
Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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MeSH Terms
Integrin alpha1beta1 regulates matrix metalloproteinases via P38 mitogen-activated protein kinase in mesangial cells: implications for Alport syndrome.
Cosgrove D, Meehan DT, Delimont D, Pozzi A, Chen X, Rodgers KD, Tempero RM, Zallocchi M, Rao VH
(2008) Am J Pathol 172: 761-73
MeSH Terms: Animals, Autoantigens, Biphenyl Compounds, Cells, Cultured, Collagen Type IV, Disease Models, Animal, Gene Expression Regulation, Enzymologic, Integrin alpha1beta1, Matrix Metalloproteinases, Mesangial Cells, Mice, Mice, Knockout, Nephritis, Hereditary, Organic Chemicals, Phenylbutyrates, Tissue Inhibitor of Metalloproteinases, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added February 24, 2014
Previous work has shown that integrin alpha1-null Alport mice exhibit attenuated glomerular disease with decreased matrix accumulation and live much longer than strain-matched Alport mice. However, the mechanism underlying this observation is unknown. Here we show that glomerular gelatinase expression, specifically matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-14, was significantly elevated in both integrin alpha1-null mice and integrin alpha1-null Alport mice relative to wild-type mice; however, only MMP-9 was elevated in glomeruli of Alport mice that express integrin alpha1. Similarly, cultured mesangial cells from alpha1-null mice showed elevated expression levels of all three MMPs, whereas mesangial cells from Alport mice show elevated expression levels of only MMP-9. In both glomeruli and cultured mesangial cells isolated from integrin alpha1-null mice, activation of the p38 and ERK branches of the mitogen-activated protein kinase pathway was also observed. The use of small molecule inhibitors demonstrated that the activation of the p38, but not ERK, pathway was linked to elevated MMP-2, -9, and -14 expression levels in mesangial cells from integrin alpha1-null mice. In contrast, elevated MMP-9 levels in mesangial cells from Alport mice were linked to ERK pathway activation. Blockade of gelatinase activity using a small molecule inhibitor (BAY-12-9566) ameliorated progression of proteinuria and restored the architecture of the glomerular basement membrane in alpha1 integrin-null Alport mice, suggesting that elevated gelatinase activity exacerbates glomerular disease progression in these mice.
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1 Members
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17 MeSH Terms
Targeting prostaglandin E2 receptors as an alternative strategy to block cyclooxygenase-2-dependent extracellular matrix-induced matrix metalloproteinase-9 expression by macrophages.
Pavlovic S, Du B, Sakamoto K, Khan KM, Natarajan C, Breyer RM, Dannenberg AJ, Falcone DJ
(2006) J Biol Chem 281: 3321-8
MeSH Terms: Animals, Blotting, Western, Bucladesine, Celecoxib, Cell Line, Colforsin, Cyclooxygenase 2, Extracellular Matrix, Gene Silencing, MAP Kinase Signaling System, Macrophages, Matrix Metalloproteinase 9, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Naphthalenes, Oligonucleotides, Peritoneum, Phenylbutyrates, Phosphorylation, Pyrazoles, RNA, Small Interfering, Receptors, Prostaglandin E, Reverse Transcriptase Polymerase Chain Reaction, Sulfonamides, Time Factors, Transfection
Show Abstract · Added December 21, 2013
COX-2-dependent prostaglandin (PG) E2 synthesis regulates macrophage MMP expression, which is thought to destabilize atherosclerotic plaques. However, the administration of selective COX-2 inhibitors paradoxically increases the frequency of adverse cardiovascular events potentially through the loss of anti-inflammatory prostanoids and/or disturbance in the balance of pro- and anti-thrombotic prostanoids. To avoid these collateral effects of COX-2 inhibition, a strategy to identify and block specific prostanoid-receptor interactions may be required. We previously reported that macrophage engagement of vascular extracellular matrix (ECM) triggers proteinase expression through a MAPKerk1/2-dependent increase in COX-2 expression and PGE2 synthesis. Here we demonstrate that elicited macrophages express the PGE2 receptors EP1-4. When plated on ECM, their expression of EP2 and EP4, receptors linked to PGE2-induced activation of adenylyl cyclase, is strongly stimulated. Forskolin and dibutryl cyclic-AMP stimulate macrophage matrix metalloproteinase (MMP)-9 expression in a dose-dependent manner. However, an EP2 agonist (butaprost) has no effect on MMP-9 expression, and macrophages from EP2 null mice exhibited enhanced COX-2 and MMP-9 expression when plated on ECM. In contrast, the EP4 agonist (PGE1-OH) stimulated macrophage MMP-9 expression, which was inhibited by the EP4 antagonist ONO-AE3-208. When compared with COX-2 silencing by small interfering RNA or inhibition by celecoxib, the EP4 antagonist was as effective in inhibiting ECM-induced proteinase expression. In addition, ECM-induced MMP-9 expression was blocked in macrophages in which EP4 was silenced by small interfering RNA. Thus, COX-2-dependent ECM-induced proteinase expression is effectively blocked by selective inhibition of EP4, a member of the PGE2 family of receptors.
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27 MeSH Terms
New drugs on the horizon: matrix metalloproteinase inhibitors.
Rothenberg ML, Nelson AR, Hande KR
(1999) Stem Cells 17: 237-40
MeSH Terms: Antineoplastic Agents, Azepines, Biphenyl Compounds, Humans, Hydroxamic Acids, Metalloendopeptidases, Organic Chemicals, Phenylalanine, Phenylbutyrates, Protease Inhibitors, Pyrazines, Sulfonamides, Thiophenes
Added March 5, 2014
0 Communities
1 Members
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13 MeSH Terms