Investigation of the role of transporters on the hepatic elimination of an LAT1 selective inhibitor JPH203

2013 ◽  
Vol 102 (9) ◽  
pp. 3228-3238 ◽  
Author(s):  
Junko Toyoshima ◽  
Hiroyuki Kusuhara ◽  
Michael F. Wempe ◽  
Hitoshi Endou ◽  
Yuichi Sugiyama
Keyword(s):  
Selective Inhibitor ◽  
Hepatic Elimination

Selective targeting of cyclooxygenase-2 reveals its role in renal medullary interstitial cell survival

1999 ◽  
Vol 277 (3) ◽  
pp. F352-F359 ◽  
Author(s):  
Chuan-Ming Hao ◽  
Martin Kömhoff ◽  
Youfei Guan ◽  
Reyadh Redha ◽  
Matthew D. Breyer
Keyword(s):  
Cell Survival ◽  
Interstitial Cell ◽  
Renal Medulla ◽  
Selective Inhibitor ◽  
Nuclear Fragmentation ◽  
Major Site ◽  
Associated Injury ◽  
Selective Targeting ◽  
Inflammatory Drugs

Renal medullary interstitial cells (MICs) are a major site of cyclooxygenase (COX)-mediated PG synthesis. These studies examined the role of COX in MIC survival. Immunoblot and nuclease protection demonstrate that cultured MICs constitutively express COX2, with little constitutive COX1 expression. SC-58236, a COX2-selective inhibitor, but not SC-58560, a COX1 inhibitor, preferentially blocks PGE2 synthesis in MICs. Transduction with a COX2 antisense adenovirus reduced MIC COX2 protein expression and also decreased PGE2production. Antisense downregulation of COX2 was associated with MIC death, whereas a control adenovirus was without effect. Similarly, the COX2-selective inhibitor SC-58236 (30 μM) and several nonselective COX-inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac, ibuprofen, and indomethacin, all caused MIC death. In contrast, SC-58560, a COX1-selective inhibitor, was 100-fold less potent for inducing MIC death than its structural congener SC-58236. NSAID-induced MIC death was associated with DNA laddering and nuclear fragmentation, consistent with apoptosis. These results suggest that COX2 plays an important role in MIC survival. COX2 inhibition may contribute to NSAID-associated injury of the renal medulla.

Role of cytokines in experimentally induced lung cancer and chemoprevention by COX-2 selective inhibitor, etoricoxib

2012 ◽  
Vol 372 (1-2) ◽  
pp. 101-112 ◽  
Author(s):  
Neeti Nadda ◽  
Shruti Setia ◽  
Vivek Vaish ◽  
Sankar Nath Sanyal
Keyword(s):  
Lung Cancer ◽  
Selective Inhibitor ◽  
Cox 2 ◽  
Experimentally Induced

Role of Nitric Oxide in the Enhancement of Pentylenetetrazole-Induced Seizures Caused by Shigella dysenteriae

1999 ◽  
Vol 67 (12) ◽  
pp. 6364-6368 ◽  
Author(s):  
Judith Balter-Seri ◽  
Yael Yuhas ◽  
Abraham Weizman ◽  
Yehuda Nofech-Mozes ◽  
Elizabeth Kaminsky ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Animal Model ◽  
Potent Inhibitor ◽  
Elevated Serum ◽  
Selective Inhibitor ◽  
No Synthase ◽  
Shigella Dysenteriae ◽  
Contrast Injection ◽  
The Mean

ABSTRACT Convulsions and encephalopathy are frequent complications of childhood shigellosis. We studied the role of nitric oxide (NO) inShigella-related seizures in an animal model. Pretreatment of mice with Shigella dysenteriae 60R sonicate elevated serum NO levels and enhanced the convulsive response to pentylenetetrazole (PTZ), as indicated by a higher mean convulsion score and a higher number of mice responding with seizures. Treatment of the mice with S-methylisothiourea sulfate (SMT), a potent inhibitor of inducible NO synthase (NOS), prevented the elevation of serum NO levels and concomitantly reduced the enhanced response to PTZ. The mean convulsion scores were 0.7, 0.7, 1.3, and 0.8 for mice treated with saline, saline and SMT, S. dysenteriae 60R sonicate, and S. dysenteriae60R sonicate with SMT, respectively (P = 0.001 for 60R sonicate versus saline and P = 0.013 for 60R sonicate versus 60R sonicate with SMT). The corresponding seizure rates were 40, 44, 75, and 47% for saline, saline with SMT, S. dysenteriae 60R sonicate, and S. dysenteriae 60R sonicate with SMT, respectively (P = 0.0004 for 60R sonicate versus saline and P = 0.005 for 60R sonicate versus 60R sonicate with SMT). In contrast, injection of N-nitro-l-arginine, a selective inhibitor of constitutive NOS, neither abolished the elevation of serum NO nor attenuated the enhancement of seizures. These findings indicate that NO, induced by S. dysenteriae 60R sonicate, is involved in enhancing the susceptibility to seizures caused by S. dysenteriae.

Abstract 51: A Critical Role for Outside-In Signaling of Integrin AlphalIIIb/Beta3 in Shear-Dependent Platelet Microvesicle Formation and Phosphatidylerine Exposure

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Aiming Pang ◽  
Yujie Cui ◽  
Michael K Delaney ◽  
Aleksandra Stojanovic-Terpo ◽  
Xiaoping Du
Keyword(s):  
Flow Cytometry ◽  
Shear Stress ◽  
Critical Role ◽  
Selective Inhibitor ◽  
Wild Type ◽  
Activated Platelets ◽  
Binding Function ◽  
Integrin Antagonists ◽  
Dependent Signaling Pathway

Platelets promote coagulation mainly by exposing membrane phosphatidylserine (PS) and releasing PS-expressing microvesicles (MV). We have recently shown that PS exposure and MV release induced by platelet agonists requires shear stress. To identify the receptor responsible for the shear-dependent signaling leading to PS exposure and MV release, we compared platelets from β 3 -/- mice and wild-type mice in MV release and PS exposure under defined shear stress introduced using a cone-plate rheometer. MV release and PS exposure were determined using flow cytometry. Shear-dependent PS exposure and MV release were significantly suppressed in β 3 -/- platelets. Similarly, Wild type platelets treated with integrin antagonists also showed defective PS exposure and MV release. These data indicate an important role for the ligand binding function of integrin αιιb/β3 in shear-dependent MV release and PS exposure. To determine whether the role of integrin αιιb/β3 is due to its outside-in signaling, β 3 -/- platelets were transplanted with wild type β 3 or a mutant β 3 with the critical Gα13 binding site of the β 3 cytoplasmic domain (EEE) changed to alanines (AAA), which was previously shown to selectively abolish outside-in signaling of αIIb/β 3 . Transplantation of wild type β 3 rescued the defective MVs release and PS exposure of β 3 -/- platelets. In contrast, AAA mutant failed to rescue these defects. Consistently, wild type platelets treated with the selective inhibitor of Gα13-integrin interaction, inhibited integrin outside-in signaling and also PS exposure and MV release under shear stress. Furthermore, we also showed that the inhibition of Src, which is important in outside-in signaling downtream of Gα13, also abolished shear-dependent MV release and PS exposure. These data suggest that integrin outside-in signaling mediated by the Gα13-β 3 interaction and Src-dependent signaling pathway plays an important role in transmitting shear-induced mechanical signals leading to MV release and PS exposure in activated platelets.

Abstract 5873: BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors

2018 ◽  
Author(s):  
Clara Lemos ◽  
Volker K. Schulze ◽  
Benjamin Bader ◽  
Clara D. Christ ◽  
Hans Briem ◽  
...  
Keyword(s):  
Selective Inhibitor
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