Abstract:
:Aldose reductase (AKR1B1) is a critical drug target because of its involvement in diabetic complications, inflammation, and tumorigenesis. However, to date, development of clinically useful inhibitors has been largely unsuccessful. Cyclopentenone prostaglandins (cyPGs) are reactive lipid mediators that bind covalently to proteins and exert anti-inflammatory and antiproliferative effects in numerous settings. By pursuing targets for modification by cyPGs we have found that the cyPG PGA1 binds to and inactivates AKR1B1. A PGA1-AKR1B1 adduct was observed, both by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and by SDS-PAGE using biotinylated PGA1 (PGA1-B). Insight into the molecular interactions between AKR1B1 and PGA1 was advanced by molecular modeling. This anticipated the addition of PGA1 to active site Cys298 and the potential reversibility of the adduct, which was supported experimentally. Indeed, loss of biotin label from the AKR1B1-PGA1-B adduct was favored by glutathione, indicating a retro-Michael reaction, which unveils new implications of cyPG-protein interaction. PGA1 elicited only marginal inhibition of aldehyde reductase (AKR1A1), considered responsible for the severe adverse effects of many AKR1B1 inhibitors. Interestingly, other prostaglandins (PGs) inhibited the enzyme, including non-electrophilic PGE1 and PGE2, currently used in clinical practice. Moreover, both PGA1 and PGE1 reduced the formation of sorbitol in an ex-vivo model of diabetic cataract to an extent comparable to that attained by the known AKR inhibitor epalrestat. Taken together, these results highlight the role of PGs as AKR1B1 inhibitors and the interest in PG-related molecules as leads for the development of novel pharmacological tools.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Díez-Dacal B,Sánchez-Gómez FJ,Sánchez-Murcia PA,Milackova I,Zimmerman T,Ballekova J,García-Martín E,Agúndez JA,Gharbi S,Gago F,Stefek M,Pérez-Sala Ddoi
10.1124/mol.115.100693subject
Has Abstractpub_date
2016-01-01 00:00:00pages
42-52issue
1eissn
0026-895Xissn
1521-0111pii
mol.115.100693journal_volume
89pub_type
杂志文章abstract::The incorporation of leucine into protein was studied in Ca2+-depleted and Ca2+-restored preparations of normal liver cells isolated from fed, adult male rats. Ca2+-restored cells incorporated amino acid 5-10-fold more rapidly than did Ca2+-depleted cells for incubation periods up to 1 hr. Readdition of Ca2+ at suprap...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-01-01 00:00:00
abstract::It is established that agmatine, an endogenously formed decarboxylated arginine, is a weak competitive inhibitor of neuronal nitric-oxide synthase (nNOS) with an apparent Ki value of 660 microM [Biochem J 316:247-249, 1996]. Although agmatine is known to bind to alpha-adrenergic and imidazoline receptors, it has been ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.1.24
更新日期:2001-01-01 00:00:00
abstract::Melanocortins (MCs) have various physiological actions on the brain. The recent cloning of neural MC receptors opened new avenues to study the effects of these neuropeptides on the nervous system. Here we investigated the structure-activity relationships (SARs) of peptides derived from adrenocorticotropic hormone (ACT...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-12-01 00:00:00
abstract::Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the researc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.080689
更新日期:2013-01-01 00:00:00
abstract::Valproic acid (VPA) is a widely used antiepileptic agent that is undergoing clinical evaluation for anticancer therapy. We assessed the effects of VPA on angiogenesis in vitro and in vivo. In human umbilical vein endothelial cells, therapeutically relevant concentrations of VPA (0.25 to 1 mM) inhibited proliferation, ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.3.520
更新日期:2004-03-01 00:00:00
abstract::Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)eth...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.115.099747
更新日期:2015-11-01 00:00:00
abstract::Multidrug and toxin extrusion 1 (MATE1/SLC47A1) is important for excretion of organic cations in the kidney and liver, where it is located on the luminal side. Although its functional and regulatory characteristics have been clarified, its pharmacokinetic roles in vivo have yet to be elucidated. In the present study, ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.056242
更新日期:2009-06-01 00:00:00
abstract::4-PIOL is a structural analog of GABA that has low efficacy at GABAA receptor CI- channels and activates a nondesensitizing CI- conductance in central neurons. We investigated the biophysical mechanisms of its low efficacy in embryonic olfactory bulb neurons, which express a limited number of GABAA receptor subunit tr...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-08-01 00:00:00
abstract::The metabotropic glutamate receptor subtype 5 (mGlu5) activates calcium mobilization via binding of glutamate, the major excitatory neurotransmitter in the central nervous system. Allosteric modulation of the receptor has recently emerged as a promising alternative method of regulation to traditional regulation throug...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.016139
更新日期:2005-12-01 00:00:00
abstract::Isoform-specific expression of endothelin-converting enzyme (ECE)-1, the major big endothelin-processing enzyme, is controlled by alternative promoters. Signaling pathways and transcriptional mechanisms of ECE-1 mRNA expression are largely unknown. To investigate ECE-1 isoform expression after protein kinase C (PKC) a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.60.6.1332
更新日期:2001-12-01 00:00:00
abstract::The mechanism of adenylyl cyclase desensitization by carbachol, an agent that stimulates polyphosphoinositide hydrolysis, was studied in thyroid cells. Incubation of cultured dog thyroid cells with 10 microM carbachol for 2-4 hr reduced the subsequent thyrotropic hormone (TSH) stimulation of adenylyl cyclase activity ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-01-01 00:00:00
abstract::Studies investigating the effects of beta-naphthoflavone (beta NF) on insulin receptor binding and its intrinsic protein kinase activity in rat liver and placenta were performed. Membranes were prepared from maternal liver and placenta on gestation day 11 and used for [125I]insulin radioreceptor assay. Scatchard analy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-03-01 00:00:00
abstract::Activation of endothelial nitric-oxide synthase (eNOS) has been shown to occur through various pathways involving increases in the cytosolic Ca(2+) concentration, activation of the phosphatidylinositol-3' kinase/Akt pathway, as well as regulation by other kinases and by protein-protein interactions. We have recently r...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.4.886
更新日期:2003-04-01 00:00:00
abstract::To study behavior of activated G(alpha)(s) in living cells, green fluorescent protein (GFP) was inserted within the internal amino acid sequence of G(alpha)(s) to generate a G(alpha)(s)-GFP fusion protein. The fusion protein maintained a bright green fluorescence and was identified by immunoblotting with antibodies ag...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.2.352
更新日期:2002-02-01 00:00:00
abstract::Up-regulation of fractalkine is involved in vascular and tissue damage in inflammatory conditions. Resveratrol has been shown to have anti-inflammatory, antioxidant, and antitumor activities. Its regulatory effects on expression of fractalkine in vascular endothelial cells and fractalkine receptor CX3CR1 in monocytes ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.022392
更新日期:2006-07-01 00:00:00
abstract::In the hippocampus, two distinct forms of GABAergic inhibition have been identified, phasic inhibitory postsynaptic currents that are the consequence of the vesicular release of GABA and a tonic conductance that is activated by low ambient concentrations of extracellular GABA. It is not known what accounts for the dis...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.1.2
更新日期:2003-01-01 00:00:00
abstract::It is widely accepted that cAMP signaling is compartmentalized within cells. However, our knowledge of how receptors, cAMP signaling enzymes, effectors, and other key proteins form specific signaling complexes to regulate specific cell responses is limited. The multicomponent nature of these systems and the spatiotemp...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.117.110825
更新日期:2018-04-01 00:00:00
abstract::Pyrethroid insecticides are synthetic neurotoxins patterned after the naturally occurring pyrethrins. Their mechanism of action is thought to involve effects primarily at the voltage-sensitive sodium channel of both insect and mammalian neurons, although recent studies have raised the possibility that these compounds ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-07-01 00:00:00
abstract::Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 (IL-24), a member of the IL-10 cytokine gene family, preferentially induces cell death in neoplastic epithelial cells types while sparing their normal counterparts. The effects of mda-7/IL-24 in acute myeloid leukemia (AML) cells have not been extensive...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.068007
更新日期:2010-12-01 00:00:00
abstract::The heptadecapeptide orphanin FQ (OFQ) has been identified as the endogenous ligand for a G protein-coupled receptor (OFQ-R), which, despite its high degree of sequence similarity to opioid receptors, fails to bind opioid ligands. We developed two radioligands for the OFQ-R: a tritiated native OFQ peptide ([3H]OFQ) an...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.5.816
更新日期:1997-05-01 00:00:00
abstract::Arrestins mediate G protein-coupled receptor desensitization, internalization, and signaling. Dopamine D(2) and D(3) receptors have similar structures but distinct characteristics of interaction with arrestins. The goals of this study were to compare arrestin-binding determinants in D(2) and D(3) receptors other than ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.050534
更新日期:2009-01-01 00:00:00
abstract::When exposed to the beta-agonist (-)-isoproterenol, rat glioma C6 cells exhibited a time-and concentration-dependent reduction in isoproterenol responsiveness (desensitization) and a loss of beta-adrenergic receptors (down-regulation). Other agents, such as dibutyryl cyclic AMP, isobutylmethylxanthine, and cholera tox...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-09-01 00:00:00
abstract::Aldosterone synthase (AS) regulates blood volume by synthesizing the mineralocorticoid aldosterone. Overproduction of aldosterone in the adrenal gland can lead to hypertension, a major cause of heart disease and stroke. Aldosterone production depends upon stimulation of AS expression by the renin-angiotensin system, w...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.076471
更新日期:2012-03-01 00:00:00
abstract::Folate receptor-targeted cancer therapies constitute a promising treatment for the approximately one third of human cancers that overexpress the folate receptor (FR). However, the potencies of all folate-receptor targeted therapies depend on 1) the rate of folate-linked drug conjugate binding to the cancer cell surfac...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.003723
更新日期:2004-12-01 00:00:00
abstract::Aldehyde hydrogenases (ALDHs) belong to a large gene family involved in oxidation of both endogenous and exogenous compounds in mammalian tissues. Among ALDHs, the rat ALDH1A7 gene displays a curious strain dependence in phenobarbital (PB)-induced hepatic expression: the responsive RR ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.119.117424
更新日期:2019-11-01 00:00:00
abstract::Merbarone (5-[N-phenyl carboxamido]-2-thiobarbituric acid) is an anticancer drug that inhibits the catalytic activity of DNA topoisomerase II (topo II) without damaging DNA or stabilizing DNA-topo II cleavable complexes. Although the cytotoxicity of the complex-stabilizing DNA-topo II inhibitors such as VP-16 (etoposi...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1999-03-01 00:00:00
abstract::Benzamide riboside (BR) and tiazofurin (TR) are converted to analogs of NAD that inhibit IMP dehydrogenase (IMPDH), resulting in cellular depletion of GTP and dGTP and inhibition of proliferation. The current work was undertaken to identify the human nucleoside transporters involved in cellular uptake of BR and TR and...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.004408
更新日期:2005-01-01 00:00:00
abstract::This study assessed how conformational information encoded by ligand binding to δ-opioid receptors (DORs) is transmitted to Kir3.1/Kir3.2 channels. Human embryonic kidney 293 cells were transfected with bioluminescence resonance energy transfer (BRET) donor/acceptor pairs that allowed us to evaluate independently reci...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.081950
更新日期:2013-02-01 00:00:00
abstract::Based on biochemical and ligand binding studies in various tissues and species, evidence for several alpha 2-adrenergic receptor subtypes has accumulated. The current alpha 2-adrenergic receptor classification (alpha 2A, alpha 2B, alpha 2C) is based exclusively on pharmacological criteria. The molecular cloning of thr...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-11-01 00:00:00
abstract::Excitotoxin-induced destruction of striatal neurons, proposed as a model of Huntington's disease, involves a process having the biochemical stigmata of apoptosis. Recent studies suggested that transcription factor nuclear factor (NF)-kappa B may be involved in excitotoxicity. To further analyze the contribution of NF ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.53.1.33
更新日期:1998-01-01 00:00:00