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Pharmaceuticals, Volume 3, Issue 11 (November 2010), Pages 3355-3493

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Research

Jump to: Review

Open AccessArticle Multiple Routes to Oestrogen Antagonism
Pharmaceuticals 2010, 3(11), 3417-3434; doi:10.3390/ph3113417
Received: 26 September 2010 / Revised: 19 October 2010 / Accepted: 25 October 2010 / Published: 29 October 2010
Cited by 1 | PDF Full-text (451 KB) | HTML Full-text | XML Full-text
Abstract
Several lines of evidence attest to the existence of alternative ligand binding sites on the oestrogen receptor (ER), including non-competitive inhibition by trilostane or tamoxifen. It is possible that the inhibitory action of conventional oestrogen agonists at high concentrations may indicate that they
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Several lines of evidence attest to the existence of alternative ligand binding sites on the oestrogen receptor (ER), including non-competitive inhibition by trilostane or tamoxifen. It is possible that the inhibitory action of conventional oestrogen agonists at high concentrations may indicate that they too interact at alternative ER sites, albeit at low affinity. To test this possibility an oestrogen reporter assay was used to compare the activity of different oestrogens and antagonists in breast cancer and prostate cell lines. All four cell lines tested contained different amounts of oestrogen receptor α (ERα), ERβ, progesterone receptor and coregulator mRNA. Though differences were observed in response to stimulation and inhibition, these correlated only with the presence or absence of ERα, and not with the other components. Thus stimulation of the reporter by oestradiol and oestrone was biphasic in the breast cancer cells, while prostate cells were unable to respond. Only T47D cells were stimulated by oestriol or diethylstilboestrol, however reporter activity of all the cell lines was repressed by 10mM diethylstilboestrol. Reporter activity of MCF-7 cells was inhibited by tamoxifen, raloxifene and ICI 182,780, but stimulated by trilostane, yet all these antioestrogens inhibited agonist-stimulated activity. Trilostane also inhibited the agonism seen in cells co-treated with E2 and tamoxifen. It is clear that several of the compounds tested may have either agonist or antagonist effects under different conditions and at different concentrations, acting through ERα alone. Though biphasic dose response curves, or hormesis, have been attributed to various mechanisms, we here provide evidence that alternative ligand binding sites may contribute to this phenomenon. Full article
(This article belongs to the Special Issue Allosteric Modulation)

Review

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Open AccessReview Inactivation of Anandamide Signaling: A Continuing Debate
Pharmaceuticals 2010, 3(11), 3355-3370; doi:10.3390/ph3113355
Received: 25 August 2010 / Revised: 9 October 2010 / Accepted: 25 October 2010 / Published: 28 October 2010
Cited by 3 | PDF Full-text (186 KB) | HTML Full-text | XML Full-text
Abstract
Since the first endocannabinoid anandamide was identified in 1992, extensive research has been conducted to characterize the elements of the tightly controlled endocannabinoid signaling system. While it was established that the activity of endocannabinoids are terminated by a two-step process that includes cellular
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Since the first endocannabinoid anandamide was identified in 1992, extensive research has been conducted to characterize the elements of the tightly controlled endocannabinoid signaling system. While it was established that the activity of endocannabinoids are terminated by a two-step process that includes cellular uptake and degradation, there is still a continuing debate about the mechanistic role of these processes in inactivating anandamide signals. Full article
(This article belongs to the Special Issue Cannabinoids)
Open AccessReview Nanomedicine Faces Barriers
Pharmaceuticals 2010, 3(11), 3371-3416; doi:10.3390/ph3113371
Received: 31 August 2010 / Revised: 5 October 2010 / Accepted: 25 October 2010 / Published: 28 October 2010
Cited by 9 | PDF Full-text (916 KB) | HTML Full-text | XML Full-text
Abstract
Targeted nanoparticles have the potential to improve drug delivery efficiencies by more than two orders of magnitude, from the ~ 0.1% which is common today. Most pharmacologically agents on the market today are small drug molecules, which diffuse across the body’s blood-tissue barriers
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Targeted nanoparticles have the potential to improve drug delivery efficiencies by more than two orders of magnitude, from the ~ 0.1% which is common today. Most pharmacologically agents on the market today are small drug molecules, which diffuse across the body’s blood-tissue barriers and distribute not only into the lesion, but into almost all organs. Drug actions in the non-lesion organs are an inescapable part of the drug delivery principle, causing “side-effects” which limit the maximally tolerable doses and result in inadequate therapy of many lesions. Nanoparticles only cross barriers by design, so side-effects are not built into their mode of operation. Delivery rates of almost 90% have been reported. This review examines the significance of these statements and checks how far they need qualification. What type of targeting is required? Is a single targeting sufficient? What new types of clinical challenge, such as immunogenicity, might attend the use of targeted nanoparticles? Full article
(This article belongs to the Special Issue Neuroactive Compounds)
Figures

Open AccessReview Spotlight on Human LL-37, an Immunomodulatory Peptide with Promising Cell-Penetrating Properties
Pharmaceuticals 2010, 3(11), 3435-3460; doi:10.3390/ph3113435
Received: 4 October 2010 / Revised: 23 October 2010 / Accepted: 29 October 2010 / Published: 1 November 2010
Cited by 8 | PDF Full-text (948 KB) | HTML Full-text | XML Full-text
Abstract
Cationic antimicrobial peptides are major components of innate immunity and help control the initial steps of the infectious process. They are expressed not only by immunocytes, but also by epithelial cells. They share an amphipathic secondary structure with a polar cationic site, which
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Cationic antimicrobial peptides are major components of innate immunity and help control the initial steps of the infectious process. They are expressed not only by immunocytes, but also by epithelial cells. They share an amphipathic secondary structure with a polar cationic site, which explains their tropism for prokaryote membranes and their hydrophobic site contributing to the destructuration of these membranes. LL-37 is the only cationic antimicrobial peptide derived from human cathelicidin. LL-37 can also cross the plasma membrane of eukaryotic cells, probably through special domains of this membrane called lipid rafts. This transfer could be beneficial in the context of vaccination: the activation of intracellular toll-like receptors by a complex formed between CpG oligonucleotides and LL-37 could conceivably play a major role in the building of a cellular immunity involving NK cells. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
Open AccessReview Allosteric Modulation of αβδ GABAA Receptors
Pharmaceuticals 2010, 3(11), 3461-3477; doi:10.3390/ph3113461
Received: 13 September 2010 / Revised: 1 November 2010 / Accepted: 2 November 2010 / Published: 3 November 2010
Cited by 6 | PDF Full-text (312 KB) | HTML Full-text | XML Full-text
Abstract
GABAA receptors mediate the majority of the fast inhibition in the mature brain and play an important role in the pathogenesis of many neurological and psychiatric disorders. The αβδ GABAA receptor localizes extra- or perisynaptically and mediates GABAergic tonic inhibition. Compared
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GABAA receptors mediate the majority of the fast inhibition in the mature brain and play an important role in the pathogenesis of many neurological and psychiatric disorders. The αβδ GABAA receptor localizes extra- or perisynaptically and mediates GABAergic tonic inhibition. Compared with synaptically localized αβγ receptors, αβδ receptors are more sensitive to GABA, display relatively slower desensitization and exhibit lower efficacy to GABA agonism. Interestingly, αβδ receptors can be positively modulated by a variety of structurally different compounds, even at saturating GABA concentrations. This review focuses on allosteric modulation of recombinant αβδ receptor currents and αβδ receptor-mediated tonic currents by anesthetics and ethanol. The possible mechanisms for the positive modulation of αβδ receptors by these compounds will also be discussed. Full article
(This article belongs to the Special Issue Allosteric Modulation)
Open AccessReview Jak2 Tyrosine Kinase: A Potential Therapeutic Target for AT1 Receptor Mediated Cardiovascular Disease
Pharmaceuticals 2010, 3(11), 3478-3493; doi:10.3390/ph3113478
Received: 21 September 2010 / Revised: 27 October 2010 / Accepted: 8 November 2010 / Published: 9 November 2010
Cited by 2 | PDF Full-text (307 KB) | HTML Full-text | XML Full-text
Abstract
Patients with hypertension often manifest a dysregulated renin-angiotensin-aldosterone system (RAAS). Most of the available treatment approaches for hypertension are targeted towards the RAAS including direct renin inhibition, ACE inhibition, angiotensin II type 1 receptor (AT1-R) blockade, and aldosterone receptor antagonism. The
[...] Read more.
Patients with hypertension often manifest a dysregulated renin-angiotensin-aldosterone system (RAAS). Most of the available treatment approaches for hypertension are targeted towards the RAAS including direct renin inhibition, ACE inhibition, angiotensin II type 1 receptor (AT1-R) blockade, and aldosterone receptor antagonism. The Jak2 signaling pathway is intricately coupled to the AT1-R signaling processes involved in hypertension. Here, we review the involvement of Jak2 in the pathogenesis of hypertension, and its potential as a therapeutic target for treatment of AT1-R mediated cardiovascular disease. Jak2 may provide a rational therapeutic approach for patients whose blood pressure is not controlled by standard therapies. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)

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