Current Drug Targets

ISSN: 1389-4501


OPEN ACCESS PLUS


Contents


Properties and Therapeutic Potential of Transient Receptor Potential Channels with Putative Roles in Adversity: Focus on TRPC5, TRPM2 and TRPA1, 2011, 12, 724-736
L.H. Jiang, N. Gamper and D.J. Beech
[Abstract] [Full Text Article]


The Molecular Mechanisms of Glucocorticoids-Mediated Neutrophil Survival, 2011, 12, 556-562
Arash S. Saffar, Heather Ashdown and Abdelilah S. Gounni
[Abstract] [Full Text Article]


Heme Oxygenase-1 in Tumor Biology and Therapy, 2010, 11, 1551-1570
Halina Was, Jozef Dulak and Alicja Jozkowicz
[Abstract] [Full Text Article]


Involvement of the Toxic AGEs (TAGE)-RAGE System in the Pathogenesis of Diabetic Vascular Complications: A Novel Therapeutic Strategy, 2010, 11, 1468-1482
Masayoshi Takeuchi, Jun-ichi Takino and Sho-ichi Yamagishi
[Abstract] [Full Text Article]


Targeting Karyotypic Complexity and Chromosomal Instability of Cancer Cells, 2010, 11, 1341-1350
Anna V. Roschke and Ilan R. Kirsch
[Abstract] [Full Text Article]


The Macrophage Stimulating Protein/Ron Pathway as a Potential Therapeutic Target to Impede Multiple Mechanisms Involved in Breast Cancer Progression, 2010, 11, 1157-1168
Kelsi L. Kretschmann, Henok Eyob, Saundra S. Buys and Alana L. Welm
[Abstract] [Full Text Article]


MicroRNA-21: From Cancer to Cardiovascular Disease, 2010, 11, 926-935
V. Jazbutyte and T. Thum
[Abstract] [Full Text Article]


Activated Protein C and Acute Kidney Injury: Selective Targeting of PAR-1, 2009, 10, 1212-1226
Akanksha Gupta, Mark D. Williams, William L. Macias, Bruce A. Molitoris and Brian W. Grinnell
[Abstract] [Full Text Article]


Inflammatory Systemic Biomarkers in Setting Acute Coronary Syndromes - Effects of the Diurnal Variation, 2009, 10, 1001-1008
A. Dominguez-Rodriguez, P. Abreu-Gonzalez and J.C. Kaski
[Abstract] [Full Text Article]


Metabotropic Glutamate Receptors (mGluRs) and Diabetic Neuropathy, 2008, 9, 85-93
M. Anjaneyulu, A. Berent-Spillson and J.W. Russell
[Abstract] [Full Text Article]


Atherosclerosis and Arterial Blood Pressure in Mice, 2007, 8, 1181-1189
H. Lu, L.A. Cassis and A. Daugherty
[Abstract] [Full Text Article]


GSK3 at the Edge: Regulation of Developmental Specification and Cell Polarization, 2006, 7, 1411-1419
L. Kim and A.R. Kimmel
[Abstract] [Full Text Article]



Abstracts

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Properties and Therapeutic Potential of Transient Receptor Potential Channels with Putative Roles in Adversity: Focus on TRPC5, TRPM2 and TRPA1
L.H. Jiang, N. Gamper and D.J. Beech

[Full Text Article]

Mammals contain 28 genes encoding Transient Receptor Potential (TRP) proteins. The proteins assemble into cationic channels, often with calcium permeability. Important roles in physiology and disease have emerged and so there is interest in whether the channels might be suitable therapeutic drug targets. Here we review selected members of three subfamilies of mammalian TRP channel (TRPC5, TRPM2 and TRPA1) that show relevance to sensing of adversity by cells and biological systems. Summarized are the cellular and tissue distributions, general properties, endogenous modulators, protein partners, cellular and tissue functions, therapeutic potential, and pharmacology. TRPC5 is stimulated by receptor agonists and other factors that include lipids and metal ions; it heteromultimerises with other TRPC proteins and is involved in cell movement and anxiety control. TRPM2 is activated by hydrogen peroxide; it is implicated in stress-related inflammatory, vascular and neurodegenerative conditions. TRPA1 is stimulated by a wide range of irritants including mustard oil and nicotine but also, controversially, noxious cold and mechanical pressure; it is implicated in pain and inflammatory responses, including in the airways. The channels have in common that they show polymodal stimulation, have activities that are enhanced by redox factors, are permeable to calcium, and are facilitated by elevations of intracellular calcium. Developing inhibitors of the channels could lead to new agents for a variety of conditions: for example, suppressing unwanted tissue remodeling, inflammation, pain and anxiety, and addressing problems relating to asthma and stroke.


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The Molecular Mechanisms of Glucocorticoids-Mediated Neutrophil Survival
Arash S. Saffar, Heather Ashdown and Abdelilah S. Gounni

[Full Text Article]

Neutrophil-dominated inflammation plays an important role in many airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiolitis and cystic fibrosis. In cases of asthma where neutrophil-dominated inflammation is a major contributing factor to the disease, treatment with corticosteroids can be problematic as corticosteroids have been shown to promote neutrophil survival which, in turn, accentuates neutrophilic inflammation. In light of such cases, novel targeted medications must be developed that could control neutrophilic inflammation while still maintaining their antibacterial/anti-fungal properties, thus allowing individuals to maintain effective innate immune responses to invading pathogens. The aim of this review is to describe the molecular mechanisms of neutrophil apoptosis and how these pathways are modulated by glucocorticoids. These new findings are of potential clinical value and provide further insight into treatment of neutrophilic inflammation in lung disease.


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Heme Oxygenase-1 in Tumor Biology and Therapy
Halina Was, Jozef Dulak and Alicja Jozkowicz

[Full Text Article]

Heme oxygenase-1 (HO-1) degrades heme to carbon monoxide (CO), biliverdin, and ferrous iron. As HO-1 expression is highly increased by stressful conditions, the major role of the enzyme is the protection against oxidative injury. Additionally, it regulates cell proliferation, modulates inflammatory response and facilitates angiogenesis. Beneficial activities of HO-1 have been recognized in many pathological states e.g. atherosclerosis, diabetes, ischemia/reperfusion injury or organ transplantation. Interestingly HO-1 expression is very often boosted in tumor tissues and could be further elevated in response to radio-, chemo-, or photodynamic therapy. A growing body of evidence suggests that HO-1 may play a role in tumor induction and can potently improve the growth and spread of tumors. This review discusses the implications of HO-1 properties for tumor proliferation and cell death, differentiation, angiogenesis and metastasis, and tumor-related inflammation. Finally, it suggests that pharmacological agents that regulate HO activity or HO-1 gene silencing may become powerful tools for preventing the onset or progression of various cancers and sensitize them to anticancer therapies.


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Involvement of the Toxic AGEs (TAGE)-RAGE System in the Pathogenesis of Diabetic Vascular Complications: A Novel Therapeutic Strategy
Masayoshi Takeuchi, Jun-ichi Takino and Sho-ichi Yamagishi

[Full Text Article]

Diabetic vascular complications are leading causes of acquired blindness, end-stage renal failure, a variety of neuropathies, and accelerated atherosclerosis, which may be involved in the disabilities and high mortality rates suffered by diabetic patients. Continuous hyperglycemia is involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including increased generation of various types of advanced glycation end-products (AGEs). Recently, we demonstrated that glyceraldehyde-derived AGEs (Glycer-AGEs), the predominant components of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, a growing body of evidence suggests that the interaction of TAGE with the receptor for AGEs (RAGE) alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes observed in diabetic vascular complications. Therefore, the inhibition of TAGE formation, blockade of TAGE-RAGE interaction, and the suppression of RAGE expression or its downstream pathways are promising targets for therapeutic interventions against diabetic vascular complications. In this review, we discuss the pathophysiological role of the TAGE-RAGE-oxidative stress system and related therapeutic interventions for preventing the development and progression of diabetic vascular complications.


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Targeting Karyotypic Complexity and Chromosomal Instability of Cancer Cells
Anna V. Roschke and Ilan R. Kirsch

[Full Text Article]

Multiple karyotypic abnormalities and chromosomal instability are characteristic features of many cancers that are relatively resistant to chemotherapeutic agents currently used in the clinic. These same features represent potentially targetable “states” that are essentially tumor specific. The assessment of the chromosomal state of a cancer cell population may provide a guide for the selection or development of drugs active against aggressive and intractable cancers.


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The Macrophage Stimulating Protein/Ron Pathway as a Potential Therapeutic Target to Impede Multiple Mechanisms Involved in Breast Cancer Progression
Kelsi L. Kretschmann, Henok Eyob, Saundra S. Buys and Alana L. Welm

[Full Text Article]

Macrophage Stimulating Protein (MSP) is the only known ligand for the receptor tyrosine kinase Ron. The MSP/Ron pathway is involved in several important biological processes, including macrophage activity, wound healing, and epithelial cell behavior. A role for MSP/Ron in breast cancer has recently been elucidated, wherein this pathway regulates tumor growth, angiogenesis, and metastasis. Here, we review the recent literature surrounding MSP/Ron function in tumor cells, inflammatory cells, and osteoclasts – cell types that often coexist in breast tumor microenvironments. We discuss the potential implications of MSP/Ron activity occurring concurrently in these cell types on tumor progression and metastasis. Lastly, we outline the potential for targeting MSP/Ron as a novel therapy for breast cancer, and for other cancer types.


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MicroRNA-21: From Cancer to Cardiovascular Disease
V. Jazbutyte and T. Thum

[Full Text Article]

MicroRNA-21 (miR-21) expression is activated in multiple types of cancers, such as breast, liver, brain, prostate, myometrial cancers but also in cardiovascular disease. MiR-21 regulates a plethora of target proteins which are involved in cellular survival, apoptosis and cell invasiveness. MiR-21 regulation is complex due to an own promoter that is target for various transcription factors and hormones. The consistent miR-21 overexpression under pathophysiological conditions points to miR-21 as a valuable tool for new therapeutic strategies. In this review, we present and analyze current data about miR-21 expression in various pathologies ranging from cancer to cardiovascular disease. Further, miR-21 regulatory mechanisms and miR-21 downstream targets are discussed. Finally, we highlight the particular role of miR-21 as a therapeutic target in various diseases.


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Activated Protein C and Acute Kidney Injury: Selective Targeting of PAR-1
Akanksha Gupta, Mark D. Williams, William L. Macias, Bruce A. Molitoris and Brian W. Grinnell

[Full Text Article]

Protein C is a plasma serine protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. Activated protein C (APC) has a dual mechanism of action via the feedback inhibition of thrombin generation, and as an agonist of protease activated receptor-1 (PAR-1). Through different cofactor interactions, this dual mechanism of antithrombotic and cytoprotective activity results in the ability of APC to modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability, apoptosis, and modulating leukocyte migration and adhesion. Deficiency in protein C, which occurs during systemic inflammatory activation, is highly associated with organ dysfunction. APC has shown efficacy in a number of preclinical models of thrombosis and ischemia, and the recombinant human APC drotrecogin alfa (activated), reduces mortality in patients with high-risk severe sepsis. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC plays a key role in the adaptive response to protect the vessel wall from insult and to enhance endothelial, cellular, and organ survival. The focus of this review will be to summarize the emerging data suggesting the potential therapeutic benefit of APC and related members of the pathway in the prevention and treatment of acute kidney injury.


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Inflammatory Systemic Biomarkers in Setting Acute Coronary Syndromes - Effects of the Diurnal Variation
A. Dominguez-Rodriguez, P. Abreu-Gonzalez and J.C. Kaski

[Full Text Article]

Clinicians have used additional tools to aid clinical assessment and to enhance their ability to identify the “vulnerable” patient at risk for cardiovascular diseases. Circulating biomarkers are one such tool used for identifying better high-risk individuals and to prognosticate effectively and treat patients with disease. A persistent immune activation is a main feature of atherosclerosis. The inflammatory activity is not only detectable in the vascular wall, but also in peripheral blood. Patients with coronary artery disease show increased numbers of neutrophils and T cells as well as elevated levels of several inflammatory mediators. On the other hand, several cardiovascular disease states show a daily cycle of activity, i.e. a peak incidence of cerebrovascular and cardiovascular events has been documented in the early morning hours. Several studies have shown diurnal variations in inflammatory systemic markers in patients with acute coronary syndrome.

Diurnal variations can alter the analysis of blood-derived samples. Prior to the analysis of a blood sample, multiple steps are necessary to generate the desired specimen. The knowledge of diurnal variations is a prerequisite to understand and control their impact. This brief review comments the effect of the diurnal variation on the most important inflammatory systemic biomarkers in the setting acute coronary syndrome: interleukin-6, neopterin, matrix metalloproteinases, vascular cell adhesion molecule-1, intercellular adhesión molecule-1, soluble CD40 ligand, and C-reactive protein.


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Metabotropic Glutamate Receptors (mGluRs) and Diabetic Neuropathy
M. Anjaneyulu, A. Berent-Spillson and J.W. Russell

[Full Text Article]

Multiple in vivo and in vitro studies show that excessive release of glutamate, and subsequent activation of ionotropic glutamate receptors (iGluRs) and some metabotropic glutamate receptors (mGluRs) cause neuronal cell death through either necrosis or apoptosis. However, recently alternative evidence has shown that mGluRs have modulatory effects on excitotoxicity and neuronal cell death. Metabotropic glutamate receptors form a family of eight subtypes (mGluR1-8), subdivided into three groups (I-III) that initiate their biological effects by G protein-linked intracellular signal transduction. Their expression throughout the mammalian nervous system implicates these receptors as essential mediators of a cell's fate during injury to the nervous system. Activation of group-II (mGluR2 and -3) or group-III metabotropic glutamate receptors (mGluR4, -6, -7 and -8) has been established to be neuroprotective in vitro and in vivo. In contrast, group-I mGluRs (mGluR1 and -5) need to be antagonized in order to evoke protection. The pathological signaling pathways associated with diabetic neuropathy are complex and this influences development of appropriate therapies. The Group II mGluRs target several signaling pathways affected in diabetic neuropathy, prevent cellular injury in the peripheral nervous system, and may provide a novel mechanism for treatment of diabetic neuropathy. Direct or indirect activation of mGluR2/3 in animal models protects against development of diabetic neuropathy. The potential mechanisms and role of mGluRs in protection against diabetic neuropathy will be reviewed.


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Atherosclerosis and Arterial Blood Pressure in Mice
H. Lu, L.A. Cassis and A. Daugherty

[Full Text Article]

Increased blood pressure is a consistent risk factor for the development of atherosclerotic diseases in humans, although the basis for this relationship is unknown. Genetically engineered mice are now commonly used to study mechanisms of atherosclerosis. More recently, blood pressure can be reliably measured in conscious mice using either tail cuff or telemetric techniques. Thus, mouse models permit the investigation of the complex interactions of blood pressure and atherogenesis. Most mouse models exhibiting hypertension have increased atherosclerotic lesion size, although there have been exceptions to these findings. Also, there are several reports that have used methods to decrease blood pressure and demonstrated reduced atherosclerosis. In contrast, there are many studies in which atherosclerosis has been altered without changes in blood pressure, and conversely, studies in which blood pressure changes did not alter atherosclerosis. Studies that have specifically defined the role of elevated systolic blood pressure on the development of atherosclerosis have uniformly demonstrated that pressure per se is not responsible for changes in lesion development. Thus, while increased systolic blood pressure is frequently associated with atherosclerosis, the stimulus for the hypertension appears to be the major determinant of atherogenesis rather than pressure per se. A consistent theme in the literature has been that perturbations of the renin angiotensin system display the strongest correlations between blood pressure and atherosclerosis.


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GSK3 at the Edge: Regulation of Developmental Specification and Cell Polarization
L. Kim and A.R. Kimmel

[Full Text Article]

GSK3 is a multifunctional protein kinase that is pivotal for the regulation of metabolism, the cytoskeleton, and gene expression. Multicellular eukaryotes utilize GSK3 as a molecular switch to specify distinct cell fates, but also to organize these cells spatially within the developing organism. We discuss the central role of GSK3 in control of the Wnt, Hedgehog, cAMP (in Dictyostelium), and other signaling pathways, but also focus on significant new evidence that GSK3 is required to establish cell polarity.