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OPEN ACCESS PLUS
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Contents
11(2): Pp. 92 - 98
Bradley T. Andresen
[Open Access Plus] |
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Biased agonism is one of the fastest growing topics in G protein-coupled receptor pharmacology; moreover, biased agonists are used in the clinic today: carvedilol (Coreg®) is a biased agonist of beta-adrenergic receptors. However, there is a general lack of understanding of biased agonism when compared to traditional pharmacological terminology. Therefore, this review is designed to provide a basic introduction to classical pharmacology as well as G protein-coupled receptor signal transduction in order to clearly explain biased agonism for the non-scientist clinician and pharmacist. Special emphasis is placed on biased agonists of the beta-adrenergic receptors, as these drugs are highly prescribed, and a hypothetical scenario based on current clinical practices and proposed mechanisms for treating disease is discussed in order to demonstrate the need for a more thorough understanding of biased agonism in clinical settings. Since biased agonism provides a novel mechanism for treating disease, greater emphasis is being placed to develop biased agonists; therefore, it is important for biased agonism to be understood in equal measure of traditional pharmacological concepts. This review, along with many others, can be used to teach the basic concepts of biased agonism, and this review also serves to introduce the subsequent reviews that examine, in more depth, the relevance of biased agonism towards the angiotensin type 1 receptor, parathyroid hormone receptor, and natural biased ligands towards chemokine receptors.
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10(4): Pp. 348 - 366
Joan M. Cook-Mills and Christine A. McCary
[Open Access Plus] |
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Vitamin E regulation of disease has been extensively studied in humans, animal models and cell systems. Most of these studies focus on the α-tocopherol isoform of vitamin E. These reports indicate contradictory outcomes for anti-inflammatory functions of the α-tocopherol isoform of vitamin E, especially with regards to clinical studies of asthma and atherosclerosis. These seemingly disparate clinical results are consistent with recently reported unrecognized properties of isoforms of vitamin E. Recently, it has been reported that physiological levels of purified natural forms of vitamin E have opposing regulatory functions during inflammation. These opposing regulatory functions by physiological levels of vitamin E isoforms impact interpretations of previous studies on vitamin E. Moreover, additional recent studies also indicate that the effects of vitamin E isoforms on inflammation are only partially reversible using physiological levels of a vitamin E isoform with opposing immunoregulatory function. Thus, this further influences interpretations of previous studies with vitamin E in which there was inflammation and substantial vitamin E isoforms present before the initiation of the study. In summary, this review will discuss regulation of inflammation by vitamin E, including alternative interpretations of previous studies in the literature with regards to vitamin E isoforms.
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7(3): Pp. 153 - 166
Michel R. Hoenig, Karam M. Kostner, Stephen J. Read, Philip J. Walker and John J. Atherton
[Open Access Plus] |
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Obesity and the metabolic syndrome are becoming one of the biggest health challenges of the 21st century. Cholesterol metabolism is significantly altered in both obesity and metabolic syndrome in that cholesterol synthesis is increased and absorption reduced and this has important implications for the treatment of lipid disorders in both obesity and the metabolic syndrome. In the present review we discuss these changes in detail especially in the context of a more standardized approach for cholesterol reduction like the TARGET LDL trial. Customized care is topical in lipidology as we strive to achieve LDL cholesterol and non-HDL cholesterol targets in every patient.
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7(2): Pp. 111 - 123
Udai P. Singh, Chandrasekar Venkataraman, Rajesh Singh and James W. Lillard Jr.
[Open Access Plus] |
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There is a great need for new intervention and prevention strategies against Crohns disease (CD), a chronic, relapsing tissue-destructive inflammatory bowel disease (IBD). Estimates indicate more than 1 million cases of IBD in the United States occur annually, with 50% involving CD. The clinical features of CD correlate with certain mouse models of colitis, including the spontaneous colitis observed in interleukin-10 deficient (IL-10-/-), senescence accelerated mice (SAMP1/Yit) and trinitrobenzene sulfonic acid (TNBS)-treated mice. Chemokines undoubtedly play a pivotal role in the regulation (i.e., initiation, maintenance, and suppression) of mucosal inflammation and tissue destruction. A number of key advances have led to greater understanding of the steps responsible for colitis and the roles played by chemokines. In fact, CXCR3 and the ligands for this chemokine receptor, monokine-induced by interferon-γ (IFN-γ) (MIG/CXCL9), IFN- γ-inducible 10 kDa protein (IP-10/CXCL10), and IFN-γ-inducible T cell α-chemoattractant (I-TAC/CXCL11) are differentially expressed at sites of colitis in IL-10-/- mice and in clinical cases of CD. While we have demonstrated that antibodies directed against CXCL10 could both prevent the onset and cure of pre-existing colitis in IL-10-/- mice, studies by other investigators have shown the efficacy of CXCR3 blockade to mitigate colitis and other inflammatory diseases. This review describes the hallmarks of IBD, CXCL9-11, and CXCR3 expression during murine colitis and IBD, gives an overview of the antagonist therapies targeting the CXCR3 axis, details current and pending bio-therapies for IBD, and discusses what is known about the cellular and CXCR3-mediated mechanisms of colitis.
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