Current Molecular Pharmacology

ISSN: 1874-4672 - Volume 1, 3 Issues 2008

Current Molecular Pharmacology
Volume 1, Number 3, November 2008

Contents



Neuropharmacology of the Olfactory Bulb Pp. 181-190
Simon O’Connor and Tim J.C. Jacob
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Hepatitis B Vaccination in HIV-Infected Subjects Pp. 191-194
Marco Bongiovanni and Maddalena Casana
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Biologic Therapies Against Inflammatory Bowel Disease: A Dysregulated Immune System and the Cross Talk with Gastrointestinal Mucosa Hold the Key Pp. 195-212
Poonam Dharmani and Kris Chadee
[Abstract] [Purchase Article]


Trends in the Exploration of Anticancer Targets and Strategies in Enhancing the Efficacy of Drug Targeting Pp. 213-232
F. Zhu, C.J. Zheng, L.Y. Han, B. Xie, J. Jia, X. Liu, M.T. Tammi, S.Y. Yang, Y.Q. Wei and Y.Z. Chen
[Abstract] [Purchase Article]


Polyphenols: Biological Activities, Molecular Targets, and the Effect of Methylation Pp. 233-243
K.R. Landis-Piwowar and Q.P. Dou
[Abstract] [Purchase Article]


Pharmacological Inhibition of the Bcl-2 Family of Apoptosis Regulators as Cancer Therapy Pp. 244-254
Alan Richardson and Stanley B. Kaye
[Abstract] [Purchase Article]


TRPV1: On the Road to Pain Relief Pp. 255-269
Andrés Jara-Oseguera, Sidney A. Simon and Tamara Rosenbaum
[Abstract] [Purchase Article]


Can Increased Food Intake Improve Psychosis? A Brief Review and Hypothesis Pp. 270-272
T. Treuer, J. Karagianis and V.P. Hoffmann
[Abstract] [Purchase Article]


Functional Selectivity in Cannabinoid Signaling Pp. 273-284
E.V. Varga, T. Georgieva, S. Tumati, I. Alves, Z. Salamon, G. Tollin, H.I. Yamamura and W.R. Roeske
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Abstracts



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Neuropharmacology of the Olfactory Bulb
Simon O’Connor and Tim J.C. Jacob

The olfactory bulb is located at the start of a hierarchical chain of sensory processing mechanisms. The relative ease of its isolation allows the possibility that models of these mechanisms might be integrated to develop a detailed understanding of function. In this sensory processing chain odour molecules evoke signal transduction in the olfactory receptor neurons. These signals represent the diverse range of molecular binding affinities of the olfactory receptor proteins. The first level of processing of this sensory input is performed by the neurons of the olfactory bulb. The olfactory system needs to filter the vast amount of sensory input it receives to be able to select the subset of biological significance. The importance of the olfactory bulb in this filtering process is suggested by its wide range of modulatory mechanisms. These mechanisms include an array of centrifugal inputs from other regions of the brain as well as numerous intrinsic feedback circuits. Given the complexity of the olfactory bulb and the range of its modulatory activity, the process of isolation of its components produces some difficulties of interpretation. This is mainly due to the removal of some of the effects of interaction and the change in balance that results. We present a summary of the current understanding of the interacting modulatory elements that are found in the olfactory bulb and a detailed account of the properties of mitral/tufted cells, the projection neurons of the olfactory bulb. This is followed by a discussion of the intrinsic and extrinsic modulatory systems acting on these cells. A consideration of the integration of the effects of these modulatory systems allows an understanding of how the output of the mitral/tufted cells is controlled.

While significant progress has been made in the elucidation of the individual components as a result of advances in techniques over the last decade we suggest that there is a need for computational studies as a further aid to the understanding and interpretation of the weight of individual modulatory components in this dynamic interacting system.


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Hepatitis B Vaccination in HIV-Infected Subjects
Marco Bongiovanni and Maddalena Casana

Subjects at risk of infection with human immunodeficiency virus (HIV) are also at high risk of acute and chronic hepatitis B virus (HBV) infection. HIV is associated with higher HBV viraemia and with the risk of HBV reactivation, chronic active HBV infection, cirrhosis and death. Therefore, hepatitis B vaccination is recommended for all HIV-infected subjects lacking prior immunity. However, the immune response to hepatitis B vaccine is frequently suboptimal in this population. High CD4+ cell counts and low HIV viraemia are well known factors associated with a better rate of response. Moreover, higher hepatitis B vaccine doses and/or prolongation of the vaccination schedule, as implemented for patients with immune deficiencies other than HIV, may be considered. New vaccination cycles should be considered if post-vaccination titers of antibodies to hepatitis B surface antigen are < 10 mIU/mL (< 10 UI/L). The immunization of all young and middle-aged adults appears to be the most useful strategy to protect all patient-populations at high risk of sexually transmitted diseases.


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Biologic Therapies Against Inflammatory Bowel Disease: A Dysregulated Immune System and the Cross Talk with Gastrointestinal Mucosa Hold the Key
Poonam Dharmani and Kris Chadee

Inflammatory bowel disease (IBD) is a GI tract disorder that manifests as either Ulcerative colitis (UC) or Crohn’s disease (CD). The precise etiology of IBD is still not completely elucidated but research into the immunopathogenesis of IBD suggests that dysfunctions of the intestinal immune system and cross-reactivity against host epithelial cells hold the key. In both UC and CD, polarized immune activity towards Th1 (marked by upregulation of TNF-α, IL-1β, IFN-γ, IL-6) and Th17 (marked by IL-17 secretion) response is reported, while UC appears to exhibit an added contribution of Th2 responses (characterized by secretion of IL-4, IL-5, and IL-13). Additionally, other molecules involved in leukocyte trafficking (adhesion molecules), chemokines (IL-8) and tissue repair molecules (PGE₂ and its receptors) are also crucial. Emergence of these new paradigms in the pathogenesis of IBD led to a recent trend of novel biological therapies that specifically inhibit molecules involved in the inflammatory cascade. In this review, we critically discuss recent advances in the pathogenesis of IBD, drug therapies (conventional versus biologic), drug efficacy and pharmacokinetics (murine versus human versus chimeric) and their adverse effects. We also discuss emerging novel biological therapies targeting pro-inflammatory cytokines including TNF-α and IFN-γ, cytokine receptors and those targeting adhesion molecules-anti-integrin and anti-ICAM antibodies. Other potential approaches using anti-inflammatory cytokines (IL-10), anti-sense oligonucleotide and probiotics are also discussed. Finally, we summarized few imperative targets whose more detailed exploration can help to pave the way for an efficacious IBD therapy.


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Trends in the Exploration of Anticancer Targets and Strategies in Enhancing the Efficacy of Drug Targeting
F. Zhu, C.J. Zheng, L.Y. Han, B. Xie, J. Jia, X. Liu, M.T. Tammi, S.Y. Yang, Y.Q. Wei and Y.Z. Chen

A number of therapeutic targets have been explored for developing anticancer drugs. Continuous efforts have been directed at the discovery of new targets as well as the improvement of therapeutic efficacy of agents directed at explored targets. There are 84 and 488 targets of marketed and investigational drugs for the treatment of cancer or cancer related illness. Analysis of these targets, particularly those of drugs in clinical trials and US patents, provides useful information and perspectives about the trends, strategies and progresses in targeting key cancer-related processes and in overcoming the difficulties in developing efficacious drugs against these targets. The efficacy of anticancer drugs directed at these targets is frequently compromised by counteractive molecular interactions and network crosstalk, negative and adverse secondary effects of drugs, and undesired ADMET profiles. Multi-component therapies directed at multiple targets and improved drug targeting methods are being explored for alleviating these efficacy-reducing processes. Investigation of the modes of actions of these combinations and targeting methods offers clues to aid the development of more effective anticancer therapies.


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Polyphenols: Biological Activities, Molecular Targets, and the Effect of Methylation
K.R. Landis-Piwowar and Q.P. Dou

Polyphenolic compounds are widely distributed in the plant kingdom and the anticancer benefits obtained from their consumption have been studied extensively. However, polyphenols are subject to various biotransformation reactions within the human body including methylation. Likewise, naturally occurring polyphenols may contain O-methylations in place of the hydroxyls of the parent compounds. While some studies suggest that methylations can increase the bioavailability of polyphenols, other studies indicate a decrease in the anticancer benefits of methylated polyphenols. This review will focus on the cellular activities of polyphenols, their potential molecular targets and their biological effects after enzymatic methylation. Furthermore, an assessment of the positive and negative aspects of polyphenol methylation on the anticancer activity will be discussed. Finally, the future of polyphenols in both cancer prevention and cancer intervention will be addressed.


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Pharmacological Inhibition of the Bcl-2 Family of Apoptosis Regulators as Cancer Therapy
Alan Richardson and Stanley B. Kaye

Conventional chemotherapy for cancer utilizes cytotoxic agents which elicit their therapeutic effect in part through the induction of apoptosis. In contrast, drugs which have been developed more recently and which are referred to as “targeted therapy” may exhibit less unwanted toxicity but in some cases these drugs are cytostatic. The recent development of drugs which target the apoptotic machinery offers a means to combine these two approaches. The intrinsic apoptotic pathway is controlled by the balance between anti-apoptotic proteins belonging to the Bcl-2 family and pro-apoptotic proteins bearing a single BH3 domain. Anti-apoptotic Bcl-2 family members are able to sequester the pro-apoptotic proteins by binding their BH3 domain. Compounds which inhibit this interaction are expected to promote apoptosis by preventing sequestration of the pro-apoptotic protein. Recently, a number of drugs have been developed which accomplish this, eg ABT-737, and some of these are progressing to clinical trials in oncology. These drugs may induce apoptosis on their own or synergize with existing chemotherapy. For example, ABT-737 is able to induce apoptosis when used as a single agent to treat leukemic and lung cancer cells and has also been shown to synergize with conventional chemotherapeutic agents in several cancer types. The spectrum of Bcl-2 family members expressed in a tumor cell, and the specificity of the inhibitor for these different anti-apoptotic proteins, helps determine whether Bcl-2 antagonists induce apoptosis when used as single agents. The ability of cytotoxic drugs to alter the expression of pro- and anti-apoptotic proteins is likely to help determine whether Bcl-2 antagonists synergize with cytotoxic therapy. Finally, as we begin to understand the pathways that regulate the expression of pro- and anti-apoptotic pathways, several new therapeutic strategies can be envisioned.


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TRPV1: On the Road to Pain Relief
Andrés Jara-Oseguera, Sidney A. Simon and Tamara Rosenbaum

Historically, drug research targeted to pain treatment has focused on trying to prevent the propagation of action potentials in the periphery from reaching the brain rather than pinpointing the molecular basis underlying the initial detection of the nociceptive stimulus: the receptor itself. This has now changed, given that many receptors of nociceptive stimuli have been identified and/or cloned. Transient Receptor Potential (TRP) channels have been implicated in several physiological processes such as mechanical, chemical and thermal stimuli detection. Ten years after the cloning of TRPV1, compelling data has been gathered on the role of this channel in inflammatory and neuropathic states. TRPV1 activation in nociceptive neurons, where it is normally expressed, triggers the release of neuropeptides and transmitters resulting in the generation of action potentials that will be sent to higher CNS areas where they will often be perceived as pain. Its activation also will evoke the peripheral release of pro-inflammatory compounds that may sensitize other neurons to physical, thermal or chemical stimuli. For these reasons as well as because its continuous activation causes analgesia, TRPV1 has become a viable drug target for clinical use in the management of pain. This review will provide a general picture of the physiological and pathophysiological roles of the TRPV1 channel and of its structural, pharmacological and biophysical properties. Finally, it will provide the reader with an overall view of the status of the discovery of potential therapeutic agents for the management of chronic and neuropathic pain.


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Can Increased Food Intake Improve Psychosis? A Brief Review and Hypothesis
T. Treuer, J. Karagianis and V.P. Hoffmann

Weight gain, diabetes, and changes in serum lipid profiles have been reported during treatment with typical and atypical antipsychotics. An association between diabetes and psychotic disorders was described long before the introduction of pharmacological agents for the treatment of schizophrenia. Several theories have been proposed to explain the baseline weight increase and metabolic disturbances in schizophrenia. Some studies suggest that increased food intake may improve psychotic symptoms in patients with schizophrenia but there have been conflicting results. Available clinical and basic research findings are discussed to evaluate the hypothesis that increased food intake may decrease sensitivity to dopamine signaling in the striatum. More research is needed to evaluate this potential link. However, basic animal research and evolutionary approaches can provide insights into metabolic disturbances associated with schizophrenia.


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Functional Selectivity in Cannabinoid Signaling
E.V. Varga, T. Georgieva, S. Tumati, I. Alves, Z. Salamon, G. Tollin, H.I. Yamamura and W.R. Roeske

Cannabinoid (CB) agonists exhibit numerous potentially useful pharmacological properties, but unwanted side effects limit their use in clinical practice. Thus, novel strategies are needed to identify potential CB pharmaceuticals with fewer side effects. Activated CB receptors initiate multiple parallel intracellular signal transduction cascades. In the present paper we will review experimental data indicating that structurally different classes of CB agonists may exhibit selectivity toward individual subsets of intracellular signaling pathways. In support of this, recent findings indicate that chemically distinct classes of CB agonists frequently differ in their rank order of potency to produce analgesia versus other central nervous system effects in vivo. Structurally different agonists were also found to differ in their abilities to activate individual G protein types in vitro. Since it was suggested earlier that structurally distinct CB agonists may interact differently with the CB receptors, it has been hypothesized that different classes of cannabinoid agonists may stabilize unique active CB receptor conformations, leading to functional selectivity in CB receptor signaling. In order to obtain a direct proof for this hypothesis, we recently employed a highly sensitive biophysical method, plasmon-waveguide resonance (PWR) spectroscopy. PWR experiments have provided a direct proof that structurally different CB agonists produce qualitatively distinct changes in the shape and/or membrane orientation of the CB1 receptors, leading to functional selectivity in G protein activation. We expect that by identification of CB agonists that selectively activate preferred intracellular signaling pathways novel pharmacological lead structures can be identified for the design of improved CB analgesics with fewer side effects.