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1.  [No title available] 
PMCID: PMC3947247  PMID: 24134902
2.  [No title available] 
PMCID: PMC3947248  PMID: 24134903
3.  [No title available] 
PMCID: PMC3947254  PMID: 24140083
4.  [No title available] 
PMCID: PMC3982918  PMID: 24076266
5.  Trichloroethylene: Mechanistic, Epidemiologic and Other Supporting Evidence of Carcinogenic Hazard 
Pharmacology & therapeutics  2013;141(1):10.1016/j.pharmthera.2013.08.004.
The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including from hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. Strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin's lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE.
doi:10.1016/j.pharmthera.2013.08.004
PMCID: PMC3867557  PMID: 23973663
trichloroethylene; cancer; mechanisms; metabolism; kidney; human
6.  Glycogen synthase kinase-3 inhibitors: Rescuers of cognitive impairments 
Pharmacology & therapeutics  2013;141(1):10.1016/j.pharmthera.2013.07.010.
Impairment of cognitive processes is a devastating outcome of many diseases, injuries, and drugs affecting the central nervous system (CNS). Most often, very little can be done by available therapeutic interventions to improve cognitive functions. Here we review evidence that inhibition of glycogen synthase kinase-3 (GSK3) ameliorates cognitive deficits in a wide variety of animal models of CNS diseases, including Alzheimer's disease, Fragile X syndrome, Down syndrome, Parkinson's disease, spinocerebellar ataxia type 1, traumatic brain injury, and others. GSK3 inhibitors also improve cognition following impairments caused by therapeutic interventions, such as cranial irradiation for brain tumors. These findings demonstrate that GSK3 inhibitors are able to ameliorate cognitive impairments caused by a diverse array of diseases, injury, and treatments. The improvements in impaired cognition instilled by administration of GSK3 inhibitors appear to involve a variety of different mechanisms, such as supporting long-term potentiation and diminishing long-term depression, promotion of neurogenesis, reduction of inflammation, and increasing a number of neuroprotective mechanisms. The potential for GSK3 inhibitors to repair cognitive deficits associated with many conditions warrants further investigation of their potential for therapeutic interventions, particularly considering the current dearth of treatments available to reduce loss of cognitive functions.
doi:10.1016/j.pharmthera.2013.07.010
PMCID: PMC3867580  PMID: 23916593
Alzheimer's disease; Fragile X Syndrome; glycogen synthase kinase-3; learning; lithium; LTP
7.  Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong? 
Pharmacology & therapeutics  2013;140(3):267-279.
Substantial genetic contributions to addiction vulnerability are supported by data from twin studies, linkage studies, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS). Parallel to this work, animal studies have attempted to identify the genes that may contribute to responses to addictive drugs and addiction liability, initially focusing upon genes for the targets of the major drugs of abuse. These studies identified genes/proteins that affect responses to drugs of abuse; however, this does not necessarily mean that variation in these genes contributes to the genetic component of addiction liability. One of the major problems with initial linkage and candidate gene studies was an a priori focus on the genes thought to be involved in addiction based upon the known contributions of those proteins to drug actions, making the identification of novel genes unlikely. The GWAS approach is systematic and agnostic to such a priori assumptions. From the numerous GWAS now completed several conclusions may be drawn: (1) addiction is highly polygenic; each allelic variant contributing in a small, additive fashion to addiction vulnerability; (2) unexpected, compared to our a priori assumptions, classes of genes are most important in explaining addiction vulnerability; (3) although substantial genetic heterogeneity exists, there is substantial convergence of GWAS signals on particular genes. This review traces the history of this research; from initial transgenic mouse models based upon candidate gene and linkage studies, through the progression of GWAS for addiction and nicotine cessation, to the current human and transgenic mouse studies post-GWAS.
doi:10.1016/j.pharmthera.2013.07.006
PMCID: PMC3797854  PMID: 23872493
Addiction; drug abuse; Genome-wide association study; linkage; nicotine cessation; transgenic; knockout; genetics
8.  Multiplicity of Effectors of the Cardioprotective Agent, Diazoxide 
Pharmacology & therapeutics  2013;140(2):167-175.
Diazoxide has been identified over the past 50 years to have a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Today it is used clinically to treat these conditions. More recently, another important mode of action emerged: diazoxide has powerful protective properties against cardiac ischemia. The heart has intrinsic protective mechanisms against ischemia injury; one of which is ischemic preconditioning. Diazoxide mimics ischemic preconditioning. The purpose of this treatise is to review the literature in an attempt to identify the many effectors of diazoxide and discuss how they may contribute diazoxide’s cardioprotective properties. Particular emphasis is placed on the concentration ranges in which diazoxide affects its different targets and how this compares with the concentrations commonly used to study cardioprotection. It is concluded that diazoxide may have several potential effectors that may potentially contribute to cardioprotection, including KATP channels in the pancreas, smooth muscle, endothelium, neurons and the mitochondrial inner membrane. Diazoxide may also affect other ion channels and ATPases and may directly regulate mitochondrial energetics. It is possible that the success of diazoxide lies in this promiscuity and that the compound acts to rebalance multiple physiological processes during cardiac ischemia.
doi:10.1016/j.pharmthera.2013.06.007
PMCID: PMC3795896  PMID: 23792087
Cardioprotection; Ischemia; Ischemic preconditioning; Diazoxide; KATP channels; Mitochondria
9.  Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment 
Pharmacology & therapeutics  2003;97(2):153-179.
The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-d-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.
PMCID: PMC4203361  PMID: 12559388
Schizophrenia; Glutamate; Neuroplasticity; Neurotoxicity; Antipsychotic drugs; Neuropathology
10.  Delta opioid receptors in brain function and diseases 
Pharmacology & therapeutics  2013;140(1):112-120.
Evidence that the delta opioid receptor (DOR) is an attractive target for the treatment of brain disorders has strengthened in recent years. This receptor is broadly expressed in the brain, binds endogenous opioid peptides, and shows as functional profile highly distinct from those of mu and kappa opioid receptors. Our knowledge of DOR function has enormously progressed from in vivo studies using pharmacological tools and genetic approaches. The important role of this receptor in reducing chronic pain has been extensively overviewed; therefore this review focuses on facets of delta receptor activity relevant to psychiatric and other neurological disorders. Beneficial effects of DOR agonists are now well established in the context of emotional responses and mood disorders. DOR activation also regulates drug reward, inhibitory controls and learning processes, but whether delta compounds may represent useful drugs in the treatment of drug abuse remains open. Epileptogenic and locomotor-stimulating effects of delta agonists appear drug-dependent, and the possibility of biased agonism at DOR for these effects is worthwhile further investigations to increase benefit/risk ratio of delta therapies. Neuroprotective effects of DOR activity represent a forthcoming research area. Future developments in DOR research will benefit from in-depth investigations of DOR function at cellular and circuit levels.
doi:10.1016/j.pharmthera.2013.06.003
PMCID: PMC3775961  PMID: 23764370
Delta opioid receptor; Knockout; Pharmacology; in vivo; pathology
11.  Epigenetic Modifications by Dietary Phytochemicals: Implications for Personalized Nutrition 
Pharmacology & therapeutics  2012;138(1):1-17.
In last two decades, the study of epigenetic modification emerged as one of the major areas of cancer treatment targeted by dietary phytochemicals. Recent studies with various types of cancers revealed that the epigenetic modifications are associated with the food source corresponds to dietary phytochemicals. The dietary phytochemicals have been used in Asian countries for thousands of years to cure several diseases including cancer. They have been reported to modulate the several biological processes including histone modification, DNA methylation and non-coding microRNA expression. These events play a vital role in carcinogenesis. Various studies suggest that a number of dietary compounds present in vegetables, spices and other herbal products have epigenetic targets in cancer cells. Dietary phytochemicals have been reported to repair DNA damage by enhancing histone acetylation that helps to restrain cell death, and also alter DNA methylation. These phytochemicals are able to modulate epigenetic modifications and their targets to cure several cancers. Epigenetic aberrations dynamically contribute to cancer pathogenesis. Given the individualized traits of epigenetic biomarkers, the personalized nutrition will help us to prevent various types of cancer. In this review, we will discuss the effect of dietary phytochemicals on genetic and epigenetic modifications and how these modifications help to prevent various types of cancers and improve health outcomes.
doi:10.1016/j.pharmthera.2012.11.002
PMCID: PMC4153856  PMID: 23159372
Epigenetics; Phytochemicals; DNA-methylation; Histone-modification; miRNA; Carcinogenesis
12.  Microglia During Development and Aging 
Pharmacology & therapeutics  2013;139(3):313-326.
Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, andaxonal degeneration. Changes inmicroglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microgliapotentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging.
doi:10.1016/j.pharmthera.2013.04.013
PMCID: PMC3737416  PMID: 23644076
microglia; P2X receptors; aging; development; synapse stripping
13.  Phosphoprotein enriched in astrocytes (PEA)-15: A potential therapeutic target in multiple disease states 
Pharmacology & Therapeutics  2014;143(3):265-274.
Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these protein–protein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases.
doi:10.1016/j.pharmthera.2014.03.006
PMCID: PMC4127788  PMID: 24657708
PEA-15; ERK1/2; Proliferation; Apoptosis; Cancer; Type 2 diabetes; CaMKII, calcium/calmodulin-dependent protein kinase II; DED, death effector domain; DISC, death initiation signalling complex; ERK1/2, extracellular signal-regulated kinases 1/2; FADD, Fas-associated death domain protein; GLUT, glucose transporter; HNF-4α, hepatocyte nuclear factor 4alpha; IL, interleukin; MAP, mitogen-activated protein; PEA-15, phosphoprotein enriched in astrocytes-15; PCOS, polycystic ovary syndrome; PDGF, platelet-derived growth factor; PKC, protein kinase C; PLD1, phospholipase D1; NSCLC, non-small cell lung cancer; RSK, ribosomal s6 kinase; TGF-β1, transforming growth factor-β1; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand; VSM, vascular smooth muscle
14.  Stromal derived factor 1α: A chemokine that delivers a two-pronged defence of the myocardium☆ 
Pharmacology & Therapeutics  2014;143(3):305-315.
Alleviating myocardial injury associated with ST elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) has dual potential benefit in this regard. Firstly, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (AMI) and regulates stem cell migration to sites of injury. SDF-1α delivery to the myocardium after AMI is associated with improved stem cell homing, angiogenesis, and left ventricular function in animal models, and improvements in heart failure and quality of life in humans. Secondly, SDF-1α may have a role in remote ischaemic conditioning (RIC), the phenomenon whereby non-lethal ischaemia–reperfusion applied to an organ or tissue remote from the heart protects the myocardium from lethal ischaemia–reperfusion injury (IRI). SDF-1α is increased in the serum of rats subjected to RIC and protects against myocardial IRI in ex vivo studies. Despite these potential pleiotropic effects, a limitation of SDF-1α is its short plasma half-life due to cleavage by dipeptidyl peptidase-4 (DPP-4). However, DPP-4 inhibitors increase the half-life of SDF-1α by preventing its degradation and are also protective against lethal IRI. In summary, SDF-1 potentially delivers a ‘two-pronged’ defence of the myocardium: acutely protecting it from IRI while simultaneously stimulating repair by recruiting stem cells to the site of injury. In this article we examine the evidence for acute and chronic cardioprotective roles of SDF-1α and discuss potential therapeutic manipulations of this mechanism with DPP-4 inhibitors to protect against lethal tissue injury in the clinical setting.
doi:10.1016/j.pharmthera.2014.03.009
PMCID: PMC4127789  PMID: 24704323
SDF; DPP-4; Cardioprotection; AMI; Ischemic conditioning; CXCR4
15.  Insulin in the Brain: There and Back Again 
Pharmacology & therapeutics  2012;136(1):82-93.
Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BEC), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, is itself regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BEC, protect the integrity of the BBB and its ability to transport insulin. Most of insulin’s known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer’s disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain.
doi:10.1016/j.pharmthera.2012.07.006
PMCID: PMC4134675  PMID: 22820012
Blood-brain barrier; insulin; glucose; brain; central nervous system; resistance; transport
16.  The Brain’s Heart – Therapeutic Opportunities for Patent Foramen Ovale (PFO) and Neurovascular Disease 
Pharmacology & therapeutics  2013;139(2):111-123.
Patent foramen ovale (PFO), a common congenital cardiac abnormality, is a connection between the right and left atria in the heart. As a “back door to the brain”, PFO can serve as a conduit for paradoxical embolism, allowing venous thrombi to enter the arterial circulation, avoiding filtration by the lungs, and causing ischemic stroke. PFO-related strokes affect more than 150,000 people per year in the US, and PFO is present in up to 60% of migraine patients with aura, and in one out of four normal individuals. So, in such a highly prevalent condition, what are the best treatment and prevention strategies? Emerging studies show PFO-related neurovascular disease to be a multi-organ condition with varying individual risk factors that may require individualized therapeutic approaches – opening the field for new pharmacologic and therapeutic targets. The anatomy of PFO suggests that, in addition to thrombi, it can also allow harmful circulatory factors to travel directly from the venous to the arterial circulation, a concept important in finding novel therapeutic targets for PFO-related neurovascular injury. Here, we: 1) review emerging data on PFO-related injuries and clinical trials; 2) discuss potential mechanisms of PFO-related neurovascular disease in the context of multi-organ interaction and heart-brain signaling; and 3) discuss novel therapeutic targets and research frontiers. Clinical studies and molecular mapping of the circulatory landscape of this multi-organ disease will both be necessary in order to better individualize clinical treatment for a condition affecting more than a quarter of the world’s population.
doi:10.1016/j.pharmthera.2013.03.007
PMCID: PMC3740210  PMID: 23528225
Patent Foramen Ovale; PFO; Stroke; Migraine; CLOSURE I trial; RESPECT trial; Neurovascular Injury; Serotonin (5-HT)
17.  Notch Inhibitors for Cancer Treatment 
Pharmacology & therapeutics  2013;139(2):95-110.
Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been developed. Most of these inhibitors had shown anti-tumor effects in preclinical studies. At the same time, the combinatorial effect of these inhibitors with current chemotherapeutical drugs still under study in different clinical trials. In this review, we describe the basics of Notch signaling and the role of Notch in normal and cancer stem cells as a logic way to develop different Notch inhibitors and their current stage of progress for cancer patient’s treatment.
doi:10.1016/j.pharmthera.2013.02.003
PMCID: PMC3732476  PMID: 23458608
Notch signaling; Notch inhibitors; cancer; cancer stem cells
18.  Substance use disorders: Psychoneuroimmunological mechanisms and new targets for therapy 
Pharmacology & therapeutics  2013;139(2):289-300.
An estimated 76.4 million people worldwide meet criteria for alcohol use disorders, and 15.3 million meet criteria for drug use disorders. Given the high rates of addiction and the associated health, economic, and social costs, it is essential to develop a thorough understanding of the impact of substance abuse on mental and physical health outcomes and to identify new treatment approaches for substance use disorders (SUDs). Psychoneuroimmunology is a rapidly expanding, multidisciplinary area of research that may be of particular importance to addiction medicine, as its focus is on the dynamic and complex interactions among behavioral factors, the central nervous system, and the endocrine and immune systems (Ader, 2001). This review, therefore, focuses on: 1) the psychoneuroimmunologic effects of SUDs by substance type and use pattern, and 2) the current and future treatment strategies, including barriers that can impede successful recovery outcomes. Evidence-based psychosocial and pharmacotherapeutic treatments are reviewed. Psychological factors and central nervous system correlates that impact treatment adherence and response are discussed. Several novel therapeutic approaches that are currently under investigation are introduced; translational data from animal and human studies is presented, highlighting immunotherapy as a promising new direction for addiction medicine.
doi:10.1016/j.pharmthera.2013.04.011
PMCID: PMC3725980  PMID: 23631821
Addiction; Drug discovery; Inflammation; Psychoneuroimmunology; Substance use disorders; Treatment strategies
19.  Flufenamic acid as an ion channel modulator 
Pharmacology & therapeutics  2013;138(2):272-284.
Flufenamic acid has been known since the 1960s to have anti-inflammatory properties attributable to the reduction of prostaglandin synthesis. Thirty years later, flufenamic acid appeared to be an ion channel modulator. Thus, while its use in medicine diminished, its use in ionic channel research expanded. Flufenamic acid commonly affects non-selective cation channels and chloride channels, but also modulates potassium, calcium and sodium channels with effective concentrations ranging from 10-6 M in TRPM4 channel inhibition to 10-3 M in two-pore outwardly rectifying potassium channel activation. Because flufenamic acid effects develop and reverse rapidly, it is a convenient and widely used tool. However, given the broad spectrum of its targets, experimental results have to be interpreted cautiously. Here we provide an overview of ion channels targeted by flufenamic acid to aid in interpreting its effects at the molecular, cellular, and systems levels. If it is used with good practices, flufenamic acid remains a useful tool for ion channel research. Understanding the targets of FFA may help reevaluate its physiological impacts and revive interest in its therapeutic potential.
doi:10.1016/j.pharmthera.2013.01.012
PMCID: PMC4116821  PMID: 23356979
Flufenamic acid; flufenamate; TRP; non-selective cation channel; chloride channels; channel blockers
20.  Matrix Metalloproteinase (MMP)-9: a proximal biomarker for cardiac remodeling and a distal biomarker for inflammation 
Pharmacology & therapeutics  2013;139(1):32-40.
Adverse cardiac remodeling following myocardial infarction (MI) remains a significant cause of congestive heart failure. Additional and novel strategies that improve our ability to predict, diagnose, or treat remodeling are needed. Numerous groups have explored single and multiple biomarker strategies to identify diagnostic prognosticators of remodeling progression, which will improve our ability to promptly and accurately identify high-risk individuals. The identification of better clinical indicators should further lead to more effective prediction and timely treatment.
Matrix metalloproteinase (MMP-9) is one potential biomarker for cardiac remodeling, as demonstrated by both animal models and clinical studies. In animal MI models, MMP-9 expression significantly increases and is linked with inflammation, diabetic microvascular complications, extracellular matrix degradation and synthesis, and cardiac dysfunction. Clinical studies have also established a relationship between MMP-9 and post-MI remodeling and mortality, making MMP-9 a viable candidate to add to the multiple biomarker list.
By definition, a proximal biomarker shows a close relationship with its target disease, whereas a distal biomarker exhibits non-targeted disease modifying outcomes. In this review, we explore the ability of MMP-9 to serve as a proximal biomarker for cardiac remodeling and a distal biomarker for inflammation. We summarize the current molecular basis and clinical platform that allow us to include MMP-9 as a biomarker in both categories.
doi:10.1016/j.pharmthera.2013.03.009
PMCID: PMC3660444  PMID: 23562601
biomarker; cardiovascular; congestive heart failure; inflammation; MMP-9; myocardial infarction
21.  Pharmacogenomics of Breast Cancer Therapy: An Update 
Pharmacology & therapeutics  2013;139(1):1-11.
Clinical and histopathologic characteristics of breast cancer have long played an important role in treatment decision-making. Well-recognized prognostic factors include tumor size, node status, presence or absence of metastases, tumor grade, and hormone receptor expression. High tumor grade, presence of hormone receptors, and HER2-positivity are a few predictive markers of response to chemotherapy, endocrine manipulations, and anti-HER2 agents, respectively. However, there is much heterogeneity of outcomes in patients with similar clinical and pathologic features despite equivalent treatment regimens. Some of the difference in response to specific therapies can be attributed to somatic tumor characteristics, such as degree of estrogen receptor expression and HER2 status. In recent years, there has been great interest in evaluating the role that pharmacogenetics/pharmacogenomics, or variations in germline DNA, play in alteration of drug metabolism and activity, thus leading to disparate outcomes among patients with similar tumor characteristics. The utility of these variations in treatment decision-making remains debated. Here we review the data available to date on genomic variants that may influence response to drugs commonly used to treat breast cancer. While none of the variants reported to date have demonstrated clinical utility, ongoing prospective studies and increasing understanding of pharmacogenetics will allow us to better predict risk of toxicity or likelihood of response to specific treatments and to provide a more personalized therapy.
doi:10.1016/j.pharmthera.2013.03.001
PMCID: PMC3660522  PMID: 23500718
22.  Epigenetics: A novel therapeutic approach for the treatment of Alzheimer’s disease 
Pharmacology & therapeutics  2013;139(1):41-50.
Alzheimer’s disease (AD) is the most common type of dementia in the elderly. It is characterized by the deposition of two forms of aggregates within the brain, the amyloid β plaques and tau neurofibrillary tangles. Currently, no disease-modifying agent is approved for the treatment of AD. Approved pharmacotherapies target the peripheral symptoms but they do not prevent or slow down the progression of the disease. Although several disease-modifying immunotherapeutic agents are in clinical development, many have failed due to lack of efficacy or serious adverse events. Epigenetic changes including DNA methylation and histone modifications are involved in learning and memory and have been recently highlighted for holding promise as potential targets for AD therapeutics. Dynamic and latent epigenetic alterations are incorporated in AD pathological pathways and present valuable reversible targets for AD and other neurological disorders. The approval of epigenetic drugs for cancer treatment has opened the door for the development of epigenetic drugs for other disorders including neurodegenerative diseases. In particular, methyl donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders. This review explores the area of epigenetics for potential AD interventions and presents the most recent findings in this field.
doi:10.1016/j.pharmthera.2013.03.010
PMCID: PMC3693222  PMID: 23562602
Alzheimer’s disease; DNA methylation; Epigenetics; Histone modification; Memory; Therapy
23.  Neuroimmune Communication in Hypertension and Obesity: A new therapeutic angle? 
Pharmacology & therapeutics  2013;138(3):428-440.
Hypertension is an epidemic health concern and a major risk factor for the development of cardiovascular disease. Although there are available treatment strategies for hypertension, numerous hypertensive patients do not have their clinical symptoms under control and it is imperative that new avenues to treat or prevent high blood pressure in these patients are developed. It is well established that increases in sympathetic nervous system (SNS) outflow and enhanced renin-angiotensin system (RAS) activity are common features of hypertension and various pathological conditions that predispose individuals to hypertension. More recently, hypertension has also become recognized as an immune condition and accumulating evidence suggests that interactions between the RAS, SNS and immune systems play a role in blood pressure regulation. This review summarizes what is known about the interconnections between the RAS, SNS and immune systems in the neural regulation of blood pressure. Based on the reviewed studies, a model for RAS/neuroimmune interactions during hypertension is proposed and the therapeutic potential of targeting RAS/neuroimmune interactions in hypertensive patients is discussed. Special emphasis is placed on the applicability of the proposed model to obesity-related hypertension.
doi:10.1016/j.pharmthera.2013.02.005
PMCID: PMC3646992  PMID: 23458610
angiotensin; renin; inflammation; sympathetic nervous system; microglia; blood pressure
24.  Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review 
Pharmacology & therapeutics  2013;138(3):333-408.
Despite considerable progress in genome- and proteome-based high-throughput screening methods and in rational drug design, the increase in approved drugs in the past decade did not match the increase of drug development costs. Network description and analysis not only gives a systems-level understanding of drug action and disease complexity, but can also help to improve the efficiency of drug design. We give a comprehensive assessment of the analytical tools of network topology and dynamics. The state-of-the-art use of chemical similarity, protein structure, protein-protein interaction, signaling, genetic interaction and metabolic networks in the discovery of drug targets is summarized. We propose that network targeting follows two basic strategies. The “central hit strategy” selectively targets central node/edges of the flexible networks of infectious agents or cancer cells to kill them. The “network influence strategy” works against other diseases, where an efficient reconfiguration of rigid networks needs to be achieved. It is shown how network techniques can help in the identification of single-target, edgetic, multi-target and allo-network drug target candidates. We review the recent boom in network methods helping hit identification, lead selection optimizing drug efficacy, as well as minimizing side-effects and drug toxicity. Successful network-based drug development strategies are shown through the examples of infections, cancer, metabolic diseases, neurodegenerative diseases and aging. Summarizing >1200 references we suggest an optimized protocol of network-aided drug development, and provide a list of systems-level hallmarks of drug quality. Finally, we highlight network-related drug development trends helping to achieve these hallmarks by a cohesive, global approach.
doi:10.1016/j.pharmthera.2013.01.016
PMCID: PMC3647006  PMID: 23384594
Cancer; Diabetes; Drug target; Network; Side-effects; Toxicity
25.  Polarity Proteins as Regulators of Cell Junction Complexes: Implications for Breast Cancer 
Pharmacology & therapeutics  2013;138(3):418-427.
The epithelium of multicellular organisms possesses a well-defined architecture, referred to as polarity that coordinates the regulation of essential cell features. Polarity proteins are intimately linked to the protein complexes that make the tight, adherens and gap junctions; they contribute to the proper localization and assembly of these cell-cell junctions within cells and consequently to functional tissue organization. The establishment of cell-cell junctions and polarity are both implicated in the regulation of epithelial modifications in normal and cancer situations. Uncovering the mechanisms through which cell-cell junctions and epithelial polarization are established and how their interaction with the microenvironment direct cell and tissue organization has opened new venues for the development of cancer therapies. In this review, we focus on the breast epithelium to highlight how polarity and cell-cell junction proteins interact together in normal and cancerous contexts to regulate major cellular mechanisms such as migration. The impact of these proteins on epigenetic mechanisms responsible for resetting cells towards oncogenesis is discussed in light of increasing evidence that tissue polarity modulates chromatin function. Finally, we give an overview of recent breast cancer therapies that target proteins involved in cell-cell junctions.
doi:10.1016/j.pharmthera.2013.02.004
PMCID: PMC3648792  PMID: 23458609
Breast cancer; Cell junction; Differentiation; Epigenetics; Mammary epithelial Cell; Polarity

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