Cardiac repair by epicardial EMT: Current targets and a potential role for the primary cilium Pharmacol. Therapeut. (IF 11.127) Pub Date : 2018-01-17 Jessica N. Blom, Qingping Feng
Despite therapeutic advances that have prolonged life, myocardial infarction (MI) remains a leading cause of death worldwide and imparts a significant economic burden. The advancement of treatments to improve cardiac repair post-MI requires the discovery of new targeted treatment strategies. Recent studies have highlighted the importance of the epicardial covering of the heart in both cardiac development and lower vertebrate cardiac regeneration. The epicardium serves as a source of cardiac cells including smooth muscle cells, endothelial cells and cardiac fibroblasts. Mammalian adult epicardial cells are typically quiescent. However, the fetal genetic program is reactivated post-MI, and epicardial epithelial-to-mesenchymal transition (EMT) occurs as an inherent mechanism to support neovascularization and cardiac healing. Unfortunately, endogenous EMT is not enough to encourage sufficient repair. Recent developments in our understanding of the mechanisms supporting the EMT process has led to a number of studies directed at augmenting epicardial EMT post-MI. With a focus on the role of the primary cilium, this review outlines the newly demonstrated mechanisms supporting EMT, the role of epicardial EMT in cardiac development, and promising advances in augmenting epicardial EMT as potential therapeutics to support cardiac repair post-MI.
Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy? Pharmacol. Therapeut. (IF 11.127) Pub Date : 2018-01-17 Eloísa Rubio-Beltrán, Alejandro Labastida-Ramírez, Carlos M. Villalón, Antoinette MaassenVanDenBrink
Migraine is a neurovascular disorder that involves activation of the trigeminovascular system and cranial vasodilation mediated by release of calcitonin gene-related peptide (CGRP). The gold standard for acute migraine treatment are the triptans, 5-HT1B/1D/(1F) receptor agonists. Their actions are thought to be mediated through activation of: (i) 5-HT1B receptors in cranial blood vessels with subsequent cranial vasoconstriction; (ii) prejunctional 5-HT1D receptors on trigeminal fibres that inhibit trigeminal CGRP release; and (iii) 5-HT1B/1D/1F receptors in central nervous system involved in (anti)nociceptive modulation. Unfortunately, coronary arteries also express 5-HT1B receptors whose activation would produce coronary vasoconstriction; hence, triptans are contraindicated in patients with cardiovascular disease. In addition, since migraineurs have an increased cardiovascular risk, it is important to develop antimigraine drugs devoid of vascular (side) effects. Ditans, here defined as selective 5-HT1F receptor agonists, were developed on the basis that most of the triptans activate trigeminal 5-HT1F receptors, which may explain part of the triptans' antimigraine action. Amongst the ditans, lasmiditan: (i) fails to constrict human coronary arteries; and (ii) is effective for the acute treatment of migraine in preliminary Phase III clinical trials. Admittedly, the exact site of action is still unknown, but lasmiditan possess a high lipophilicity, which suggests a direct action on the central descending antinociceptive pathways. Furthermore, since 5-HT1F receptors are located on trigeminal fibres, they could modulate CGRP release. This review will be particularly focussed on the similarities and differences between the triptans and the ditans, their proposed sites of action, side effects and their cardiovascular risk profile.
Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities ☆ Pharmacol. Therapeut. (IF 11.127) Pub Date : 2018-01-09 Sang-Bing Ong, Sauri Hernández-Reséndiz, Gustavo E. Crespo-Avilan, Regina T. Mukhametshina, Xiu-Yi Kwek, Hector A. Cabrera-Fuentes, Derek J. Hausenloy
Acute myocardial infarction (AMI) and the heart failure that often follows, are major causes of death and disability worldwide. As such, new therapies are required to limit myocardial infarct (MI) size, prevent adverse left ventricular (LV) remodeling, and reduce the onset of heart failure following AMI. The inflammatory response to AMI, plays a critical role in determining MI size, and a persistent pro-inflammatory reaction can contribute to adverse post-MI LV remodeling, making inflammation an important therapeutic target for improving outcomes following AMI. In this article, we provide an overview of the multiple players (and their dynamic roles) involved in the complex inflammatory response to AMI and subsequent LV remodeling, and highlight future opportunities for targeting inflammation as a therapeutic strategy for limiting MI size, preventing adverse LV remodeling, and reducing heart failure in AMI patients.
The Hippo pathway in normal development and cancer Pharmacol. Therapeut. (IF 11.127) Pub Date : 2018-01-03 Marcello Maugeri-Saccà, Ruggero De Maria
The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway. Over the past two decades, the Hippo pathway has increasingly been connected with developmental processes and tissue repair, being intimately tied to the function of tissue-specific progenitor cells. Pervasive activation of YAP/TAZ has been recognized in a multitude of human tumors and connected with the acquisition of malignant traits, including resistance to anticancer therapies, distant dissemination and maintenance of cancer stem cells. On this ground, Hippo-related biomarkers are increasingly investigated in translational studies striving to identify prognostic and predictive factors. In addition, the dependency of many tumors on YAP/TAZ may be exploited for therapeutic purposes. Albeit no direct inhibitors are currently available, drug repositioning approaches provided hints that YAP/TAZ inhibition can be achieved with old drugs, such as cholesterol-lowering agents or compounds blocking bone resorption.
Chronopathophysiological Implications of Orexin in Sleep Disturbances and Lifestyle-Related Disorders Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-29 Hiroshi Tsuneki, Tsutomu Wada, Toshiyasu Sasaoka
Sleep, a mysterious behavior, has recently been recognized as a crucial factor for health and longevity. The daily sleep/wake cycle provides the basis of biorhythms controlling whole-body homeostasis and homeodynamics; therefore, disruption of sleep causes several physical and psychological disorders, including cardiovascular disease, obesity, diabetes, cancer, anxiety, depression, and cognitive dysfunction. However, the mechanism linking sleep disturbances and sleep-related disorders remains unknown. Orexin (also known as hypocretin) is a neuropeptide produced in the hypothalamus. Central levels of orexin oscillate with the daily rhythm and peak at the awake phase. Orexin plays a major role in stabilizing the wakefulness state. Orexin deficiency causes sleep/wake-state instability, resulting in narcolepsy. Hyper-activation of the orexin system also causes sleep disturbances, such as insomnia, and hence, suvorexant, an orexin receptor antagonist, has been clinically used to treat insomnia. Importantly, central actions of orexin regulate motivated behaviors, stress response, and energy/glucose metabolism by coordinating the central-autonomic nervous systems and endocrine systems. These multiple actions of orexin maintain survival. However, it remains unknown whether chronopharmacological interventions targeting the orexin system ameliorate sleep-related disorders as well as sleep in humans. To understand the significance of adequate orexin action for prevention of these disorders, this review summarizes the physiological functions of daily orexin action and pathological implications of its mistimed or reduced action in sleep disturbances and sleep-related disorders (lifestyle-related physical and neurological disorders in particular). Timed administration of drugs targeting the orexin system may prevent lifestyle-related diseases by improving the quality of life in patients with sleep disturbances.
Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-28 Hitisha K. Patel, Teeru Bihani
Breast cancer is the most frequently diagnosed cancer in women, with estrogen receptor positive (ER +) breast cancer making up approximately 75% of all breast cancers diagnosed. Given the dependence on active ER signaling in these tumors, the predominant treatment strategy has been to inhibit various aspects of this pathway including directly antagonizing ER with the use of selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). Interestingly, the dependence on ER for breast cancer growth is often retained even after progression through several lines of antiestrogen therapy, making ER a bonafide biomarker for this cancer subtype and driving the continued research and development of novel ER-targeted therapeutics to treat this patient population. This, combined with the continuous discovery of mechanisms underlying endocrine resistance, is resulting in a continually evolving treatment landscape for ER + breast cancer. This review discusses various ER antagonists investigated for the treatment of breast cancer, outlining their pharmacological and tissue-specific mechanisms of action as well as their specified use within the ER + breast cancer setting. In addition, mechanisms of resistance to SERMs and SERDs, the use of ER antagonists in combination therapy strategies, and the ongoing development of novel drugs are also reviewed in the context of the changing clinical landscape of ER + breast cancer. Lastly, the role of SERMs and SERDs in non-breast cancer indications is also discussed.
Persistent induction of goblet cell differentiation in the airways: Therapeutic approaches Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-27 Andrew T. Reid, Punnam Chander Veerati, Reinoud Gosens, Nathan W. Bartlett, Peter A. Wark, Chris L. Grainge, Stephen M. Stick, Anthony Kicic, Fatemeh Moheimani, Philip M. Hansbro, Darryl A. Knight
Dysregulated induction of goblet cell differentiation results in excessive production and retention of mucus and is a common feature of several chronic airways diseases. To date, therapeutic strategies to reduce mucus accumulation have focused primarily on altering the properties of the mucus itself, or have aimed to limit the production of mucus-stimulating cytokines. Here we review the current knowledge of key molecular pathways that are dysregulated during persistent goblet cell differentiation and highlights both pre-existing and novel therapeutic strategies to combat this pathology.
Which place of pharmacological approaches beyond continuous positive airway pressure to treat vascular disease related to obstructive sleep apnea? ☆ Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-23 Elodie Gautier-Veyret, Jean-Louis Pépin, Françoise Stanke-Labesque
Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial or complete upper airway obstruction, occurring during sleep, leading to chronic intermittent hypoxia (IH), which harms the cardiovascular system. OSA is associated with both functional and structural vascular alterations that contribute to an increased prevalence of fatal and non-fatal cardiovascular events. OSA is a heterogeneous disease with respect to the severity of hypoxia, the presence of daytime symptoms, obesity, and cardiovascular comorbidities. Various clusters of OSA phenotypes have been described leading to more highly personalized treatment. The aim of this review is to describe the various therapeutic strategies including continuous positive airway pressure (CPAP), oral appliances, surgery, weight loss, and especially pharmacological interventions that have been evaluated to reduce vascular alterations in both OSA patients and preclinical animal models. Conventional therapies, predominantly CPAP, have a limited impact on vascular alterations in the presence of co-morbidities. A better knowledge of pharmacological therapies targeting IH-induced vascular alterations will facilitate the use of combined therapies and is crucial for designing clinical trials in well-defined OSA phenotypes.
Prostaglandin E2 as a Regulator of Immunity to Pathogens ☆ Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-22 Giovanny J. Martínez-Colón, Bethany B. Moore
The body is exposed to foreign pathogens every day, but remarkably, most pathogens are effectively cleared by the innate immune system without the need to invoke the adaptive immune response. Key cellular components of the innate immune system include macrophages and neutrophils and the recruitment and function of these cells are tightly regulated by chemokines and cytokines in the tissue space. Innate immune responses are also known to regulate development of adaptive immune responses often via the secretion of various cytokines. In addition to these protein regulators, numerous lipid mediators can also influence innate and adaptive immune functions. In this review, we cover one particular lipid regulator, prostaglandin E2 (PGE2) and describe its synthesis and signaling and what is known about the ability of this lipid to regulate immunity and host defense against viral, fungal and bacterial pathogens.
Recent advances in mass spectrometry-based approaches for proteomics and biologics: Great contribution for developing therapeutic antibodies Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-22 Noriko Iwamoto, Takashi Shimada
Since the turn of the century, mass spectrometry (MS) technologies have continued to improve dramatically, and advanced strategies that were impossible a decade ago are increasingly becoming available. The basic characteristics behind these advancements are MS resolution, quantitative accuracy, and information science for appropriate data processing. The spectral data from MS contain various types of information. The benefits of improving the resolution of MS data include accurate molecular structural-derived information, and as a result, we can obtain a refined biomolecular structure determination in a sequential and large-scale manner. Moreover, in MS data, not only accurate structural information but also the generated ion amount plays an important rule. This progress has greatly contributed a research field that captures biological events as a system by comprehensively tracing the various changes in biomolecular dynamics. The sequential changes of proteome expression in biological pathways are very essential, and the amounts of the changes often directly become the targets of drug discovery or indicators of clinical efficacy. To take this proteomic approach, it is necessary to separate the individual MS spectra derived from each biomolecule in the complexed biological samples. MS itself is not so infinite to perform the all peak separation, and we should consider improving the methods for sample processing and purification to make them suitable for injection into MS.The above-described characteristics can only be achieved using MS with any analytical instrument. Moreover, MS is expected to be applied and expand into many fields, not only basic life sciences but also forensic medicine, plant sciences, materials, and natural products. In this review, we focus on the technical fundamentals and future aspects of the strategies for accurate structural identification, structure-indicated quantitation, and on the challenges for pharmacokinetics of high-molecular-weight protein biopharmaceuticals.
Bispecific antibodies for cancer therapy: A review ☆ Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-18 Anuradha Krishnamurthy, Antonio Jimeno
The ability to produce monoclonal antibodies with defined and distinct specificities has resulted in a vast spectrum of therapeutic monoclonal antibodies including bispecific antibodies (BsAbs). Several types of BsAbs have been produced but the most well-known of these are trispecific antibodies (TrAbs or TrioMabs) and bispecific T cell engager antibodies (BiTE). TrAbs have two variable segments for antigen binding and an Fc component to recruit immune cells. Catumaxomab is a TrAb that has orphan drug status from the Food and Drug Administration (FDA) for EpCam positive gastric and ovarian tumors and was previously approved by the European Medicinal Agency (EMA) for the same indication. One arm of catumaxomab binds to EpCAM, the other binds to CD3 on T cells and the Fc portion recruits immune cells. Catumaxomab is no longer being produced by the manufacturer due to logistic considerations and hence not available in the European market. Blinatumomab is a BiTE that comprises of two variable segments only with one arm binding to CD19 and the other binding to CD3. Blinatumomab has been approved for relapsed or refractory B-cell precursor ALL in adults and children by the FDA. There are over 50 bispecific antibodies currently on clinical trials for various malignancies and the hope is that in the future many of these, with better understanding of principles and techniques of production, will provide treatment options for many different types of cancer.
Mechanistic understanding of insulin receptor modulation: Implications for the development of anti-diabetic drugs Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-18 Na-Oh Yunn, Jaeyoon Kim, Youndong Kim, Ingo Leibiger, Per-Olof Berggren, Sung Ho Ryu
The insulin receptor is an important regulator of metabolic processes in the body, and in particular of glucose homeostasis, including glucose uptake into peripheral tissues. Thus, insulin administration is an effective treatment for diabetes, which is characterized by chronic elevation of blood glucose. However, insulin is not only a metabolic regulator, but also functions as a growth hormone. Accordingly, studies of long-term insulin administration and of the hyperinsulinemia associated with type 2 diabetes have raised concerns about possible increases in the risks of cancer and atherosclerosis, due to excessive stimulation of cell proliferation. Interestingly, some insulin receptor ligands that have been developed based on a peptide, an antibody, and an aptamer selectively have metabolic effects exerted through the insulin receptor but do not cause significant cellular proliferation. Although these ligands therefore have potential as anti-diabetic drugs for advanced diabetes care, the mechanism whereby they specifically activate the insulin receptor is still unclear. Recently, studies of the structure of the insulin receptor have progressed considerably, and have provided further mechanistic understanding of insulin receptor activation. Based on this progress, we propose a mechanistic model of this specificity and discuss the potential for the development of novel anti-diabetic drugs that would not have the adverse effects caused by excessive mitogenic action.
Potential for Therapeutic Targeting of AKAP Signaling Complexes in Nervous System Disorders Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-17 Angela R. Wild, Mark L. Dell’Acqua
A common feature of neurological and neuropsychiatric disorders is a breakdown in the integrity of intracellular signal transduction pathways. Dysregulation of ion channels and receptors in the cell membrane and the enzymatic mediators that link them to intracellular effectors can lead to synaptic dysfunction and neuronal death. However, therapeutic targeting of these ubiquitous signaling elements can lead to off-target side effects due to their widespread expression in multiple systems of the body. A-kinase anchoring proteins (AKAPs) are multivalent scaffolding proteins that compartmentalize a diverse range of receptor and effector proteins to streamline signaling within nanodomain signalosomes. A number of essential neurological processes are known to critically depend on AKAP-directed signaling and an understanding of the role AKAPs play in nervous system disorders has emerged in recent years. Selective targeting of AKAP protein-protein interactions may be a means to uncouple pathologically active signaling pathways in neurological disorders with a greater degree of specificity. In this review we will discuss the role of AKAPs in both regulating normal nervous system function and dysfunction associated with di7sease, and the potential for therapeutic targeting of AKAP signaling complexes.
The Aryl Hydrocarbon Receptor in the Crossroad of Signalling Networks with Therapeutic Value Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-16 Ángel C. Roman, José M. Carvajal-Gonzalez, Jaime M. Merino, Sonia Mulero-Navarro, Pedro M. Fernández-Salguero
The aryl hydrocarbon receptor (AhR) is well-known for its major contributions to the cellular responses against environmental toxins and carcinogens. Notably, AhR has also emerged as a key transcription factor controlling many physiological processes including cell proliferation and apoptosis, differentiation, adhesion and migration, pluripotency and stemness. These novel functions have broadened our understanding of the signaling pathways and molecular intermediates interacting with AhR under both homeostatic and pathological conditions. Recent discoveries link AhR with the function of essential organs such as liver, skin and gonads, and with complex organismal structures including the immune and cardiovascular systems. The identification of potential endogenous ligands able to regulate AhR activity, opens the possibility of designing ad hoc molecules with pharmacological and/or therapeutic value to treat human diseases in which AhR may have a causal role. Integration of experimental data from in vitro and in vivo studies with “omic” analyses of human patients affected with cancer, immune diseases, inflammation or neurological disorders will likely contribute to validate the clinical relevance of AhR and the possible benefits of modulating its activity by pharmacologically-driven strategies. In this review, we will highlight signaling pathways involved in human diseases that could be targetable by AhR modulators and discuss the feasibility of using such molecules in therapy. The pros and cons of AhR-aimed approaches will be also mentioned.
Medications for Alcohol Use Disorders: An Overview Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-12-02 Mohammed Akbar, Mark Egli, Young-Eun Cho, Byoung-Joon Song, Antonio Noronha
Patients who suffer from alcohol use disorders (AUDs) usually go through various socio-behavioral and pathophysiological changes that take place in the brain and other organs. Recently, consumption of unhealthy food and excess alcohol along with a sedentary lifestyle has become a norm in both developed and developing countries. Despite the beneficial effects of moderate alcohol consumption, chronic and/or excessive alcohol intake is reported to negatively affect the brain, liver and other organs, resulting in cell death, organ damage/failure and death. The most effective therapy for alcoholism and alcohol related comorbidities is alcohol abstinence, however, chronic alcoholic patients cannot stop drinking alcohol. Therefore, targeted therapies are urgently needed to treat such populations. Patients who suffer from alcoholism and/or alcohol abuse experience harmful effects and changes that occur in the brain and other organs. Upon stopping alcohol consumption, alcoholic patients experience acute withdrawal symptoms followed by a protracted abstinence syndrome resulting in the risk of relapse to heavy drinking. For the past few decades, several drugs have been available for the treatment of AUDs. These drugs include medications to reduce or stop severe alcohol withdrawal symptoms during alcohol detoxification as well as recovery medications to reduce alcohol craving and support abstinence. However, there is no drug that completely antagonizes the adverse effects of excessive amounts of alcohol. This review summarizes the drugs which are available and approved by the FDA and their mechanisms of action as well as the medications that are under various phases of preclinical and clinical trials. In addition, the repurposing of the FDA approved drugs, such as anticonvulsants, antipsychotics, antidepressants and other medications, to prevent alcoholism and treat AUDs and their potential target mechanisms are summarized.
Orphan neuropeptides and receptors: Novel therapeutic targets Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-22 Lloyd D. Fricker, Lakshmi A. Devi
Neuropeptides are the largest class of intercellular signaling molecules, contributing to a wide variety of physiological processes. Neuropeptide receptors are therapeutic targets for a broad range of drugs, including medications to treat pain, addiction, sleep disorders, and nausea. In addition to > 100 peptides with known functions, many peptides have been identified in mammalian brain for which the cognate receptors have not been identified. Similarly, dozens of “orphan” G protein-coupled receptors have been identified in the mammalian genome. While it would seem straightforward to match the orphan peptides and receptors, this is not always easily accomplished. In this review we focus on peptides named PEN and big LEN, which are among the most abundant neuropeptides in mouse brain, and their recently identified receptors: GPR83 and GPR171. These receptors are co-expressed in some brain regions and are able to interact. Because PEN and big LEN are produced from the same precursor protein and co-secreted, the interaction of GPR83 and GPR171 is physiologically relevant. In addition to interactions of these two peptides/receptors, PEN and LEN are co-localized with neuropeptide Y and Agouti-related peptide in neurons that regulate feeding. In this review, using these peptide receptors as an example, we highlight the multiple modes of regulation of receptors and present the emerging view that neuropeptides function combinatorially to generate a network of signaling messages. The complexity of neuropeptides, receptors, and their signaling pathways is important to consider both in the initial deorphanization of peptides and receptors, and in the subsequent development of therapeutic applications.
TGFβ pathway inhibition in the treatment of non-small cell lung cancer Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-10 Pınar Ö. Eser, Pasi A. Jänne
Advanced non-small cell lung cancer (NSCLC) continues to be an incurable family of thoracic malignancies that is chronically managed with chemotherapy, targeted therapy, and immunotherapy. While the discovery of driver oncogenes and the advent of targeted and immunotherapies in the last decade have vastly improved clinical disease management for patients harboring druggable mutations, the mainstay treatment for the majority of NSCLC patients remains cytotoxic chemotherapy. The clinical efficacy of targeted, immune, and cytotoxic therapies is limited by the development of drug resistance. Transforming growth factor beta (TGFβ) signaling, a crucial mediator of embryonic development and peripheral immune tolerance, may be dysregulated in some malignant contexts, including lung cancer, and has been correlated with poor prognosis in advanced cancers. Aberrant upregulation of TGFβ expression in the tumor microenvironment has also been implicated in promoting NSCLC progression and metastasis, as well as driving the development of resistance to cytotoxic, targeted, and immunomodulatory therapeutic interventions. Here, we examine the mechanisms underlying TGFβ-mediated drug resistance in NSCLC, and consider TGFβ as a combinatorial therapeutic intervention to circumvent or delay the development of NSCLC treatment resistance.
Post-Stroke Depression: Mechanisms and Pharmacological Treatment Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-09 Roberto Federico Villa, Federica Ferrari, Antonio Moretti
Depression, the most frequent psychiatric disorder following ischaemic stroke, negatively affects survivals' functional outcome, response to rehabilitation and quality of life. Approximately, one-third of them are affected by post-stroke depression (PSD), making it a serious social and public health problem and anti-depressant preventive and curative therapies worth investigating. However, a two-way association between depression and stroke has been also established: stroke increases the risk of PSD, but depression is an independent risk factor for stroke. The pathophysiology of PSD is presumably multifactorial, involving a combination of various ischaemia-induced neurobiological dysfunctions in the context of psychosocial distress. The damage of frontal-basal ganglia brainstem pathway suggested alterations of monoaminergic neurotransmitter systems. Several lines of evidence point to a relationship between neuroinflammatory response to acute ischaemic stroke, stress activation of the hypothalamic-pituitary-adrenal (HPA) axis and the impairment of adaptative response (neurogenesis) within a background of altered energy metabolism (i.e. mitochondrial dysfunction). The complexity of PSD mechanisms makes its biologically-based prevention and treatment a difficult task. So far, especially the selective serotonin (5-hydroxytriptamine, 5-HT) reuptake inhibitors (SSRIs) have mainly proved to be clinically active in preventing and treating PSD, although their effects have not been demonstrated unequivocally and they may cause bleeding and intracerebral haemorrhage. Besides the primary pharmacological activity of SSRIs (i.e. the inhibition of neuronal 5-HT reuptake) there is evidence supporting their pleiotropic mechanisms of action: anti-inflammatory and enhanced neurogenesis through the up-regulation of neurotrophins, conceivably supported by the stimulation of mitochondrial energy metabolism. In the future, novel developments might point at anti-cytokine modulators which can improve symptoms of depression, especially in subjects affected by inflammation processes. This review will address the various areas of epidemiology, pathophysiology, preventive and therapeutic strategies for PSD. The activity of SSRIs in clinical trials, as well as their pharmacology, pharmacokinetics, safety and mechanisms of action, will be examined in detail. A final section will deal with the effect of depression as risk factor for stroke. The literature on PubMed from 1990 to 2017 was reviewed.
Role of kinase-coupled TRP channels in mineral homeostasis Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-09 Vladimir Chubanov, Lorenz Mittermeier, Thomas Gudermann
Transient receptor potential (TRP) proteins TRPM6 and TRPM7 are α-kinase-coupled divalent cation-selective channels activated upon a reduction of cytosolic levels of Mg2 + and Mg·ATP. Emerging evidence indicate that one of the main physiological functions of TRPM6 and TRPM7 is maintaining of cellular metabolism of Mg2 + and likely other essential metals such as Ca2 + and Zn2 +. Recent experiments with genetic animal models have shown that TRPM6 and TRPM7 are essential for epithelial Mg2 + transport in the placenta and intestine. In addition, mutations in TRPM6 or TRPM7 have been linked to Mg2 + deficiency in humans. However, many key functional aspects of these remarkable proteins as well as mechanisms of the associated channelopathies remain incompletely understood. The present review article highlights the recent significant progress in the field with the focus on the vital roles of TRPM7 and TRPM7 in mineral homeostasis.
The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: recent findings and new perspectives Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-08 Andrea Huwiler, Uwe Zangemeister-Wittke
The immunomodulatory drug fingolimod (FTY720, GilenyaR) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P1 subtype by induction of receptor downregulation. Since S1P1 is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression. Numerous preclinical studies have since been performed with the aim to increase the spectrum of potential indications for fingolimod with emphasis on other autoimmune disorders and diseases associated with inflammation and uncontrolled cell proliferation, including cancer. As an alternative to fingolimod, novel S1PR modulators with a more selective receptor activation profile and improved pharmacokinetic performance and tolerability have also been developed. Preclinical and clinical studies are ongoing to investigate their therapeutic potential for various indications. This review discusses the most relevant preclinical and clinical findings from S1PR-targeting and from less-well defined off-target effects reported in the literature, and reveals perspectives for using fingolimod and functionally-related derivatives and new formulations in the management of an increasing number of diseases.
Readers of DNA methylation, the MBD family as potential therapeutic targets ☆ Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-08 Gordon D. Ginder, David C. Williams Jr.
DNA methylation represents a fundamental epigenetic modification that regulates chromatin architecture and gene transcription. Many diseases, including cancer, show aberrant methylation patterns that contribute to the disease phenotype. DNA methylation inhibitors have been used to block methylation dependent gene silencing to treat hematopoietic neoplasms and to restore expression of developmentally silenced genes. However, these inhibitors disrupt methylation globally and show significant off-target toxicities. As an alternative approach, we have been studying readers of DNA methylation, the 5-methylcytosine binding domain family of proteins, as potential therapeutic targets to restore expression of aberrantly and developmentally methylated and silenced genes. In this review, we discuss the role of DNA methylation in gene regulation and cancer development, the structure and function of the 5-methylcytosine binding domain family of proteins, and the possibility of targeting the complexes these proteins form to treat human disease.
Hormesis as a mechanistic approach to understanding herbal treatments in traditional Chinese medicine Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-08 Dali Wang, Edward J. Calabrese, Baoling Lian, Zhifen Lin, Vittorio Calabrese
Traditional Chinese medicine (TCM) has been long practiced and is becoming ever more widely recognized as providing curative and/or healing treatments for a number of diseases and physiological conditions. This paper posits that herbal medicines used in TCM treatments may act through hormetic dose-response mechanisms. It is proposed that the stimulatory (i.e., low dose) and inhibitory (i.e., high dose) components of the hormetic dose response correspond to respective “regulating” and “curing” aspects of TCM herbal treatments. Specifically, the “regulating” functions promote adaptive or preventive responses, while “curing” treatments alleviate the clinical symptoms. Patterns of hormetic responses are described, and the applicability of these processes to herbal medicines of TCM are explicated. It is noted that a research agenda aimed at elucidating these mechanisms and patterns would be expansive and complex. However, we argue its value, in that hormesis may afford something akin to a Rosetta Stone with which to interpret, translate, and explain TCM herbology in ways that are aligned with biomedical perspectives that could enable a more integrative approach to medicine.
Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-08 Sabine Hombach-Klonisch, Maryam Mehrpour, Shahla Shojaei, Craig Harlos, Marshall Pitz, Ahmed Hamai, Krzysztof Siemianowicz, Wirginia Likus, Emilia Wiechec, Brian D. Toyota, Reyhane Hoshyar, Amir Seyfoori, Zahra Sepehri, Sudharsana R. Ande, Forough Khadem, Mohsen Akbari, Adrienne M. Gorman, Afshin Samali, Thomas Klonisch, Saeid Ghavami
Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15 months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.
Therapeutic potential of omega-3 fatty acid-derived epoxyeicosanoids in cardiovascular and inflammatory diseases Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-07 Wolf-Hagen Schunck, Anne Konkel, Robert Fischer, Karsten-Henrich Weylandt
Numerous benefits have been attributed to dietary long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs), including protection against cardiac arrhythmia, triglyceride-lowering, amelioration of inflammatory, and neurodegenerative disorders. This review covers recent findings indicating that a variety of these beneficial effects are mediated by “omega-3 epoxyeicosanoids”, a class of novel n-3 LC-PUFA-derived lipid mediators, which are generated via the cytochrome P450 (CYP) epoxygenase pathway. CYP enzymes, previously identified as arachidonic acid (20:4n-6; AA) epoxygenases, accept eicosapentaenoic acid (20:5n-3; EPA) and docosahexaenoic acid (22:6n-3; DHA), the major fish oil n-3 LC-PUFAs, as efficient alternative substrates. In humans and rodents, dietary EPA/DHA supplementation causes a profound shift of the endogenous CYP-eicosanoid profile from AA- to EPA- and DHA-derived metabolites, increasing, in particular, the plasma and tissue levels of 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP). Based on preclinical studies, these omega-3 epoxyeicosanoids display cardioprotective, vasodilatory, anti-inflammatory, and anti-allergic properties that contribute to the beneficial effects of n-3 LC-PUFAs in diverse disease conditions ranging from cardiac disease, bronchial disorders, and intraocular neovascularization, to allergic intestinal inflammation and inflammatory pain. Increasing evidence also suggests that background nutrition as well as genetic and disease state-related factors could limit the response to EPA/DHA-supplementation by reducing the formation and/or enhancing the degradation of omega-3 epoxyeicosanoids. Recently, metabolically robust synthetic analogs mimicking the biological activities of 17,18-EEQ have been developed. These drug candidates may overcome limitations of dietary EPA/DHA supplementation and provide novel options for the treatment of cardiovascular and inflammatory diseases.
G protein-coupled receptors as anabolic drug targets in osteoporosis Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-11-07 Natalie Diepenhorst, Patricia Rueda, Anna E. Cook, Philippe Pastoureau, Massimo Sabatini, Christopher J. Langmead
Osteoporosis is a progressive bone disorder characterised by imbalance between bone building (anabolism) and resorption (catabolism). Most therapeutics target inhibition of osteoclast-mediated bone resorption, but more recent attention in early drug discovery has focussed on anabolic targets in osteoblasts or their precursors. Two marketed agents that display anabolic properties, strontium ranelate and teriparatide, mediate their actions via the G protein-coupled calcium-sensing and parathyroid hormone-1 receptors, respectively. This review explores their activity, the potential for improved therapeutics targeting these receptors and other putative anabolic GPCR targets, including Smoothened, Wnt/Frizzled, relaxin family peptide, adenosine, cannabinoid, prostaglandin and sphingosine-1-phosphate receptors.
Allosteric pathways in nuclear receptors — Potential targets for drug design Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-31 Elias J. Fernandez
The nuclear receptor family of transcription factor proteins mediates endocrine function and plays critical roles in the development, physiology and pharmacology. Malfunctioning nuclear receptors are associated with several disease states. The functional activity of nuclear receptors is regulated by small molecular hormonal and synthetic molecules. Multiple sources of evidence have identified and distinguished between the different allosteric pathways initiated by ligands, DNA and cofactors such as co-activators and co-repressors. Also, these biophysical studies are attempting to determine how these pathways that regulate co-activator and DNA recognition can control gene transcription. Thus, there is a growing interest in determining the genome-scale impact of allostery in nuclear receptors. Today, it is accepted that a detailed understanding of the allosteric regulatory pathways within the nuclear receptor molecular complex will enable the development of efficient drug therapies in the long term.
Emerging tumor spheroids technologies for 3D in vitro cancer modeling Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-31 Tânia Rodrigues, Banani Kundu, Joana Silva-Correia, S.C. Kundu, Joaquim M. Oliveira, Rui L. Reis, Vitor M. Correlo
Cancer is a leading cause of mortality and morbidity worldwide. Around 90% of deaths are caused by metastasis and just 10% by primary tumor. The advancement of treatment approaches is not at the same rhythm of the disease; making cancer a focal target of biomedical research. To enhance the understanding and promts the therapeutic delivery; concepts of tissue engineering are applied in the development of in vitro models that can bridge between 2D cell culture and animal models, mimicking tissue microenvironment. Tumor spheroid represents highly suitable 3D organoid-like framework elucidiating the intra and inter cellular signaling of cancer, like that formed in physiological niche. However, spheroids are of limited value in studying critical biological phenomenon such as tumor-stroma interactons involving extra cellular matrix or immune system. Therefore, a compelling need of tailoring spheroid technologies with physiologically relevant biomaterials or in silico models, is ever emerging. The diagnostic and prognostic role of spheroids rearrangements within biomaterials or microfluidic channel is indicative of patient management; particularly for the decision of targated therapy. Fragmented information on available in vitro spheroid models and lack of critical analysis on transformation aspects of these strategies; pushes the urge to comprehensively overview the recent technological advancements (e.g. bioprinting, micro-fluidic technologies or use of biomaterials to attain the third dimension) in the shed of tranlationable cancer research. In present article, relationships between current models and their possible exploitation in clinical success is explored with the highlight of existing challenges in defining therapeutic targets and screening of drug efficacy.
Analysis of Natural Product Regulation of Opioid Receptors in the treatment of Human Disease Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-31 S. Badal, S. Turfus, R. Rajnarayanan, C. Wilson-Clarke, S.L. Sandiford
Opioid receptors (ORs), μOR, δOR, κOR and ORL1 mediate numerous signaling cascades, most importantly, through the modulation of ion channels. Research demonstrates the role of OR mediated signal transduction in treating pain, cancer, neurodegenerative disorders and cardiac insults. Yet, the primary application of drugs that modulate ORs is analgesia. Current opioids like morphine that are mainly μOR orthosteric agonists attract many undesirable side-effects (constipation, urinary retention, respiratory depression and hypotension) and the existing modus operandi against these is the inclusion of a μOR antagonist (for example. naloxone) which itself produces side-effects. As such, there is a current thrust to delineate the anti-nociceptive pathways mediated by ORs from the pathways involved in their induction of debilitating side-effects, in order to develop enhanced lead molecules. This review discusses the effects of natural products on the OR-induced signaling cascades and compares these to current synthetic leads and drugs. Important to these discussions is the complexity of OR signaling which involves OR trafficking, de- and re-sensitization, homo- and hetero-dimerization, the type of ligand binding (agonist, antagonist, reverse antagonist, orthosteric and allosteric agonist and antagonist in the context of biased agonism) and reasons for dysregulation that primarily occur because of inter-individual variations. Our current understanding of the different forms of ORs has expanded, thus introducing the concept of allosterism, which is also discussed. The authors present possible combination therapies to be explored towards developing the ‘Holy Grail’ of analgesics, for example, ignavine, the natural μOR positive allosteric modulator (PAM) with codeine and the natural fascaplysin, a balanced agonist with fentanyl. There remain many gaps in natural products research on ORs, more so on ORL1 and δ- and ҡ receptors. Furthermore, additional exploration of ORs’ modulation is needed for ameliorating other associated disease conditions of global concern.
Conserved structural and functional aspects of the tripartite motif gene family point towards therapeutic applications in multiple diseases Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-31 Liubov V. Gushchina, Thomas A. Bodnar, Sayak Bhattacharya, Noah L. Weisleder
The tripartite motif (TRIM) gene family is a highly conserved group of E3 ubiquitin ligase proteins that can establish substrate specificity for the ubiquitin-proteasome complex and also have proteasome-independent functions. While several family members were studied previously, it is relatively recent that over 80 genes, based on sequence homology, were grouped to establish the TRIM gene family. Functional studies of various TRIM genes linked these proteins to modulation of inflammatory responses showing that they can contribute to a wide variety of disease states including cardiovascular, neurological and musculoskeletal diseases, as well as various forms of cancer. Given the fundamental role of the ubiquitin-proteasome complex in protein turnover and the importance of this regulation in most aspects of cellular physiology, it is not surprising that TRIM proteins display a wide spectrum of functions in a variety of cellular processes. This broad range of function and the highly conserved primary amino acid sequence of family members, particularly in the canonical TRIM E3 ubiquitin ligase domain, complicates the development of therapeutics that specifically target these proteins. A more comprehensive understanding of the structure and function of TRIM proteins will help guide therapeutic development for a number of different diseases. This review summarizes the structural organization of TRIM proteins, their domain architecture, common and unique post-translational modifications within the family, and potential binding partners and targets. Further discussion is provided on efforts to target TRIM proteins as therapeutic agents and how our increasing understanding of the nature of TRIM proteins can guide discovery of other therapeutics in the future.
Effect fingerprinting of new psychoactive substances (NPS): What can we learn from in vitro data? Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-31 Laura Hondebrink, Anne Zwartsen, Remco H.S. Westerink
The use of new psychoactive substances (NPS) is increasing and currently > 600 NPS have been reported. However, limited information on neuropharmacological and toxicological effects of NPS is available, hampering risk characterization.We reviewed the literature on the in vitro neuronal modes of action to obtain effect fingerprints of different classes of illicit drugs and NPS. The most frequently reported NPS were selected for review: cathinones (MDPV, α-PVP, mephedrone, 4-MEC, pentedrone, methylone), cannabinoids (JWH-018), (hallucinogenic) phenethylamines (4-fluoroamphetamine, benzofurans (5-APB, 6-APB), 2C-B, NBOMes (25B-NBOMe, 25C-NBOMe, 25I-NBOMe)), arylcyclohexylamines (methoxetamine) and piperazine derivatives (mCCP, TFMPP, BZP).Our effect fingerprints highlight the main modes of action for the different NPS studied, including inhibition and/or reversal of monoamine reuptake transporters (cathinones and non-hallucinogenic phenethylamines), activation of 5-HT2 receptors (hallucinogenic phenethylamines and piperazines), activation of cannabinoid receptors (cannabinoids) and inhibition of NDMA receptors (arylcyclohexylamines). Importantly, we identified additional targets by relating reported effect concentrations to the estimated human brain concentrations during recreational use. These additional targets include dopamine receptors, α- and β-adrenergic receptors, GABAA receptors and acetylcholine receptors, which may all contribute to the observed clinical symptoms following exposure.Additional data is needed as the number of NPS continues to increase. Also, the effect fingerprints we have obtained are still incomplete and suffer from a large variation in the reported effects and effect sizes. Dedicated in vitro screening batteries will aid in complementing specific effect fingerprints of NPS. These fingerprints can be implemented in the risk assessments of NPS that are necessary for eventual control measures to reduce Public Health risks.
Cytokines as therapeutic targets in primary Sjögren syndrome Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-29 Soledad Retamozo, Alejandra Flores-Chavez, Marta Consuegra-Fernández, Francisco Lozano, Manuel Ramos-Casals, Pilar Brito-Zerón
Primary Sjögren syndrome (SjS) is a systemic autoimmune disease that may affect 1 in 1000 people (overwhelmingly women) and that can be a serious disease with excess mortality due to severe organ-specific involvements and the development of B cell lymphoma; systemic involvement clearly marks the disease prognosis, and strongly suggests the need for closer follow-up and more robust therapeutic management. Therapy is established according to the organ involved and severity. As a rule, the management of systemic SjS should be organ-specific, with glucocorticoids and immunosuppressive agents limited to potentially-severe involvements; unfortunately, the limited evidence available for these drugs, together with the potential development of serious adverse events, makes solid therapeutic recommendations difficult. The emergence of biological therapies has increased the therapeutic armamentarium available to treat primary SjS. Biologics currently used in SjS patients are used off-label and are overwhelmingly agents targeting B cells, but the most recent studies are moving on into the evaluation of targeting specific cytokines involved in the SjS pathogenesis. The most recent etiopathogenic advances in SjS are shedding some light in the search for new highly-selective biological therapies without the adverse effects of the standard drugs currently used (corticosteroids and immunosuppresants drugs). This review summarizes the potential pharmacotherapeutic options targeting the main cytokine families involved in the etiopathogenesis of primary SjS and analyzes potential insights for developing new therapies.
Live or let die: Neuroprotective and anti-cancer effects of nutraceutical antioxidants Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-18 Xiao-Yuan Mao, Ming-Zhu Jin, Jin-Fei Chen, Hong-Hao Zhou, Wei-Lin Jin
Diet sources are closely involved in the pathogenesis of diverse neuropsychiatric disorders and cancers, in addition to inherited factors. Currently, natural products or nutraceuticals (commonly called medical foods) are increasingly employed for adjunctive therapy of these patients. However, the potential molecular mechanisms of the nutrient efficacy remain elusive. In this review, we summarized the neuroprotective and anti-cancer mechanisms of nutraceuticals. It was concluded that the nutraceuticals exerted neuroprotection and suppressed tumor growth possibly through the differential modulations of redox homeostasis. In addition, the balance between reactive oxygen species (ROS) production and ROS elimination was manipulated by multiple molecular mechanisms, including cell signaling pathways, inflammation, transcriptional regulation and epigenetic modulation, which were involved in the therapeutic potential of nutraceutical antioxidants against neurological diseases and cancers. We specifically proposed that ROS scavenging was integral in the neuroprotective potential of nutraceuticals, while alternation of ROS level (either increase or decrease) or disruption of redox homeostasis (ROS addiction) constituted the anti-cancer property of these compounds. We also hypothesized that ROS-associated ferroptosis, a novel type of lipid ROS-dependent regulatory cell death, was likely to be a critical mechanism for the nutraceutical antioxidants. Targeting ferroptosis is advantageous to develop new nutraceuticals with more effective and lower adverse reactions for curing patients with neuropsychiatric diseases or carcinomas.
CYP-mediated drug metabolism in the brain impacts drug response Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-10 Douglas M. McMillan, Rachel F. Tyndale
The functional role of cytochrome P450 (CYP) enzymes in the brain is an exciting and evolving field of research. CYPs are present and active in the brain, with heterogeneous patterns of expression, activity, and sensitivity to modulation across cell types, regions, and species. Despite total brain CYP expression being a fraction of hepatic CYP expression, the expanding literature of in vitro and in vivo experiments have provided evidence that brain CYPs can impact acute and chronic drug response, susceptibility to damage by neurotoxins, and are associated with altered personality, behaviour, and risk of neurological disease. They may also play a role in endogenous neurotransmitter and neurosteroid homeostasis. This review goes through the characterization of brain CYPs across species, the patterns of susceptibility of brain CYPs to exogenous induction, and recent preclinical evidence of the potential role of brain CYPs in vivo (e.g. CYP2D), along with the development of experiment paradigms that allow modulation of brain CYP activity without affecting CYP activity in the liver. Understanding brain CYP function, and changes therein, may provide unique strategies for the development of CNS-acting therapeutics metabolized locally in the brain, as well as therapeutics to target brain CYPs directly.
Antimicrobial Peptides, Nanotechnology, and Natural Metabolites as Novel Approaches for Cancer Treatment Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-10 Michel L. Leite, Nicolau B. da Cunha, Fabricio F. Costa
Despite the advances in tumor identification and treatment, cancer remains the primary driver of death around the world. Also, regular treatments for the disease are incapable of targeting particular cancer types at different stages since they are not specifically focused on harmful cells since they influence both solid and tumor cells, causing side effects and undesirable symptoms. Therefore, novel strategies should be developed to treat this disease. Several efforts have been made in this direction to find more effective alternatives to cancer treatment, such as the use of antimicrobial peptides (AMPs) with antitumoral activity, nanocarriers and natural compounds from a variety of sources. AMPs are more specific to their targets because of electrostatic interaction between AMPs and the cancer cells’ plasma membrane. Nanocarriers may be used for the delivery of non-soluble drugs, which are poorly stable or require a controlled release. In addition, natural compounds have been a rich source of anti-cancer agents for decades. In this review, these three approaches will be discussed, showing recent advances and advantages of using these strategies to treat cancer as well as the combination of these approaches increasing anticancer activity.
In vivo potency revisited – Keep the target inl sight Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-10 Johan Gabrielsson, Lambertus A. Peletier, Stephan Hjorth
Potency is a central parameter in pharmacological and biochemical sciences, as well as in drug discovery and development endeavors. It is however typically defined in terms only of ligand to target binding affinity also in in vivo experimentation, thus in a manner analogous to in in vitro studies. As in vivo potency is in fact a conglomerate of events involving ligand, target, and target-ligand complex processes, overlooking some of the fundamental differences between in vivo and in vitro may result in serious mispredictions of in vivo efficacious dose and exposure. The analysis presented in this paper compares potency measures derived from three model situations. Model A represents the closed in vitro system, defining target binding of a ligand when total target and ligand concentrations remain static and constant. Model B describes an open in vivo system with ligand input and clearance (Cl(L)), adding in parallel to the turnover (ksyn, kdeg) of the target. Model C further adds to the open in vivo system in Model B also the elimination of the target-ligand complex (ke(RL)) via a first-order process. We formulate corresponding equations of the equilibrium (steady-state) relationships between target and ligand, and complex and ligand for each of the three model systems and graphically illustrate the resulting simulations. These equilibrium relationships demonstrate the relative impact of target and target-ligand complex turnover, and are easier to interpret than the more commonly used ligand-, target- and complex concentration-time courses. A new potency expression, labelled L50, is then derived. L50 is the ligand concentration at half-maximal target and complex concentrations and is an amalgamation of target turnover, target-ligand binding and complex elimination parameters estimated from concentration-time data. L50 is then compared to the dissociation constant Kd (target-ligand binding affinity), the conventional Black & Leff potency estimate EC50, and the derived Michaelis-Menten parameter Km (target-ligand binding and complex removal) across a set of literature data. It is evident from a comparison between parameters derived from in vitro vs. in vivo experiments that L50 can be either numerically greater or smaller than the Kd (or Km) parameter, primarily depending on the ratio of kdeg-to-ke(RL). Contrasting the limit values of target R and target-ligand complex RL for ligand concentrations approaching infinity demonstrates that the outcome of the three models differs to a great extent. Based on the analysis we propose that a better understanding of in vivo pharmacological potency requires simultaneous assessment of the impact of its underlying determinants in the open system setting. We propose that L50 will be a useful parameter guiding predictions of the effective concentration range, for translational purposes, and assessment of in vivo target occupancy/suppression by ligand, since it also encompasses target turnover – in turn also subject to influence by pathophysiology and drug treatment. Different compounds may have similar binding affinity for a target in vitro (same Kd), but vastly different potencies in vivo. L50 points to what parameters need to be taken into account, and particularly that closed-system (in vitro) parameters should not be first choice when ranking compounds in vivo (open system).
Direct antiviral agents (DAAs) - a new age in the treatment of hepatitis C virus infection Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-10 Ulrich Spengler
Hepatitis C virus (HCV) is a global health problem, because infection frequently leads to chronic hepatitis C eventually progressing to liver cirrhosis and liver cancer. Improved insights into the HCV replication cycle and the role of HCV non-structural proteins has recently enabled to identify drugs directly acting on specific HCV target structures. Agents from three drug classes have been developed and approved by the health authorities. Combinations of two or more drugs from different classes achieve high (> 90%) HCV clearance rates and are well tolerated. This interferon-free DAA (direct antiviral agent) therapy has revolutionized antiviral therapy in hepatitis C so that successful hepatitis C treatment can be offered to virtually all patients irrespective of their co-morbidity. This review provides an overview over currently approved regimens and outlines their use in clinical practice. In addition potential short-comings of the current therapeutic options such as drug-drug interactions and selection of viral resistance are addressed. DAA combination therapy has the potential to obtain global control over hepatitis C. However, easy access to DAAs, availability of reliable HCV diagnostics, and affordable costs remain still important goals, which must be reached to globally eliminate hepatitis C.
The role of human dopamine transporter in NeuroAIDS ☆ Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-05 Jun Zhu, Subramaniam Ananthan, Chang-Guo Zhan
HIV-associated neurocognitive disorder (HAND) remains highly prevalent in HIV infected individuals and represents a special group of neuropathological disorders, which are associated with HIV-1 viral proteins, such as transactivator of transcription (Tat) protein. Cocaine abuse increases the incidence of HAND and exacerbates its severity by enhancing viral replication. Perturbation of dopaminergic transmission has been implicated as a risk determinant of HAND. The presynaptic dopamine (DA) transporter (DAT) is essential for DA homeostasis and dopaminergic modulation of the brain function including cognition. Tat and cocaine synergistically elevate synaptic DA levels by acting directly on human DAT (hDAT), ultimately leading to dysregulation of DA transmission. Through integrated computational modeling and experimental validation, key residues have been identified in hDAT that play a role in Tat-induced inhibition of DAT and induce transporter conformational transitions. This review presents current information regarding neurological changes in DAT-mediated dopaminergic system associated with HIV infection, DAT-mediated adaptive responses to Tat as well as allosteric modulatory effects of novel compounds on hDAT. Understanding the molecular mechanisms by which Tat induces DAT-mediated dysregulation of DA system is of great clinical interest for identifying new targets for an early therapeutic intervention for HAND.
The longevity gene INDY (I’m Not Dead Yet) in metabolic control: Potential as pharmacological target Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-05 Diana M. Willmes, Anica Kurzbach, Christine Henke, Grit Zahn, Alexander Heifetz, Jens Jordan, Stephen L. Helfand, Andreas L. Birkenfeld
The regulation of metabolic processes by the Indy (I’m Not Dead Yet) (SLC13A5/NaCT) gene was revealed through studies in Drosophila melanogaster and Caenorhabditis elegans. Reducing the expression of Indy in these species extended their life span by a mechanism resembling caloric restriction, without reducing food intake. In D. melanogaster, mutating the Indy gene reduced body fat content, insulin-like proteins and reactive oxygen species production. Subsequent studies indicated that Indy encodes a citrate transporter located on the cell plasma membrane. The transporter is highly expressed in the mammalian liver. We generated a mammalian knock out model deleting the mammalian homolog mIndy (SLC13A5). The knock out animals were protected from HFD induced obesity, fatty liver and insulin resistance. Moreover, we have shown that inducible and liver selective knock down of mIndy protects against the development of fatty liver and insulin resistance and that obese humans with type 2 diabetes and non-alcoholic fatty liver disease have increased levels of mIndy. Therefore, the transporter mINDY (NaCT) has been proposed to be an ‘ideal target for the treatment of metabolic disease’. A small molecule inhibitor of the mINDY transporter has been generated, normalizing glucose levels and reducing fatty liver in a model of diet induced obese mice. Taken together, studies from lower organisms, mammals and humans suggest that mINDY (NaCT) is an attractive target for the treatment of metabolic disease.
An Insight into the Complex Roles of Metallothioneins in Malignant Diseases with Emphasis on (Sub)Isoforms/Isoforms and Epigenetics Phenomena Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-05 Sona Krizkova, Marta Kepinska, Gabriella Emri, Tomas Eckschlager, Marie Stiborova, Petra Pokorna, Zbynek Heger, Vojtech Adam
Metallothioneins (MTs) belong to a group of small cysteine-rich proteins that are ubiquitous throughout all kingdoms. The main function of MTs is scavenging of free radicals and detoxification and homeostating of heavy metals. In humans, 16 genes localized on chromosome 16 have been identified to encode four MT isoforms labelled by numbers (MT-1 – MT-4). MT-2, MT-3 and MT-4 proteins are encoded by a single gene. MT-1 comprises many (sub)isoforms. The known active MT-1 genes are MT-1A, -1B, -1E, -1F, -1G, -1H, -1M and -1X. The rest of the MT-1 genes (MT-1C,-1D,-1I,-1J and -1L) are pseudogenes. The expression and localization of individual MT (sub)isoforms and pseudogenes vary at intra-cellular level and in individual tissues. Changes in MTs expression are associated with the process of carcinogenesis of various types of human malignancies, or with a more aggressive phenotype and therapeutic resistance. Hence, MT (sub)isoforms profiling status could be utilized for diagnostics and therapy of tumour diseases. This review aims on a comprehensive summary of methods for analysis of MTs at (sub)isoforms levels, their expression in single tumour diseases and strategies how this knowledge can be utilized in anticancer therapy.
Lung development, regeneration and plasticity: From disease physiopathology to drug design using induced pluripotent stem cells Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-04 Engi Ahmed, Caroline Sansac, Said Assou, Delphine Gras, Aurélie Petit, Isabelle Vachier, Pascal Chanez, John De Vos, Arnaud Bourdin
Lungs have a complex structure composed of different cell types that form approximately 17 million airway branches of gas-delivering bronchioles connected to 500 million gas-exchanging alveoli. Airways and alveoli are lined by epithelial cells that display a low rate of turnover at steady-state, but can regenerate the epithelium in response to injuries. Here, we review the key points of lung development, homeostasis and epithelial cell plasticity in response to injury and disease, because this knowledge is required to develop new lung disease treatments. Of note, canonical signaling pathways that are essential for proper lung development during embryogenesis are also involved in the pathophysiology of most chronic airway diseases. Moreover, the perfect control of these interconnected pathways is needed for the successful differentiation of induced pluripotent stem cells (iPSC) into lung cells. Indeed, differentiation of iPSC into airway epithelium and alveoli is based on the use of biomimetics of normal embryonic and fetal lung development. In vitro iPSC-based models of lung diseases can help us to better understand the impaired lung repair capacity and to identify new therapeutic targets and new approaches, such as lung cell therapy.
Mitochondria, telomeres and cell senescence: Implications for lung ageing and disease Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-04 Jodie Birch, Peter J. Barnes, Joao F. Passos
Cellular senescence, the irreversible loss of replicative capacity in somatic cells, plays a causal role in the development of age-related pathology and in a number of age-related chronic inflammatory diseases. The ageing lung is marked by an increasing number of senescent cells, and evidence is mounting that senescence may directly contribute to a number of age-related respiratory diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Telomere dysfunction and alterations in mitochondrial homeostasis frequently occur in cellular senescence and are important to the development of the often detrimental senescence-associated secretory phenotype (SASP). The roles of telomeres, the mitochondria and cellular senescence in lung ageing and disease are discussed. Therapeutic interventions targeting cellular senescence are considered for delaying or potentially reversing age-related respiratory disease.
Toll-like receptors and their role in persistent pain Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-04 Michael J. Lacagnina, Linda R. Watkins, Peter M. Grace
One of the fundamental mechanisms whereby the innate immune system coordinates inflammatory signal transduction is through Toll-like receptors (TLRs), which function to protect and defend the host organism by initiating inflammatory signaling cascades in response to tissue damage or injury. TLRs are positioned at the neuroimmune interface, and accumulating evidence suggests that the inflammatory consequences of TLR activation on glia (including microglia and astrocytes), sensory neurons, and other cell types can influence nociceptive processing and lead to states of exaggerated and unresolved pain. In this review, we summarize our current understanding of how different TLRs and their accessory molecules can contribute to the development and maintenance of persistent pain. The challenges and opportunities of targeting TLRs for new treatment strategies against chronic pain are discussed, including the therapeutic context of TLR-mediated signaling in opioid analgesia and chemotherapy-induced pain. Considering the prevalence of persistent pain and the insufficient efficacy and safety of current treatment options, a deeper understanding of Toll-like receptors holds the promise of novel therapies for managing pathological pain.
The immature electrophysiological phenotype of iPSC-CMs still hampers in vitro drug screening: Special focus on IK1 Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-10-03 Birgit Goversen, Marcel A.G. van der Heyden, Toon A.B. van Veen, Teun P. de Boer
Preclinical drug screens are not based on human physiology, possibly complicating predictions on cardiotoxicity. Drug screening can be humanised with in vitro assays using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). However, in contrast to adult ventricular cardiomyocytes, iPSC-CMs beat spontaneously due to presence of the pacemaking current If and reduced densities of the hyperpolarising current IK1. In adult cardiomyocytes, IK1 finalises repolarisation by stabilising the resting membrane potential while also maintaining excitability. The reduced IK1 density contributes to proarrhythmic traits in iPSC-CMs, which leads to an electrophysiological phenotype that might bias drug responses. The proarrhythmic traits can be suppressed by increasing IK1 in a balanced manner. We systematically evaluated all studies that report strategies to mature iPSC-CMs and found that only few studies report IK1 current densities. Furthermore, these studies did not succeed in establishing sufficient IK1 levels as they either added too little or too much IK1. We conclude that reduced densities of IK1 remain a major flaw in iPSC-CMs, which hampers their use for in vitro drug screening.
Hypoxia inducible factor as a therapeutic target for atherosclerosis Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-09-20 Tanmay Jain, Eleni Aliki Nikolopoulou, Aijuan Qu, Qingbo Xu
Atherosclerosis is a highly prevalent disease that can significantly increase the risk of major vascular events, such as myocardial or cerebral infarctions. The anoxemia theory states that a disparity between oxygen supply and demand contributes to atherosclerosis. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric protein, part of the basic helix-loop-helix family and one of the main regulators of cellular responses in a low‑oxygen environment. It plays a key role in the development of atherosclerosis through cell-specific responses, acting on endothelial cells, vascular smooth muscle cells (SMCs) and macrophages. Through the upregulation of VEGF, NO, ROS and PDGF, HIF-1 is able to cause endothelial cell dysfunction, proliferation, angiogenesis and inflammation. Activation of the NF-kB pathway in endothelial cells is an important contributor to inflammation and positively feedbacks to HIF-1. HIF-1 also plays a significant role in both the proliferation and migration of smooth muscle cells – two important features of atherosclerosis, while the formation of foam cells (lipid-laden macrophages) is also a critical step in atherosclerosis and mediated by HIF-1 through various mechanisms such as dysfunctional efflux pathways in macrophages. Overall, HIF-1 exerts its effect on the pathogenesis of atherosclerosis via a variety of molecular and cellular events in the process. In this review article, we examine the effects HIF-1 on vascular cells and macrophages in the development of atherosclerosis, highlighting the environmental cues and signalling pathways that control HIF-1 expression/activation within the vasculature. We will highlight the potential of HIF-1 as a therapeutic target on the disease development.
Immunoproteasome-selective and non selective inhibitors: A promising approach for the treatment of multiple myeloma Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-09-11 Roberta Ettari, Maria Zappalà, Silvana Grasso, Caterina Musolino, Vanessa Innao, Alessandro Allegra
The ubiquitin-proteasome system (UPS) is the major non-lysosomal proteolytic system for the degradation of abnormal or damaged proteins no longer required. The proteasome is involved in degradation of numerous proteins which regulate the cell cycle, indicating a role in controlling cell proliferation and maintaining cell survival. Defects in the UPS can lead to anarchic cell proliferation and to tumor development.For these reasons UPS inhibition has become a significant new strategy for drug development in cancer treatment.In addition to the constitutive proteasome, which is expressed in all cells and tissues, higher organisms such as vertebrates possess two immune-type proteasomes, the thymoproteasome and the immunoproteasome. The thymoproteasome is specifically expressed by thymic cortical epithelial cells and has a role in positive selection of CD8 + T cells, whereas the immunoproteasome is predominantly expressed in monocytes and lymphocytes and is responsible for the generation of antigenic peptides for cell-mediated immunity. Recent studies demonstrated that the immunoproteasome has a preservative role during oxidative stress and is up-regulated in a number of pathological disorders including cancer, inflammatory and autoimmune diseases. As a consequence, immunoproteasome-selective inhibitors are currently the focus of anticancer drug design. At present, the commercially available proteasome inhibitors bortezomib and carfilzomib which have been validated in multiple myeloma and other model systems, appear to target both the constitutive and immunoproteasomes, indiscriminately. This lack of specificity may, in part, explain some of the side effects of these agents, such as peripheral neuropathy and gastrointestinal effects, which may be due to targeting of the constitutive proteasome in these tissues. In contrast, by selectively inhibiting the immunoproteasome, it may be possible to maintain the antimyeloma and antilymphoma efficacy while reducing these toxicities, thereby increasing the therapeutic index.This review article will be focused on the discussion of the most promising immunoproteasome specific inhibitors which have been developed in recent years. Particular attention will be devoted to the description of their mechanism of action, their structure-activity relationship, and their potential application in therapy.
Paving the Rho in cancer metastasis: Rho GTPases and beyond Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-09-11 Sepp Jansen, Reinoud Gosens, Thomas Wieland, Martina Schmidt
Malignant carcinomas are often characterized by metastasis, the movement of carcinoma cells from a primary site to colonize distant organs. For metastasis to occur, carcinoma cells first must adopt a pro-migratory phenotype and move through the surrounding stroma towards a blood or lymphatic vessel. Currently, there are very limited possibilities to target these processes therapeutically.The family of Rho GTPases is an ubiquitously expressed division of GTP-binding proteins involved in the regulation of cytoskeletal dynamics and intracellular signaling. The best characterized members of the Rho family GTPases are RhoA, Rac1 and Cdc42. Abnormalities in Rho GTPase function have major consequences for cancer progression. Rho GTPase activation is driven by cell surface receptors that activate GTP exchange factors (GEFs) and GTPase-activating proteins (GAPs). In this review, we summarize our current knowledge on Rho GTPase function in the regulation of metastasis. We will focus on key discoveries in the regulation of epithelial-mesenchymal-transition (EMT), cell-cell junctions, formation of membrane protrusions, plasticity of cell migration and adaptation to a hypoxic environment. In addition, we will emphasize on crosstalk between Rho GTPase family members and other important oncogenic pathways, such as cyclic AMP-mediated signaling, canonical Wnt/β-catenin, Yes-associated protein (YAP) and hypoxia inducible factor 1α (Hif1α) and provide an overview of the advancements and challenges in developing pharmacological tools to target Rho GTPase and the aforementioned crosstalk in the context of cancer therapeutics.
Bevacizumab-induced hypertension: Clinical presentation and molecular understanding Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-09-04 Megan Li, Deanna L. Kroetz
Bevacizumab is a vascular endothelial growth factor-A-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of several types of cancer. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy and lead to other cardiovascular complications. The factors that contribute to interindividual variability in blood pressure response to bevacizumab treatment are not well understood. In this review, we outline research efforts to understand the mechanisms and pathophysiology of hypertension resulting from bevacizumab treatment. Moreover, we highlight current knowledge of the pharmacogenetics of bevacizumab-induced hypertension, which may be used to develop strategies to prevent or minimize this toxicity.
The role of osteoprotegerin in the crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-09-01 Luc Rochette, Alexandre Meloux, Eve Rigal, Marianne Zeller, Yves Cottin, Catherine Vergely
Among the numerous molecules that are being studied for their potential utility as biomarkers of cardiovascular diseases, much interest has been shown in the superfamily of tumor necrosis factor (TNF) receptors. Members of this family include osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). These signals may be expressed and regulated, and their functions could be involved in several physiological and pathological processes. The relationship between bone regulatory proteins and vascular biology has attracted attention, and it has been suggested that OPG may mediate vascular calcification and cardiometabolic diseases. OPG is steadily released from vascular endothelial cells in response to inflammatory stimuli, suggesting that it plays a modulatory role in vascular injury, inflammation, and atherosclerosis. Vascular calcification, a hallmark of atherosclerosis, is similar to bone remodeling. It is an actively regulated mechanism that includes both inductive and inhibitory processes. There is a temporal link between the development of osteoporosis and vascular calcification, which is particularly marked in post-menopausal women and the elderly. The precise nature of the link between bone metabolism, vascular calcification and cardiovascular disease is largely unknown but increasing evidence suggests that the triad of RANK/RANKL/OPG may be important in the initiation of various diseases. An increased release of OPG is associated with increased cardiovascular risk and it is suggested that increased OPG levels resulting from vascular damage correspond to a protective mechanism. Circulating OPG levels could be used as independent biomarkers of cardiovascular disease in patients with acute or chronic cardiometabolic disease and thus an improved prognosis.
Cannabis Use during Pregnancy: Pharmacokinetics and Effects on Child Development Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-25 Kimberly S. Grant, Rebekah Petroff, Nina Isoherranen, Nephi Stella, Thomas M. Burbacher
The broad-based legalization of cannabis use has created a strong need to understand its impact on human health and behavior. The risks that may be associated with cannabis use, particularly for sensitive subgroups such as pregnant women, are difficult to define because of a paucity of dose-response data and the recent increase in cannabis potency. Although there is a large body of evidence detailing the mode of action of Δ9-tetrahydrocannabinol (THC) in adults, little work has focused on understanding how cannabis use during pregnancy may impact the development of the fetal nervous system and whether additional plant-derived cannabinoids might participate. This manuscript presents an overview of the historical and contemporary literature focused on the mode of action of THC in the developing brain, comparative pharmacokinetics in both pregnant and nonpregnant model systems and neurodevelopmental outcomes in exposed offspring. Despite growing public health significance, pharmacokinetic studies of THC have focused on nonpregnant adult subjects and there are few published reports on disposition parameters during pregnancy. Data from preclinical species show that THC readily crosses the placenta although fetal exposures appear lower than maternal exposures. The neurodevelopmental data in human and preclinical species suggest that prenatal exposure to THC may lead to subtle, persistent changes in targeted aspects of higher-level cognition and psychological well-being. There is an urgent need for well-controlled studies in humans and preclinical models on THC as a developmental neurotoxicant. Until more information is available, pregnant women should not assume that using cannabis during pregnancy is safe.
Non-canonical function of Tat in regulating host microtubule dynamics: Implications for the pathogenesis of lentiviral infections Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-25 Min Liu, Xin Du, Jun Zhou
Lentiviruses are a class of genetically unique retroviruses that share similar features, despite their wide variety of host species. Transactivator of transcription (Tat) proteins of lentiviruses are critical for the regulation of viral transcription and replication. Recent studies demonstrate that in addition to mediating transactivation, Tat binds to the microtubule cytoskeleton of the host cell and interferes with microtubule dynamics, ultimately triggering apoptosis. This non-canonical function of Tat appears to be critical for the pathogenesis of lentiviral diseases, such as acquired immunodeficiency syndrome. Here, we compare the structure and activity of Tat proteins from three different types of lentiviruses, focusing on the roles of these proteins in the alteration of host microtubule dynamics and induction of apoptosis. We propose that further investigation of the Tat-microtubule interaction will provide important insight into the process of lentiviral pathogenesis and elucidate new avenues for the development of antiviral therapies.
Pharmacotherapeutic potential of ginger and its compounds in age-related neurological disorders Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-24 Jin Gyu Choi, Sun Yeou Kim, Minsun Jeong, Myung Sook Oh
Age-related neurological disorders (ANDs), including neurodegenerative diseases, are multifactorial disorders with a risk that increases with aging. ANDs are generally characterized by common neuropathological conditions of the central nervous system, such as oxidative stress, neuroinflammation, and protein misfolding. Recently, efforts have been made to overcome ANDs because of the increase in age-dependent prevalence. Ginger, the rhizome of Zingiber officinale Roscoe, is a popular food spice and has a long history of use in traditional medicine for treating various disease symptoms. The structure-activity relationships of ginger phytochemicals show that ginger can be used to treat ANDs by targeting different ligand sites. This review shows that ginger and its constituents, such as 6-gingerol, 6-shogaol, 6-paradol, zingerone, and dehydrozingerone, are effective for ameliorating the neurological symptoms and pathological conditions of ANDs through by modulating cell death or cell survival signaling molecules. From this review, we conclude that the active ingredients in ginger have therapeutic potential in ANDs.
Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacological targets Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-23 Vikas Mishra, Jaspreet Banga, Patricia Silveyra
Asthma is a complex inflammatory disease characterized by airway inflammation and hyperresponsiveness. The mechanisms associated with the development and progression of asthma have been widely studied in multiple populations and animal models, and these have revealed involvement of various cell types and activation of intracellular signaling pathways that result in activation of inflammatory genes. Significant contributions of Toll-like-receptors (TLRs) and transcription factors such as NF-кB, have been reported as major contributors to inflammatory pathways. These have also recently been associated with mechanisms of oxidative biology. This is of important clinical significance as the observed inefficacy of current available treatments for severe asthma is widely attributed to oxidative stress. Therefore, targeting oxidizing molecules in conjunction with inflammatory mediators and transcription factors may present a novel therapeutic strategy for asthma. In this review, we summarize TLRs and NF-кB pathways in the context of exacerbation of asthma pathogenesis and oxidative biology, and we discuss the potential use of polyphenolic flavonoid compounds, known to target these pathways and possess antioxidant activity, as potential therapeutic agents for asthma.
T cell engaging bispecific antibody (T-BsAb): from technology to therapeutics Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-20 Zhihao Wu, Nai-Kong V. Cheung
Harnessing the power of the human immune system to treat cancer is the essence of immunotherapy. Monoclonal antibodies engage the innate immune system to destroy targeted cells. For the last 30 years, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity have been the main mechanisms of anti-tumor action of unconjugated antibody drugs. Efforts to exploit the potentials of other immune cells, in particular T cells, culminated in the recent approval of two T cell engaging bispecific antibody (T-BsAb) drugs, thereby stimulating new efforts to accelerate similar platforms through preclinical and clinical trials. In this review, we have compiled the worldwide effort in exploring T cell engaging bispecific antibodies. Our special emphasis is on the lessons learned, with the hope to derive insights in this fast evolving field with tremendous clinical potential.
EMT: mechanisms and therapeutic implications Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-20 Mohini Singh, Nicolas Yelle, Chitra Venugopal, Sheila K. Singh
Metastasis, the dissemination of cancer cells from primary tumors, represents a major hurdle in the treatment of cancer. The epithelial-mesenchymal transition (EMT) has been studied in normal mammalian development for decades, and it has been proposed as a critical mechanism during cancer progression and metastasis. EMT is tightly regulated by several internal and external cues that orchestrate the shifting from an epithelial-like phenotype into a mesenchymal phenotype, relying on a delicate balance between these two stages to promote metastatic development. EMT is thought to be induced in a subset of metastatic cancer stem cells (MCSCs), bestowing this population with the ability to spread throughout the body and contributing to therapy resistance. The EMT pathway is of increasing interest as a novel therapeutic avenue in the treatment of cancer, and could be targeted to prevent tumor cell dissemination in early stage patients or to eradicate existing metastatic cells in advanced stages. In this review, we describe the sequence of events and defining mechanisms that take place during EMT, and how these interactions drive cancer cell progression into metastasis. We summarize clinical interventions focused on targeting various aspects of EMT and their contribution to preventing cancer dissemination.
The Role of the Leukemia Inhibitory Factor Receptor in Neuroprotective Signaling Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-19 Stephanie M. Davis, Keith R. Pennypacker
Several neurotropic cytokines relay their signaling through the leukemia inhibitory factor receptor. This 190 kDa subunit couples with the 130 kDa gp130 subunit to transduce intracellular signaling in neurons and oligodendrocytes that leads to expression of genes associated with neurosurvival. Moreover, activation of this receptor alters the phenotype of immune cells to an anti-inflammatory one. Although cytokines that activate the leukemia inhibitory factor receptor have been studied in the context of neurodegenerative disease, therapeutic targeting of the specific receptor subunit has been understudied in by comparison. This review examines the role of this receptor in the CNS and immune system, and its application in the treatment in stroke and other brain pathologies.
Members of FOX family could be drug targets of cancers Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-19 Jinhua Wang, Wan Li, Ying Zhao, De Kang, Weiqi Fu, Xiangjin Zheng, Xiaocong Pang, Guanhua Du
FOX families play important roles in biological processes, including metabolism, development, differentiation, proliferation, apoptosis, migration, invasion and longevity. Here we are focusing on roles of FOX members in cancers, FOX members and drug resistance, FOX members and stem cells. Finally, FOX members as drug targets of cancer treatment were discussed. Future perspectives of FOXC1 research were described in the end.
Binge-eating disorder: Clinical and therapeutic advances Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-19 Peter H. Hutson, Iris M. Balodis, Marc N. Potenza
Binge-eating disorder (BED) is the most prevalent eating disorder with estimates of 2–5% of the general adult population. Nonetheless, its pathophysiology is poorly understood. Furthermore, there exist few therapeutic options for its effective treatment. Here we review the current state of binge-eating neurobiology and pharmacology, drawing from clinical therapeutic, neuroimaging, cognitive, human genetic and animal model studies. These studies, which are still in their infancy, indicate that while there are many gaps in our knowledge, several key neural substrates appear to underpin binge-eating and may be conserved between human and animals. This observation suggests that behavioral intermediate phenotypes or endophenotypes relevant to BED may be modeled in animals, facilitating the identification and testing of novel pharmacological targets. The development of novel, safe and effective pharmacological therapies for the treatment of BED will enhance the ability of clinicians to provide optimal care for people with BED.
The potential for targeted rewriting of epigenetic marks in COPD as a new therapeutic approach Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-19 Dan-Dan Wu, Juan Song, Sabine Bartel, Susanne Krauss-Etschmann, Marianne G. Rots, Machteld N. Hylkema
Chronic obstructive pulmonary disease (COPD) is an age and smoking related progressive, pulmonary disorder presenting with poorly reversible airflow limitation as a result of chronic bronchitis and emphysema. The prevalence, disease burden for the individual, and mortality of COPD continues to increase, whereas no effective treatment strategies are available. For many years now, a combination of bronchodilators and anti-inflammatory corticosteroids has been most widely used for therapeutic management of patients with persistent COPD. However, this approach has had disappointing results as a large number of COPD patients are corticosteroid resistant. In patients with COPD, there is emerging evidence showing aberrant expression of epigenetic marks such as DNA methylation, histone modifications and microRNAs in blood, sputum and lung tissue. Therefore, novel therapeutic approaches may exist using epigenetic therapy. This review aims to describe and summarize current knowledge of aberrant expression of epigenetic marks in COPD. In addition, tools available for restoration of epigenetic marks are described, as well as delivery mechanisms of epigenetic editors to cells. Targeting epigenetic marks might be a very promising tool for treatment and lung regeneration in COPD in the future.
Endothelial and cardiac progenitor cells for cardiovascular repair: A controversial paradigm in cell therapy Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-19 Vanessa Bianconi, Amirhossein Sahebkar, Petri Kovanen, Francesco Bagaglia, Biagio Ricciuti, Paolo Calabrò, Giuseppe Patti, Matteo Pirro
Stem cells have the potential to differentiate into cardiovascular cell lineages and to stimulate tissue regeneration in a paracrine/autocrine manner; thus, they have been extensively studied as candidate cell sources for cardiovascular regeneration. Several preclinical and clinical studies addressing the therapeutic potential of endothelial progenitor cells (EPCs) and cardiac progenitor cells (CPCs) in cardiovascular diseases have been performed. For instance, autologous EPC transplantation and EPC mobilization through pharmacological agents contributed to vascular repair and neovascularization in different animal models of limb ischemia and myocardial infarction. Also, CPC administration and in situ stimulation of resident CPCs have been shown to improve myocardial survival and function in experimental models of ischemic heart disease. However, clinical studies using EPC- and CPC-based therapeutic approaches have produced mixed results. In this regard, intracoronary, intra-myocardial or intramuscular injection of either bone marrow-derived or peripheral blood progenitor cells has improved pathological features of tissue ischemia in humans, despite modest or no clinical benefit has been observed in most cases. Also, the intriguing scientific background surrounding the potential clinical applications of EPC capture stenting is still waiting for a confirmatory proof. Moreover, clinical findings on the efficacy of CPC-based cell therapy in heart diseases are still very preliminary and based on small-size studies.Despite promising evidence, widespread clinical application of both EPCs and CPCs remains delayed due to several unresolved issues. The present review provides a summary of the different applications of EPCs and CPCs for cardiovascular cell therapy and underlies their advantages and limitations.
Molecular pathogenesis and therapeutic implications in pediatric high-grade gliomas Pharmacol. Therapeut. (IF 11.127) Pub Date : 2017-08-19 Tareq A. Juratli, Nan Qin, Daniel P. Cahill, Mariella G. Filbin
High-grade gliomas (HGG) are the most common malignant brain tumors in the pediatric population and account for a large subset of all pediatric central nervous system neoplasms. The management of pediatric HGG continues to be challenging, with poor outcome in many cases despite aggressive treatments. Consequently, parallel research efforts have been focused on identifying the underlying genetic and biological basis of pediatric HGG in order to more clearly define prognostic subgroups for treatment stratification as well as identify new treatment targets. These cutting-edge advances have revolutionized pediatric neuro-oncology and have revealed novel oncogenic vulnerabilities that are being therapeutically leveraged. Promising treatments – including pathway-targeting small molecules as well as epigenetic therapy – are being evaluated in clinical trials, and recent genomic discoveries in rare glioma subgroups have led to the identification of additional new potentially-actionable alterations. This review summarizes the current state of knowledge about the molecular characterization of pediatric HGG in correlation to the revised World Health Organization (WHO) classification, as well as provides an overview of some targeted treatment approaches in the modern clinical management of high-grade gliomas.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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