ROCK inhibition in models of neurodegeneration and its potential for clinical translation Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-03 Jan Christoph Koch, Lars Tatenhorst, Anna-Elisa Roser, Kim-Ann Saal, Lars Tönges, Paul Lingor
Neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis are affecting a rapidly increasing population worldwide. While common pathomechanisms such as protein aggregation, axonal degeneration, dysfunction of protein clearing and an altered immune response have been characterized, no disease-modifying therapies have been developed so far. Interestingly, a significant involvement of the Rho kinase (ROCK) signaling pathway has been described in all of these mechanisms making it a promising target for new therapeutic approaches.In this article, we first review current knowledge of the involvement of ROCK in neurodegenerative disorders and the utility of its inhibition as a disease-modifying therapy in different neurodegenerative disorders. After a detailed description of the biochemical characteristics of ROCK and its molecular interactors, differences of ROCK-expression under physiological and pathological conditions are compared. Next, different pharmacological and molecular-genetic strategies to inhibit ROCK-function are discussed, focusing on pharmacological ROCK-inhibitors. The role of the ROCK-pathway in cellular processes that are central in neurodegenerative disorders pathology like axonal degeneration, autophagy, synaptic and glial function is explained in detail. Finally, all available data on ROCK-inhibition in different animal models of neurodegenerative disorders is reviewed and first approaches for translation into human patients are discussed.Taken together, there is now extensive evidence from preclinical studies in several neurodegenerative disorders that characterize ROCK as a promising drug target for further translational research in neurodegenerative disorders.
Double-barreled gun: Combination of PARP inhibitor with conventional chemotherapy Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-03 Yanxin Lu, Yang Liu, Ying Pang, Karel Pacak, Chunzhang Yang
DNA repair pathways are evolutionarily conserved molecular mechanisms that maintain the integrity of genomic DNA. In cancer therapies, the integrity and activity of DNA repair pathways predict therapy resistance and disease outcome. Members of the poly (ADP-ribose) polymerase (PARP) family initiate and organize the biologic process of DNA repair, which counteracts many types of chemotherapies. Since the first development in approximately 3 decades ago, PARP inhibitors have greatly changed the concept of cancer therapy, leading to encouraging improvements in tumor suppression and disease outcomes. Here we summaries both pre-clinical and clinical findings of PARP inhibitors applications, particularly for combination therapies.
Cancer development and therapy resistance: spotlights on the dark side of the genome Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-10 Eleonora Leucci
Cancer research has been focusing so far on genetic alterations in protein-coding genes. However, mounting evidence underlines the importance of epigenetic and post-transcriptional events in cancer progression and therapy resistance. Moreover, recent genome-wide studies show that disease-causing mutations and chromosome rearrangements often span areas of the genome that do not contain any known protein-coding gene. This finding is not surprising, considering that even though the vast majority of the human genome is transcribed, only a minor portion (accounting for less than 2%) encodes for proteins. Among the various classes of transcribed RNAs, long non-coding RNAs are attractive biomarkers and therapeutic targets due to their disease- and stage-restricted expression.In addition, by taking part in all the major epigenetic and post-transcriptional programs in the cell, long non-coding RNAs are emerging as key regulators of stress responses and therefore they are important non-genetic players in cancer development and progression. Here I discuss the role of lncRNAs in cancer and their promises and pitfalls as biomarkers and therapeutic targets.
Natural killer cells and their therapeutic role in pancreatic cancer: A systematic review Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-13 Jonas R.M. Van Audenaerde, Geert Roeyen, Phillip K. Darcy, Michael H. Kershaw, M. Peeters, Evelien L.J. Smits
Pancreatic cancer is among the three deadliest cancers worldwide with the lowest 5-year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to their expectations. Therefore, other horizons have to be explored. Natural Killer (NK) cells are gaining more and more interest as a highly attractive target for cancer immunotherapies, both as pharmaceutical target and for cell therapies. In this systematic review we summarise the pathophysiological adaptions of NK cells in pancreatic cancer and highlight possible (future) therapeutic NK cell-related targets. Furthermore, an extensive overview of recent therapeutic approaches with an effect on NK cells is given, including cytokine-based, viro- and bacteriotherapy and cell therapy. We also discuss ongoing clinical trials that might influence NK cells. In conclusion, although several issues regarding NK cells in pancreatic cancer remain unsolved and need further investigation, extensive evidence is already provided that support NK cell oriented approaches in pancreatic cancer.
Tools and drugs for uracil nucleotide-activated P2Y receptors Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-13 Muhammad Rafehi, Christa E. Müller
P2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14, which represent current or potential future drug targets. Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y2 (UTP, also ATP and dinucleotides), P2Y4 (UTP), P2Y6 (UDP), and P2Y14 (UDP, UDP-glucose, UDP-galactose). The physiological agonists are metabolically unstable due to their fast hydrolysis by ectonucleotidases. A number of agonists with increased potency, subtype-selectivity and/or enzymatic stability have been developed in recent years. Useful P2Y2R agonists include MRS2698 (6-01, highly selective) and PSB-1114 (6-05, increased metabolic stability). A potent and selective P2Y2R antagonist is AR-C118925 (10-01). For studies of the P2Y4R, MRS4062 (3-15) may be used as a selective agonist, while PSB-16133 (10-06) is a selective antagonist. Several potent P2Y6R agonists have been developed including 5-methoxyuridine 5′-O-((Rp)α-boranodiphosphate) (6-12), PSB-0474 (3-11), and MRS2693 (3-26). The isocyanate MRS2578 (10-08) is used as a selective P2Y6R antagonist, although its reactivity and low water-solubility are limiting. With MRS2905 (6-08), a potent and metabolically stable P2Y14R agonist is available, while PPTN (10-14) represents a potent and selective P2Y14R antagonist. The radioligand [3H]UDP can be used to label P2Y14Rs. In addition, several fluorescent probes have been developed. Uracil nucleotide-activated P2YRs show great potential as drug targets, especially in inflammation, cancer, cardiovascular and neurodegenerative diseases.
DNA mismatch repair in cancer Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-15 Marina Baretti, Dung T. Le
Microsatellite instability (MSI) refers to the hypermutator phenotype secondary to frequent polymorphism in short repetitive DNA sequences and single nucleotide substitution, as consequence of DNA mismatch repair (MMR) deficiency. MSI secondary to germline mutation in DNA MMR proteins is the molecular fingerprint of Lynch syndrome (LS), while epigenetic inactivation of these genes is more commonly found in sporadic MSI tumors. MSI occurs at different frequencies across malignancies, although original methods to assess MSI or MMR deficiency have been developed mostly in LS related cancers. Here we will discuss the current methods to detect MSI/MMR deficiency with a focus of new tools which are emerging as highly sensitive detector for MSI across multiple tumor types.Due to high frequencies of non-synonymous mutations, the presence of frameshift-mutated neoantigens, which can trigger a more robust and long-lasting immune response and strong TIL infiltration with tumor eradication, MSI has emerged as an important predictor of sensitivity for immunotherapy-based strategies, as showed by the recent FDA's first histology agnostic-accelerated approval to immune checkpoint inhibitors for refractory, adult and pediatric, MMR deficient (dMMR) or MSI high (MSI-H) tumors. Moreover, it is known that MSI status may predict cancer response/resistance to certain chemotherapies.Here we will describe the complex interplay between the genetic and clinical-pathological features of MSI/dMMR tumors and the cancer immunotherapy, with a focus on the predictive and prognostic role of MMR status for immune checkpoint inhibitors (ICIs) and providing some suggestions on how to conceive better predictive markers for immunotherapy in the next future.
Vitamin C for the treatment of sepsis: The scientific rationale Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-21 Paul E. Marik
Most vertebrates can synthesize vitamin C with synthesis increasing during stress. Humans, however, have lost the ability to synthesize vitamin C. Vitamin C is an important anti-oxidant and an enzyme cofactor for many important biological reactions. Sepsis results in the overwhelming production of reactive oxygen species with widespread endothelial, cellular and mitochondrial injury leading to progressive organ failure. Sepsis is associated with an acute deficiency of vitamin C. In experimental sepsis models, intravenous vitamin C reduces organ injury and improves survival. In addition, emerging evidence suggests that the combination of vitamin C, corticosteroids and thiamine may act synergistically to reverse sepsis induced organ dysfunction. These findings are supported by a recent observational study. Randomized controlled trials are underway to investigate this novel approach to the treatment of sepsis.
The G protein-coupled receptor GPR34 – The past 20 years of a grownup Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-22 Torsten Schöneberg, Jaroslawna Meister, Alexander Bernd Knierim, Angela Schulz
Research on GPR34, which was discovered in 1999 as an orphan G protein-coupled receptor of the rhodopsin-like class, disclosed its physiologic relevance only piece by piece. Being present in all recent vertebrate genomes analyzed so far it seems to improve the fitness of species although it is not essential for life and reproduction as GPR34-deficient mice demonstrate. However, closer inspection of macrophages and microglia, where it is mainly expressed, revealed its relevance in immune cell function. Recent data clearly demonstrate that GPR34 function is required to arrest microglia in the M0 homeostatic non-phagocytic phenotype. Herein, we summarize the current knowledge on its evolution, genomic and structural organization, physiology, pharmacology and relevance in human diseases including neurodegenerative diseases and cancer, which accumulated over the last 20 years.
Imaging techniques to study drug transporter function in vivo Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-22 Nicolas Tournier, Bruno Stieger, Oliver Langer
Transporter systems involved in the permeation of drugs and solutes across biological membranes are recognized as key determinants of pharmacokinetics. Typically, the action of membrane transporters on drug exposure to tissues in living organisms is inferred from invasive procedures, which cannot be applied in humans. In recent years, imaging methods have greatly progressed in terms of instruments, synthesis of novel imaging probes as well as tools for data analysis. Imaging allows pharmacokinetic parameters in different tissues and organs to be obtained in a non-invasive or minimally invasive way. The aim of this overview is to summarize the current status in the field of molecular imaging of drug transporters. The overview is focused on human studies, both for the characterization of transport systems for imaging agents as well as for the determination of drug pharmacokinetics, and makes reference to animal studies where necessary. We conclude that despite certain methodological limitations, imaging has a great potential to study transporters at work in humans and that imaging will become an important tool, not only in drug development but also in medicine. Imaging allows the mechanistic aspects of transport proteins to be studied, as well as elucidating the influence of genetic background, pathophysiological states and drug-drug interactions on the function of transporters involved in the disposition of drugs.
Bile acid regulation: A novel therapeutic strategy in non-alcoholic fatty liver disease Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-22 Qinwei Yu, Zhenzhou Jiang, Luyong Zhang
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat deposition in the liver in the absence of significant alcohol consumption. Dysregulated bile acid (BA) metabolism is an important indicator in the pathology of NAFLD, which could progress into more severe forms of liver injury. Lipid metabolism, immune environment and intestinal bacteria are all affected by dysregulated BA metabolism directly, but the mechanisms remain unclear. Several drug candidates that target BA metabolism, either used alone or in combination with other agents, are currently under development for treatment of NAFLD. Here, we summarize the relationship of dysregulated BA metabolism and NAFLD, discuss the effects and mechanisms of dysregulated BAs-induced lipid metabolism disorder. Challenges in developing novel treatments are also discussed.
Anticancer drug-induced cardiac rhythm disorders: Current knowledge and basic underlying mechanisms Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-24 Joachim Alexandre, Javid J. Molsehi, Kevin R. Bersell, Christian Funck-Brentano, Dan M. Roden, Joe-Elie Salem
Significant advances in cancer treatment have resulted in decreased cancer related mortality for many malignancies with some cancer types now considered chronic diseases. Despite these improvements, there is increasing recognition that many cancer patients or cancer survivors can develop cardiovascular diseases, either due to the cancer itself or as a result of anticancer therapy. Much attention has focused on heart failure; however, other cardiotoxicities, notably cardiac rhythm disorders, can occur without underlying cardiomyopathy.Supraventricular tachycardias occur in cancer patients treated with cytotoxic chemotherapy (anthracyclines, gemcitabine, cisplatin and alkylating-agents) or kinase-inhibitors (KIs) such as ibrutinib. Ventricular arrhythmias, with a subset of them being torsades-de-pointes (TdP) favored by QTc prolongation have been reported: this may be the result of direct hERG-channel inhibition or a more recently-described mechanism of phosphoinositide-3-kinase inhibition. The major anticancer drugs responsible for QTc prolongation in this context are KIs, arsenic trioxide, anthracyclines, histone deacetylase inhibitors, and selective estrogen receptor modulators.Anticancer drug-induced cardiac rhythm disorders remain an underappreciated complication even by experienced clinicians. Moreover, the causal relationship of a particular anticancer drug with cardiac arrhythmia occurrence remains challenging due in part to patient comorbidities and complex treatment regimens. For example, any cancer patient may also be diagnosed with common diseases such as hypertension, diabetes or heart failure which increase an individual's arrhythmia susceptibility. Further, anticancer drugs are generally usually used in combination, increasing the challenge around establishing causation.Thus, arrhythmias appear to be an underappreciated adverse effect of anticancer agents and the incidence, significance and underlying mechanisms are now being investigated.
Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-27 Shizuo Yamada, Yoshihiko Ito, Saori Nishijima, Katsumi Kadekawa, Kimio Sugaya
Antimuscarinic agents are now widely used as the pharmacological therapy for overactive bladder (OAB) because neuronal (parasympathetic nerve) and non-neuronal acetylcholine play a significant role for the bladder function. In this review, we will highlight basic and clinical aspects of eight antimuscarinic agents (oxybutynin, propiverine, tolterodine, solifenacin, darifenacin, trospium, imidafenacin, and fesoterodine) clinically used to treat urinary dysfunction in patients with OAB. The basic pharmacological characteristics of these eight antimuscarinic agents include muscarinic receptor subtype selectivity, functional bladder selectivity, and muscarinic receptor binding in the bladder and other tissues. The measurement of drug-receptor binding after oral administration of these agents allows for clearer understanding of bladder selectivity by the integration of pharmacodynamics and pharmacokinetics under in vivo conditions. Their central nervous system (CNS) penetration potentials are also discussed in terms of the feasibility of impairments in memory and cognitive function in elderly patients with OAB. The clinical aspects of efficacy focus on improvements in the daytime urinary frequency, nocturia, bladder capacity, the frequency of urgency, severity of urgency, number of incontinence episodes, OAB symptom score, and quality of life (QOL) score by antimuscarinic agents in patients with OAB. The safety of and adverse events caused by treatments with antimuscarinic agents such as dry mouth, constipation, blurred vision, erythema, fatigue, increased sweating, urinary retention, and CNS adverse events are discussed. A dose-dependent relationship was observed with adverse events, because the risk ratio generally increased with elevations in the drug dose of antimuscarinic agents. Side effect profiles may be additive to or contraindicated by other medications.
Post-translational modifications of transporters Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-30 Lindsay C. Czuba, Kathleen M. Hillgren, Peter W. Swaan
Drug transporter proteins are critical to the distribution of a wide range of endogenous compounds and xenobiotics such as hormones, bile acids, peptides, lipids, sugars, and drugs. There are two classes of drug transporters– the solute carrier (SLC) transporters and ATP-binding cassette (ABC) transporters –which predominantly differ in the energy source utilized to transport substrates across a membrane barrier. Despite their hydrophobic nature and residence in the membrane bilayer, drug transporters have dynamic structures and adopt many conformations during the translocation process. Whereas there is significant literature evidence for the substrate specificity and structure-function relationship for clinically relevant drug transporters proteins, there is less of an understanding in the regulatory mechanisms that contribute to the functional expression of these proteins. Post-translational modifications have been shown to modulate drug transporter functional expression via a wide range of molecular mechanisms. These modifications commonly occur through the addition of a functional group (e.g. phosphorylation), a small protein (e.g. ubiquitination), sugar chains (e.g. glycosylation), or lipids (e.g. palmitoylation) on solvent accessible amino acid residues. These covalent additions often occur as a result of a signaling cascade and may be reversible depending on the type of modification and the intended fate of the signaling event. Here, we review the significant role in which post-translational modifications contribute to the dynamic regulation and functional consequences of SLC and ABC drug transporters and highlight recent progress in understanding their roles in transporter structure, function, and regulation.
Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-30 John D. Imig
Therapeutics for arachidonic acid pathways began with the development of non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX). The enzymatic pathways and arachidonic acid metabolites and respective receptors have been successfully targeted and therapeutics developed for pain, inflammation, pulmonary and cardiovascular diseases. These drugs target the COX and lipoxygenase pathways but not the third branch for arachidonic acid metabolism, the cytochrome P450 (CYP) pathway. Small molecule compounds targeting enzymes and CYP epoxy-fatty acid metabolites have evolved rapidly over the last two decades. These therapeutics have primarily focused on inhibiting soluble epoxide hydrolase (sEH) or agonist mimetics for epoxyeicosatrienoic acids (EET). Based on preclinical animal model studies and human studies, major therapeutic indications for these sEH inhibitors and EET mimics/analogs are renal and cardiovascular diseases. Novel small molecules that inhibit sEH have advanced to human clinical trials and demonstrate promise for cardiovascular diseases. Challenges remain for sEH inhibitor and EET analog drug development; however, there is a high likelihood that a drug that acts on this third branch of arachidonic acid metabolism will be utilized to treat a cardiovascular or kidney disease in the next decade.
Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-30 Lillian R. Klug, Jason D. Kent, Michael C. Heinrich
Mutations within the activation loop of members of the class III receptor tyrosine kinase (RTK) subfamily, which includes KIT, PDGFRA, and FLT3, have been observed in multiple human tumor types. These mutations confer constitutive activation as well as resistance to the type II tyrosine kinase inhibitors (TKI) that are currently clinically available, such as imatinib and sunitinib. It is now understood that activation loop mutations in class III RTKs shift the activation state equilibrium away from inactive states, to which type II TKIs bind, to the active state by destabilizing the inactive conformation. Recently, type I TKIs, which can bind to active kinase conformations, have been developed with specificity for class III RTK members. Some type I TKIs, such as crenolanib and avapritinib (BLU-285), have entered clinical studies for patients with activation loop mutations in KIT, PDGFRA, or FLT3. Preliminary results suggest that these type I TKIs show activity in these patient populations that previously lacked effective treatments. This article reviews the inactive and active structures of KIT, PDGFRA, and FLT3, how the mutations seen in human cancers affect kinase structure, and the clinical implications of these mutations in terms of type I vs. type II TKI binding.
Cardiotoxicity mechanisms of the combination of BRAF-inhibitors and MEK-inhibitors Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-28 Enrico Bronte, Giuseppe Bronte, Giuseppina Novo, Gaetana Rinaldi, Fabrizio Bronte, Francesco Passiglia, Antonio Russo
Many new drugs have appeared in last years in the oncological treatment scenario. Each drug carries an important set of adverse events, not less, cardiovascular adverse events. This aspect is even more important considering the increasing use of combination therapies with two drugs, or three drugs as in some ongoing clinical trials. Besides it represents a growing problem for Cardiologists, that face it in every day clinical practice and that will face it probably more and more in the coming years. This work reviews the mechanism of action of BRAF-inhibitors and MEK-inhibitors used together, the pathophysiological mechanisms that lead to cardiovascular toxicity. Particularly, it focuses on hypertension and ejection fraction reduction development. Then, it follows the examination of published data for each combination therapy. A Literature research was carried out using Pubmed selecting review articles, original studies and clinical trials, but mainly focusing on phase 3 studies. This work aims to summarize the knowledge about BRAF-inhibitor and MEK-inhibitor treatment and its cardiovascular toxicity to make it usable and give the basic tools to Cardiologists and Oncologists for a better management of cancer patient undergoing this treatment. Besides a deeper knowledge of the cardiovascular adverse events linked to this treatment and the magnitude of their expression and frequency can lead to a targeted cardiological treatment.
Glycosylation as new pharmacological strategies for diseases associated with excessive angiogenesis Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-29 Simon Bousseau, Luisa Vergori, Raffaella Soleti, Guy Lenaers, M. Carmen Martinez, Ramaroson Andriantsitohaina
Angiogenesis is a complex process describing the growth of new blood vessels from existing vasculature, and is triggered by local pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which increase the metabolism of endothelial cells (ECs). Angiogenesis takes part in various physiological conditions such as embryogenesis, placental growth, and in pathological conditions such as tumor growth, diabetic retinopathy, rheumatoid arthritis (RA) and ischemic diseases. Current therapies against excessive angiogenesis target vascular growth signaling. However, tumors often counteract these therapies through adaptive mechanisms, thus novel alternative anti-angiogenic strategies are needed. Targeting metabolism is a new anti-angiogenic paradigm, especially through the inhibition of energy metabolism and glycosylation, with the perspective of maintaining the delicate balance between the beneficial and deleterious effects of excessive angiogenesis in patients. Recent studies described a role for EC glycolysis and its main regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the regulation of angiogenesis, but only few studies are related to the role of the hexosamine biosynthesis pathway during angiogenesis. Glycosylation allows the formation of glycoproteins, glycolipids and proteoglycans and impacts many pathways. The addition of glycans to N-linked proteins is catalyzed by the enzymatic activity of N-acetylglucosaminyltransferases (GnTs), which regulates the glycosylation status of key angiogenic factors such as VEGF receptor 2 (VEGFR2) and Notch. In addition, glycan-galectin (Gal) interactions regulate vascular signaling programs and may contribute to tumor adaptations to anti-angiogenic strategies. Herein, we review novel pharmacological strategies targeting glycosylation, which could be used to decrease excessive angiogenesis in pathological conditions.
Approaches to target IgE antibodies in allergic diseases Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-27 Bianca Balbino, Eva Conde, Thomas Marichal, Philipp Starkl, Laurent L. Reber
IgE is the antibody isotype found at the lowest concentration in the circulation. However IgE can undeniably play an important role in mediating allergic reactions; best exemplified by the clinical benefits of anti-IgE monoclonal antibody (omalizumab) therapy for some allergic diseases. This review will describe our current understanding of the interactions between IgE and its main receptors FcεRI and CD23 (FcεRII). We will review the known and potential functions of IgE in health and disease: in particular, its detrimental roles in allergic diseases and chronic spontaneous urticaria, and its protective functions in host defense against parasites and venoms. Finally, we will present an overview of the drugs that are in clinical development or have therapeutic potential for IgE-mediated allergic diseases.
Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-25 Stefano Aringhieri, Marco Carli, Shivakumar Kolachalam, Valeria Verdesca, Enrico Cini, Mario Rossi, Peter J. McCormick, Giovanni U. Corsini, Roberto Maggio, Marco Scarselli
The introduction of atypical antipsychotics (AAPs) since the discovery of its prototypical drug clozapine has been a revolutionary pharmacological step for treating psychotic patients as these allow a significant recovery not only in terms of hospitalization and reduction in severity symptoms, but also in terms of safety, socialization and better rehabilitation in the society. Regarding the mechanism of action, AAPs are weak D2 receptor antagonists and they act beyond D2 antagonism, involving other receptor targets which regulate dopamine and other neurotransmitters. Consequently, AAPs present a significant reduction of deleterious side effects like parkinsonism, hyperprolactinemia, apathy and anhedonia, which are all linked to the strong blockade of D2 receptors.This review revisits previous and current findings within the class of AAPs and highlights the differences in terms of receptor properties and clinical activities among them. Furthermore, we propose a continuum spectrum of “atypia” that begins with risperidone (the least atypical) to clozapine (the most atypical), while all the other AAPs fall within the extremes of this spectrum.Clozapine is still considered the gold standard in refractory schizophrenia and in psychoses present in Parkinson's disease, though it has been associated with adverse effects like agranulocytosis (0.7%) and weight gain, pushing the scientific community to find new drugs as effective as clozapine, but devoid of its side effects. To achieve this, it is therefore imperative to characterize and compare in depth the very complex molecular profile of AAPs. We also introduce relatively new concepts like biased agonism, receptor dimerization and neurogenesis to identify better the old and new hallmarks of “atypia”.Finally, a detailed confrontation of clinical differences among the AAPs is presented, especially in relation to their molecular targets, and new means like therapeutic drug monitoring are also proposed to improve the effectiveness of AAPs in clinical practice.
Novel therapeutic strategy for cancer and autoimmune conditions: Modulating cell metabolism and redox capacity Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-25 Xing-Xing Fan, Hu-Dan Pan, Ying Li, Rui-Jin Guo, Elaine Lai-Han Leung, Liang Liu
Dysregulation of cell metabolism and redox balance is implicated in the pathogenesis and progression of cancer and autoimmune diseases. Because the cell proliferation and apoptotic regulatory pathways are interconnected with metabolic and redox signalling pathways, the current mono-target treatment is ineffective, and multi-drug resistance remains common. Complex diseases are often implicated in a network-based context of pathology; therefore, a new holistic intervention approach is required to block multi-crosstalk in such complicated circumstances. The use of therapeutic agents isolated from herbs to holistically modulate metabolism and redox state has been shown to relieve carcinoma growth and the inflammatory response in autoimmune disorders. Multiple clinically applied or novel herbal chemicals with metabolic and redox modulatory capacity as well as low toxicity have recently been identified. Moreover, new metabolic targets and mechanisms of drug action have been discovered, leading to the exploration of new pathways for drug repositioning, clinical biomarker spectra, clinical treatment strategies and drug development. Taken together with multiple supporting examples, the modulation of cell metabolism and the redox capacity using herbal chemicals is emerging as a new, alternative strategy for the holistic treatment of cancer and autoimmune disorders. In the future, the development of new diagnostic tools based on the detection of metabolic and redox biomarkers, reformulation of optimized herbal compositions using artificial intelligence, and the combination of herbs with mono-targeting drugs will reveal new potential for clinical application.
Neurosteroids: non-genomic pathways in neuroplasticity; involvement in neurological diseases Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-25 Marina Schverer, Laurence Lanfumey, Etienne-Emile Baulieu, Nicolas Froger, Isabelle Villey
Neurosteroids are neuroactive brain-born steroids. They can act through non-genomic and/or through genomic pathways. Genomic pathways are largely described for steroid hormones: the binding to nuclear receptors leads to transcription regulation. Pregnenolone, Dehydroepiandrosterone, their respective sulfate esters and Allopregnanolone have no corresponding nuclear receptor identified so far whereas some of their non-genomic targets have been identified. Neuroplasticity is the capacity that neuronal networks have to change their structure and function in response to biological and/or environmental signals; it is regulated by several mechanisms, including those that involve neurosteroids.In this review, after a description of their biosynthesis, the effects of Pregnenolone, Dehydroepiandrosterone, their respective sulfate esters and Allopregnanolone on their targets will be exposed. We then shall highlight that neurosteroids, by acting on these targets, can regulate neurogenesis, structural and functional plasticity. Finally, we will discuss the therapeutic potential of neurosteroids in the pathophysiology of neurological diseases in which alterations of neuroplasticity are associated with changes in neurosteroid levels.
More than fishing for a cure: The promises and pitfalls of high throughput cancer cell line screens Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-25 Alexander Ling, Robert F. Gruener, Jessica Fessler, R. Stephanie Huang
High-throughput screens in cancer cell lines (CCLs) have been used for decades to help researchers identify compounds with the potential to improve the treatment of cancer and, more recently, to identify genomic susceptibilities in cancer via genome-wide shRNA and CRISPR/Cas9 screens. Additionally, rich genomic and transcriptomic data of these CCLs has allowed researchers to pair this screening data with biological features, enabling efforts to identify biomarkers of treatment response and gene dependencies. In this paper, we review the major CCL screening efforts and the large datasets these screens have made available. We also assess the CCL screens collectively and include a resource with harmonized CCL and compound identifiers to facilitate comparisons across screens. The CCLs in these screens were found to represent a wide range of cancer types, with a strong correlation between the representation of a cancer type and its associated mortality. Patient ages and gender distributions of CCLs were generally as expected, with some notable exceptions of female underrepresentation in certain disease types. Also, ethnicity information, while largely incomplete, suggests that African American and Hispanic patients may be severely underrepresented in these screens. Nearly all genes were targeted in the genetic perturbations screens, but the compounds used for the drug screens target less than half of known cancer drivers, likely reflecting known limitations in our drug design capabilities. Finally, we discuss recent developments in the field and the promise they hold for enabling future screens to overcome previous limitations and lead to new breakthroughs in cancer treatment.
Autophagy as an emerging target in cardiorenal metabolic disease: From pathophysiology to management Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-22 Yingmei Zhang, Adam T. Whaley-Connell, James R. Sowers, Jun Ren
Although advances in medical technology and health care have improved the early diagnosis and management for cardiorenal metabolic disorders, the prevalence of obesity, insulin resistance, diabetes, hypertension, dyslipidemia, and kidney disease remains high. Findings from numerous population-based studies, clinical trials, and experimental evidence have consolidated a number of theories for the pathogenesis of cardiorenal metabolic anomalies including resistance to the metabolic action of insulin, abnormal glucose and lipid metabolism, oxidative and nitrosative stress, endoplasmic reticulum (ER) stress, apoptosis, mitochondrial damage, and inflammation. Accumulating evidence has recently suggested a pivotal role for proteotoxicity, the unfavorable effects of poor protein quality control, in the pathophysiology of metabolic dysregulation and related cardiovascular complications. The ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathways, two major although distinct cellular clearance machineries, govern protein quality control by degradation and clearance of long-lived or damaged proteins and organelles. Ample evidence has depicted an important role for protein quality control, particularly autophagy, in the maintenance of metabolic homeostasis. To this end, autophagy offers promising targets for novel strategies to prevent and treat cardiorenal metabolic diseases. Targeting autophagy using pharmacological or natural agents exhibits exciting new strategies for the growing problem of cardiorenal metabolic disorders.
CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-19 Filipa Lynce, Ayesha N. Shajahan-Haq, Sandra M. Swain
Dysregulation of the cyclin dependent kinase pathway in luminal breast cancer creates a new therapeutic opportunity for estrogen receptor positive breast cancer. Initial pan-CDK inhibitors were associated with extensive toxicities but in recent years, the development of potent specific CDK inhibitors with favorable tolerability has driven renewed interests in this class of targeted therapies. Palbociclib, ribociclib and abemaciclib are specific CDK4/6 inhibitors that have been approved by the U.S. Food and Drug Administration for use in combination with endocrine therapy for women with advanced hormone receptor positive breast cancer. These three anticancer therapeutics were approved based on progression free survival benefit seen on phase III trials with the most common grade 3 treatment-related side effects being neutropenia, fatigue, nausea and diarrhea. Except for estrogen receptor positivity, no biomarkers predictive of response to CDK4/6 inhibitors have been identified to date. Based on mechanistic insights here described, CDK4/6 inhibitors are currently being explored in combination with other agents, including targeted therapies, immunotherapy and chemotherapy.
Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we? Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-20 Jenny Beebe, Jing-Yuan Liu, Jian-Ting Zhang
Signal transducer and activator of transcription 3 (STAT3) controls many biological processes including differentiation, survival, proliferation, and angiogenesis. In normal healthy cells, STAT3 is tightly regulated to maintain a momentary active state. However, aberrant or constitutively activated STAT3 has been observed in many different cancers and constitutively activated STAT3 has been shown to associate with poor prognosis and tumor progression. For this reason, STAT3 has been studied as a possible target in the treatment of many different types of cancers. However, despite decades of research, a FDA-approved STAT3 inhibitor has yet to emerge. In this review, we will analyze past studies targeting STAT3 for drug discovery, understand possible causes of failure in these studies, and provide potential insights for future efforts to overcome these roadblocks.
Progress and challenges of selective Farnesoid X receptor modulation Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-20 Vittoria Massafra, Roberto Pellicciari, Antimo Gioiello, Saskia W.C. van Mil
Bile acids are amphipathic molecules that were previously known to serve as fat solubilizers in the intestine in postprandial conditions. In the last two decades, bile acids have been recognized as signaling molecules regulating energy metabolism pathways via, amongst others, the farnesoid X receptor (FXR). Upon bile acid activation, FXR controls expression of genes involved in bile acid, lipid, glucose and amino acid metabolism. In addition, FXR activation has been shown to limit the inflammatory response. The central role of FXR in various aspects of metabolism and inflammation makes FXR an attractive drug target for several diseases, such as obesity, metabolic syndrome, non-alcoholic steatohepatitis, cholestasis and chronic inflammatory diseases of the liver and intestine. However, most of the currently available compounds impact on all discovered FXR-mediated functions and may have, on top of beneficial effects, undesired biological actions depending on the disease. Therefore, research efforts are increasingly focused on the development of selective FXR modulators, i.e. selective bile acid receptor modulators (SBARMs), aimed at limiting the potential side-effects of conventional full FXR agonists upon chronic treatment. Here, we review the rationale for the design of SBARMs comprising dissociation between metabolic and inflammatory signaling, gene-selective and tissue-specific targeting. We discuss the potential structural mechanisms underlying the binding properties of dissociating ligands of FXR in light of ongoing efforts on the generation of dissociated ligands for other nuclear receptors, as well as their pharmacological and therapeutic potential.
Chloroquine and nanoparticle drug delivery: A promising combination Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-20 Joe Pelt, Sara Busatto, Mauro Ferrari, E. Aubrey Thompson, Kabir Mody, Joy Wolfram
Clinically approved cancer therapies include small molecules, antibodies, and nanoparticles. There has been major progress in the treatment of several cancer types over recent decades. However, many challenges remain for optimal use of conventional and nanoparticle-based therapies in oncology including poor drug delivery, rapid clearance, and drug resistance. The antimalarial agent chloroquine has been found to mitigate some of these challenges by modulating cancer cells and the tissue microenvironment. Particularly, chloroquine was recently found to reduce immunological clearance of nanoparticles by resident macrophages in the liver, leading to increased tumor accumulation of nanodrugs. Additionally, chloroquine has been shown to improve drug delivery and efficacy through normalization of tumor vasculature and suppression of several oncogenic and stress-tolerance pathways, such as autophagy, that protect cancer cells from cytotoxic agents. This review will discuss the use of chloroquine as combination therapy to improve cancer treatment.
Antiepileptic drugs as analgesics/adjuvants in inflammatory pain: current preclinical evidence ☆ Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-15 Tomić Maja, Pecikoza Uroš, Micov Ana, Vučković Sonja, Stepanović-Petrović Radica
Inflammatory pain is the most common type of pain that is treated clinically. The use of currently available treatments (classic analgesics - NSAIDs, paracetamol and opioids) is limited by insufficient efficacy and/or side effects/tolerance development. Antiepileptic drugs (AEDs) are widely used in neuropathic pain treatment, but there is substantial preclinical evidence on their efficacy against inflammatory pain, too. In this review we focus on gabapentinoids (gabapentin and pregabalin) and dibenzazepine AEDs (carbamazepine, oxcarbazepine, and recently introduced eslicarbazepine acetate) and their potential for relieving inflammatory pain. In models of somatic, visceral and trigeminal inflammatory pain, that have a translational value for inflammatory conditions in locomotor system, viscera and head/face, AEDs have demonstrated analgesic activity. This activity was mostly consistent, dependent on the dose and largely independent on the site of inflammation and method of its induction, nociceptive stimuli, species, specific drug used, its route of administration and dosing schedule. AEDs exerted comparable efficacy with classic analgesics. Effective doses of AEDs are lower than toxic doses in animals and, when expressed as equivalent human doses, they are largely overlapping with AEDs doses already used in humans for treating epilepsy/neuropathic pain. The main mechanism of antinociceptive/antihyperalgesic action of gabapentinoids in inflammatory pain models seems to be α2δ-dependent suppression of voltage-gated calcium channels in primary sensory neurons that leads to reduced release of neurotransmitters in the spinal/medullar dorsal horn. The suppression of NMDA receptors via co-agonist binding site primarily at spinal sites, activation of various types of K+ channels at spinal and peripheral sites, and activation of noradrenergic and serotonergic descending pain modulatory pathways may also contribute. Inhibition of voltage-gated sodium channels along the pain pathway is probably the main mechanism of antinociceptive/antihyperalgesic effects of dibenzazepines. The recruitment of peripheral adrenergic and purinergic mechanisms and central GABAergic mechanisms may also contribute. When co-administered with classic/other alternative analgesics, AEDs exerted synergistic/additive interactions. Reviewed data could serve as a basis for clinical studies on the efficacy/safety of AEDs as analgesics/adjuvants in patients with inflammatory pain, and contribute to the improvement of the treatment of various inflammatory pain states.
Regulation of prostate cancer by hormone-responsive G protein-coupled receptors Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-15 Wei Wang, Zhao-Xia Chen, Dong-Yu Guo, Ya-Xiong Tao
Regulation of prostate cancer by androgen and androgen receptor (AR), and blockade of AR signaling by AR antagonists and steroidogenic enzyme inhibitors have been extensively studied. G protein-coupled receptors (GPCRs) are a family of membrane receptors that regulate almost all physiological processes. Nearly 40% of FDA-approved drugs in the market target GPCRs. A variety of GPCRs that mediate reproductive function have been demonstrated to be involved in the regulation of prostate cancer. These GPCRs include gonadotropin-releasing hormone receptor, luteinizing hormone receptor, follicle-stimulating hormone receptor, relaxin receptor, ghrelin receptor, and kisspeptin receptor. We highlight here GPCR regulation of prostate cancer by these GPCRs. Further therapeutic approaches targeting these GPCRs for the treatment of prostate cancer are summarized.
Targeting phosphatases of regenerating liver (PRLs) in cancer Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-06-05 Min Wei, Konstantin V. Korotkov, Jessica S. Blackburn
The phosphatase of regenerating liver (PRL) family, also known as protein tyrosine phosphatase 4A (PTP4A), are dual-specificity phosphatases with largely unknown cellular functions. However, accumulating evidence indicates that PRLs are oncogenic across a broad variety of human cancers. PRLs are highly expressed in advanced tumors and metastases compared to early stage cancers or matched healthy tissue, and high expression of PRLs often correlates with poor patient prognosis. Consequentially, PRLs have been considered potential therapeutic targets in cancer. Persistent efforts have been made to define their role and mechanism in cancer progression and to create specific PRL inhibitors for basic research and drug development. However, targeting PRLs with small molecules remains challenging due to the highly conserved active site of protein tyrosine phosphatases and a high degree of sequence similarity between the PRL protein families. Here, we review the current PRL inhibitors, including the strategies used for their identification, their biological efficacy, potency, and selectivity, with a special focus on how PRL structure can inform future efforts to develop specific PRL inhibitors.
Evolving targets for the treatment of atherosclerosis Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-04 Ankita Solanki, Lokesh Kumar Bhatt, Thomas P. Johnston
Atherosclerosis is a progressive disease of large arteries and a leading cause of cardiovascular diseases and stroke. Chronic inflammation, aberrant immune response, and disturbances to key enzymes involved with lipid metabolism are characteristic features of atherosclerosis. Apart from targeting the derangements in lipid metabolism, therapeutic modulation to regulate chronic inflammation and the immune system response may prove to be very promising strategies in the management of atherosclerosis. In recent years, various targets have been studied for the treatment of atherosclerosis. PCSK9, a serine protease, actively targets the LDL-R and causes lysosomal degradation, which leads to excessive accumulation of LDL-C. Regulatory T cells (Tregs) and Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) affects the adaptive and innate immune response, respectively, and thus, therapeutic intervention of either of these targets would directly modulate disease progression. Advanced atherosclerotic lesions are characterized by an accumulation of apoptotic cells. Cluster of differentiation-47 (CD47), an anti-phagocytic known as the “don't eat me” signaling molecule, inhibits efferocytosis, which causes accumulation of cell debris in plaque. ADAMTS and Notch signaling potentially affect the formation of neointima by modulation of extracellular matrix components such as macrophages and vascular smooth muscle cells. This review provides insights on the molecular targets for therapeutic intervention of atherosclerosis, their effect at various stages of atherosclerosis development, and the therapies that have been designed and currently being evaluated in clinical trials.
Targeting cancer stem cells in the clinic: Current status and perspectives Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-05 Stephanie Annett, Tracy Robson
Resistance to chemotherapy and cancer relapse are major clinical challenges attributed to a sub population of cancer stem cells (CSCs). The concept of CSCs has been the subject of intense research by the oncology community since evidence for their existence was first published over twenty years ago. Emerging data indicates that they are also able to evade novel therapies such as targeted agents, immunotherapies and anti-angiogenics. The inability to appropriately identify and isolate CSCs is a major hindrance to the field and novel technologies are now being utilized. Agents that target CSC-associated cell surface receptors and signaling pathways have generated promising pre-clinical results and are now entering clinical trial. Here we discuss and evaluate current therapeutic strategies to target CSCs.
Efferocytosis in atherosclerotic lesions: Malfunctioning regulatory pathways and control mechanisms Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-11 Amir Tajbakhsh, Mehdi Rezaee, Petri T. Kovanen, Amirhossein Sahebkar
Atherosclerosis is a dynamic and progressive inflammatory process in the intimal layer of large and medium-sized arteries, and it is the major contributor to the atherosclerotic cardiovascular disease (ACVD), the leading cause of death worldwide. In an atherosclerotic plaque, phagocytosis of apoptotic cells occurs through an intricate process designated efferocytosis. Defective efferocytosis has emerged as a causal factor in the etiopathogenesis of atherosclerosis and its progression into overt ACVD. Both specialized phagocytes (macrophages and dendritic cells) and non-specialized cells with phagocytic capabilities (smooth muscle and endothelial cells) are involved in the efferocytotic process. Moreover, several signaling and regulatory molecules are involved in the different steps of efferocytosis, and they include “Find-Me” signals (lysophosphatidylcholine), “Eat-Me” signals [phosphatidylserine, Mer tyrosine kinase (MerTK), and milk fat globule-EGF factor 8], and “Don't Eat-Me” signals [cluster of differentiation 47 (CD47)]. Regulation of efferocytosis is in a close nexus with inflammation, the key component in atherosclerosis. The predominance of pro-inflammatory and anti-inflammatory molecules plays a crucial role in lesion progression and regression, respectively. Polarization of macrophages towards the M1 phenotype causes them to secrete proinflammatory cytokines, while polarization towards the M2 phenotype causes them to secrete of anti-inflammatory cytokines, including interleukin-10 and transforming growth factor β, so tending to shift the balance towards resolution of the inflammation. Dysfunction of any regulatory signal may cause expansion of the necrotic core of an atherosclerotic plaque with ensuing conversion of the plaque into an unstable plaque with an increased susceptibility to rupture and to atherothrombotic complication. In this review we aim at elucidating the determinant factors and pathways of efferocytosis which can be considered as potential novel targets when striving to develop more personalized and efficient treatment regimens for patients with ACVD.
Serelaxin as a novel therapeutic opposing fibrosis and contraction in lung diseases Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-12 Maggie Lam, Simon G. Royce, Chrishan S. Samuel, Jane E. Bourke
The most common therapies for asthma and other chronic lung diseases are anti-inflammatory agents and bronchodilators. While these drugs oppose disease symptoms, they do not reverse established structural changes in the airways and their therapeutic efficacy is reduced with increasing disease severity. The peptide hormone, relaxin, is a Relaxin Family Peptide Receptor 1 (RXFP1) receptor agonist with unique combined effects in the lung that differentiates it from these existing therapies. Relaxin has previously been reported to have cardioprotective effects in acute heart failure as well anti-fibrotic actions in several organs. This review focuses on recent experimental evidence of the beneficial effects of chronic relaxin treatment in animal models of airways disease demonstrating inhibition of airway hyperresponsiveness and reversal of established fibrosis, consistent with potential therapeutic benefit. Of particular interest, accumulating evidence demonstrates that relaxin can also acutely oppose contraction by reducing the release of mast cell-derived bronchoconstrictors and by directly eliciting bronchodilation. When used in combination, chronic and acute treatment with relaxin has been shown to enhance responsiveness to both glucocorticoids and β2-adrenoceptor agonists respectively. While the mechanisms underlying these beneficial actions remain to be fully elucidated, translation of these promising combined preclinical findings is critical in the development of relaxin as a novel alternative or adjunct therapeutic opposing multiple aspects of airway pathology in lung diseases.
Circular RNA and its mechanisms in disease: From the bench to the clinic Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-14 Bing Han, Jie Chao, Honghong Yao
The emerging recognition of the functional roles of circular RNAs (circRNAs) has given rise to a new perspective regarding our understanding of cellular physiology and disease pathogenesis. Unlike linear RNAs, circRNAs are covalently closed continuous loops that act as gene regulators in mammals, and their sequence composition determines the mode of circRNA biogenesis. The availability and integrated use of advanced genome analysis platforms have allowed the identification of a large number of these molecules. Their high abundance, stability and evolutionary conservation among species endow circRNAs with numerous potential functions, such as acting as microRNA (miRNA) sponges or binding to RNA-associated proteins to form RNA-protein complexes that regulate gene transcription. Moreover, circRNAs have been shown to be expressed in a tissue-specific manner and in pathological conditions, which has stimulated significant interest in their role in human disease and cancer. In this concise review, we outline the characteristics, functions and mechanisms of action of circRNAs as well as their involvement in different diseases. Although their exact roles and mechanisms of gene regulation remain to be clarified, circRNAs have potential applications as disease biomarkers and novel therapeutic targets.
Signalling pathways regulating galactosaminoglycan synthesis and structure in vascular smooth muscle: Implications for lipoprotein binding and atherosclerosis Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-15 Rizwana Afroz, Yingnan Cao, Muhamad Ashraf Rostam, Hang Ta, Suowen Xu, Wenhua Zheng, Narin Osman, Danielle Kamato, Peter J. Little
Atherosclerosis commences with the trapping of low density lipoproteins (LDLs) in blood vessels by modified proteoglycans (PGs) with hyperelongated glycosaminoglycan (GAG) chains. GAG chain synthesis and growth factor mediated hyperelongation regulates the composition and size of PGs in a manner that would cause low density lipoprotein (LDLs) retention in vessel wall. Galactosaminoglycans are a class of GAGs, commonly observed on PGs. Multiple enzymes are involved in galactosaminoglycan biosynthesis. Galactosaminoglycan synthesis is regulated by various signalling pathways which are amenable to pharmacological manipulation to treat atherosclerosis. Receptor mediated signalling pathways including protein tyrosine kinase receptors (PTKRs), serine/threonine kinase receptors (S/TKRs) and G-protein coupled receptors (GPCRs) pathways regulate galactosaminoglycan synthesizing enzyme expression. Increased expression of these enzymes modify galactosaminoglycan chain structure by making them hyperelongated. This review focuses on the signalling pathways regulating the expression of genes involved in galactosaminoglycan synthesis and modification. Furthermore, there are multiple other processes for inhibiting the interactions between LDL and galactosaminoglycans such as peptide mimetics of ApoB100 and anti-galactosaminoglycan antibodies and the therapeutic potential of these strategies is also addressed.
Nucleosidic DNA demethylating epigenetic drugs – A comprehensive review from discovery to clinic Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-15 Khushboo Agrawal, Viswanath Das, Pankhuri Vyas, Marián Hajdúch
DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development. This review is a comprehensive report of the literature published in past 40 years, on so far discovered nucleosidic DNA methylation inhibitors in chronological order. The review will provide a complete insight to the readers about the mechanisms of action, efficacy to demethylate and re-express various cancer-related genes, anti-tumor activity, cytotoxicity profile, stability, and bioavailability of these drugs. The review further presents the far known mechanisms of primary and secondary resistance to azanucleoside drugs. Finally, the review highlights the ubiquitous role of DNA hypomethylating epi-drugs as chemosensitizers and/or priming agents, and recapitulate the combinatorial cancer preventive effects of these drugs with other epigenetic agents, conventional chemo-drugs, or immunotherapies. This comprehensive review analyzes the beneficial characteristics and drawbacks of nucleosidic DNA methylation inhibitors, which will assist the pre-clinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy.
ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-16 Andrew M. Kidger, James Sipthorp, Simon J. Cook
The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is de-regulated in a variety of cancers due to mutations in receptor tyrosine kinases (RTKs), negative regulators of RAS (such as NF1) and core pathway components themselves (RAS, BRAF, CRAF, MEK1 or MEK2). This has driven the development of a variety of pharmaceutical agents to inhibit RAF-MEK1/2-ERK1/2 signalling in cancer and both RAF and MEK inhibitors are now approved and used in the clinic. There is now much interest in targeting at the level of ERK1/2 for a variety of reasons. First, since the pathway is linear from RAF-to-MEK-to-ERK then ERK1/2 are validated as targets per se. Second, innate resistance to RAF or MEK inhibitors involves relief of negative feedback and pathway re-activation with all signalling going through ERK1/2, validating the use of ERK inhibitors with RAF or MEK inhibitors as an up-front combination. Third, long-term acquired resistance to RAF or MEK inhibitors involves a variety of mechanisms (KRAS or BRAF amplification, MEK mutation, etc.) which re-instate ERK activity, validating the use of ERK inhibitors to forestall acquired resistance to RAF or MEK inhibitors. The first potent highly selective ERK1/2 inhibitors have now been developed and are entering clinical trials. They have one of three discrete mechanisms of action – catalytic, “dual mechanism” or covalent – which could have profound consequences for how cells respond and adapt. In this review we describe the validation of ERK1/2 as anti-cancer drug targets, consider the mechanism of action of new ERK1/2 inhibitors and how this may impact on their efficacy, anticipate factors that will determine how tumour cells respond and adapt to ERK1/2 inhibitors and consider ERK1/2 inhibitor drug combinations.
Modulation of CYP1A1 metabolism: From adverse health effects to chemoprevention and therapeutic options Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-17 Melina Mescher, Thomas Haarmann-Stemmann
The human cytochrome P450 (CYP) 1A1 gene encodes a monooxygenase that metabolizes multiple exogenous and endogenous substrates. CYP1A1 has become infamous for its oxidative metabolism of benzo[a]pyrene and related polycyclic aromatic hydrocarbons, converting these chemicals into very potent human carcinogens. CYP1A1 expression is mainly controlled by the aryl hydrocarbon receptor (AHR), a transcription factor whose activation is induced by binding of persistent organic pollutants, including polycyclic aromatic hydrocarbons and dioxins. Accordingly, induction of CYP1A1 expression and activity serves as a biomarker of AHR activation and associated xenobiotic metabolism as well as toxicity in diverse animal species and humans. Determination of CYP1A1 activity is integrated into modern toxicological concepts and testing guidelines, emphasizing the tremendous importance of this enzyme for risk assessment and regulation of chemicals. Further, CYP1A1 serves as a molecular target for chemoprevention of chemical carcinogenesis, although present literature is controversial on whether its inhibition or induction exerts beneficial effects. Regarding therapeutic applications, first anti-cancer prodrugs are available, which require a metabolic activation by CYP1A1, and thus enable a specific elimination of CYP1A1-positive tumors. However, the application range of these drugs may be limited due to the frequently observed downregulation of CYP1A1 in various human cancers, probably leading to a reduced metabolism of endogenous AHR ligands and a sustained activation of AHR and associated tumor-promoting responses. We here summarize the current knowledge on CYP1A1 as a key player in the metabolism of exogenous and endogenous substrates and as a promising target molecule for prevention and treatment of human malignancies.
WNT receptor signalling in lung physiology and pathology Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-17 Wioletta Skronska-Wasek, Reinoud Gosens, Melanie Königshoff, Hoeke Abele Baarsma
The WNT signalling cascades have emerged as critical regulators of a wide variety of biological aspects involved in lung development as well as in physiological and pathophysiological processes in the adult lung. WNTs (secreted glycoproteins) interact with various transmembrane receptors and co-receptors to activate signalling pathways that regulate transcriptional as well as non-transcriptional responses within cells. In physiological conditions, the majority of WNT receptors and co-receptors can be detected in the adult lung. However, dysregulation of WNT signalling pathways contributes to the development and progression of chronic lung pathologies, including idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma and lung cancer. The interaction between a WNT and the (co-)receptor(s) present at the cell surface is the initial step in transducing an extracellular signal into an intracellular response. This proximal event in WNT signal transduction with (cell-specific) ligand-receptor interactions is of great interest as a potential target for pharmacological intervention. In this review we highlight the diverse expression of various WNT receptors and co-receptors in the aforementioned chronic lung diseases and discuss the currently available biologicals and pharmacological tools to modify proximal WNT signalling.
The relaxin receptor as a therapeutic target – perspectives from evolution and drug targeting Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-17 Ross A.D. Bathgate, Martina Kocan, Daniel J. Scott, M. Akhter Hossain, Sara V. Good, Sergey Yegorov, Jan Bogerd, Paul R. Gooley
The peptide relaxin was first identified as an important circulating hormone during pregnancy over 90 years ago. Research over many years defined the numerous biological roles that relaxin plays throughout pregnancy in many mammalian species. These important biological actions have led to the testing of relaxin as a therapeutic agent for a number of indications. The discovery of the relaxin receptor, RXFP1, in 2002 facilitated the better understanding of the cellular targets of relaxin, its mechanism of action and enabled the development of relaxin mimetics and screening for small molecule agonists. Additionally, the rapid expansion of the genome databases and bioinformatics tools has significantly advanced our understanding of the evolution of the relaxin/RXFP1 signaling system. It is now clear that the relaxin-RXFP1 signaling axis is far more ancient than previously appreciated with important roles for invertebrate relaxin-like peptides in reproductive and non-reproductive functions. This review summarizes these advances as well as developments in drug targeting of RXFP1. Hence the complex mode of activation of RXFP1 is discussed as is the discovery and development of a peptide mimetic and small molecule agonist. Detailed signaling studies are summarized which highlight the cell specific signaling of a peptide mimetic and biased signaling of a small molecule agonist. These studies highlight the complexities of targeting peptide GPCRs such as RXFP1.
Safer approaches to therapeutic modulation of TGF-β signaling for respiratory disease Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-17 Philippe Lachapelle, Meina Li, Jo Douglass, Alastair Stewart
The transforming growth factor (TGF)-β cytokines play a central role in development and progression of chronic respiratory diseases. TGF-β overexpression in chronic inflammation, remodeling, fibrotic process and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including asthma, COPD, lung cancer and idiopathic pulmonary fibrosis. Despite the overwhelming burden of respiratory diseases in the world, new pharmacological therapies have been limited in impact. Although TGF-β inhibition as a therapeutic strategy carries great expectations, the constraints in avoiding compromising the beneficial pleiotropic effects of TGF-β, including the anti-proliferative and immune suppressive effects, have limited the development of effective pharmacological modulators. In this review, we focus on the pathways subserving deleterious and beneficial TGF-β effects to identify strategies for selective modulation of more distal signaling pathways that may result in agents with improved safety/efficacy profiles. Adverse effects of TGF-β inhibitors in respiratory clinical trials are comprehensively reviewed, including those of the marketed TGF-β modulators, pirfenidone and nintedanib. Precise modulation of TGF-β signaling may result in new safer therapies for chronic respiratory diseases.
Inflammasome biology, molecular pathology and therapeutic implications Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-18 Fawaz Awad, Eman Assrawi, Camille Louvrier, Claire Jumeau, Sophie Georgin-Lavialle, Gilles Grateau, Serge Amselem, Irina Giurgea, Sonia-Athina Karabina
Inflammasomes are intracellular multiprotein signaling complexes, mainly present in myeloid cells. They commonly assemble around a cytoplasmic receptor of the nucleotide-binding leucine-rich repeat containing receptor (NLR) family, although other cytoplasmic receptors like pyrin have been shown to form inflammasomes. The nucleation of the multiprotein scaffolding platform occurs upon detection of a microbial, a danger or a homeostasis pattern by the receptor that will, most commonly, associate with the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) through homotypic domain interactions resulting in recruitment of procaspase-1. This will lead to the autoproteolytic activation of caspase-1, which regulates the secretion of proinflammatory IL1β and IL18 cytokines and pyroptosis, a caspase-1-mediated form of cell death. Pyroptosis occurs through cleavage of Gasdermin D, a membrane pore forming protein. Recently, non-canonical inflammasomes have been described, which directly sense intracellular pathogens through caspase-4 and -5 in humans, leading to pyroptosis. Inflammasomes are important in host defense; however, a deregulated activity is associated with a number of inflammatory, immune and metabolic disorders. Furthermore, mutations in inflammasome receptor coding genes are causal for an increasing number of rare autoinflammatory diseases. Biotherapies targeting the products of inflammasome activation as well as molecules that directly or indirectly inhibit inflammasome nucleation and activation are promising therapeutic areas. This review discusses recent advances in inflammasome biology, the molecular pathology of several inflammasomes, and current therapeutic approaches in autoinflammatory diseases and in selected common multifactorial inflammasome-mediated disorders.
Biogenesis and function of extracellular vesicles in cancer Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-21 Maarten P. Bebelman, Martine J. Smit, D. Michiel Pegtel, S. Rubina Baglio
Nutraceuticals and osteoarthritis pain Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-24 Angela Wang, Daniel J. Leong, Luis Cardoso, Hui B. Sun
Arthritis is a chronic disease of joints. It is highly prevalent, particularly in the elderly, and is commonly associated with pain that interferes with quality of life. Because of its chronic nature, pharmacological approaches to pain relief and joint repair must be safe for long term use, a quality many current therapies lack. Nutraceuticals refer to compounds or materials that can function as nutrition and exert a potential therapeutic effect, including the relief of pain, such as pain related to arthritis, of which osteoarthritis (OA) is the most common form. Of interest, nutraceuticals have recently been shown to have potential in relieving OA pain in human clinical trials. Emerging evidence indicates nutraceuticals may represent promising alternatives for the relief of OA pain. In this paper, we will overview OA pain and the use of nutraceuticals in OA pain management, focusing on those that have been evaluated by clinical trials. Furthermore, we discuss the biologic and pharmacologic actions underlying the nutraceutical effects on pain relief based on the potential active ingredients identified from traditional nutraceuticals in OA pain management and their potential for drug development. The review concludes by sharing our viewpoints that future studies should prioritize elucidating the mechanisms of action of nutraceuticals in OA and developing nutraceuticals that not only relieve OA pain, but also mitigate OA pathology.
Newer therapeutic strategies for soft-tissue sarcomas Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-02-24 Kevin Bourcier, Antoine Italiano
Metastatic soft-tissue sarcoma (STS), a devastating disease, has a median overall survival of only 12–18 months. Until recently, therapeutic options were limited and relied primarily on the use of anthracycline-based chemotherapy. Over the past two decades, improvement in the knowledge of the biology of STS has allowed the investigation of new therapeutic strategies including new cytotoxic agents, epigenetic drugs, specific targeted therapies, and immunotherapeutic treatments.
The long-lived Octodon degus as a rodent drug discovery model for Alzheimer's and other age-related diseases Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-03-04 Michael J. Hurley, Robert M.J. Deacon, Katrin Beyer, Elena Ioannou, Agustin Ibáñez, Jessica L. Teeling, Patricia Cogram
Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disease. Despite decades of research, no disease modifying therapy is available and a change of research objectives and/or development of novel research tools may be required. Much AD research has been based on experimental models using animals with a short lifespan that have been extensively genetically manipulated and do not represent the full spectrum of late-onset AD, which make up the majority of cases. The aetiology of AD is heterogeneous and involves multiple factors associated with the late-onset of the disease like disturbances in brain insulin, oxidative stress, neuroinflammation, metabolic syndrome, retinal degeneration and sleep disturbances which are all progressive abnormalities that could account for many molecular, biochemical and histopathological lesions found in brain from patients dying from AD. This review is based on the long-lived rodent Octodon degus (degu) which is a small diurnal rodent native to South America that can spontaneously develop cognitive decline with concomitant phospho-tau, β-amyloid pathology and neuroinflammation in brain. In addition, the degu can also develop several other conditions like type 2 diabetes, macular and retinal degeneration and atherosclerosis, conditions that are often associated with aging and are often comorbid with AD. Long-lived animals like the degu may provide a more realistic model to study late onset AD.
The role of TAM family receptors and ligands in the nervous system: From development to pathobiology Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-03-04 Bridget Shafit-Zagardo, Ross C. Gruber, Juwen C. DuBois
Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K–dependent growth arrest-specific protein 6 (Gas6). Gas6 and the TAMs are abundantly expressed in the nervous system. Gas6, secreted by neurons and endothelial cells, is the sole ligand for Axl. ProteinS1 (ProS1), another vitamin K–dependent protein functions mainly as an anti-coagulant, and independent of this function can activate Tyro3 and Mertk, but not Axl. This review will focus on the role of the TAM receptors and their ligands in the nervous system. We highlight studies that explore the function of TAM signaling in myelination, the visual cortex, neural cancers, and multiple sclerosis (MS) using Gas6−/− and TAM mutant mice models.
Canine sarcomas as a surrogate for the human disease Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-03-09 Daniel L. Gustafson, Dawn L. Duval, Daniel P. Regan, Douglas H. Thamm
Pet dogs are becoming increasingly recognized as a population with the potential to inform medical research through their treatment for a variety of maladies by veterinary health professionals. This is the basis of the One Health initiative, supporting the idea of collaboration between human and animal health researchers and clinicians to study spontaneous disease processes and treatment in animals to inform human health. Cancer is a major health burden in pet dogs, accounting for approximately 30% of deaths across breeds. As such, pet dogs with cancer are becoming increasingly recognized as a resource for studying the pharmacology and therapeutic potential of anticancer drugs and therapies under development. This was recently highlighted by a National Academy of Medicine Workshop on Comparative Oncology that took place in mid-2015 (http://www.nap.edu/21830). One component of cancer burden in dogs is their significantly higher incidence of sarcomas as compared to humans. This increased incidence led to canine osteosarcoma being an important component in the development of surgical approaches for osteosarcoma in children. Included in this review of sarcomas in dogs is a description of the incidence, pathology, molecular characteristics and previous translational therapeutic studies associated with these tumors. An understanding of the patho-physiological and molecular characteristics of these naturally occurring canine sarcomas holds great promise for effective incorporation into drug development schemas, for evaluation of target modulation or other pharmacodynamic measures associated with therapeutic response. These data could serve to supplement other preclinical data and bolster clinical investigations in tumor types for which there is a paucity of human patients for clinical trials.
Discovery of Leonuri and therapeutical applications: From bench to bedside Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-03-09 Yi Zhun Zhu, Weijun Wu, Qing Zhu, Xinhua Liu
Despite several advances in percutaneous coronary intervention and the discovery of new drugs, the incidence of myocardial infarction and deaths due to cardiovascular diseases (CVD) has not decreased markedly in China. The quality of life is affected seriously, which further results in great social and family burden. Many drugs, from the century-old aspirin to the newly FDA-approved Byvalson, have been proven to be effective in the treatment and prevention of CVD. As clinically reported, those life-saving drugs still have their side effects in regards to the narrow therapeutic indexes influenced by individual genetic variations. Herba Leonuri, also known as Chinese Motherwort, which are naturally present in plants and traditionally are used for the uterotonic action, postpartum blood stasis, breast pain as well as other gynecological disorders in China for thousands of years. Since the last two decades, our group has reported leonurine, a unique alkaloid found in Herba Leonuri, exhibits various bioactivities such as antioxidant, anti-apoptotic effects, free radical scavenging and anti-inflammatory effects, in addition to improving micro-circulation. These bioactivities are related to the underlying mechanisms of ischemic heart diseases and cardiac fibrosis. Pharmacological studies have proven leonurine to be effective in treating CVD in various ways, particularly ischemic heart diseases. Besides the cardio protective effects, which are similar in the central nervous system, more specifically, inhibited mitochondrial reactive oxygen species production together with the restored mitochondrial function and redox state were observed in middle cerebral artery occlusion rats by leonurine treatment, which strongly reveals its neuroprotective effects and carries a therapeutic potential for recovery and prevention of stroke. Based on their mode of action, we propose that leonurine can be developed as drugs to treat ischemic heart diseases. Taking advantage of the most recent findings in pharmacological research including the effects of low toxicity and good pharmacokinetics characteristics, leonurine has a very attractive prospect of clinical application. Our recent promising pharmacological results may be able to eradicate the barrier hindering its sale on market. In sum, from bench to bedside is no longer a long way for leonurine.
Racing the clock: The role of circadian rhythmicity in addiction across the lifespan Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-03-15 Danielle Gulick, Joshua J. Gamsby
Although potent effects of psychoactive drugs on circadian rhythms were first described over 30 years ago, research into the reciprocal relationship between the reward system and the circadian system – and the impact of this relationship on addiction – has only become a focus in the last decade. Nonetheless, great progress has been made in that short time toward understanding how drugs of abuse impact the molecular and physiological circadian clocks, as well as how disruption of normal circadian rhythm biology may contribute to addiction and ameliorate the efficacy of treatments for addiction. In particular, data have emerged demonstrating that disrupted circadian rhythms, such as those observed in shift workers and adolescents, increase susceptibility to addiction. Furthermore, circadian rhythms and addiction impact one another longitudinally – specifically from adolescence to the elderly. In this review, the current understanding of how the circadian clock interacts with substances of abuse within the context of age-dependent changes in rhythmicity, including the potential existence of a drug-sensitive clock, the correlation between chronotype and addiction vulnerability, and the importance of rhythmicity in the mesocorticolimbic dopamine system, is discussed. The primary focus is on alcohol addiction, as the preponderance of research is in this area, with references to other addictions as warranted. The implications of clock-drug interactions for the treatment of addiction will also be reviewed, and the potential of therapeutics that reset the circadian rhythm will be highlighted.
Sirtuin activators and inhibitors: Promises, achievements, and challenges Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-03-22 Han Dai, David A. Sinclair, James L. Ellis, Clemens Steegborn
The NAD+-dependent protein lysine deacylases of the Sirtuin family regulate various physiological functions, from energy metabolism to stress responses. The human Sirtuin isoforms, SIRT1–7, are considered attractive therapeutic targets for aging-related diseases, such as type 2 diabetes, inflammatory diseases and neurodegenerative disorders. We review the status of Sirtuin-targeted drug discovery and development. Potent and selective pharmacological Sirt1 activators and inhibitors are available, and initial clinical trials have been carried out. Several promising inhibitors and activators have also been described for other isoforms. Progress in understanding the mechanisms of Sirtuin modulation by such compounds provides a rational basis for further drug development.
Targeting the replication stress response in cancer Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-03-24 Josep V. Forment, Mark J. O’Connor
Many conventional chemotherapies used in cancer treatment exert their effect by inflicting DNA damage. Highly proliferative tissues, as well as tumour cells, are particularly vulnerable to this damage resulting in unwanted toxicities. In contrast, a targeted therapeutic approach has the aim of specifically eliminating cancer cells but with a reduced effect on healthy tissue. New therapies have been developed that target the replication stress response (RSR), a branch of the broader DNA damage response that specifically deals with interferences of the normal DNA replication program. Different pharmaceutical companies have developed inhibitors of the RSR kinases ATR, CHK1 and WEE1, which are currently at different phases of clinical development. Here, we review how the RSR works at the molecular level, what is the rationale for its targeting, and how we envisage its best use in the clinic, based on patient selection and combination therapies supported by in vitro and in vivo preclinical studies.
Arthropod toxins and their antinociceptive properties: From venoms to painkillers Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-03-29 Victoria Monge-Fuentes, Claudia Arenas, Priscilla Galante, Jacqueline Coimbra Gonçalves, Márcia Renata Mortari, Elisabeth Ferroni Schwartz
The complex process of pain control commonly involves the use of systemic analgesics; however, in many cases, a more potent and effective polypharmacological approach is needed to promote clinically significant improvement. Additionally, considering side effects caused by current painkillers, drug discovery is once more turning to nature as a source of more efficient therapeutic alternatives. In this context, arthropod venoms contain a vast array of bioactive substances that have evolved to selectively bind to specific pharmacological targets involved in the pain signaling pathway, playing an important role as pain activators or modulators, the latter serving as promising analgesic agents. The current review explores how the pain pathway works and surveys neuroactive compounds obtained from arthropods' toxins, which function as pain modulators through their interaction with specific ion channels and membrane receptors, emerging as promising candidates for drug design and development.
Vascular effects of Apelin: Mechanisms and therapeutic potential Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-05-25 Amreen Mughal, Stephen T. O'Rourke
Apelin is a vasoactive peptide and is an endogenous ligand for APJ receptors, which are widely expressed in blood vessels, heart, and cardiovascular regulatory regions of the brain. A growing body of evidence now demonstrates a regulatory role for the apelin/APJ receptor system in cardiovascular physiology and pathophysiology, thus making it a potential target for cardiovascular drug discovery and development. Indeed, ongoing studies are investigating the potential benefits of apelin and apelin-mimetics for disorders such as heart failure and pulmonary arterial hypertension. Apelin causes relaxation of isolated arteries, and systemic administration of apelin typically results in a reduction in systolic and diastolic blood pressure and an increase in blood flow. Nonetheless, vasopressor responses and contraction of vascular smooth muscle in response to apelin have also been observed under certain conditions. The goal of the current review is to summarize major findings regarding the apelin/APJ receptor system in blood vessels, with an emphasis on regulation of vascular tone, and to identify areas of investigation that may provide guidance for the development of novel therapeutic agents that target this system.
Therapeutic targeting of cathepsin C: from pathophysiology to treatment Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-05-26 Brice Korkmaz, George H. Caughey, Iain Chapple, Francis Gauthier, Josefine Hirschfeld, Dieter E. Jenne, Ralph Kettritz, Gilles Lalmanach, Anne-Sophie Lamort, Conni Lauritzen, Monika Legowska, Adam Lesner, Sylvain Marchand-Adam, Sarah J. McKaig, Celia Moss, John Pedersen, Helen Roberts, Adrian Schreiber, Seda Seren, Nalin S. Thakkar
Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials.
Pharmacological modulation of the CO2/HCO3−/pH-, calcium-, and ATP- sensing soluble adenylyl cyclase Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-05-26 Shakarr V. Wiggins, Clemens Steegborn, Lonny R. Levin, Jochen Buck
Cyclic AMP (cAMP), the prototypical second messenger, has been implicated in a wide variety of (often opposing) physiological processes. It simultaneously mediates multiple, diverse processes, often within a single cell, by acting locally within independently-regulated and spatially-restricted microdomains. Within each microdomain, the level of cAMP will be dependent upon the balance between its synthesis by adenylyl cyclases and its degradation by phosphodiesterases (PDEs). In mammalian cells, there are many PDE isoforms and two types of adenylyl cyclases; the G protein regulated transmembrane adenylyl cyclases (tmACs) and the CO2/HCO3−/pH-, calcium-, and ATP- sensing soluble adenylyl cyclase (sAC). Discriminating the roles of individual cyclic nucleotide microdomains requires pharmacological modulators selective for the various PDEs and/or adenylyl cyclases. Such tools present an opportunity to develop therapeutics specifically targeted to individual cAMP dependent pathways. The pharmacological modulators of tmACs have recently been reviewed, and in this review, we describe the current status of pharmacological tools available for studying sAC.
Advances in stroke pharmacology Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-05-25 Zhenhua Zhou, Jianfei Lu, Wen-Wu Liu, Anatol Manaenko, Xianhua Hou, Qiyong Mei, Jun-Long Huang, Jiping Tang, John H. Zhang, Honghong Yao, Qin Hu
Stroke occurs when a cerebral blood vessel is blocked or ruptured, and it is the major cause of death and adult disability worldwide. Various pharmacological agents have been developed for the treatment of stroke either through interrupting the molecular pathways leading to neuronal death or enhancing neuronal survival and regeneration. Except for rtPA, few of these agents have succeeded in clinical trials. Recently, with the understanding of the pathophysiological process of stroke, there is a resurrection of research on developing neuroprotective agents for stroke treatment, and novel molecular targets for neuroprotection and neurorestoration have been discovered to predict or offer clinical benefits. Here we review the latest major progress of pharmacological studies in stroke, especially in ischemic stroke; summarize emerging potential therapeutic mechanisms; and highlight recent clinical trials. The aim of this review is to provide a panorama of pharmacological interventions for stroke and bridge basic and translational research to guide the clinical management of stroke therapy.
Prenatal inflammation exposure-programmed cardiovascular diseases and potential prevention Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-05-25 Youcai Deng, Liang Song, Xuqiang Nie, Weinian Shou, Xiaohui Li
In recent years, the rapid development of medical and pharmacological interventions has led to a steady decline in certain noncommunicable chronic diseases (NCDs), such as cancer. However, the overall incidence of cardiovascular diseases (CVDs) has not seemed to decline. CVDs have become even more prevalent in many countries and represent a global health threat and financial burden. An increasing number of epidemiological and experimental studies have demonstrated that maternal insults not only can result in birth defects but also can cause developmental functional defects that contribute to adult NCDs. In the current review, we provide an overview of evidence from both epidemiological investigations and experimental animal studies supporting the concept of developmental reprogramming of adult CVDs in offspring that have experienced prenatal inflammation exposure (PIE) during fetal development (PIE-programmed CVDs), a disease-causing event that has not been effectively controlled. This review describes the epidemiological observations, data from animal models, and related mechanisms for the pathogenesis of PIE-programmed CVDs. In addition, the potential therapeutic interventions of PIE-programmed CVDs are discussed. Finally, we also deliberate the need for future mechanistic studies and biomarker screenings in this important field, which creates a great opportunity to combat the global increase in CVDs by managing the adverse effects of inflammation for prepregnant and pregnant individuals who are at risk for PIE-programmed CVDs.
The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-05-25 Chadi G. Abdallah, Gerard Sanacora, Ronald S. Duman, John H. Krystal
The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper summarizes our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review focuses on the role of glutamate neurotransmission – reviewing the history of the “glutamate inhibition” and “glutamate activation” hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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