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Garden of therapeutic delights: new targets in rheumatic diseases
Jean M Waldburger, Gary S Firestein
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2556
Abstract: The development of new therapies for rheumatic diseases was mainly empiric until recently. Most of the drugs that we used until the 1990s, including standards like methotrexate, were originally discovered for other purposes or were accidentally noted to be beneficial in autoimmunity. As the molecular mechanisms of disease have been unraveled, newer targeted therapies have been a stunning success. Understanding the importance of cytokine networks in rheumatoid arthritis (RA) led to the biologics era with agents that block tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6. These biologics are also effective in other diseases, including seronegative spondyloarthropathies, autoinflammatory syndromes, and perhaps gout.Despite notable achievements, currently available therapies are not effective in many patients with rheumatic diseases. The new biologics are ineffective in many individuals; in some situations, like systemic lupus erythematosus (SLE), no new effective therapies have been approved for decades. As our knowledge of disease pathogenesis expands, new pathways and mechanisms that can be exploited are emerging. In this review, we will discuss some promising targets that have arisen from recent research. Due to the breadth and depth of current research and space limitations, this is not an exhaustive review, but it does provide a taste of what is to come (Figure 1).The most dramatic therapeutic advances in the 'modern' era of rheumatology have focused on anti-cytokine therapy. As the cytokine network becomes increasingly complex, new and exciting possibilities arise. In this section, a few key cytokine targets are discussed.Of the cytokines relevant to autoimmunity, IL-17 and its family have perhaps generated the most anticipation. In murine models of autoimmune disease, the Th17 subtype of T lymphocytes that produce IL-17 plays a pivotal role in pathogenesis [1]. While the function of this factor in humans is less certain, it represents a unique T cell-
New therapeutic targets in the management of urothelial carcinoma of the bladder
Sverrisson EF, Espiritu PN, Spiess PE
Research and Reports in Urology , 2013, DOI: http://dx.doi.org/10.2147/RRU.S29131
Abstract: herapeutic targets in the management of urothelial carcinoma of the bladder Review (442) Total Article Views Authors: Sverrisson EF, Espiritu PN, Spiess PE Video abstract presented by Philippe E Spiess Views: 28 Published Date March 2013 Volume 2013:5 Pages 53 - 65 DOI: http://dx.doi.org/10.2147/RRU.S29131 Received: 08 December 2012 Accepted: 25 January 2013 Published: 01 March 2013 Einar F Sverrisson, Patrick N Espiritu, Philippe E Spiess Department of Genitourinary Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USA Abstract: Urothelial carcinoma of the bladder, despite the myriad of treatment approaches and our progressively increasing knowledge into its disease processes, remains one of the most clinically challenging problems in modern urological clinical practice. New therapies target biomolecular pathways and cellular mediators responsible for regulating cell growth and metabolism, both of which are frequently overexpressed in malignant urothelial cells, with the intent of inducing cell death by limiting cellular metabolism and growth, creating an immune response, or selectively delivering or activating a cytotoxic agent. These new and novel therapies may offer a potential for reduced toxicity and an encouraging hope for better treatment outcomes, particularly for a disease often refractory or not amenable to the current therapeutic approaches.
MAPKs represent novel therapeutic targets for gastrointestinal motility disorders  [cached]
Eikichi Ihara,Hirotada Akiho,Kazuhiko Nakamura,Sara R Turner
World Journal of Gastrointestinal Pathophysiology , 2011, DOI: 10.4291/wjgp.v2.i2.19
Abstract: The number of patients suffering from symptoms associated with gastrointestinal (GI) motility disorders is on the rise. GI motility disorders are accompanied by alteration of gastrointestinal smooth muscle functions. Currently available drugs, which can directly affect gastrointestinal smooth muscle and restore altered smooth muscle contractility to normal, are not satisfactory for treating patients with GI motility disorders. We have recently shown that ERK1/2 and p38MAPK signaling pathways play an important role in the contractile response not only of normal intestinal smooth muscle but also of inflamed intestinal smooth muscle. Here we discuss the possibility that ERK1/2 and p38MAPK signaling pathways represent ideal targets for generation of novel therapeutics for patients with GI motility disorders.
New Therapeutic Targets for Intraocular Pressure Lowering  [PDF]
A. Rocha-Sousa,J. Rodrigues-Araújo,Petra Gouveia,Jo?o Barbosa-Breda,S. Azevedo-Pinto,P. Pereira-Silva,A. Leite-Moreira
ISRN Ophthalmology , 2013, DOI: 10.1155/2013/261386
Abstract: Primary open-angle glaucoma (POAG) is a leading cause of irreversible and preventable blindness and ocular hypertension is the strongest known risk factor. With current classes of drugs, management of the disease focuses on lowering intraocular pressure (IOP). Despite of their use to modify the course of the disease, none of the current medications for POAG is able to reduce the IOP by more than 25%–30%. Also, some glaucoma patients show disease progression despite of the therapeutics. This paper examines the new described physiological targets for reducing the IOP. The main cause of elevated IOP in POAG is thought to be an increased outflow resistance via the pressure-dependent trabecular outflow system, so there is a crescent interest in increasing trabecular meshwork outflow by extracellular matrix remodeling and/or by modulation of contractility/TM cytoskeleton disruption. Modulation of new agents that act mainly on trabecular meshwork outflow may be the future hypotensive treatment for glaucoma patients. There are also other agents in which modulation may decrease aqueous humour production or increase uveoscleral outflow by different mechanisms from those drugs available for glaucoma treatment. Recently, a role for the ghrelin-GHSR system in the pathophysiology modulation of the anterior segment, particularly regarding glaucoma, has been proposed. 1. Introduction Glaucoma is a progressive optic neuropathy caused by death of the retinal ganglion cells (RGCs) and is the leading cause of irreversible blindness worldwide. The mechanism by which this progressive RGC death occurs is not fully understood. It is clear that multiple causes may give rise to the common effect of ganglion cell death. Clinically, it is well accepted that the major risk factor for glaucoma is elevated intraocular pressure (IOP) [1, 2]. In open angle glaucoma (OAG), elevated IOP occurs from an imbalance between production and outflow of aqueous humor (AH). The mechanical theory argues the importance of direct compression of the axonal fibers and support structures of the anterior optic nerve by elevated IOP resulting in the death of the RGCs. Lowering the IOP (baroprotection) remains the only current therapeutic approach for preserving visual function in glaucoma patients. The six classes of drugs available for glaucoma treatment (miotics, beta-blockers, alfa-agonists, epinephrine derivatives, carbonic anhydrase inhibitors, and prostaglandin analogues) act by decreasing aqueous humor production and/or by improving trabecular meshwork-Schlemm’s canal or uveoscleral outflow. Better
Ion pumps as targets for therapeutic intervention: Old and new paradigms
Perlin,David S.;
Electronic Journal of Biotechnology , 1998,
Abstract: the development of an effective target for therapeutic intervention remains a critical part of the drug discovery process. one such target class is the p-type ion translocating atpases, which include the na+,k+-atpase of cardiac cells and the h+,k+-atpase of gastric parietal cells. these enzymes serve as selective targets for digoxin and omeprazole, which are used to treat heart disease and gastrointestinal ulcers, and are two of the leading prescribed therapeutics worldwide. it is the exquisite selectivity that can be achieved between family members that continues to make the p-type enzymes desirable targets for developing new therapeutics including a new generation of antiulcer therapeutic and a new class of antifungal therapeutic.
New therapeutic targets in the management of urothelial carcinoma of the bladder  [cached]
Sverrisson EF,Espiritu PN,Spiess PE
Research and Reports in Urology , 2013,
Abstract: Einar F Sverrisson, Patrick N Espiritu, Philippe E SpiessDepartment of Genitourinary Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USAAbstract: Urothelial carcinoma of the bladder, despite the myriad of treatment approaches and our progressively increasing knowledge into its disease processes, remains one of the most clinically challenging problems in modern urological clinical practice. New therapies target biomolecular pathways and cellular mediators responsible for regulating cell growth and metabolism, both of which are frequently overexpressed in malignant urothelial cells, with the intent of inducing cell death by limiting cellular metabolism and growth, creating an immune response, or selectively delivering or activating a cytotoxic agent. These new and novel therapies may offer a potential for reduced toxicity and an encouraging hope for better treatment outcomes, particularly for a disease often refractory or not amenable to the current therapeutic approaches.Keywords: targeted therapy, intravesical agents, systemic therapies
DISC1 Pathway in Brain Development: Exploring Therapeutic Targets for Major Psychiatric Disorders  [PDF]
Atsushi Kamiya,Thomas W. Sedlak,Mikhail V. Pletnikov
Frontiers in Psychiatry , 2012, DOI: 10.3389/fpsyt.2012.00025
Abstract: Genetic risk factors for major psychiatric disorders play key roles in neurodevelopment. Thus, exploring the molecular pathways of risk genes is important not only for understanding the molecular mechanisms underlying brain development, but also to decipher how genetic disturbances affect brain maturation and functioning relevant to major mental illnesses. During the last decade, there has been significant progress in determining the mechanisms whereby risk genes impact brain development. Nonetheless, given that the majority of psychiatric disorders have etiological complexities encompassing multiple risk genes and environmental factors, the biological mechanisms of these diseases remain poorly understood. How can we move forward to our research for discovery of the biological markers and novel therapeutic targets for major mental disorders? Here we review recent progress in the neurobiology of disrupted in schizophrenia 1 (DISC1), a major risk gene for major mental disorders, with a particular focus on its roles in cerebral cortex development. Convergent findings implicate DISC1 as part of a large, multi-step pathway implicated in various cellular processes and signal transduction. We discuss links between the DISC1 pathway and environmental factors, such as immune/inflammatory responses, which may suggest novel therapeutic targets. Existing treatments for major mental disorders are hampered by a limited number of pharmacological targets. Consequently, elucidation of the DISC1 pathway, and its association with neuropsychiatric disorders, may offer hope for novel treatment interventions.
Disruption of biological rhythms as a core problem and therapeutic target in mood disorders: the emerging concept of 'rhythm regulators'
Konstantinos N Fountoulakis
Annals of General Psychiatry , 2010, DOI: 10.1186/1744-859x-9-3
Abstract: Biological rhythms have always been considered to be disrupted in depression [1]. In the seminal paper by Akiskal and McKinney [2] it has been concluded that depression is related to hyperarousal, because depressive patients have lower threshold for awakening, rapid eye movement (REM) sleep disorders and loss of delta waves related sleep, which is the deepest stage of non-REM sleep. By 'hyperarousal', it is denoted that depressed patients manifest both higher reactivity to environmental stimuli and sympathetic nervous system (SNS) hyperactivity. According to this approach, sleep disorders are considered in the frame of higher vigilance [3]. Some authors reject this theory and suggest that only somatisation can involve altered central nervous system (CNS) processing (hyperarousal) of somatic stimuli [4]. Theoretically, a disturbance of biological rhythms could be a core feature in the etiopathogenesis of depression [5-7].However, from a clinical point of view depression is not a uniform clinical entity. Even for unipolar depression it is not known whether it is a single disorder or a spectrum of different disorders with overlapping clinical manifestations. Clinically, depressed patients do not manifest sleep disorders alone (difficulty in initiating or sustaining sleep or low sleep quality). The same patients, when awake, manifest concentration difficulties, reduced psychomotor activity, fatigue, somnolence and so on, and these symptoms could be independent from the sleep they experienced the previous night (that is, they are not always consequences of poor sleeping).Melancholic patients in particular typically manifest sleep disorders during the night (insomnia) and fatigue, concentration difficulties and anhaedonia with a lack of prominent anxiety during the daytime. These could be suggestive of a reduction of the arousal level variation span. According to this theory, the arousal level is not sufficiently reduced during the night so as to lead to normal sleep, whi
Chronic Unpredictable Stress (CUS)-Induced Anxiety and Related Mood Disorders in a Zebrafish Model: Altered Brain Proteome Profile Implicates Mitochondrial Dysfunction  [PDF]
Sumana Chakravarty, Bommana R. Reddy, Sreesha R. Sudhakar, Sandeep Saxena, Tapatee Das, Vuppalapaty Meghah, Cherukuvada V. Brahmendra Swamy, Arvind Kumar, Mohammed M. Idris
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063302
Abstract: Anxiety and depression are major chronic mood disorders, and the etiopathology for each appears to be repeated exposure to diverse unpredictable stress factors. Most of the studies on anxiety and related mood disorders are performed in rodents, and a good model is chronic unpredictable stress (CUS). In this study, we have attempted to understand the molecular basis of the neuroglial and behavioral changes underlying CUS-induced mood disorders in the simplest vertebrate model, the zebrafish, Danio rerio. Zebrafish were subjected to a CUS paradigm in which two different stressors were used daily for 15 days, and thorough behavioral analyses were performed to assess anxiety and related mood disorder phenotypes using the novel tank test, shoal cohesion and scototaxis. Fifteen days of exposure to chronic stressors appears to induce an anxiety and related mood disorder phenotype. Decreased neurogenesis, another hallmark of anxiety and related disorders in rodents, was also observed in this zebrafish model. The common molecular markers of rodent anxiety and related disorders, corticotropin-releasing factor (CRF), calcineurin (ppp3r1a) and phospho cyclic AMP response element binding protein (pCREB), were also replicated in the fish model. Finally, using 2DE FTMS/ITMSMS proteomics analyses, 18 proteins were found to be deregulated in zebrafish anxiety and related disorders. The most affected process was mitochondrial function, 4 of the 18 differentially regulated proteins were mitochondrial proteins: PHB2, SLC25A5, VDAC3 and IDH2, as reported in rodent and clinical samples. Thus, the zebrafish CUS model and proteomics can facilitate not only uncovering new molecular targets of anxiety and related mood disorders but also the routine screening of compounds for drug development.
Galectins as New Prognostic Markers and Potential Therapeutic Targets for Advanced Prostate Cancers  [PDF]
Diego J. Laderach,Lucas Gentilini,Felipe M. Jaworski,Daniel Compagno
Prostate Cancer , 2013, DOI: 10.1155/2013/519436
Abstract: A better understanding of multimolecular interactions involved in tumor dissemination is required to identify new effective therapies for advanced prostate cancer (PCa). Several groups investigated protein-glycan interactions as critical factors for crosstalk between prostate tumors and their microenvironment. This review both discusses whether the “galectin-signature” might serve as a reliable biomarker for the identification of patients with high risk of metastasis and assesses the galectin-glycan lattices as potential novel targets for anticancer therapies. The ultimate goal of this review is to convey how basic findings related to galectins could be in turn translated into clinical settings for patients with advanced PCa. 1. Introduction Prostate cancer (PCa) is the second most common cancer in men and represents a significant cause of mortality worldwide [1]. About 15%–20% of men with PCa will certainly develop metastatic disease and die. Early diagnosis and rapid treatment play a critical role in the final outcome of the disease. At present, surgical and radiation treatments are efficient against clinically localized PCa, whereas androgen ablation is mainly recommended for advanced PCa [2]. However, metastatic cancer is essentially fatal due to disease evolution towards a castration-resistant PCa (CRPC). Novel alternative approaches are therefore essential to prevent tumor dissemination and progression to this incurable stage. Effective cancer therapies for PCa typically capitalize on molecular differences between healthy and neoplastic tissues that can be targeted with drugs [3]. In the past years, delineating gene and protein expression profiles has been critical in dissecting the molecular underpinnings of cellular function; the arising information has been exploited for the design of rational therapeutic strategies. In the postgenomic era, the study of the “glycome” has enabled the association of specific glycan structures with the transition from normal to neoplastic tissue [4]. Glycans abundantly decorate the surface of all mammalian cells and the extracellular matrix with which they interact [5]. In general, mammalian glycans are the product of a repertoire of glycosyltransferases and glycosidases acting sequentially and dictating the glycosylation signature of each cell type [6]. It has been recognized that the structure of cell surface glycans can change under different physiological and pathological conditions. In fact, malignant transformation is associated with abnormal glycosylation resulting in the synthesis of altered glycan
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