Current Drug Targets (v.16, #5)

Meet Our Editorial Board Member by Subhash C. Basu (409-409).

Pathophysiology of Erectile Dysfunction by Hotaka Matsui, Nikolai A. Sopko, Johanna L. Hannan, Trinity J. Bivalacqua (411-419).
Erectile dysfunction (ED) is a major health problem as the population ages. Basic science research for the last two decades has expanded the knowledge on ED and identified several key molecular changes associated with the pathogenesis of ED, including nitric oxide (NO) / cyclic guanosine monophosphate (cGMP) / protein kinase G (PKG) pathway, RhoA/Rho-associated protein kinase (ROCK) signaling pathway, reactive oxygen species (ROS), renin-angiotensin system (RAS) and tumor necrosis factor-alpha (TNF-α). The causes of ED are classified into aging, vasculogenic, neurogenic, endocrinological, drug-induced and psychogenic. ED is often associated with systemic diseases, such as diabetes and cardiovascular diseases. In this review, we will review the molecular mechanisms of ED and known mechanisms behind ED associated with systemic diseases.

PDE-5 Inhibitors: Clinical Points by Michael Doumas, Antonios Lazaridis, Niki Katsiki, Vasilios Athyros (420-426).
Erectile dysfunction is usually of vascular origin and is frequently encountered in men with cardiovascular disease. The introduction of phosphodiesterase-5 inhibitors has revolutionized the management of patients with erectile dysfunction. Currently available phosphodiesterase-5 inhibitors have distinct pharmacokinetic and pharmacodynamic properties, thus permitting for tailoring sexual therapy according to patient characteristics and needs. Phosphodiesterase-5 inhibitors possess vasorelaxing properties and exert systemic hemodynamic effects, which need to be taken into account when other cardiovascular drugs are co-administered. Special caution is needed with alpha-blockers, while the co-administration with nitrates is contra-indicated due to the risk of life-threatening hypotension. This review presents the advent of sexual therapy, describes the mechanism of action and the specific characteristics of commercially available phosphodiesterase-5 inhibitors, summarizes the efficacy and safety of these drugs with special emphasis on the cardiovascular system, and discusses the clinical criteria used for the selection of each drug for the individual patient.

Introduction: Erectile dysfunction (ED) has reached epidemic proportions not expected to abate because of population aging and chronic diseases that accompany advanced age. Vasculopathy is a main cause, but damage to penile innervation also underlies many cases of ED. Phosphodiesterase inhibitor therapies do not help all men with ED, making the search for novel therapeutic drug and treatment targets of utmost importance. Aims: To review the literature to identify potential new treatment targets to fill a gap in therapeutic options for men with ED, with a focus on treatments for vasculogenic ED, but including novel treatment targets for ED due to penile nerve damage, a frequent consequence of pelvic surgery in men. Methods: The recent literature was searched for publications on in vitro, in vivo, pre-clinical and observational human studies, when available, that would identify potential new targets for ED therapies not previously, or not extensively reviewed. Results: Literature searches identified microparticles, myeloperoxidase, and heme oxygenase-1 as emerging molecular targets to treat vasculogenic ED. Novel regenerative therapy targets, including sonic hedgehog, galanin, and cell-based treatments were also reviewed as potential future treatments for ED due to damage to penile innervation. Conclusion: Novel molecular targets and cell-based therapies offer great hope for advances in ED treatment. Concerns regarding efficacy, toxicity, off target effects, safety, and convenience apply to these targets; much work remains to confirm these as viable targets to pursue for effective ED treatments. To complement targets discussed in this review relevant review papers were cited for the interested reader. To complement targets discussed in this review relevant review papers were cited for the interested reader

There is a Link Between Erectile Dysfunction and Heart Failure: It could be Inflammation by Fernanda Luciano Rodrigues, Rafael Sobrano Fais, Rita C. Tostes, Fernando S. Carneiro (442-450).
The rates of erectile dysfunction (ED) in heart failure (HF) are extremely high. Limited capacity of patients with HF to exercise and coronary artery disease are considered to be the main causative mechanisms. Both HF and ED are associated with increased levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL- 8). The increased levels of proinflammatory cytokines in ED suggest that inflammatory markers act as important active agents in ED development. The innate immune system also reacts to danger signals released by damaged cells. Damage-associated molecular patterns (DAMPs) are molecules released as a result of tissue injury acting on immune activation during non-infectious inflammation. DAMPs may also reach the circulation and mediate pathophysiological processes that occur in distant organs to the injured site. Cardiomyocytes possess abundant mitochondria and during tissue damage, it is likely that the heart releases high amounts of mitochondrial DNA (mtDNA), which acts as a potent ligand for Toll-like receptor 9 (TLR9). Accordingly, in the present manuscript we review the literature pertaining the relationship between HF and ED and the subjacent inflammatory process associated to both diseases. In addition, we propose the hypothesis that TLR9 activation by DAMPs released in HF leads to inflammation, vascular dysfunction and functional changes in cavernosal tissue, providing an additional mechanism that connects HF to ED. Since TNF-α usually is a product of TLRs activation and seems to be a common link between HF and ED, our hypothesis provide two possible targets to treat the ED associated to HF and may have important preventative and therapeutic implications.

Penile Rehabilitation After Radical Prostatectomy by David Jacques Cohen, Sidney Glina (451-458).
Erectile dysfunction (ED) is the main and most frequent side effect after radical prostatectomy. Also, ED is the primary impact factor for quality of life after radical prostatectomy. ED post radical prostatectomy is mainly due to lesions in the neurovascular bundles which can occur by partial or total sectioning, by stretching (the most common), or by thermal lesion of the nervous fibers, leading to a condition called 'neuropraxia'. The term penile rehabilitation (PR) after prostatectomy has been defined as any intervention with the intent of reestablishing preoperative erectile function and includes the isolated or combined use of phosphodiesterase 5 inhibitors (PDE5i), intracavernous injection, vacuum erectile device therapy, and use of intraurethral drugs. The use of intracavernous drugs, of intraurethral prostaglandin and the use of vacuum therapy have a poorly defined role regarding postoperative penile rehabilitation and must be better investigated through further studies. The use of PDE5i as PR is strongly supported by experimental research, but most clinical trials found controversial results.

Despite nerve-sparing techniques, erectile dysfunction remains commonly observed after radical prostatectomy due to neuropraxia to the cavernous nerves during surgery. Preservation and rehabilitation of erectile function after radical prostatectomy remains challenging and many men stay undertreated with the current armory of therapies available in clinical practice. In this article we provide a comprehensive overview of the pathophysiology of the nerve injury occurring during radical prostatectomy and describe different strategies aimed at enhancing neuroprotection and regeneration of the cavernous nerves in order to improve erectile function recovery. These strategies include immunomodulatory, neurotrophic, growth factor and stem cell therapy have convincingly shown improved erectile function and recovery in rat animal models after cavernous nerve injury. Furthermore we describe the rationale for penile rehabilitation with PDE5i out of a neuronal recovery point of view. Many of these strategies reviewed have the potential to optimize erectile function recovery after radical prostatectomy when translated from pre-clinical models to clinical practice.

Molecular Pathophysiology of Priapism: Emerging Targets by Uzoma A. Anele, Belinda F. Morrison, Arthur L. Burnett (474-483).
Priapism is an erectile disorder involving uncontrolled, prolonged penile erection without sexual purpose, which can lead to erectile dysfunction. Ischemic priapism, the most common of the variants, occurs with high prevalence in patients with sickle cell disease. Despite the potentially devastating complications of this condition, management of recurrent priapism episodes historically has commonly involved reactive treatments rather than preventative strategies. Recently, increasing elucidation of the complex molecular mechanisms underlying this disorder, principally involving dysregulation of nitric oxide signaling, has allowed for greater insights and exploration into potential therapeutic targets. In this review, we discuss the multiple molecular regulatory pathways implicated in the pathophysiology of priapism. We also identify the roles and mechanisms of molecular effectors in providing the basis for potential future therapies.

Management of Peyronie's Disease after Collagenase (Xiaflex:®) by Amjad Alwaal, Ahmed Aly Hussein, Uwais B. Zaid, Tom F. Lue (484-494).
Although the prevalence of Peyronie's disease (PD) is reported to be 3-9% in men, the true prevalence is likely higher due to under-reporting. Many treatment modalities have been described for PD with varying degrees of success. In this article, we review and summarize the current literature pertaining to all pharmacotherapies (oral, intralesional, iontophoresis, and topical) and minimally invasive treatments available for PD (vacuum, traction device, shock wave therapy, and radiation treatment). Additionally, we discuss emerging therapies for PD that are still in pre-clinical development, including stem cell therapy.

Immobilization and Detection Strategies for Multifunctional Glycochips by Gangliang Huang, Xinya Mei, Qilin Tang, Xin Chen (495-498).
Glycochips can be used to map the carbohydrate-protein interactions in high-throughput manner. Carbohydrates are immobilized on the support surface by covalent or noncovalent binding. The immobilization strategies for glycochips were summarized herein. In addition, some recently developed techniques for detection of carbohydrate-protein interactions were also involved.

Targeting the Multifaceted HuR Protein, Benefits and Caveats by Chiara Zucal, Vito D’Agostino, Rosa Loffredo, Barbara Mantelli, NatthakanThongon, Preet Lal, Elisa Latorre, Alessandro Provenzani (499-515).
The RNA-binding protein (RBP) HuR is one of the most widely studied regulators of the eukaryotic posttranscriptional gene expression and it plays a physiological role in mediating the cellular response to apoptotic, proliferating and survival stimuli. Following physiological or stress stimuli, HuR protein binds to Adenylate-Urydinilate rich elements (AREs) generally contained in the 3'UTR of transcripts, then it shuttles from the nucleus to the cytoplasm and regulates the half-life and/or translation of cargo mRNAs. Derangements in sub-cellular localization and expression of HuR have been associated with the pathophysiology of many diseases and this protein has been proposed as a potential drug target. Recent findings also re-evaluated HuR as a splicing and polyadenylation factor, expanding its spectrum of functional activity up to the maturation of pre-mRNAs. In this review, we generate a comprehensive picture of HuR functionality to discuss the implications of considering HuR as pharmacological target and the detrimental or positive impact that can be expected upon its modulation. Firstly, we focus on the recent findings about the mechanistic role of HuR in the nucleus and in the regulation of long non coding RNAs; then we describe the animal models and the clinical association and significance in cancer; finally, we have reviewed the pharmacological tools that influence HuR's post-transcriptional control and the efforts made to identify specific HuR inhibitors.

Regulating the Beta Cell Mass as a Strategy for Type-2 Diabetes Treatment by Imane Song, Christo Muller, Johan Louw, Luc Bouwens (516-524).
The incidence of type 2 diabetes (T2D) increases dramatically worldwide and has created an enormous health care burden. Obesity, dyslipidemia and insulin resistance are major risk factors for the development of T2D, but the major factor leading to the disease is failure of the insulin-producing beta cell mass to compensate for increasing insulin demands of the body. Progression of the disease further diminishes the beta cell mass as a result of lipotoxicity and glucotoxicity for which beta cells are particularly sensitive. Hence, treatment aiming to prevent beta cell loss or increase the number of beta cells could inhibit diabetes progression or lead to restoration of normal metabolism. Whereas current and new antidiabetic drugs are mainly targeting insulin secretion and action or glucose uptake, newer interventions must be found that prevent beta cell loss or increase beta cell number. The targets for this are beta cell proliferation, neogenesis and survival. This review examines major evidence from animal experiments suggesting that it is feasible to regulate the beta cell mass by bioactive compounds like growth factors, cytokines, hormones, phytochemicals and small molecules. Often the mode of action remains unclear due to inadequate methods to assess the effects of the compounds on the beta cell dynamics. Furthermore, a major challenge is to identify compounds with sufficient specificity in order to avoid unwanted effects on other cell types. Provided such safety issues can be solved, this may provide a curative approach for diabetes treatment.