Current Molecular Pharmacology

Publications in this journal

• Article: ENaC inhibitors and airway re-hydration in cystic fibrosis: state of the art

  Mike Althaus
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  ABSTRACT: Cystic fibrosis (CF) is a hereditary disease caused by mutations in the gene encoding the chloride channel "cystic fibrosis transmembrane conductance regulator" (CFTR). The lack of functional CFTR in CF airways leads to impaired ion and fluid homeostasis of the fluid layer which lines the airway surfaces (ASL). The ASL is important for proper ciliary beat and clearance of mucus from the airways. According to the "low volume hypothesis", CF airway epithelia hyper-absorb sodium via the epithelial sodium channel (ENaC). Although the contribution of ENaC to CF pathogenesis is still under debate, there is convincing data demonstrating that re-hydration of the ASL might improve mucociliary clearance in CF patients. ASL re-hydration might, amongst other things, be achieved by a block of airway transepithelial sodium absorption with inhibitors of ENaC. This mini-review article describes the role of ENaC in ASL fluid homeostasis and re-hydration, and summarizes the current state of the art in the discovery and establishment of compounds which inhibit ENaC activity and may represent pharmacological tools for the treatment of CF.
  Current Molecular Pharmacology 06/2013;
• Article: Kinases as targets for ENaC regulation.

  Deborah Baines
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  ABSTRACT: Amiloride-sensitive epithelial sodium channels (ENaC) transport Na+ and are essential for salt and fluid homeostasis across epithelial tissues. Severalpathological conditions of renal and pulmonary tissues are associated with abnormal ENaC function. The signalling pathways that regulate ENaC activity utilise a number of kinases. Over recent years,more have been identified and their mechanisms of action expanded. The actions of SGK and PKA are the best understood and both up-regulate ENaC activity. SGK is an important target for the action of PI3K via PDK1 and TORC2 whilst PKA is linked with the activity of other kinases that have complementary effects. CK2, GRK2, IKKβ and PKD1 also up-regulate ENaC. In contrast, PKC, ERK1/2 and AMPK are inhibitory. Two keyconvergence targets for kinase action persist. These are phosphorylation of Nedd4-2 and the β and γsubunits of ENaC. Depending on the sites targeted, phosphorylation predominantlypromotes or decreases associationbetween these proteins toregulate ENaC retrieval and its subsequent abundance in the membrane. Alternative emerging targets include proteins involved in the translocation and recycling of ENaC channels to the membrane. Targeting kinases to modify ENaC function in vivohas shown some promise. Inactivation of SGK has produced mild but positive effects on renal function. Activating PKA has shown potential in lung pathologies. Inhibition of PI3K and PKB may prove useful in diabetic related alterations in renal Na+ handling, as could activation of AMPK, which may also have potential in the treatment of pulmonary pathologies associated with elevated ENaC activity.
  Current Molecular Pharmacology 03/2013;
• Article: Novel Activators and Inhibitors of Epithelial Sodium Channels (Enacs): State Of the Art.

  Wolfgang Clauss
  Current Molecular Pharmacology 03/2013;
• Article: ENaC modulators and renal disease.

  Diego Alvarez de la Rosa, Juan F Navarro-González, Teresa Giraldez
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  ABSTRACT: The epithelial sodium channel (ENaC) plays an essential role in transepithelial sodium reabsorption in the renal connecting tubule and collecting duct. Therefore, controlling ENaC activity is an important regulatory event in electrolyte and extracellular volume homeostasis, and thus in the control of blood pressure. Many independent signaling pathways converge on ENaC, although the most important for its physiological role is the enhancement of channel activity by the steroid hormone aldosterone. In this review, we briefly summarize current knowledge about ENaC regulation and the different chemical compounds available to directly or indirectly modify channel function. In addition, current and possible clinical uses of ENaC and aldosterone antagonists are highlighted.
  Current Molecular Pharmacology 03/2013;
• Article: ENaC in the brain-future perspectives and pharmacological implications.

  Teresa Giraldez, Jaime Domínguez, Diego Alvarez de la Rosa
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  ABSTRACT: The epithelial sodium channel/degenerin (ENaC/deg) family of ion channels is formed by a large number of genes with variable tissue expression patterns and physiological roles. ENaC is a non-voltage gated, constitutively active channel highly selective for sodium. ENaC is formed by three homologous subunits, α, β and γ, and a fourth subunit (δ) has been found in human and monkeys that can substitute α to form functional channels. The best-characterized role of ENaC is to serve as a rate-limiting step in transepithelial sodium reabsorption in the distal part of the kidney tubule and other tight epithelia. However, ENaC subunits are also found in the peripheral and central nervous system, where their functional roles are only beginning to be understood. In this review, we mainly focus on the putative pathophysiological roles of ENaC channels in the central nervous system and their potential value as drug targets in neurodegenerative disorders and the central control of blood pressure.
  Current Molecular Pharmacology 03/2013;
• Article: ENaC regulation by proteases and shear stress.

  Shujie Shi, Marcelo D Carattino, Rebecca P Hughey, Thomas R Kleyman
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  ABSTRACT: Epithelial Na+ channels (ENaCs) are comprised of subunits that have large extracellular regions linked to membrane spanning domains where the channel pore and gate reside. A variety of external factors modify channel activity by interacting at sites within extracellular regionsthat lead to conformational changes that are transmitted to the channel gate and alter channel open probability. Our review addresses two external factors that have important roles in regulating channel activity, proteases and laminar shear stress.
  Current Molecular Pharmacology 03/2013;
• Article: Treatment of Pulmonary Edema by ENaC Activators/Stimulators.

  Martin Fronius
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  ABSTRACT: Lungs contain a particular amount of fluid that is crucial for proper lung function. This fluid content is tightly controlled within certain limits. Fluid accumulation in the alveolar airspace impairs gas exchange and represents a life-threatening condition referred to as pulmonary edema. Ion transport processes by pulmonary epithelia represent a mechanism, responsible for fluid absorption from the airspace. Thus, it is obvious to consider ion transport processes as target for therapeutic interventions in pulmonary edema. The principle mechanism responsible for fluid absorption from the airspace is: Na+ diffuses through luminal Na+ channels into epithelial cells and is extruded by Na+/K+-ATPases at the basolateral side. This process generates an osmotic gradient that represents the driving force for fluid absorption. The rate of Na+ absorption is limited by the number/activity of Na+ channels in the luminal membrane of alveolar epithelial cells. Although different Na+ channels have been identified, the epithelial Na+ channel (ENaC) is a major player that participates in Na+-driven fluid absorption and thus a suitable target for the treatment of pulmonary edema. This article reviews cellular mechanisms by which ENaC activity can be increased in alveolar epithelia (lectins, proteases, β-adrenoceptors, mineralo-/glucocorticoid-receptors). These mechanisms are involved in regulating ENaC-dependent fluid absorption under physiological conditions. Additionally, pre-clinical as well as some preliminary clinical studies revealed that "ENaC-activators/stimulators" (β-adrenoceptor agonists and mineralo-/glucocorticoid-receptor agonists) could be beneficial fortherapeutic interventions in patients with pulmonary edema. However, the outcome of subsequently performed multicenter clinical trials with "ENaC-activators/stimulators" for treatment of patients with pulmonary edema was disappointing.
  Current Molecular Pharmacology 03/2013;
• Article: Molecular Mechanisms Mediating Nociceptin/Orphanin FQ Receptor Signaling, Desensitization and Internalization.

  Monica Baiula, Andrea Bedini, Gioia Carbonari
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  ABSTRACT: In 1994, the isolation of an opioid receptor-related clone soon led to the isolation and characterization of a novel neuropeptide, termed nociceptin or orphanin FQ (N/OFQ). This heptadecapeptide binds to the N/OFQ receptor (NOP) with high affinity, but does not interact directly with classical opioid receptors. The regional distribution of N/OFQ and of its receptor suggest any possible involvement of this neurotransmission system in motor and balance control, reinforcement and reward, nociception, stress response, sexual behavior, aggression and autonomic control of physiological processes as well as of immune functions. The actions of N/OFQ may also be uniquely dependent on contextual factors, both genetic and environmental. As for most of the G protein coupled receptors, NOP C-terminal sequences are believed to interact with proteins that are mandatory for anchoring receptor at the plasma membrane, internalization, recycling, or degradation after ligand binding. Increasing details of how NOP receptors are activated and removed from the plasma membrane have been elucidated in vitro, and more importantly in a physiological context. Details of how these receptors travel and recycle following internalization have also shed light on the importance of such mechanisms for any potential therapeutic use of NOP ligands. A picture of the pathways and proteins involved in these processes is beginning to emerge. This review will address molecular events contributing to NOP receptor signaling and trafficking.
  Current Molecular Pharmacology 01/2013;
• Article: Estrogen receptor expression and its relevant signaling pathway in prostate cancer: a target of therapy.

  Yasuhiro Nakamura, Keely McNamara, Hironobu Sasano
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  ABSTRACT: Estrogens have been recently postulated as potential agents in the development and progression of prostate cancer. Previous studies have demonstrated presence of both variants of estrogen receptor (ER); ER alpha (ERα) and ER beta (ERβ) in differing proportions between normal prostate and prostate cancer. It has been previously suggested that estrogens may either accelerate or inhibit growth of prostate cancer cell growth, depending on ER status. In particular, ERβ is considered to have a growth inhibitory role in prostate tissue. ERβ is significantly expressed in human prostate cancer cells, and hence it is considered a key factor for anti-cancer therapy. Therefore, various types of ERβ ligands have been investigated to clarify the mechanism of ERβ-mediated pathway of inhibitory effects on prostate cancer cells. Herein, we review recent examinations of ERs in prostate cancer, and the significance of ER mediated signaling pathways, with a focus on ERβ as prospective therapeutic targets in prostate cancer.
  Current Molecular Pharmacology 01/2013;
• Article: Bevacizumab and Angiogenesis Inhibitors in the Treatment of CNS metastases: the Road less Travelled.

  Irina Veytsman, Jeanny B Aragon-Ching, Sandra M Swain
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  ABSTRACT: The incidence of central nervous system (CNS) metastases secondary to solid tumors is increasing. As more effective systemic therapy is being used in patients with solid tumors, patients with cancer live longer and are ultimately at higher risk for CNS metastases. However, CNS metastases remain challenging to treat because of limited available therapeutic options. This article reviews mechanisms of CNS metastases, the use of bevacizumab and other angiogenesis inhibitors in the treatment of recurrent and front-line CNS metastases, as well as emerging issues of resistance to anti-angiogenic therapy.
  Current Molecular Pharmacology 01/2013;
• Article: Molecular and pharmacological aspects of existing and experimental bone anabolic therapies.

  Naibedya Chattopadhyay
  Current Molecular Pharmacology 06/2012; 5(2):125-6.
• Article: G-protein coupled receptor resensitization-appreciating the balancing act of receptor function.

  Maradumane L Mohan, Neelakantan T Vasudevan, Manveen K Gupta, Elizabeth E Martelli, S V Naga Prasad
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  ABSTRACT: G-protein coupled receptors (GPCRs) are seven transmembrane receptors that are pivotal regulators of cellular responses including vision, cardiac contractility, olfaction, and platelet activation. GPCRs have been a major target for drug discovery due to their role in regulating a broad range of physiological and pathological responses. GPCRs mediate these responses through a cyclical process of receptor activation (initiation of downstream signals), desensitization (inactivation that results in diminution of downstream signals), and resensitization (receptor reactivation for next wave of activation). Although these steps may be of equal importance in regulating receptor function, significant advances have been made in understanding activation and desensitization with limited effort towards resensitization. Inadequate importance has been given to resensitization due to the understanding that resensitization is a homeostasis maintaining process and is not acutely regulated. Evidence indicates that resensitization is a critical step in regulating GPCR function and may contribute towards receptor signaling and cellular responses. In light of these observations, it is imperative to discuss resensitization as a dynamic and mechanistic regulator of GPCR function. In this review we discuss components regulating GPCR function like activation, desensitization, and internalization with special emphasis on resensitization. Although we have used β-adrenergic receptor as a proto-type GPCR to discuss mechanisms regulating receptor function, other GPCRs are also described to put forth a view point on the universality of such mechanisms.
  Current Molecular Pharmacology 05/2012;
• Article: microRNA, Cancer and Cancer Chemoprevention.

  Xun Che, Chuanshu Huang
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  ABSTRACT: microRNA(miRNA) is a kind of non-coding RNA that has a regulatory function on coding miRNA. miRNA can target the 3 UTR of mRNA and inhibit its gene expression by either inhibiting its translation or promoting its degradation. miRNAs are thus considered to be oncogenic or antineoplastic, depending on their downstream target mRNAs. Besides their clinical application in cancer treatment, diagnosis, and prognosis, miRNA has also recently been reported to be involved in cancer chemotherapy and chemoprevention. This review focuses on the implication of miRNA in cancer chemoprevention and cancer control as well as molecular mechanisms underlying those biological effects.
  Current Molecular Pharmacology 05/2012;
• Article: Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists on glycemic control, lipid profile and cardiovascular risk.

  Giuseppe Derosa, Pamela Maffioli
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  ABSTRACT: Peroxisome proliferator-activated receptor (PPAR) is involved in the pathology of numerous diseases including obesity, diabetes, and atherosclerosis, because of its role in decreasing insulin resistance and inflammation. Type 2 diabetes mellitus and obesity are the most frequent endocrine-metabolic diseases and their pathogenic basis are characterized by insulin resistance and insulin secretion defects that can be demonstrated through several alterations in carbohydrates, lipids, and protein metabolism. For that reason a class of compounds, called thiazolidinediones, has been developed for the management of type 2 diabetes mellitus. Thiazolidinediones are PPAR-γ agonists regulating the expression of several genes involved in the regulation of glucose, lipid and protein metabolism, enhancing the action of insulin in insulin-sensitive tissue by increasing glucose uptake in skeletal muscle and adipose tissue, and decreasing hepatic glucose production. Pioglitazone is the only available PPAR-γ agonist for the treatment of type 2 diabetes after rosiglitazone withdrawal from several countries. This review discusses the safety and effectiveness of pioglitazone in the clinical practice for the treatment of type 2 diabetes mellitus.
  Current Molecular Pharmacology 11/2011; 5(2):272-81.
• Article: Base excision repair factors are promising prognostic and predictive markers in cancer.

  Lucy Gossage, Christina Perry, Rachel Abbotts, Srinivasan Madhusudan
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  ABSTRACT: The cytotoxicity of both chemotherapy and radiotherapy is to a large extent directly related to their ability to induce DNA damage. The ability of cancer cells to recognise and repair this damage contributes to therapeutic resistance. Sub-optimal DNA repair in normal tissue may impair normal tissue tolerance. Inter-individual differences in DNA repair pathways may also influence the natural history and progression of cancer and hence prognosis. The base excision repair (BER) pathway has evolved to repair base damage induced by endogenous and exogenous base targeting agents. Polymorphic variants of genes, mRNA expression and alterations in protein expression within BER, may alter DNA repair capacity and influence both cancer progression and clinical responses to chemotherapy and radiotherapy. We discuss the role of BER genes as potential predictive and prognostic markers in human cancer and review the current state of play within this field.
  Current Molecular Pharmacology 11/2011; 5(1):115-24.
• Article: PPAR ligands and cardiovascular disorders: friend or foe.

  Pitchai Balakumar, Gowraganahalli Jagadeesh
  Current Molecular Pharmacology 11/2011; 5(2):219-23.
• Article: Evolving drug targets in DNA base excision repair for cancer therapy.

  Srinivasan Madhusudan
  Current Molecular Pharmacology 11/2011; 5(1):1-2.
• Article: Use of clinically available PPAR agonists for heart failure; do the risks outweigh the potential benefits?

  Satyam Sarma
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  ABSTRACT: PPAR agonists represent a heterogeneous group of compounds that have been used in the treatment of cardiovascular and metabolic diseases for over thirty years. While the primary indications for PPAR agonist therapy focus on hyperlipidemia and diabetes, there is a growing body of pre-clinical data that suggests they may be beneficial in the treatment of heart failure; a disease marked by abnormal myocardial metabolism, fibrosis and insulin insensitivity. PPAR agonist treatment in numerous animal models of systolic heart failure have demonstrated improvement in cardiac function with decreased fibrosis, improved contractility and endothelial function. However, considerable controversy exists on the cardiac safety profile of PPAR agonists, particularly concern for inducing lipotoxicty and precipitating or worsening heart failure. In addition during pre-clinical testing, many compounds have been associated with increased death and adverse cardiovascular outcomes casting a pall over their future use for treating disorders of myocardial function. This article will review cardiac pathways involved in PPAR activation and their potential regulation of maladaptive pathways involved in heart failure and highlight molecular mechanisms that may contribute to adverse events and raise safety concerns. Specific attention will be focused on PPAR alpha and gamma, subtypes for which commercially available PPAR agonists are currently available.
  Current Molecular Pharmacology 11/2011; 5(2):255-63.
• Article: Healing the diabetic heart: modulation of cardiometabolic syndrome through peroxisome proliferator activated receptors (PPARs).

  Tom Hsun-Wei Huang, Basil D Roufogalis
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  ABSTRACT: Cardiometabolic syndrome is a mixture of interrelated risk factors predisposing individuals to elevated risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Nuclear receptors, specifically peroxisome proliferator-activated receptors (PPARs), were identified to play a pivotal role in the regulation of metabolic homeostasis. However, with rosiglitazone currently under intense scrutiny great concerns have arisen regarding the safety of the thiazolidinedione PPAR-γ agonist family as a whole. This review discusses the current concern with PPAR-γ agonists by exploring if PPARs can still be considered worth pursuing as a viable target for cardiovascular diseases. We examine current research focusing on identifying ligands that are dual and pan-PPAR agonists, selective PPAR-γ modulators, PPAR-β/δ agonists and that are of natural origin.
  Current Molecular Pharmacology 11/2011; 5(2):241-7.