The healthy immune system protects against infection and malignant transformation without causing significant damage to host tissues. Immune dysregulation results in diverse pathologies including autoimmune disease, chronic inflammatory disorders, allergies as well as immune deficiencies and cancer. Phosphoinositide 3-kinase (PI3K) signalling has been shown to be a key pathway in the regulation of the immune response and continues to be the focus of intense research. In recent years we have gained detailed understanding of PI3K signalling, and saw the development of potent and highly selective small molecule inhibitors, of which several are currently in clinical trials for the treatment of immune-related disorders and cancer. The role of PI3K signalling in the immune response has been the subject of detailed reviews; here we focus on relevant recent progress in pre-clinical and clinical development of PI3K inhibitors.
Prostate cancer may be the most common preventable cancer among men in the United States (US) and the rest of the developed world. Emerging insights into the molecular pathogenesis of prostate cancer suggest that damage to the prostate epithelium, potentially inflicted by a variety of exposures, triggers procarcinogenic inflammatory processes to promote disease development. In this milieu, the damaged epithelium may generate proliferative inflammatory atrophy (PIA) lesions, which may progress to prostatic intraepithelial neoplasia (PIN) or to prostate cancer. To attenuate prostatic carcinogenesis driven by chronic or recurrent prostate inflammation, rational chemoprevention has thus far featured anti-inflammatory drugs and antioxidants. Results from clinical trials of these approaches have been mixed, emphasizing the need for mechanistic studies of the contribution of inflammation to prostatic carcinogenesis, more extensive analyses of the pharmacology, including distribution of drugs into target tissue, and, rational development of biomarkers to identify patients that are most likely to respond to anti-inflammatory drugs and antioxidants (targeted chemoprevention), alone, or in combination (combination chemoprevention).
G protein-coupled receptors (GPCRs) utilize (at least) two signal transduction pathways to elicit cellular responses including the classic G protein-dependent, and the more recently discovered β-arrestin-dependent, signaling pathways. In human and murine models of asthma, agonist-activation of β2-adrenergic receptor (β2AR) or Protease-activated-receptor-2 (PAR2) results in relief from bronchospasm via airway smooth muscle relaxation. However, chronic activation of these receptors, leads to pro-inflammatory responses. One plausible explanation underlying the paradoxical effects of β2AR and PAR2 agonism in asthma is that the beneficial and harmful effects are associated with distinct signaling pathways. Specifically, G protein-dependent signaling mediates relaxation of airway smooth muscle, whereas β-arrestin-dependent signaling promotes inflammation. This review explores the evidence supporting the hypothesis that β-arrestin-dependent signaling downstream of β2AR and PAR2 is detrimental in asthma and examines the therapeutic opportunities for selectively targeting this pathway.
The M3 and M2 muscarinic acetylcholine receptors (mAChRs) and beta-2-adrenoceptors (β2ARs) are important regulators of airway cell function, and drugs targeting these receptors are among the first line drugs in the treatment of the obstructive lung diseases asthma and chronic obstructive lung disease (COPD). Cross-regulation or crosstalk between mAChRs and β2ARs in airway smooth muscle (ASM) helps determine the contractile state of the muscle, thus airway diameter and resistance to airflow. In this review we will detail mAChR and β2AR-signaling and crosstalk, focusing on events in the ASM cell but also addressing the function of these receptors in other cell types that impact airway physiology. We conclude by discussing how recent advances in GPCR pharmacology offer a unique opportunity to fine tune mAChR and β2AR signaling and their crosstalk, and thereby produce superior therapeutics for obstructive lung and other diseases.
Purpose of review
Respiratory syncytial virus (RSV) represents the most common respiratory pathogen observed worldwide in infants and young children and may play a role in the inception of recurrent wheezing and asthma in childhood. We discuss herein the recent hypothesis that RSV vertically transmitted from the mother to the fetus in utero causes persistent structural and functional changes in the developing lungs of the offspring, thereby predisposing to postnatal airway obstruction.
A number of observations in humans support the notion that extrapulmonary tissues may be infected hematogenously by RSV and harbor this virus allowing the persistence of latent infection. More recent data from animal models suggest that RSV can be transmitted across the placenta from the respiratory tract of the mother to that of the fetus, and persist in the lungs both during development, as well as during adulthood. Vertical RSV infection is associated with dysregulation of critical neurotrophic pathways during ontogenesis, leading to aberrant parasympathetic innervation and airway hyperreactivity after postnatal reinfection.
These new data challenge the current paradigm that acquisition of RSV infection occurs only after birth and shift attention to the prenatal effects of the virus, with the potential to result in more severe and lasting consequences by interfering with critical developmental processes. The most immediate implication is that prophylactic strategies targeted to the mother-fetus dyad may reduce the incidence of postviral sequelae like childhood wheezing and asthma.
Asthma; Bronchiolitis; Nerve Growth Factor; Lung Development; Vertical Infection
β-blockers are used for a wide range of diseases from hypertension to glaucoma. In some diseases/conditions all β-blockers are effective, while in others only certain subgroups are therapeutically beneficial. The best-documented example for only a subset of β-blockers showing clinical efficacy is in heart failure, where members of the class have ranged from completely ineffective, to drugs of choice for treating the disease.. Similarly, β-blockers were tested in murine asthma models and two pilot clinical studies. A different subset was found to be effective for this clinical indication. These findings call into question the current system of classifying these drugs. To consider “β-blockers”, as a single class is misleading when considering their rigorous pharmacological definition and their appropriate clinical application.
Muscarinic acetylcholine receptor antagonists are widely used as bronchodilating drugs in pulmonary medicine. The therapeutic efficacy of these agents depends on the blockade of M3 muscarinic receptors expressed on airway smooth muscle cells. All muscarinic antagonists currently used as bronchodilating agents show high affinity for all five muscarinic receptor subtypes, thus increasing the likelihood of unwanted side effects. Recent X-ray crystallographic studies have provided detailed structural information about the nature of the orthosteric muscarinic binding site (the conventional acetylcholine binding site) and an 'outer' receptor cavity that can bind allosteric (non-orthosteric) drugs. These new findings should guide the development of selective M3 receptor blockers that have little or no effect on other muscarinic receptor subtypes.
We are becoming increasingly aware that the manner in which our skeleton ages is not uniform within and between populations. Pharmacological treatment options with the potential to combat age-related reductions in skeletal strength continue to become available on the market, notwithstanding our current inability to fully utilize these treatments by accounting for an individual’s unique biomechanical needs. Revealing new molecular mechanisms that improve the targeted delivery of pharmaceuticals is important; however, this only addresses one part of the solution for differential age-related bone loss. To improve current treatment regimes, we must also consider specific biomechanical mechanisms that define how these molecular pathways ultimately impact whole bone fracture resistance. By improving our understanding of the relationship between molecular and biomechanical mechanisms, clinicians will be better equipped to take full advantage of the mounting pharmacological treatments available. Ultimately this will enable us to reduce fracture risk among the elderly more strategically, more effectively, and more economically. In this interest, the following review summarizes the biomechanical basis of current treatment strategies while defining how different biomechanical mechanisms lead to reduced fracture resistance. It is hoped that this may serve as a template for the identification of new targets for pharmacological treatments that will enable clinicians to personalize care so that fracture incidence may be globally reduced.
Angiotensin II (AngII) is an octapeptide hormone that plays a central role in regulation of sodium balance, plasma volume, and blood pressure. Its role in the pathogenesis of hypertension is highlighted by the wide use of inhibitors of the renin-angiotensin system (RAS) as the first-line antihypertensive therapy. However, despite intensive investigation, the mechanism of AngII-induced hypertension is still incompletely understood. Although diverse pathways are likely involved, increasing evidence suggests that the activation of intrarenal RAS may represent a dominant mechanism of AngII-induced hypertension. (Pro)renin receptor (PRR), a potential regulator of intrarenal RAS, is expressed in the intercalated cells of the collecting duct (CD) and induced by AngII, in parallel with increased renin in the principal cells of the CD. Activation of PRR elevated PGE2 release and COX-2 expression in renal inner medullary cells whereas COX-2-derived PGE2
via the EP4 receptor mediates the upregulation of PRR during AngII infusion, thus forming a vicious cycle. The mutually stimulatory relationship between PRR and COX-2 in the distal nephron may play an important role in mediating AngII-induced hypertension.
Obesity-induced inflammation is associated with numerous pathologies and is an independent risk factor of Chronic Kidney Disease (CKD). The prevalence of CKD is escalating and current therapeutic strategies are seriously lacking in efficacy, and immunomodulation has been suggested as a potential new therapeutic approach. Indeed, specialized pro-resolving mediators (SPMs), such as lipoxins (LXs), resolvins and protectins, have demonstrated protection in adipose inflammation, restoring insulin sensitivity and adiponectin production, while modulating leukocyte infiltration and promoting resolution in visceral adipose tissue. Furthermore, SPMs display direct renoprotective effect. Thus we review current evidence of immunomodulation as a potential strategy to subvert obesity-related CKD.
Severe asthma is a complex and heterogeneous phenotype where management can be challenging. While many patients with severe asthma respond to high-dose inhaled corticosteroids in combination with a long-acting β-agonist, there remains a significant subset of patients that require oral corticosteroids to control symptoms. Alternative therapies are needed to help reduce the need for continuous oral corticosteroids; however, there are currently very few effective options. Several new alternatives to oral corticosteroids have been evaluated in severe asthma as add-on to conventional therapy. These include macrolide antibiotics, omalizumab, tumor necrosis factor-α inhibitors, cytokine receptor antagonists, and bronchial thermoplasty. The challenge with these entities is determining the appropriate phenotype of severe asthma where effectiveness is demonstrated, given the significant heterogeneity of the disease. Therefore, there is a crucial need to better understand the mechanisms and pathophysiology of severe asthma so more effective immunomodulators and biologic therapies can emerge.
The efficacy of antiarrhythmic drug therapy is incomplete, with responses ranging from efficacy to no effect to severe adverse effects, including paradoxical drug-induced arrhythmia. Most antiarrhythmic drugs were developed at a time when mechanism underlying arrhythmias were not well-understood. In the last decade, a range of experimental approaches have advanced our understanding of the molecular and genomic contributors to the generation of an arrhythmia-prone heart, and this information is directly informing targeted therapy with existing drugs or the development of new ones. The development of inexpensive whole genome sequencing holds the promise of identifying patients susceptible to arrhythmias in a presymptomatic phase, and thus implementing preventive therapies.
genomics; pharmacogenomics; arrhythmia; long QT syndrome; atrial fibrillation
The term channelopathy refers to human genetic disorders caused by mutations in genes encoding ion channels or their interacting proteins. Recent advances in this field have been enabled by next-generation DNA sequencing strategies such as whole exome sequencing with several intriguing and unexpected discoveries. This review highlights important discoveries implicating ion channels or ion channel modulators in cardiovascular disorders including cardiac arrhythmia susceptibility, cardiac conduction phenotypes, pulmonary and systemic hypertension. These recent discoveries further emphasize the importance of ion channels in the pathophysiology of human disease and as important druggable targets.
Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel.
Large conductance, Ca-activated K channels are abundantly located in cells of vasculature, glomerulus and distal nephron, where they are involved in maintaining blood volume, blood pressure and K homeostasis. In mesangial cells and smooth muscle cells of vessels, the BK-α pore associates with BK-β1 subunits and regulates contraction in a Ca-mediated feedback manner. The BK-β1 also resides in connecting tubule cells of the nephron. BK-β1 knockout mice (β1KO) exhibit fluid retention, hypertension, and compromised K handling. The BK-α/β4resides in acid/base transporting intercalated cells (IC) of the distal nephron, where they mediate K secretion in mammals on a high K, alkaline diet. BK-α expression in IC is increased by a high K diet via aldosterone. The BK-β4 subunit and alkaline urine are necessary for the luminal expression and function of BK-α in mouse IC. In distal nephron cells, membrane BK-α expression is inhibited by WNK4 in in vitro expression systems, indicating a role in the hyperkalemic phenotype in patients with familial hyperkalemic hypertension type 2 (FHHt2). β1KO and BK-β4 knockout mice (β4KO) are hypertensive because of exaggerated ENaC-mediated Na retention in an effort to secrete K via only ROMK. BK hypertension is resistant to thiazides and furosemide, and would be more amenable to ENaC and aldosterone inhibiting drugs. Activators of BK-α/β1 or BK-α/β4 might be effective blood pressure lowering agents for a subset of hypertensive patients. Inhibitors of renal BK would effectively spare K in patients with Bartter Syndrome, a renal K wasting disease.
Arrhythmogenic cardiovascular disease is associated with significant morbidity and mortality and, in spite of therapeutic advances, remains an enormous public health burden. The scope of this problem motivates efforts to delineate the molecular, cellular and systemic mechanisms underlying increased arrhythmia risk in inherited and acquired cardiac and systemic disease. The mouse is used increasingly in these efforts owing to the ease with which genetic strategies can be exploited and mechanisms can be probed. The question then arises whether the mouse has proven to be a useful model system to delineate arrhythmogenic cardiovascular disease mechanisms. Rather than trying to provide a definite answer, the goal here is to consider the issues that arise when using mouse models and to highlight the opportunities.
Sudden Cardiac Death; Long QT Syndrome; Short QT Syndrome; Brugada Syndrome; Dravet Syndrome; Wolf-Parkinson White Syndrome
Inward rectifier potassium (Kir) channels play fundamental roles in cardiac and renal function and may represent unexploited drug targets for cardiovascular diseases. However, the limited pharmacology of Kir channels has slowed progress toward exploring their integrative physiology and therapeutic potential. Here, we review recent progress toward developing the small-molecule pharmacology for Kir2.x, Kir4.1, and Kir7.1 and discuss common mechanistic themes that may help guide future Kir channel-directed drug discovery efforts.
The maintenance of gastrointestinal mucosal integrity depends on the rapid alarm of protective mechanisms in the face of pending injury. Two populations of extrinsic primary afferent neurons, vagal and spinal, subserve this goal through different mechanisms. These sensory neurons react to gastrointestinal insults by triggering protective autonomic reflexes including the so-called cholinergic anti-inflammatory reflex. Spinal afferents, in addition, can initiate protective tissue reactions at the site of assault through release of calcitonin gene-related peptide from their peripheral endings. The protective responses triggered by sensory neurons comprise alterations in gastrointestinal blood flow, secretion and motility as well as modifications of immune function. This article focusses on significant advances that during the past couple of years have been made in identifying molecular nocisensors on afferent neurons and in dissecting the signalling mechanisms whereby afferent neurons govern inflammatory processes in the gut.
Acid-sensing ion channel-3 (ASIC3); calcitonin gene-related peptide (CGRP); cholinergic anti-inflammatory reflex; gastroduodenal bicarbonate secretion; gastrointestinal blood flow; gastrointestinal immune system; primary afferent neurons; transient receptor potential vanilloid 1 (TRPV1) ion channel
Secretory diarrheas caused by bacterial and viral enterotoxins remain a significant cause of morbidity and mortality. Enterocyte Cl− channels represent an attractive class of targets for diarrhea therapy, as they are the final, rate-limiting step in enterotoxin-induced fluid secretion in the intestine. Activation of cyclic nucleotide and/or Ca2+ signalling pathways in secretory diarrheas increases the conductance of Cl− channels at the enterocyte luminal membrane, which include the cystic fibrosis transmembrane conductance regulator (CFTR) and Ca2+-activated Cl− channels (CaCCs). High-throughput screens have yielded several chemical classes of small molecule CFTR and CaCC inhibitors that show efficacy in animal models of diarrheas. Natural-product diarrhea remedies with Cl− channel inhibition activity have also been identified, with one product recently receiving FDA approval for HIV-associated diarrhea.
diarrhea; cholera; chloride channels; CFTR; CaCC; rotavirus
Recent studies have identified the proton-coupled folate transporter (PCFT) as the mechanism by which folates are absorbed across the apical brush-border membrane of the small intestine and across the basolateral membrane of the choroid plexus into the cerebrospinal fluid. Both processes are defective when there are loss-of-function mutations in this gene as occurs in the autosomal recessive disorder hereditary folate malabsorption. Because this transporter functions optimally at low pH, antifolates are being developed that are highly specific for PCFT in order to achieve selective delivery to malignant cells within the acidic environment of solid tumors. PCFT has a spectrum of affinities for folates and antifolates that narrows and increases at low pH. Residues have been identified that play a role in folate and proton binding, proton coupling, and oscillation of the carrier between its conformational states.
Summary and recent advances
Recent findings suggest that embryonic stem cells and stem cells derived from adult tissues, including bone marrow and umbilical cord blood, could be utilized in repair and regeneration of injured or diseased lungs. This is an exciting and rapidly moving field that holds promise as a therapeutic approach for variety of lung diseases. Although initial emphasis was on engraftment of stem cells in lung, more, recent studies demonstrate that mesenchymal stem cells (MSCs) can modulate local inflammatory and immune responses in mouse lung disease models including acute lung injury and pulmonary fibrosis. Further, based on initial reports of safety and efficacy following allogeneic administration of MSCs to patients with Crohn’s disease or with graft-versus-host disease, a recent trial has been initiated to study the effect of MSCs in patients with chronic obstructive pulmonary disease. Notably, several recent clinical trials have demonstrated potential benefit of autologous stem cell administration in patient with pulmonary hypertension. In this review, we will describe recent advances in cell therapy with the focus on MSCs and their potential roles in lung development and repair.
Mesenchymal Stem Cells; Lung; Cell Therapy; Tissue Bioengineering
Infections caused by bacterial biofilms are a significant global health problem, causing considerable patient morbidity and mortality and contributing to the economic burden of infectious disease. This review describes diverse strategies to combat bacterial biofilms, focusing firstly on small molecule interference with bacterial communication and signaling pathways, including quorum sensing and two-component signal transduction systems. Secondly we discuss enzymatic approaches to the degradation of extracellular matrix components to effect biofilm dispersal. Both these approaches are based upon non-microbicidal mechanisms of action, and thereby do not place a direct evolutionary pressure on the bacteria to develop resistance. Such approaches have the potential to, in combination with conventional antibiotics, play an important role in the eradication of biofilm based bacterial infections.
Biomedical applications of porous silicon include drug delivery, imaging, diagnostics and immunotherapy. This review summarizes new silicon particle fabrication techniques, dynamics of cellular transport, advances in the multistage vector approach to drug delivery, and the use of porous silicon as immune adjuvants. Recent findings support superior therapeutic efficacy of the multistage vector approach over single particle drug delivery systems in mouse models of ovarian and breast cancer. With respect to vaccine development, multivalent presentation of pathogen-associated molecular patterns on the particle surface creates powerful platforms for immunotherapy, with the porous matrix able to carry both antigens and immune modulators.
porous silicon; vaccine; immunotherapy; chemotherapeutics; drug delivery
Fungal infections are on the rise as advances in modern medicine prolong the lives of severely ill patients. Fungi are eukaryotic organisms and there are a limited number of targets for antifungal drug development; as a result the antifungal arsenal is exceedingly limited. Azoles, polyenes and echinocandins, constitute the mainstay of antifungal therapy for patients with life-threatening mycoses. One of the main factors complicating antifungal therapy is the formation of fungal biofilms, microbial communities displaying resistance to most antifungal agents. A better understanding of fungal biofilms provides for new opportunities for the development of urgently needed novel antifungal agents and strategies.