In dilated cardiomyopathy, a condition characterized by chamber enlargement and reduced myocardial contractility, decreases in β-adrenergic receptor density and increases in Gαi and β-adrenergic receptor kinase activities attenuate the stimulation of adenylyl cyclase in response to catecholamines. PDE3 inhibitors have been used to ‘overcome’ the reduction in cAMP generation by blocking cAMP hydrolysis. These drugs increase contractility in the short-term, but long-term administration leads to an increase in mortality that correlates with an increase in sudden cardiac death. Whether separate mechanisms account for these beneficial and harmful effects, and, if so, whether PDE3 can be targeted so as to increase contractility without increasing mortality are questions that remain unanswered.
► Reduced ocular perfusion pressure is a risk factor for the prevalence, incidence and progression of glaucoma. ► The death of retinal ganglion cells appears to involve primary and secondary insults. ► Reduced OPP may enhance both primary and secondary insults. ► Abnormal autoregulation and neurovascular coupling may lead to ganglion cell death.
Glaucoma is a progressive optic neuropathy of unknown origin. It has been hypothesized that a vascular component is involved in glaucoma pathophysiology. This hypothesis has gained support from studies showing that reduced ocular perfusion pressure is a risk factor for the disease. The exact nature of the involvement is, however, still a matter of debate. Based on recent evidence we propose a model including primary and secondary insults in glaucoma. The primary insult appears to happen at the optic nerve head. Increased intraocular pressure and ischemia at the post-laminar optic nerve head affects retinal ganglion cell axons. Modulating factors are the biomechanical properties of the tissues and cerebrospinal fluid pressure. After this primary insult retinal ganglion cells function at a reduced energy level and are sensitive to secondary insults. These secondary insults may happen if ocular perfusion pressure falls below the lower limit of autoregulation or if neurovascular coupling fails. Evidence for both faulty autoregulation and reduced hyperemic response to neuronal stimulation has been provided in glaucoma patients. The mechanisms appear to involve vascular endothelial dysfunction and impaired astrocyte-vessel signaling. A more detailed understanding of these pathways is required to direct neuroprotective strategies via the neurovascular pathway.
Phosphodiesterase-3 (PDE3) is a major cAMP-hydrolyzing PDE in vascular smooth muscle cells (VSMCs) and oocytes. The exact role and contribution of the two PDE3 isoforms, PDE3A and PDE3B, in VSMC growth regulation and oocyte maturation was examined using PDE3A (3A) and PDE3B (3B) knockout (KO) mouse models. PDE3A-deficient VSMCs exhibit marked reduction in mitogen-induced cell growth due to cell cycle arrest at Go-G1 phase, which resulted from dysregulation of cAMP/Protein kinase A (PKA)- and Mitogen-activated protein kinase (MAPK)-signaling pathways, as well as from alterations in key cell cycle regulatory proteins. Similarly, PDE3A-deficient oocytes exhibit cell cycle arrest at G2/M phase because increased cAMP/PKA signaling in KO oocytes most likely inhibits Cdc25B-catalyzed dephosphorylation/activation of Cdc2 (maturation promoting factor), a key regulator of G2/M transition.
Pathological vascular remodeling is a hallmark of most vascular disorders such as atherosclerosis, postangioplasty restenosis, allograft vasculopathy, and pulmonary hypertension. Pathological vascular remodeling is a multi-cell dependent process leading to detrimental changes of vessel structure and eventual vessel occlusion. Cyclic nucleotide signaling regulates a variety of vascular functions ranging from cell contractility to cell growth. Cyclic nucleotide phosphodiesterases (PDEs), a large family of structurally and functionally distinct isozymes, regulate cyclic nucleotide levels and compartmentalization through catalyzing their degradation reaction. Increasing evidence has suggested that one of the important mechanisms for specific cyclic nucleotide regulation is exerted through selective activation or inhibition of distinct PDE isozymes. This review summarizes the work done to characterize the role and therapeutic potential of PDE1 isozymes in pathological vascular remodeling.
MicroRNAs (miRs) have recently emerged as a novel class of gene expression regulators. The number of studies documenting an altered miR expression pattern in cancer continues to expand rapidly. Critical information is continuously gained regarding how aberrantly expressed miRs contribute to carcinogenesis. Current studies provide evidence that analyses of miR expression patterns have potential clinical applications toward developing tumor biomarkers to identify the presence and dissemination of esophageal cancer, as well as to assess tumor chemo- or radiosensitivity. The incidence of esophageal cancer is on the rise, and this disease continues to portend a poor prognosis. The current review addresses ways in which altered miR expression contributes to esophageal carcinogenesis, along with how recent discoveries may be applied clinically.
microRNA; esophageal cancer; esophageal adenocarcinoma; Barrett’s esophagus; esophageal squamous cell cancer
The incidence of obesity in the developed world is increasing at an alarming rate. Concurrent with the increase in the incidence of obesity is an increase in the incidence of type 2 diabetes. Cyclic AMP (cAMP) and cGMP are key second messengers in all cells; for example, when it comes to processes of relevance for the regulation of energy metabolism, cAMP is a key mediator in the regulation of lipolysis, glycogenolysis, gluconeogenesis and pancreatic β cell insulin secretion. PDE3B, one of several enzymes which hydrolyze cAMP and cGMP, is expressed in cells of importance for the regulation of energy homeostasis, including adipocytes, hepatocytes, hypothalamic cells, and β cells. It has been shown, using PDE3 inhibitors and gene targeting approaches in cells and animals, that altered levels of PDE3B result in a number of changes in the regulation of glucose and lipid metabolism and in overall energy homeostasis. This article highlights the complexity involved in the regulation of PDE3B by hormones, and in the regulation of downstream metabolic effects by PDE3B in several interacting tissues.
γ-Hydroxybutyric acid (GHB) is a naturally occurring γ-aminobutyric acid (GABA) metabolite that has been proposed as a neurotransmitter/neuromodulator that acts via its own receptor (GHBR). Its exogenous administration, however, elicits central nervous system-dependent effects (e.g. memory impairment, increase in sleep stages 3 and 4, dependence, seizures and coma) that are mostly mediated by GABAB receptors. The past few years have seen important developments in our understanding of GHB neurobiology: a putative GHBR has been cloned; a transgenic model of GHB aciduria has been developed; GABAB receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABAB receptors; and some of the cellular mechanisms underlying the dependence/abuse properties of GHB, and its ability to elicit absence seizures and an increase in sleep stages 3 and 4, have been clarified. Nevertheless, the physiological significance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABAB receptor-mediated actions of GHB are caused by GHB itself acting directly on GABAB receptors or by a GHB-derived GABA pool (or both).
Recent major findings from studies of SLC6A4 and its corresponding protein, the serotonin (5-HT) transporter (SERT) in humans, rodents and non-human primates indicate that combinations of SLC6A4 non-coding 5′, 3′ UTRs and intronic regions plus coding variants acting together can change 5HT transport as much as 40-fold in vitro. In vivo, SLC6A4 variants in humans and other species lead to marked physiological changes, despite mitigating neurodevelopmental adaptations in 5-HT receptors plus compensatory alterations in 5-HT synthesis and metabolism. Polymorphisms in SLC6A4 are associated with differences in emotional, endocrine, and personality characteristics as well as many diseases. This gene, in combinations with gene x gene (G x G) and gene x environment (G x E) interactions nonetheless remains incompletely understood, with some association findings remaining controversial. Considering its primary importance in the regulation and function of the entire serotonergic system (as evidenced by the consequences of SERT-mediated reuptake inhibition by SRIs like fluoxetine in humans and of genetically-engineered changes in mice and rats), it seems likely that SLC6A4 and SERT will remain areas of high interest in our field’s attempts to better understand and treat 5-HT-related disorders.
The increasing prevalence of multidrug-resistant Gram-negative bacteria worldwide has led to a re-evaluation of the previously discarded antibiotic, colistin. Despite its important role as salvage therapy for otherwise untreatable infections, dosage guidelines for the prodrug colistin methanesulfonate (CMS) are not scientifically based and have led to treatment failure and increased colistin resistance. In this review we summarise the recent progress made in the understanding of the pharmacokinetics of CMS and formed colistin with an emphasis on critically-ill patients. The pharmacodynamics of colistin is also reviewed, with special attention given to the relationship between pharmacokinetics and pharmacodynamics and how the emerging data can be used to inform design of optimal dosage regimens. Recent data suggest the current dosage regimens of CMS are sub-optimal in many critically-ill patients.
The current understanding of the mechanism of anti-tuberculosis drug resistance has been shaped by the history of development of anti-tuberculosis drugs in the past 60 years and was arrived at as part of inductive generalization. Recently, these standard beliefs have been tested in controlled hollow fiber systems experiments. Drug resistance in Mycobacterium tuberculosis was shown to be related to pharmacokinetic-pharmacodynamic (PK/PD) factors, and factors such as pharmacokinetic variability. Poor PK/PD exposures due to our current non-optimized dosing regimens initiate a chain of evolution driven events, starting with induction of multi-drug efflux pumps, followed by the development of chromosomal mutations in time, which together lead to high level resistance multi-drug resistant tuberculosis and extremely drug resistant tuberculosis.
Identifying the molecular and cellular basis of complex neuropsychiatric disorders (cNPDs) has been limited by the inaccessibility of central neurons, variability within broad diagnostic classifications, and the interplay of genetic and environmental factors. Recent work utilizing neuronally differentiated human induced pluripotent stem cells (hiPSCs) from Mendelian and polygenic cNPDs is beginning to illuminate neuritic, synaptic or cell body variations accompanied by specific gene or protein expression alterations largely mimicking known pathology. In some cases, phenotypes have only emerged after application of cellular stress or long duration of differentiation. Pathological and cellular expression features are fully or partially responsive to pharmacological treatment highlighting the potential utility of differentiated hiPSCs for discovery of personalized therapeutics and for identifying pathogenetically relevant targets in subgroups of patients within a broad syndromic classification. Because of the inherent variability in developing and differentiating hiPSC lines and the multiple comparisons implicit in ‘omics technologies, rigorous algorithms for assuring statistical significance and independent confirmation of results, will be required for robust modeling of cNPDs.
Coordinated migratory events by naïve and memory T cells are key to effective immunity. Naïve T cells predominantly recirculate through secondary lymphoid tissue until antigen encounter, while primed T cells efficiently localize to antigen-rich lymphoid and non-lymphoid tissue. Tissue-selective targeting by primed T cells is achieved by a combination of inflammatory signals and tissue-selective homing receptors acquired by T cells during activation and differentiation. A large number of molecular mediators and interactions promoting memory T cell migration to non-lymphoid sites of inflammation have been identified. Recently, additional antigen-driven mechanisms have been proposed, which orchestrate the targeted delivery of memory T cells to antigen-rich tissue. Importantly, recent studies have revealed that the T cell metabolic status influences their differentiation and homing patterns. We here summarize these key observations and discuss their relevance for the manipulation of immune anatomy in therapeutic settings.
Expression of chemokine receptors on T helper 2 cells and eosinophils has been postulated to be the mechanism by which these cells are selectively recruited to the lung during allergic inflammatory reactions. Mouse models have provided evidence to show that blocking the ligands for these receptors is successful in abrogating the pathophysiological effects of allergen challenge. However, recent studies describing the effect of genetic deletions of these chemokine receptors have not confirmed the results obtained with ligand knockouts or neutralising antibodies. Coupled with the realisation that, because of a lack of species cross-reactivity, it is not possible to test small molecule antagonists against human receptors in the original in vivo animal models, the future of chemokine receptor therapeutics is in question. However, recent advances have been made regarding the therapeutic potential of blocking the chemokine receptors CCR3, CCR4 and CCR8 in allergic airway disease.
Cytokines are critical for normal cell growth and immunoregulation but also contribute to growth of malignant cells and drive immune-mediated disease. A major subset of immunoregulatory cytokines, roughly 60, use the type I and type II cytokine receptors and pharmacological targeting of these cytokines/cytokines receptors has proven to be efficacious in treating immune and inflammatory diseases. These receptors rely on Janus family of kinases (Jaks) for signal transduction and recently the first Jak inhibitor has been approved by the FDA. Many other Jakinibs are likely to follow and in this brief review, we will discuss the state-of-the art of this new class of pharmacological agents.
Various neuropeptides have emerged recently as potent immunomodulatory factors with potential for their therapeutic use on immune disorders. Here we highlight the most recent data relevant in the field and we offer our opinion how neuropeptide therapy might impact clinical immune diseases, and the challenges in this field that must be overcome before achieving medical progress. We also review recent reports describing the antimicrobial effects showed by some neuropeptides and the therapeutic, physiological and evolutionary consequences of this new finding. Finally, we discuss how a physiologically functional neuropeptide system contributes to general health and how neuropeptides educate our immune system to be tolerant.
Neuropeptide; Autoimmunity; Inflammation; Antimicrobial; Tolerance; Parasite; Neuroimmunology
FK506 binding protein 51 (FKBP51, also called FKBP5) belongs to a family of immunophilins, FK506 binding proteins (FKBPs). FKBP family members are targets for drugs such as rapamycin. Although FKBP51 shares characteristics with other FKBPs, it also has unique features, especially the role in its regulation of important signaling pathways such as the AKT kinase/protein kinase B pathway. In this review, we will focus on the function of FKBP51 as a scaffolding protein in the regulation of AKT activation and, in turn, its role in tumorigenesis and response to chemotherapy.
AKT; AKT phosphorylation; FKBP51; Scaffolding protein; chemoresistance; chemosensitivity
Best established as components of steroid hormone receptor complexes, it is now clear that the large molecular weight immunophilins, FKBP52 and FKBP51, play important regulatory roles elsewhere in the cell. This review outlines what is known about the organization of the genes, FKBP4 and FKBP5 respectively, encoding these proteins and describes their diverse actions in the nervous system, reproduction, and cancer. The organization of FKBP4 and FKBP5 is very similar among the chordates, and gene expression is influenced by both genetic and epigenetic mechanisms. Recent studies identifying roles of FKBP52 and FKBP51 in regulation of the microtubule-associated protein tau and microtubule assembly are discussed, as is their interaction with and influence on the transient receptor potential canonical subfamily of ion channel proteins.
The large FK506-binding protein FKBP52 has been characterized as an important positive regulator of androgen, glucocorticoid and progesterone receptor signaling pathways. FKBP52 associates with receptor-Hsp90 complexes and is proposed to have roles in both receptor hormone binding and receptor subcellular localization. Data from biochemical and cellular studies has been corroborated in whole animal models as fkbp52-deficient male and female mice display characteristics of androgen, glucocorticoid and/or progesterone insensitivity. FKBP52 receptor specificity and the specific phenotypes displayed by the fkbp52-deficient mice have firmly established FKBP52 as a promising target for the treatment of a variety of hormone-dependent diseases. Recent studies demonstrated that the FKBP52 FK1 domain and the proline-rich loop within this domain are functionally important for FKBP52 regulation of receptor function. Based on these data, efforts are currently underway to target the FKBP52 FK1 domain and the proline-rich loop with small molecule inhibitors.
FK506-binding protein 51 (FKBP51) is gaining increased recognition for its essential roles in cell biology. Originally discovered as a component of steroid receptor complexes, it is now known to regulate a diverse set of transcription factors, enzymes and structural proteins. Its cellular properties suggest numerous possible functions for FKBP51 in physiology, and the best clue to its potential importance may be the following: FKBP51 is a glucocorticoid-induced negative regulator of the glucocorticoid receptor. Thus, FKBP51 is intricately involved in regulation of the most pleiotropic hormone known to biology. In contrast to glucocorticoid receptor, FKBP51 is a positive regulator of the androgen receptor, suggesting that it functions as a reciprocal modulator of glucocorticoid- and androgen-mediated physiology. In this work, we evaluate this hypothesis by examining recent cellular and physiological evidence.
Airway protection is a critically important function that prevents/limits the intrusion of foreign material into the pulmonary tree. A host of different behaviors participate in this process. The control, coordination, and execution of these behaviors is a complex process which has recently received increased attention. Data from human clinical and animal studies support the concept of a coordinated neural control system that governs the appropriate expression and sequencing of airway protective behaviors. Our current knowledge of the proposed neural control network for breathing, cough, swallow and other airway protective behaviors indicates that it is a highly complex system that can “rewire” (reconfigure) itself to perform several different functions. Computational modeling and simulation have been used as tools to investigate this system. The results of modeling efforts have yielded motor output patterns of upper airway and respiratory muscles that are very similar to those recorded in vivo. Regulation and coordination of multiple different airway protective behaviors have been successfully simulated. Outcomes of simulation efforts support the hypothesis that computational modeling of airway protection can yield important testable hypotheses regarding brainstem neural network functions and organization. Modeling of complex systems can be challenging but the open availability of straight-forward computational tools is likely to result in increased implementation of modeling and simulation as adjuncts to traditional methods of investigation of the control of the upper airway.
cough; breathing; swallow; computational modeling; airway
Chronic unproductive coughing and dyspnea are symptoms that severely diminish the quality of life in a substantial proportion of the population. There are presently few if any drugs that effectively treat these symptoms. Rational drug targets for cough and dyspnea have emerged over the recent years based on developments in our understanding of the innervation of the respiratory tract. These drug targets can be subcategorized into those that target the vagal afferent nerve endings, and those that target neural activity within the CNS. This review focuses on targets presumed to be in the peripheral terminals of afferent nerves within the airways. Conceptually, the activity of peripheral afferent nerves involved with unwanted urge-to-cough or dyspnea sensations can be inhibited by limiting the intensity of the stimulus, inhibiting the amplitude of the stimulus-induced generator potential, or inhibiting the transduction between the generator potential and action potential discharge and conduction. These mechanisms reveal many therapeutic strategies for anti-tussive and anti-dyspnea drug development with peripheral sites of action.
Saphenous vein grafts used in coronary artery bypass graft surgery suffer from lower patency rates compared to left internal mammary artery. A number of clinical trials and observational studies have demonstrated a significant benefit of statin treatment on vein graft patency. Aside from their well-known lipid-lowering capacities, statins exert pleiotropic effects by direct inhibition of the mevalonate pathway in the wall of these grafts. This leads to reduced geranylgeranylation of small GTPases such as Rho and Rac. Through this LDL-independent mechanism, statins improve endothelial function and reduce vascular inflammation and oxidative stress, inhibiting also smooth muscle cell proliferation and migration. Although the existing evidence support a beneficial effect of statins on vein grafts biology, more clinical trials focused on the effect of aggressive statin treatment on vein graft patency are required, in order to safely translate this strategy into clinical practice.
Coronary Artery Bypass Grafting; Endothelial dysfunction; Pleiotropic Effects; Saphenous Vein Grafts; Statins
Inhalation or aspiration of acid solution evokes airway defense responses such as cough and reflex bronchoconstriction, resulting from activation of vagal bronchopulmonary C-fibers and Aδ afferents. The stimulatory effect of hydrogen ion on these sensory nerves is generated by activation of two major types of ion channels expressed in these neurons: a rapidly activating and inactivating current mediated through ASICs, and a slow sustaining current via activation of TRPV1. Recent studies have shown that these acid-evoked responses are elevated during airway inflammatory reaction, revealing the potential convergence of a wide array of inflammatory signaling on these ion channels. Since pH in the airway fluid drops substantially in patients with inflammatory airway diseases, these heightened stimulatory effects of acid on airway sensory nerves may play a part in the manifestation of airway irritation and excessive cough under those pathophysiological conditions.