The hypocretins (abbreviated “Hcrts”—also called “orexins”) are two neuropeptides secreted exclusively by a small population of neurons in the lateral hypothalamus. These peptides bind to two receptors located throughout the brain in nuclei associated with diverse cognitive and physiological functions. Initially, the brain Hcrt system was found to have a major role in the regulation of sleep/wake transitions. More recent studies indicate Hcrts may play a role in other physiological functions, including food intake, addiction, and stress. Taken together, these studies suggest a general role for Hcrts in mediating arousal, especially when an organism must respond to unexpected stressors and challenges in the environment.
Antimicrobial peptides from either microbial sources, or based on host defense peptides (HDPs) from higher organisms, show promising activity against human pathogens. Lantibiotics have been extensively engineered by either molecular biology approaches or chemistry and both natural and modified entities have been shown to have good efficacy in animal models of infection. Amongst HDPs either truncated peptides or non-peptide mimetic molecules show substantial promise both for their direct antibiotic action and also modulation of host functions. Members of both classes have reached clinical development for therapy of systemic infections and Clostridium difficile infection of the gastrointestinal tract.
Increased oxidative stress occurs in the lungs and systemically in COPD, which plays a role in many of the pathogenic mechanisms in COPD. Hence, targeting local lung and systemic oxidative stress with agents that modulate the antioxidants/redox system or boost endogenous antioxidants would be a useful therapeutic approach in COPD. Thiol antioxidants (N-acetyl-L-cysteine and N-acystelyn, carbocysteine, erdosteine, and fudosteine have been used to increase lung thiol content. Modulation of cigarette smoke induced oxidative stress and its consequent cellular changes have also been reported to be effected by synthetic molecules, such as spin traps (α-phenyl-N-tert-butyl nitrone), catalytic antioxidants (superoxide dismutase [ECSOD] mimetics), porphyrins, and lipid peroxidation and protein carbonylation blockers/inhibitors (edaravone and lazaroids/tirilazad). Pre-clinical and clinical trials have shown that these antioxidants can reduce oxidative stress, affect redox and glutathione biosynthesis genes, and pro-inflammatory gene expression. In this review the approaches to enhance lung antioxidants in COPD and the potential beneficial effects of antioxidant therapy on the course of the disease are discussed.
Cigarette smoke; antioxidants; oxidants; glutathione; thiols; Nrf2; Chronic Obstructive Pulmonary Disease
The Ras superfamily of small GTPases is a group of more than 150 small G proteins, all of which share some degree of homology to the founding member Ras. These small GTPases function as molecular switches within cells, impacting nearly all cellular processes. The Ras superfamily can be further divided into several smaller subfamilies, with those proteins that most closely resemble Ras belonging to the Ras subfamily. While heavily studied within the field of cancer biology, the Ras family of proteins also plays cardinal roles in immunity and inflammation. Here we review the roles of these molecular switches in regulating immune cell homeostasis and functions.
Fibrocytes are unique cells possessing the proinflammatory properties of macrophages and the tissue remodeling properties of fibroblasts. Because these cells display a strong association with many human diseases characterized by chronic and dysregulated inflammatory responses the study of fibrocytes is important and timely. This review presents recent data regarding fibrocyte origin, identification, differentiation, and appearance in diseased tissue. The available data regarding the association of fibrocytes with several forms of chronic tissue inflammation seen in the setting of lung disease, autoimmunity, liver disease, and normal aging will be presented. This review concludes by putting these data in perspective and by suggesting future areas of investigation. It is hoped that this information will lead to additional investigations in this burgeoning field and improve our understanding of the novel role fibrocytes may play in human disease.
Protein-protein interactions lie at the heart of cellular signaling pathways and the deregulation of which has frequently led to diseases. In contrast to inhibitors that bind to distinctive enzyme active sites, molecules targeting protein surface topologies have been underexploited in drug development. The challenges in developing protein surface antagonists or agonists originate from the relatively large and flat surface areas that lack well-defined cavities required for sufficient binding affinity. In the past decade, our understanding of protein recognition has served as solid basis for the design of synthetic mimetics to modulate these protein-protein interactions. Herein, we summarize recent successes in the development of synthetic α-helix mimetics, proteomimetics, and biologics with the therapeutic potentials of inhibiting tumourgenesis or cancer-related viral infections.
The genetics of skeletal muscle lineage commitment are deceptively complicated. MyoD overexpression is sufficient to convert fibroblasts into skeletal muscle myotubes. In vivo, there are a number of different steps of differentiation that require a large network of transcription factors that control differentiation and homeostasis of skeletal muscle progenitors. Each transcription factor has been shown to have the ability to promote the next factor in the cascade, but the mechanisms regulating the transitions remain incomplete. Recently, microRNAs have been shown to be important for a large number of developmental and oncogenic processes. In this review, we will discuss recent advances in the understanding of how microRNA is critical for skeletal muscle development by interacting with protein-coding genes that had previously been shown to be important for myogenesis.
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.
► GPR55 is a putative cannabinoid receptor. ► GPR55 shares little homology (10–15%) with cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors. ► GPR55 expression is found in the gastrointestinal (GI) tract. ► GPR55 mRNA expression is increased in intestinal inflammation. ► GPR55 agonists reduce intestinal inflammation.
Despite sharing little homology (10–15%) with cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors, the G protein-coupled receptor 55 (GPR55) was initially thought to be a new member of the cannabinoid receptor family. Apart from being activated by various exogenous cannabinoids, GPR55 is also activated by endocannabinoids like anandamide, which is found in organs with high GPR55 expression such as the brain and the gastrointestinal (GI) tract. The phylogenetic distance to the classical CB receptors and its pharmacological responsiveness to certain cannabinoids suggests that GPR55 may constitute a novel class of cannabinoid receptors. GPR55 influences mechanisms in the nervous system, vasculature, kidney and bone. Recent research revealed that GPR55 is also involved in cancer development and inflammatory pain. Because of its presence in the GI tract, several studies have started to focus on the involvement of GPR55 in the physiology and pathophysiology of the gut. The following article intends to discuss the potential role of GPR55 in GI functions.
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