Damage-associated molecular patterns and their receptors in upper airway pathologies

Inflammation of the nasal (rhinitis) and sinus mucosa (sinusitis) are prevalent medical conditions of the upper airways that are concurrent in many patients; hence the terminology “rhinosinusitis”. The disease status is further defined to be “chronic” in case symptoms persist for more than 12 weeks without resolution. A diverse spectrum of external factors including viral and bacterial insults together with epithelial barrier malfunctions could be implicated in the chronicity of the inflammatory responses in chronic rhinosinusitis (CRS). However, despite massive research efforts in an attempt to unveil the pathophysiology, the exact reason for a lack of resolution still remains poorly understood. A novel set of molecules that could be implicated in sustaining the inflammatory reaction may be found within the host itself. Indeed, besides mediators of inflammation originating from outside, some endogenous intracellular and/or extracellular matrix (ECM) components from the host can be released into the extracellular space upon damage induced during the initial inflammatory reaction where they gain functions distinct from those during normal physiology. These “host-self” molecules are known to modulate inflammatory responses under pathological conditions, potentially preventing resolution and contributing to the development of chronic inflammation. These molecules are collectively classified as damage-associated molecular patterns (DAMPs). This review summarizes the current knowledge regarding DAMPs in upper airway pathologies, also covering those that were previously investigated for their intracellular and/or ECM functions often acting as an antimicrobial agent or implicated in tissue/cell homeostasis, and for which their function as a danger signaling molecule was not assessed. It is, however, of importance to assess these molecules again from a point of view as a DAMP in order to further unravel the pathogenesis of CRS.     

Impulse propagation from the SA-node to the ventricles

Normally the pacemaker of the mammalian heart is located in the sinus node. In the rabbit the sinus node can be subdivided into two regions, the center of the node where the impulse originates and the border zone through which the impulse is conducted towards the atrium. Conduction properties of both regions were investigated. It appeared that conduction velocity increases and refractoriness decreases when one goes from the nodal center towards the atrium. The tissue mass of the atrium is large in comparison to the sinus node and normally the resting membrane potential of atrial fibers is more negative than that of nodal fibers; consequently, a potential difference exists causing a current flow between both areas. Evidently this hyperpolarizing current flow depresses impulse formation in the border zone fibers which have better intrinsic pacemaker properties than fibers in the nodal center. If the impulse has reached the atrium it is conducted with a relatively high safety factor and will reach the AV node in principle without difficulty. The AV node, if deprived of sinus nodal dominance, develops spontaneous activity originating from the lower nodal fibers. Also in this structure, electrotonic depression by surrounding tissue causes deceleration of the pacemaker.     

Impulse propagation from the SA-node to the ventricles

Summary Normally the pacemaker of the mammalian heart is located in the sinus node. In the rabbit the sinus node can be subdivided into two regions, the center of the node where the impulse originates and the border zone through which the impulse is conducted towards the atrium. Conduction properties of both regions were investigated. It appeared that conduction velocity increases and refractoriness decreases when one goes from the nodal center towards the atrium. The tissue mass of the atrium is large in comparison to the sinus node and normally the resting membrane potential of atrial fibers is more negative than that of nodal fibers; consequently, a potential difference exists causing a current flow between both areas. Evidently this hyperpolarizing current flow depresses impulse formation in the border zone fibers which have better intrinsic pacemaker properties than fibers in the nodal center. If the impulse has reached the atrium it is conducted with a relatively high safety factor and will reach the AV node in principle without difficulty. The AV node, if deprived of sinus nodal dominance, develops spontaneous activity originating from the lower nodal fibers. Also in this structure, electrotonic depression by surrounding tissue causes deceleration of the pacemaker.     

Hedgehog signaling in pancreas development and disease

Since its discovery, numerous studies have shown that the Hedgehog (Hh) signaling pathway plays an instrumental role during diverse processes of cell differentiation and organ development. More recently, it has become evident that Hh signaling is not restricted to developmental events, but retains some of its activity during adult life. In mature tissues, Hh signaling has been implicated in the maintenance of stem cell niches in the brain, renewal of the gut epithelium and differentiation of hematopoietic cells. In addition to the basal function in adult tissue, deregulated signaling has been implicated in a variety of cancers, including basal cell carcinoma, glioma and small cell lung cancer. Here, we will focus on the role of Hh signaling in pancreas development and pancreatic diseases, including diabetes mellitus, chronic pancreatitis and pancreatic cancer. Received 5 August 2005; received after revision 4 November 2005; accepted 22 November 2005     

Modulator role of prostaglandins (Pg) in adrenergic neurotransmission in carotid sinus]

In Rabbit carotid sinus, the presence of sympathetic nerve endings capable of releasing noradrenaline has been demonstrated. The release of NA in response to sympathetic nerve stimulation was decreased by PgE2 and a precursor of Pg (arachidonic acid) but was strongly increased by an inhibitor of Pg biosynthesis (indomethacin). The experiments carried out demonstrated that freshly synthesized Pg acts in the same way as exogenous Pg and suggested that Pg could have a regulating effect on adrenergic neurotransmission in carotid sinus. The role of this regulating mechanism in the physiology of carotid sinus has been discussed.     

Retinoblastoma family proteins: insights gained through genetic manipulation of mice

The retinoblastoma (Rb) gene was identified as the first tumor suppressor gene two decades ago. Since this initial discovery, it has become clear that deregulated Rb function constitutes a hallmark of human malignancies. Rb is a well-established regulator of the cell cycle. Rb has also been implicated in playing a role in a wide variety of cellular processes including DNA repair, cellular senescence, cell fate determination and apoptosis. Animals lacking Rb and/or its family members p107 and p130 have led scientists to uncover new and exciting roles for this protein family in development as well as tumor suppression. The ability to ablate Rb in a temporal and cell-type-specific manner has offered further, often unexpected, insights into Rb function. This review summarizes the phenotypic consequences of Rb family ablation in mice, and discusses how these findings contribute to the increasingly complex picture of Rb family function in development and tumor suppression. Received 11 October 2005; received after revision 16 November 2005; accepted 28 November 2005     

Role of p21-activated kinases in cardiovascular development and function

p21-activated kinases (Paks) are a group of six serine/threonine kinases (Pak1-6) that are involved in a variety of biological processes. Recently, Paks, more specifically Pak1, -2, and -4, have been shown to play important roles in cardiovascular development and function in a range of model organisms including zebrafish and mice. These functions include proper morphogenesis and conductance of the heart, cardiac contractility, and development and integrity of the vasculature. The mechanisms underlying these effects are not fully known, but they likely differ among the various Pak isoforms and include both kinase-dependent and -independent functions. In this review, we discuss aspects of Pak function relevant to cardiovascular biology as well as potential therapeutic implications of small-molecule Pak inhibitors in cardiovascular disease.     

Janus head: the dual role of HLA-G in CNS immunity

The central nervous system (CNS) is considered an immune-privileged organ that maintains an adaptable immune surveillance system. Dysregulated immune function within the CNS contributes to the development of brain tumor growth, and robust immune activation results in excessive inflammation. Human lymphocyte antigen-G (HLA-G) proteins with tolerogenic immunoreactivity have been implicated in various pathophysiological processes including immune surveillance, governing homeostasis and immune regulation. In this review, we describe the wealth of evidence for the involvement of HLA-G in the CNS under physiological and pathological conditions. Further, we review regulatory functions that may be applicable as beneficial strategies in the therapeutic manipulation of immune-mediated CNS immune responses. Additionally, we try to understand how this molecule cooperates with other CNS-resident cells to maintain normal immune homeostasis, while still facilitating the development of the appropriate immune responses.     

Biochemistry and biology of mammalian DNA methyltransferases

DNA methylation is a stable but not irreversible epigenetic signal that silences gene expression. It has a variety of important functions in mammals, including control of gene expression, cellular differentiation and development, preservation of chromosomal integrity, parental imprinting and X-chromosome inactivation. In addition, it has been implicated in brain function and the development of the immune system. Somatic alterations in genomic methylation patterns contribute to the etiology of human cancers and ageing. It is tightly interwoven with the modification of histone tails and other epigenetic signals. Here we review our current understanding of the molecular enzymology of the mammalian DNA methyltransferases Dnmt1, Dnmt3a, Dnmt3b and Dnmt2 and the roles of the enzymes in the above-mentioned biological processes.     

Platelets as crucial partners for tumor metastasis: from mechanistic aspects to pharmacological targeting

Platelets are anucleated cells that circulate in the blood as sentinels of tissue integrity. In fact, they are rich in a plethora of proteins and other factors stored in different granules which they selectively release upon stimulation. Moreover, platelets synthesize a vast number of lipids and release various types of vesicles, including exosomes which are rich in genetic material. Platelets possess a central function to interact with other cell types, including inflammatory cells and cancer cells. Recent findings have enlightened the capacity of platelets to induce changes in the phenotype of cancer cells which acquire invasiveness thus enhancing their metastatic potential. Thus, it has been hypothesized that targeting the platelet may represent a novel strategy to prevent the development and progression of cancer. This is supported by the efficacy of the antiplatelet agent low-dose aspirin. Studies are ongoing to verify whether other antiplatelet agents share the anticancer effectiveness of aspirin.     

Crustacean neuropeptides

Crustaceans have long been used for peptide research. For example, the process of neurosecretion was first formally demonstrated in the crustacean X-organ–sinus gland system, and the first fully characterized invertebrate neuropeptide was from a shrimp. Moreover, the crustacean stomatogastric and cardiac nervous systems have long served as models for understanding the general principles governing neural circuit functioning, including modulation by peptides. Here, we review the basic biology of crustacean neuropeptides, discuss methodologies currently driving their discovery, provide an overview of the known families, and summarize recent data on their control of physiology and behavior.     

The neuroligin and neurexin families: from structure to function at the synapse

Proper brain connectivity and neuronal transmission rely on the accurate assembly of neurotransmitter receptors, cell adhesion molecules and several other scaffolding and signaling proteins at synapses. Several new exciting findings point to an important role for the neuroligin family of adhesion molecules in synapse development and function. In this review, we summarize current knowledge of the structure of neuroligins and neurexins, their potential binding partners at the synapse. We also discuss their potential involvement in several aspects of synapse development, including induction, specificity and stabilization. The implication of neuroligins in cognitive disorders such as autism and mental retardation is also discussed. Received 6 February 2006; received after revision 17 March 2006; accepted 26 April 2006     

Functional aspects of animal microRNAs

MicroRNAs (miRNAs) are a recently discovered family of small regulatory molecules that function by modulating protein production. There are approximately 500 known mammalian miRNA genes, and each miRNA may regulate hundreds of different protein-coding genes. Mature miRNAs bind to target mRNAs in a protein complex known as the miRNA-induced silencing complex (miRISC), sometimes referred to as the miRNP (miRNA-containing ribonucleoprotein particles), where mRNA translation is inhibited or mRNA is degraded. These actions of miRNAs have been shown to regulate several developmental and physiological processes including stem cell differentiation, haematopoiesis, cardiac and skeletal muscle development, neurogenesis, insulin secretion, cholesterol metabolism and the immune response. Furthermore, aberrant expression has been implicated in a number of diseases including cancer and heart disease. The role of miRNAs in these developmental, physiological and pathological processes will be reviewed. Received 3 August 2007; received after revision 3 October 2007; accepted 5 October 2007