The corticotropin-releasing factor (CRF) family of peptides as local modulators of adrenal function

Corticotropin-releasing factor (CRF), also termed corticotropin-releasing hormone (CRH) or corticoliberin, is the major regulator of the adaptive response to internal or external stresses. An essential component of the adaptation mechanism is the adrenal gland. CRF regulates adrenal function indirectly through the central nervous system (CNS) via the hypothalamic-pituitary-adrenal (HPA) axis and via the autonomic nervous system by way of locus coeruleus (LC) in the brain stem. Accumulating evidence suggests that CRF and its related peptides also affect the adrenals directly, i.e. not through the CNS but from within the adrenal gland where they form paracrine regulatory loops. Indeed, CRF and its related peptides, the urocortins (UCNs: UCN1, UCN2 and UCN3), their receptors CRF type 1 (CRF₁) and 2 (CRF₂) as well as the endogenous pseudo-receptor CRF-binding protein (CRF-BP) are all expressed in adrenal cortical, medullary chromaffin and resident immune cells. The intra-adrenal CRF-based regulatory system is complex and depends on the balance between the local concentration of CRF ligands and the availability of their receptors. Received 19 December 2006; received after revision 20 February 2007; accepted 26 March 2007     

The role of growth hormone and insulin-like growth factors in the immune system

Growth hormone (GH) and insulin-like growth factor I (IGF-I) can modulate the development and function of the immune system. In this chapter, we present data on the expression of receptors for GH and IGFs and the in vitro and in vivo effects of these proteins. We show that expression of GH and IGFs in the immune system opens up the possibility that these proteins are not only involved in endocrine control of the immune system but can also play a role as local growth and differentiation factors (cytokines). Endocrine control of GH could be direct or mediated via endocrine or autocrine/paracrine IGF-I. In addition, GH can act as an autocrine or paracrine factor itself. Furthermore, IGF-I in the immune system has been shown to be regulated by cytokines, such as interleukin-1 and interferon-γ, alluding to a cytokine-like function of IGF-I. In addition to data on the function of GH and IGF-I in the immune system, we present new findings which imply a possible function of IGF-II and IGF-binding proteins.     

Proteinases in cutaneous wound healing

Cutaneous wound healing is a complex and highly coordinated process where a number of different cell types participate to renew the damaged tissue under the strict regulation of soluble and insoluble factors. One of the most versatile processes involved in wound repair is proteolysis. During cell migration, proteins of extracellular matrix are cleaved, often creating biologically active cleavage products, and proteolysis of cellular contacts leads to increased cell motility and division. Moreover, proteases activate various growth factors and other proteases in wound and regulate growth factor signaling by shedding growth factor receptors on cell surface. Normally, proteolysis is strictly controlled, and changes in protease activity are associated with alterations in wound closure and scar formation. Here, we present the current view on the role of metalloproteinases and the plasmin-plasminogen system in normal and aberrant cutaneous wound repair and discuss their role as potential therapeutic targets for chronic ulcers or fibrotic scars. Received 07 July 2008; received after revision 11 August 2008; accepted 13 August 2008     

Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases

In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis, psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines. This “cholinergic anti-inflammatory pathway” modulates the immune system through cholinergic mechanisms that act on alpha7 receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory components.     

New concepts in regulation and function of the insulin-like growth factors: implications for understanding normal growth and neoplasia

The insulin-like growth factors (IGFs) are a ubiquitous family of growth factors, binding proteins and receptors that are involved in normal growth and development. They are also implicated in numerous pathological states, including malignancy. IGF-II is a commonly expressed growth factor in many tumors and may enhance tumor growth, acting via the overexpressed IGF-I receptor, a cell-surface tyrosine kinase receptor. The IGF-I receptor may be overexpressed due to mutations in tumor suppression gene products such as p53 and WT-1 or growth factors such as bFGF and PDGF. Thus, this family of growth factors, especially the IGF-I receptor, may present an excellent target for new therapeutic agents in the treatment of cancer and other disorders of excessive cellular proliferation.     

HLA-G in organ transplantation: towards clinical applications

HLA-G plays a particular role during pregnancy in which its expression at the feto–maternal barrier participates into the tolerance of the allogenic foetus. HLA-G has also been demonstrated to be expressed in some transplanted patients, suggesting that it regulates the allogenic response. In vitro data indicate that HLA-G modulates NK cells, T cells, and DC maturation through its interactions with various inhibitory receptors. In this paper, we will review the data reporting the HLA-G involvement of HLA-G in human organ transplantation, then factors that can modulate HLA-G, and finally the use of HLA-G as a therapeutic tool in organ transplantation.     

The innate immunity of the central nervous system in chronic pain: The role of Toll-like receptors

Toll-like receptors (TLRs) are a family of pattern recognition receptors that mediate innate immune responses to stimuli from pathogens or endogenous signals. Under various pathological conditions, the central nervous system (CNS) mounts a well-organized innate immune response, in which glial cells, in particular microglia, are activated. Further, the innate immune system has emerged as a promising target for therapeutic control of development and persistence of chronic pain. Especially, microglial cells respond to peripheral and central infection, injury, and other stressor signals arriving at the CNS and initiate a CNS immune activation that might contribute to chronic pain facilitation. In the orchestration of this limited immune reaction, TLRs on microglia appear to be most relevant in triggering and tailoring microglial activation, which might be a driving force of chronic pain. New therapeutic approaches targeting the CNS innate immune system may achieve the essential pharmacological control of chronic pain. Received 21 November 2006; received after revision 8 January 2007; accepted 7 February 2007     

γ-Aminobutyric acid (GABA) signalling in plants

The role of γ-aminobutyric acid (GABA) as a signal in animals has been documented for over 60 years. In contrast, evidence that GABA is a signal in plants has only emerged in the last 15 years, and it was not until last year that a mechanism by which this could occur was identified—a plant ‘GABA receptor’ that inhibits anion passage through the aluminium-activated malate transporter family of proteins (ALMTs). ALMTs are multigenic, expressed in different organs and present on different membranes. We propose GABA regulation of ALMT activity could function as a signal that modulates plant growth, development, and stress response. In this review, we compare and contrast the plant ‘GABA receptor’ with mammalian GABA_A receptors in terms of their molecular identity, predicted topology, mode of action, and signalling roles. We also explore the implications of the discovery that GABA modulates anion flux in plants, its role in signal transduction for the regulation of plant physiology, and predict the possibility that there are other GABA interaction sites in the N termini of ALMT proteins through in silico evolutionary coupling analysis; we also explore the potential interactions between GABA and other signalling molecules.     

Epigenetic regulation of mmp-9 gene expression

Matrix metalloproteinase 9 (MMP-9) is one of the most studied enzymes in cancer. MMP-9 can cleave proteins of the extracellular matrix and a large number of receptors and growth factors. Accordingly, its expression must be tightly regulated to avoid excessive enzymatic activity, which is associated with disease progression. Although we know that epigenetic mechanisms play a central role in controlling mmp-9 gene expression, predicting how epigenetic drugs could be used to suppress mmp-9 gene expression is not trivial because epigenetic drugs also regulate the expression of key proteins that can tip the balance towards activation or suppression of MMP-9. Here, we review how our understanding of the biology and expression of MMP-9 could be exploited to augment clinical benefits, most notably in terms of the prevention and management of degenerative diseases and cancer.     

Chaperone-mediated autophagy: machinery,regulation and biological consequences

Degradation of dysfunctional intracellular components in the lysosome system can occur through three different pathways, i.e., macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). In this review, we focus on CMA, a type of autophagy distinct from the other two autophagic pathways owing to its selectivity, saturability and competitivity by which a subset of long-lived cytosolic soluble proteins are directly delivered into the lysosomal lumen via specific receptors. CMA participates in quality control to maintain normal cell functions by clearing “old” proteins and provides energy to cells under nutritional stress. Deregulation of CMA has recently been shown to underlie some diseases, especially neurodegenerative disorders for which the decline with age in the activity of CMA may become a major aggravating factor. Therefore, targeting aberrant alteration in CMA under pathological conditions could serve as a potential therapeutic strategy for treating related diseases.     

Galanin – 25 years with a multitalented neuropeptide

The neuropeptide galanin and its receptors are localized in brain pathways mediating learning and memory. Central microinjection of galanin impairs performance of a variety of cognitive tasks in rats. Transgenic mice overexpressing galanin display deficits in some learning and memory tests. The inhibitory role of galanin in cognitive processes, taken together with the overexpression of galanin in Alzheimer's disease, suggests that galanin antagonists may offer a novel therapeutic approach to treat memory loss in Alzheimer's patients.     

Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease. Although a major cause of AD is the accumulation of amyloid-β (Aβ) peptide that induces neuronal loss and cognitive impairments, our understanding of its neurotoxic mechanisms is limited. Recent studies have identified putative Aβ-binding receptors that mediate Aβ neurotoxicity in cells and models of AD. Once Aβ interacts with a receptor, a toxic signal is transduced into neurons, resulting in cellular defects including endoplasmic reticulum stress and mitochondrial dysfunction. In addition, Aβ can also be internalized into neurons through unidentified Aβ receptors and induces malfunction of subcellular organelles, which explains some part of Aβ neurotoxicity. Understanding the neurotoxic signaling initiated by Aβ-receptor binding and cellular defects provide insight into new therapeutic windows for AD. In the present review, we summarize the findings on Aβ-binding receptors and the neurotoxicity of oligomeric Aβ.     

Vimentin in cancer and its potential as a molecular target for cancer therapy

Vimentin, a major constituent of the intermediate filament family of proteins, is ubiquitously expressed in normal mesenchymal cells and is known to maintain cellular integrity and provide resistance against stress. Vimentin is overexpressed in various epithelial cancers, including prostate cancer, gastrointestinal tumors, tumors of the central nervous system, breast cancer, malignant melanoma, and lung cancer. Vimentin’s overexpression in cancer correlates well with accelerated tumor growth, invasion, and poor prognosis; however, the role of vimentin in cancer progression remains obscure. In recent years, vimentin has been recognized as a marker for epithelial–mesenchymal transition (EMT). Although EMT is associated with several tumorigenic events, vimentin’s role in the underlying events mediating these processes remains unknown. By virtue of its overexpression in cancer and its association with tumor growth and metastasis, vimentin serves as an attractive potential target for cancer therapy; however, more research would be crucial to evaluate its specific role in cancer. Our recent discovery of a vimentin-binding mini-peptide has generated further impetus for vimentin-targeted tumor-specific therapy. Furthermore, research directed toward elucidating the role of vimentin in various signaling pathways would reveal new approaches for the development of therapeutic agents. This review summarizes the expression and functions of vimentin in various types of cancer and suggests some directions toward future cancer therapy utilizing vimentin as a potential molecular target.     

Discoidin domain receptors: a proteomic portrait

The discoidin domain receptors (DDRs) are collagen-binding receptor tyrosine kinases that have been implicated in a number of fundamental biological processes ranging from growth and development to immunoregulation. In this review, we examine how recent proteomic technologies have enriched our understanding of DDR signaling mechanisms. We provide an overview on the use of large-scale proteomic profiling and chemical proteomics to reveal novel insights into DDR therapeutics, signaling networks, and receptor crosstalk. A perspective of how proteomics may be harnessed to answer outstanding fundamental questions including the dynamic regulation of receptor activation kinetics is presented. Collectively, these studies present an emerging molecular portrait of these unique receptors and their functional role in health and disease.     

Role of plasminogen activator-plasmin system in tumor angiogenesis

New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and, conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand, genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.     

Netrin-1: when a neuronal guidance cue turns out to be a regulator of tumorigenesis

Netrin-1 has been shown to play a crucial role in neuronal navigation during nervous system development mainly through its interaction with its receptors DCC and UNC5H. However, initially the DCC (deleted in colorectal cancer) gene was proposed as a putative tumor suppressor gene. It was then difficult to reconcile the two activities of DCC until the observation that DCC belongs to an emerging family of receptors named dependence receptors. Such receptors share the property of inducing apoptosis in the absence of ligand, hence creating a cellular state of dependence on the ligand. Thus, netrin-1 may not only be a chemotropic factor for neurons but also a survival factor. We will review here the identification of netrin-1 and its receptors, the signaling pathways initiated in the presence or absence of netrin-1. We will suggest some possible roles of netrin-1 in nervous system development, neovascularisation, adhesion and tumorigenesis.     

Molecular and cellular basis of small- and intermediate-conductance, calcium-activated potassium channel function in the brain

Small conductance calcium-activated potassium (SK or K_Ca2) channels link intracellular calcium transients to membrane potential changes. SK channel subtypes present different pharmacology and distribution in the nervous system. The selective blocker apamin, SK enhancers and mice lacking specific SK channel subunits have revealed multifaceted functions of these channels in neurons, glia and cerebral blood vessels. SK channels regulate neuronal firing by contributing to the afterhyperpolarization following action potentials and mediating I_AHP, and partake in a calcium-mediated feedback loop with NMDA receptors, controlling the threshold for induction of hippocampal long-term potentiation. The function of distinct SK channel subtypes in different neurons often results from their specific coupling to different calcium sources. The prominent role of SK channels in the modulation of excitability and synaptic function of limbic, dopaminergic and cerebellar neurons hints at their possible involvement in neuronal dysfunction, either as part of the causal mechanism or as potential therapeutic targets. Received 23 April 2008; received after revision 29 May 2008; accepted 4 June 2008