Sensory neurons link the nervous system and autoimmune diabetes

The initial factors that trigger the autoimmune response against pancreatic islets in the nonobese diabetic (NOD) mouse are still unknown. In this issue of Cell, propose that a defect in a subset of sensory neurons innervating the pancreas plays a major role in initiating the chain of events that will lead to local inflammation, islet destruction, and autoimmune diabetes.     

Stress, cognition and the nervous system

Stress, as defined by Selye, is the non-specific response of an organism to any demand made upon it. The response varies in intensity, depending on age, experience and genetic makeup. These demands, or stressors, can be physical, social or psychological. This concept has been challenged by others and the importance of perception and cognition in the stress response is argued strongly here. The role or cognition in reacting to external stressors is reviewed in the light of the three brain model and the differing functions of the right and left hemisphere. Techniques such as drugs and cognitive restructuring for altering perception and cognition are discussed. Cognitive restructuring is an important technique used in psychotherapy to enable patients to achieve more appropriate emotional responses and consequent behaviours.     

Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation

The products of nonenzymatic glycation and oxidation of proteins and lipids, the advanced glycation end products (AGEs), accumulate in a wide variety of environments. AGEs may be generated rapidly or over long times stimulated by a range of distinct triggering mechanisms, thereby accounting for their roles in multiple settings and disease states. A critical property of AGEs is their ability to activate receptor for advanced glycation end products (RAGE), a signal transduction receptor of the immunoglobulin superfamily. It is our hypothesis that due to such interaction, AGEs impart a potent impact in tissues, stimulating processes linked to inflammation and its consequences. We hypothesize that AGEs cause perturbation in a diverse group of diseases, such as diabetes, inflammation, neurodegeneration, and aging. Thus, we propose that targeting this pathway may represent a logical step in the prevention/treatment of the sequelae of these disorders.     

RAGE and RAGE ligands in cancer

The receptor for advanced glycation end-products (RAGE) is a multifunctional receptor with multiple ligands that is known to play a key role in several diseases, including diabetes, arthritis, and Alzheimer's disease. Recent evidence indicates that this receptor also has an important role in cancer. RAGE ligands, which include the S100/calgranulins and high-mobility group box 1 (HMGB1) ligands, are expressed and secreted by cancer cells and are associated with increased metastasis and poorer outcomes in a wide variety of tumors. These ligands can interact in an autocrine manner to directly activate cancer cells and stimulate proliferation, invasion, chemoresistance, and metastasis. RAGE ligands derived from cancer cells can also influence a variety of important cell types within the tumor microenvironment, including fibroblasts, leukocytes, and vascular cells, leading to increased fibrosis, inflammation, and angiogenesis. Several of the cells in the tumor microenvironment also produce RAGE ligands. Most of the cancer-promoting effects of RAGE ligands are the result of their interaction with RAGE. However, these ligands also often have separate intracellular roles, and some may interact with other extracellular targets, so it is not currently possible to assign all of their effects to RAGE activation. Despite these complications, the bulk of the evidence supports the premise that the ligand-RAGE axis is an important target for therapeutic intervention in cancer.     

Soluble RAGE but not endogenous secretory RAGE is associated with albuminuria in patients with type 2 diabetes

Aims

Type 2 diabetes is characterised by increased plasma concentrations of pro-inflammatory cytokines [such as tumour necrosis factor – alpha; TNF-α] and soluble forms of adhesion molecules involved in leukocyte – endothelial interactions. These molecules are synthesised as transmembrane proteins and the plasma soluble forms are generated by ectodomain cleavage from the cell surface by members of the ADAM [a disintegrin and metalloproteinase] proteinase family. We hypothesised that plasma low density lipoprotein [LDL] from subjects with Type 2 diabetes would influence in vitro monocytic ADAM and matrix metalloproteinase [MMP] gene expression differently compared to control LDL.

Methods

We examined relative mRNA expression by real time PCR in a monocytic cell line [THP-1] cultured for 4, 8 and 24 hrs with human plasma LDL derived from subjects with [n = 5] or without [n = 4] Type 2 diabetes. Gene expression for MMP-1 and 9, and ADAM – 8, 15, 17 and 28 was studied.

Results

Type 2 diabetes LDL significantly increased gene expression of MMP – 1 [p < 0.01] MMP – 9 [p < 0.001], and ADAM 17 [p < 0.05], – 28 [p < 0.01] and – 15 [p < 0.01] compared to control LDL. Type 2 diabetes LDL had disparate effects on inhibitors of MMP.

Conclusion

These data suggest that Type 2 diabetes LDL could lead to increased adhesion molecule and TNF alpha cell surface shedding, and vascular plaque instability, by promoting increased expression of ADAM and MMP genes.     

Localization of allatostatin-immunoreactive material in the central nervous system,stomatogastric nervous system,and gut of the cockroach Blattella germanica

Immunoreactivity against peptides of the allatostatin family having a typical YXFGL-NH₂ C-terminus has been localized in different areas of the central nervous system, stomatogastric nervous system and gut of the cockroach Blattella germanica. In the protocerebrum, the most characteristic immunoreactive perikarya are situated in the lateral and median neurosecretory cell groups. Immunoreactive median neurosecretory cells send their axons around the circumesophageal connectives to form arborizations in the anterior neuropil of the tritocerebrum. A group of cells in the lateral aspect of the tritocerebrum project to the antennal lobes in the deutocerebrum, where immunoreactive arborizations can be seen in the periphery of individual glomeruli. Nerve terminals were shown in the corpora allata. These terminals come from perikarya situated in the lateral neurosecretory cells in the pars lateralis and in the subesophageal ganglion. Immunoreactive axons from median neurosecretory cells and from cells positioned in the anteriormost part of the tritocerebrum enter together in the stomatogastric nervous system and innervate foregut and midgut, especially the crop and the valve between the crop and the midgut. The hindgut is innervated by neurons whose perikarya are located in the last abdominal ganglion. Besides immunoreactivity in neurons, allatostatin-immunoreactive material is present in endocrine cells distributed within the whole midgut epithelium. Possible functions for these peptides according to their localization are discussed. Arch. Insect Biochem. Physiol. 37:269–282, 1998. © 1998 Wiley-Liss, Inc.     

Growth factors, feeding regulation and the nervous system

A variety of growth factors and their receptors are present in the nervous system. Growth factors can modulate specific nervous system functions others than those related to growth, development, and tissue repair. The presence of growth factors in the brain and cerebrospinal fluid is the result of local synthesis (by neuronal, glial, vascular, and mononuclear phagocyte components), and uptake from the peripheral blood through the blood-brain barrier (in specific cases) and circumventricular organs. This paper focuses on the effects of a heterogeneous group of growth factors (acidic and basic fibroblast growth factors, insulin-like growth factors, epidermal growth factor, platelet-derived growth factor, interleukin-1 and others) on the central nervous system (CNS), in particular, on feeding regulation. Recent evidence supporting participation of growth factors in the regulation of feeding by a direct action at the level of the CNS is reviewed. Various growth factors have the ability to suppress short- and long-term food intake (FI), whereas others affect only short-term FI, or do not affect FI. Acute and chronic pathological processes stimulate the synthesis and release of growth factors in various cellular systems, and monitoring of growth factors by the CNS could be part of the regulatory signals that induce FI suppression frequently accompanying acute and chronic disease. Thus, it is proposed that a system regulating FI through growth factor-dependent mechanisms may be operative during specific physiological or pathological conditions.     

Apoptosis and the nervous system

Abstract: Apoptosis is now recognized as a normal feature in the development of the nervous system and may also play a role in neurodegenerative diseases and aging. This phenomenon has been investigated intensively during the last 6-7 years, and the progress made in this field is reviewed here. Besides a few in vivo studies, a variety of neuronal preparations from various parts of the brain, the majority of which were primary cultures, and some cell lines have been investigated. Several apoptosis-inducing agents have been identified, and these include lack of neurotrophic support, neurotransmitters, neurotoxicants, modulators of protein phosphorylation and calcium homeostasis, DNA-damaging agents, oxidative stress, nitric oxide, and ceramides. The precise signaling cascade is not well established, and there are lacunae in many suggested pathways. However, it appears certain that the Bcl family of proteins is involved in the apoptotic pathway, and these proteins in turn affect the processing of interleukin-1β converting enzyme (ICE)/caspases. The available evidence suggests that there may be several apoptotic pathways that may depend on the cell type and the inducing agent, and most of the pathways may converge at the ICE/caspases step.     

Cyclic nucleotides, phosphorylated proteins, and the nervous system.

Some postsynaptic effects of several classes of neurotransmitters appear to be mediated or modulated through the cyclic nucleotides, cyclic AMP and cyclic GMP. Available evidence suggests that the molecular mechanism by which the cyclic nucleotides carry out this second messenger role in nerve cells involves regulation of the state of phosphorylation of specific neuronal proteins. Phosphorylated proteins also appear to be involved in mediating certain of the actions of several other classes of regulatory agents, including calcium and the steroid hormones.     

Diet, central nervous system, and aging.

A variety of morphological, structural, and chemical changes have been described in the central nervous systems of aging humans and animals. Brain size and volume decline during senescence, and the brain atrophy is accompanied by changes in the number, size, and ultrastructural characteristics of nerve and glial cells. Moreover, recent evidence suggests that the ability of central nervous system cells to communicate with one another via the release of neurotransmitter compounds might be impaired in the elderly. Nutritional factors may play important roles in the aging process of the central nervous system by influencing brain neurotransmission, or by accelerating or retarding geriatric changes in central nervous system structure.     

Neuronal evolution: analysis of regulatory genes in a first-evolved nervous system, the hydra nervous system

Cnidarians represent the first animal phylum with an organized nervous system and a complex active behavior. The hydra nervous system is formed of sensory-motoneurons, ganglia neurons and mechanoreceptor cells named nematocytes, which all differentiate from a common stem cell. The neurons are organized as a nerve net and a subset of neurons participate in a more complex structure, the nerve ring that was identified in most cnidarian species at the base of the tentacles. In order to better understand the genetic control of this neuronal network, we analysed the expression of evolutionarily conserved regulatory genes in the hydra nervous system. The Prd-class homeogene prdl-b and the nuclear orphan receptor hyCOUP-TF are expressed at strong levels in proliferating nematoblasts, a lineage where they were found repressed during patterning and morphogenesis, and at low levels in distinct subsets of neurons. Interestingly, Prd-class homeobox and COUP-TF genes are also expressed during neurogenesis in bilaterians, suggesting that mechanoreceptor and neuronal cells derive from a common ancestral cell. Moreover, the Prd-class homeobox gene prdl-a, the Antp-class homeobox gene msh, and the thrombospondin-related gene TSP1, which are expressed in distinct subset of neurons in the adult polyp, are also expressed during early budding and/or head regeneration. These data strengthen the fact that two distinct regulations, one for neurogenesis and another for patterning, already apply to these regulatory genes, a feature also identified in bilaterian related genes.     

Soluble RAGE in type 2 diabetes: association with oxidative stress

Advanced glycation end products (AGEs) contribute to diabetic vascular complications by engaging the AGE receptor (RAGE). A soluble RAGE form (sRAGE) acts as a decoy domain receptor, thus decreasing AGE cellular binding. A cross-sectional comparison of sRAGE, asymmetric dimethylarginine (ADMA) plasma levels (index of endothelial dysfunction), and urinary 8-iso-prostaglandin (PG)F(2alpha) (marker of oxidative stress) was performed between 86 diabetic patients and 43 controls. Plasma sRAGE levels were significantly lower and ADMA levels were significantly higher in diabetic patients as compared to controls (P<0.0001). HbA1c and urinary 8-iso-PGF(2alpha) were correlated inversely with sRAGE and directly with ADMA. On multivariate analysis HbA1c was independently related to sRAGE levels in diabetic patients. Twenty-four of 86 patients with newly diagnosed diabetes and 12 patients in poor metabolic control were reevaluated after treatment with a hypoglycemic agent or insulin, respectively. Improvement in metabolic control by oral agents or insulin resulted in a significant increase in sRAGE and decrease in ADMA levels (P<0.0001). Thus, poor glycemic control reduces sRAGE levels, in association with enhanced oxidative stress and endothelial dysfunction in diabetes. These abnormalities are susceptible to modulation by improvement in metabolic control.     

Sex hormones, central nervous system and pain

The aim of the present review, which highlights some relationships between sex hormones, the CNS and pain, is to provide reference points for discussion on one of the most intriguing aspects of pain pathophysiology: the presence of sex differences in the response threshold to phasic painful stimuli and in the incidence of chronic pain syndromes. The first part of the review deals with sex steroids and their mechanisms of action. In the second part, the connections between sex steroids, the CNS and pain are illustrated to introduce possible areas of discussion in the study of sex differences in experimental and clinical pain.