During angiogenesis, new vessels emerge from existing endothelial lined vessels to promote the degradation of the vascular basement membrane and remodel the extracellular matrix (ECM), followed by endothelial cell migration, and proliferation and the new generation of matrix components. Matrix metalloproteinases (MMPs) participate in the disruption, tumor neovascularization, and subsequent metastasis while tissue inhibitors of metalloproteinases (TIMPs) downregulate the activity of these MMPs. Then, the angiogenic response can be directly or indirectly mediated by MMPs through the modulation of the balance between pro-and anti-angiogenic factors. This review analyzes recent knowledge on MMPs and their participation in angiogenesis.

The benefits of garlic to health have been proclaimed for centuries; however, only recently have Allium sativum and its derivatives been proposed as promising candidates for maintaining the homeostasis of the immune system. The complex biochemistry of garlic makes it possible for variations in processing to yield different preparations with differences in final composition and compound proportion. In this review, we assess the most recent experimental results, which indicate that garlic appears to enhance the functioning of the immune system by stimulating certain cell types, such as macrophages, lymphocytes, natural killer (NK) cells, dendritic cells, and eosinophils, by mechanisms including modulation of cytokine secretion, immunoglobulin production, phagocytosis, and macrophage activation. Finally, because immune dysfunction plays an important role in the development and progress of several diseases, we critically examined immunoregulation by garlic extracts and compounds isolated, which can contribute to the treatment and prevention of pathologies such as obesity, metabolic syndrome, cardiovascular disorders, gastric ulcer, and even cancer. We concluded that A. sativum modulates cytokine secretion and that such modulation may provide a mechanism of action for many of their therapeutic effects.

Serotonin (5-HT) induces concentration-dependent metabolic effects in diverse cell types, including neurons, entherochromaffin cells, adipocytes, pancreatic beta-cells, fibroblasts, smooth muscle cells, epithelial cells, and leukocytes. Three classes of genes regulating 5-HT function are constitutively expressed or induced in these cells: (a) membrane proteins that regulate the response to 5-HT, such as SERT, 5HTR-GPCR, and the 5HT3-ion channels; (b) downstream signaling transduction proteins; and (c) enzymes controlling 5-HT metabolism, such as IDO and MAO, which can generate biologically active catabolites, including melatonin, kynurenines, and kynurenamines. This review covers the clinical and experimental mechanisms involved in 5-HT-induced immunomodulation. These mechanisms are cell-specific and depend on the expression of serotonergic components in immune cells. Consequently, 5-HT can modulate several immunological events, such as chemotaxis, leukocyte activation, proliferation, cytokine secretion, anergy, and apoptosis. The effects of 5-HT on immune cells may be relevant in the clinical outcome of pathologies with an inflammatory component. Major depression, fibromyalgia, Alzheimer disease, psoriasis, arthritis, allergies, and asthma are all associated with changes in the serotonergic system associated with leukocytes. Thus, pharmacological regulation of the serotonergic system may modulate immune function and provide therapeutic alternatives for these diseases.

No abstract

Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.

No abstract

Changes in cytokine levels in major depression and during treatment have been reported in adults. However, few studies have examined cytokine levels in an adolescent sample despite this being a common age of onset. Methods. We measured proinflammatory (IL-2, IFN-γ, IL-1β, TNF-α, IL-6, IL-12, and IL-15) and anti-inflammatory (IL-4, IL-5, IL-13, IL-1Ra, and IL-10) cytokine serum levels in 22 adolescents with major depression and 18 healthy volunteers. Cytokines were measured by multiplex bead-based immunoassays at baseline, and 4 and 8 weeks after commencement of fluoxetine administration in the clinical group. Results. Compared to healthy volunteers, adolescents with major depression at baseline showed significant increases in all pro- and anti-inflammatory cytokines, except IL-1Ra and IL-10. Significant changes were observed in fluoxetine treatment compared to baseline: proinflammatory cytokines IFN-γ, IL-1β, TNF-α, IL-6, IL-12, and IL-15 were decreased only at week 4 whereas IL-2 was increased only at week 8; anti-inflammatory cytokines IL-4 and IL-5 were increased at week 8 while IL-1Ra was reduced only at week 4. There were no significant correlations between cytokine levels and symptomatic improvement in HDRS. Discussion. The results suggest a significant interplay between cytokine levels, the depressive state, and the stage of treatment with an SSRI. To the best of our knowledge, this is the first report in depressed adolescents with elevated IL-12, IL-13, and IL-15 levels. Further studies are necessary to clarify the role and mechanisms of altered cytokine levels in the pathogenesis and physiopathology of major depressive disorder.

Glucosamine-6-phosphate deaminase (EC 3.5.99.6) is an allosteric enzyme that catalyzes the reversible conversion of D-glucosamine-6-phosphate into D-fructose-6-phosphate and ammonium. Here we describe the existence of two mammalian glucosamine-6-phosphate deaminase enzymes. We present the crystallographic structure of one of them, the long human glucosamine-6-phosphate deaminase, at 1.75 A î resolution. Crystals belong to the space group P2 1 2 1 2 1 and present a whole hexamer in the asymmetric unit. The active-site lid (residues 162^182) presented signi¢cant structural di¡erences among monomers. Interestingly the region with the largest di¡erences, when compared with the Escherichia coli homologue, was found to be close to the active site. These structural di¡erences can be related to the kinetic and allosteric properties of both mammalian enzymes. ß