A Characterization of Scale Invariant Responses in Enzymatic Networks

An ubiquitous property of biological sensory systems is adaptation: a step increase in stimulus triggers an initial change in a biochemical or physiological response, followed by a more gradual relaxation toward a basal, pre-stimulus level. Adaptation helps maintain essential variables within acceptable bounds and allows organisms to readjust themselves to an optimum and non-saturating sensitivity range when faced with a prolonged change in their environment. Recently, it was shown theoretically and experimentally that many adapting systems, both at the organism and single-cell level, enjoy a remarkable additional feature: scale invariance, meaning that the initial, transient behavior remains (approximately) the same even when the background signal level is scaled. In this work, we set out to investigate under what conditions a broadly used model of biochemical enzymatic networks will exhibit scale-invariant behavior. An exhaustive computational study led us to discover a new property of surprising simplicity and generality, uniform linearizations with fast output (ULFO), whose validity we show is both necessary and sufficient for scale invariance of enzymatic networks. Based on this study, we go on to develop a mathematical explanation of how ULFO results in scale invariance. Our work provides a surprisingly consistent, simple, and general framework for understanding this phenomenon, and results in concrete experimental predictions

Assessment of the direct effects of DDAH I on tumour angiogenesis in vivo

Nitric oxide (NO) has been strongly implicated in glioma progression and angiogenesis. The endogenous inhibitors of NO synthesis, asymmetric dimethylarginine (ADMA) and N-monomethyl-l-arginine (l-NMMA), are metabolized by dimethylarginine dimethylaminohydrolase (DDAH), and hence, DDAH is an intracellular factor that regulates NO. However, DDAH may also have an NO-independent action. We aimed to investigate whether DDAH I has any direct role in tumour vascular development and growth independent of its NO-mediated effects, in order to establish the future potential of DDAH inhibition as an anti-angiogenic treatment strategy. A clone of rat C6 glioma cells deficient in NO production expressing a pTet Off regulatable element was identified and engineered to overexpress DDAH I in the absence of doxycycline. Xenografts derived from these cells were propagated in the presence or absence of doxycycline and susceptibility magnetic resonance imaging used to assess functional vasculature in vivo. Pathological correlates of tumour vascular density, maturation and function were also sought. In the absence of doxycycline, tumours exhibited high DDAH I expression and activity, which was suppressed in its presence. However, overexpression of DDAH I had no measurable effect on tumour growth, vessel density, function or maturation. These data suggest that in C6 gliomas DDAH has no NO-independent effects on tumour growth and angiogenesis, and that the therapeutic potential of targeting DDAH in gliomas should only be considered in the context of NO regulation

Microparticles Carrying Sonic Hedgehog Favor Neovascularization through the Activation of Nitric Oxide Pathway in Mice

BACKGROUND: Microparticles (MPs) are vesicles released from plasma membrane upon cell activation and during apoptosis. Human T lymphocytes undergoing activation and apoptosis generate MPs bearing morphogen Shh (MPs(Shh+)) that are able to regulate in vitro angiogenesis.METHODOLOGY/PRINCIPAL FINDINGS: Here, we investigated the ability of MPs(Shh+) to modulate neovascularization in a model of mouse hind limb ischemia. Mice were treated in vivo for 21 days with vehicle, MPs(Shh+), MPs(Shh+) plus cyclopamine or cyclopamine alone, an inhibitor of Shh signalling. Laser doppler analysis revealed that the recovery of the blood flow was 1.4 fold higher in MPs(Shh+)-treated mice than in controls, and this was associated with an activation of Shh pathway in muscles and an increase in NO production in both aorta and muscles. MPs(Shh+)-mediated effects on flow recovery and NO production were completely prevented when Shh signalling was inhibited by cyclopamine. In aorta, MPs(Shh+) increased activation of eNOS/Akt pathway, and VEGF expression, being inhibited by cyclopamine. By contrast, in muscles, MPs(Shh+) enhanced eNOS expression and phosphorylation and decreased caveolin-1 expression, but cyclopamine prevented only the effects of MPs(Shh+) on eNOS pathway. Quantitative RT-PCR revealed that MPs(Shh+) treatment increased FGF5, FGF2, VEGF A and C mRNA levels and decreased those of α5-integrin, FLT-4, HGF, IGF-1, KDR, MCP-1, MT1-MMP, MMP-2, TGFβ1, TGFβ2, TSP-1 and VCAM-1, in ischemic muscles. CONCLUSIONS/SIGNIFICANCE: These findings suggest that MPs(Shh+) may contribute to reparative neovascularization after ischemic injury by regulating NO pathway and genes involved in angiogenesis

PPARα Is Essential for Microparticle-Induced Differentiation of Mouse Bone Marrow-Derived Endothelial Progenitor Cells and Angiogenesis

BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for neovascularization. We hypothesized that microparticles (MPs), small fragments generated from the plasma membrane, can activate angiogenic programming of EPCs. METHODOLOGY/PRINCIPAL FINDINGS: We studied the effects of MPs obtained from wild type (MPs(PPARalpha+/+)) and knock-out (MPs(PPARalpha-/-)) mice on EPC differentiation and angiogenesis. Bone marrow-derived cells were isolated from WT or KO mice and were cultured in the presence of MPs(PPARalpha+/+) or MPs(PPARalpha-/-) obtained from blood of mice. Only MPs(PPARalpha+/+) harboring PPAR(alpha) significantly increased EPC, but not monocytic, differentiation. Bone marrow-derived cells treated with MPs(PPARalpha+/+) displayed increased expression of pro-angiogenic genes and increased in vivo angiogenesis. MPs(PPARalpha+/+) increased capillary-like tube formation of endothelial cells that was associated with enhanced expressions of endothelial cell-specific markers. Finally, the effects of MPs(PPARalpha+/+) were mediated by NF-kappaB-dependent mechanisms. CONCLUSIONS/SIGNIFICANCE: Our results underscore the obligatory role of PPARalpha carried by MPs for EPC differentiation and angiogenesis. PPARalpha-NF-kappaB-Akt pathways may play a pivotal stimulatory role for neovascularization, which may, at least in part, be mediated by bone marrow-derived EPCs. Improvement of EPC differentiation may represent a useful strategy during reparative neovascularization

Curcumin Alleviates Matrix Metalloproteinase-3 and -9 Activities during Eradication of Helicobacter pylori Infection in Cultured Cells and Mice

Current therapy-regimens against Helicobacter pylori (Hp) infections have considerable failure rates and adverse side effects that urge the quest for an effective alternative therapy. We have shown that curcumin is capable of eradicating Hp-infection in mice. Here we examine the mechanism by which curcumin protects Hp infection in cultured cells and mice. Since, MMP-3 and -9 are inflammatory molecules associated to the pathogenesis of Hp-infection, we investigated the role of curcumin on inflammatory MMPs as well as proinflammatory molecules. Curcumin dose dependently suppressed MMP-3 and -9 expression in Hp infected human gastric epithelial (AGS) cells. Consistently, Hp-eradication by curcumin-therapy involved significant downregulation of MMP-3 and -9 activities and expression in both cytotoxic associated gene (cag)+ve and cag-ve Hp-infected mouse gastric tissues. Moreover, we demonstrate that the conventional triple therapy (TT) alleviated MMP-3 and -9 activities less efficiently than curcumin and curcumin's action on MMPs was linked to decreased pro-inflammatory molecules and activator protein-1 activation in Hp-infected gastric tissues. Although both curcumin and TT were associated with MMP-3 and -9 downregulation during Hp-eradication, but unlike TT, curcumin enhanced peroxisome proliferator-activated receptor-γ and inhibitor of kappa B-α. These data indicate that curcumin-mediated healing of Hp-infection involves regulation of MMP-3 and -9 activities

Thrombospondins in the heart: potential functions in cardiac remodeling

Cardiac remodeling after myocardial injury involves inflammation, angiogenesis, left ventricular hypertrophy and matrix remodeling. Thrombospondins (TSPs) belong to the group of matricellular proteins, which are non-structural extracellular matrix proteins that modulate cell–matrix interactions and cell function in injured tissues or tumors. They interact with different matrix and membrane-bound proteins due to their diverse functional domains. That the expression of TSPs strongly increases during cardiac stress or injury indicates an important role for them during cardiac remodeling. Recently, the protective properties of TSP expression against heart failure have been acknowledged. The current review will focus on the biological role of TSPs in the ischemic and hypertensive heart, and will describe the functional consequences of TSP polymorphisms in cardiac disease

Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain

The immune response in the brain has been widely investigated and while many studies have focused on the proinflammatory cytotoxic response, the brain’s innate immune system demonstrates significant heterogeneity. Microglia, like other tissue macrophages, participate in repair and resolution processes after infection or injury to restore normal tissue homeostasis. This review examines the mechanisms that lead to reduction of self-toxicity and to repair and restructuring of the damaged extracellular matrix in the brain. Part of the resolution process involves switching macrophage functional activation to include reduction of proinflammatory mediators, increased production and release of anti-inflammatory cytokines, and production of cytoactive factors involved in repair and reconstruction of the damaged brain. Two partially overlapping and complimentary functional macrophage states have been identified and are called alternative activation and acquired deactivation. The immunosuppressive and repair processes of each of these states and how alternative activation and acquired deactivation participate in chronic neuroinflammation in the brain are discussed