| 1. |
- Bykov, Igor, et al.
(författare)
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Complement C3 contributes to ethanol-induced liver steatosis in mice.
- 2006
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Ingår i: Annals of medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 38:4, s. 280-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: It is becoming increasingly clear that liver steatosis, a typical early consequence of alcohol exposure, sensitizes the liver to more severe inflammatory and fibrotic changes. On the other hand, activation of the key complement component C3, a central player in causing inflammation and tissue damage, is also known to be involved in the regulation of lipid metabolism. This prompted us to study the development of alcoholic liver steatosis in mice lacking C3 (C3-/-). RESULTS: Both C3-/- and normal C3+/+ mice were fed a steatosis-promoting high-fat diet with or without ethanol for 6 weeks. The diet without ethanol caused moderate liver steatosis in C3-/- but not in C3+/+ mice. As expected, ethanol-containing diet caused marked macrovesicular steatosis and increased the liver triglyceride content in C3+/+ mice. In contrast, ethanol diet tended to reduce steatosis and had no further effect on liver triglycerides in C3-/- mice. Furthermore, while in normal mice ethanol significantly increased the liver/body weight ratio, liver malondialdehyde level and serum alanine aminotransferase (ALT) activity, these effects were absent or small in C3-/- mice. A separate experiment with mice on chow diet confirmed the aberrant steatotic effect of ethanol in C3-/-mice: 4 hours after acute dosing of ethanol the liver triglyceride level had increased by 138% in C3+/+ mice (P<0.001), but only by 64% in C3-/- mice (n.s.). CONCLUSION. In C3-/- mice alcohol-induced liver steatosis is absent or strongly reduced after chronic or acute alcohol exposure. This suggests that the complement system and its component C3 contribute to the development of alcohol-induced fatty liver and its consequences.
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| 2. |
- Bykov, Igor, et al.
(författare)
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Effect of chronic ethanol consumption on the expression of complement components and acute-phase proteins in liver.
- 2007
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Ingår i: Clinical immunology (Orlando, Fla.). - : Elsevier BV. - 1521-6616. ; 124:2, s. 213-20
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Tidskriftsartikel (refereegranskat)abstract
- The complement system can provoke but also participate in the repair of liver injury. Here we investigated by microarray analysis the effect of chronic ethanol consumption on hepatic mRNA expression of complement components and acute-phase proteins in complement C3-deficient (C3(-/-)) and wild-type (C3(+/+)) mice. Up-regulation by ethanol of factor B, C1qA-chain and clusterin but down-regulation of factor H, Masp-2, factor D and the terminal components C6, C8alpha and C9 was seen in both strains. Ethanol up-regulated C2 and down-regulated C4bp only in C3(+/+) mice, while in C3(-/-) mice up-regulation of C1qB-chain and vitronectin was observed. The expression of factor B, C6, C1qB and factor I was lower but that of factor D higher in C3(-/-) than in C3(+/+) mice. Ethanol induced mRNA synthesis of many acute-phase proteins including SPARC and lipocalin-2, but reduced the expression of SAP. The induction of early classical and alternative pathway components and suppression of terminal pathway components and soluble regulators may thus contribute to alcohol-induced liver injury. Lipocalin-2 and SPARC emerge as new candidate markers for early detection of liver damage.
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| 3. |
- Li, Lizhen, 1977, et al.
(författare)
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Protective role of reactive astrocytes in brain ischemia.
- 2008
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 28:3, s. 468-81
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Tidskriftsartikel (refereegranskat)abstract
- Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-mediated control of gap junctions, and PAI-1 expression.
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| 4. |
- Paglialunga, Sabina, et al.
(författare)
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Acylation-stimulating protein deficiency and altered adipose tissue in alternative complement pathway knockout mice.
- 2008
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 294:3
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Tidskriftsartikel (refereegranskat)abstract
- Acylation-stimulating protein (C3adesArg/ASP) is an adipokine that acts on its receptor C5L2 to stimulate triglyceride (TG) synthesis in adipose tissue. The present study investigated ASP levels in mouse models of obesity and leanness and the effect of ASP deficiency in C3 knockout (C3KO) mice on adipose tissue morphology. Plasma ASP levels in wild-type (WT) mice correlated positively with plasma nonesterified fatty acids (NEFA) (R = 0.664, P < 0.001) and total cholesterol (R = 0.515, P < 0.001). Plasma ASP was increased by 85% in obese ob/ob leptin-deficient mice and decreased in lean diacylglycerol acyltransferase 1 (DGAT1) KO mice (-54%) and C/EBPalpha(beta/beta) transgenic mice (-70%) compared with WT. Mice lacking alternative complement factor B or adipsin (FBKO or ADKO), required for ASP production, were also ASP deficient. Both FBKO and C3KO mice had delayed postprandial TG and NEFA clearance on low-fat (LF) and high-fat (HF) diets, suggesting that lack of ASP, not C3, drives the metabolic phenotype. Adipocyte size distribution in C3KO mice was polarized (increased number of both small and large cells), with decreased adipsin expression (-33% gonadal HF), DGAT1 expression (-31% to -50%) and DGAT activity (-41%). Overall, a reduction/deficiency in ASP is associated with an antiadipogenic state and ASP may provide a target for controlling fat storage.
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| 5. |
- Pekny, Milos, 1965, et al.
(författare)
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The role of astrocytes and complement system in neural plasticity.
- 2007
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Ingår i: International review of neurobiology. - 0074-7742. ; 82, s. 95-111
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Forskningsöversikt (refereegranskat)abstract
- In neurotrauma, brain ischemia or neurodegenerative diseases, astrocytes become reactive (which is known as reactive gliosis) and this is accompanied by an altered expression of many genes. Two cellular hallmarks of reactive gliosis are hypertrophy of astrocyte processes and the upregulation of the part of the cytoskeleton known as intermediate filaments, which are composed of nestin, vimentin, and GFAP. Our aim has been to better understand the function of reactive astrocytes in CNS diseases. Using mice deficient for astrocyte intermediate filaments (GFAP(-/-)Vim(-/-)), we were able to attenuate reactive gliosis and slow down the healing process after neurotrauma. We demonstrated the key role of reactive astrocytes in neurotrauma-at an early stage after neurotrauma, reactive astrocytes have a neuroprotective effect; at a later stage, they facilitate the formation of posttraumatic glial scars and inhibit CNS regeneration, specifically, they seem to compromise neural graft survival and integration, reduce the extent of synaptic regeneration, inhibit neurogenesis in the old age, and inhibit regeneration of severed CNS axons. We propose that reactive astrocytes are the future target for the therapeutic strategies promoting regeneration and plasticity in the brain and spinal cord in various disease conditions. Through its involvement in inflammation, opsonization, and cytolysis, complement protects against infectious agents. Although most of the complement proteins are synthesized in CNS, the role of the complement system in the normal or ischemic CNS remains unclear. Complement activiation in the CNS has been generally considered as contributing to tissue damage. However, growing body of evidence suggests that complement may be a physiological neuroprotective mechanism as well as it may participate in maintenance and repair of the adult brain.
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| 6. |
- Persson, Linda, 1971, et al.
(författare)
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Immunoglobulin treatment reduces atherosclerosis in apolipoprotein E-/- low-density lipoprotein receptor-/- mice via the complement system.
- 2005
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Ingår i: Clinical and experimental immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 142:3, s. 441-5
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is associated with activation of the immune system. Intravenously applied normal polyclonal immunoglobulins (IVIg) have broad therapeutic applications in the treatment of autoimmune and systemic inflammatory diseases. Recently, IVIg have been shown to inhibit atherogenesis in experimental animal models. To investigate the role of the complement system in this process, we used third complement component-deficient (C3(-/-)) and control atherosclerosis-prone apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) double knock-out mice fed a normal diet. IVIg treatment reduced lesion fraction area in the aortic root of complement-sufficient mice whereas the lesion fraction area of C3(-/-) mice was not affected. Thus, complement activation plays a role in the anti-atherosclerotic effects of IVIg, possibly by C3-derived fragments generated through Fc-dependent complement activation.
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| 7. |
- Persson, Mikael, 1979, et al.
(författare)
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The complement-derived anaphylatoxin C5a increases microglial GLT-1 expression and glutamate uptake in a TNF-alpha-independent manner.
- 2009
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Ingår i: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 29:2, s. 267-74
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Tidskriftsartikel (refereegranskat)abstract
- Microglia can express Na+-dependent high-affinity glutamate transporters during pathological conditions in the CNS. The transporter expression seems to be activation dependent, and we therefore sought to identify factors that could induce it, in addition to the well-known effect of lipopolysaccharide (LPS) that is mediated by tumour necrosis factor-alpha (TNF-alpha). The complement-derived anaphylatoxins C3a and C5a are of potential interest as the complement system is activated in nearly all insults to the nervous system, and both C3a and C5a have been shown to protect against excitotoxicity. We have found that C5a, but not C3a, increased the expression of the microglial glutamate transporter GLT-1 in a dose-dependent manner without eliciting or modulating the release of TNF-alpha. However, the increase was not as prominent as the one induced by LPS, indicating that the microglia are in different activity states. The increase in microglial GLT-1 expression led to an increased functional uptake of glutamate without affecting the release. This suggests that C5a-stimulated microglia can be self- and neuroprotective by removing extracellular glutamate.
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| 8. |
- Rahpeymai Bogestål, Yalda, 1977, et al.
(författare)
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Signaling through C5aR is not involved in basal neurogenesis.
- 2007
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Ingår i: Journal of neuroscience research. - : Wiley. - 0360-4012 .- 1097-4547. ; 85:13, s. 2892-7
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Tidskriftsartikel (refereegranskat)abstract
- The complement system, an important part of the innate immune system, provides protection against invading pathogens, in part through its proinflammatory activities. Although most complement proteins are synthesized locally in the brain and the relevant complement receptors are expressed on resident brain cells, little is known about brain-specific role(s) of the complement system. C3a and C5a, complement-derived peptides with anaphylatoxic properties, have been implicated in noninflammatory functions, such as tissue regeneration and neuroprotection. Recently, we have shown that signaling through C3a receptor (C3aR) is involved in the regulation of neurogenesis. In the present study, we assessed basal neurogenesis in mice lacking C5a receptor (C5aR(-/-)) and mice expressing C3a and C5a, respectively in the CNS under the control of glial fibrillary acidic protein (GFAP) promoter (C3a/GFAP and C5a/GFAP, respectively) and thus without the requirement for complement activation. We did not observe any difference among C5aR(-/-), C3a/GFAP and C5a/GFAP mice and their respective controls in the number of newly formed neuroblasts and newly formed neurons in the subventricular zone (SVZ) of lateral ventricles and hippocampal dentate gyrus, the two neurogenic niches in the adult brain, or the olfactory bulb, the final destination of new neurons formed in the SVZ. Our results indicate that signaling through C5aR is not involved in basal neurogenesis in adult mice and that basal neurogenesis in adult C3a/GFAP and C5a/GFAP mice is not altered. (c) 2007 Wiley-Liss, Inc.
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| 9. |
- Rahpeymai, Yalda, 1977, et al.
(författare)
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Complement: a novel factor in basal and ischemia-induced neurogenesis.
- 2006
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Ingår i: The EMBO journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 25:6, s. 1364-74
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Tidskriftsartikel (refereegranskat)abstract
- Through its involvement in inflammation, opsonization, and cytolysis, the complement protects against infectious agents. Although most of the complement proteins are synthesized in the central nervous system (CNS), the role of the complement system in the normal or ischemic CNS remains unclear. Here we demonstrate for the first time that neural progenitor cells and immature neurons express receptors for complement fragments C3a and C5a (C3a receptor (C3aR) and C5a receptor). Mice that are deficient in complement factor C3 (C3(-/-)) lack C3a and are unable to generate C5a through proteolytic cleavage of C5 by C5-convertase. Intriguingly, basal neurogenesis is decreased both in C3(-/-) mice and in mice lacking C3aR or mice treated with a C3aR antagonist. The C3(-/-) mice had impaired ischemia-induced neurogenesis both in the subventricular zone, the main source of neural progenitor cells in adult brain, and in the ischemic region, despite normal proliferative response and larger infarct volumes. Thus, in the adult mammalian CNS, complement activation products promote both basal and ischemia-induced neurogenesis.
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| 10. |
- Shinjyo, Noriko, et al.
(författare)
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Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells.
- 2009
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Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 27:11, s. 2824-32
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Tidskriftsartikel (refereegranskat)abstract
- Anaphylatoxin C3a is a third complement component (C3)-derived peptide, the multiple functions of which range from stimulation of inflammation to neuroprotection. In a previous study, we have shown that signaling through C3a receptor positively regulates in vivo neurogenesis in adult mouse brain. Here, we studied the direct effects of C3a on adult mouse whole brain-derived neural progenitor cells (NPCs) in vitro. Our results demonstrate that NPCs bind C3a in a specific and reversible manner and that C3a stimulates neuronal differentiation of NPCs. Furthermore, C3a stimulated the migration of NPCs induced by low concentrations of stromal cell-derived factor (SDF)-1alpha, whereas it inhibited NPC migration at high concentration of SDF-1alpha. In the same manner, C3a modulated SDF-1alpha-induced extracellular-signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation in these cells. In addition, C3a had inhibitory effect on SDF-1alpha-induced neuronal differentiation of NPCs. These data show that C3a modulates SDF-1alpha-induced differentiation and migration of these cells, conceivably through the regulation of ERK1/2 phosphorylation. Our results provide the first evidence that C3a regulates neurogenesis by directly affecting the fate and properties of NPCs.
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