Kegg Pathway: Complement and coagulation cascades

PLoS One. 2009; 4(10): e7641
Guo Y, Zhang X, Huang J, Zeng Y, Liu W, Geng C, Li KW, Yang D, Wu S, Wei H, Han Z, Qian X, Jiang Y, He F

In fetal hematopoietic organs, the switch from hematopoiesis is hypothesized to be a critical time point for organogenesis, but it is not yet evidenced. The transient coexistence of hematopoiesis will be useful to understand the development of fetal liver (FL) around this time and its relationship to hematopoiesis. Here, the temporal and the comparative transcriptomic and proteomic profiles were observed during the critical time points corresponding to the initiation (E11.5), peak (E14.5), recession (E15.5), and disappearance (3 ddp) of mouse FL hematopoiesis. We found that E11.5-E14.5 corresponds to a FL hematopoietic expansion phase with distinct molecular features, including the expression of new transcription factors, many of which are novel KRAB (Kruppel-associated box)-containing zinc finger proteins. This time period is also characterized by extensive depression of some liver functions, especially catabolism/utilization, immune and defense, classical Complement cascades, and intrinsic blood coagulation. Instead, the other liver functions increased, such as xenobiotic and sterol metabolism, synthesis of carbohydrate and glycan, the alternate and lectin Complement cascades and extrinsic blood coagulation, and etc. Strikingly, all of the liver functions were significantly increased at E14.5-E15.5 and thereafter, and the depression of the key pathways attributes to build the hematopoietic microenvironment. These findings signal hematopoiesis emigration is the key to open the door of liver maturation.

Semin Cardiothorac Vasc Anesth. 2009 Jun; 13(2): 87-94
Landis RC

From the first description of the "systemic inflammatory response" in the early 1990s, it has been recognized that this is a multifaceted response of the body to the combined insult of cardiothoracic surgery with bypass, involving causation by "activation of Complement, coagulation, fibrinolytic, and kallikrein cascades, activation of neutrophils with degranulation and protease enzyme release, oxygen radical production, and the synthesis of various cytokines from mononuclear cells." Yet the intervening 15 years have seen a narrowing of research into individual systems and interventions naively targeted at single pathways without achieving clinically meaningful benefits. The time has come to redefine the systemic inflammatory response so that research can be more productively focused on objectively measuring and interdicting this multisystem disorder. A key concept of this new understanding is that translation into a hard adverse event occurs when the systemic imbalance is combined with a localized trigger. Triggers might be inadvertently provided by transient episodes of ischemia/malperfusion to vulnerable organs or handling trauma to major vessels. Future research should be directed at suppressing systemic activation with combinations of drugs and improved circuit coating, whereas changes in clinical practice and continuous monitoring of perfusion parameters can help eliminate localized triggering events.

Physiol Genomics. 2009 Aug 7; 38(3): 386-401
Song MO, Li J, Freedman JH

Copper is an essential trace element; however, at supraphysiological levels, it can be extremely toxic. Microarray data from HepG2 cells exposed to 100, 200, 400, and 600 microM copper for 4, 8, 12 and 24 h were generated and analyzed. Principal components, K-means, and hierarchical clustering, interactome, and pathway mapping analyses indicated that these exposure conditions induce physiological and toxicological changes in the HepG2 transcriptome. As a general trend, when the level of toxicity increases, the number and diversity of affected genes, Gene Ontology categories, regulatory pathways, and complexity of interactomes increase. Physiological responses to copper include transition metal ion binding and responses to stress/stimulus, whereas toxicological responses include apoptosis, morphogenesis, and negative regulation of biomolecule metabolism. The global gene expression profile was overlaid onto biomolecular interaction networks and signal transduction cascades using pathway mapping and interactome identification. This analysis indicated that copper modulates signal transduction pathways associated with MAPK, NF-kappaB, death receptor, IGF-I, hypoxia, IL-10, IL-2, IL-6, EGF, Toll-like receptor, protein ubiquitination, xenobiotic metabolism, leukocyte extravasation, Complement and coagulation, and sonic hedgehog signaling. These results provide insights into the global and molecular mechanisms regulating the physiological and toxicological responses to metal exposure.

Physiol Genomics. 2009 Aug 7; 38(3): 303-18
Camateros P, Kanagaratham C, Henri J, Sladek R, Hudson TJ, Radzioch D

Resiquimod is a compound belonging to the imidazoquinoline family of compounds known to signal through Toll-like receptor 7. Resiquimod treatment has been demonstrated to inhibit the development of allergen induced asthma in experimental models. The aim of the present study was to elucidate the molecular processes that were altered following resiquimod treatment and allergen challenge in a mouse model of allergic asthma. Employing microarray analysis, we have characterized the "asthmatic" transcriptome of the lungs of A/J and C57BL/6 mice and determined that it includes genes involved in the control of cell cycle progression, the Complement and coagulation cascades, and chemokine signaling. Our results demonstrated that resiquimod treatment resulted in the normalization of the expression of genes involved with airway remodeling, and generally, chemokine signaling. Resiquimod treatment also altered the expression of cell adhesion molecules, and molecules involved in natural killer (NK) cell-mediated cytotoxicity. Furthermore, we have demonstrated that systemic resiquimod administration resulted in the recruitment of NK cells to the lungs and livers of the mice, although no causal relationship between NK cell recruitment and treatment efficacy was found. Overall, our findings identified several genes, important in the development of asthma pathology, that were normalized following resiquimod treatment, thus improving our understanding of the molecular consequences of resiquimod treatment in the lung milieu. The recruitment of NK cells to the lungs may also have application in the treatment of virally induced asthma exacerbations.

Fertil Steril. 2009 Mar 26;
Tseng LH, Chen I, Chen MY, Yan H, Wang CN, Lee CL

OBJECTIVE: To assess the molecular signatures underlying endometrial disorder using cDNA microarray. DESIGN: Gene expression-based oligonucleotide array of the normal endometrium. SETTING: University hospital. PATIENT(S): Humans. INTERVENTION(S): Endometrial tissues were obtained from 28 normal cycling women undergoing endometrial biopsy. RNA was extracted from each tissue and all labeled samples were hybridized to Affymetrix Human U133 plus 2.0 array. MAIN OUTCOME MEASURE(S): Transcriptional response. RESULT(S): Hierarchical cluster analysis with the Mahalanobis distance revealed a "126-gene" model, which are up-regulated at mid-secretory phase, moderately expressed at late-secretary phase, and down-regulated at late-secretory phase. Furthermore, the mechanisms underlying the receptivity of human endometrium at mid-secretary phase can be summarized: first, complex metabolic reactions are involved. Second, the activation of Complement and coagulation cascades promotes muscle contraction, chemotaxis, phagocyte recruitment, and peritoneal inflammation. Third, Ephrin A-mediated axon guidance promotes retrograde menstruation. Fourth, autophagic degradation is suggested to be responsible for the new blood vessel formation. In addition, DKK1 is up-regulated, indicating that WNT signaling pathway may contribute to the development of endometrial disorders. CONCLUSION(S): The success of this innovation has supported the use of microarray-based genome expression profiling as a single standardized platform for diagnosis of endometrial disorders.

Front Biosci. 2009; 14: 3782-94
Vincenza Carriero M, Franco P, Vocca I, Alfano D, Longanesi-Cattani I, Bifulco K, Mancini A, Caputi M, Stoppelli MP

Urokinase (uPA) is a serine protease which converts plasminogen to plasmin, a broad-spectrum protease active on extracellular matrix (ECM) components. Like many components of the blood coagulation, fibrinolytic and Complement cascades, uPA has a modular structure, including three conserved domains: a growth factor-like domain (GFD, residues 1 - 49), a kringle domain (residues 50 - 131), linked by an interdomain linker or "connecting peptide" (CP, residues 132 - 158) to the serine protease domain (residues 159 - 411). Although direct molecular interactions with urokinase receptor and integrins have been extensively described, the function of single uPA domains is not completely understood. Because of the causal involvment of uPA in cancer invasion and metastasis, the blockade of uPA interactions and activity with specific inhibitors is of interest for novel strategies in cancer therapy. New inhibitors derived from the interdomain linker or "connecting peptide" are coming into focus. This review summarizes the recent findings on the uPA structure-function relationship and provides further information on existing inhibitors of uPA multiple functions.

Eur J Clin Invest. 2009 Mar; 39(3): 239-45
Lin ZY, Chuang WL, Chuang YH

BACKGROUND: Amphotericin B (AmB) has a discordant influence on epirubicin (4'-epidoxorubicin) cytotoxicity in hepatocellular carcinoma (HCC). This indicates that the cellular function of HCC may be significantly influenced by AmB. Whether the influence of AmB on HCC has any possibility to influence cancer growth has not been studied. This study was to try and clarify this issue. MATERIALS AND METHODS: Two HCC cell lines including one without augmentation of the epirubicin cytotoxicity by AmB (cell line A; HCC24/KMUH) and one with this effect (cell line B; HCC38/KMUH) were studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and whole human genome microarray (experimental group: 2.5 microg mL(-1) AmB). RESULTS: Differential expressions of genes induced by AmB in two cell lines had no influence on cell proliferation as determined by MTT assay. Only cell line B showed up-regulation of genes related to oxidative stress, acute phase reaction, cytokine-cytokine receptor interaction and Complement and coagulation cascades. Among the chemokine genes up-regulated by AmB, five genes (CCL2, CXCL1, CXCL5, CXCL6, IL8) were angiogenic. Cell line B also showed up-regulation of one angiogenic C10orf10 gene and down-regulation of one angiostatic chemokine gene (CXCL10). Up- or down-regulation of other genes in cell line A and B did not show any evidence to promote angiogenesis. CONCLUSION: AmB has the capacity to concomitantly up-regulate angiogenic genes in HCC cells susceptible to AmB-induced oxidative stress.

Transplant Proc. 2009 Jan-Feb; 41(1): 67-8
Tokodai K, Goto M, Imura T, Ogawa N, Fujimori K, Kurokawa Y, Okada H, Satomi S

BACKGROUND: The instant blood-mediated inflammatory reaction, characterized by activation of both the coagulation and Complement cascades, is a serious obstacle to successful islet engraftment. No attractive protocol is clinically available as yet. The objective of the present study was to examine whether Complementary peptide against an active region of C5a in combination with a clinically available anticoagulant could provide an effective protocol for suppression of the instant blood-mediated inflammatory reaction. METHODS: Three islet equivalents per gram of syngeneic rat grafts were transplanted intraportally into 6 pairs of rats with streptozotocin-induced diabetes. Islets from the same donor were transplanted into each pair. In each pair, one rat was treated with C5a inhibitory peptide in addition to continuous intravenous infusion of gabexate mesilate and the other rat, injected with equivalent amount of saline solution, served as the control. In addition, 6 rats that received transplants from irrelevant donors were treated with the same dose of gabexate mesilate. We evaluated the cure rate, time to normoglycemia, liver insulin concentration in recipients, and results of in vivo glucose tolerance tests. RESULTS: The cure rate was remarkably improved and the time to normoglycemia in cured animals was significantly shortened with C5a inhibitor plus gabexate treatment. In six rats that received only gabexate mesilate, normoglycemia was not restored during the study. CONCLUSIONS: These data suggest that C5a inhibitory peptide combined with gabexate mesilate could be an attractive drug candidate without adverse effects to control the detrimental innate immune responses induced in clinical islet transplantation.

Virol J. 2009; 6: 20
Djavani M, Crasta OR, Zhang Y, Zapata JC, Sobral B, Lechner MG, Bryant J, Davis H, Salvato MS

BACKGROUND: Rhesus macaques infected with lymphocytic choriomeningitis virus (LCMV) provide a model for human Lassa fever. Disease begins with flu-like symptoms and progresses rapidly with fatal consequences. Previously, we profiled the blood transcriptome of LCMV-infected monkeys (M. Djavani et al J. Virol. 2007) showing distinct pre-viremic and viremic stages that discriminated virulent from benign infections. In the present study, changes in liver gene expression from macaques infected with virulent LCMV-WE were compared to gene expression in uninfected monkeys as well as to monkeys that were infected but not diseased. RESULTS: Based on a functional pathway analysis of differentially expressed genes, virulent LCMV-WE had a broader effect on liver cell function than did infection with non-virulent LCMV-Armstrong. During the first few days after infection, LCMV altered expression of genes associated with energy production, including fatty acid and glucose metabolism. The transcriptome profile resembled that of an organism in starvation: mRNA for acetyl-CoA carboxylase, a key enzyme of fatty acid synthesis was reduced while genes for enzymes in gluconeogenesis were up-regulated. Expression was also altered for genes associated with Complement and coagulation cascades, and with signaling pathways involving STAT1 and TGF-beta. CONCLUSION: Most of the 4500 differentially expressed transcripts represented a general response to both virulent and mild infections. However, approximately 250 of these transcripts had significantly different expression in virulent infections as compared to mild infections, with approximately 30 of these being differentially regulated during the pre-viremic stage of infection. The genes that are expressed early and differently in mild and virulent disease are potential biomarkers for prognosis and triage of acute viral disease.

Autoimmun Rev. 2009 May; 8(6): 525-8
Amaral MC, Alves JD

Multi-organic failure in the context of autoimmune diseases is a multi-factorial condition where different pathways concur to produce a global system breakdown. Some of these pathways include the coagulation, fibrinolysis, kinin and Complement cascades which in normal conditions work together to provide a comprehensive response to injury. In pathologic conditions these regulatory mechanisms are replaced by positive feed-back loops. The common response pattern is the activation of the immune system via endothelium activation. Furthermore, these different plasma-driven mechanisms may induce standardised endothelial cell responses of which the most relevant are the activation of p38, JNK, NF-kbeta and IRF-3 pathways. In this paper we review the common points between these major pathways and how they become activated, contributing to a global clinical picture. We present two examples of apparently different clinical settings, caused by the same global dysfunction: the Macrophage Activation Syndrome and the iatrogenic "cytokine storm" triggered by the administration of anti-CD28 monoclonal antibody TGN1412 in a phase 1 trial.

Heart Surg Forum. 2008; 11(5): E316-22
Landis RC, Arrowsmith JE, Baker RA, de Somer F, Dobkowski WB, Fisher G, Jonas RA, Likosky DS, Murkin JM, Poullis M, Stump DA, Verrier ED

The causal factors of the systemic inflammatory response to cardiopulmonary bypass (CPB) were correctly identified in the early 1990 s: "... activation of Complement, coagulation, fibrinolytic, and kallikrein cascades, activation of neutrophils with degranulation and protease enzyme release, oxygen radical production, and the synthesis of various cytokines from mononuclear cells" [Butler 1993]. Why therefore have clinical advances to curb the systemic inflammatory response proven such a disappointment? Part of the problem is that cardiac surgery has never taken intellectual ownership of this issue, borrowing its diagnosis from critical care medicine and failing to define the minimal criteria that should be measured when reporting on the systemic inflammatory response. An evidence based review of the current literature by many of the coauthors on this paper found that the majority of studies on the systemic inflammatory response did not measure a single one of the causal factors listed above - thus hindering our ability to identify mechanisms of causation and identify drug targets [Landis 2008]. A panel of experts convened at the Outcomes XII meeting, Barbados 2008, drafted the present consensus document in order to provide a framework to guide future studies and interdictions of the systemic inflammatory response. Herein, we have recommended: 1) mandatory reporting of minimal CPB and perfusion criteria that may affect outcomes, 2) reporting of a minimal set of causal inflammatory markers linked to adverse sequelae, and 3) reporting of at least one clinical end-point of organ injury, from a list of endpoints and markers of organ injury that balance practicality with clinical meaningfulness. It is our collective belief that this document will serve as a foundation for furthering our understanding of the influence of CPB practice with the systemic inflammatory response by standardizing the reporting of research findings in the peer-reviewed literature.

Adv Exp Med Biol. 2008; 632: 71-9
Amara U, Rittirsch D, Flierl M, Bruckner U, Klos A, Gebhard F, Lambris JD, Huber-Lang M

The Complement system as a main column of innate immunity and the coagulation system as a main column in hemostasis undergo massive activation early after injury. Interactions between the two cascades have often been proposed but the precise molecular pathways of this interplay are still in the dark. To elucidate the mechanisms involved, the effects of various coagulation factors on Complement activation and generation of anaphylatoxins were investigated and summarized in the light of the latest literature. Own in vitro findings suggest, that the coagulation factors FXa, FXIa and plasmin may cleave both C5 and C3, and robustly generate C5a and C3a (as detected by immunoblotting and ELISA). The produced anaphylatoxins were found to be biologically active as shown by a dose-dependent chemotactic response of neutrophils and HMC-1 cells, respectively. Thrombin did not only cleave C5 (Huber-Lang et al. 2006) but also in vitro-generated C3a when incubated with native C3. The plasmin-induced cleavage activity could be dose-dependently blocked by the serine protease inhibitor aprotinin and leupeptine. These findings suggest that various serine proteases belonging to the coagulation system are able to activate the Complement cascade independently of the established pathways. Moreover, functional C5a and C3a are generated, both of which are known to be crucially involved in the inflammatory response.

Prostate. 2009 Jan 1; 69(1): 49-61
Goo YA, Liu AY, Ryu S, Shaffer SA, Malmström L, Page L, Nguyen LT, Doneanu CE, Goodlett DR

BACKGROUND: Functional development of the prostate is governed by stromal mesenchyme induction and epithelial response. Stromal/epithelial signaling can be mediated through direct cell-cell contact and diffusible factors and their cell surface receptors. These inducers are likely secreted or membrane-associated extracellular proteins. Given the importance of intercellular communication, it is possible that diseases like cancer could arise from a loss of this communication. One approach to gain a molecular understanding of stromal cells is to identify, as a first step, secreted stromal signaling factors. We proposed to do this by comparative analysis between bladder and prostate. METHODS: Secreted proteins were identified from cultured normal prostate and bladder stromal mesenchyme cells by glycopeptide-capture method followed by mass spectrometry. Differences in protein abundance between prostate and bladder were quantified from calculated peptide ion current area (PICA) followed by Western validation. Functional and pathway analyses of the proteins were carried out by Gene Ontology (GO) and Teranode software. RESULTS: This analysis produced a list of 116 prostate and 84 bladder secreted glycoproteins with ProteinProphet probability scores > or =0.9. Stromal proteins upregulated in the prostate include cathepsin L, follistatin-related protein, neuroendocrine convertase, tumor necrosis factor receptor, and others that are known to be involved in signal transduction, extracellular matrix interaction, differentiation and transport. CONCLUSIONS: We have identified a number of potential proteins for stromal signaling and bladder or prostate differentiation program. The prostate stromal/epithelial signaling may be accomplished through activation of the ECM-receptor interaction, Complement and coagulation cascades, focal adhesion and cell adhesion pathways.

Pharmacogenomics. 2008 Aug; 9(8): 1035-54
Llaverias G, Pou J, Ros E, Zambón D, Cofán M, Sánchez A, Vázquez-Carrera M, Sánchez RM, Laguna JC, Alegret M

AIM: The genetic origin of familial combined hyperlipidemia (FCH) is not well understood. We used microarray profiling of peripheral blood monocytes to search novel genes and pathways involved in FCH. METHODS: Fasting plasma for determination of lipid profiles, inflammatory molecules and adipokines was obtained and peripheral blood monocytes were isolated from male FCH patients basally and after 4 weeks of atorvastatin treatment. Sex-, age- and adiposity-matched controls were also studied. Gene-expression profiles were analyzed using Affymetrix Human Genome U133A 2.0 GeneChip arrays. RESULTS: Analysis of gene expression by cDNA microarrays showed that 82 genes were differentially expressed in FCH monocytes compared with controls. Atorvastatin treatment modified the expression of 86 genes. Pathway analysis revealed the over-representation of the Complement and coagulation cascades, the hematopoietic cell lineage and the arachidonic acid metabolism pathways. Changes in the expression of some genes, confirmed by real-time RT-PCR, (CD36, leucine-rich repeats and immunoglobulin-like domains-1, tissue factor pathway inhibitor 2, myeloid cell nuclear differentiation antigen, tumor necrosis factor receptor superfamily, member 25, CD96 and lipoprotein lipase), may be related to a proinflammatory environment in FCH monocytes, which is partially reversed by atorvastatin. Higher plasma levels of triglycerides and free fatty acids and lower levels of adiponectin in FCH patients could also trigger changes in gene expression that atorvastatin cannot modify. CONCLUSION: Our results show clear differences in gene expression in FCH monocytes compared with those of matched healthy controls, some of which are influenced by atorvastatin treatment.

Physiol Genomics. 2008 Oct 8; 35(2): 165-72
Rajasekaran NS, Firpo MA, Milash BA, Weiss RB, Benjamin IJ

Protein aggregation cardiomyopathy is a life-threatening manifestation of a multisystem disorder caused by the exchange mutation in the gene encoding the human small heat shock protein alphaB-crystallin (hR120GCryAB). Genetic studies in mice have established cardiac hR120GCryAB expression causes increased activity of glucose 6-phosphate dehydrogenase (G6PD) and "reductive stress" (Rajasekaran et al., Cell 130: 427-439, 2007). However, the initiating molecular events in the pathogenesis of this novel toxic gain-of-function mechanism remain poorly defined. In an integrated systems approach using gene expression profiling, we identified a "biosignature," whose features can be validated to predict the onset, rate of progression, and clinical outcome of R120GCryAB cardiomyopathy. At the 3 mo disease-related but compensated stage, we demonstrate that transcripts were only upregulated in three distinct pathways: stress response (e.g., Hsp70, Hsp90), glutathione metabolism (Gpx1, Gpx3, glutathione S-transferase), and Complement and coagulation cascades in hR120GCryAB transgenic mouse hearts compared with either hCryAB WT transgenic mice or nontransgenic controls. In 6 mo old myopathic hearts, ribosomal synthesis and cellular remodeling associated with increased cardiac hypertrophy were additional upregulated pathways. In contrast, the predominant downregulated pathways were for oxidative phosphorylation, fatty acid metabolism, intermediate metabolism, and energetic balance, supporting their primary pathogenic roles by which G6PD-dependent reductive stress causes cardiac decompensation and overt heart failure in hR120GCryAB cardiomyopathy. This study extends and confirms our previous findings that reductive stress is a causal mechanism for hR120G CryAB cardiomyopathy and demonstrates that alteration in glutathione pathway gene expression is an early biosignature with utility for presymptomatic detection.

Eur J Cardiothorac Surg. 2008 Sep; 34(3): 653-60
Banz Y, Rieben R, Zobrist C, Meier P, Shaw S, Lanz J, Carrel T, Berdat P

OBJECTIVE: Contact of blood with artificial surfaces and air as well as ischemia/reperfusion injury to the heart and lungs mediate systemic and local inflammation during cardiopulmonary bypass (CPB). Activation of Complement and coagulation cascades leads to and accompanies endothelial cell damage. Therefore, endothelial-targeted cytoprotection with the Complement inhibitor and endothelial protectant dextran sulfate (DXS, MW 5000) may attenuate CBP-associated myocardial and pulmonary injury. METHODS: Eighteen pigs (DXS, n=10; phosphate buffered saline [PBS], n=8) underwent standard cardiopulmonary bypass. After aortic cross-clamping, cardiac arrest was initiated with modified Buckberg blood cardioplegia (BCP), repeated after 30 and 60 min with BCP containing either DXS (300 mg/10 ml, equivalent to 5mg/kg) or 10 ml of PBS. Following 30 min reperfusion, pigs were weaned from CPB. During 2h of observation, cardiac function was monitored by echocardiography and invasive pressure measurements. Inflammatory and coagulation markers were assessed regularly. Animals were then sacrificed and heart and lungs analyzed. RESULTS: DXS significantly reduced CK-MB levels (43.4+/-14.8 ng/ml PBS, 35.9+/-11.1 ng/ml DXS, p=0.042) and significantly diminished cytokine release: TNFalpha (1507.6+/-269.2 pg/ml PBS, 222.1+/-125.6 pg/ml DXS, p=0.0071), IL1beta (1081.8+/-203.0 pg/ml PBS, 110.7+/-79.4 pg/ml DXS, p=0.0071), IL-6 (173.0+/-91.5 pg/ml PBS, 40.8+/-19.4 pg/ml DXS, p=0.002) and IL-8 (304.6+/-81.3 pg/ml PBS, 25.4+/-14.2 pg/ml DXS, p=0.0071). Tissue endothelin-1 levels were significantly reduced (6.29+/-1.90 pg/100mg PBS, 3.55+/-1.15 pg/100mg DXS p=0.030) as well as thrombin-anti-thrombin formation (20.7+/-1.0 microg/ml PBS, 12.8+/-4.1 microg/ml DXS, p=0.043). Also DXS reduced cardiac and pulmonary Complement deposition, neutrophil infiltration, hemorrhage and pulmonary edema (measured as lung water content, 81+/-3% vs 78+/-3%, p=0.047), indicative of attenuated myocardial and pulmonary CPB-injury. Diastolic left ventricular function (measured as dp/dt(min)), pulmonary artery pressure (21+/-3 mmHg PBS, 19+/-3 mmHg DXS, p=0.002) and right ventricular pressure (21+/-1 mmHg PBS, 19+/-3 mmHg DXS p=0.021) were significantly improved with the use of DXS. CONCLUSIONS: Addition of DXS to the BCP solution ameliorates post-CPB injury and to a certain extent improves cardiopulmonary function. Endothelial protection in addition to myocyte protection may improve post-CPB outcome and recovery.

Physiol Genomics. 2008 Aug 15; 34(3): 285-303
Nilsen AJ, Landin MA, Haug KH, Fonnum F, Berger U, Osmundsen H

Pentadecafluorooctanoic acid is an established peroxisome proliferator. Little is known about effects of treatment with 1H,1H,2H,2H-heptadecafluorodecan-1-ol, which is metabolized to pentadecafluorooctanoic acid. We compared effects of various dosages (3, 10, or 25 mg/kg body wt) of each of these compounds on hepatic gene expression in rats with microarrays. Microarray data were validated by real-time RT-PCR. Expression data were also correlated with hepatic activities of selected enzymes and with hepatic levels of pentadecafluorooctanoic acid and 1H,1H,2H,2H-heptadecafluorodecan-1-ol. Pentadecafluorooctanoic acid caused the more powerful change in gene expression, in terms of both number of genes affected and extent of change in expression. Across the dosages used pentadecafluorooctanoic acid and 1H,1H,2H,2H-heptadecafluorodecan-1-ol caused significant (P < or = 0.05) changes in expression for 441 and 105 genes, respectively. With 1H,1H,2H,2H-heptadecafluorodecan-1-ol approximately 38% of the 105 genes exhibited decreased expression with a dose of 25 mg/kg body wt, these genes also appearing less responsive to treatment at the lower dosages. Bioinformatic analysis suggested that these genes are associated with regulatory functions. With pentadecafluorooctanoic acid, increasing dosage up to 10 mg/kg body wt brought about progressive increase in expression of affected genes. Pathways analysis suggested similar effects of the two compounds on lipid and amino acid metabolism. Marked differences were also found, particularly with respect to effects on genes related to oxidative phosphorylation, oxidative metabolism, free radical scavenging, xenobiotic metabolism, and Complement and coagulation cascades.

Front Biosci. 2008; 13: 7046-63
Sonenshine DE, Hynes WL

Compared to insects, little is known about innate immunity in ticks. This chapter addresses the molecular processes that recognize non-self and the cellular and molecular processes mobilized to phagocytose, engulf, inhibit or kill invaders. We discuss the receptors that recognize pathogen associated molecular patterns (PAMPs) and the putative up-regulation of regulatory cascades that lead, ultimately, to cellular or molecular responses. We describe the molecular events that activate the cellular processes and the array of humoral factors that are mobilized against invading organisms, including antimicrobial peptides, proteases and protease inhibitors, lectins, coagulation factors and others. Special attention is directed to the antimicrobial activity of the midgut, the initial site of contact for microbes ingested with the blood. Blood feeding and digestion alone up-regulates an impressive array of proteins, e.g. oxidative stress reducing proteins, lectins, protease inhibitors, proteases, hydrolases, protein/lipid binding agents. Finally, we compare the innate immune responses of ticks with insects and other invertebrates and note deficiencies in our knowledge tick innate immunity.

Lipids Health Dis. 2007; 6: 35
Das UN, Rao AA

Obesity is an important component of metabolic syndrome X and predisposes to the development of type 2 diabetes mellitus. The incidence of obesity, type 2 diabetes mellitus and metabolic syndrome X is increasing, and the cause(s) for this increasing incidence is not clear. Although genetics could play an important role in the higher prevalence of these diseases, it is not clear how genetic factors interact with environmental and dietary factors to increase their incidence. We performed gene expression profile in subjects with obesity and type 2 diabetes mellitus with and without family history of these diseases. It was noted that genes involved in carbohydrate, lipid and amino acid metabolism pathways, glycan of biosynthesis, metabolism of cofactors and vitamin pathways, ubiquitin mediated proteolysis, signal transduction pathways, neuroactive ligand-receptor interaction, nervous system pathways, neurodegenerative disorders pathways are upregulated in obesity compared to healthy subjects. In contrast genes involved in cell adhesion molecules, cytokine-cytokine receptor interaction, insulin signaling and immune system pathways are downregulated in obese. Genes involved in signal transduction, regulation of actin cytoskeleton, antigen processing and presentation, Complement and coagulation cascades, axon guidance and neurodegenerative disorders pathways are upregulated in subjects with type 2 diabetes with family history of diabetes compared to those who are diabetic but with no family history. Genes involved in oxidative phosphorylation, immune, nervous system, and metabolic disorders pathways are upregulated in those with diabetes with family history of diabetes compared to those with diabetes but with no family history. In contrast, genes involved in lipid and amino acid pathways, ubiquitin mediated proteolysis, signal transduction, insulin signaling and PPAR signaling pathways are downregulated in subjects with diabetes with family history of diabetes. It was noted that genes involved in inflammatory pathway are differentially expressed both in obesity and type 2 diabetes. These results suggest that genes concerned with carbohydrate, lipid and amino acid metabolic pathways, neuronal function and inflammation play a significant role in the pathobiology of obesity and type 2 diabetes.

Endocrinology. 2007 Nov; 148(11): 5549-57
Buffat C, Boubred F, Mondon F, Chelbi ST, Feuerstein JM, Lelièvre-Pégorier M, Vaiman D, Simeoni U

In this study, low birth weight was induced in rats by feeding the dams with a low-protein diet during pregnancy. Kidneys from the fetuses at the end of gestation were collected and showed a reduction in overall and relative weight, in parallel with other tissues (heart and liver). This reduction was associated with a reduction in nephrons number. To better understand the molecular basis of this observation, a transcriptome analysis contrasting kidneys from control and protein-deprived rats was performed, using a platform based upon long isothermic oligonucleotides, strengthening the robustness of the results. We could identify over 1800 transcripts modified more than twice (772 induced and 1040 repressed). Genes of either category were automatically classified according to functional criteria, making it possible to bring to light a large cluster of genes involved in coagulation and Complement cascades. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites, suggesting an overrepresentation of the AP1R binding site, together with the transcription induction of factors actually binding to this site in the set of induced genes. The induction of coagulation cascades in the kidney of low-birth-weight rats provides a putative rationale for explaining thrombo-endothelial disorders also observed in intrauterine growth-restricted human newborns. These alterations in the kidneys have been reported as a probable cause for cardiovascular diseases in the adult.