Retransfusion of thoracic wound blood during heart surgery obscures biocompatibility of the extracorporeal circuit.
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Antithrombin III↗
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Novel roles for acylation stimulating protein/C3adesArg: a review of recent in vitro and in vivo evidence.
Recent experimental evidence is shedding more light on the physiological actions of acylation-stimulating protein (ASP)/C3adesArg. The role of ASP in regulating lipid metabolism has primarily focused on its participation in the stimulation of triglyceride synthesis (TGS) and glucose transport. Although there is no doubt that ASP, an adipocyte-produced hormone, plays a key physiological role, accumulating evidence suggests that the effects of ASP go beyond its acute effects on lipid metabolism. In this review, we present novel findings of ASP/C3adesArg effects on preadipocyte differentiation. In 3T3-L1 and 3T3-F442A cells, ASP can substitute for insulin and enhance differentiation as measured by intracellular lipid droplet accumulation, clonal expansion, and increased expression of differentiation markers. Specifically, ASP increased basal TGS by 250% after 9 days differentiation, with similar effects induced by insulin. With ASP treatment, expression of C/EBPdelta was up-regulated early in differentiation (day 2) and decreased thereafter. Expression of PPARgamma and late markers of differentiation, such as adipsin and diacylglycerol acyltransferase-1, were also increased. Effects on clonal expansion were indicated by a twofold increase in [(3)H] thymidine incorporation in 3T3-L1 cells compared to treatment with IBMX + DX alone. Further, the effects of ASP extended beyond adipose tissue to endocrine effects on hormone secretion of insulin (pancreatic cells); cytokines TNFalpha, IL-1beta, and IL-6 (myeloid cells); prolactin, growth hormone, and adrenocorticotropin (pituitary cells). Finally, the potential implication of C5L2, the newly discovered ASP receptor, and its expression profile in various tissues are discussed relative to ASP function.
Adipocytes↗
Complement activation and high-dose of interleukin-2.
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Adult↗
Enhanced glial activation and expression of specific CNS inflammation-related molecules in aged versus young rats following cortical stab injury.
Aging is associated with increased glial responsiveness that may enhance the brain's susceptibility to injury and disease. To determine whether unique age-related molecular responses occur in brain injury, we assessed mRNA levels of representative central nervous system (CNS) inflammation-related molecules in young (3 months) and aged (36 months) Fisher 344/Brown Norwegian F1 hybrid rats following cortical stab. Enhanced glial activation in older animals was accompanied by increased expression of a subset of inflammation-related mRNAs, including IL-1beta, TNFalpha, IL-6, ICAM-1, inducible nitric oxide synthase (iNOS), metalloproteinase-9 (MMP-9), and complement 3alpha-chain 1 (C3alpha1). Recognition of these age-specific differences may guide development of novel treatment regimes for older individuals.
Aging↗
Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues.
We have investigated the difference in gene expression of six proteins secreted by adipocytes in paired biopsies from visceral and abdominal subcutaneous adipose tissue in nine individuals with various degrees of obesity. The mRNAs levels of leptin, TNFalpha, angiotensinogen, acylation stimulating protein (ASP), cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP) were quantified by RT-competitive PCR. ASP and angiotensinogen mRNA levels were higher in the visceral fat, whereas the mRNA levels of leptin and CETP were higher in the subcutaneous depot. TNFalpha mRNA expression was similar in the two sites. For angiotensinogen, the difference was more pronounced in the subjects with body mass index (BMI) lower than 30 kg/m(2) whereas for ASP, CETP and leptin, the difference was observed regardless the BMI of the subjects. PLTP mRNA levels in subcutaneous, but not in the visceral, adipose tissue were positively related to the BMI of the subjects. These results strongly suggest that visceral and subcutaneous adipocytes may have different properties in the production of bioactive molecules.
Adipocytes↗
Early onset of rejection in concordant hamster xeno hearts display signs of necrosis, but not apoptosis, correlating to the phosphocreatine concentration.
BACKGROUND: The importance of apoptosis contra necrosis for ischemia/reperfusion (RP) and acute rejection in concordant rodent xenotransplantation is largely unknown. We explored this question by comparing rodent allo and concordant xenotransplants with different morphological methods to detect apoptosis and biochemical data on the levels of high-energy phosphates obtained with in vitro 31Phosphorous Magnetic Resonance Spectroscopy (31P MRS). More specifically, we applied a hitherto unused method in transplantation research, apoptosis specific biotin labeled oligonucleotides designed with a 10 base pair stem region and a 20 nucleotides large loop that form a hairpin like shape. The results obtained with this method were compared to results obtained with the more widely used in situ 3'-end labeling of DNA (TUNEL) assay and extraction and gel electrophoresis of labeled DNA (DNA laddering). METHODS: Cervical heart transplantations were performed between inbred Lewis (L) (RT1l) to L, L to DA (RT1a) rats, hamster (H) to H and H to L (X) (n=5 for all groups except for X, n=9). All hearts were subjected to 30 min of cold ischemia (+4 degrees C) and 6 h of RP before explantation. In vitro 31P MRS was used to determine the phosphocreatine (PCr), beta-adenosine triphosphate (beta-ATP) concentrations and the PCr/beta-ATP ratio of the transplants. We correlated the biochemical data to haematoxylin and eosin (H & E) stained tissue slides scored for rejection, infiltration of antibodies and complement depositions, DNA extraction and gel electrophoresis of labeled DNA (DNA laddering), in situ 3'-end labeling of DNA (TUNEL) and the apoptosis specific hairpin probe assays scoring. RESULTS: The rejection score of the xeno grafts differed significantly compared to their syngeneic hamster to hamster controls (2.40 +/- 0.25 vs. 1.20 +/- 0.20; P=0.005) and they had a significantly higher TUNEL score, 228 +/- 15 vs. 2.44 +/- 0.32 (P=0.009), that correlated to changes in PCr concentration (P<0.001) and to the PCr/beta-ATP ratio (P=0.01). The uptake was mainly (90-95%) located to 1-2 microm large extra cellular 'granule'. A picture resembling early necrosis was seen on the H & E stainings and reflected in the Billingham rejection score above. CONCLUSIONS: After 6 h of RP the onset of acute rejection in the concordant hamster xeno hearts displayed features of early, possibly mitochondrial, necrosis, but not apoptosis, which correlated to changes in the PCr concentration and the PCr/beta-ATP ratio. The mechanism for the early rejection observed is unclear and might be caused by other factors in the sera apart from cellular components, antibodies and complement factors. Identification of the underlying mechanisms could enable us to design rational therapies that prevent activation of the recipient's innate immune response.
Adenosine Triphosphate↗
von Willebrand factor and urinary albumin excretion are possible indicators of endothelial dysfunction in cardiopulmonary bypass.
OBJECTIVE: Experimental evidence suggests that cardiopulmonary bypass (CPB) associated inflammatory response leads to endothelial injury and increased permeability, but this has been difficult to show clinically. We have investigated the use of von Willebrand factor (vWF), and urinary albumin excretion, as measured by the urinary albumin creatinine ratio (ACR), to demonstrate this. METHODS: A total of 23 patients undergoing elective coronary artery bypass grafting were studied. Complement fragment C3a, leukotrienne B4 (LTB4), interleukin 6 (IL6), neutrophil elastase, vWF and ACR were measured on anaesthetic induction (baseline), 20 min after starting CPB, 5 min after cross-clamp removal, 5 min, 2, 6 and 24 h after termination of CPB. Anaesthetic, CPB and myocardial protection techniques were standardised. ANOVA was performed by using the distribution free Friedman test for each measured parameter. When significance differences were found (P < 0.05), post hoc analysis with Wilcoxon signed rank test was used for comparison of each time point with the base line level and differences were only accepted as significant following the Bonferroni correction (P < 0.008). Summary measures of peak versus peak and area under the cure were also analysed for ACR with vWF. RESULTS: Peak vs. baseline levels for C3a were 4.9 vs. 2.1 microg/ml (P < 0.0001), LTB4 was 800 vs. 20 pg/ml (P < 0.0001), neutrophil elastase was 250 vs. 115 ng/ml (P < 0.001), IL6 was 620 vs. 1.4 pg/ml (P < 0.0001), vWF was 2.2 vs. 1.3 IU/ml (P < 0.0001) and ACR was 17.6 vs. 2.0 mg/mmol (P < 0.0001). C3a, LTB4 and ACR peaked during the operation. Neutrophil elastase peaked at 2 h following CPB. IL6 and vWF peaked at 6 h following CPB. The correlation coefficient between vWF and ACR following peak versus peak analysis was 0.48 (P = 0.035), and area under the curve analysis was 0.6 (P < 0.01). CONCLUSION: These results demonstrate that endothelial permeability and injury, as measured by urinary albumin excretion and vWF, respectively, are related and the use of these easily detectable and sensitive biochemical markers warrants further investigation.
Aged↗
Purification and characterization of acylation stimulating protein from porcine serum.
A method for purifying acylation stimulating protein (ASP) from porcine serum is described. The mRNA encoding ASP was cloned by reverse transcriptase-polymerase chain reaction which predicted a 76 residue peptide. Based on this sequence, we generated antisera to a C-terminal peptide (ASP(1-20)) which aided ASP purification. Identity of the purified protein was verified by N-terminal sequencing. The molecular mass of porcine ASP is 8926. Porcine ASP stimulated esterification of fatty acid into triacylglycerol in cultured human cells with potency similar to that of human ASP (twofold at 5 microM). Based on this evidence that ASP exists in porcine blood, and that it has acylation stimulating activity, we propose that ASP may play a role in regulation of energy storage in adipose tissue in the pig.
Amino Acid Sequence↗
Cloning of hibernation-related genes of bullfrog (Rana catesbeiana) by cDNA subtraction.
Seven genes specifically expressed during hibernation in the bullfrog (Rana catesbeiana) were cloned from a subtracted cDNA library constructed from livers of winter bullfrogs. Those genes were fibrinogen alpha-subunit, fibrinogen gamma-subunit, complement component C3, alpha-1-microglobulin/bikunin precursor (AMBP), transferrin, apoferritin middle subunit and one novel gene. Northern hybridization has indicated that these seven genes were specifically induced or enhanced in winter. Above all, expression of the novel gene was specifically induced in winter in liver, though the expression of that was neither induced in bullfrog nor Xenopus laevis by cold treatment. The novel gene, which was designated as rc-hirp (Rana catesbeiana hibernation-related protein), encoded 420 base pairs length and a putative protein of 139 amino acid residues. Annual analyses of the expression of these genes have suggested that the seven winter-specific genes are playing an important role in hibernation processes.
Amphibian Proteins↗
Improvement in the long-term stability of an amperometric glucose sensor system by introducing a cellulose membrane of bacterial origin.
Classical amperometric glucose sensors that use cellulose membranes of wood origin (Cuprophan) suffer from the fact that their long-term stability in blood is short; therefore, their clinical use is limited. In the present study, a classical amperometric glucose sensor was covered with a bacterial cellulose (BC) membrane. Its surface in comparison to that of the classical glucose sensor (Cuprophan) and its long-term stability were tested in vitro and in vivo. The surface element composition was approximately 44% oxygen and approximately 56% carbon in both membranes and thus typical for cellulose. BC membranes exhibited fiber structure, whereas cup membranes did not. There was also a qualitative difference in protein adsorption between both membranes on exposure to bovine serum albumin. Treatment with Trogamid of one site of the BC membranes allowed linear glucose detection between 0 and 40 mM. Hemocompatibility of BC membranes was improved in comparison to cup membranes on the basis of complement activation (C3a and C5a). In diluted blood (1:10), the BC-covered sensor exhibited a long-term stability of more than 200 h; in undiluted blood it was stable for about 24 h, which is about 6-7 times longer than the stability of the classical Cup membrane-covered sensor. In in vivo studies, where the BC membrane-covered sensors were connected to the jugular vein of rats, blood glucose levels could be monitored for at least 24 h. In summary, the use of a modified bacterial cellulose membrane to cover the classical amperometric glucose sensor significantly improves the sensor's long-term stability both in vitro and in vivo.
Acetobacter↗
Blood interactions with plasticized poly(vinyl chloride): relevance of plasticizer selection.
An investigation has been made of blood interactions with plasticized poly(vinyl chloride) (PVC) biomaterials in tubular form, taking into account the influence on the blood response of the polymer, antithrombotic agent, blood condition and test procedure. In vitro and ex vivo procedures were used to achieve a comparison between PVC plasticized with di- (2-ethylhexyl)phthalate (DEHP) and with tri-(2-ethylhexyl)trimellitate (TEHTM). The blood response was monitored in terms of the measurement of fibrinogen adsorption capacity, thrombin-antithrombin III complex (TAT) and the complement component C3a. Surface characterization of the polymers was performed by X-ray photoelectron spectroscopy (XPS). The data obtained indicate that in comparison with DEHP-PVC, there is a higher reactivity for TEHTM-PVC, which correlates with the plasticizer distribution at the polymer surface.
Journal Article↗
Biocompatibility of dialysis membranes: effects of chronic complement activation.
The ability of three dialysis membranes (cuprophane, cellulose acetate, and polymethylmethacrylate) to activate complement was studied prospectively in ten chronic dialysis patients using new and reused membranes. Patients were dialyzed for 1 month with each type of membrane. New cuprophane membranes caused the most intense activation, while polymethylmethacrylate (PMMA) surfaces caused the least degree of complement activation. Reuse decreases the capacity of the cuprophane membrane to activate complement but does not significantly alter the capacity of cellulose acetate membranes. The extent of complement activation paralleled the ability of these membranes to induce neutropenia. Recurrent dialysis with new cuprophane and cellulose acetate membranes leads to a decrease in pre-dialysis and "rebound leukocytosis" neutrophil count, as well as a more intense activation of complement and an enhanced endogenous clearance of products of complement activation. The clinical sequelae of recurrent complement activation are discussed.
Biocompatible Materials↗
Acute intradialytic well-being: results of a clinical trial comparing polysulfone with cuprophan. Bergamo Collaborative Dialysis Study Group.
We conducted a multicenter, randomized, double-blind, controlled clinical trial to compare the effects of a synthetic, high-flux polysulfone membrane with a standard cuprophan one on acute clinical complications during a diffusive dialysis procedure. The principal end-point, that is, the number of hypotensive episodes, was similar in polysulfone (39; 23.8%) and cuprophan (32; 19.5%). Likewise, no significant difference was found between the two membranes as far as the secondary end-point was concerned, that is, the effect on headache, nausea, pruritus and sense of well-being. We conclude that high-flux polysulfone, acutely used in standard diffusive dialysis, has no favorable influence on hypotensive episodes and does not affect some typical dialysis-related symptoms any differently from cuprophan membrane. The need is stressed for well-controlled studies specifically designed to assess the worth of new dialysis techniques and materials that may vastly raise the cost of dialysis treatment.
Adolescent↗
Platelet-leukocyte aggregation during hemodialysis.
Hemodialysis is associated with simultaneous changes in leukocytes and platelets, but it is unclear whether these alterations affect the interactions between these cell types. To evaluate this process, we examined the appearance of platelet specific antigens (CD41) on leukocytes as an index of platelet-leukocyte aggregation during hemodialysis using three different synthetic membranes. Patients with end-stage renal disease (ESRD) on long-term hemodialysis treatment were enrolled. Flow cytometric techniques and platelet specific monoclonal antibodies (MoAb) that recognize the glycoprotein complex on resting and activated platelets (anti-CD41), the activated GPIIb-IIIa complex receptor (anti-LIBS1), and the p selectin GMP140, that is exposed on platelet plasma membrane after activation and platelet degranulation (anti-CD62), were used. Subjects with ESRD had a lower predialysis platelet surface expression of CD41 and LIBS1 compared to normal controls, but unchanged CD62 expression. In parallel, patients with ESRD manifested a uniformly reduced platelet-leukocyte microaggregates predialysis compared to normal controls. When examined across the dialyzer, however, an increase in platelet-neutrophil and platelet-monocyte microaggregates was observed with all three synthetic membranes at both 15 and 30 minutes after initiation of dialysis. This phenomenon could be duplicated in vitro by physiologic concentrations of the platelet specific agonist ADP, but not by the complement factors C3a or C5a. We conclude that platelet-leukocyte aggregates occur during dialysis likely related to a primary platelet activation mechanism. This phenomenon may serve as a new biocompatibility parameter and may shed light on some of the biologic consequences of hemodialysis.
Adolescent↗
Bivariate linkage between acylation-stimulating protein and BMI and high-density lipoproteins.
OBJECTIVE: Given the importance of visceral adiposity in the metabolic syndrome, whether levels of adipokines have shared genetic effects (pleiotropy) with aspects of the metabolic syndrome should be addressed. Acylation-stimulating protein (ASP), an adipose-derived protein, influences lipid metabolism, obesity, and glucose use. Therefore, our objective was to examine the genetic regulation of ASP and associated pleiotropic effects. RESEARCH METHODS AND PROCEDURES: We assayed serum ASP levels in 435 Mexican Americans participating in the San Antonio Family Heart Study and performed univariate and bivariate variance components analysis. RESULTS: Additive genetic heritability of ASP was 26% (p = 0.0004). Bivariate genetic analysis detected significant genetic correlations between ASP and several lipid measures but not between ASP and adiposity or diabetes measures. We detected two potential quantitative trait loci influencing ASP levels. The strongest signal was on chromosome 17 near marker D17S1303 [log of the odds ratio (LOD) = 2.7]. The signal on chromosome 15 reached its peak near marker D15S641 (LOD = 2.1). Both signals localize in regions reported to harbor quantitative trait loci influencing obesity and lipid phenotypes in this population. Bivariate linkage analysis yielded LODs of 4.7 for ASP and BMI on chromosome 17 and 3.2 for ASP and high-density lipoprotein2a on chromosome 15. DISCUSSION: Given these findings, there seems to be a significant genetic contribution to variation in circulating levels of ASP and an interesting pattern of genetic correlation (i.e., pleiotropy) with other risk factors associated with the metabolic syndrome.
Adolescent↗
ASP stimulates glucose transport in cultured human adipocytes.
OBJECTIVE: The purpose of the present study was to examine the effect of Acylation Stimulating Protein (ASP) on glucose transport in cultured subcutaneous adipocytes. DESIGN AND SUBJECTS: Subcutaneous adipose tissue was obtained from non-obese, healthy females (18-32 y old) undergoing mammoplasty reduction. Preadipocytes were isolated and differentiated into adipocytes. MEASUREMENTS: Following the exposure of preadipocytes and adipocytes to ASP or insulin, glucose transport was assessed as [3H] 2-deoxy glucose uptake. The measurements were normalised per total cell protein. RESULTS: ASP increases specific membrane glucose transport in both preadipocytes and adipocytes in a time and concentration dependent manner. Stimulation in both cell types is rapid (within minutes), reaching a maximal effect between 1 and 4 h. However, after 24 h exposure to ASP, there is a downregulation in the response. The ASP response is greater following differentiation of preadipocytes to adipocytes and is compared to that of insulin. Dose response studies demonstrated a five-fold greater sensitivity of adipocytes (half-maximal concentration of ASP on adipocytes = 0.5 microM, preadipocytes = 2.3 microM). CONCLUSION: These results demonstrate that ASP not only stimulates triglyceride synthesis, but also glucose transport in differentiated human adipocytes and is consistent with a physiologically important role for ASP in postprandial energy storage.
Adipocytes↗
Acylation stimulating protein (ASP) acute effects on postprandial lipemia and food intake in rodents.
BACKGROUND: In vitro studies have shown that acylation stimulating protein (ASP) stimulates triglyceride (TG) synthesis and storage in adipocytes. We have previously demonstrated that intraperitoneal (i.p.) injection of ASP in C57BL/6J mice accelerated TG clearance following an orally-administered fat load as well as reducing postprandial glucose levels. RESULTS: In the present study, we first examined the effect of i.p. and intracerebroventricular (i.c.v.) injection of ASP on food intake in Sprague-Dawley rats. Intraperitoneal injection resulted in a short-term increase in food intake (maximum increase 29.3% within the first hour, P<0.025) decreasing thereafter as compared to vehicle alone. i.c.v. Administration of a comparable dose of ASP resulted in a similar but delayed increase in food intake with a maximum at 2-4 h, suggesting that the actions of ASP are peripherally mediated. However, there was no significant difference in 24 h food intake with either i.p. or i.c.v. injection. We also examined the effects of ASP on TG clearance in two obese mouse strains with different metabolic profiles: ob/ob (C57BL/6J-Lep(ob)) and db/db (C57BLKS/J-Lepr(db)). In a crossover design, the response to an oral fat load was determined with and without i.p. injection of exogenous ASP. In ob/ob mice, there was a 44% greater clearance of postprandial TG (area under the curve (AUC)=245+/-49 control vs 138+/-43 mg/dl h with ASP; P<0.05 by RM ANOVA). The db/db mice showed a greater response, with a 62% decrease in postprandial TG (AUC=4080+/-1489 control vs 1540+/-719 mg/dl h with ASP; P=0.004 by RM ANOVA). In addition there were decreases in postprandial glucose and non-esterified fatty acid (NEFA) levels in response to ASP. CONCLUSION: These results are the first to report that ASP can increase food intake in rats and also enhance postprandial TG clearance in obese animals. These data therefore support previous in vitro evidence pointing to ASP as a regulator of lipid metabolism.
Animals↗
Acylation stimulating protein stimulates insulin secretion.
Acylation stimulating protein (ASP) is a hormone produced by adipocytes and is of importance for the storage of energy as fat. We examined whether ASP might also have effects on islet function. In clonal INS-1 cells, ASP dose-dependently augmented glucose-stimulated insulin secretion. The lowest effective dose of ASP at 10 mmol/l glucose was 5 micro mol/l. The effect was glucose-dependent because ASP did not increase insulin secretion at 1 mmol/l glucose but had clear effect at 10 and 20 mmol/l glucose. Similarly, ASP augmented glyceraldehyde-induced insulin secretion but the hormone did not enhance insulin secretion in response to depolarization by 20 mmol/l of KCl. ASP-induced insulin secretion was completely abolished by competitive inhibition of glucose phosphorylation by glucokinase with 5-thio-glucose and was partially inhibited by the calcium channel blocker, nifedipine, and by the protein kinase C inhibitor, GF109203. Furthermore, thapsigargin, an inhibitor of Ca(2+)-ATPase in the endoplasmic reticulum, did not affect ASP-induced insulin secretion. ASP (>5 micro mol/l) also augmented glucose-stimulated insulin secretion from islets isolated from C57BL/6J mice, and intravenous administration of ASP (50 nmol/kg) augmented the acute (1 and 5 min) insulin response to intravenous glucose (1 g/kg) in C57BL/6J mice. This was accompanied by an increased rate of glucose disposal. Minimal model analyses of data derived from the intravenous glucose tolerance test revealed that whereas ASP augmented insulin secretion, the hormone did not affect insulin sensitivity (S(I)) or glucose effectiveness (S(G)). We conclude that ASP augments glucose-stimulated insulin secretion through a direct action on the islet beta cells. The effect is dependent on glucose phosphorylation, calcium uptake and protein kinase C. Stimulation of insulin secretion by ASP in vivo results in augmented glucose disposal.
Animals↗