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PubMed2006

Composition effect on peptide interaction with lipids and bacteria: variants of C3a peptide CNY21.

The effect of peptide hydrophobicity and charge on peptide interaction with model lipid bilayers was investigated for the C3a-derived peptide CNY21 by fluorescence spectroscopy, circular dichroism, ellipsometry, z-potential, and photon correlation spectroscopy measurements. For both zwitterionic and anionic liposomes, the membrane-disruptive potency for CNY21 variants increased with increasing net positive charge and mean hydrophobicity and was completely lost on elimination of all peptide positive charges. Analogous effects of elimination of the peptide positive net charge in particular were found regarding bacteria killing for both Pseudomonas aeruginosa and Bacillus subtilis. The peptides, characterized by moderate helix content both in buffer and when attached to the liposomes, displayed high adsorption for the net positively charged peptide variants, whereas adsorption was non-measurable for the uncharged peptide. That electrostatically driven adsorption represents the main driving force for membrane disruption in lipid systems was also demonstrated by a drastic reduction in both liposome leakage and peptide adsorption with increasing ionic strength, and this salt inactivation can be partly avoided by increasing the peptide hydrophobicity. This increased electrolyte resistance translates also to a higher antibacterial effect for the hydrophobically modified variant at high salt concentration. Overall, our findings demonstrate the importance of the peptide adsorption and resulting peptide interfacial density for membrane-disruptive effects of these peptides.

Adsorption↗
PubMed2005

C5L2 is a functional receptor for acylation-stimulating protein.

C5L2 binds acylation-stimulating protein (ASP) with high affinity and is expressed in ASP-responsive cells. Functionality of C5L2 has not yet been demonstrated. Here we show that C5L2 is expressed in human subcutaneous and omental adipose tissue in both preadipocytes and adipocytes. In mice, C5L2 is expressed in all adipose tissues, at levels comparable with other tissues. Stable transfection of human C5L2 cDNA into HEK293 cells results in ASP stimulation of triglyceride synthesis (TGS) (193 +/- 33%, 5 microM ASP, p < 0.001, where basal = 100%) and glucose transport (168 +/- 21%, 10 microM ASP, p < 0.001). C3a similarly stimulates TGS (163 +/- 12%, p < 0.001), but C5a and C5a des-Arg have no effect. The ASP mechanism is to increase Vmax of glucose transport (149%) and triglyceride (TG) synthesis activity (165%) through increased diacylglycerolacyltransferase activity (200%). Antisense oligonucleotide down-regulation of C5L2 in human skin fibroblasts decreases cell surface C5L2 (down to 54 +/- 4% of control, p < 0.001, comparable with nonimmune background). ASP response is coordinately lost (basal TGS = 14.6 +/- 1.6, with ASP = 21.0 +/- 1.4 (144%), with ASP + oligonucleotides = 11.0 +/- 0.8 pmol of TG/mg of cell protein, p < 0.001). In mouse 3T3-L1 preadipocytes, antisense oligonucleotides decrease C5L2 expression to 69.5 +/- 0.5% of control, p < 0.001 (comparable with nonimmune) with a loss of ASP stimulation (basal TGS = 22.4 +/- 2.9, with ASP = 39.6 +/- 8.8 (177%), with ASP + oligonucleotides = 25.3 +/- 3.0 pmol of TG/mg of cell protein, p < 0.001). C5L2 down-regulation and decreased ASP response correlate (r = 0.761, p < 0.0001 for HSF and r = 0.451, p < 0.05 for 3T3-L1). In HEK-hC5L2 expressing fluorescently tagged beta-arrestin, ASP induced beta-arrestin translocation to the plasma membrane and formation of endocytic complexes concurrently with increased phosphorylation of C5L2. This is the first demonstration that C5L2 is a functional receptor, mediating ASP triglyceride stimulation.

Animals↗
PubMed1993

Beta 2-microglobulin generation and removal in long slow and short fast hemodialysis.

We studied the influence of different modes of hemodialysis (HD) on plasma levels of beta 2-microglobulin (P-beta 2-m) and its correlation to changes in leukocyte count, complement activation (C3a), and elastase generation. The influence of dialyzer membrane, membrane surface area, duration of treatment, and blood flow was analyzed with respect to post-HD levels of P-beta 2-m. Twenty patients underwent 12 modes of bicarbonate hemodialysis in random order (n = 252) using three different membranes (Cuprophan [CU], hemophan [HE], or polyamide [PA], two dialyzer areas, and fast (400 mL/min) or slow (200 mL/min) blood flow (Qb) for 2 or 4 hours, respectively. All dialysate was collected and beta 2-m was analyzed (D-beta 2-m). After correction for hemoconcentration, P-beta 2-m concentrations were found to have decreased significantly during treatment with all three membranes (CU, 0.9 +/- 0.3 mg/L, P = 0.002; HE, 1.2 +/- 0.3 mg/L, P < 0.001; and PA, 8.3 +/- 0.3 mg/L, P < 0.001). Elimination of P-beta 2-m was influenced by type of membrane (P < 0.001) and ultrafiltration volume (P = 0.0019) but not by membrane area or Qb. The largest reduction in P-beta 2-m (-10.4 mg/L) was achieved by the following treatment combination: PA membrane, large dialyzer area, and low Qb for 4 hours. P-beta 2-m decreased more during PA dialysis at low Qb for 4 hours (-9.9 +/- 0.5 mg/L) than during high Qb for 2 hours (-6.8 +/- 0.5 mg/L, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

The effects of cholesterol-3-sulfate (CH-3S) on the phosphorylation of human C3a (hC3a) in vitro and on the ability of hC3a to induce vascular permeability in rats.

The phosphorylation of human C3a (hC3a, anaphylatoxin) by two distinct protein kinases (PKA and CK-I) and the effect of cholesterol-3-sulfate (CH-3S) on this phosphorylation were biochemically investigated in vitro. It was found that (i) hC3a functions as a phosphate acceptor for PKA and CK-I, but not for CK-II; (ii) the CK-I-mediated phosphorylation of hC3a requires the presence of 3 microM CH-3S in a manner similar to the phosphorylation of HMG1 (CH-3S-binding protein) by CK-I; and (iii) CH-3S inhibits the PKA-mediated phosphorylation of hC3a in a dose-dependent manner (ID50=approximately 2 microM). As expected, hC3a containing high levels of Arg- and Lys-residues stimulated approx. 3-fold CK-II activity (phosphorylation of alpha-casein) in vitro. However, no significant effect of hC3a on CK-II activity was observed when hC3a was preincubated with CH-3S or fully phosphorylated by PKA in vitro. Furthermore, preincubation of hC3a with CH-3S diminished the ability of hC3a to induce vascular permeability in rats. The results provided here suggest that (i) hC3a is a CH-3S-binding protein; and (ii) CH-3S functions as a potent inhibitor for its physiological activities, including phosphorylation by PKA and CK-I, in vitro.

Animals↗
PubMed1985

Effects of the C5a anaphylatoxin and its relationship to cyclo-oxygenase metabolites in rabbit vascular strips.

Strips of rabbit blood vessels were suspended in vitro and responses to complement peptides C3a and C5a were recorded isotonically. Human C3a (up to 1.5 microM) was inactive on rabbit vascular strips. Human C5a (2.9-59 nM) decreased spontaneous activity of the rabbit portal vein under resting baseline tension. The C5a relaxed strips of portal vein and pulmonary artery that were precontracted with noradrenaline (NA, 200 nM). On the portal vein, C5a-induced relaxation was preceded by a transient contractile phase which decreased with repeated applications of C5a. The magnitude of C5a-induced relaxation of both vessels increased with repeated stimulation by C5a. Maximal levels of relaxation for the third application of C5a at 59 nM averaged 44% and 17% of the NA-induced contraction plateau in portal vein and pulmonary artery, respectively. Strips of rabbit aorta responded minimally to C5a. Indomethacin (5.6 microM) significantly inhibited C5a-induced relaxation of the portal vein and pulmonary artery but had no effect on the early contractile response of the portal vein. Mepyramine (10 microM) failed to modify the C5a response from either vessel, but it reduced the contractile phase of the C5a response on the portal vein when applied in conjunction with indomethacin. The drug SKF 88046, an end organ antagonist of thromboxane (TX) A2 and some contractile prostaglandins, reduced the contractile phase and increased relaxation of the portal vein to C5a but did not modify the response of the pulmonary artery. Radioimmunoassays for 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and TXB2 were performed on the fluid bathing rabbit isolated blood vessels. C5a promoted release of 6-keto-PGF1, over the basal release rate in rabbit tissues. Only trace quantities of TXB2 were produced by rabbit vessels exposed to C5a. 7 It is concluded that the mechanical response of blood vessels to C5a is mainly determined by the type of cyclo-oxygenase products released and by the sensitivity of each blood vessel to these active lipids. Tissue histamine release is also responsible for a component of the response of rabbit portal vein to C5a. The relaxant effect of C5a on rabbit blood vessels may be a phenomenon related to the previously reported hypotensive action of classical anaphylatoxins in vivo.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Fasting and postprandial plasma concentrations of acylation-stimulation protein (ASP) in lean and obese Pima Indians compared to Caucasians.

OBJECTIVE: ASP stimulates the clearance of free fatty acids (FFA) from the circulation and the synthesis of triglycerides (TG) in adipose tissue. We tested whether fasting and post-prandial plasma ASP concentrations are increased in Pima Indians, a population with a very high prevalence of obesity, but a remarkably low prevalence of dyslipidemia. RESEARCH METHODS AND PROCEDURES: Plasma concentrations of ASP, TG, FFA, total cholesterol (CHOL), and insulin (INS) were measured in 15 Pima Indians (P) and 15 Caucasians (C) closely matched for age, sex, and body weight [7 lean and 8 obese subjects, body mass index (BMI) cut-off 30 kg/m2], before and for 4 hours after a standard mixed meal (20% of daily caloric requirements, 41% carbohydrate, 44% fat, 15% protein). RESULTS: Fasting ASP was positively related to percent body fat (dual energy X-ray absorptiometry; r=0.49, p<0.01) and to TG and FFA, independently of percent body fat (partial r = 0.42 and 0.46, respectively, both p<0.05). There were no differences in fasting TG, FFA, CHOL, INS, or ASP between lean C and lean P. In contrast, obese P had lower TG, lower CHOL, higher INS and, on average, 27% lower ASP compared to obese C. The ethnic difference in ASP remained after adjustment for TG, FFA, and percent body fat. ASP decreased in response to the meal in all four groups with no differences between groups. There was a significant inverse correlation between preprandial ASP and the change in FFA 60 minutes after the meal (r=-0.56, p<0.001). DISCUSSION: Pima Indians do not have higher plasma ASP concentrations than Caucasians. Whether other alterations in the ASP-pathway, such as increased sensitivity of adipocytes to ASP, contribute to the high prevalence of obesity and low prevalence of dyslipidemia in Pima Indians, remains to be elucidated.

Adult↗
PubMed1988

Treatment of hypercholesterolemia by chemical adsorption of lipoproteins.

Dextran sulfate (Mr 5,000) was covalently linked to porous cellulose beads, and the dissociation constant (Kd) and the maximum binding level (S) of the beads were calculated for the human plasma lipoproteins VLDL, LDL, and HDL. The S values for VLDL and LDL were 2 and 7 g cholesterol/liter of the wet beads and that for HDL was almost negligible, although the apparent Kd were all in the same order. In fact, LDL and VLDL were exclusively adsorbed by the beads from human plasma in vitro. Bound LDL was desorbed with 0.35 M NaCl. The beads were packed in a column (25-ml) and used with polysulfone hollow fibers in experimental LDL-apheresis for WHHL rabbits; LDL cholesterol was reduced from 500 to 200 mg/dl, while HDL, total plasma protein, and major blood cell counts did not change. For LDL apheresis of familial hypercholesterolemia, the sorbent column, 400-ml, was used with the polysulfone hollow fiber filter. The maximum removal of LDL + VLDL cholesterol was 6 to 8 g with a single column resulting in its reduction by 250 to 300 mg/dl after 3.5 liters plasma treatment. Adsorption was negligible with albumin, HDL, IgA, G, M, apoA-I, A-II, C-II, enzymes, and electrolytes. Activated complement fragments, C3a and C5a, were completely adsorbed. By periodic removal of LDL, an increase of HDL cholesterol was observed in some cases. In order to increase LDL removal in a single treatment and to reduce the extracorporeal circulation volume, two small columns (150 ml each) were used alternatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Acylation stimulating protein (ASP), an adipocyte autocrine: new directions.

Acylation stimulating protein (ASP) is an adipocyte-derived protein which has potent anabolic effects on human adipose tissue for both glucose and free fatty acid (FFA) storage. Our hypothesis is that: (i) ASP is produced by adipocytes in specific response to stimuli that initiate efficient fat storage; (ii) ASP interacts with a specific adipocyte receptor triggering an intracellular signalling pathway which activates triglyceride synthesis and fat storage; and (iii) that absence (ASP knockout mouse) or excess (in normal or obese mice) of ASP will result in physiological changes of plasma fat clearance and adipose tissue metabolism. The present review focuses on advances in ASP within the last 2 years with particular emphasis on these three aspects of ASP.

Adipocytes↗
PubMed1980

Immune complexes in multiple sclerosis: relation to clinical pattern.

Using a C1q binding test, circulating immune complexes (IC) were detected in 33.3% of sera from 138 patients and in 19.4% of 124 spinal fluid samples from patients with multiple sclerosis. Most often they occur in sera alone. As a rule their detectable amount is small in sera as well as in spinal fluids. IC were observed with equal frequency during acute exacerbations and in stable phases of the disease. In patients with early MS of less than 3 months duration, IC were detected only rarely, whereas their frequency increased up to 50% in patients with longer standing disease. Immunosuppressive therapy has no influence on IC formation. Patients with immune complexes exhibited a more rapid clinical deterioration if compared as a group with IC-negativ ones. No correlations were found between immune complex formation and the CSF-IgG index or the rate of pleocytosis in spinal fluids. Neither the complement factors C3, C4, C3A nor total hemolytic complement activities (CH50) in serum were significantly decreased in patients with IC formation in serum as compared with the IC-negative group. The results demonstrate that IC formation probably is of no importance in the pathogenesis of multiple sclerosis.

Acute Disease↗
PubMed1989

Complement-derived polypeptide C3adesArg as a mediator of inflammation at the blood-brain barrier in a new experimental cat model.

The effect of the complement-derived polypeptide C3adesArg as a mediator of inflammation in the central nervous system was examined. Twenty-five anesthetized cats received 4 mg of this polypeptide by intraventricular injection, 20 cats who served as controls received saline. Cerebrospinal fluid (CSF) was sampled 3 h after intraventricular injection and the brains were removed. For assessment of the permeability of the blood-brain barrier the CSF penetration of four antibiotics, which were given intravenously was measured. Five control animals were employed for each antibiotic (tobramycin, ampicillin, imipenem, fosfomycin), whereas six C3adesArg-treated animals were used for each antibiotic and seven for tobramycin. Besides CSF levels of glucose, the prostanoids 6-keto-prostaglandin F1 alpha, thromboxane B2 and prostaglandin E2 were measured. The morphological examinations in the CSF sediments and histological brain sections in the C3adesArg-treated animals disclosed a distinct inflammation with leptomeningeal and perivascular infiltration of polymorphonuclear granulocytes compared to normal findings in the controls. The CSF/serum ratios of all of the antibiotics were markedly elevated compared to controls, indicating a blood-brain barrier disruption. The levels of all prostanoids were significantly higher in the treatment group than in the control group, whereas the glucose levels were lower. These findings are in accordance with a granulocytic meningitis as seen in some infections at the acute stage. It is concluded that C3adesArg acts as a mediator of inflammation in the central nervous system.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

C1-inhibitor substitution therapy in septic shock and in the vascular leak syndrome induced by high doses of interleukin-2.

C1-inhibitor (C1-INH) is the major plasma inhibitor of the complement and contact systems. Activation of either system has been shown to occur in patients with septic shock and is associated with a poor outcome. Functional levels of C1-INH tend to be normal in septic patients although paradoxically this inhibitor is an acute phase protein. Moreover, levels of proteolytically inactivated C1-INH are increased in sepsis pointing to an increased turn-over. These observations suggest a relative deficiency of biologically active C1-INH in sepsis. Complement and contact activation have also been shown to occur in the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2), which syndrome may be regarded as a human model for septic shock. The similarity between VLS and sepsis encompasses more than complement and contact activation since a number of other inflammatory mediators considered to play a role in the pathogenesis of septic shock, are also involved in the development of VLS. The role and the mechanisms of complement and contact activation in sepsis and in the VLS are reviewed in this paper. Initial results of intervention therapy with high doses of C1-INH in these syndromes are also reported. It is concluded that high doses of C1-INH can be safely administered to patients with septic shock or with the VLS and may attenuate complement and contact activation in these conditions. Double-blind controlled studies are needed to definitely proved these effects and to establish whether this treatment is able to reduce mortality and morbidity of these syndromes.

Blood Coagulation↗
PubMed1993

Bioreactor based on suspended particles of immobilized enzyme.

A bioreactor for blood detoxification was developed in which oscillation-induced secondary flows suspend particles of immobilized enzyme in a reactor operating at clinically useful flowrates. Torsional oscillation of the reactor about its axis created a pair of counterrotating toroidal vortices which were readily observed in flow-visualization studies. Oscillation frequencies were selected to provide spatially uniform particle dispersion, as assessed visually. As a model system, blood deheparinization by reactors containing heparinase immobilized to agarose particles was investigated. Identical deheparinization profiles were observed in the continuous-flow reactor and in independent batch studies, done in well mixed test tubes of blood, demonstrating that the oscillating reactor design minimizes external mass transfer limitations. Identical heparin neutralization profiles and rates were also observed in the first and the second of consecutive heparin neutralization studies (0-2 h and 2-4 h, respectively) demonstrating an effective half-life of the immobilized enzyme in the oscillating reactor of at least 4 h. No significant decrease in red or white blood cell count, platelet count, or hematocrit, and clinically acceptable levels of plasma hemoglobin and activated complement were observed with 2 h (20 passes) of in vitro recirculation of human blood through the reactor. High, stable efficacy, operational stability, and excellent biocompatibility are attributed to secondary flow induced liquid-particle mixing within the oscillating reactor.

Biocompatible Materials↗
PubMed1991

Effect of acylation stimulating protein on the triacylglycerol synthetic pathway of human adipose tissue.

Acylation stimulating protein (ASP) is a 14 kDa plasma protein which causes in vitro triacylglycerol synthesis in human adipocytes and fibroblasts to increase substantially. ASP was found to stimulate human adipose tissue microsomal glycerophosphate acyltransferase and diacylglycerol acyltransferase activities by 23% and 90%, respectively. However, phosphatidate phosphohydrolase activity showed no increase in activity, nor did microsomal acyl-CoA synthetase activity. Moreover, ASP did not decrease the apparent Km of diacylglycerol acyltransferase (DGAT), but rather increased its apparent Vmax suggesting direct interaction of ASP with DGAT.

Acyltransferases↗
PubMed1997

Influence of some immune factors on the IL-6 and soluble IL-2 receptors in haemodialysed patients.

In respect to the immune deficiency state of long-term haemodialysed patients, both cytokines and their receptor disturbances have been taken into consideration. The purpose of our study was to evaluate the effect of uraemic and haemodialysis factors on the interleukin-6 and interleukin-2 soluble receptor levels and the reactivity after influenza vaccination. We have found that IL-6 and IL-2 receptor levels were statistically significantly elevated (98.8 +/- 39 pg/ml and 1557 +/- 544 U/ml, respectively) in serum of haemodialysed patients. The fact that increased immune complexes statistically correlated with soluble IL-2 receptor levels (p < 0.01) was very interesting for us. In order to study the immunological response after vaccination, 10 patients have been investigated after influenza vaccination. Plasma samples were collected before, as well as 1 and 4 weeks after vaccine administration. Antibody titres measured by haemagglutinin inhibition showed decreased antibody levels in haemodialysed patients. We conclude that the interleukin disturbance and the elevated interleukin-2 receptor levels together with the presence of circulating immune complexes can influence in some way the immune response of haemodialysed patients.

Adult↗