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[Effects of perindopril on plasma soluble TRAIL and receptor soluble DR5 in patients with congestive heart failure].

AIM: To explore the levels of soluble TRAIL and DR5 in plasma of patients with congestive heart failure (CHF) and the effects of perindopril. METHODS: 58 CHF patients were randomly divided into two groups, namely perindopril treatment group (30 cases) and routine treatment group (28 cases). The levels of sTRAIL and sDR5 in plasma of 30 CHF patients treated with perindopril, 28 CHF patients treated with routine method before and after treatment and 20 healthy persons were detected by ELISA. RESULTS: (1)The mean levels of sTRAIL in plasma of 58 CHF patients and 20 healthy persons were (1.43+/-0.47) microg/L and (0.93+/-0.12) microg/L, respectively, the comparison between the patients and healthy persons had no notable difference (P>0.05), suggesting that plasma sTRAIL level had no significant relation to injured level of cardiac function. As for sDR5 level, the mean level in plasma of 58 CHF patients was (39.67+/-6.78) ng/L, this value was significantly higher than that of healthy control group, and the level of sDR5 was increased with the injured level of cardic function.(2)The plasma levels of sTRAIL in both perindopril group and conventional treatment group decreased after treatment, but there was no significant difference. The mean levels of plasma sDR5 in perindopril group were (31.23+/-10.16 ) ng/L and (8.50+/-2.14) ng/L; the levels in conventional group (48.81+/-8.74) ng/L and (26.64+/-6.27) ng/L, respectively, the perindopril group was lower than the conventional group descending rates were 72.7% and 45.3% respectively.(3)The level of plasma sDR5 in CHF patients resulting from hypertensive cardiopathy was much higher than that in CHF patients resulting from any other etiological factors. CONCLUSION: DR5 may play an important role in the occurrence and progress of myocardium apoptosis of CHF patients. Perindopril can down-regulate the level of plasma sDR5, therefore, it may have the great effect on retarding course of ventricular remodeling, protecting and improving cardial function of CHF patients.

Apoptosis↗

[Method of detection of soluble HLA-I and soluble HLA-I level alteration in storage blood].

Aim of this study was to develop the detection method of soluble human leukocyte antigens I (sHLA-I) and to explore sHLA-I level alteration in storage blood and its significance. sHLA-I level in sera of 60 Guangdong normal individuals and sHLA-I concentration in blood components from 20 donors quantitatively were detected by sandwich ELISA. The results showed that sensitivity of this assay was 2.84 ng/ml. Coefficients of variation were 5.80% within assays and 9.00% between assays respectively. The recovery rate was >/= 98.57%. The sHLA-I level of normal individuals in Guangdong was (699.54 +/- 360.10) ng/ml. sHLA-I in red blood cells stored for 28 days and in random-donor platelets were significantly higher than that in other blood components and their amount was proportionate to the number of residual donor leukocytes and to the length of storage. In conclusion, sandwich ELISA assay for detection of sHLA-I is a sensitive, specific and stable technique. Blood components with different concentration of sHLA-I may be chosen for clinical transfusion.

Apoptosis↗

Levels and value of soluble P-selectin following acute myocardial infarction: evaluating the link between soluble P-selectin levels and recruitment of circulating white blood cells and the marker for the rapid diagnosis of chest pain.

BACKGROUND: Platelet activation that results from coronary plaque rupture is important in the pathogenesis of acute myocardial infarction (AMI). Soluble p-selectin (sP-selectin) is crucial in modulating leukocyte adhesion to both platelets and endothelial cells during inflammatory response and thrombus formation. We hypothesized that sP-selectin, an index of both platelet activation and acute inflammation, rapidly increases and modulates the recruitment of circulating white blood cells (WBC) in patients following AMI. METHODS: We conducted a prospective cohort study of 142 consecutive patients with ST-segment elevated AMI of onset < 12 h who were undergoing primary percutaneous coronary intervention. Blood samples for plasma levels of sP-selectin were obtained in the catheterization laboratory before coronary angiography was performed. The plasma levels of sP-selectin were also measured in 30 risk control subjects and 20 healthy control subjects. RESULTS: The plasma level of sP-selectin and the circulating WBC count were significantly higher in patients with AMI than in either the risk control or healthy subjects (all of p values < 0.0001). Additionally, repeated measures of ANOVA demonstrated that there were no significant differences in plasma levels of sP-selectin (p > 0.10) in three intervals from the start of chest pain to blood sample collection (< 180 min, > or = 180 < 360, and > or = 360 < 720) following AMI. Correlation analysis demonstrated that the increase in the plasma level of sP-selectin was significantly related to the circulating WBC count (r = 0.248, p = 0.003). CONCLUSIONS: sP-selectin was markedly elevated in an early phase of AMI. sP-selectin may be involved in modulating the recruitment of circulating WBC during AMI. These findings raise the need for a prospective investigation of sP-selectin as a potential reliable clinical tool for rapidly diagnosing AMI.

Adult↗

[Soluble CD40 and soluble CD40L concentrations in the serum and the cerebrospinal fluid of patients with tick borne encephalitis and neuroborreliosis].

BACKGROUND AND PURPOSE: The interaction between CD40 and CD40L is essential in generating of an immunological response also intrathecally. The aim of the study was estimation of a concentration soluble form of CD40, CD40L (CD154) in the bacterial and viral inflammation of the central nervous system in two compartments - blood circulation and intrathecally, before and after the treatment. MATERIAL AND METHODS: sCD40 and sCD40L were tested twice before and after treatment in pairs serum and CSF of 40 patients treated in the Dept. of Infectious Diseases and Neuroinfections. Patients were divided in two groups: (n=20) patients with tick borne encephalitis (TBE) (group I, n=20) and patients with neuroborreliosis in the form of lymphocytic meningitis (group II, n=20). ELISA assays were performed. RESULTS: Significantly increased concentrations of sCD40, sCD40L in CSF (higher in neuroborreliosis) were measured. We found also an increased concentration of sCD40L in inflammatory CSF in both tested groups (in neuroboreliosis lasting also after 4 weeks of treatment), compared with the control group (below the detection limit in normal CSF). CONCLUSIONS: Results of estimation of the sCD40 and sCD40L concentrations indicate their role in the intrathecal inflammation process of bacterial and viral etiology. The increased serum concentration of sCD40L in TBE and CD40 in neuroborreliosis indicate that peripheral activation of the immunological system persists after cessation of treatment and after the clinical recovery. The defense mechanisms are more pronounced in neuroborreliosis than in tick borne encephalitis.

Adult↗

The cooperative antioxidant role of glutathione with a lipid-soluble and a water-soluble antioxidant during peroxidation of liposomes initiated in the aqueous phase and in the lipid phase.

A study is made of the effect of GSH as a co-antioxidant with vitamin E during free radical chain autoxidation inhibition studies of dilinoleoylphosphatidylcholine (DLPC) liposomes. Oxidations are initiated in the aqueous phase with azobis(2-amidinopropane hydrochloride) and in the bilayer phase of DLPC with azobis(2,4-dimethylvaleronitrile) under known conditions of the rate of free radical chain initiation (Ri). In reactions initiated in the aqueous phase, GSH is not an efficient antioxidant when acting alone; however, in cooperation with vitamin E in the bilayers, it does effect significant extensions of the efficient induction period of vitamin E. Quantitative studies show that GSH "spares" 0.4 molecules of vitamin E in the bilayer/molecule of GSH and therefore terminates approximately 0.8 peroxyl radical chains as a co-antioxidant with vitamin E. In contrast, GSH is not an effective co-antioxidant with an efficient water-soluble antioxidant, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate (Trolox). GSH spares only 0.08 molecules of Trolox/molecule of GSH during autoxidation initiated in the aqueous phase with azobis(2-amidinopropane hydrochloride). The inhibition rate constant for GSH in trapping aqueous phase peroxyls is at least an order of magnitude less than that of Trolox. When peroxidation is initiated in the bilayer phase of DLPC with azobis(2,4-dimethylvaleronitrile), GSH is not an effective co-antioxidant with either vitamin E in the bilayer or Trolox in the water. Comparatively higher ratios of GSH to E (GSH/E = 50) or Trolox (GSH/Trolox = 30) are required to give significant extensions of the E or Trolox induction periods. GSH is estimated to preserve only approximately one vitamin E or Trolox molecule for a hundred GSH for peroxidations initiated in the DLPC bilayers. From the kinetic studies and GSH decay studies during inhibition periods, it is concluded that GSH does not act synergistically by regenerating ArOH from the phenoxyl, ArO, radical of vitamin E or Trolox. The mode of antioxidant action of GSH is concluded to be that of trapping peroxyl radicals in the aqueous phase and thereby indirectly sparing vitamin E in the bilayer.

Antioxidants↗

Constitutive secretion of soluble interleukin-2 receptor by human T cell lymphoma xenografted into SCID mice. Correlation of tumor volume with concentration of tumor-derived soluble interleukin-2 receptor in body fluids of the host mice.

Increased serum concentration of soluble alpha-chain receptor for interleukin-2 (sIL-2R) has been noted in patients with a variety of inflammatory conditions and lymphoid malignancies including T cell leukemia and lymphoma. Elevated sIL-2R serum levels seen in lymphoid malignancies appear to correlate with the clinical stage of disease. However, because sIL-2R is produced by normal activated lymphocytes, it has been uncertain whether serum sIL-2R in such conditions is derived from tumor cells or normal immune cells responding to the tumor. To address this question, we used a model of human (CD30+) anaplastic, large T cell lymphoma transplanted into immunodeficient SCID mice. Reverse transcription polymerase chain reaction of tumor RNA showed that the tumor, designated mJB6, contains mRNA for alpha-chain of human IL-2R. Furthermore, 15 to 25% of tumor cells stained with anti-human IL-2R alpha-chain mAb. Solid phase ELISA analysis of serum samples from mice bearing mJB6 lymphoma showed high concentrations of human sIL-2R. None of the control mice without lymphoma or with human nonlymphoid tumors (prostatic carcinoma, ovarian carcinoma, and glioblastoma multiforme) showed detectable human sIL-2R. The sIL-2R serum titers of mJB6-bearing mice correlated strongly with tumor volume (P < 0.0001). Tumors as small as 0.4 to 0.8 mm3 could be detected by this method. The sensitivity of sIL-2R ELISA exceeded at least 150 times the sensitivity of conventional radioisotopic tumor detection. Total resection of mJB6 tumors resulted in complete clearance of sIL-2R from the murine serum within 48 hours with a half-life of 6 hours. Accordingly, partial resection led to a significant decrease in sIL-2R followed by gradual increase with tumor regrowth. sIL-2R was also detected in the urine of mJB6-transplanted mice. As in serum, urine concentrations of sIL-2R were proportional to tumor mass (P < 0.02). Based on these findings we postulate that malignant cells are a major source of serum sIL-2R in patients with lymphoid tumors. In addition, our data further support monitoring sIL-2R concentration in body fluids as a sensitive method to detect change in tumor volume in such patients.

Animals↗

Soluble factors in tolerance and contact sensitivity to 2,4-dinitrofluorobenzene in mice. I. Suppression of contact sensitivity by soluble suppressor factor released in vitro by lymph node cell populations containing specific suppressor cells.

Tolerance to 2,4-dinitrofluorobenzene (DNFB) contact sensitivity is in part mediated by suppressor thymus-derived cells (T cells) which are induced by pretreatment with the hapten 2,4-dinitrobenzenesulfonate. If lymph node cell suspensions containing suppressor cells are cultured in vitro, soluble suppressor factor (SSF) is released into the supernatant. When DNFB-immune lymph node cells are incubated with SSF, their ability to transfer contact sensitivity to normal recipients is suppressed. In order for SSF to be produced and/or released, it was necessary to paint the tolerant animals with DNFB 16 to 20 hr before the lymph node cells were cultured, suggesting that SSF was made in response to antigen stimulation. Specificity studies showed that SSF was both antigen specific and strain specific in its action. In addition, it was found that SSF could be absorbed by 2,4-dinitrophenyl-keyhold limpet hemocyanin (DNP-KLH) (not by KLH alone) and by anti-H-2 antibodies but not by trinitrophenyl-KLH, anti-immunoglobulin, or anti-DNP antibodies. Taken together, these results indicate that SSF is a product of the major histocompatibility complex which, although not antibody, has affinity and specificity for the hapten DNP. Furthermore, in order for SSF to suppress DNFB sensitivity, identity is required among genes in the H-2 complex between the donor of SSF and the immune lymph node cells.

Animals↗

Soluble cytokine receptors as carrier proteins: effects of soluble interleukin-4 receptors on the pharmacokinetics of murine interleukin-4.

Soluble interleukin-4 (IL-4) receptors (sIL-4R) can have either enhancing or inhibitory effects on the activity of IL-4 in vivo, depending on the relative concentration ratios of sIL-4R to IL-4. Whereas competition with membrane IL-4 receptors is the basis for their inhibitory action, the mechanisms responsible for the potentiation of IL-4 activity are not completely clear but may involve alterations in the half-life and biodistribution of IL-4 in vivo. To better understand the basis for the enhancing effect of sIL-4R, we have analyzed their effects on the pharmacokinetic properties of IL-4. Studies with radiolabeled recombinant IL-4 demonstrated that, when injected alone, IL-4 was rapidly cleared from the circulation and eliminated through the kidneys in a proteolytically degraded form. Administration of IL-4 in combination with increasing concentrations of sIL-4R resulted in a dose-dependent enhancement in the blood levels of IL-4 and a concomitant reduction in its clearance from circulation and excretion in the urine. Differences between measurements of IL-4 concentrations based on radioactivity and enzyme-linked immunosorbent assays indicated that the injected IL-4 was rapidly inactivated in vivo and that the presence of sIL-4R diminished this process. The inactivation of IL-4 was mediated through the membrane IL-4 receptors and required receptor internalization and intact lysosomal function. Taken together, these results suggest that sIL-4R are able to alter the pharmacokinetic properties of IL-4, prolonging its half-life in the circulation and reducing its clearance through diminished renal excretion and/or interference with inactivation. These effects are consistent with the ability of sIL-4R to potentiate IL-4 activity in vivo.

Animals↗

Soluble factors in tolerance and contact sensitivity to DNFB in mice. II. Genetic requirements for suppression of contact sensitivity by soluble suppressor factor.

Active suppression of contact sensitivity to DNFB in mice is mediated by a soluble suppressor factor (SSF) which is released in vitro by cultures of LN cells that contain antigen-specific suppressor T cells. For SSF-mediated suppression to occur, identity is required among genes in the H-2 complex between the donor of SSF and the donar of DNFB-immune LN cells. Identity in either the left half or right half of the H-2 complex was found to be both sufficient and required. Additional experiments using congeneic strains with intra-H-2 recombinants showed that the genetic homology which was required mapped to genes contained in the H-2K and/or H-2D regions of the H-2 complex.

Animals↗

Separation and characterization of the colloidal phases produced on digestion of common formulation lipids and assessment of their impact on the apparent solubility of selected poorly water-soluble drugs.

Colloidal mixtures containing bile salts (BS), phosphatidylcholine (PC), and medium and long-chain monoglycerides and fatty acids were prepared as model systems to represent typical intestinal contents after digestion of formulation derived lipids under both low (5 mM BS/1.25 mM PC) and high (20 mM BS/5 mM PC) BS and PC conditions. Size-exclusion chromatography of the colloidal species that formed in the medium-chain digests indicated the presence of vesicles, mixed micelles, and simple micelles, whereas the long-chain digests contained only vesicles and mixed micelles. In the long-chain digests the mixed micellar phase was the predominant drug solubilizing species for griseofulvin, danazol, and halofantrine, although for increasingly lipophilic drugs, the vesicular phase contributed an increasing proportion of the solubilization capacity. In contrast, the solubilization capacity of the vesicular phase was predominant in the medium-chain digests, and no clear trends were evident in the relationship between drug lipophilicity and proportional solubilization. These data highlight the need to consider the colloidal species that form in the small intestine during the digestion of common formulation lipids and the coincident enhancement in drug solubilization provided under these circumstances.

Chemistry, Pharmaceutical↗