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PubMed1992

RGD-albumin conjugate: expression of tissue regeneration activity.

Albumin conjugated with Arg-Gly-Asp (RGD) has cellular adhesive activity comparable to that of fibronectin in vitro. This study examined whether RGD-albumin conjugate (RGD-ALB) can promote soft tissue ingrowth into a porous matrix in vivo. Polyurethane sponges with 150-500 microns pore size adsorbed with RGD-ALB, fibronectin and albumin were implanted in the subcutaneous tissue of rats. The RGD-ALB-adsorbed sponge exhibited tissue ingrowth comparable to that of the fibronectin-adsorbed sponge at the early period of implantation. On the other hand, the tissue ingrowth was markedly retarded for non-adsorbed and albumin-adsorbed sponges. The enhanced tissue ingrowth found for RGD-ALB and fibronectin was deduced to be mainly a result of its cell-adhesion activity. It is concluded that RGD-ALB exhibits tissue ingrowth-promoting activity at the initial stage of wound healing as effectively as fibronectin.

Albumins↗
PubMed1991

Vitamin D binding protein: genomic structure, functional domains, and mRNA expression in tissues.

The vitamin D binding protein (DBP), alternatively known as Gc-globulin, is a member of the albumin (ALB) and alpha-fetoprotein (AFP) gene family. The rat DBP gene is expressed at high levels in liver and at moderate levels in kidney, testis, abdominal fat, and yolk sac. Very low levels of DBP as well as ALB and AFP transcripts can be detected in all other tissues studied by the reverse transcriptase/polymerase chain reaction technique. During development, liver DBP gene transcripts are detectable at 14 days of gestation and levels rise gradually until adulthood in parallel with ALB. DBP present on the surface of U937 monocyte-derived cells is acquired from serum, suggesting cell surface binding sites for DBP. The rat DBP gene has been cloned and characterized. It spans 35 kb and contains 13 exons and 12 introns. The DBP gene contains two fewer exons than the ALB or AFP genes, accounting for the shortest size of its mRNA and protein product. Its 5'-flanking region contains a high degree of structural similarity to both ALB and AFP promoters.

Amino Acid Sequence↗
PubMed2005

Variation of plasma protein parameters in four free-ranging reindeer herds and in captive reindeer under defined feeding conditions.

Plasma total protein (TP), albumin (ALB) and globulin (GLOB) concentrations and albumin/globulin ratio (A/G) were analysed from blood samples collected from free-ranging reindeer (Rangifer tarandus tarandus) herds at varying times of year. The same parameters were followed in nine captive reindeer with varying protein and energy intake. Variation in the blood constituents of free-ranging reindeer was analysed in relation to different extrinsic and intrinsic factors and compared to findings from captive animals, allowing the analysis of effects of protein and energy intake. There was large overall variation in TP, ALB, GLOB and A/G ratio in the free-ranging animals, ranging between 36-110 g/L, 18-59 g/L, 17-59 g/L and 0.5-2.1. The variation between months and years was significant for all variables except the A/G ratio, where no year effect was noted. Increase in live body mass was associated with a small significant increase and pregnancy with a small significant decrease in all dependent variables, except for the A/G ratio. Age did not have a significant effect on any of the blood constituents when body mass was included in the same model. In captive animals, feeding lichens with low protein content was related to a significant decline in TP, ALB and GLOB, but not in the A/G ratio, whereas feeding commercial ration increased plasma TP, ALB and GLOB significantly. Extrinsic factors such as season and year explained majority of variation in the blood constituents of free-ranging reindeer, whereas body mass, pregnancy and age had only a minor influence. It is concluded that plasma TP and ALB, and to a lesser extent GLOB and A/G ratio may serve as nutritional biomarkers of reindeer.

Animals↗
PubMed2005

In vitro differentiation of mouse bone marrow mononuclear cells into hepatocyte-like cells.

AIM: : It is imperative to explore some ways to gain the functional hepatocytes for hepatocyte transplantation. Bone marrow stem cells can differentiate into hepatocytes in vivo and in vitro. We select fibroblast growth factor-4 (FGF-4), oncostatin M (OSM), hepatocyte growth factor (HGF) and epithermal growth factor (EGF) as differentiation factors, and design the appropriate directed differentiation medium in order to gain hepatocytes through directed differentiation of bone marrow stem cells. METHODS: : Bone marrow mononuclear cells (BMMCs) were cultured in the directed differentiation media including FGF-4, OSM, HGF and EGF. In the course of cell differentiation, cell morphology was observed, and the expression patterns of some genes of the hepatocyte were validated and confirmed by RT-PCR. The ALB-, and CK18-expressed cells were gone further step to be confirmed by Western blot analysis, immunofluorescence and flow cytometric analysis. Hepatocyte functional activity, including glycogen synthesis and urea production, were confirmed by periodic acid-Shiff (PAS) staining and urea assay. RESULTS: : Some epithelial-like cells or polygonal cells appeared in the directed differentiation medium within 12 days, and the number and sizes of colonies of epithelial-like cells or polygonal cells increased in the course of the cell directed differentiation. AFP, HNF-3ss, ALB and CK18 mRNA expressions first appeared within day 7, and lasted throughout the later directed differentiation. TTR, G-6-P and TAT mRNA expressions could be detected within day 14, and their expressions lasted in the course of the later directed differentiation. ALB and CK18 were confirmed to exist in the differentiated BMMCs by Western blot analysis. ALB was found in the cytoplasm and cell membrane, while CK18 scattered in the cytoplasm by immunofluorescent staining. On day 21,the ratio of ALB-positive cells was 69.45%, and the ratio of CK18-positive cells was 67.36%. The accumulation of glucogen was detected in the cytoplasm of the differentiated cells. The directed differentiated BMMCs produced urea 3 days later, and they produced urea in a time-dependent manner. CONCLUSIONS: : BMMCs could differentiate into hepatocytes or hepatocyte-like cells in the differentiation media including HGF, FGF-4, EGF, and OSM. These hepatocyte-like cells were identified at the gene level and protein level. Furthermore, these hepatocyte-like cells had some hepatocellular synthesis and metabolism functions.

Journal Article↗
PubMed2006

Dynamics of interferon-specific gene expression in peripheral blood of interferon alfa-naïve patients with genotype 1 chronic hepatitis C infection treated with albumin-interferon alfa.

Albumin-interferon alfa (alb-IFN) is a novel recombinant protein derived from IFNalpha-2b genetically fused to human albumin, which combines in a single polypeptide the antiviral properties of IFNalpha with the long serum half-life of albumin. Interferon alfa (IFNalpha) mediated biological responses stem from the engagement of IFNalpha with its target receptor and subsequent modulation of interferon-specific gene (ISG) expression. The dynamics of ISG expression were evaluated in a Phase 2a study conducted in IFNalpha naïve patients with genotype 1 chronic hepatitis C (CHC) treated with alb-IFN. Whole blood was obtained pre-dose and on days 7 and 28 from 47 patients enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts ranging from 200 to1200mug. Gene expression of nine candidate genes including four ISGs was determined by a TaqMan Real-time PCR assay. There was sustained >5-fold median induction on days 7 and 28 of the ISG's- OAS1, IRF7, IFI44 and IFI27. While all subjects showed a molecular response to alb-IFN, individual variability in pre-treatment gene expression levels and fold of modulation during treatment was observed. At days 7 and 28, induction of OAS1, IFI44 and IRF7 showed significant pair-wise correlation in individual patients (r>0.7 and P<0.001). There was no correlation of baseline expression or induction of gene expression with antiviral response. In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the molecular response associated with an IFNalpha.

Journal Article↗
PubMed1999

Segmental allergen challenge induces plasma protein leakage into the airways of asthmatic subjects at 4 hours but not at 5 minutes after challenge.

We have investigated whether increased plasma protein leakage is present early after segmental allergen challenge in allergic asthma. Seven asthmatic subjects with mild allergy (AA group) and 5 non-asthmatic subjects with allergy (ANA group) were challenged with allergen doses based on similar early skin reactions; 5 healthy control subjects without allergy (C group) were challenged with the highest dose applied in the subjects with allergy. Bronchoalveolar lavage (BAL) fluid was obtained before, at 5 minutes after, and at 4 hours after challenge from different segments. Levels of albumin (Alb) and alpha2-macroglobulin (A2M) were measured in BAL fluid and serum. In addition, we calculated the relative coefficient of excretion as follows: RCE = ((A2M in BAL fluid)/(A2M in serum))/((Alb in BAL fluid)/(Alb in serum)). Also, levels of tryptase as a marker of mast cell activation and tumor necrosis factor-alpha (TNF-alpha), a possible inducer of plasma protein leakage, were determined. At 5 minutes after challenge, in none of the groups was a significant change found in the parameters for protein leakage. Levels of tryptase were increased in the subjects with allergy at 5 minutes after challenge only (P = .004). At 4 hours after challenge, levels of Alb (P = .03) and A2M (P = .04) and the RCE (P = .04) were increased in the AA group only. At 4 hours, levels of TNF-alpha were increased, with no significant differences among the three groups. In the asthmatic subjects with allergy, levels of TNF-alpha correlated with levels of Alb (r = 0.85, P = .02). In conclusion, at 4 hours after segmental allergen challenge, plasma protein leakage was increased in the asthmatic subjects only. The increase in levels of TNF-alpha in all groups indicates that the presence of TNF-alpha alone was not sufficient to cause plasma protein leakage within 4 hours after allergen challenge. Our results confirm the concept that plasma exudation after allergen exposure is a pathophysiologic event associated with asthma.

Allergens↗
PubMedDate not supplied

Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer's disease.

BACKGROUND: Recently it has been reported that activation of the inflammatory response system (IRS) may play a role in the aging process and in the pathogenesis of the degenerative changes associated with Alzheimer's disease (SDAT). The aims of the present study were to examine the peripheral IRS in normal aging and in SDAT patients. METHODS: Serum zinc (Zn), total serum protein (TSP), albumin (Alb), SP electrophoresis, and serum interleukin-6 (IL-6) and the stimulated production of tumor necrosis factor-alpha (TNFalpha) were determined in younger versus elderly healthy subjects and in SDAT patients vs. age-matched, healthy volunteers. RESULTS: Serum Zn and Alb were significantly lower in elderly than in younger healthy volunteers and were significantly and inversely correlated with age. The production of TNFalpha was significantly higher in elderly than in younger healthy volunteers and was significantly and positively correlated with age. In SDAT patients, no significant changes in serum Zn or TNFalpha production could be found. Serum Alb was significantly lower and serum IL-6 and the alpha1 and alpha2 globulin fractions significantly higher in SDAT patients than in controls. CONCLUSIONS: Activation of the IRS appears to accompany the normal aging process, i.e. lower serum Zn and Alb and increased TNFalpha production, as well as SDAT, i.e. lower serum Alb and increased serum IL-6 and alpha1 and alpha2 globulin fractions. The findings suggest that not all indicators of IRS activation in SDAT are related to those of the normal ageing process.

Adult↗
PubMedDate not supplied

NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure--implications for anxiety associated with posttraumatic stress disorder.

It has been proposed that NMDA-dependent long-term potentiation (LTP) of limbic system circuits controlling defensive behavior underlies stressor-induced lasting increases in anxiety-like behavior (ALB). Findings in cats given the stress-inducing beta-carboline, FG-7142, support this hypothesis. An animal model of lasting affective change following traumatic stress has recently been developed. In this model, lasting increases in anxiety-like behavior (ALB) assessed in the elevated plus maze are produced by a single 5-min exposure of a rat to a cat. Rats become more anxious in the plus maze for up to 3 weeks after the exposure. The present study demonstrates that blockade of NMDA receptors in rats with MK-801, AP7, or CPP, given 30 min prior to exposure to a cat, prevents the increase in ALB assessed 1 week later. MK-801 or AP7, given 30 min after exposure to a cat, do not prevent the increase in ALB seen 1 week later, however. MK-801, but not CPP or AP7, promotes approaches to cats during exposure. This "fearlessness" may reflect some anxiolytic action of MK-801. Approach to cats following injection of MK-801 was eliminated by prior injection of Prazosin. Prazosin did not interfere with the block of increases in ALB following cat exposure, however. These findings are consistent with the view that NMDA receptors are involved in initiation, but not maintenance of neural changes mediating lasting increases in anxiety following severe stress. The significance of these findings for PTSD are discussed.

Amygdala↗
PubMed2004

Safety, tolerability, efficacy and plasma concentrations of diethylcarbamazine and albendazole co-administration in a field study in an area endemic for lymphatic filariasis in India.

Filariasis control programmes are moving towards a strategy of repeated single-dose mass treatment of endemic populations. Using a combination, such as albendazole (ALB) to diethylcarbamazine (DEC) gives both macrofilaricidal and anti-helmintic activity. However, the safety of the combination versus DEC alone should be established in field studies in large populations prior to incorporation into national programmes. The present study compared the safety, tolerability, and efficacy of single doses of DEC 6 mg/kg + ALB placebo with DEC 6 mg/kg + ALB 400 mg in populations living in two filariasis endemic villages in the district of Wardha in western India. The study was double blind, parallel group, and randomized. Safety and tolerability study were studied in males and females older than 5 years. Safety was assessed by monitoring if adverse events (AEs) over 5 days affected daily acivities. Subjects in the 2 treatment groups experienced insignificantly different effects on daily activities and the combination was shown to be safe. Efficacy was evaluated by microfilaraemia (Mf), immunochromatographic test (ICT) and ultrasonography (USG) at 0, 3, 6, and 12 months of follow up. The efficacy study enrolled 103 male patients (aged 18-50 years) in microfilariae positive, clinical disease and asymptomatic, amicrofilaremic groups. There was no significant difference in efficacy between groups at 12 months. Within the Mf positive group, significant differences were seen in microfilaraemia (P < 0.001) with both treatments, and in USG (P < 0.001 and P < 0.004 respectively), at 12 months. The present field study has shown the combination of DEC + ALB to be as safe as the single drug DEC and thus the combination can be put in use in the national filariasis control programmes. Both drugs were adequately absorbed. The study at present does not provide evidence for the greater efficacy of the combination at 12 months follow up. While the safety of the combination has been ascertained, the incorporation or otherwise of ALB into national programmes for greater efficacy must await results of studies with longer follow up.

Adolescent↗
PubMed1999

Autologous blood use in percutaneous nephrolithotomy.

OBJECTIVES: Preoperative autologous blood (AUB) donation has decreased patient exposure to allogenic blood (ALB) products and associated infectious risk. The risk of contracting hepatitis C and human immunodeficiency virus is 1 in 103,000 and 1 in 678,000, respectively, after receiving 1 U ALB. Elective surgical procedures require surgeons to offer preoperative AUB donation in California. Unused AUB is discarded. We report our use of AUB obtained for percutaneous nephrolithotomy. METHODS: A retrospective study of 144 consecutive patients who underwent 193 percutaneous nephrolithotomies between January 1994 and April 1998 at one of four teaching hospitals at the University of California, San Francisco was performed. Preoperative AUB donation, transfusion rates, hemoglobin levels, blood use, and costs were analyzed. RESULTS: Ninety-six units of blood were collected from 63 patients (44%) and were available for 70 procedures (36%). The overall transfusion rate per procedure was 7%, with 13 patients receiving a total of 24 U, 7 AUB and 17 ALB. Eighty-nine units (92.7%) of AUB were discarded, and the transfusion rate in donors and nondonors was similar. There was no significant difference in preoperative hemoglobin or operative blood loss between donors and nondonors. The 13 transfused patients had a lower preoperative hemoglobin ( 11.5 versus 12.8 g/dL; P = 0.029) and higher operative blood loss as measured by hemoglobin level (3.2 versus 1.6 g/dL; P <0.001). Blood bank charges for ALB and AUB were $ 119/U and $244 to $498/U, respectively, depending on transportation and thawing charges. CONCLUSIONS: Routine preoperative blood donation adds substantial cost for minimal benefit, given the low infectious risk of ALB and the two- to fourfold higher cost of AUB. In our series, women had an increased incidence of blood transfusion compared with men. AUB donation may provide peace of mind but is rarely used and is discarded 93% of the time.

Adolescent↗
PubMed1998

Neural plasticity, neuropeptides and anxiety in animals--implications for understanding and treating affective disorder following traumatic stress in humans.

Exposure of rats to cats (predator stress) lastingly increases rodent anxiety-like behavior (ALB) in the elevated plus-maze. Previous work shows that lasting changes in ALB following predator stress depend on NMDA and CCKB receptors. In this paper we describe the effects of differing degrees of predator exposure on behavior. Effects depend on the behavioral measure. In general, exposure to predator odor is less provocative of lasting change in ALB than is unprotected exposure to a cat. In addition, we examine the development of effects of unprotected predator exposure over time. Lasting effects on ALB begin at 30 min to 1 h after predator stress and persist for at least 3 weeks. We also report a complex pattern of effects of predator stress on neuroendocrine and stress peptide (bombesin, CRF and AVP) levels in a variety of brain areas. Not surprisingly, predator exposure increases plasma levels of corticosterone and ACTH. Central changes in peptide content in the hypothalamo-pituitary axis, related hypothalamic nuclei, limbic and brain stem areas are also noted. Finally, path analysis demonstrates a replicable relationship between cat behavior, rat defensive behavior and degree of increase in ALB one week later. It is proposed that behavioral changes following predator stress may model anxiety associated with PTSD.

Animals↗
PubMed1994

The association of intradialytic parenteral nutrition administration with survival in hemodialysis patients.

Hemodialysis patients who had received intradialytic parenteral nutrition (IDPN) during 1991 were identified. These patients were compared with unexposed controls after adjusting for demographic variables, baseline renal diagnosis, diabetic status, serum albumin (ALB), creatinine (CRE), and urea reduction ratio. At lower levels of ALB (< or = 3.4 g/dL), treatment with IDPN was associated with a reduction in the odds of death at 1 year, an effect that became stronger at lower levels of CRE (< or = 8.0 mg/dL). In contrast, treatment with IDPN in patients with normal ALB was associated with increased mortality. Time trend analyses of ALB and CRE demonstrated progressive increases toward pretreatment levels in IDPN recipients that were not evident in control subjects. These time trend data suggest that in undernourished hemodialysis patients, IDPN can effect the serum levels of valid biochemical surrogates of visceral and somatic protein nutrition. Albeit retrospective, the improvement in survival at year's end among patients with ALB < or = 3.4 g/dL suggests that malnutrition and its attendant ill effects in hemodialysis patients may respond to aggressive therapeutic intervention, such as IDPN. These important findings should be prospectively confirmed in a randomized clinical trial.

Creatinine↗
PubMed2001

Circulating tumor cell mRNAs in peripheral blood from hepatocellular carcinoma patients under radiotherapy, surgical resection or chemotherapy: a quantitative evaluation.

We assessed whether current therapies could lead to hematogenous dissemination of malignant hepatocytes in hepatocellular carcinoma (HCC) patients using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) for alpha-fetoprotein (afp) and albumin (alb) mRNAs. We analyzed 137 peripheral blood samples before, during and after treatment from 84 patients under radiotherapy, surgical resection or chemotherapy. As compared to the upper limit for 53 healthy/non-HCC controls, alb- mRNA levels increased 2-10-fold in 6% of patients pre-treatment and 2-2.6x10(4)-fold in 32% post-treatment. Levels of afp- mRNA increased 3-210-fold in 17% pre-treatment and 4-5x10(5)-fold in 30% post-treatment. During a longitudinal follow-up of eight patients under radiotherapy or radiotherapy/resection, alb-mRNA levels were normal before treatment, whereas afp-mRNA levels increased 10-fold in two patients. During treatment, alb-mRNA and afp-mRNA levels increased 2-61-fold in three patients and 2.5-5-fold in two patients, respectively. After treatment, alb-mRNA levels declined to normal in all three patients within 3.5 months, but afp-mRNA levels increased 127-5x10(5)-fold in three patients within 5 months. We show evidence that HCC cells disseminating mostly post-treatment may be the 'seed' of recurrence/metastasis. In conjunction with the serum alpha-fetoprotein test, sequential afp-mRNA quantification could predict clinical metastasis/recurrence in 56% of patients during a 4-year follow-up.

Biomarkers, Tumor↗
PubMedDate not supplied

An informational approach to likelihood of malnutrition.

Unidentified protein-energy malnutrition (PEM) is associated with comorbidities and increased hospital length of stay. We developed a model for identifying severe metabolic stress and likelihood of malnutrition using test patterns of albumin (ALB), cholesterol (CHOL), and total protein (TP) in 545 chemistry profiles. Pattern classes were derived by converting decision values to a number code using cutoff values for nonmalnourished (0), moderate (1), and severe (2) of: ALB 35, 27 g/L; TP 63, 53 g/L; and CHOL 3.9, 2.8 mumol/L. Patterns defined by combinations of normal and abnormal laboratory results had decreased the likelihood of PEM from an all-2 to all-0 pattern. They were compressed to four final classes. ALB (F = 170), CHOL (F = 21), and TP (F = 5.6) predicted PEM class (r2 = 0.806, F = 214; P < E-6), but pattern class was the best predictor (r2 = 0.900, F = 1200, P < E-10). Kruskal-Wallis analysis of class by ranks was significant for pattern class (E-18), ALB (E-18), CHOL (E-14), and TP (2E-16). The means and SEM for tests in three PEM classes (mild, moderate, severe) were: ALB-35.7, 0.8; 30.9, 0.5; 24.2, 0.5 g/L; CHOL-3.93, 0.26; 3.98, 0.16; 3.03, 0.18 mumol/L, and TP-68.8, 1.7; 60.0, 1.0; 50.6, 1.1 g/L. We classified patients at risk of malnutrition using truth table comprehension. The pattern classes formed by the tests are a better classifier than the tests themselves.

Biomarkers↗
PubMed1975

Kinetic studies on the five principal components of normal adult human hemoglobin.

The five principal components of human hemoglobin (Ala, Alb, Alc, Ao, and A2) have been isolated by column chromatography and by preparative isoelectric focusing in gels. The isoelectric points and a number of kinetic parameters have been determined for each hemoglobin. The greatest kinetic differences are found in the binding of CO to the deoxy conformation. At pH 7, A0 and A2 are nearly identical in their overall reaction with CO, whereas the initial lag phase characteristic of crude hemolysate and A0 is greatly reduced in Ala and Alc and is essentially absent in Alb. The general effect of p-mercuribenzoate bindind on CO association is to magnify kinetic differences among the hemoglobins, diminish the initial lag phase, and increase the overall rate of CO binding. Hemoglobin Ala is anomalous in that the overall CO binding rate actually decreases after reaction with the mercurial. In terms of an Adair model with four association constants the rate constant for the binding of the first molecule of CO (1l') showed the greatest variation among the five hemoglobins, with A0 having the smallest constant, and Alb the largest. For the native hemoglobins, 1l' for Alb was more than twice that for A0; for the mercurated hemoglobins, the difference was greater than threefold. Raising the pH form 7 to 8 increases 1l' for all hemoglobins, but Ala is anomalous in having a slower overall rate for CO binding at the higher pH. At pH 9, the time course of CO binding is biphasic for all hemoglobins, with A0, the fastest, and Ala, the slowest, differing by nearly threefold in rate. The equilibrium constant for the tetramer-dimer equilibrium was determined by flash photolysis. The largest dissociation constant occurs for Ala and is 4.4 times that for A0, and 5.6 times that for Alc, the least dissociated of the hemoglobins. The overall oxygen dissociation reaction is biphasic for Ala and Alb, with the two phases differing by a factor of 5; the dissociation reactions for the other three hemoglobins appear essentially monophasic. The kinetics of dissociation of the first oxygen molecule from oxyhemoglobin are very similar for all five hemoglobins, as are the association kinetics for CN-minus and N3-minus binding to the five methemoglobins.

Adult↗
PubMedDate not supplied

Characterization of chlorinated adducts of hemoglobin and albumin following administration of pentachlorophenol to rats.

Five cysteinyl adducts (including one with multiple isomeric forms) of hemoglobin (Hb) and albumin (Alb) have been characterized in the blood of Sprague-Dawley rats following administration of pentachlorophenol (PCP). Three of these adducts were formed by multiple substitution reactions of tetrachloro-1,4-benzoquinone (Cl4-1,4-BQ) and its products, and two arose from reactions of tetrachloro-1,4-benzosemiquinone (Cl4-1,4-SQ) and tetrachloro-1,2-benzosemiquinone (Cl4-1,2-SQ). Adducts of tetrachloro-1,2-benzoquinone (Cl4-1,2-BQ) were not observed. Regarding adducts of Cl4-1,4-BQ and its products, specific structures were assigned to monosubstituted, disubstituted, and trisubstituted adducts of Hb and Alb following modification of rat blood with Cl4-1,4-BQ (0-45 microM) in vitro and after metabolism of PCP (0-40 mg/kg body weight) in Sprague-Dawley rats, in vivo. The formation of all adducts was linear over the ranges tested, with Alb adducts being more abundant than Hb adducts. The levels of the adducts measured were in the following order: monosubstituted > disubstituted > trisubstituted. The observation that Cl4-1,4-BQ can produce multisubstituted adducts with proteins suggests that protein-protein cross links may be formed, with inherent toxicological implications. Regarding adducts of the semiquinones (detected only in vivo), linear production of Hb and Alb adducts was observed with increasing dosage of PCP for adducts of both Cl4-1,4-SQ and Cl4-1,2-SQ. Higher levels of the semiquinone adducts were observed in Hb than in Alb, in contrast to the results with the quinone adducts. In a separate in vivo experiment (20 mg PCP/kg body weight), where animals were sacrificed at intervals up to 336 h postadministration, adducts were eliminated at rates which were comparable among the different adducts of a given protein.

Administration, Oral↗
PubMed1997

Blockade of CCK(B) but not CCK(A) receptors before and after the stress of predator exposure prevents lasting increases in anxiety-like behavior: implications for anxiety associated with posttraumatic stress disorder.

Lasting increases in anxiety-like behavior (ALB) in rodents in the elevated plus maze have been reported to follow brief (5 min) exposures to a cat. This study examined the role of CCK(A) and CCK(B) receptors in lasting increases in ALB following exposure to a cat. Block of CCK(B) receptors 30 min before and after cat exposure prevented increases in ALB assessed 1 week later in the elevated plus maze. Blocks of CCK(A) receptors either before or after cat exposure were without effect on increases in ALB measured 1 week later. Changes in activity or exploration could not account for the results. Effects of cat exposure on ALB, startle, and corticosteroid levels have been proposed as a model of affective disorder in posttraumatic stress disorder (PTSD). Implications of these findings for mechanisms of initiation of anxiety in PTSD and posttrauma pharmacological prophylaxis in PTSD are discussed.

Agonistic Behavior↗
PubMed1990

Stimulus-response coupling in human platelets activated by monoclonal antibodies to the CD9 antigen, a 24 kDa surface-membrane glycoprotein.

The CD9 molecule is a 24 kDa surface-membrane glycoprotein present on platelets and a variety of haematopoetic and non-haematopoetic tissues. In the present study we utilized specific inhibitors of thromboxane A2 (TxA2) formation (aspirin), protein kinase C [H-7 [1-(5-isoquinolinesulphonyl)-2-methylpiperazine]] and autocrine stimulation by secreted ADP (apyrase) to modify platelet activation by a monoclonal antibody ALB-6 to the CD9 antigen. This activation is only partially inhibited by aspirin alone but, in combination with either H-7 or apyrase, more than 50% inhibition of platelet aggregation and secretion was observed. This combination of inhibitors was also required to inhibit effectively the phosphorylation of myosin light chain and the 47 kDa substrate of protein kinase C. Intracellular Ca2+ flux monitored by the fluorescent dye fura-2 showed that this was almost completely mediated by the aspirin-sensitive TxA2 pathway. We suggest that the aspirin-insensitive pathway is primarily mediated by phospholipase C formation of diacylglycerol to activate protein kinase C. The inhibition by apyrase suggests a strong dependency on autocrine stimulation by secreted ADP to fully activate both phospholipase C and express fibrinogen-binding sites mediating platelet aggregation. This alternate pathway of phospholipase C activation by ALB-6 may be mediated by cytoplasmic alkalinization [monitored by SNARF-1 (5'(6')-carboxy-10-bismethylamino-3-hydroxy-spiro-[7H- benzo[c]xanthine-1',7(3H)-isobenzofuran]-3'-one) fluorescence of the dye]. Both activation pathways are dependent on intact antibodies, since F(ab')2 fragments of SYB-1, a monoclonal antibody against the CD9 antigen with activation characteristics identical with those of ALB-6, do not elicit activation. Besides thrombin, collagen is another physiological agonist shown to induce aspirin-insensitive activation. Similarities to ALB-6 in collagen sensitivity to apyrase in combination with aspirin inhibitors were noted with respect to aggregation and secretion, as well as a complete block of Ca2+ flux by aspirin. However, it is unlikely that collagen activation is mediated by the CD9 antigen, since SYB-1 F(ab')2 fragments had no effect on collagen activation and aspirin also completely blocked the alkalinization response to collagen, in contrast with ALB-6.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗