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PubMed1994

Comparison of immunoturbidimetric and Lowry methods for measuring concentration of very low density lipoprotein apolipoprotein B-100 in plasma.

To assess whether the Lowry-tetramethylurea method for measuring apolipoprotein B-100 (apo-B) in very low density lipoprotein (VLDL) could be replaced by direct assay of VLDL apo-B using a highly practicable immunological method. Seventy five fasting blood samples were collected from patients attending the lipid clinic at this hospital. Plasma was separated immediately and VLDL isolated by preparative ultracentrifugation at solution density 0.93-1.006 kg/l. Apo-B was precipitated from an aliquot of the VLDL fraction using the tetramethylurea (TMU) technique and protein mass determined by the Lowry method (LM); mean apo-B 83.02 micrograms/ml (SD 74.85). Apo-B was also measured in VLDL using direct immunoturbidimetry on the Cobas-Fara analyser; mean apo-B 82.32 micrograms/ml (SD 72.88). There was a very close correlation between methods (immunoturbidimetry = 0.94.LM + 3.95, r = 0.97, p < 0.001). The mean difference between methods (constant error) was small (0.70 microgram/ml) and not significant (p = 0.742). Random error was 13.01 micrograms/ml by analysis of variance. It is concluded that immunoturbidimetry, a more rapid and convenient test, may replace the LM and TMU techniques for measuring VLDL apo-B concentration and that this method could be applied to research studies requiring analysis of large numbers of samples.

Apolipoprotein B-100↗
PubMed1983

Metabolism of NG-monomethyl-L-arginine.

Rat kidney contains an enzyme which hydrolyzes NG-monomethyl-L-arginine to give rise to the formation of ornithine and N-methylurea. Confirmation of formation of these reaction products is carried out colorimetrically as well as radiochemically employing NG-monomethyl-L-[ornithine-14C(U)]arginine. This pattern of reaction products suggests that the enzyme responsible is an arginase type. However, the kidney enzyme is quite distinct from the hepatic arginase; commercial bovine hepatic arginase (L-arginine amidinohydrolase, EC 3.5.3.1) is completely inactive toward NG-monomethyl-L-arginine. Among various rat tissues examined, the hydrolytic activity is the highest in kidney, followed by the activity in liver and pancreas.

Animals↗
PubMed2002

Biochemical and pharmacological activities of SSR 146977, a new potent nonpeptide tachykinin NK3 receptor antagonist.

SSR 146977 is a potent and selective antagonist of the tachykinin NK3 receptor. In Chinese hamster ovary cells expressing the human tachykinin NK3 receptor, SSR 146977 inhibited the binding of radioactive neurokinin B to NK3 receptors (Ki = 0.26 nM), senktide (10 nM) induced inositol monophosphate formation (IC50 = 7.8-13 nM), and intracellular calcium mobilization (IC50 = 10 nM). It antagonized [MePhe7]neurokinin B induced contractions of guinea pig ileum (pA2 = 9.07). Senktide (30 nM) induced firing rate increase of noradrenergic neurons in the guinea pig locus coeruleus and dopaminergic neurons in the guinea pig substantia nigra was also blocked by SSR 146977 (50 and 100 nM, respectively). In vivo, in the respiratory system, SSR 146977 inhibited bronchial hyperresponsiveness to acetylcholine, bronchial microvascular permeability hypersensitivity to histamine (doses of 0.1-1 mg/kg i.p.), and cough (doses of 0.03-1 mg/kg i.p.) provoked by citric acid in guinea pigs. In the central nervous system, SSR 146977 inhibited turning behaviour (ID50 = 0.2 mg/kg i.p. and 0.4 mg/kg p.o.) and prevented the decrease of locomotor activity (10 and 30 mg/kg i.p) mediated by the stimulation of NK3 receptors in gerbils. In guinea pigs, SSR 146977 antagonized senktide-induced acetylcholine release in the hippocampus (0.3 and 1 mg/kg i.p) and norepinephrine release in the prefrontal cortex (0.3 mg/kg i.p.). It also prevented haloperidol-induced increase of the number of spontaneously active dopamine A10 neurons (1 and 3 mg/kg i.p.).

Animals↗
PubMed2006

Acute regulation of mUT-A3 urea transporter expressed in a MDCK cell line.

Renal facilitative urea transporters play a vital role in the urinary concentrating mechanism. UT-A3 is a phloretin-sensitive urea transporter that in the mouse is expressed on the basolateral membrane of renal inner medullary collecting duct (IMCD) cells. In this study, we engineered a Madin-Darby canine kidney (MDCK) I cell line that stably expresses mouse UT-A3 (MDCK-mUT-A3). Immunoblotting using the UT-A-targeted antibody ML446 detected a approximately 40-kDa signal in MDCK-mUT-A3 protein that corresponds to mUT-A3. Using cultured epithelial monolayers, radioactive (14)C-urea flux experiments determined that basolateral urea transport was no different between MDCK-mUT-A3 and control MDCK-FLZ cells under basal conditions [not significant (NS), ANOVA]. However, exposure to arginine vasopressin (AVP) significantly stimulated basolateral urea flux in MDCK-mUT-A3 monolayers (P < 0.05, ANOVA), while it had no effect in control MDCK-FLZ monolayers (NS, ANOVA). The AVP-stimulated basolateral urea transport in MDCK-mUT-A3 was inhibited by 1,3 dimethyl urea (P < 0.05, ANOVA) or phloretin (P < 0.05, ANOVA), both known inhibitors of facilitative urea transporters. MDCK-mUT-A3 basolateral urea flux was also stimulated by increasing intracellular levels of cAMP, via forskolin (P < 0.05, ANOVA), or intracellular calcium, via ATP (P < 0.05, ANOVA). Finally, 1-h preincubation with a specific PKA inhibitor, H89, significantly inhibited the increase in urea transport produced by AVP (P < 0.05, ANOVA). In conclusion, we have produced the first renal cell line to stably express the mUT-A3 urea transporter. Our results indicate that mUT-A3 is acutely regulated by AVP, via a PKA-dependent pathway. These findings have important implications for the regulation of urea transport in the renal IMCD and the urinary concentrating mechanism.

Animals↗
PubMed2005

In vitro and in vivo clinical pharmacology of dimethyl benzoylphenylurea, a novel oral tubulin-interactive agent.

Dimethyl benzoylphenylurea (BPU) is a novel tubulin-interactive agent with poor and highly variable oral bioavailability. In a phase I clinical trial of BPU, higher plasma exposure to BPU and metabolites was observed in patients who experienced dose-limiting toxicity. The elucidation of the clinical pharmacology of BPU was sought. BPU, monomethylBPU, and aminoBPU were metabolized by human liver microsomes. Studies with cDNA-expressed human cytochrome P450 enzymes revealed that BPU was metabolized predominantly by CYP3A4 and CYP1A1 but was also a substrate for CYP2C8, CYP2D6, CYP3A5, and CYP3A7. BPU was not a substrate for the efflux transporter ABCG2. Using simultaneous high-performance liquid chromatography/diode array and tandem mass spectrometry detection, we identified six metabolites in human liver microsomes, plasma, or urine: monomethylBPU, aminoBPU, G280, G308, G322, and G373. In patient urine, aminoBPU, G280, G308, and G322 collectively represented <2% of the given BPU dose. G280, G308, G322, and G373 showed minimal cytotoxicity. When BPU was given p.o. to mice in the presence and absence of the CYP3A and ABCG2 inhibitor, ritonavir, there was an increase in BPU plasma exposure and decrease in metabolite exposure but no overall change in cumulative exposure to BPU and the cytotoxic metabolites. Thus, we conclude that (a) CYP3A4 and CYP1A1 are the predominant cytochrome P450 enzymes that catalyze BPU metabolism, (b) BPU is metabolized to two cytotoxic and four noncytotoxic metabolites, and (c) ritonavir inhibits BPU metabolism to improve the systemic exposure to BPU without altering cumulative exposure to BPU and the cytotoxic metabolites.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1988

Influence of hydroxyl radical scavengers on platelet function.

The influence of four hydroxil radical (OH.) scavengers on platelet function was investigated. OH. scavengers inhibited ADP, collagen, arachidonic acid, PAF-induced platelet aggregation, and platelet cyclooxygenase pathway activation, which was studied by evaluating platelet malondialdehyde and serum thromboxane A2 formation. The latter was not affected by superoxide dismutase, catalase, or metal ion chelants such as desferioxamine or DETAPAC. The detection of deoxyribose degradation by stimulated platelets suggested that platelets produce OH.. This study shows that activated platelets produce free radicals and that antioxidant agents such as OH. scavengers inhibit platelet function.

Adult↗
PubMed1980

Effects of the differentiating agents (inducers) dimethylacetamide, di- and tetramethylurea on epidermal tumor promotion by retinyl (vitamin A) acetate and croton oil in hamster cheek pouch.

The cell-differentiating agents (inducers) dimethylacetamide, dimethylurea and tetramethylurea significantly lowered the yields and/or incidences of total tumors, benign plaques, benign hyperkeratotic lesions and advanced tumors promoted by retinyl acetate or croton oil after initiation by 7,12-dimethylbenz(a)anthracene. The percentage of plaques was increased by the inducers suggesting that they inhibited progression of plaques to more advanced tumors. These results suggest that topical application of inducers might have therapeutic potential in epidermal carcinoma.

Acetamides↗
PubMed1989

Bacterial cell surface hydrophobicity properties in the mediation of in vitro adhesion by the rabbit enteric pathogen Escherichia coli strain RDEC-1.

The role of hydrophobicity in the attachment of enteropathogens to gastrointestinal mucosa is controversial. In vitro binding of Escherichia coli RDEC-1 to rabbit intestine is dependent on the expression of pili. We examined in vitro adherence of piliated RDEC-1 after altering either the hydrophobicity of the organisms, the hydrophobicity of the substrate for attachment, or the surface tension of the suspending liquid. Hydrophobicity of RDEC-1 was determined using four complementary methods. In each assay piliated RDEC-1 demonstrated relatively more hydrophobic properties compared with both organisms grown to suppress pilus expression and a mutant that cannot express mannose-resistant pili. When piliated RDEC-1 were pretreated with tetramethyl urea to disrupt hydrophobic bonds surface hydrophobicity decreased. Concurrently, bacterial adherence to rabbit ileal microvillus membranes, mucus and mucin was reduced. Binding of piliated organisms to hydrophobic surfaces was significantly higher compared to both nonpiliated bacteria and the adherence of piliated RDEC-1 to relatively hydrophilic surfaces. Addition of propanol reduced the surface tension of the suspending liquid, and decreased adhesion of piliated RDEC-1 to polystyrene by 80%. Conversely, adherence of piliated organisms to a hydrophilic surface increased 12-fold after lowering the surface tension of the suspending liquid. We conclude that hydrophobic properties have a role in mediating in vitro adherence of this E. coli enteric pathogen.

Animals↗
PubMed1992

Binding of nonmucoid Pseudomonas aeruginosa to normal human intestinal mucin and respiratory mucin from patients with cystic fibrosis.

Lung infections due to Pseudomonas aeruginosa and Pseudomonas cepacia are common in patients with cystic fibrosis. Initial colonization is due to nonmucoid P. aeruginosa, while later mucoid variants emerge and are associated with chronic infection. P. cepacia colonization tends to be more prevalent in older patients. The present study was conducted to discover whether highly purified mucins (from cystic fibrosis sputum and control intestinal secretions) exhibited specific binding of nonmucoid P. aeruginosa. In vitro solid phase microtiter binding assays (with or without a blocking agent) as well as solution phase assays were conducted. Bacteria bound to both mucins via bacterial pili, but no differences in binding capacity were noted between the mucins. Unlike P. cepacia (described in the accompanying manuscript) there was also no preferential binding of P. aeruginosa to mucins versus bovine serum albumin, casein, gelatin, or a host of structurally unrelated proteins and glycoproteins. Carbohydrate hapten inhibition studies did not suggest the existence of specific mucin carbohydrate receptors for P. aeruginosa. In solid phase assays a low concentration (0.05 M) of tetramethylurea abolished P. aeruginosa bacterial binding to both mucins as well as to BSA, whereas in solution phase assays mucin binding to bacteria was not completely disrupted by tetramethylurea. Specific monoclonal antipilus antibodies did not inhibit binding to a greater extent than did Fab fragments of normal mouse IgG. Binding of strains PAO1 and PAK (and isolated PAK pili) to buccal epithelial cells was not influenced by the presence of mucin in binding assay mixtures. Our findings do not support the widely held notion that specific mucin receptors are responsible for the attachment of P. aeruginosa pili, nor do they support the idea that there is a competitive interference by mucins of bacterial binding to respiratory cells. In patients with cystic fibrosis, it would seem unlikely therefore that initial colonization of the lungs by P. aeruginosa is due to a 'selective tropism' of these bacteria for respiratory mucin.

Bacterial Adhesion↗
PubMed1997

Sensitivity of Kaposi's sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy.

Using a cell line (termed BCBL-1) derived from a peripheral effusion (body cavity-based) lymphoma latently infected with Kaposi's sarcoma-associated herpesvirus (KSHV), we recently reported the successful induction of KSHV replication in culture (Renne, R., W. Zhong, B. Herndier, M. McGrath, N. Abbey, D. Kedes, and D. Ganem. 1996. Nat. Med. 2:342-346). Here we report the first use of this system for establishing the susceptibility of KSHV to available antiviral drugs. Latently infected BCBL-1 cells were induced to lytic replication with phorbol esters; such cells secrete large numbers of KSHV virions into the culture medium. We assayed the ability of the antivirals to block KSHV production, as measured by the release of encapsidated viral DNA. The results show that KSHV replication is insensitive to acyclovir (9-[(2-hydroxyethoxy)-methyl]guanine) (50% inhibitory concentration [IC50] = 60-80 microM), but sensitive to ganciclovir (9-[1,3-dihydroxy-2-propoxymethyl]guanine) (IC50 = 2.7-4 microM), foscarnet (trisodium phosphonoformate hexahydrate) (IC50 = 80-100 microM), and cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine) (IC50 = 0.5-1 microM).

Acyclovir↗
PubMed1993

Do the hydrolysis products, methylamine and N,N'-dimethylurea, play any role in the methyl isocyanate-induced haematological and biochemical changes in rabbits?

The subcutaneous administration of methyl isocyanate (MIC) to female rabbits, resulted in significant increases in haemoglobin concentration, erythrocyte volume fraction and leucocyte number in blood, as well as plasma total proteins, and urea. The present study was designed to investigate whether the hydrolytic products of MIC, methylamine (MA) and N,N'-dimethylurea (DMU) play any role in eliciting these changes. Both MA and DMU administered subcutaneously in an equimolar dose to that of 1.0 LD50 MIC, 2.2 mmol kg-1, had no influence on these parameters, although there was a marginal increase in the plasma urea level shortly after the administration of DMU. This study establishes that the observed haematological and biochemical changes induced by MIC intoxication in rabbits are mostly due to MIC.

Animals↗
PubMed1978

Isolation and characterization of fragments of reduced and S-carbamidomethylated human growth hormone produced by plasmin digestion. I. Chemistry.

Reduced and S-carbamidomethylated human GH (RCAM-hGH) was digested with human plasmin, yielding a mixture of products. These were partially separated by chromatography on DEAE-cellulose, yielding three major fractions: Da and Db, which were equipotent with native hGH in the weight gain test; and Dc, which was about half as active as hGH. Each of these was further purified by gel filtration, yielding a number of subfractions which were characterized as follows: Da1 is a very stable noncovalent complex of residues 1--134 and 141--191 of RCAM-hGH; Da2 represents residues 20--41; Db1 is very similar to Da1, but appears to have lost one or more amide groups; Db3 represents residues 95--134; Dc2 is a heterogenous fraction containing a further deamidated version of Da1 and Db1 plus a similar complex of residues 42--134 and 141--191, apparently with some carboxyterminal heterogeneity; Dc3, like Db3, represents residues 95--134. The biological activities of these fragments are discussed in the accompanying paper. Earlier work has shown that native hGH, upon digestion with plasmin, is cleaved primarily at residues 134 and 140. It is shown here that when RCAM-hGH is digested with plasmin, in about 87% of the molecules at least one cleavage takes place in addition to those at residues 134 and 140.

Animals↗
PubMed1989

Studies on the mechanisms causing inhibition of insulin secretion in rat pancreatic islets exposed to human interleukin-1 beta indicate a perturbation in the mitochondrial function.

This study aimed at a more detailed characterization of the mechanisms by which interleukin 1 (IL-1) inhibits insulin secretion. For this purpose, isolated rat pancreatic islets were kept in tissue culture for 5 days in medium RPMI 1640 plus 10% calf serum. The islets were subsequently transferred to the same culture medium containing various test substances plus 1% human serum with or without 25 U/ml human recombinant IL-1 beta. After a culture period of 48 h the islet structure was examined in the electron microscope and the islet function studied in short term incubations in the absence of IL-1. Islets exposed to IL-1 showed ultrastructural signs of degeneration in 10-20% of the B cells while such changes were not found in other types of islet cells. An increased number of secondary lysosomes and occasional myelin figures were observed in the B cells exposed to IL-1. These ultrastructural alterations were, however, reversed in islets cultured in cytokine-free medium for 6 days after the IL-1 treatment. In islets cultured in the presence of 11.1 mM glucose only, or 11.1 mM glucose plus 10 mM nicotinamide, 61 mM dimethyl area, 2 micrograms/ml indomethacin, 10 microM 4-bromophenacyl bromide or 10 microM nordihydroguaiaretic acid, 10 microM phenantroline, and 0.1 or 1.0 microgram/ml cyclosporin A, IL-1 reduced the insulin release by 64-85%. Culture at 5.6 mM glucose did not modify the IL-1-induced inhibition of insulin release, whereas a significant protective effect was observed at 28 or 56 mM glucose. The DNA content in IL-1-exposed islets cultured at 11.1 mM glucose was decreased by about 20% but not in islets cultured at other glucose concentrations. The D-[5-3H]glucose utilization at 16.7 mM glucose was unaffected by IL-1, whereas the oxidation of D-[6-14C]glucose was reduced by 50%. The present results suggest that IL-1-induced inhibition of insulin secretion is related to a disturbed mitochondrial function. This effect is not counteracted by a poly(ADP-ribose) synthetase inhibitor, a hydroxyl radical scavenger, an iron chelator, a T lymphocyte-specific immunosuppressive drug, or inhibitors of phospholipase A2 or inhibitors of prostaglandin and leukotriene synthesis. Thus, IL-1-induced inhibition of insulin secretion seems not to be mediated by the same mechanisms as those causing alloxan- or streptozotocin-induced damage of B cells. Furthermore, the action of IL-1 does not appear to be mediated via arachidonic acid metabolism. Glucose affords some protection, probably by enhancing the B cell mitochondrial function.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetophenones↗
PubMed1992

Interleukin-1 beta increases the activity of superoxide dismutase in rat pancreatic islets.

The suppressive effects of interleukin-1 beta (IL-1 beta) on the function of pancreatic islets may be related to induction of gene transcription and protein synthesis. Presently, the effects of human recombinant IL-1 beta (rIL-1 beta) on the activities of superoxide dismutase (SOD) and the expression of corresponding genes were studied in rat pancreatic islets. Islets that were exposed to rIL-1 beta for 48 h showed a 2.6-fold greater activity of mitochondrial manganese containing SOD (MnSOD) than control islets. The cytosolic copper- and zinc-containing SOD (CuZnSOD) was, however, less affected by rIL-1 beta. Also, brief exposure of the islets to rIL-beta induced an increase in SOD activities. Hence, 12 h after a 1-h exposure of the islets to rIL-1 beta, there was a 1.4-fold increase in the activity of both MnSOD and CuZnSOD. The early induction of SOD by rIL-1 beta was inhibited by an interleukin-1 receptor antagonist protein and actinomycin-D, which is a blocker of gene transcription. This suggests that the effects of rIL-1 beta on the islet SOD activities are dependent on binding to membrane receptors and activation of gene transcription. Northern blot analysis showed a 4-fold increase in islet MnSOD mRNA content after a 90-min incubation and a 10-fold increase after a 180-min incubation with rIL-1 beta. Thus, the enhanced MnSOD activity in the islets reflects increased gene expression. To evaluate a possible role for free oxygen radicals as mediators of the early action of rIL-1 beta on the pancreatic B-cells, isolated islets were exposed to rIL-1 beta only or to rIL-1 beta plus various free radical scavengers. None of the scavengers, single or in combinations, could counteract the suppressive action of rIL-1 beta on islet insulin secretion. The present data suggest that rIL-1 beta induces increased activity of SOD, in particular MnSOD, in pancreatic islets. This may be due to a direct action of rIL-1 beta that is mediated by an increase in gene transcription.

Actins↗
PubMed2000

O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate-N-hydroxysuccinimide-CuCl2: a facile and reliable system for racemization-free coupling of peptides having a carboxy-terminal N-methylamino acid.

Simultaneous use of N-hydroxysuccinimide (HOSu) and CuCl2 with a HOSu-based uronium coupling reagent, O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate, has been found to eliminate the racemization of the carboxy-terminal N-methylamino acid residue during the segment condensation.

Amino Acids↗