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PubMedDate not supplied

The effect of accelerated aging on the wear of UHMWPE.

Oxidative degradation of UHMWPE has been found to be a cause of elevated wear rate of the polymer in total joint replacement leading to failure of these devices. In order to evaluate long term stability of polymers, various accelerated aging methods have been developed. In this study, wear rates of shelf aged UHMWPE and "accelerated aged" UHMWPE were compared using a multi-directional pin-on-plate wear test machine in order to evaluate the effect of the accelerated aging on wear. Wear factors of the aged materials were found to depend on their density, which is a measure of oxidation level. Finally, accelerated aging was calibrated against shelf aging in terms of wear rate.

Journal Article↗

PubMed2001

Superoxide dismutase in senescence-accelerated mouse retina.

To examine the relationship between retinal ageing and superoxide dismutase, we studied the dismutase, with immunohistochemistry and immunoquantitative analysis, in the retina of senescence-accelerated mice P8/Ta (SAMP8/Ta) 3 and 12 months after birth. Accelerated senescence-resistant mice R1TA (SAMR1TA), which show no acceleration of senescence, were used as controls. In SAMP8/Ta, copper-zinc superoxide dismutase and manganese superoxide dismutase immunoreactivity in the photoreceptor inner segments, the outer nuclear layer and the inner nuclear layer increased earlier than in the controls. The increase in both superoxide dismutases with age occurred not only in SAMP8/Ta retinas but also in the controls. In conclusion, we propose the possibility that SAMP8/Ta undergo deterioration not only of learning and memory but also acceleration of senescence in the retina. The dismutases also appear to increase with normal ageing in the retina.

Aging↗

PubMed2002

Choice of parametric accelerated life and proportional hazards models for survival data: asymptotic results.

We discuss the impact of misspecifying fully parametric proportional hazards and accelerated life models. For the uncensored case, misspecified accelerated life models give asymptotically unbiased estimates of covariate effect, but the shape and scale parameters depend on the misspecification. The covariate, shape and scale parameters differ in the censored case. Parametric proportional hazards models do not have a sound justification for general use: estimates from misspecified models can be very biased, and misleading results for the shape of the hazard function can arise. Misspecified survival functions are more biased at the extremes than the centre. Asymptotic and first order results are compared. If a model is misspecified, the size of Wald tests will be underestimated. Use of the sandwich estimator of standard error gives tests of the correct size, but misspecification leads to a loss of power. Accelerated life models are more robust to misspecification because of their log-linear form. In preliminary data analysis, practitioners should investigate proportional hazards and accelerated life models; software is readily available for several such models.

Data Interpretation, Statistical↗

PubMed2002

Role of prostaglandins, nitric oxide, sensory nerves and gastrin in acceleration of ulcer healing by melatonin and its precursor, L-tryptophan.

Melatonin, a major hormone of pineal gland, was recently shown to attenuate acute gastric lesions induced by strong irritants because of the scavenging of free radicals but its role in ulcer healing has been little investigated. In this study we compared the effects of intragastric (i.g.) administration of melatonin and its precursor, L-tryptophan, with or without concurrent treatment with luzindole, a selective antagonist of melatonin MT2 receptors, on healing of chronic gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2). The involvement of endogenous prostaglandins (PG), nitric oxide (NO) and sensory nerves in ulcer healing action of melatonin and L-tryptophan was studied in rats treated with indomethacin and NG-nitro-L-arginine (L-NNA) to suppress, respectively, cyclo-oxygenases (COX) and NO synthases or in those with functionally deactivated sensory nerves with capsaicin. The influence of melatonin on gastric secretion during ulcer healing was tested in separate group of rats with gastric ulcer equipped with gastric fistulas (GF). At day 8 and 15 upon the ulcer induction, the area of gastric ulcers was measured by planimetry, the mucosal blood flow (GBF) was determined by H2-gas clearance technique and gastric luminal NO2-/NO3- levels was assessed by Griess reaction. Plasma melatonin and gastrin levels were measured by specific radioimmunoassay (RIA). Biopsy mucosal samples were taken for expression of constitutive NO-synthase (cNOS) and inducible NOS (iNOS) by reverse transcriptase-polymerase chain reaction (RT-PCR). Melatonin (2.5-20 mg/kg-d i.g.) and L-tryptophan (25-100 mg/kg-d i.g.) dose-dependently accelerated ulcer healing, the dose inhibiting by 50% (ED50) of ulcer area being 10 and 115 mg/kg, respectively. This inhibitory effect of melatonin (10 mg/kg-d i.g.) and L-tryptophan (100 mg/kg-d i.g.) on ulcer healing was accompanied by a significant rise in the GBF at ulcer margin and an increase of plasma melatonin. luminal NO2-/NO3- and plasma gastrin levels. Gastric acid and pepsin outputs were significantly inhibited during the ulcer healing in melatonin-treated gastric mucosa as compared with those in vehicle-treated animals. Luzindole abolished completely the healing effects of melatonin and L-tryptophan and attenuated significantly the rise in plasma gastrin evoked by the hormone and its precursor. Indomethacin (5 mg/kg-d i.p). that blocked PG biosynthesis by 90% or L-NAME (20 mg/kg i.v), inhibitor of NOS. that suppressed luminal NO release, attenuated significantly melatonin and L-tryptophan-induced acceleration of ulcer healing and accompanying rise in GBF at ulcer margin and luminal NO release. The melatonin-induced acceleration of ulcer healing, hyperemia at ulcer margin and increase in the release of NO were enhanced when L-arginine but not D-arginine was added to L-NAME. The ulcer healing and the GBF effects of melatonin and L-tryptophan were significantly impaired in rats with capsaicin-induced denervation of sensory nerves and both, ulcer healing and the hyperemia at ulcer margin were restored in these rats by addition of exogenous CGRP to melatonin and L-tryptophan. Expression of cNOS mRNA was detected by RT-PCR in the intact gastric mucosa as well as at the edge of gastric ulcers treated with both, vehicle and melatonin, while iNOS mRNA that was undetectable in the intact gastric mucosa, appeared during ulcer healing and especially this was strongly up-regulated in the melatonin-treated gastric mucosa. We conclude that (1) exogenous melatonin and that derived from its precursor, L-tryptophan, accelerate ulcer healing probably via interaction with MT2 receptors; (2) this ulcer healing action is caused by an enhancement by melatonin of the microcirculation at the ulcer margin possibly mediated by COX-derived PG and NO because of overexpression of iNOS and (3) gastrin, which exhibits trophic activity in the gastric mucosa and calcitonin gene related peptide (CGRP), released from sensory nerves, may also contribute to the ulcer healing action of melatonin.

Actins↗

PubMed2001

Temporal evolution of the electric field accelerating electrons away from the auroral ionosphere.

The bright night-time aurorae that are visible to the unaided eye are caused by electrons accelerated towards Earth by an upward-pointing electric field. On adjacent geomagnetic field lines the reverse process occurs: a downward-pointing electric field accelerates electrons away from Earth. Such magnetic-field-aligned electric fields in the collisionless plasma above the auroral ionosphere have been predicted, but how they could be maintained is still a matter for debate. The spatial and temporal behaviour of the electric fields-a knowledge of which is crucial to an understanding of their nature-cannot be resolved uniquely by single satellite measurements. Here we report on the first observations by a formation of identically instrumented satellites crossing a beam of upward-accelerated electrons. The structure of the electric potential accelerating the beam grew in magnitude and width for about 200 s, accompanied by a widening of the downward-current sheet, with the total current remaining constant. The 200-s timescale suggests that the evacuation of the electrons from the ionosphere contributes to the formation of the downward-pointing magnetic-field-aligned electric fields. This evolution implies a growing load in the downward leg of the current circuit, which may affect the visible discrete aurorae.

Journal Article↗

PubMed1992

Chronic metabolic acidosis accelerates whole body proteolysis and oxidation in awake rats.

Previous work has documented an acceleration of proteolysis and branched-chain amino acid oxidation when muscles from rats with chronic metabolic acidosis were incubated in vitro. The present study examines the impact of chronic metabolic acidosis on whole body amino acid turnover and oxidation in chronically catheterized awake male Sprague-Dawley rats using stochastic modeling and a primed continuous infusion of L-[1-14C] leucine. Whole body protein turnover was accelerated by acidosis as reflected in a 70% increase in proteolysis and a 55% increase in protein synthesis. Amino acid oxidation was increased 145% in rats with chronic metabolic acidosis relative to control rats receiving diets identical in protein and calories based on a reciprocal pool model and plasma alpha-ketoisocaproate specific radioactivity. These changes were accompanied by a 104% increase in liver branched-chain ketoacid dehydrogenase (BCKAD) activity in rats with acidosis, similar to previously documented increases in skeletal muscle BCKAD activity caused by acidosis. In contrast, kidney BCKAD activity was decreased 38% by acidosis, illustrating the tissue-specificity of the changes that were present. We conclude that chronic metabolic acidosis accelerates whole body protein turnover and affects the reincorporation of amino acid into body proteins by accelerating amino acid oxidation.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed2006

Laser acceleration of quasi-monoenergetic MeV ion beams.

Acceleration of particles by intense laser-plasma interactions represents a rapidly evolving field of interest, as highlighted by the recent demonstration of laser-driven relativistic beams of monoenergetic electrons. Ultrahigh-intensity lasers can produce accelerating fields of 10 TV m(-1) (1 TV = 10(12) V), surpassing those in conventional accelerators by six orders of magnitude. Laser-driven ions with energies of several MeV per nucleon have also been produced. Such ion beams exhibit unprecedented characteristics--short pulse lengths, high currents and low transverse emittance--but their exponential energy spectra have almost 100% energy spread. This large energy spread, which is a consequence of the experimental conditions used to date, remains the biggest impediment to the wider use of this technology. Here we report the production of quasi-monoenergetic laser-driven C5+ ions with a vastly reduced energy spread of 17%. The ions have a mean energy of 3 MeV per nucleon (full-width at half-maximum approximately 0.5 MeV per nucleon) and a longitudinal emittance of less than 2 x 10(-6) eV s for pulse durations shorter than 1 ps. Such laser-driven, high-current, quasi-monoenergetic ion sources may enable significant advances in the development of compact MeV ion accelerators, new diagnostics, medical physics, inertial confinement fusion and fast ignition.

Journal Article↗

PubMed2001

Voltage-dependent acceleration of Ca(v)1.2 channel current decay by (+)- and (-)-isradipine.

Inhibition of Ca(v)1.2 by antagonist 1,4 dihydropyridines (DHPs) is associated with a drug-induced acceleration of the calcium (Ca(2+)) channel current decay. This feature is contradictorily interpreted as open channel block or as drug-induced inactivation. To elucidate the underlying molecular mechanism we investigated the effects of (+)- and (-)-isradipine on Ca(v)1.2 inactivation gating at different membrane potentials. alpha(1)1.2 Constructs were expressed together with alpha(2)-delta- and beta(1a)- subunits in Xenopus oocytes and drug-induced changes in barium current (I(Ba)) kinetics analysed with the two microelectrode voltage clamp technique. To study isradipine effects on I(Ba) decay without contamination by intrinsic inactivation we expressed a mutant (V1504A) lacking fast voltage-dependent inactivation. At a subthreshold potential of -30 mV a 200-times higher concentration of (-)-isradipine was required to induce a comparable amount of inactivation as by (+)-isradipine. At +20 mV the two enantiomers were equally efficient in accelerating the I(Ba) decay. Faster recovery from (-)- than from (+)-isradipine-induced inactivation at -80 mV in a Ca(v)1.2 construct (tau((-)-isr.(Cav1.2))=0.74 s<tau((+)-isr.(Cav1.2))=2.85 s) and even more rapid recovery of V1504A (tau((-)-isr.(V1504A))=0.39 s<tau((+)-isr.(V1504A))=1.98 s) indicated that drug-induced determinants and determinants of intrinsic inactivation (V1504) stabilize the DHP-induced channel conformation in an additive manner. In the voltage range between -25 and 20 mV where the channels inactivate predominantly from the open state the (+)- and (-)-isradipine-induced acceleration of the I(Ba) decay in V1504A displayed similar voltage-dependence as intrinsic fast inactivation of Ca(v)1.2. Our data suggest that the isradipine-induced acceleration of the Ca(v)1.2 current decay reflects enhanced fast voltage-dependent inactivation and not open channel block.

Amino Acid Substitution↗

PubMed2000

Failure of L-arginine to induce hypotension in patients with a history of accelerated-malignant hypertension.

A profound elevation of blood pressure on exercises or after withdrawal of antihypertensive drugs has been reported in patients with a history of accelerated-malignant hypertension. We tested the hypothesis that severe endothelial dysfunction is responsible for the profound hypertensive response in these patients. Responses of blood pressure, heart rate and plasma cyclic guanosine monophosphate to intravenously infused L-arginine, a precursor of nitric oxide, was investigated in hypertensive patients with (group A) or without any history of accelerated-malignant hypertension (group B) in order to evaluate endothelial function. Casual blood pressure or severity of hypertension was not different between group A and B. Infusion of L-arginine decreased mean blood pressure in group B (97.4 +/- 8.7 to 81.7 +/- 6.9 mm Hg), but not in group A (99.0 +/- 10.2 to 101.5 +/- 8.7 mm Hg). Plasma levels of cyclic guanosine monophosphate were increased after infusion of L-arginine in group B (5.4 +/- 2.0 to 7. 7 +/- 1.7 pmol/ml, P< 0.01), while no significant changes were observed in group A (5.4 +/- 2.1 to 5.9 +/- 2.1 pmol/ml). There was a significant correlation between decrease in mean blood pressure and increase in plasma levels of cyclic guanosine monophosphate (r = 0.83, P < 0.001). The results indicated that much more severe endothelial dysfunction is present in hypertensive patients with a history of accelerated-malignant hypertension as compared to those without the history. The difference in the endothelial function may account for the different pressor responses to exercises or other stimuli observed in hypertensive patients with and without a history of accelerated-malignant hypertension. Journal of Human Hypertension (2000) 14, 485-488

Aged↗

PubMed1998

Heparin accelerates the inhibition of cathepsin G by mucus proteinase inhibitor: potent effect of O-butyrylated heparin.

Heparin tightly binds cathepsin G and so protects the enzyme from inhibition by alpha1-antichymotrypsin, alpha1-proteinase inhibitor and eglin c, three proteins which do not bind heparin [Ermolieff J., Boudier C., Laine A., Meyer B. and Bieth J.G. (1994) J. Biol. Chem. 269, 29502-29508]. Here we show that heparin no longer protects cathepsin G from inhibition when the enzyme is reacted with mucus proteinase inhibitor (MPI), a heparin-binding protein. Heparin fragments of Mr=4500 and 8100 and O-butyrylated heparin of Mr=8000 form tight complexes with cathepsin G (Kd=0.5-2.2 nM) and MPI (Kd=0. 4-0.8 muM) and accelerate the MPI-promoted inhibition of cathepsin G by a factor of 17-26. They also accelerate the inhibition of neutrophil elastase and pancreatic chymotrypsin. The rate acceleration is due to the binding of heparin to MPI. Butyrylation of heparin slightly decreases its affinity for cathepsin G and MPI but sharply decreases the ionic interactions between the positively charged proteins and the negatively charged polyanion. The butyrylated heparin derivative is the best rate accelerator: it increases the rate constant for the MPI-induced inhibition of cathepsin G and elastase by factors of 26 and 23, respectively. This, together with the fact that it has a good bioavailability and a very low anticoagulant activity, suggests that it might be an adjuvant of MPI-based therapy of cystic fibrosis.

Animals↗

PubMed2002

Analysis of the influence of diurnal variation in maternal movements on fetal heart rate acceleration.

To determine the influence of diurnal variation in maternal movements (MM) on fetal heart rate (FHR) accelerations, 24-hour maternal heart rates (MHR), MM and FHR recordings were made simultaneously on nine healthy pregnant women at 36-39 weeks of gestation. Correlations between the diurnal variations in maternal factors and FHR parameters; that is, baseline FHR, amplitude, duration and hourly percentage of time spent in accelerations, were examined. Only a few cases showed a significant correlation between acceleration parameters and the diurnal variation of MHR or MM, while most cases indicated a high correlation between the diurnal variation in baseline FHR and that of maternal factors. In conclusion, the occurrence and form of accelerations might be independent of maternal activity.

Analysis of Variance↗

PubMed2002

Accelerated hepatitis B vaccination schedule in childhood.

BACKGROUND: For children travelling to a hepatitis B virus (HBV) endemic area or before a treatment by blood or blood productions, the conventional HBV vaccination schedule takes too long to be completed. There may be problems in the completion of the whole vaccination schedule in developing countries because of particular problems. In these situations an accelerated schedule may be useful for HBV vaccination. METHODS: In this study, 40 children were randomly divided into two groups. Groups were vaccinated according to two different schedules; schedule A: one dose at 0, 1, and 6 months and schedule B: one dose at 0, 10, and 21 days (Engerix B, 10 mcg/0.5 ml, GlaxoSmithKline). Follow-up blood samples were obtained at 1, 6 and 12 months after the first vaccine injection. RESULTS: Seroconversion rates were 35 and 80% 1 month after the first vaccine injection, 95 and 80% at 6 months, 95 and 100% at 12 months, in groups A and B respectively. Seroprotection rates were 20 and 65% 1 month after the first vaccine injection, 85 and 70% at 6 months, 95 and 95% at 12 months, in groups A and B respectively. Seroconversion and seroprotection rates was significantly different at day 28 in accelerated vaccination schedule (P < 0.005). CONCLUSIONS: In conclusion, an accelerated vaccination course against HBV (three doses at 0, 10, and 21 days) elicited protective levels of anti-HBs antibodies more rapidly than a classic course (three doses at 0, 1, and 6 months) and without a difference in the rate of seroprotection after 1 year. The accelerated 3-week recombinant HBV vaccination schedule should be recommended for HBV prophylaxis when children, such as hurried travellers, who have to have blood and blood productions, or an estimated irregular vaccination, where they have < 1 month to complete the standard HBV vaccination schedule before travelling to HBV endemic areas.

Child↗

PubMed1997

Perlecan binds to the beta-amyloid proteins (A beta) of Alzheimer's disease, accelerates A beta fibril formation, and maintains A beta fibril stability.

Perlecan is a specific heparan sulfate proteoglycan that accumulates in the fibrillar beta-amyloid (A beta) deposits of Alzheimer's disease. Perlecan purified from the Engelbreth-Holm-Swarm tumor was used to define perlecan's interactions with A beta and its effects on A beta fibril formation. Using a solid-phase binding immunoassay, freshly solubilized full-length A beta peptides bound immobilized perlecan at two sites, representing both high-affinity [K(D) = approximately 5.8 x 10(-11) M for A beta (1-40); K(D) = approximately 6.5 x 10(-12) M for A beta (1-42)] and lower-affinity [K(D) = 3.5 x 10(-8) M for A beta (1-40); K(D) = 4.3 x 10(-8) M for A beta (1-42)] interactions. An increase in the binding capacity of A beta (1-40) to perlecan correlated with an increase in A beta amyloid fibril formation during a 1-week incubation period. The high-capacity binding of A beta (1-40) to perlecan was similarly observed using perlecan heparan sulfate glycosaminoglycans and was completely abolished by heparin, but not by chondroitin-4-sulfate. Using a thioflavin T fluorometry assay, perlecan accelerated the rate of A beta (1-40) amyloid fibril formation, causing a significant increase in A beta fibril assembly over a 2-week incubation period at 1 h (2.8-fold increase), 1 day (3.6-fold increase), and 3 days (2.8-fold increase) in comparison with A beta (1-40) alone. Perlecan also initially accelerated the formation of A beta (1-42) fibrils within 1 h and maintained significantly higher levels of A beta (1-42) thioflavin T fluorescence throughout a 2-week experimental period in comparison with A beta (1-42) alone, suggesting perlecan's ability to maintain amyloid fibril stability. Perlecan's effects on A beta (1-40) fibril formation and maintenance of A beta (1-42) fibril stability occurred in a dose-dependent manner and was also mediated primarily by perlecan's glycosaminoglycan chains. Perlecan was the most effective enhancer and accelerator of A beta fibril formation when compared directly with other amyloid plaque components, including apolipoprotein E, alpha1-antichymotrypsin, P component, C1q, and C3. This study, therefore, demonstrates that perlecan not only binds to the predominant isoforms of A beta, but also accelerates A beta fibril formation and stabilizes amyloid fibrils once formed, confirming pivotal roles for perlecan in the pathogenesis of A beta amyloidosis in Alzheimer's disease.

Alzheimer Disease↗

PubMedDate not supplied

Development of angiotensin (1-7) as an agent to accelerate dermal repair.

Angiotensin II has been shown to be a potent agent in the acceleration of wound repair. Angiotensin (1-7), a fragment of angiotensin II that is not hypertensive, was found to be comparable to angiotensin II in accelerating dermal healing. This activity was evaluated in four models: rat and diabetic mouse full-thickness excisional wounds; rat random flap; and guinea pig partial thickness thermal injury. In all models, angiotensin (1-7) was comparable to angiotensin II. Angiotensin (1-7) accelerated the closure of wounds in diabetic mice and rats. In diabetic mice the resultant tissue at day 25 after injury was more comparable to normal tissue than the fibrotic scar observed in placebo-treated wounds. In the random flap model, angiotensin (1-7) was comparable to angiotensin II in maintaining flap viability (approximately 82%) and flap survival (40%). Finally, angiotensin (1-7) increased proliferation in the hair follicles at the edge of the wound and site of thermal injury, and the number of patent blood vessels on day 7 after partial thickness thermal injury. These data may be partially explained by the effect of angiotensin II and angiotensin (1-7) on keratinocyte proliferation. While platelet-derived growth factor had no effect on keratinocyte proliferation, angiotensin II and angiotensin (1-7) significantly increased keratinocyte proliferation. These data show that angiotensin(1-7) is comparable to angiotensin II in accelerating skin repair. Furthermore, the hypertensive and wound healing effects can be separated within the family of angiotensin peptides.

Angiotensin I↗

PubMed2002

Hypofractionated and accelerated radiotherapy with amifostine cytoprotection (HypoARC): a new concept in radiotherapy and encouraging results in breast cancer.

Tumors with low intrinsic radiosensitivity, low alpha/beta-ratios and, eventually, hypoxic tumors unable to undergo reoxygenation (because of intrinsic reasons or radiotherapy acceleration that delivers the total dose before the onset of reoxygenation) are likely to respond better to large fractions of radiotherapy. Accelerating the course of hypofractionated radiotherapy would further target tumors with high repopulation ability. Such hypofractionated and accelerated schedules are expected to confer unacceptable toxicity. Accordingly, we investigated the cytoprotective efficacy of amifostine as a potential key to permit the safe administration of such highly toxic regimens. Hypofractionated and accelerated radiotherapy with amifostine cytoprotection (HypoARC; 3.5 to 4 Gy/d x 12 days) was tested in phase I and II trials in patients with breast cancer. Early radiation skin toxicity was significantly lower, and late toxicity from breast, lung, muscle/bone structures, and nerves compared favorably with that associated with standard radiotherapy. The reduced overall treatment time (16 days v 44 days) renders HypoARC appealing, especially to older patients or patients residing some distance from radiotherapy centers. Molecular studies showed that HypoARC significantly improves local relapse-free survival in patients with highly proliferating tumors or tumors overexpressing proteins linked to increased resistance to radiation-induced apoptosis (ie, c-erbB-2 and mutant p53). Further clinical trials have been designed to test the safety and efficacy of HypoARC in other tumor types.

Amifostine↗

PubMed1985

Deficiency of the complement regulatory protein, "decay-accelerating factor," on membranes of granulocytes, monocytes, and platelets in paroxysmal nocturnal hemoglobinuria.

Erythrocytes from patients with paroxysmal nocturnal hemoglobinuria are deficient in decay-accelerating factor, a membrane protein that inhibits the complement C3 convertases. We studied the expression of this protein on leukocytes and platelets from four patients with paroxysmal nocturnal hemoglobinuria, using cytofluorographic analysis and antibody to decay-accelerating factor. The granulocytes and monocytes had a bimodal distribution of fluorescence, indicating antigen-deficient and antigen-positive subpopulations of cells. In contrast, granulocytes and monocytes from normal donors and patients with other diseases had no antigen-deficient cells. Platelets from the four patients with paroxysmal nocturnal hemoglobinuria had less fluorescence than normal platelets. Furthermore, surface-radiolabeled granulocytes and platelets from one of the four patients, which were maximally deficient in decay-accelerating factor, also lacked antigen that was immunoprecipitable by specific antibody to this protein. Thus, paroxysmal nocturnal hemoglobinuria is a clonal disorder characterized by deficient membrane expression of decay-accelerating factor on granulocytes, monocytes, and platelets, as well as on erythrocytes.

Adult↗

PubMed1981

Insulin-induced receptor loss in cultured human lymphocytes is due to accelerated receptor degradation.

We have measured the turnover rate of the polypeptide subunits of the insulin receptor in cultured human lymphocytes (IM-9 line) and have investigated the mechanism of insulin-induced receptor loss. To estimate the rate of receptor degradation, lymphocytes were either pulse-labeled with [35S]methionine or surface labeled with Na125I and lactoperoxidase. The insulin receptor was isolated by immunoprecipitation with anti-receptor antibody, and the rate of loss of radioactivity from each receptor subunit was determined after sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Two major (Mr 135,000 and 95,000) and one minor (Mr 210,000) subunits were found. By both labeling methods, the half-lives of the major insulin receptor subunits were 9--12 hr in normal media. When the cells were cultured in media containing 1 microM insulin the turnover was accelerated 2.5- to 3.5-fold (half-life approximately 3 hr). The increase in degradation rate was dependent on the insulin concentration and correlated well with the ability to "down-regulate" the receptor. Guinea pig insulin was about 2% as active as porcine insulin in accelerating degradation, and human growth hormone was without effect. The acceleration of receptor degradation induced by insulin was partially blocked by 100 microM cycloheximide. The rate of biosynthesis of the insulin receptor did not appear to be altered in the presence of 1 microM insulin after correction for the change in degradation rate. In conclusion, these data demonstrate that insulin-induced receptor loss in cultured lymphocytes is due to accelerated receptor degradation.

Animals↗

PubMed1986

Human fibroblasts accelerate the inhibition of thrombin by protease nexin.

Protease nexin (PN) is a protein protease inhibitor secreted by human fibroblasts in culture that complexes and inhibits certain regulatory serine proteases. The PN-protease complexes then bind to these cells and are rapidly internalized and degraded. This report shows that the fibroblast surface accelerates the formation of PN-thrombin complexes. In contrast, it did not accelerate the formation of complexes between thrombin and antithrombin III, a closely related protease inhibitor found in plasma. These results support a role for PN in the regulation of certain proteases in the extravascular compartment at and near the surface of tissue cells. The activity that accelerated PN-thrombin complex formation was membrane-associated, since fixed cells, purified membranes, and extracellular matrix preparations all contained this activity. The ability of cells to accelerate the reaction between PN and thrombin was inhibited by protamine, suggesting that the activity was similar to that of heparin. Heparitinase digestion of plasma membranes prior to assay reduced the activity by about 80%, suggesting that heparan sulfate may account for most of the accelerative activity.

Amyloid beta-Protein Precursor↗