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PubMed2005

Cdc25A and ERK interaction: EGFR-independent ERK activation by a protein phosphatase Cdc25A inhibitor, compound 5.

Extracellular signal-regulated kinase (ERK) plays a central role in regulating cell growth, differentiation, and apoptosis. We previously found that 2-(2-mercaptoethanol)-3-methyl-1,4-napthoquinone or Compound 5 (Cpd 5), is a Cdc25A protein phosphatase inhibitor and causes prolonged, strong ERK phosphorylation which is triggered by epidermal growth factor receptor (EGFR) activation. We now report that Cpd 5 can directly cause ERK phosphorylation by inhibiting Cdc25A activity independently of the EGFR pathway. We found that Cdc25A physically interacted with and de-phosphorylated phospho-ERK both in vitro and in cell culture. Inhibition of Cdc25A activity by Cpd 5 resulted in ERK hyper-phosphorylation. Transfection of Hep3B human hepatoma cells with inactive Cdc25A mutant enhanced Cpd 5 action on ERK phosphorylation, whereas over-expression of Cdc25A attenuated this Cpd 5 action. Furthermore, endogenous Cdc25A knock-down by Cdc25A siRNA resulted in a constitutive-like ERK phosphorylation and Cpd 5 treatment further enhanced it. In EGFR-devoid NR6 fibroblasts and MEK (ERK kinase) mutated MCF7 cells, Cpd 5 treatment also resulted in ERK phosphorylation, providing support for the idea that Cpd 5 can directly act on ERK phosphorylation by inhibiting Cdc25A activity. These data suggest that phospho-ERK is likely another Cdc25A substrate, and Cpd 5-caused ERK phosphorylation is probably regulated by both EGFR-dependent and EGFR-independent pathways.

Cell Line, Tumor↗
PubMed2006

Phosphorylation regulates Myc expression via prolonged activation of the mitogen-activated protein kinase pathway.

We previously showed that prolonged and strong ERK phosphorylation induced by Compound 5 (Cpd 5), a Cdc25A protein phosphatase inhibitor, was involved in its mechanism of cell growth inhibition. To study the relationship between ERK phosphorylation and cell growth inhibition, we used Cpd 5 as a tool to investigate ERK-regulated c-Myc expression in Hep3B hepatoma cells. We found that ERK phosphorylation caused by Cpd 5 induced c-Myc phosphorylation, but suppressed c-Myc expression at the mRNA and protein levels. Furthermore, Cpd 5 inhibited c-Myc transcriptional activity and DNA binding ability, and this inhibition was antagonized by ERK kinase (MEK) inhibitor U-0126, implying that the ERK pathway was involved in regulating c-Myc expression. Since the participation of c-Myc protein in transcription requires its dimerization with Max protein, we examined the Myc-Max association in Cpd 5-treated cells and found that Cpd 5 suppressed Myc-Max dimerization. Transfection of Hep3B cells with mutated ERK (T188A/Y190F), which has lost its dual-phosphorylation sites, attenuated the actions of Cpd 5 on Myc-Max association. To further demonstrate whether Myc phosphorylation by Cpd 5-induced ERK activation was able to directly regulate c-myc gene expression, a chromatin immunoprecipitation (ChIP) assay was used to examine the binding of phospho-Myc to the c-myc promoter region. We found that phospho-Myc induced by Cpd 5 had lost its ability to bind to the c-myc promoter, whereas MEK inhibitor U-0126 antagonized this inhibitory effect. These data suggest that an increase in c-Myc phosphorylation in response to prolonged ERK phosphorylation negatively auto-regulates c-Myc gene expression, leading to the suppression of its target gene expression and cell cycle block.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed2005

Spinal canal narrowing during simulated frontal impact.

Between 23 and 70% of occupants involved in frontal impacts sustain cervical spine injuries, many with neurological involvement. It has been hypothesized that cervical spinal cord compression and injury may explain the variable neurological profile described by frontal impact victims. The goals of the present study, using a biofidelic whole cervical spine model with muscle force replication, were to quantify canal pinch diameter (CPD) narrowing during frontal impact and to evaluate the potential for cord compression. The biofidelic model and a sled apparatus were used to simulate frontal impacts at 4, 6, 8, and 10 g horizontal accelerations of the T1 vertebra. The CPD was measured in the intact specimen in the neutral posture (neutral posture CPD), under static sagittal pure moments of 1.5 Nm (pre-impact CPD), during dynamic frontal impact (dynamic impact CPD), and again under static pure moments following each impact (post-impact CPD). Frontal impact caused significant (P<0.05) dynamic CPD narrowing at C0-dens, C2-C3, and C6-C7. The narrowest dynamic CPD was observed at C0-dens during the 10 g impact and was 25.9% narrower than the corresponding neutral posture CPD. Interpretation of the present results indicate that the neurological symptomatology reported by frontal impact victims is most likely not due to cervical spinal cord compression. Cord compression due to residual spinal instability is also not likely.

Acceleration↗
PubMed1991

Hemispheric asymmetry in the processing of absolute versus relative spatial frequency.

Observers indicated whether a stimulus presented to one visual field or the other consisted of two sine-wave gratings (the baseline stimulus) or those same two gratings with the addition of a 2 cycle per degree (cpd) component. When the absolute spatial frequencies of the baseline stimulus were low (0.5 and 1.0 cpd), there was a left visual field-right hemisphere (LVF-RH) advantage in reaction time (RT) to respond to the baseline stimulus which disappeared when the 2 cpd component was added (i.e., the stimulus consisted of 0.5, 1.0, and 2.0 cpd components). When the absolute spatial frequencies of the baseline stimulus were moderate to high (4.0 and 8.0 cpd), a right visual field-left hemisphere advantage in RT to respond to the baseline stimulus approached significance and shifted to a significant LVF-RH advantage when the 2 cpd component was added (i.e., the stimulus consisted of 2.0, 4.0, and 8.0 cpd components. That is, adding the same 2 cpd component caused opposite shifts in visual laterality depending on whether 2 cpd was a relatively high or relatively low frequency compared to the baseline.

Dominance, Cerebral↗
PubMed1998

Spatial-frequency and contrast tuning of the transient-stereopsis system.

The tuning of the transient-stereopsis system to luminance contrast and spatial-frequency (SF) was investigated with narrow-band gabor targets with a constant sigma of 1 degree. They were presented for brief (140 ms) durations and subtended a large (6 degrees) disparity. When dichoptic gabor stimuli were matched in SF (0-5 cpd), transient stereo performance was either uniform across SF or greater at frequencies below 1 cpd. When dichoptic stimuli had unmatched SF (0.5 + 0-5 cpd) and matched contrast (100%), stereo performance was impaired below that of the matched SF condition. Stereo performance with matched SF at 0.5 cpd was impaired when contrast of one eye's image was reduced, demonstrating a contrast-paradox effect (i.e. contrast tuning) for transient stereopsis. Performance with three dichoptic unmatched SF conditions (0.5 and 1.0 cpd; 0.5 and 5.0 cpd; 1.5 and 3.5 cpd) was improved when the contrasts of the low SF gabor was reduced while holding the contrast of the high SF gabor constant at 100%. However stereo performance was not improved by reducing the contrast of a high SF gabor (3.5 cpd) while holding the contrast of the lower SF gabor (1.5 cpd) constant at 100%. We interpret these findings as indicating that transient-stereopsis performance is mediated by a single spatial-channel that has low-pass spatial-frequency sensitivity and which compares the ocular based signals prior to binocular combination so that signals that are not balanced in terms of their strength lead to a weaker binocular signal, as per the model proposed by Kontsevich and Tyler (Vis Res 1994; 3417:2317-2329) for sustained stereopsis.

Contrast Sensitivity↗
PubMed1996

Fungal peritonitis in a large chronic peritoneal dialysis population: a report of 55 episodes.

Fungal peritonitis (FP) is a rare but serious complication of chronic peritoneal dialysis (CPD) therapy and is associated with high morbidity and CPD drop-out. Risk factors and management of FP remain controversial. We reviewed our experience with FP in an attempt to identify risk factors and to examine outcome in relation to treatment strategies. Between March 1984 and August 1994, 704 patients were maintained on CPD therapy in our unit. A total of 1,712 episodes of peritonitis were identified among these patients. Fungal peritonitis accounted for 55 (3.2%) of these episodes. The patients on CPD therapy who developed FP were similar to those who did not develop FP with regard to age, gender, underlying etiology for end-stage renal disease, and comorbid disease. Prior antibiotic use was noted in 87.3% of episodes of FP. The peritonitis rate in the patients who developed FP was one episode every 5.1 months compared with one episode every 9.9 patient-months in the CPD patients who did not develop this infection. Candida sp caused 74.5% of the episodes of FP. All patients were treated with antifungal drugs. In 85.5% of infections the Tenckhoff catheter was removed within 1 week of the diagnosis of FP; 31.9% of the patients who had the Tenckhoff catheter removed did not have the catheter replaced because of death or transfer to hemodialysis. In the patients who developed FP, 68.1% had the Tenckhoff catheter replaced; of these patients, 90.6% and 59.4% were on CPD therapy 1 and 6 months after catheter replacement, respectively. We conclude that risk factors identified in our population include peritonitis rate and prior antibiotic use. Fungal peritonitis is rare in our CPD population, and although it leads to significant CPD drop-out, it can be managed in many patients with antifungal therapy, early catheter removal, and temporary hemodialysis. Of the catheters replaced between 2 and 8 weeks after the diagnosis of FP, 91% functioned successfully, allowing continuation of CPD.

Amphotericin B↗
PubMed1998

Contrast sensitivity and glare disability with diffractive and refractive multifocal intraocular lenses.

PURPOSE: To compare contrast sensitivity and glare disability provided by diffractive and refractive multifocal intraocular lenses (IOLs). SETTING: University Eye Clinic Vienna, Austria. METHOD: This study evaluated the contrast sensitivity and glare disability in 29 eyes with a diffractive multifocal IOL (3M815LE) and 12 with a three-piece, five-zone refractive multifocal IOL (AMO Array SSM 26 NB). The Brightness Acuity Tester (Mentor, Inc.) was used with stationary sinusoidal gratings at spatial frequencies of 0.5, 1, 3, 6, 11.4, and 22.8 cycles per degree (cpd) generated on a television monitor (Nicolet CS 2000). RESULTS: The contrast sensitivity functions of both multifocal IOL groups were within the reference range and were identical at 0.5, 1, and 22.8 cpd spatial frequencies. At 3, 6, and 11.4 cpd, the contrast sensitivity function in the diffractive IOL group was 6, 9, and 10% lower than in the refractive IOL group, and the difference between groups was statistically significant at 6 cpd. When glare was present, contrast sensitivity in the diffractive IOL group was generally in the lower limit of the reference range and remained below at 3 and 6 cpd. Contrast sensitivity in the refractive IOL group remained below the reference range at 3 cpd. At 0.5 and 1 cpd, there were no differences between the groups. At the middle and high spatial frequencies (3, 6, 11.4, 22.8 cpd), contrast sensitivity in the diffractive group was 8, 16, 11, and 12% lower than in the refractive group. At 6 cpd, the between-group difference was statistically significant. CONCLUSION: Diffractive multifocal IOLs provided decreased contrast sensitivity and greater glare disability than refractive multifocal IOLs.

Adult↗
PubMedDate not supplied

Contrast adaptation in retinal and cortical evoked potentials: no adaptation to low spatial frequencies.

Contrast adaptation occurs in both the retina and the cortex. Defining its spatial dependence is crucial for understanding its potential roles. We thus asked to what degree contrast adaptation depends on spatial frequency, including cross-adaptation. Measuring the pattern electroretinogram (PERG) and the visual evoked potential (VEP) allowed separating retinal and cortical contributions. In ten subjects we recorded simultaneous PERGs and VEPs. Test stimuli were sinusoidal gratings of 98% contrast with spatial frequencies of 0.5 or 5.0 cpd, phase reversing at 17 reversals/s. Adaptation was controlled by prolonged presentation of these test stimuli or homogenous gray fields of the same luminance. When adaptation and test frequency were identical, we observed significant contrast adaptation only at 5 cpd: an amplitude reduction in the PERG (-22%) and VEP (-58%), and an effective reduction of latency in the PERG (-0.95 ms). When adapting at 5 cpd and testing at 0.5 cpd, the opposite effect was observed: enhancement of VEP amplitude by +26% and increase in effective PERG latency by + 1.35 ms. When adapting at 0.5 cpd and testing at 5 cpd, there was no significant amplitude change in PERG and VEP, but a small effective PERG latency increase of +0.65 ms. The 0.5-cpd channel was not adapted by spatial frequencies of 0.5 cpd. The adaptability of the 5-cpd channel may mediate improved detail recognition after prolonged blur. The existence of both adaptable and nonadaptable mechanisms in the retina allows for the possibility that by comparing the adaptational state of spatial-frequency channels the retina can discern between overall low contrast and defocus in emmetropization control.

Adaptation, Physiological↗
PubMed2005

New features in the catalytic cycle of cytochrome P450 during the formation of compound I from compound 0.

Density functional theory (DFT) is applied to the dark section of the catalytic cycle of the enzyme cytochrome P450, namely, the formation of the active species, Compound I (Cpd I), from the ferric-hydroperoxide species (Cpd 0) by a protonation-assisted mechanism. The chosen 96-atom model includes the key functionalities deduced from experiment: Asp(251), Thr(252), Glu(366), and the water channels that relay the protons. The DFT model calculations show that (a) Cpd I is not formed spontaneously from Cpd 0 by direct protonation, nor is the process very exothermic. The process is virtually thermoneutral and involves a significant barrier such that formation of Cpd I is not facile on this route. (b) Along the protonation pathway, there exists an intermediate, a protonated Cpd 0, which is a potent oxidant since it is a ferric complex of water oxide. Preliminary quantum mechanical/molecular mechanical calculations confirm that Cpd 0 and Cpd I are of similar energy for the chosen model and that protonated Cpd 0 may exist as an unstable intermediate. The paper also addresses the essential role of Thr(252) as a hydrogen-bond acceptor (in accord with mutation studies of the OH group to OMe).

Amino Acids↗
PubMed1996

Serum albumin in continuous peritoneal dialysis: its predictors and relationship to urea clearance.

We investigated the predictors of serum albumin and the relationship between serum albumin and urea kinetic indices in continuous peritoneal dialysis (CPD). In a training set (TS) of 143 urea kinetic studies performed in 92 CPD patients, stepwise logistic regression identified high/high-average peritoneal solute transport, diabetes, advanced age and high daily drain volume normalized by body water as predictors of low serum albumin (< 35 g/liter). This analysis was then substantiated in a validation set (VS) of 187 kinetic studies performed in another 102 CPD patients. The calculated area under the receiver operating characteristic (ROC) curve by this logistic regression model was 0.782 (95% CI, 0.745 to 0.819). Logistic regression was repeated in the TS using only the first kinetic study from each patient, and it identified high/high-average peritoneal solute transport, diabetes, and advanced age as predictors of low albumin. Using only the first kinetic study from each patient in the VS, the second logistic regression model calculated an area under the ROC curve equal to 0.850 (95% CI, 0.810 to 0.890). The relative risk (RR) of serum albumin < 35 g/liter was computed for all kinetic studies after combining the TS and the VS and using non-diabetic CPD subjects aged < or = 61 years with low/low average peritoneal solute transport as the reference group. The RR with only one risk factor present ranged from 1.076 (age > 61 years) to 6.792 (high/high-average transport). The RR with two risk factors present ranged from 5.200 to 9.729. The RR with all three risk factors present was 9.100 (95% CI, range 3.923 to 21.111). A subset of 37 CPD patients had a second urea kinetic study 8 +/- 5 months after an increase in the amount of dialysis due to low urea clearance and/or uremic symptoms. The weekly KT/V urea increased from 1.40 +/- 0.24 to 2.10 +/- 0.31 after the increase in the CPD dose. With the increase in dialysis, the protein catabolic rate increased substantially; however, the mean serum albumin remained stable (from 33.9 +/- 4.6 to 33.3 +/- 6.2 g/liter; decrease 18; increase 15; same 4). In comparison to the subjects who had a decrease in serum albumin after the increase in KT/V, those with the increase in serum albumin were younger (44.2 +/- 11.2 vs. 54.3 +/- 16.2 years, P = 0.044) and had a higher serum urea after the increase in the dose of CPD (22.4 +/- 7.8 vs. 17.0 +/- 6.0 mmol/liter, P = 0.037). We conclude that the major predictors of low serum albumin in CPD are advanced age, diabetes, and high/high-average peritoneal solute transport, but not urea kinetic studies. An increase in the dose of dialysis does not cause a consistent rise in serum albumin in underdialyzed CPD subjects. However, a subset of younger patients may be able to increase their serum albumin in response to the increase in KT/V.

Adult↗
PubMed2005

British Dental Journal based Continuing Professional Development: a survey of participating dentists and their views.

OBJECTIVE: There is little information available on journal based verifiable continuing professional development (CPD). The aim of this study was to survey those dentists who have undertaken this form of CPD and elicit their views. DESIGN: A questionnaire survey. METHOD: Four hundred dentists who had registered to undertake CPD with the British Dental Journal (BDJ) were randomly selected and sent a questionnaire. RESULTS: Three hundred and twelve questionnaires were returned (78%) of these 181 (58%) were male and 131 (42%) were female. Of the 312, 307 had undertaken the BDJ CPD initiative. Two hundred and sixty eight respondents (87.3%) agreed/strongly agreed that the BDJ CPD satisfied their personal CPD needs. Two hundred and eighty three (92.2%) agreed/strongly agreed that their knowledge has been increased as a result of undertaking the BDJ CPD initiative. Two hundred and twenty agreed/strongly agreed (71.7%) that an element of their clinical practice had changed as a result of undertaking the BDJ CPD initiative. CONCLUSION: Journal based learning appears to be an effective way of undertaking verifiable CPD.

Adult↗
PubMed2001

Children with hypoalbuminemia on continuous peritoneal dialysis are at risk for technique failure.

BACKGROUND: Few data are available on the clinical significance of hypoalbuminemia [serum albumin (SA) <35 g/L] in children with end-stage renal disease (ESRD) on continuous peritoneal dialysis (CPD). This study was conducted to analyze the prevalence of hypoalbuminemia, its predictive factors, and its clinical impact in these children. METHODS: A retrospective analysis was done of 180 patients on CPD over the last 22 years. Patients were excluded from the study if they were on CPD for less than four months or had nephrotic syndrome. Demographic, clinical, and biochemical variables were studied. Children continued on CPD until they received a transplant or were transferred to an adult unit or to hemodialysis as a result of technique failure. The subjects were divided into two groups based on SA levels at last follow-up. RESULTS: A total of 135 children was included. After a mean duration of CPD of 573 +/- 437 (120 to 2960) days, 54 children (40%) were observed to have hypoalbuminemia. Four patients (2.9%) died, 7 (5.2%) continued on continuous cyclic peritoneal dialysis, and 13 (9.6%) were transferred to an adult unit for continuation of CPD. Ninety-five (70.3%) were transplanted, and 16 (11.8%) were transferred to hemodialysis because of technique failure. Children in group I (N = 54, SA <35 g/L), compared with group II (N = 81, SA > or =35 g/L), were younger at initiation of PD, more likely to have hypoalbuminemia at one month and six months after initiation of PD, and have more episodes of peritonitis. No differences were seen between the groups in gender, modality of CPD, body surface area, initial body mass index, and presence of hypertension or acidosis. The only factors predictive of hypoalbuminemia on follow-up were low SA at one month after PD and recurrent peritonitis using multiple logistic regression analysis. Evaluating the clinical impact of hypoalbuminemia, we observed a higher incidence of failed PD in children who had hypoalbuminemia. CONCLUSION: Low SA at one month after PD and recurrent peritonitis are predictive of hypoalbuminemia in children on CPD, which is associated with an increased incidence of CPD failure.

Adolescent↗
PubMed2004

NMR study of repair mechanism of DNA photolyase by FAD-induced paramagnetic relaxation enhancement.

Cyclobutane pyrimidine dimer (CPD) photolyases, which contain FAD as a cofactor, use light to repair CPDs. We performed structural analyses of the catalytic site of the Thermus thermophilus CPD photolyase-DNA complex, using FAD-induced paramagnetic relaxation enhancement (PRE). The distances between the tryptophan residues and the FAD calculated from the PRE agree well with those observed in the x-ray structure (with an error of <3 A). Subsequently, a single-stranded DNA containing 13C-labeled CPD was prepared, and the FAD-induced PRE of the NMR resonances from the CPD lesion in complex with the CPD photolyase was investigated. The distance between the FAD and the CPD calculated from the PRE is 16 +/- 3 A. The FAD-induced PRE was also observed in the CPD photolyase-double-stranded DNA complex. Based on these results, a model of the CPD photolyase-DNA complex was constructed, and the roles of Arg-201, Lys-240, Trp-247, and Trp-353 in the CPD-repair reaction are discussed.

Base Sequence↗
PubMed2005

Vitamin K analog (compound 5) induces apoptosis in human hepatocellular carcinoma independent of the caspase pathway.

A systemic vitamin K analog, compound 5 (Cpd 5), possesses the ability to inhibit cell growth of tumor cells. Therefore, we investigated the effect of Cpd 5 in human hepatocellular carcinoma (HCC) cell lines and evaluated its role in apoptosis. Human HCC cell lines were cultured and treated with Cpd 5. Apoptosis was assessed using DAPI staining and Annexin-V membrane staining. The expression of caspases, XIAP and Bcl-xL was also investigated. Cpd 5 decreased cell viability in a dose-dependent manner in two HCC cells (HLE and SK-Hep1) containing mutant p53, but not in the HepG2 cell line, which contained wild-type p53. Cpd 5-treated HLE and SK-Hep1 cells showed typical apoptotic features, nuclear condensation and nuclear fragmentation upon DAPI staining. Positive membranous staining for Annexin-V was also seen in these cells. Both caspase-8 and caspase-3 activities were up-regulated slightly. Pro-caspase-8 protein levels decreased slightly in both cells. Although the expression of Bcl-xL was not influenced by Cpd 5, that of XIAP decreased in HLE cells. However, the pan-caspase inhibitor, zVAD, could not significantly prevent Cpd 5-induced apoptosis and Cpd 5 could not augment TRAIL-induced apoptosis. These results demonstrate that Cpd 5 induced apoptosis in human HCC cell lines, mainly independently of caspase activities. This may contribute to its highly potent cytotoxicity toward HCC cells.

Apoptosis↗
PubMed1997

Efficacy of 5-day cefpodoxime proxetil for recurrent pharyngitis in adults. A comparative study with 10-day penicillin V or amoxycillin---clavulanate.

OBJECTIVE: To compare the clinical and bacteriologic efficacy of a 5-day course of cefpodoxime proxetil (CPD) with that of a 10-day course of penicillin V (PNV) or amoxycillin---clavulanate (AMC) in recurrent pharyngitis in adults. A cost-effectiveness study (reported elsewhere) was carried out at the same time. METHODS: This multicenter, randomized, open label trial involved 580 adult patients consulting general practitioners for clinical recurrent pharyngitis (greater-than-or-equal3 episodes within the last 12 months) regardless of the bacterial etiology. Patients were treated for 5 days with CPD, 100 mg twice daily, or for 10 days with PNV, 1x106 IU three times a day, or for 10 days with AMC, 500 mg (amoxycillin) three times a day. Clinical and bacteriologic outcomes were noted at the end of treatment, and cases of clinical recurrence were recorded during a 6-month follow-up period. RESULTS: At the end of treatment, clinical response was satisfactory in 157 of 170 (92.3%) patients on CPD, 147 of 166 (88.5%) patients on PNV, and 168 of 177 (94.9%) patients on AMC. Group A beta-hemolytic streptococci (GABHS) were eradicated in 22 of 23 (95.65%) patients on CPD, 16 of 16 (100%) patients on PNV, and 19 of 20 (95%) patients on AMC. The rates of clinical success and GABHS eradication were not significantly different between the groups. Compliance (p<0.001) and tolerance (p<0.001) were significantly better in the CPD group than in the other two groups. Among the 389 patients evaluable 6 months after the end of treatment, the recurrence rate of acute pharyngitis (due to any bacterium) was significantly lower in the CPD group (p=0.01 versus PNV; p<0.01 versus AMC). A Kaplan---Meier analysis (469 patients over 6 months) of the rate of non-recurrence, with comparison by the log-rank test, also showed a significant difference in favor of CPD. CONCLUSIONS: A 5-day treatment of recurrent pharyngitis with CPD was as effective and better tolerated than a 10-day treatment with PNV or AMC. The risk of recurrence was lower with CPD.

Journal Article↗
PubMed2001

Carboxypeptidase D is up-regulated in raw 264.7 macrophages and stimulates nitric oxide synthesis by cells in arginine-free medium.

Membrane-bound carboxypeptidase D (CPD) is a B-type carboxypeptidase that specifically cleaves C-terminal Arg or Lys from peptides and proteins. RAW 264.7 cells contained significant membrane-bound CPD activity as shown by activity assays and immunoprecipitation. To determine whether CPD can increase nitric oxide (NO) synthesis by releasing precursor Arg, cells were activated in Arg-free medium with 50 U/ml interferon-gamma (IFN-gamma) and 0.1 microg/ml lipopolysaccharide (LPS) to up-regulate inducible NO synthase. Addition of the specific carboxypeptidase substrate, 200 microM furylacryloyl-Ala-Arg, stimulated NO production by 6-fold and this effect was blocked 83% by a specific inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGTA). MGTA did not inhibit NO synthesis stimulated by added free Arg. Lys, an inhibitor of Arg transport, also blocked the effect of the carboxypeptidase substrate. In cells stimulated with IFN-gamma and LPS in Arg-free medium, CPD activity increased 2- to 3-fold between 8 and 16 h after treatment, but did not change in cells stimulated in medium containing 0.4 mM Arg. The NO synthase inhibitor N-monomethyl-L-arginine blocked the inhibitory Arg effect and the NO donor S-nitroso-acetylpenicillamine mimicked it, indicating that high levels of NO block the up-regulation of CPD. Immunohistochemical staining and Western analysis revealed an increase in CPD protein, and Northern analysis showed increased CPD mRNA upon stimulation of cells in Arg-free medium. CPD was localized both on the plasma membrane and in the Golgi. These data suggest that CPD expression is enhanced during inflammatory processes and may stimulate NO production by cleaving Arg from peptide substrates.

Animals↗
PubMed1992

Purification and characterization of two serine carboxypeptidases from Aspergillus niger and their use in C-terminal sequencing of proteins and peptide synthesis.

A procedure was developed to prepare in large amounts two carboxypeptidases, CPD-I and CPD-II, from Aspergillus niger. They were each shown to be serine proteases and single-chain monomers with molecular masses of ca. 81 kDa and containing 22% carbohydrates. Amino acid analysis, carbohydrate determination, and N-terminal sequencing (20 to 25 residues) were performed on each enzyme. CPD-I showed sequence homologies with malt carboxypeptidase II, while the N terminus of CPD-II was different from that of any known serine carboxypeptidase. Like carboxypeptidase Y from Saccharomyces cerevisiae and carboxypeptidase III from malt, CPD-II contained a free sulfhydryl group that could play a role in catalysis. Both A. niger enzymes had pH optima of about 4 and were unstable above pH 7. Their specificities for substrate positions P1 and P'1 were characterized by use of, as substrates, a series of N-blocked amino acid esters and dipeptides. Both enzymes were specific for Arg, Lys, and Phe in P1. CPD-I preferred hydrophobic residues in P'1, while CPD-II was highly specific for Arg and Lys in this position. Each displayed an original specificity when P1 and P'1 were considered together. The specificities were also studied by analyzing the time course of the release of amino acids from eight different peptides of various lengths. CPD-I and CPD-II appeared to be quite suitable for C-terminal sequence studies as well as for the synthesis of peptide bonds. The latter was studied with two peptide esters as aminolysis substrates and a series of amino acid amides as nucleophiles.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1979

Structure-activity relationship of 5-hydroxykynurenamine analogues in isolated dog cerebral arteries.

In helically-cut strips of cerebral arteries isolated from dogs, analogues of 5-hydroxykynurenamine (5-HK), including 2-(3'-aminopropyl)-aniline (Cpd. I), 2'-amino-3-dimethylamino-3'-hydroxypropiophenone(CPD. II), 2'-amino-3-dimethylamino-5'-hydroxypropiophenone (Cpd. III) and 2',3-diamino-propiophenone (kynurenamine), caused a dose-related contraction which was antagonized by treatment with methysergide. The potency for inducing contractions was in the order of 5-hydroxytryptamine greater than 5-HK greater than Cpd. III greater than kynurenamine, Cpd. I and Cpd. II. Treatment with the 5-HK analogues antagonized the contractile response to 5-hydroxytryptamine in a dose-dependent manner, the antagonistic potency being in the order of 5-HK greater than Cpd. III greater than kynurenamine, Cpd. II greater than Cpd. I. Alterations in the hydroxy group on the benzene ring and/or radicals of long side chain of 5-HK attenuated the agonistic and antagonistic actions of 5-HK; however, the attenuation of these actions differed. Thus, the radicals appear to be involved in the agonistic and antagonistic actions to a different extent.

Aniline Compounds↗