Gene/Protein Disease Symptom Drug Enzyme Compound
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This study was conducted to determine the effects of acute and chronic administration of GH-releasing peptide-2 (D-Ala-D-beta Nal-Ala-Trp-D-Phe-Lys-NH2, GHRP-2 or KP102) on GH responsiveness in male Holstein calves. In the dose response study of acute administration, six calves were injected iv with saline or 6.25, 12.5 and 25.0 micrograms/kg body weight (BW) of KP102. The GH AUC (area under curve, ng/ml.min, mean +/- SEM) for 60 min was significantly increased with 6.25 (676.3 +/- 125.6), 12.5 (1574.8 +/- 318.0) and 25.0 (1578.7 +/- 214.6) micrograms/kgBW of KP102 than with saline (78.6 +/- 36.1) (P < 0.01). GH responses were decreased by multiple injections of 12.5 micrograms/kgBW KP102 at every 2 h for 8 h. The GH AUC for 60 min was decreased from the first injection (1162.9 +/- 313.3) to the second injection (604.7 +/- 131.9), but the response was significantly higher for the first and second injections than the third (304.4 +/- 173.1) and fourth injections (320.7 +/- 144.2) (P < 0.05). In the chronic administration, 8 calves were implanted subcutaneously with osmotic pumps (Alzet pump). Each of the 4 calves was given with 12.5 micrograms/kgBW per hour KP102 and the other 4 calves served as the control. During the 14 day period, average daily gain was significantly increased (36.4%) over the control (P < 0.05). Food efficiency was not significant, but numerically higher (29.4%) than the control. The plasma GH concentration was not increased by chronic administration of KP102, but IGF-I appeared to increase in KP102-treated calves more than the control. These results suggest that the synthetic KP102 can be used for enhancing the growth performance in domestic animals.
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PMID:Characteristics of growth hormone secretion responsiveness to growth hormone-releasing peptide-2 (GHRP-2 or KP102) in calves. 888 23

The elimination, disposition and protein binding of ibuprofen (IBU) in premature infants were studied for use in the prevention of intraventricular hemorrhage and closure of patent ductus arteriosus. The kinetic profile of i.v. IBU lysine (10 mg/kg bolus) given within the first 3 h after birth was studied in 21 premature neonates (mean birthweight = 944.7 g, range: 575-1450 g; gestational age: 26.8 weeks, range: 22-31 weeks). Blood samples (0.3 ml/sample) were obtained at time 0 and at 1, 3, 6, 12, 24, 48, and 72 h post-dose for IBU by high-performance liquid chromatography (HPLC). Kinetic analyses assumed applicability of one open-compartment model and calculations from the model-independent areas under the time concentration curve (AUC). Data (mean +/- SEM) show that apparent volume of distribution (AVd) was 62.1 +/- 3.9 ml/kg, plasma t1/2 beta was 30.5 +/- 4.2 h, elimination rate constant (Kel) was 0.032 +/- 0.004 h-1, plasma clearance was 2.06 +/- 0.33 ml/kg/h and plasma concentration (Cp) at 1 h was 180.6 +/- 11.1 mg/l. Gestational age and birthweight were not related to drug elimination. In 10 neonates, IBU maintenance dose of 5 mg/kg once daily on days 2 and 3 generated mean Cp of 116.6 +/- 54.5 mg/l and 113.6 +/- 58.2 mg/l, respectively. Protein binding by ultrafiltration and capillary electrophoresis showed that the percentage bound IBU was significantly lower in full term cord plasma (94.98 +/- 0.39%, n = 26) compared to adult plasma protein (mean +/- SE = 98.73 +/- 0.31%, n = 8, p < 0.0001). Compared to data from adults and older children, IBU elimination is markedly prolonged in neonates and protein binding is slightly lower. Thus, investigational and clinical therapeutic regimens should be adjusted to account for decreased drug disposition to ensure safe and effective therapy.
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PMID:Pharmacokinetics and protein binding of intravenous ibuprofen in the premature newborn infant. 909 19

Tissue transglutaminase is a calcium-dependent enzyme that catalyzes the cross-linking of polypeptide chains, including those of extracellular matrix (ECM) proteins, through the formation of epsilon-(gamma-glutamyl) lysine bonds. This crosslinking leads to the formation of protein polymers that are highly resistant to degradation. As a consequence, the enzyme has been implicated in the deposition of ECM protein in fibrotic diseases such as pulmonary fibrosis and atherosclerosis. In this study, we have investigated the involvement of tissue transglutaminase in the development of kidney fibrosis in adult male Wistar rats submitted to subtotal nephrectomy (SNx). Groups of six rats were killed on days 7, 30, 90, and 120 after SNx. As previously described, these rats developed progressive glomerulosclerosis and tubulo-interstitial fibrosis. The tissue level of epsilon-(gamma-glutamyl) lysine cross-link (as determined by exhaustive proteolytic digestion followed by cation exchange chromatography) increased from 3.47+/- 0.94 (mean+/-SEM) in controls to 13.24+/-1.43 nmol/g protein 90 d after SNx, P </= 0.01. Levels of epsilon-(gamma-glutamyl) lysine cross-link correlated well with the renal fibrosis score throughout the 120 observation days (r = 0.78, P </= 0.01). Tissue homogenates showed no significant change in overall transglutaminase activity (14C putrescine incorporation assay) unless adjusted for the loss of viable tubule cells, when an increase from 5.77+/-0.35 to 13.93+/-4.21 U/mg DNA in cytosolic tissue transglutaminase activity was seen. This increase was supported by Western blot analysis, showing a parallel increase in renal tissue transglutaminase content. Immunohistochemistry demonstrated that this large increase in epsilon-(gamma-glutamyl) lysine cross-link and tissue transglutaminase took place predominantly in the cytoplasm of tubular cells, while immunofluorescence also showed low levels of the epsilon-(gamma-glutamyl) lysine cross-link in the extracellular renal interstitial space. The number of cells showing increases in tissue transglutaminase and its cross-link product, epsilon-(gamma-glutamyl) lysine appeared greater than those showing signs of typical apoptosis as determined by in situ end-labeling. This observed association between tissue transglutaminase, epsilon-(gamma-glutamyl) lysine cross-link, and renal tubulointerstitial scarring in rats submitted to SNx suggests that tissue transglutaminase may play an important role in the development of experimental renal fibrosis and the associated loss of tubule integrity.
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PMID:The role of transglutaminase in the rat subtotal nephrectomy model of renal fibrosis. 918 19

This experiment studied the effects on endocrine and birth parameters of parturient pigs produced by restricting maternal freedom of movement without otherwise altering environment. Six primiparous pigs (gilts) were each given a jugular catheter under anaesthesia 7 days before parturition and commenced birth in a strawed pen, 2.0 m x 1.5 m in size. Continuous automated blood sampling (3 ml min-1) from unrestrained gilts began following the birth of the first piglet (stage 1) and continued for 2 h. After at least 30 min of blood collection, maternal space was reduced to 2.0 m x 0.55 m by placing rails across the pen (stage 2). The scope for movement in stage 2 was similar to that offered by a farrowing crate. After at least 25 min each gilt was given the opioid antagonist naloxone (1 mg kg-1 i.v.: stage 3). At each stage, vagino-cervical stimulation (VCS) was applied to mimic foetal ejection. Non-cervically stimulated oxytocin (OT) secretion between stages 1 and 2 was unchanged (P > 0.05) but increased significantly relative to both stages 1 and 2 following naloxone treatment for 15-20 min (P < 0.05, paired t-tests on log10 data). Following VCS in all stages plasma OT rose (P < 0.05) for 1-2 min in a similar way to that seen previously following foetal ejection, the increases being proportionally similar irrespective of stage or baseline secretion. Cortisol secretion did not increase as a consequence of space restriction (mean +/- SEM concentrations were 28.6 +/- 8.51 pmol l-1 and 32.3 +/- 11.8 pmol l-1 in stages 1 and 2, respectively). In addition, VCS did not significantly affect cortisol output. Lysine vasopressin concentrations were not affected as a consequence of either stage or VCS. Parturition was not interrupted following space restriction of gilts. These data suggest that reducing maternal space allowance during parturition is not stressful when the process does not involve the movement of animals to novel surroundings.
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PMID:Restricting maternal space during parturition in the pig. Effects on oxytocin, vasopressin and cortisol secretion following vagino-cervical stimulation and administration of naloxone. 923 Dec 64

The primed, continuous intravenous infusion of amino acids labeled with 13C together with measurement of isotopic enrichment in plasma is commonly used to study amino acid metabolism. However, a less invasive, oral infusion that also produces an isotopic steady state in CO2 and urine would be useful, particularly for pediatric studies. We measured the 13C enrichments of expired CO2, plasma and urine free phenylalanine and lysine and estimated flux and oxidation rates in adult humans (n = 12) who received a 4-h oral, primed, equal dose infusion of either L-[1-13C]phenylalanine, L-[1-13C]lysine (D-lysine = 1.6%) or L-[1-13C]lysine (D-lysine </= 0.2%). Steady fed state conditions were established by feeding subjects eight hourly meals beginning 4 h before the start of the oral infusion protocol. Isotopic plateau in CO2, plasma and urine was achieved within 120 min of phenylalanine or lysine infusion. At isotopic plateau, the mean ratio of plasma to urine enrichment was 1.0 +/- 0.04 (SEM), 0. 39 +/- 0.03 and 0.97 +/- 0.02 for L-[1-13C]phenylalanine, L-[1-13C]lysine (D-lysine = 1.6%) and L-[1-13C]lysine (D-lysine</= 0. 2%), respectively. There was good agreement between isotopic enrichment in plasma and urine for L-[1-13C]phenylalanine and L-[1-13C]lysine (D-lysine </= 0.2%). However, use of L-[1-13C]lysine (D-lysine = 1.6%) resulted in significantly higher enrichment in urine, probably due to renal tubular discrimination of D-lysine. Mean flux rates for phenylalanine and lysine were consistent with the literature. Thus, the oral, primed, equal dose infusion produces the isotopic steady-state condition required for amino acid flux and oxidation determination within an 8-h period.
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PMID:Development of a minimally invasive protocol for the determination of phenylalanine and lysine kinetics in humans during the fed state. 980 42

Heat and alkali treatment of food may increase the concentrations of protein-bound D-amino acids and cross-links such as lysinoalanine (LAL). To examine how protein treatment affects digestibility, purified test meals [total protein 150 g/kg dry matter (DM), 0.44 MJ/(kg BW(0.75). d)] were prepared, containing (g/kg DM) casein, 75; beta-lactoglobulin, 50; or wheat protein, 40. Each was (15)N-labeled. Test proteins were used either in their native form or after treatment for 6 or 24 h at 65 degrees C, pH 10.5-11.5. Each meal was fed to nine adult miniature pigs (twofold complete cross-classification). Chyme was collected continuously over 33 h postprandially via T-fistulas in the terminal ileum, and digestibilities of test proteins and individual L- and D-amino acids were calculated on the basis of recovery of (15)N and the respective amino acids in the chyme. Treatment of casein, beta-lactoglobulin or wheat protein for 24 h increased levels of D-amino acid residues. L-Asparagine and aspartate (L-Asx) were particularly susceptible; 14. 7 +/- 0.4, 11.7 +/- 0.2 and 11.0 +/- 0.9%, respectively, underwent racemization. LAL levels increased in parallel; 11.7 +/- 0.3, 13.6 +/- 0 and 14.8 +/- 0.0%, respectively, of total lysine was converted to LAL. At the same time, prececal protein digestibility was decreased by 13.4 +/- 2.3, 15.3 +/- 1.4 and 17.8 +/- 1.2% units, respectively (P < 0.05; mean +/- SEM, n = 9). Digestibility of individual L-amino acids decreased by 10-15%, but L-amino acids prone to peptic cleavage, such as L-phenylalanine and L-tyrosine, were not affected. Digestibilities of D-amino acids and LAL were approximately 35%. It seems that mainly D-amino acids, and to a lesser extent LAL, were responsible for lower digestibility by interfering with peptic cleavage.
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PMID:Protein-bound D-amino acids, and to a lesser extent lysinoalanine, decrease true ileal protein digestibility in minipigs as determined with (15)N-labeling. 1091 20

Fusogenic peptides derived from viral coat proteins cause perturbation of the endosomal membrane and are often used to improve the transfection efficiency of non-viral vectors in vitro. However, fusogenic peptides have limited potential for use in vivo due to their inherent immunogenicity. Totally synthetic polymers that are endosomolytic should circumvent this problem and could be useful as components of non-viral delivery systems as long as they do not immediately localise in the liver after intravenous (i.v.) injection. Linear poly(amidoamine) polymers (PAAs) having amido- and tertiary amino-groups along the main polymer undergo pH-dependent conformational change and thus provide an ideal opportunity for design of polymers that display membrane activity at low pH. Here we describe four PAAs, ISA 1 (Mn = 6900 Da) and ISA 23 (Mn = 10,500 Da) and their analogues ISA 4 and ISA 22 (Mn approximately 8000 Da) containing approximately 1 mol% 2-p-hydroxyphenyl ethylamine to allow radioiodination and thus monitoring of their biodistribution. In vitro cytotoxicity was assessed by MTT assay after incubation of PAAs with B16F10 and Mewo cell lines. The IC50 values observed for all PAAs were > 2 mg/mL in comparison with poly(L-lysine) which displayed an IC50 in the range 0.01-0.1 mg/mL. At pH 7.4 none of the PAAs studied was haemolytic at 1 h at concentrations below 3 mg/mL. PAAs were subsequently incubated with rat red blood cells for 24 h (1 mg/mL) at different pHs. In contrast to poly(L-lysine) which was haemolytic at pH 7.4, 6.5 and 5.5, none of the PAAs was lytic at pH 7.4, but they became membrane active at lower pH (approximately 45% for ISA 4, 50% for ISA 22 and 90% for ISA 23). These observations were substantiated by SEM and confirm the pH-dependence of membrane activity. After i.v. injection to rats 125I-labelled ISA 4 was immediately taken up by the liver (> 80% recovered dose at 1 h) whereas 125I-labelled ISA 22 was not (liver uptake was < 10% recovered dose at 5 h). Furthermore, biodistribution studies in mice bearing subcutaneous B16F10 melanoma showed that 125I-labelled ISA 22 was still accumulating in tumour tissue after 5 h (2.5% dose/g). PAAs have potential as endosomolytic agents and quantitation of the endosome to cytoplasm transfer is warranted after i.v. administration.
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PMID:Poly(amidoamine)s as potential endosomolytic polymers: evaluation in vitro and body distribution in normal and tumour-bearing animals. 1093 85

A novel, biomimetic, interpenetrating polymer network (IPN) between poly-L-lysine (PLL) and ultra high molecular weight polyethylene (UHMWPE) has been synthesized in an attempt to decrease wear in joint prostheses. A biomaterial with a gradient IPN of cationic PLL and UHMWPE has been synthesized, in the surface of bulk UHMWPE, to recruit the poly-anion, hyaluronic acid, from the synovial fluid. It is hypothesized that the hyaluronic acid molecules and their associated hydration layer will improve lubrication between the articulating surfaces, thus lowering both friction and wear. The synthesis involves four steps. Silylation of the PLL-HBr to PLL-SiMe3 utilizing bis(trimethylsiyl)acetamide (BSA). Swelling of the UHMWPE in a solution of PLL-SiMe3/xylenes at 60 degrees C with ultrasonics. Crosslinking of the PLL-SiMe3 within the UHMWPE with 1,8-diisocyanatooctane (a.k.a. OMDI). Finally, de-swelling and drying of the IPN under vacuum at 50 C. Visual observations show an adhered film on the IPN surface. Reflective FTIR spectra contain the characteristic peaks associated with UHMWPE. Two additional peaks, at 3410 and 1690 cm-1, are associated with PLL. SEM shows a morphology dominated by PLL spheres with diameters ranging from < 1 micron up to 3 micron. This shows that the PLL-SiMe3 has been crosslinked by the OMDI and was not rinsed away by either xylenes or sonicated water rinses. High contact angle of the PLL in contact with the UHMWPE demonstrate that the PLL has been de-silylated and returned to its hydrophilic nature. The spheres attached to the surface of the UHMWPE indicate that PLL has infiltrated the UHMWPE physical network and is entangled there. XPS confirms the presence of nitrogen by a 3-5 atomic percent signal in the outer 100 A of the IPN surface.
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PMID:Synthesis and characterization of a novel UHMWPE interpenetrating polymer network. 1114 88

Although stable isotope methods have been used to revisit the protein and amino acid requirements of humans in the last two decades, estimates of the minimum protein requirement of the dog have mainly been based on nitrogen balance studies. The aim of this study was: (i) to assess dog protein metabolism using the (13)C-leucine method, and (ii) to test the effects of protein deprivation and amino acid deficiency on protein metabolism. Eight dogs were fed three consecutive diets: (i) a normoprotein regimen [control; 63 g crude protein (CP)/Mcal metabolizable energy (ME)]; (ii) a protein-restricted diet (PR; 32 g CP/Mcal ME); and (iii) a protein-restricted diet that was, in addition, deficient in lysine and tryptophan (D-PR; 31 g CP/Mcal ME). The energy supply was similar for the three diets. The dogs were adapted to each diet for 2 weeks. After a 24 h fasting period, a 3 h infusion of (13)C-bicarbonate was performed, followed by a 3 h continuous infusion of L-[1-(13)C]leucine. Blood and breath samples were collected before and during the last hour of each isotope infusion for determination of plasma (13)C-alpha-ketoisocaproate and breath (13)CO(2) enrichments by mass spectrometry. Rates of protein breakdown, oxidation, and synthesis were calculated from leucine appearance into plasma, oxidation, and non- oxidative disposal, respectively, and expressed in g N/kg body weight (BW)0.75 per day, assuming body protein contains 0.08 g leucine per g protein. Protein breakdown was 3.71 +/- 0.17, 3.29 +/- 0.16 and 2.73 +/- 0.18 (mean +/- SEM) for control, PR, and D-PR, respectively (p < 0.01 D-PR versus control, and p < 0.05 D-PR versus PR). Protein synthesis was 3.08 +/- 0.13, 2.77 +/- 0.13, and 2.15 +/- 0.18 for control, PR and D-PR, respectively (p < 0.001 D-PR versus control, and p < 0.05 D-PR versus PR). Protein oxidation was 0.63 +/- 0.05, 0.53 +/- 0.05 and 0.58 +/- 0.05 for control, PR and D-PR, respectively (p=NS). These data suggest that: (i) the (13)C-leucine method can be used to assess large variations of protein turnover in dogs; (ii) dogs have the capacity to adapt their protein turnover to the level and to the quality of their protein supplies; and (iii) the dog nitrogen requirement for maintenance may be between 0.41 and 0.55 g N/kg BW(0.75) per day.
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PMID:Effects of dietary protein restriction and amino acids deficiency on protein metabolism in dogs. 1168 98

Pathological-length polyglutamine (Q(n)) expansions, such as those that occur in the huntingtin protein (htt) in Huntington's disease (HD), are excellent substrates for tissue transglutaminase in vitro, and transglutaminase activity is increased in post-mortem HD brain. However, direct evidence for the participation of tissue transglutaminase (or other transglutaminases) in HD patients in vivo is scarce. We now report that levels of N(epsilon)-(gamma-L-glutamyl)-L-lysine (GGEL)--a 'marker' isodipeptide produced by the transglutaminase reaction--are elevated in the CSF of HD patients (708 +/- 41 pmol/mL, SEM, n = 36) vs. control CSF (228 +/- 36, n = 27); p < 0.0001. These data support the hypothesis that transglutaminase activity is increased in HD brain in vivo.
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PMID:N(epsilon)-(gamma-L-glutamyl)-L-lysine (GGEL) is increased in cerebrospinal fluid of patients with Huntington's disease. 1173 25


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