Peptide chemistry at Oxford before the Second World War.
The largely unnoticed and unpublished peptide science interests of Nobel Laureate Sir Robert Robinson at Oxford during the period 1936-1939 are outlined.
Biochemistry↗
Biomedical subjects
John Jones
Publications and source records attributed to John Jones.
Interaction of angiotensin II type 1 and D5 dopamine receptors in renal proximal tubule cells.
Angiotensin II type 1 (AT1) receptor and D1 and D3 dopamine receptors directly interact in renal proximal tubule (RPT) cells from normotensive Wistar-Kyoto rats (WKY). There is indirect evidence for a D5 and AT1 receptor interaction in WKY and spontaneously hypertensive rats (SHR). Therefore, we sought direct evidence of an interaction between AT1 and D5 receptors in RPT cells. D5 and AT1 receptors colocalized in WKY cells. Angiotensin II decreased D5 receptors in WKY cells in a time- and concentration-dependent manner (EC50=2.7x10(-9) M; t(1/2)=4.9 hours), effects that were blocked by an AT1 receptor antagonist (losartan). In SHR, angiotensin II (10(-8) M/24 hours) also decreased D5 receptors (0.96+/-0.08 versus 0.72+/-0.08; n=12) and to the same degree as in WKY cells (1.44+/-0.07 versus 0.92+/-0.08). However, basal D5 receptors were decreased in SHR RPT cells (SHR 0.96+/-0.08; WKY 1.44+/-0.07; n=12 per strain; P<0.05) and renal brush border membranes of SHR compared with WKY (SHR 0.54+/-0.16 versus WKY 1.46+/-0.10; n=5 per strain; P<0.05). Angiotensin II decreased AT1 receptor expression in WKY (1.00+/-0.04 versus 0.72+/-0.08; n=8; P<0.05) but increased it in SHR (0.96+/-0.04 versus 1.32+/-0.08; n=8; P<0.05). AT(1) and D5 receptors also interacted in vivo; renal D5 receptor protein was higher in mice lacking the AT1A receptor (AT1A-/-; 1.61+/-0.31; n=6) than in wild-type littermates used as controls (AT1A+/+; 0.81+/-0.08; n=6; P<0.05), and renal cortical AT1 receptor protein was higher in D5 receptor null mice than in wild-type littermates (1.18+/-0.08 versus 0.84+/-0.07; n=4; P<0.05). We conclude that D5 and AT1 receptors interact with each other. Altered interactions between AT1 and dopamine receptors may play a role in the pathogenesis of hypertension.
Angiotensin II↗
The life and work of Josef Rudinger-a postscript.
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Czechoslovakia↗
Simple surface modification of poly(epsilon-caprolactone) for apatite deposition from simulated body fluid.
Poly(epsilon-caprolactone) (PCL) with a bone-like apatite layer bound to its surface could be useful as a scaffold for tissue engineering applications. In the present study, the surface of PCL was treated with aqueous NaOH to introduce carboxylate groups onto the surface. The NaOH-treated material was subsequently dipped in aqueous CaCl(2) and K(2)HPO(4).3H(2)O alternately three times to deposit apatite nuclei on the surface. The surface-modified material successfully formed a dense and uniform bone-like surface apatite layer after incubation for 24 h in simulated body fluid with ion concentrations approximately equal to those of human blood plasma.
Absorbable Implants↗
Use of low-dose rocuronium for intubation of children during volunteer surgery abroad.
BACKGROUND: Low-dose rocuronium (ROC) might improve safety during volunteer surgery abroad (VSA) by facilitating intubation with a lower halothane concentration than is typically used. We hypothesized that 0.25 mg.kg(-1) of ROC would improve intubation conditions during 3% halothane induction and still allow for rapid return to spontaneous ventilation (SV). METHODS: During Operation Smile's 2002 mission to Honduras, patients aged 3 months-11 years were randomized to receive ROC 0.25 mg.kg(-1) (n = 19), or placebo (n = 23). Induction was with 3% halothane in 100% O(2), with ventilation assisted and controlled when possible, and normocarbia maintained. An i.v. was placed after induction, and ROC or placebo given. Direct laryngoscopy (DL) was performed 3 min later by a blinded laryngoscopist who assessed conditions according to predetermined criteria. RESULTS: Adequate intubation conditions occurred in 89 and 87% of patients (P = 0.59), and mean times from DL until the return to SV were 9.8 and 4.3 min (P = 0.003), in the ROC and placebo groups, respectively. For the placebo group, the presence of SV at DL was predictive of inadequate intubation conditions (P = 0.006). CONCLUSIONS: When administering 3% halothane for induction of VSA patients, a high frequency of adequate intubation conditions can be achieved without a relaxant, rendering the known benefits of 0.25 mg.kg(-1) of ROC unapparent. ROC 0.25 mg.kg(-1) does allow rapid return to SV.
Age Factors↗
The life and work of Josef Rudinger.
The life and work of Josef Rudinger (1924- 1975), a key figure in the history of peptide science, are outlined.
Europe↗
Pharmacology and gastrointestinal safety of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor: An integrated study.
BACKGROUND AND AIMS: Lumiracoxib is a structurally novel, acidic selective inhibitor of cyclooxygenase (COX)-2. We coordinated existing methodologies in a single study to evaluate potency, selectivity, and effect on the human gastrointestinal tract. METHODS: Twenty four healthy subjects (aged 18-45 years, 12 female) received high dose lumiracoxib (800 mg every day), standard dose naproxen (500 mg twice a day), or placebo for 8 days in a double-blind randomized crossover study. At the start and end of each dosing period, COX-2 selectivity was assessed by ex vivo serum thromboxane B(2) (COX-1) and lipopolysaccharide stimulated prostaglandin (PG) E(2) (COX-2), mucosal injury by endoscopy, and small and large bowel permeability by 0- to 5-hour and 5- to 24-hour (51)Cr-EDTA absorption. Plasma lumiracoxib was measured 2 hours after dosing on day 8 and vortex-stimulated ex vivo gastric mucosal PGE(2) synthesis at the end of each treatment period by enzyme immunoassay. RESULTS: Lumiracoxib was well absorbed and demonstrated similar potency to naproxen as a COX-2 inhibitor (77% and 66% inhibition, respectively, vs. placebo), but it differed in being more selective (24% and 97% inhibition of thromboxane B(2) vs. placebo). Gastric PGE(2) was reduced by 69% by naproxen (P < 0.001 vs. placebo) and 29% by lumiracoxib (P < 0.01 vs. placebo and naproxen). No subjects developed gastroduodenal erosions on lumiracoxib (vs. 75% on naproxen and 12.5% on placebo). (51)Cr-EDTA absorption increased significantly with naproxen but not lumiracoxib. CONCLUSIONS: Lumiracoxib is a potent selective inhibitor of COX-2 that causes little or no endoscopically detected stomach or duodenal injury or changes in bowel permeability.
Adolescent↗
Relation between smoking and biomarkers of bone resorption associated with dental endosseous implants.
The aim of this study was to determine the effects of smoking on pyridinoline concentrations in crevicular fluid collected from around dental implants. Samples of crevicular fluid were collected from 4 sites around each implant and tooth, if present, for a group of 16 patients using methylcellulose strips. Samples were collected from 104 implants and 49 teeth. Eight of the 16 patients were current smokers. Crevicular fluid samples were eluted from methylcellulose strips using phosphate-buffered saline containing 0.1% bovine serum albumin and centrifugation. Pyridinoline was quantified using a competitive enzyme immunoassay. Results showed that there were statistically insignificant differences between the amounts of pyridinoline (mean +/- standard deviation [SD]) around teeth of nonsmokers versus smokers (0.011 +/- 0.003 and 0.014 +/- 0.006 nmol/L, respectively). However, the mean (+/- SD) pyridinoline levels around the implants of nonsmokers (0.012 +/- 0.018 nmol/L) were significantly (P <0.01) less than that of smokers (0.030 +/- 0.006 nmol/L). These results demonstrate that pyridinoline levels are specifically elevated in the crevicular fluid associated with endosseous dental implants of smokers and suggest that smoking may affect implant success in part through alterations in the levels of bone resorption.
Alveolar Bone Loss↗
A peptide centenary celebration.
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History, 20th Century↗
The CINOD, AZD3582, exhibits an improved gastrointestinal safety profile compared with naproxen in healthy volunteers.
COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs in development for the treatment of acute and chronic pain. They comprise a COX-inhibiting moiety linked to a nitric-oxide-donating component and are designed to provide an innovative mechanism of action of balanced COX inhibition and controlled nitric oxide donation. Through these pathways, CINODs should provide analgesic and anti-inflammatory efficacy, while offering gastrointestinal safety through the tissue-protective effects of nitric oxide donation. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is the first agent in the CINOD class to enter extensive clinical development. Pre-clinical studies demonstrate that AZD3582 has a superior gastrointestinal safety profile to naproxen, while demonstrating analgesic and anti-inflammatory efficacy. In healthy human volunteers, AZD3582 caused little gastrointestinal damage compared with equimolar doses of naproxen. Studies to evaluate the longer-term gastrointestinal safety of AZD3582, alongside its efficacy in alleviating chronic and acute pain, are ongoing.
Journal Article↗
Heterozygous cellular glutathione peroxidase deficiency in the mouse: abnormalities in vascular and cardiac function and structure.
BACKGROUND: Oxidant stress has been implicated in the pathogenesis of atherothrombosis and other vascular disorders accompanied by endothelial dysfunction. Glutathione peroxidases (GPx) play an important role in the cellular defense against oxidant stress by utilizing glutathione (GSH) to reduce lipid hydroperoxides and hydrogen peroxide to their corresponding alcohols. Cellular GPx (GPx-1) is the principal intracellular isoform of GPx. We hypothesized that GPx-1 deficiency per se induces endothelial dysfunction and structural vascular abnormalities through increased oxidant stress. METHODS AND RESULTS: A murine model of heterozygous deficiency of GPx-1 (GPx(+/-)) was investigated to examine this hypothesis. Mesenteric arterioles in GPx-1(+/-) mice demonstrated vasoconstriction to acetylcholine compared with vasodilation in wild-type mice (maximal change in vessel diameter, -13.0+/-2.8% versus 13.2+/-2.8%, P<0.0001). We also noted an increase in the plasma and aortic levels of the isoprostane iPF(2alpha)-III, a marker of oxidant stress, in GPx-1(+/-) mice compared with wild-type mice (170.4+/-23 pg/mL plasma versus 98.7+/-7.1 pg/mL plasma, P<0.03; 11.7+/-0.87 pg/mg aortic tissue versus 8.2+/-0.55 pg/mg aortic tissue, P<0.01). Histological sections from the coronary vasculature of GPx-1(+/-) mice show increased perivascular matrix deposition, an increase in the number of adventitial fibroblasts, and intimal thickening. These structural abnormalities in the myocardial vasculature were accompanied by diastolic dysfunction after ischemia-reperfusion. CONCLUSIONS: These findings demonstrate that heterozygous deficiency of GPx-1 leads to endothelial dysfunction, possibly associated with increased oxidant stress, and to significant structural vascular and cardiac abnormalities. These data illustrate the importance of this key antioxidant enzyme in functional and structural responses of the mammalian cardiovascular system.
Animals↗