The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist

Nebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gαs and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β2-ARs, and HL-1 cardiac myocytes that express β1- and β2-ARs and no detectable β3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β2-AR, and likely β1-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β1- and/or β2-ARs. © 2013 Erickson et al

Effects of pH, Dosage, Temperature and Mixing Speed on The Efficiency of Water Melon Seed in Removing the Turbidity and Colour of Atabong River, Awka-Ibom State, Nigeria

Studies were carried out to determine the effects of operating parameters such as temperature, pH, dosage and mixing speed on the efficiency of watermelon seed in removing the turbidity and colour of Atabong River, which serves the people of Eket and their environs in Akwa-Ibom State. Results obtained showed that at an ideal pH of 7.5, temperature of 25oC, dosage of 0.6g/l and mixing speed of 120rpm the water melon coagulum removed turbidity and colour of the raw river water by 87.9% and 84.3% respectively. At this optimum conditions, water melon coagulum decreased the raw water turbidity from 67.7 to 8.18 NTU and colour, 318 to 50 TCU. The findings have demonstrated the effectiveness of water melon seeds as a possible replacement for chemicals like alum and ferric salts normally used in coagulation-flocculation water treatment

A portable centrifugal analyser for liver function screening

Mortality rates of up to 50% have been reported after liver failure due to drug-induced hepatotoxicity and certain viral infections(Gao et al. 2008). These adverse conditions frequently affect HIV and tuberculosis patients on regular medication in resource-poor settings. Here, we report full integration of sample preparation with read-out of a 5-parameter liver assay panel (LAP) on a portable, easy-to-use, fast and cost- efficient centrifugal microfluidic analysis system (CMAS). Our unique, dissolvable-film based centrifugo- pneumatic valving was employed to provide sample-to-answer fashion automation for plasma extraction (from finger-prick of blood), metering and aliquoting into separate reaction chambers for parallelized colorimetric quantification during rotation. The entire LAP completes in less than 20 minutes while using only a tenth the reagent volumes when compared with standard hospital laboratory tests. Accuracy of in-situ liver function screening was validated by 96 separate tests with an average coefficient of variance (CV) of 7.9% compared to benchtop and hospital lab tests. Unpaired two sample statistical t-tests were used to compare the means of CMAS and benchtop reader, on one hand; and CMAS and hospital tests on the other. The results demonstrate no statistical difference between the respective means with 94% and 92% certainty of equivalence, respectively. The portable platform thus saves significant time, labour and costs compared to established technologies, and therefore comply with typical restrictions on lab infrastructure, maintenance, operator skill and costs prevalent in many field clinics of the developing world. It has been successfully deployed in a centralised lab in Nigeria

Effects of dietary acid load on exercise metabolism and anaerobic exercise performance

Dietary acid load, quantified as the potential renal acid load (PRAL) of the diet, affects systemic pH and acid-base regulation. In a previous cross-sectional study, we reported that a low dietary PRAL (i.e. alkaline promoting diet) is associated with higher respiratory exchange ratio (RER) values during maximal exercise. The purpose of the present study was to confirm the previous findings with a short-term dietary intervention study. Additionally, we sought to determine if changes in PRAL affects submaximal exercise RER (as a reflection of substrate utilization) and anaerobic exercise performance. Subjects underwent a graded treadmill exercise test (GXT) to exhaustion and an anaerobic exercise performance test on two occasions, once after following a low-PRAL diet and on a separate occasion, after a high-PRAL diet. The diets were continued as long as needed to achieve an alkaline or acid fasted morning urine pH, respectively, with all being 4-9 days in duration. RER was measured during the GXT with indirect calorimetry. The anaerobic performance test was a running time-to-exhaustion test lasting 1-4 min. Maximal exercise RER was lower in the low-PRAL trial compared to the high-PRAL trial (1.10 ± 0.02 vs. 1.20 ± 0.05, p = 0.037). The low-PRAL diet also resulted in a 21% greater time to exhaustion during anaerobic exercise (2.56 ± 0.36 vs. 2.11 ± 0.31 sec, p = 0.044) and a strong tendency for lower RER values during submaximal exercise at 70% VO(2)max (0.88 ± 0.02 vs. 0.96 ± 0.04, p = 0.060). Contrary to our expectations, a short-term low-PRAL (alkaline promoting) diet resulted in lower RER values during maximal-intensity exercise. However, the low-PRAL diet also increased anaerobic exercise time to exhaustion and appears to have shifted submaximal exercise substrate utilization to favor lipid oxidation and spare carbohydrate, both of which would be considered favorable effects in the context of exercise performance

Učinci oralnog davanja mononatrijeva glutamata na morfologiju jaja i rezervu spermija u nuzjajčanom repu mladih i odraslih štakora.

The effects of oral administration of varied doses of monosodium glutamate (MSG) on the morphology of the testes and cauda epididymal sperm reserves of rats were studied using 28 four-week old (young) male Sprague-Dawley rats and 28 twelve-week-old (adult) male Sprague-Dawley rats. Increasing doses (1 mg/g body mass, 2 mg/g body mass, and 4 mg/g body mass) of a 40% aqueous solution of monosodium glutamate were administered to the male Sprague-Dawley rats every 48 hours for 6 weeks, using a rat gavage needle. The results showed that age variation did not influence the effect of MSG on the parameters studied in male rats. There was a significant reduction in the cauda epididymal sperm reserves (P<0.05) and the serum testosterone levels (P<0.05) of the rats that received monosodium glutamate relative to the control rats. The histomorphology of the testes of the rats that were given monosodium glutamate did not differ from those of the rats in the control group. No overt pathological lesions were seen in the testicular sections. These observations suggest that monosodium glutamate may have adversely affected spermatogenesis by disrupting the hypothalamic-pituitarytestis regulatory axis, and not through any direct toxic effect on the testis.Učinci oralnog davanja različitih doza mononatrijeva glutamata na morfologiju jaja i rezervu spermija už nuzjajčanom repu bili su istraživani u pokusima na 28 štakora Sprague-Dawley u dobi od četiri tjedna (mladi) i na 28 štakora Sprague-Dawley u dobi od 12 tjedana (odrasli). Štakorima su bile primijenjene povećavajuće doze (1 mg/g tjelesne mase, 2 mg/g tjelesne mase i 4 mg/g tjelesne mase) 40% tne vodene otopine mononatrijeva glutamata svakih 48 sati kroz šest tjedana iglom prilagođenom za štakore. Rezultati su pokazali da razlika u dobi nije utjecala na učinak mononatrijeva glutamata na pretraživane pokazatelje. Ustanovljeno je značajno smanjenje rezervi spermija u nuzjajčanom repu (P<0,05) kao i razina serumskog testosterona (P<0,05) u štakora kojima je primijenjen mononatrijev glutamat u odnosu na kontrolnu skupinu. Histološki nalaz tkiva jaja štakora kojima je bio primijenjen mononatrijev glutamat nije se razlikovao od onog u štakora kontrolne skupine. Nisu bili uočeni patološki poremećaji u histološkim rezovima tkiva. Ovi nalazi upućuju na zaključak da mononatrijev glutamat može imati nepovoljan utjecaj na spermatogenezu prekidanjem regulacijske osi hipotalamus-hipofizatestis, a ne putem ikakvoga izravnoga toksičnoga učinka na testese

Acetaminophen Induces Mitochondrial Permeability Transition in Rats Without Causing Necrotic Liver Damage

Mitochondrial Permeability Transition (MPT) is reported as the mechanism of acetaminophen induced hepatic damage, however, rat models are resistant to acetaminophen induced toxicity. The occurrence and degree of mitochondrial permeability transition after treatment with 400 mg kgG1 of acetaminophen in albino Wistar rats were assessed. Animals were randomly distributed into seven groups; control, 12, 24, 36, 48, 60 and 72 h based on varying time (in hour) post acetaminophen prior to sacrifice after treatment. Mitochondrial Membrane Permeability Transition (MMPT) pore opening and mitochondrial cytochrome c release were estimated. Opening of MMPT pore and cytochrome c release were observed in 12, 24, 36 and 72 h, when compared with the control group. Liver function and histological results indicated no liver damage. It is concluded that toxic dose of acetaminophen induced mitochondrial permeability transition in rat hepatic tissues without leading to necrotic damage suggesting that rat hepatic tissues evade damage by mechanisms downstream of MPT

Production of Biodiesel from Soybean Oil Using Calcium Oxide and Cow Bone as Catalysts

Biodiesel was produced from the transesterification of soybean oil using calcium oxide and cow bone (an animal waste bone that contains hydroxyapatite, a calcium phosphate mineral) as heterogeneous catalysts. The soybean oil used was characterized using gas chromatography mass spectrometer (GCMS) and the cow bone catalyst produced was characterized using X-ray diffractometer (XRD) and X-ray fluorescence (XRF) spectrometer. The effects of the variation of methanol/oil mole ratio (9–15), catalyst concentration (10–20 wt/wt%) and reaction temperature (55–65 °C) on biodiesel yield during the transesterification of soybean oil with methanol was investigated. Reaction time of 3 hours and stirring rate of 500 rpm were kept constant. It was observed that the calcination of cow bone catalyst (at 800 °C) enhanced its conversion to apatite [Ca5(PO4)3OH] and increased the yield of biodiesel obtained. Biodiesel yield results revealed an optimum condition of methanol/oil mole ratio of 9, catalyst concentration of 15 wt/wt% and reaction temperature of 55 °C. Also, the results obtained showed that the performance trends of the two catalysts used were similar. And the close values of highest biodiesel yields obtained when the two heterogenous catalysts were used separately (yields of 94.8 and 92.2% using calcium oxide and calcined cow bone catalysts respectively) implies that the use of low-cost and readily available calcined cow bone catalyst is a promising alternative to CaO catalyst

Candida albicans Hypha Formation and Mannan Masking of β-Glucan Inhibit Macrophage Phagosome Maturation

Received 28 August 2014 Accepted 28 October 2014 Published 2 December 2014 This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license. ACKNOWLEDGMENTS We thank Janet Willment, Aberdeen Fungal Group, University of Aberdeen, for kindly providing the soluble Dectin-1-Fc reporter. All microscopy was performed with the assistance of the University of Aberdeen Core Microscopy & Histology Facility, and we thank the IFCC for their assistance with flow cytometry. We thank the Wellcome Trust for funding (080088, 086827, 075470, 099215, 097377, and 101873). E.R.B. and A.J.P.B. are funded by the European Research Council (ERC-2009-AdG-249793), and J.L. is funded by a Medical Research Council Clinical Training Fellowship.Peer reviewedPublisher PD