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- Abu-Bakar, A'edah, et al.
(författare)
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Inducible bilirubin oxidase : A novel function for the mouse cytochrome P450 2A5
- 2011
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 257:1, s. 14-22
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic "BR oxidase''. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301,315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible "BR oxidase" where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced.
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- Abu-Bakar, A'edah, et al.
(författare)
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Metabolism of bilirubin by human cytochrome P450 2A6
- 2012
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 261:1, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic "Bilirubin Oxidase" (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14-22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K-i of 2.231 mu M. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301,315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human "Bilirubin Oxidase" where bilirubin is potentially a substrate and a regulator of the enzyme.
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- Abu-Bakar, A'edah, et al.
(författare)
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Regulation of CYP2A5 gene by the transcription factor nuclear factor (erythroid-derived 2)-like 2
- 2007
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Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 35:5, s. 787-794
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that cadmium, a metal that alters cellular redox status, induces CYP2A5 expression in nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2(-/-)) mice but not in the knockout (Nrf2(-/-)) mice. In the present studies, the potential role of Nrf2 in cadmium-mediated regulation of Cyp2a5 gene was investigated in mouse primary hepatocytes. Cadmium chloride (CdCl2) caused a time-dependent induction of the CYP2A5 at mRNA, protein, and activity levels, with a substantial increase observed within 3 h of exposure. Immunoblotting showed cadmium-dependent nuclear accumulation of Nrf2 within 1 h of exposure. Cotransfection of mouse primary hepatocytes with Cyp2a5 promoter-luciferase reporter plasmids and Nrf2 expression plasmid resulted in a 3-fold activation of Cyp2a5 promoter-mediated transcription relative to the control. Deletion analysis of the promoter localized the Nrf2 responsive region to an area from -2656 to -2339 base pair. Computer-based sequence analysis identified two putative stress response elements (StRE) within the region at positions -2514 to -2505 and -2386 to -2377. Chromatin immunoprecipitation and electrophoretic mobility shift assays showed that interaction of the more proximal StRE with Nrf2 was stimulated by CdCl2. Finally, site-directed mutagenesis of the proximal StRE in Cyp2a5 promoter-luciferase reporter plasmids abolished Nrf2 mediated induction. Collectively, the results indicate that Nrf2 activates Cyp2a5 transcription by directly binding to the StRE in the 5'-flanking region of the gene. This acknowledges Cyp2a5 as the first phase I xenobiotic-metabolizing gene identified under the control of the StRE-Nrf2 pathway with a potential role in adaptive response to cellular stress.
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| 7. |
- Ahmed, Saad, et al.
(författare)
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The betrayal of constant power × time : Finding the missing joules of transiently-powered computers
- 2019
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Ingår i: Proceedings of the ACM SIGPLAN Conference on Languages, Compilers, and Tools for Embedded Systems (LCTES). - New York, NY, USA : Association for Computing Machinery. - 9781450367240 ; , s. 97-109
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Konferensbidrag (refereegranskat)abstract
- Transiently-powered computers (TPCs) lay the basis for a battery-less Internet of Things, using energy harvesting and small capacitors to power their operation. This power supply is characterized by extreme variations in supply voltage, as capacitors charge when harvesting energy and discharge when computing. We experimentally find that these variations cause marked fluctuations in clock speed and power consumption, which determine energy efficiency. We demonstrate that it is possible to accurately model and concretely capitalize on these fluctuations. We derive an energy model as a function of supply voltage and develop EPIC, a compile-time energy analysis tool. We use EPIC to substitute for the constant power assumption in existing analysis techniques, giving programmers accurate information on worst-case energy consumption of programs. When using EPIC with existing TPC system support, run-time energy efficiency drastically improves, eventually leading up to a 350% speedup in the time to complete a fixed workload. Further, when using EPIC with existing debugging tools, programmers avoid unnecessary program changes that hurt energy efficiency.
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| 8. |
- Osman, Syaiful, et al.
(författare)
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Variation of chemical properties, crystalline structure and calorific values of native Malaysian bamboo species
- 2022
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Ingår i: Wood and Fiber Science. - : Society of Wood Science and Technology. - 0735-6161. ; 54:3, s. 173-186
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Tidskriftsartikel (refereegranskat)abstract
- The chemical properties of four common Malaysian bamboo species locally known as Beting (Gigantochloa levis), Semantan (Gigantochloa scortechinii), Lemang (Schizostachyum brachyladum) and Akar (Bambusa vulgaris) were studied. Chemical analysis shows that the alkaline extractive content for Malaysian bamboo species studied was within 24.4% to 25.6%, ethanol-toluene extractive content for Malaysian bamboo species was within 4.0% to 7.2% and water extractive content was within 10.4% to 12.8%. The average value of holocellulose content for Malaysian bamboo was between 64.5% to 70.67%, Klason lignin within 25.3% to 28.4%, cellulose content was between 28.5% to 33.8% and α-cellulose content for all bamboo species was within the range of 40.7% to 47.9%. The crystallinity of bamboo samples was between 42.0 to 44.4%, indicating their semi-crystalline structure. Heating value of bamboo ranged between 17.0 MJ/kg to 18.1 MJ/kg with G. scortechinii having the highest heating value.. The Inductive Couple Plasma Atomic Emission Spectroscopy (ICP-ES) analysis showed that Potassium (K) and Calcium (C) were the major elements in the ash of all bamboo samples. This study demonstrates the potential of native bamboo species as an alternative sustainable raw material to wood for a wide range of applications.
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| 9. |
- Richardson, James E., et al.
(författare)
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The influence of tectonics, sea-level changes and dispersal on migration and diversification of Isonandreae (Sapotaceae)
- 2014
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Ingår i: Botanical journal of the Linnean Society. - : Wiley-Blackwell. - 0024-4074 .- 1095-8339. ; 174:1, s. 130-140
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Tidskriftsartikel (refereegranskat)abstract
- Internal transcribed spacer (ITS) ribosomal DNA sequence data were generated for 80 of the c. 200 species of Isonandreae and were added to data from African and Neotropical representatives in subfamily Sapotoideae and outgroups in Sapotaceae. Bayesian dating and ancestral area reconstruction indicated that Isonandreae are derived from within an African grade. Multiple Australasian species or lineages are derived from Sundanian lineages in South-East Asia with stem ages originating from the late Oligocene. Sri Lankan and Indian lineages are also derived from Sundanian lineages. Our results are consistent with migration from Africa into Sundania followed by numerous over-water dispersal events across Wallace's Line into Australasia and migration from Sundania to the Indian subcontinent. Pleistocene speciation indicates that sea-level changes during that epoch could have been responsible for some species diversification in Sundania.
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