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111.
Yu Zhao Mona C Majid Jennifer M Soll Joshua R Brickner Sebastian Dango Nima Mosammaparast 《The EMBO journal》2015,34(12):1687-1703
Repair of DNA alkylation damage is critical for genomic stability and involves multiple conserved enzymatic pathways. Alkylation damage resistance, which is critical in cancer chemotherapy, depends on the overexpression of alkylation repair proteins. However, the mechanisms responsible for this upregulation are unknown. Here, we show that an OTU domain deubiquitinase, OTUD4, is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. Remarkably, we find that OTUD4 catalytic activity is completely dispensable for this function. Rather, OTUD4 is a scaffold for USP7 and USP9X, two deubiquitinases that act directly on the AlkB proteins. Moreover, we show that loss of OTUD4, USP7, or USP9X in tumor cells makes them significantly more sensitive to alkylating agents. Taken together, this work reveals a novel, noncanonical mechanism by which an OTU family deubiquitinase regulates its substrates, and provides multiple new targets for alkylation chemotherapy sensitization of tumors. 相似文献
112.
113.
Kirankumar Katta Tabasum Imran Marta Busse-Wicher Mona Gr?nning Szymon Czajkowski Marion Kusche-Gullberg 《The Journal of biological chemistry》2015,290(21):13168-13177
Heparan sulfate proteoglycans are ubiquitously located on cell surfaces and in the extracellular matrices. The negatively charged heparan sulfate chains interact with a multitude of different proteins, thereby influencing a variety of cellular and developmental processes, for example cell adhesion, migration, tissue morphogenesis, and differentiation. The human exostosin (EXT) family of genes contains five members: the heparan sulfate polymerizing enzymes, EXT1 and EXT2, and three EXT-like genes, EXTL1, EXTL2, and EXTL3. EXTL2 has been ascribed activities related to the initiation and termination of heparan sulfate chains. Here we further investigated the role of EXTL2 in heparan sulfate chain elongation by gene silencing and overexpression strategies. We found that siRNA-mediated knockdown of EXTL2 in human embryonic kidney 293 cells resulted in increased chain length, whereas overexpression of EXTL2 in the same cell line had little or no effect on heparan sulfate chain length. To study in more detail the role of EXTL2 in heparan sulfate chain elongation, we tested the ability of the overexpressed protein to catalyze the in vitro incorporation of N-acetylglucosamine and N-acetylgalactosamine to oligosaccharide acceptors resembling unmodified heparan sulfate and chondroitin sulfate precursor molecules. Analysis of the generated products revealed that recombinant EXTL2 showed weak ability to transfer N-acetylgalactosamine to heparan sulfate precursor molecules but also, that EXTL2 exhibited much stronger in vitro N-acetylglucosamine-transferase activity related to elongation of heparan sulfate chains. 相似文献
114.
Mohammad-Shafie?Rahmani Paula?M.?PijutEmail author Naghi?Shabanian Mona?Nasri 《In vitro cellular & developmental biology. Plant》2015,51(4):407-419
A protocol was established for callus induction and plant regeneration of Albizia julibrissin Durazz., a multipurpose tree. Calli were induced on hypocotyl explants excised from 10- to 14-d-old in vitro seedlings cultured on Murashige and Skoog (MS) medium supplemented with α-naphthaleneacetic acid (NAA) alone or in combination with 6-benzylaminopurine (BA) or 6-furfurylaminopurine (kinetin). The highest frequency of organogenic callus (82.2?±?3.6%) was obtained on MS medium with 10.8 μM NAA and 4.4 μM BA. Calli were then cultured on MS medium with BA or zeatin, singly or in combination, for shoot regeneration. Calli cultured on MS medium with 13.2 μM BA and 4.6 μM zeatin produced the highest frequency of adventitious shoot regeneration (75.3?±?6.3%). Maximum rooting of shoots (73.3?±?5%) was achieved using half-strength MS medium with 4.9 μM indole-3-butyric acid. The genetic fidelity of 12 plants acclimatized to the greenhouse was assessed based on analyses of start codon targeted (SCoT) polymorphism and inter-retrotransposon amplified polymorphism (IRAP). The 14 SCoT and 7 IRAP adapted primers produced 71 and 34 scoreable fragments, of which 33 (46%) and 12 (35%) were polymorphic, respectively. The in vitro-raised plants exhibited 0.129–0.438 genetic distance from the mother plant and 0.000–0.788 distance from one another according to the SCoT and IRAP analyses. Although the culture method described here may not be suitable for clonal propagation of elite genotypes, it can be used for conservation of this plant. 相似文献
115.
Glucagon signalling in the dorsal vagal complex is sufficient and necessary for high‐protein feeding to regulate glucose homeostasis in vivo 下载免费PDF全文
Mary P LaPierre Mona A Abraham Jessica TY Yue Beatrice M Filippi Tony KT Lam 《EMBO reports》2015,16(10):1299-1307
High‐protein feeding acutely lowers postprandial glucose concentration compared to low‐protein feeding, despite a dichotomous rise of circulating glucagon levels. The physiological role of this glucagon rise has been largely overlooked. We here first report that glucagon signalling in the dorsal vagal complex (DVC) of the brain is sufficient to lower glucose production by activating a Gcgr–PKA–ERK–KATP channel signalling cascade in the DVC of rats in vivo. We further demonstrate that direct blockade of DVC Gcgr signalling negates the acute ability of high‐ vs. low‐protein feeding to reduce plasma glucose concentration, indicating that the elevated circulating glucagon during high‐protein feeding acts in the brain to lower plasma glucose levels. These data revise the physiological role of glucagon and argue that brain glucagon signalling contributes to glucose homeostasis during dietary protein intake. 相似文献
116.
Thomas D Niehaus Svetlana Gerdes Kelsey Hodge-Hanson Aleksey Zhukov Arthur JL Cooper Mona ElBadawi-Sidhu Oliver Fiehn Diana M Downs Andrew D Hanson 《BMC genomics》2015,16(1)
Background
It is now recognized that enzymatic or chemical side-reactions can convert normal metabolites to useless or toxic ones and that a suite of enzymes exists to mitigate such metabolite damage. Examples are the reactive imine/enamine intermediates produced by threonine dehydratase, which damage the pyridoxal 5''-phosphate cofactor of various enzymes causing inactivation. This damage is pre-empted by RidA proteins, which hydrolyze the imines before they do harm. RidA proteins belong to the YjgF/YER057c/UK114 family (here renamed the Rid family). Most other members of this diverse and ubiquitous family lack defined functions.Results
Phylogenetic analysis divided the Rid family into a widely distributed, apparently archetypal RidA subfamily and seven other subfamilies (Rid1 to Rid7) that are largely confined to bacteria and often co-occur in the same organism with RidA and each other. The Rid1 to Rid3 subfamilies, but not the Rid4 to Rid7 subfamilies, have a conserved arginine residue that, in RidA proteins, is essential for imine-hydrolyzing activity. Analysis of the chromosomal context of bacterial RidA genes revealed clustering with genes for threonine dehydratase and other pyridoxal 5''-phosphate-dependent enzymes, which fits with the known RidA imine hydrolase activity. Clustering was also evident between Rid family genes and genes specifying FAD-dependent amine oxidases or enzymes of carbamoyl phosphate metabolism. Biochemical assays showed that Salmonella enterica RidA and Rid2, but not Rid7, can hydrolyze imines generated by amino acid oxidase. Genetic tests indicated that carbamoyl phosphate overproduction is toxic to S. enterica cells lacking RidA, and metabolomic profiling of Rid knockout strains showed ten-fold accumulation of the carbamoyl phosphate-related metabolite dihydroorotate.Conclusions
Like the archetypal RidA subfamily, the Rid2, and probably the Rid1 and Rid3 subfamilies, have imine-hydrolyzing activity and can pre-empt damage from imines formed by amine oxidases as well as by pyridoxal 5''-phosphate enzymes. The RidA subfamily has an additional damage pre-emption role in carbamoyl phosphate metabolism that has yet to be biochemically defined. Finally, the Rid4 to Rid7 subfamilies appear not to hydrolyze imines and thus remain mysterious.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1584-3) contains supplementary material, which is available to authorized users. 相似文献117.
Mohamed A. Abdel-Naby Mona Y. Osman Ahmed F. Abdel-Fattah 《World journal of microbiology & biotechnology》2011,27(12):2903-2911
The production of extracellular pullulanase by Bacillus licheniformis NRC22 was investigated using different fermentation modes. In batch culture maximal enzyme activity of 18 U/ml was obtained
after 24 h of growth. In continuous fermentation by the free cells, maximal reactor productivity (4.15 KU/l/h) with enzyme
concentration of 14.8 U/ml and specific productivity of 334.9 U/g wet cells/h was attained at a dilution rate of 0.28/h, over
a period of 25 days. B. licheniformis NRC22 cells were immobilized on Ca-alginate. The immobilization conditions with respect to matrix concentration and cell
load was optimized for maximal enzyme production. In repeated batch operation, the activity of the immobilized cells was stable
during the 10 cycles and the activity remained between 9.8 and 7.7 U/ml. Continuous production of pullulanase by the immobilized
cells was investigated in a packed–bed reactor. Maximal reactor productivity (7.0 KU/h) with enzyme concentration of 16.8 U/ml
and specific productivity of 131.64 U/g wet cells/h was attained at dilution rate of 0.42/h. The enzyme activity in the effluent
started to decline gradually to the level of 8.7 U/ml after 25 days of the operation. 相似文献
118.
The bioavailability of therapeutic agents from eye drops is usually limited due to corneal barrier functions and effective
eye protective mechanisms. Therefore, the current study aims to enhance ocular bioavailability of brimonidine, a potent antiglaucoma
drug, through the preparation of ocular inserts. Solvent casting technique was employed to prepare the inserts using polyvinylpyrrolidone
K-90 (PVP K-90) as film-forming polymer blended with different viscosity grades of bioadhesive polymers namely hydroxypropyl
methycellulose, carbopol, sodium alginate, and chitosan. The prepared ocular inserts were evaluated for various physicochemical
parameters, swelling behavior, and in vitro release patterns. Sodium alginate-based ocular inserts revealed the most sustainment in drug release (99% at 6 h), so it
was selected for further modifications via coating it, on one side or dual sides, using hydrophobic film composed of either
ethylcellulose or Eudragit RSPO. The obtained in vitro release results for the modified ocular inserts revealed that ethylcellulose is superior to Eudragit RSPO in terms of brimonidine
release sustainment effect. Ocular inserts composed of 7% PVP K-90, 1.5% low molecular weight sodium alginate with or without
ethylcellulose coat were able to sustain the in vitro release of brimonidine. Their therapeutic efficacy regarding intraocular pressure (IOP) lowering effect when inserted in
albino rabbits eyes showed superior sustainment effect compared with that of brimonidine solution. Furthermore, due to both
the mucoadhesive property and the drug sustainment effect, the one-side-coated ocular insert showed more IOP lowering effect
compared with that of its non-coated or dual-side-coated counterpart. 相似文献
119.
Ginkgo biloba extract has been therapeutically used for several decades to increase peripheral and cerebral blood flow as well as for the
treatment of dementia. The extract contains multiple compounds such as flavonoids and terpenoids that are thought to contribute
to its neuroprotective and vasotropic effects. In this study, we investigated the effect of prolonged administration of EGb
761, up to 10 weeks, on mammalian retina using Fourier transform infrared spectroscopy (FTIR). Two main groups were involved
in this study: the normal group (n = 10); and EGb-administrated group (n = 50) that received—orally—a dose of 40 mg/kg/day EGb 761. The results demonstrated that EGb administration was associated
with different beneficial effects on the retinal constituents especially the underlying amide I protein secondary structure
components as well as the NH-OH region. It concluded that the optimum daily administration period of EGb (40 mg/kg) for ophthalmic
applications that targeting the retina ranges from 5 to 8 weeks. 相似文献
120.
Houssen ME Haron MM Metwally SS Ibrahim TM 《Journal of physiology and biochemistry》2011,67(1):115-120
Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immuno-inflammatory mechanisms are
involved. Inflammatory cytokines are implicated in the development and progression of atherosclerotic lesions. Immunomodulatory
therapies have been proposed for the treatment of atherosclerosis. Therefore, the aim of this study was to investigate the
systemic anti-inflammatory and immunomodulatory effects of atorvastatin, cyclosporine A (CsA), and tacrolimus (FK506) on plasma
inflammatory markers in atherosclerotic rabbits. Male New Zealand rabbits were randomized into five groups each of 12 animals.
Standard diet-fed group served as control, and the cholesterol-fed group received a diet supplemented with 1% cholesterol
alone, cholesterol + atorvastatin, cholesterol + FK506, and cholesterol + CsA. Serum levels of lipid profile parameters (triglycerides,
cholesterol, and high-density lipoprotein) were measured using colorimetric methods. Serum levels of C-reactive protein (CRP),
interleukin-6 (Il-6), and interferon-gamma (INF-γ) were measured in all studied groups using ELISA techniques. Our results
revealed a significant decrease (p < 0.001) in the serum levels of lipid profile parameters, CRP, Il-6, and INF-γ in atorvastatin-treated group compared with
the cholesterol-fed group. On the other hand, a non-significant difference was observed for the same parameters in either
FK506- or CsA-treated groups compared with the cholesterol-fed group. In conclusion, atorvastatin has a systemic anti-inflammatory
role that far surpassed the cholesterol reduction effect alone. FK506 or CsA failed to suppress elevated plasma inflammatory
markers. Thus, low doses of these two immunomodulating drugs could not have generalized systemic anti-inflammatory or immunosuppressive
effects. 相似文献