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51.
A simple technique for sulphur dressing mice 总被引:1,自引:0,他引:1
52.
53.
Bindi Dangi Marcus Obeng Julie M. Nauroth Mah Teymourlouei Micah Needham Krishna Raman Linda M. Arterburn 《The Journal of biological chemistry》2009,284(22):14744-14759
Enzymatically oxygenated derivatives of the ω-3 fatty acids
cis-4,7,10,13,16,19-docosahexaenoic acid (DHA) and
cis-5,8,11,14,17-eicosapentaenoic acid, known as resolvins, have
potent inflammation resolution activity (Serhan, C. N., Clish, C. B., Brannon,
J., Colgan, S. P., Chiang, N., and Gronert, K. (2000) J. Exp. Med.
192, 1197–1204; Hong, S., Gronert, K., Devchand, P. R., Moussignac, R.,
and Serhan, C. N. (2003) J. Biol. Chem. 278,
14677–14687). Our objective was to determine whether similar derivatives
are enzymatically synthesized from other C-22 fatty acids and whether these
molecules possess inflammation resolution properties. The reaction of DHA,
DPAn-3, and DPAn-6 with 5-, 12-, and 15-lipoxygenases produced oxylipins,
which were identified and characterized by liquid chromatography coupled with
tandem mass-spectrometry. DPAn-6 and DPAn-3 proved to be good substrates for
15-lipoxygenase. 15-Lipoxygenase proved to be the most efficient enzyme of the
three tested for conversion of long chain polyunsaturated fatty acids to
corresponding oxylipins. Since DPAn-6 is a major component of Martek
DHA-S™ oil, we focused our attention on reaction products obtained from
the DPAn-6 and 15-lipoxygenase reaction. (17S)-hydroxy-DPAn-6 and
(10,17S)-dihydroxy-DPAn-6 were the main products of this reaction.
These compounds were purified by preparatory high performance liquid
chromatography techniques and further characterized by NMR, UV
spectrophotometry, and tandem mass spectrometry. We tested both compounds in
two animal models of acute inflammation and demonstrated that both compounds
are potent anti-inflammatory agents that are active on local intravenous as
well as oral administration. These oxygenated DPAn-6 compounds can thus be
categorized as a new class of DPAn-6-derived resolvins.Enzymatically formed oxygenation products of C-20 and C-22 long chain
polyunsaturated fatty acids
(LC-PUFAs),4 have
important biological roles in inflammation, allergies, and blood clotting and
are thus believed to have therapeutic potential in several chronic immune
diseases
(1–10)
Several biologically important products of
cis-5,8,11,14-eicosatetraenoic acid/arachidonic acid (ARA),
cis-5,8,11,14,17-eicosapentaenoic acid (EPA), and
cis-4,7,10,13,16,19-docosahexaenoic acid (DHA) have been described
(4,
11,
12). Proinflammatory
oxylipins, such as leukotrienes and some prostaglandins, are derived from ARA,
an ω-6 fatty acid. Interestingly, the same fatty acid also serves as a
precursor to anti-inflammatory or proresolution molecules like lipoxins
(13,
14). Stable analogues of
lipoxins are being developed as drugs for asthma and other inflammatory airway
diseases (15,
16). Oxylipins derived from
ω-3 fatty acids, such as DHA and EPA, known as resolvins, are primarily
anti-inflammatory in nature
(17). EPA acts as a precursor
to the E-series resolvins that have shown potential in the treatment of
colitis, arthritis, and periodontitis
(18–20).
The resolvins of the D-series derived from DHA are useful as neuroprotective
agents. 10,17-Dihydroxy-4,7,11,13,15,19-docosahexaenoic acid (10,17-HDHA) or
neuroprotectin D1 is a resolvin that is formed endogenously in the human brain
and eye and is believed to exert its protective effect against cell
injury-induced oxidative stress
(21–23).The main enzymes responsible for the production of these oxygenated LC-PUFA
products are primarily lipoxygenases and, in addition, cyclo-oxygenases and
cytochromes P450. These enzymes produce oxylipins via transcellular activity,
often involving multiple cell types
(24). This activity mainly
results in mono-, di-, and tri-hydroxylation products of fatty acids that have
varying potencies, depending on the exact structure of the compound.
Lipoxygenases are non-heme, iron-containing dioxygenases that catalyze the
regioselective and enantioselective oxidation of polyunsaturated fatty acids
containing one or more cis,cis-1,4-pentadienoic moieties to give the
corresponding hydroperoxy derivatives
(25,
26). We thus considered that,
in addition to DHA and EPA, other C-22 PUFAs containing such methylene
interrupted double bonds may also be substrates for lipoxygenases and that
resulting products may have anti-inflammatory activity similar to DHA-derived
resolvins. DPAn-6 (cis-4,7,10,13,16-docosapentaenoic acid) is present
in algal oils, and recent studies have demonstrated that this fatty acid has
anti-inflammatory activities in vitro and, in conjunction with DHA,
also has anti-inflammatory activity in
vivo.5 Also, it
has been suggested that a combination of DHA and DPAn-6 could be a beneficial
natural therapy in neuroinflammatory conditions like Alzheimer disease.
Specifically, in a 3×Tg-AD mouse model of Alzheimer disease, DPAn-6 was
shown to reduce levels of early stage phospho-Tau epitopes, which in turn
correlated with a reduction in phosphorylated c-Jun N-terminal kinase, a
putative Tau kinase (27).
Although the precise mechanism of action of DPAn-6 in these inflammatory
milieus is not known, it suggests a possible role for oxylipin products of
DPAn-6 in resolution of inflammation. Also, another LC-PUFA, DPAn-3
(cis-7,10,13,16,19-docosapentaenoic acid) usually present along with
DHA and EPA in marine oils is known to be a potent inhibitor of platelet
aggregation
(28–30).
In addition, this LC-PUFA has a potent inhibitory effect on angiogenesis
through the suppression of VEGFR-2 (vascular endothelial-cell growth factor
receptor 2) expression. Angiogenesis is known to contribute to tumor growth,
inflammation, and microangiopathy, again pointing to the possibility that
anti-inflammatory activity of DPAn-3 might be mediated through resolvin-like
products as in the case of DHA and EPA
(31).The purpose of this research was to determine whether oxylipins are formed
from the C-22 LC-PUFAs, DPAn-6 and DPAn-3, by lipoxygenase activity; to
compare them to products formed from DHA; to chemically characterize products;
to purify key oxylipin products from the DPAn-6/15-lipoxygenase reaction; and
to test whether these compounds have resolvin-like anti-inflammatory activity.
This research also sets the stage for preparation and isolation of a wide
range of other C-22 oxylipins that could be evaluated as potential
anti-inflammatory compounds. 相似文献
54.
55.
Tobbell DA Middleton BJ Raines S Needham MR Taylor IW Beveridge JY Abbott WM 《Protein expression and purification》2002,24(2):242-254
Human procathepsin S and cathepsin S were expressed as inclusion bodies in Escherichia coli. Following solubilization of the inclusion body proteins, fractional factorial protein folding screens were used to identify folding conditions for procathepsin S and cathepsin S. A primary folding screen, including eight factors each at two levels, identified pH and arginine as the main factors affecting procathepsin S folding. In a second simple screen, the yields were further improved. The in vitro folding of mature cathepsin S has never been reported previously. In this study we used a series of fractional factorial screens to identify conditions that enabled the active enzyme to be generated without the prodomain although the yields were much lower than achieved with procathepsin S. Our data show the power of fractional factorial screens to rapidly identify folding conditions even for a protein that does not easily fold into its active conformation. 相似文献
56.
Incubation of striatal membranes with tosyl-lysyl chloromethylketone (TLCK) led to the irreversible inactivation of adenylate cyclase. However, under conditions where an interaction between the catalytic unit of adenylate cyclase and the alpha-subunit of the stimulatory G-protein GS were promoted, then the ability of TLCK to inhibit adenylate cyclase was markedly attenuated. The potency of stimulatory ligands, functioning through GS, to attenuate the sensitivity of adenylate cyclase to inactivation by TLCK was paralleled by their potency to activate adenylate cyclase. The local anaesthetic and membrane-fluidizing agent benzyl alcohol amplified GS-mediated stimulation of adenylate cyclase activity, whilst diminishing the ability of GS-mediated coupling to attenuate inactivation of adenylate cyclase by TLCK. In the absence of GS-mediated coupling, benzyl alcohol exerted only a small stimulatory effect on adenylate cyclase activity and had little effect on the ability of TLCK to inactivate this enzyme. We suggest that TLCK modifies a reactive group at or near the active site of adenylate cyclase which causes the functional inactivation of this enzyme. The reactivity of this group appears to be markedly affected by conformational changes elicited through coupling of adenylate cyclase to GS. 相似文献
57.
William G. A. Brown Karina Needham Bryony A. Nayagam Paul R. Stoddart 《Journal of visualized experiments : JoVE》2013,(77)
It has been demonstrated in recent years that pulsed, infrared laser light can be used to elicit electrical responses in neural tissue, independent of any further modification of the target tissue. Infrared neural stimulation has been reported in a variety of peripheral and sensory neural tissue in vivo, with particular interest shown in stimulation of neurons in the auditory nerve. However, while INS has been shown to work in these settings, the mechanism (or mechanisms) by which infrared light causes neural excitation is currently not well understood. The protocol presented here describes a whole cell patch clamp method designed to facilitate the investigation of infrared neural stimulation in cultured primary auditory neurons. By thoroughly characterizing the response of these cells to infrared laser illumination in vitro under controlled conditions, it may be possible to gain an improved understanding of the fundamental physical and biochemical processes underlying infrared neural stimulation. 相似文献
58.
Typical preparation of seed samples for infrared (IR) microspectroscopy involves imbibition of the seed for varying time periods followed by cryosectioning. Imbibition, however, may initiate germination even at 4° C with associated changes in the chemistry of the sample. We have found that it is possible to section seeds that are sufficiently hard, such as soybeans, on a standard laboratory microtome without imbibition. The use of dry sectioning of unimbibed seeds is reported here, as well as a comparison of different mounting media and modes of analysis. Glycerol, Tissue-Tek, and ethanol were used as mounting media, and the quality of the resulting spectra was assessed. Ethanol was the preferred mountant, because it dried quickly with no residue and thus did not interfere with the spectrum of interest. Analysis in transmission mode using barium fluoride windows to hold the samples was compared with transmission-reflection analysis with sections mounted on special infrared-reflecting slides. The two modes of analysis performed well in different regions of the spectrum. The mode of analysis (transmission vs. transmission-reflection) should be based on the components of greatest interest in the sample. 相似文献
59.
Rapid flow of passive neutrophils into a 4 microns pipet and measurement of cytoplasmic viscosity 总被引:6,自引:0,他引:6
Neutrophils from five different individuals are isolated with a density separation technique. A total of 151 unactivated (passive) cells are rapidly aspirated at constant suction pressure and at room temperature into a pipet with a diameter of 4 microns. The suction pressures in excess of an initial yield threshold are 0.5, 1 and 2 kPa and are comparable to those encountered in the microcirculation. These pressures are well in excess of the small suction pressure of approximately 20 Pa that is required to form a static hemispherical bump on the cell. At a given aspiration pressure, the leading edge of an individual cell is "tracked" as it flows into the pipet. A theory based on the flow of a Newtonian liquid from either a hemisphere or a spherical segment into a cylinder is used to model the entry process. Both theory and experiment show that during most of the entry process the leading edge of the cell moves at a nearly constant velocity with a rapid acceleration at the end. For cells from five different individuals at the three different excess aspiration pressures, Newtonian theory gives a cytoplasmic viscosity of 135 +/- 54 Pa.s and overall entry times of 3.3s (0.5 kPa), 1.6s (1 kPa) and 0.82s (2 kPa). These results and those of Evans and Yeung at lower aspiration pressures indicate that the complex cytoplasm inside unactivated neutrophils behaves as a nearly Newtonian fluid with a viscosity on the order of 10(2) Pa.s over almost a two order of magnitude range in aspiration pressure and, thus, rate of deformation. 相似文献
60.