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1.
Levuglandin E2 (LGE2), a γ-ketoaldehyde produced by rearrangement of the prostaglandin endoperoxide PGH2 under the aqueous conditions of its biosynthesis, causes extensive intermolecular crosslinking of ovalbumin at pH 6 or pH 7 and 37°C. The time dependence of protein oligomerization is monitored by SDS-PAGE. Effects of pH and concentration on the extent of LGE2-induced crosslinking are examined. The efficacy of LGE2 for inducing crosslinking is compared with other oxidative metabolites of arachidonic acid (AA), including the prostaglandins PGE2, PGD2, PGA2, PGB2, and PGF2α, as well as malondialdehyde and E-4-hydroxy-non-2-enal. LGE2 is orders of magnitude more effective in crosslinking protein than any other cyclooxygenase or lipoxygenase metabolite of AA tested. 相似文献
2.
Levuglandin (LG) E2, a secoprostanoic acid levulinaldehyde derivative, is a product of free radical oxidation that forms covalent adducts with lysyl residues on proteins. Treatment of LDL with LGE2 leads to uptake and degradation by mouse peritoneal macrophages. Oxidized LDL, but not acetyl LDL efficiently competed for binding and uptake of LGE2-modified 125I-LDL. This result suggests that LGE2-modified LDL was recognized by a class of scavenger receptor that demonstrated ligand specificity for oxidized LDL but not for acetyl LDL. 相似文献
3.
Darhl Foreman Lydia Zuk Donald B. Miller Robert G. Salomon 《Prostaglandins & other lipid mediators》1987,34(1)
The effects of E2 levuglandins on the contractile activity of rat uterine horns were studied. LGE2, AnLGE2, Δ9-LGE2 and the synthetic epimer, 8-epi-Δ9-LGE2 all induced contractions in a dose-response fashion. AnLGE2 gave decreased response with increased bath concentrations. Paired comparision showed potent and selective inhibitory effects of AnLGE2 on the uterotonic activity of prostaglandins. An LGE2 inhibited the uterotonic activity of PGe2 at a 0.1:1 ratio, of PGD2 at 1:1 ratio, but did not inhibit the activity of PGF2α. Exposure of sponteneously contracting uteri to high concentrations of AnLGE2, or prolonged exposure to lower concentrations, suppressed contractions. 相似文献
4.
《Channels (Austin, Tex.)》2013,7(2):113-123
A large number of ion channels maintain their activity through direct interactions with phosphatidylinositol bisphosphate (PIP2). For such channels, hydrolysis of PIP2 causes current inhibition. It has become controversial whether the inhibitory effects on channel activity represent direct effects of PIP2 hydrolysis or of downstream PKC action. We studied Phospholipase C (PLC)-dependent inhibition of G protein-activated inwardly rectifying K+ (Kir3) channels. By monitoring simultaneously channel activity and PIP2 hydrolysis, we determined that both direct PIP2 depletion and PKC actions contribute to Kir3 current inhibition. We show that the PKC-induced effects strongly depend on the PIP2 levels in the membrane. At the same time, we show that PKC destabilizes Kir3/PIP2 interactions and enhances the effects of PIP2 depletion on channel activity. These results demonstrate that PIP2 depletion and PKC-mediated effects reinforce each other and suggest that both of these interdependent mechanisms contribute to Kir3 current inhibition. This mechanistic insight may explain how even minor changes in PIP2 levels can have profound effects on Kir3 activity. We also show that stabilization of Kir3PIP2 interactions with Gβγ attenuates both PKC and Gq-mediated current inhibition, suggesting that diverse pathways regulate Kir3 activity through modulation of channel interactions with PIP2. 相似文献
5.
Voss AA Allen PD Pessah IN Perez CF 《Biochemical and biophysical research communications》2008,366(4):988-993
We studied cation regulation of wild-type ryanodine receptor type 1 (WTRyR1), type 3 (WTRyR3), and RyR3/RyR1 chimeras (Ch) expressed in 1B5 dyspedic myotubes. Using [3H]ryanodine binding to sarcoplasmic reticulum (SR) membranes, Ca2+ titrations with WTRyR3 and three chimeras show biphasic activation that is allosterically coupled to an attenuated inhibition relative to WTRyR1. Chimeras show biphasic Mg2+ inhibition profiles at 3 and 10 μM Ca2+, no observable inhibition at 20 μM Ca2+ and monophasic inhibition at 100 μM Ca2+. Ca2+ imaging of intact myotubes expressing Ch-4 exhibit caffeine-induced Ca2+ transients with inhibition kinetics that are significantly slower than those expressing WTRyR1 or WTRyR3. Four new aspects of RyR regulation are evident: (1) high affinity (H) activation and low affinity (L) inhibition sites are allosterically coupled, (2) Ca2+ facilitates removal of the inherent Mg2+ block, (3) WTRyR3 exhibits reduced cooperativity between H activation sites when compared to WTRyR1, and (4) uncoupling of these sites in Ch-4 results in decreased rates of inactivation of caffeine-induced Ca2+ transients. 相似文献
6.
Role of Organotellurium Species in Tellurium Neuropathy 总被引:3,自引:0,他引:3
Exposure of weanling rats to a diet containing 1% elemental tellurium causes segmental demyelination of peripheral nerve, and an inhibition of squalene epoxidase. This inhibition is thought to be the mechanism of action leading to demyelination. Tellurite appears to be the active inhibitory species in a cell-free system but the active species in vivo is unknown. We examined potassium tellurite (K2TeO3) and three organotellurium compounds for their ability to inhibit squalene epoxidase in Schwann cell cultures and to induce demyelination in weanling rats. K2TeO3 had no effect on squalene epoxidase activity in cultured Schwann cells and caused no demyelination in vivo. All three organotellurium compounds caused inhibition of squalene epoxidase in vitro and caused demyelination in vivo. (CH3)2TeCl2 was the most potent of these compounds and its neuropathy most resembled that caused by elemental tellurium. These data are consistent with the hypothesis that tellurium-induced demyelination is a result of squalene epoxidase inhibition and suggest that a dimethyltelluronium compound may be the neurotoxic species presented to Schwann cells in vivo. 相似文献
7.
Pothur R. Srinivas Diane D. Deutsch Suresh T. Mathews Anton Scott Goustin Myron A. Leon George Grunberger 《Cellular signalling》1996,8(8):567-573
Insulin acts on its target tissues by specific interaction with the cell surface insulin receptor (IR). The IR possesses an intrinsic tyrosine kinase (TK) activity which is stimulated by insulin binding. This TK activity is required for many aspects of insulin signalling. We had earlier reported that human plasma α2-HS glycoprotein (α2-HSG) inhibits insulin-stimulated mitogenesis at the level of IR-TK (Mol Endo 7: 1445–1455, 1993). In the present study, using recombinant α2-HSG, which possesses 50–100 times the specific activity of plasma α2-HSG, we have further investigated the molecular basis of this effect. We examined the insulin-stimulated Ras signalling pathway in Chinese Hamster Ovary cells overexpressing the human IR, α2-HSG inhibits insulin-induced tyrosine phosphorylation of IRS-1 and the subsequent association of GRB2, as well as Sos, with IRS-1. This inhibition results in reduced guanine nucleotide exchange in p21ras. α2-HSG also inhibits the stimulation of Raf phosphorylation, in response to insulin, leading to inhibition of MEK activity. In a parallel pathway, α2-HSG also inhibits insulin-induced tyrosine phosphorylation of Shc. However, α2-HSG does not affect any of the metabolic actions of insulin tested in these cells. These results suggest that, while insulin's mitogenic effects can be abolished by inhibition of insulin-induced IR-TK, propagation of signals for metabolic activities might utilize alternate or rescue mechanisms. 相似文献
8.
Caroline Bull Melsom ?ivind ?rstavik Jan-Bj?rn Osnes Tor Skomedal Finn Olav Levy Kurt Allen Krobert 《PloS one》2014,9(9)
Background and purpose
Despite the view that only β2- as opposed to β1-adrenoceptors (βARs) couple to Gi, some data indicate that the β1AR-evoked inotropic response is also influenced by the inhibition of Gi. Therefore, we wanted to determine if Gi exerts tonic receptor-independent inhibition upon basal adenylyl cyclase (AC) activity in cardiomyocytes.Experimental approach
We used the Gs-selective (R,R)- and the Gs- and Gi-activating (R,S)-fenoterol to selectively activate β2ARs (β1AR blockade present) in combination with Gi inactivation with pertussis toxin (PTX). We also determined the effect of PTX upon basal and forskolin-mediated responses. Contractility was measured ex vivo in left ventricular strips and cAMP accumulation was measured in isolated ventricular cardiomyocytes from adult Wistar rats.Key results
PTX amplified both the (R,R)- and (R,S)-fenoterol-evoked maximal inotropic response and concentration-dependent increases in cAMP accumulation. The EC50 values of fenoterol matched published binding affinities. The PTX enhancement of the Gs-selective (R,R)-fenoterol-mediated responses suggests that Gi regulates AC activity independent of receptor coupling to Gi protein. Consistent with this hypothesis, forskolin-evoked cAMP accumulation was increased and inotropic responses to forskolin were potentiated by PTX treatment. In non-PTX-treated tissue, phosphodiesterase (PDE) 3 and 4 inhibition or removal of either constitutive muscarinic receptor activation of Gi with atropine or removal of constitutive adenosine receptor activation with CGS 15943 had no effect upon contractility. However, in PTX-treated tissue, PDE3 and 4 inhibition alone increased basal levels of cAMP and accordingly evoked a large inotropic response.Conclusions and implications
Together, these data indicate that Gi exerts intrinsic receptor-independent inhibitory activity upon AC. We propose that PTX treatment shifts the balance of intrinsic Gi and Gs activity upon AC towards Gs, enhancing the effect of all cAMP-mediated inotropic agents. 相似文献9.
Adenylyl Cyclase Interaction with the D2 Dopamine Receptor Family; Differential Coupling to Gi, Gz, and Gs 总被引:1,自引:0,他引:1
Joseph Obadiah Tomer Avidor-Reiss C. Simone Fishburn Shari Carmon Michael Bayewitch Zvi Vogel Sara Fuchs Berta Levavi-Sivan 《Cellular and molecular neurobiology》1999,19(5):653-664
1.The D2-type dopamine receptors are thought to inhibit adenylyl cyclase (AC), via coupling to pertussis toxin (PTX)-sensitive G proteins of the Gi family. We examined whether and to what extent the various D2 receptors (D2S, D2L, D3S, D3L, and D4) couple to the PTX-insensitive G protein Gz, to produce inhibition of AC activity.2.COS-7 cells were transiently transfected with the individual murine dopamine receptors alone, as well as together with the subunit of Gz. PTX treatment was employed to inactivate endogenous i, and coupling to Gi and Gz was estimated by measuring the inhibition of cAMP accumulation induced by quinpirole, in forskolin-stimulated cells.3.D2S or D2L receptors can couple to the same extent to Gi and to Gz. The D4 dopamine receptor couples preferably to Gz, resulting in about 60% quinpirole-induced inhibition of cAMP accumulation. The D3S and D3L receptor isoforms couple slightly to Gz and result in 15 and 30% inhibition of cAMP accumulation, respectively.4.We have demonstrated for the first time that the two D3 receptor isoforms, and not any of the other D2 receptor subtypes, also couple to Gs in both COS-7 and CHO transfected cells, in the presence of PTX.5.Thus, the differential coupling of the D2 dopamine receptor subtypes to various G proteins may add another aspect to the diversity of dopamine receptor function. 相似文献
10.
Suelem D. Ramalho Rajgopal Sharma Jessica K. White Neha Aggarwal Anita Chalasani Mansoureh Sameni Kamiar Moin Paulo C. Vieira Claudia Turro Jeremy J. Kodanko Bonnie F. Sloane 《PloS one》2015,10(11)
The cysteine protease cathepsin B has been causally linked to progression and metastasis of breast cancers. We demonstrate inhibition by a dipeptidyl nitrile inhibitor (compound 1) of cathepsin B activity and also of pericellular degradation of dye-quenched collagen IV by living breast cancer cells. To image, localize and quantify collagen IV degradation in real-time we used 3D pathomimetic breast cancer models designed to mimic the in vivo microenvironment of breast cancers. We further report the synthesis and characterization of a caged version of compound 1, [Ru(bpy)2(1)2](BF4)2 (compound 2), which can be photoactivated with visible light. Upon light activation, compound 2, like compound 1, inhibited cathepsin B activity and pericellular collagen IV degradation by the 3D pathomimetic models of living breast cancer cells, without causing toxicity. We suggest that caged inhibitor 2 is a prototype for cathepsin B inhibitors that can control both the site and timing of inhibition in cancer. 相似文献
11.
Gonzalo Sánchez Natalia Colettis Pablo Vázquez Carlos Cerveñansky Alejandra Aguirre Jorge A. Quillfeldt Diana Jerusalinsky Edgar Kornisiuk 《Neurochemical research》2009,34(8):1363-1371
The five muscarinic acetylcholine receptors (M1–M5) are differentially expressed in the brain. M2 and M4 are coupled to inhibition of stimulated adenylyl cyclase, while M1, M3 and M5 are mainly coupled to the phosphoinositide pathway. We studied the muscarinic receptor regulation of adenylyl cyclase activity
in the rat hippocampus, compared to the striatum and amygdala. Basal and forskolin-stimulated adenylyl cyclase activity was
higher in the striatum but the muscarinic inhibition was much lower. Highly selective muscarinic toxins MT1 and MT2—affinity
order M1 ≥ M4 >> others—and MT3—highly selective M4 antagonist—did not show significant effects on basal or forskolin-stimulated cyclic AMP production but, like scopolamine,
counteracted oxotremorine inhibition. Since MTs have negligible affinity for M2, M4 would be the main subtype responsible for muscarinic inhibition of forskolin-stimulated enzyme. Dopamine stimulated a small
fraction of the enzyme (3.1% in striatum, 1.3% in the hippocampus). Since MT3 fully blocked muscarinic inhibition of dopamine-stimulated
enzyme, M4 receptor would be responsible for this regulation.
Diana Jerusalinsky and Edgar Kornisiuk contributed equally to this paper. 相似文献
12.
We studied anionic inhibition of the reaction CO2 + OH?? HCO3? catalyzed by human red cell carbonic anhydrase B (I) and C (II), using iodide and cyanate. In the forward reaction with respect to CO2 as the substrate, inhibition was mixed but favoring noncompetitive; the back reaction, with HCO3? as the substrate, yielded strict competitive kinetics. Mean inhibition constants, KI, in the pH range 7.2–7.5 are: iodide, 0.5 mm for enzyme B and 16 mm for C; cyanate, 0.8 μm for B and 20 μm for C. When OH? was considered as the substrate for the forward reaction, cyanate and chloride behaved as competitive inhibitors. The true inhibition constant (KI0) for cyanate (calculated for infinitely low OH?) is 0.4 μm for enzyme B and 4 μm for C. Apart from the difference in anion affinity and some 10-fold higher activity of C > B, the isozymes showed similar patterns of inhibition. Data agree with generally proposed mechanisms describing the active site as ZnH2O with pKa of about 7. 相似文献
13.
The present study has been performed to investigate how PGs would participate the hatching process. Effects of indomethacin, an antagonist to PGs biosynthesis, on the hatching of mouse blastocysts were examined in vitro. Furthermore, it was studied that prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α) or 6-keto-prostaglandin F1α (6-keto-PGF1α) were added to the culture media with indomethacin. (1) The hatching was inhibited by indomethacin yet the inhibition was reversible. (2) In the groups with indomethacin and PGE2, no improvement was seen in the inhibition of hatching and the inhibition was irreversible. (3) In the groups with indomethacin and PGF2α, inhibition of hatching was improved in comparison with the group with indomethacin. (4) In the groups with indomethacin and 6-keto-PGF1α, no improvement was seen. The above results indicated that PGF2α possibly had an accelerating effect on hatching and a high concentration of PGE2 would exert cytotoxic effect on blastocysts. 相似文献
14.
Effect of photosynthetic intermediates on the magnesium inhibition of oxygen evolution by barley chloroplasts 总被引:2,自引:2,他引:0
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Huber SC 《Plant physiology》1979,63(4):754-757
Millimolar concentrations of Mg2+ inhibited CO2-dependent O2 evolution by barley (Hordeum vulgare L.) chloroplasts and also prevented the activation of NADP-glyceraldehyde-3-phosphate dehydrogenase, ribulose-5-phosphate kinase, and fructose-1,6-diphosphatase by light in intact chloroplasts. When added in the dark, 3-phosphoglycerate prevented the inhibition of O2 evolution by Mg2+ and reduced the Mg2+ inhibition of enzyme activation by light. Fructose 1,6-diphosphate and ribulose 5-phosphate also prevented the inhibition of O2 evolution by Mg2+ whereas glucose 1-phosphate, glucose 6-phosphate, ribulose 1,5-diphosphate, and citrate had no effect. Phosphoenolpyruvate gave an intermediate response. Metabolites that prevented the Mg2+ inhibition of O2 evolution shortened the lag phase of CO2-dependent O2 evolution in the absence of M2+. Loading chloroplasts in the dark with 3-phosphoglycerate reduced both the lag phase of O2 evolution and the inhibition of O2 evolution by Mg2+. The results suggested that Mg2+ inhibition was lessened either by external metabolites that compete with inorganic phosphate for transport into the chloroplast or by a high concentration of internal metabolites. 相似文献
15.
Victoria Magrioti Aikaterini Nikolaou Annetta Smyrniotou Ishita Shah Violetta Constantinou-Kokotou Edward A. Dennis George Kokotos 《Bioorganic & medicinal chemistry》2013,21(18):5823-5829
Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) has recently emerged as an important pharmaceutical target. Selective and potent GVIA iPLA2 inhibitors can be used to study its role in various neurological disorders. In the current work, we explore the significance of the introduction of a substituent in previously reported potent GVIA iPLA2 inhibitors. 1,1,1,2,2-Pentafluoro-7-(4-methoxyphenyl)heptan-3-one (GK187) is the most potent and selective GVIA iPLA2 inhibitor ever reported with a XI(50) value of 0.0001, and with no significant inhibition against GIVA cPLA2 or GV sPLA2. We also compare the inhibition of two difluoromethyl ketones on GVIA iPLA2, GIVA cPLA2, and GV sPLA2. 相似文献
16.
《BBA》1986,850(1):64-71
NAD+ supplied to purified Solanum tuberosum mitochondria caused progressive inhibition of succinate oxidation in State 3. This inhibition was especially pronounced at alkaline pH and at low succinate concentrations. Glutamate counteracted the inhibition. NAD+ promoted oxaloacetate accumulation in State 3; supplied oxaloacetate inhibited O2 uptake in the presence of succinate much more severely in State 3 than in State 4. NAD reduction linked to succinate oxidation by ATP-dependent reverse electron transport was likewise inhibited by oxaloacetate. We conclude that NAD+-induced inhibition of succinate oxidation is due to an inhibition of succinate dehydrogenase resulting from increased accumulation of oxaloacetate generated from malate oxidation via malate dehydrogenase. The results are discussed in the context of the known regulatory characteristics of plant succinate dehydrogenase. 相似文献
17.
Dey D Pal BC Biswas T Roy SS Bandyopadhyay A Mandal SK Giri BB Bhattacharya S 《Molecular and cellular biochemistry》2007,300(1-2):149-157
The decrease in insulin sensitivity to target tissues or insulin resistance leads to type 2 diabetes mellitus, an insidious
disease threatening global health. Numerous evidences made free fatty acids (FFAs) responsible for insulin resistance and
type 2 diabetes. We demonstrate here that the damage of insulin acitivity by a free fatty acid, palmitate could be prevented
by a lupinoside. An incubation of 3T3 L1 adipocytes with a FFA i.e. palmitate inhibited insulin stimulated uptake of 3H-2 deoxyglucose (2 DOG) significantly. Addition of a lupinoside purified from Pueraria tuberosa, lupinoside PA4 (LPA4) strongly prevented this inhibition. We then examined insulin signaling pathway where palmitate significantly inhibited insulin
stimulated phosphorylation of Insulin receptor tyrosine kinase, IRS 1and PI3 kinase, PDK1 and Akt/PKB. LPA4 rescued this inhibition of signaling molecule by palmitate. Insulin mediated translocation of Glut4, the glucose transporter
in insulin target cells, was effectively blocked by palmitate while, LPA4 waived this block. Administration of LPA4 to nutritionally induced diabetic rats significantly reduced the increase in plasma glucose. All these indicate LPA4 to be a potentially therapeutic agent for insulin resistance and type 2 diabetes. 相似文献
18.
Guoyong Bian Jinbo Yang Jeevithan Elango Wenhui Wu Bin Bao Chunling Bao 《化学与生物多样性》2021,18(5):e2001030
The inhibition of α-glucosidase activity is a prospective approach to attenuate postprandial hyperglycemia in the treatment of type 2 diabetes mellitus (T2DM). Herein, the inhibition of α-glucosidase by three compounds T1 – T3 of Akebia trifoliata stem, namely hederagenin ( T1 ), 3-epiakebonoic acid ( T2 ), and arjunolic acid ( T3 ) were investigated using enzyme kinetics and molecular docking analysis. The three triterpenoids exhibited excellent inhibitory activities against α-glucosidase. T1 – T3 showed the strongest inhibition with IC50 values of 42.1±5.4, 19.6±3.2, and 11.2±2.3 μM, respectively, compared to the acarbose positive control (IC50=106.3±8.2). Enzyme inhibition kinetics showed that triterpenoids T1 – T3 demonstrated competitive, mixed, and noncompetitive-type inhibition against α-glucosidase, respectively. The inhibition constant (Ki) values were 21.21, 7.70, and 3.18 μM, respectively. Docking analysis determined that the interaction of ligands T1 – T3 and α-glucosidase was mainly forced by hydrogen bonds and hydrophobic interactions, which could result in improved binding to the active site of the target enzyme. The insulin resistant (IR)-HepG2 cell model used in this study (HepG2 cells exposed to 10−7 M insulin for 24 h) and glucose uptake assays showed that compounds T1 – T3 had no cytotoxicity with concentrations ranging from 6.25 to 25 μM and displayed significant stimulation of glucose uptake in IR-HepG2 cells. Thus, triterpenoids T1 – T3 showed dual therapeutic effects of α-glucosidase inhibition and glucose uptake stimulation and could be used as potential medicinal resources to investigate new antidiabetic agents for the prevention or treatment of diabetes. 相似文献
19.
S.K. Mukerji 《Archives of biochemistry and biophysics》1977,179(1):360-365
Sulfite ion, the hydrated form of SO2 which is an air pollutant, was found to be an inhibitor of phosphoenolpyruvate carboxylase(s) isolated from corn leaves. The inhibition was partial even in the presence of excess SO32?. It inhibited the enzyme competitively with respect to HCO3?, noncompetitively with respect to phosphoenolpyruvate, and uncompetitively with respect to Mg2+. The kinetics of inhibition suggest that an alternate pathway is operative in the presence of SO32?. The enzyme(s) were activated by glucose 6-phosphate which affected primarily the affinity of the enzyme for phosphoenolpyruvate. The binding site of glucose 6-phosphate was apparently distinct from the catalytic site of the enzyme since partial destruction of the catalytic site by heat had no effect on the inhibition by SO32?, but glucose 6-phosphate lost its activating effect. The inhibition due to SO32? was relieved by glucose 6-phosphate. 相似文献
20.
1,25(OH)2D3 increases cell permeability to calcium. This increase is not mediated by proteins sensitive to cycloheximide or actinomycin D inhibition. We propose that CaBP may associate with intracellular membranes and organelles to prevent intracellular calcium accumulation and the potential cytotoxic effects of such accumulation. In support of this hypothesis, the amount of mitochondrial mineralization in chick intestinal cells was markedly increased by 1,25(OH)2D3 treatment when CaBP synthesis was simultaneously blocked by cycloheximide treatment. Mineral in membrane vesicles was increased by 1,25(OH)2D3 treatment, but was blocked by simultaneous treatment with cycloheximide. 相似文献