[Gallbladder lithiasis and cirrhosis: prevalence and risk factors in 150 patients].
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Cholelithiasis↗
Biomedical subjects
J Turk
Publications and source records attributed to J Turk.
Mechanism of arachidonic acid-induced Ca2+ mobilization from rat liver microsomes.
Recent evidence indicates that unesterified arachidonic acid functions as a mediator of intracellular Ca2+ mobilization by inducing Ca2+ release from the endoplasmic reticulum of pancreatic islet beta cells in a manner closely similar to that of inositol 1,4,5-trisphosphate. To test the generality and explore the mechanism of this phenomenon we have examined the effects of arachidonic acid on calcium accumulation and release by hepatocyte subcellular fractions enriched in endoplasmic reticulum (microsomes). At concentrations above 0.017 mumol/mg microsomal protein, arachidonate induced rapid (under 2 min) 45Ca2+ release from microsomes that had been preloaded with 45Ca2+. Arachidonate also suppressed microsomal 45Ca2+ accumulation when present during the loading period, as reflected by reduction both of 45Ca2+ accumulation at steady state and of the rate of uptake. Neither the cyclooxygenase inhibitor indomethacin nor the lipoxygenase/cyclooxygenase inhibitor BW755C suppressed arachidonate-induced 45Ca2+ release, indicating that this effect was not dependent upon oxygenation of the fatty acid to metabolites. The long-chain unsaturated fatty acids oleate and linoleate were less potent than arachidonate in inducing 45Ca2+ release, and the saturated fatty acid stearate did not exert this effect. Albumin prevented 45Ca2+ release by arachidonate, presumably by binding the fatty acid. As is the case for inositol 1,4,5-trisphosphate, the ability of arachidonate to induce 45Ca2+ release was dependent on the ambient free Ca2+ concentration. Arachidonate did not influence microsomal membrane permeability or Ca2+-ATPase activity and may exert its effects on microsomal Ca2+ handling by activation of a Ca2+ extrusion mechanism or by dissociating Ca2+ uptake from Ca2+-ATPase activity.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
The role of phospholipid-derived mediators including arachidonic acid, its metabolites, and inositoltrisphosphate and of intracellular Ca2+ in glucose-induced insulin secretion by pancreatic islets.
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Animals↗
Arachidonate lipoxygenase products and renal allograft rejection in dogs.
The production of 12-hydroxyeicosatetraenoic acid (12-HETE) and leukotriene B4 (LTB4) was studied in renal tissue obtained from renal allografts and normal kidneys of nonimmunosuppressed dogs that had undergone unilateral renal allotransplantation. We have shown that allografted renal cortex undergoing rejection synthesizes significantly greater quantities of 12-HETE than normal or autotransplanted control renal cortex. There was no significant increase in 12-HETE production by allografted medulla undergoing rejection. Production of LTB4 was significantly greater in the rejecting renal cortex compared to control renal cortex but was not different in the rejecting compared to normal renal medulla. Production of 12-HETE and LTB4 was significantly inhibited by the lipoxygenase-cyclooxygenase inhibitor BW755C, suggesting that production of these compounds was enzyme catalyzed. Histologic examination of renal tissue undergoing rejecting revealed varying degrees of tissue destruction and cellular infiltration. These histologic parameters correlated with the magnitude of 12-HETE production in the allografts. Our findings therefore indicate that arachidonate lipoxygenase products are generated in increased amounts by renal cortical tissue undergoing rejection and suggest that these products may be involved in the rejection process.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Pericardial mesothelioma.
The case of a 44-year old man, never exposed to asbestos, who died from a pericardial mesothelioma is described. The diagnosis was made by surgical examination. Two weak transient episodes of amelioration, the first accomplished with pronison administration and the other one by radiotherapy, were registered.
Adult↗
Glucose 6-phosphate regulates Ca2+ steady state in endoplasmic reticulum of islets. A possible link in glucose-induced insulin secretion.
Glucose stimulation of islets is coupled with the rapid intracellular release of myo-inositol 1,4,5-trisphosphate (IP3) and arachidonic acid which in turn mobilize Ca2+ stored in the endoplasmic reticulum (ER). The metabolism of glucose is required for insulin secretion although the link between glucose metabolism and the cellular events resulting in insulin release is unknown. In digitonin-permeabilized islets, glucose 6-phosphate (0.5-4 mM) increased significantly the ATP-dependent Ca2+ content of the ER at a free Ca2+ concentration of 1 microM. At 0.2 microM free Ca2+, glucose 6-phosphate (2-10 mM) had a smaller effect. Glucose, phosphate, mannose 6-phosphate, and fructose 1,6-diphosphate had no effect on the ATP-dependent Ca2+ content of the ER. Glucose 1-phosphate and fructose 6-phosphate also increased ATP-dependent Ca2+ content of the ER, presumably due to conversion to glucose 6-phosphate by islet phosphoglucomutase and phosphoglucoisomerase, respectively. The glucose 6-phosphate increase in the ATP-dependent Ca2+ content of the ER was shown to be mediated by glucose 6-phosphatase localized to the ER. Both arachidonic acid (10 microM) and the Ca2+ ionophore A23187 (2 microM) mobilized Ca2+ stored in the ER by glucose 6-phosphate. However, IP3-induced (10 microM) Ca2+ release from the ER was abolished in the presence of glucose 6-phosphate (0.5-10 mM). We propose that glucose 6-phosphate could provide a regulatory link between glucose metabolism and intracellular Ca2+ regulation by augmenting Ca2+ sequestered in the ER as well as attenuating IP3-induced Ca2+ release. Thus, glucose 6-phosphate would serve as an "off" signal leading to a decrease in intracellular Ca2+ when both the free Ca2+ and glucose 6-phosphate concentrations have increased following glucose stimulus.
Animals↗
Glucose-induced phospholipid hydrolysis in isolated pancreatic islets: quantitative effects on the phospholipid content of arachidonate and other fatty acids.
Our recent findings indicate that glucose-induced insulin secretion from isolated pancreatic islets is temporally associated with accumulation of substantial amounts of free arachidonic acid and that arachidonate may serve as a second messenger for intracellular calcium mobilization in islets. In an effort to determine the source of this released arachidonate, the endogenous fatty acid composition of phospholipids from islets has been determined by thin-layer chromatographic separation of the phospholipids, methanolysis to the fatty acid methyl esters, and quantitative gas chromatographic analyses. The relative abundance of phospholipids in islets as judged by their fatty acid content was phosphatidylcholine (PC), 0.63; phosphatidylethanolamine (PE), 0.23; phosphatidylinositol (PI), 0.067; phosphatidylserine (PS), 0.049. Arachidonate constituted 17% of the total islet fatty acid content, and PC contained 43% of total islet arachidonate. Islets incubated with [3H]arachidonate in the presence of 28 mM D-glucose incorporated radiolabel into PC with a considerably higher specific activity than that of PE, PS or PI. The total fatty acid content of PC from islets incubated with 28 mM glucose for 30 min was significantly lower than that of islets incubated with 3 mM glucose, and smaller effects were observed with PE, PS and PI. The molar decrement in PC arachidonate was 3.2 pmol/islet under these conditions, which is sufficient to account for the previously observed accumulation of free arachidonate (2 pmol/islet). A sensitive method involving negative ion-chemical ionization-mass spectrometric analyses of the pentafluorobenzyl esters of fatty acids derived from trace amounts of lysophosphatidylcholine (lyso-PC) was developed, and glucose-stimulation was found to reduce islet lyso-PC content by about 10-fold. These findings indicate that the insulin secretagogue D-glucose induces phospholipid hydrolysis in islets and suggest that PC may be the major source of free arachidonate which accumulates in glucose-stimulated islets.
Animals↗
Glucose-induced accumulation of inositol trisphosphates in isolated pancreatic islets. Predominance of the 1,3,4-isomer.
Anion-exchange h.p.l.c. analysis of [3H]inositol phosphates derived from glucose-stimulated isolated pancreatic islets that had been prelabelled with myo-[3H]inositol revealed that the predominant inositol trisphosphate was the 1,3,4-isomer [Ins(1,3,4)P3]. The 1,4,5-isomer [Ins(1,4,5)P3] was also detectable, as was a more polar inositol phosphate with the chromatographic properties of inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4]. Glucose-induced accumulation of Ins(1,3,4)P3 was augmented by Li+ and occurred after maximal accumulation of Ins(1,4,5)P3. These findings suggest a possible role for Ins(1,3,4)P3 or its probable precursor Ins(1,3,4,5)P4 in stimulus-secretion coupling in pancreatic islets.
Animals↗
Intracellular Ca2+ mobilization by arachidonic acid. Comparison with myo-inositol 1,4,5-trisphosphate in isolated pancreatic islets.
Previous studies have demonstrated that myo-inositol 1,4,5-trisphosphate (IP3) mobilizes Ca2+ from the endoplasmic reticulum (ER) of digitonin-permeabilized islets and that an increase in intracellular free Ca2+ stimulates insulin release. Furthermore, glucose stimulates arachidonic acid metabolism in islets. In digitonin-permeabilized islets, exogenous arachidonic acid at concentrations between 1.25 to 10 microM elicited significant Ca2+ release from the ER at a free Ca2+ concentration of 0.1 microM. Arachidonic acid-induced Ca2+ release was not due to the metabolites of arachidonic acid. Arachidonic acid induced a rapid release of Ca2+ within 2 min. Comparison of arachidonic acid-induced Ca2+ release with IP3-induced Ca2+ release revealed a similar molar potency of arachidonic acid and IP3. The combination of both arachidonic acid and IP3 resulted in a greater effect on Ca2+ mobilization from the ER than either compound alone. The mass of endogenous arachidonic acid released by islets incubated with 28 mM glucose was measured by mass spectrometric methods and was found to be sufficient to achieve arachidonic acid concentrations equal to or exceeding those required to induce release of Ca2+ sequestered in the ER. These observations indicate that glucose-induced arachidonic acid release could participate in glucose-induced Ca2+ mobilization and insulin secretion by pancreatic islets, possibly in cooperation with IP3.
Animals↗
Quantitation of myo-inositol as its hexakis(trifluoroacetyl) derivative with negative ion chemical ionization mass spectrometry.
Highly volatile hexakis(trifluoroacetyl) derivatives of myo-inositol and hexadeutero-myo-inositol have been prepared and analysed by capillary column gas chromatography/mass spectrometry. The electron impact and negative ion (methane) chemical ionization mass spectra of these compounds have been determined. Negative ion chemical ionization mass spectrometric analysis of hexakis(trifluoroacetyl)-myo-inositol achieves a sensitivity one order of magnitude greater than electron impact mass spectrometric analysis of hexakis(trimethylsilyl)-myo-inositol at appropriate selected ions. Stable isotope dilution measurement of myo-inositol versus hexadeutero-myo-inositol employing gas chromatography/negative ion chemical ionization mass spectrometry of the hexakis(trifluoroacetyl) derivatives is demonstrated, and this method is applied to the detection of inositol derived from hydrolysis of water-soluble inositol phosphates obtained from isolated pancreatic islets.
Animals↗
Ethylene glycol intoxication.
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Acidosis↗
Progressive ossifying myositis in a cat.
Progressive ossifying myositis was diagnosed in a 2-year-old female cat. Clinical signs consisted of cervical pruritus, a stiff gait involving the forelimbs, and decreased range of motion of the scapulohumeral joints. The signs progressed over a 2-month period to involve the hindlimbs and coxofemoral joints. The primary cause of this disease is unknown and treatment is palliative. Treatment with diphosphonate disodium etidronate was unsuccessful in controlling the clinical signs in this case.
Animals↗
Arachidonic acid metabolism in isolated pancreatic islets. IV. Negative ion-mass spectrometric quantitation of monooxygenase product synthesis by liver and islets.
Deuterium-labelled standards of four regionally isomeric epoxyeicosatrienoic acids (EETs) and their hydrolysis products, the dihydroxyeicosatrienoic acids (DHETs), have been prepared and analyzed by capillary column gas chromatography (GC)-negative ion (NI)-methane chemical ionization (MCI)-mass spectrometry (MS) as the pentafluorobenzyl esters. As little as 40 pg of these compounds were readily visualized by these methods, and the deuterium-labelled standards were used in a stable isotope dilution mass spectrometric assay which was linear from near the detection limit over several orders of magnitude. NADPH-dependent synthesis of both EETs and DHETs from arachidonate by hepatic microsomal cytochrome P-450-mono-oxygenase activity was demonstrable with these methods and was significantly suppressed by the compound BW755C (500 microM), but not by eicosa-5,8,11,14-tetraynoic acid (ETYA, 20 microM) or by nordihydroguaiaretic acid (NDGA, 50 microM). All three compounds suppress glucose-induced insulin secretion and 12-hydroxyeicosatetraenoic acid (12-HETE) synthesis by isolated pancreatic islets with similar concentration dependence. Microsomes derived from isolated pancreatic islets synthesized less than 3% of the EET and DHET compounds as a comparable amount of hepatic microsomes. Intact islets synthesized less than 3% by mass of the EET and DHET compounds compared to the mass of 12-HETE produced by the islets. Islets also failed to convert 3H-labelled arachidonate to 3H-labelled EETs or DHETs under conditions where conversion to [3H]12-HETE and to [3H]prostaglandin E2 (but not to [3H]leukotriene C4, D4, or E4) was clearly demonstrable. Neither exogenous EETs nor leukotriene C4 stimulated insulin secretion from the isolated islets or reversed the suppression of glucose-induced secretion by the lipoxygenase inhibitor BW755C. The cytochrome P-450-monooxygenase inhibitor, metyrapone (50 microM), did not influence insulin secretion from the isolated islets under conditions where the lipoxygenase inhibitor, NDGA, suppressed glucose-induced secretion. These observations argue against the recently suggested hypothesis that EETs derived from arachidonate by monooxygenase action participate in glucose-induced insulin secretion by isolated pancreatic islets.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
Arachidonic acid metabolism in isolated pancreatic islets. III. Effects of exogenous lipoxygenase products and inhibitors on insulin secretion.
Isolated pancreatic islets from the rat have been demonstrated by stable isotope dilution-mass spectrometric methods to synthesize the 12-lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE) in amounts of 1.7 to 2.8 ng per 10(3) islets. No detectable amounts of 5-HETE and only trace amounts of 15-HETE could be demonstrated by these methods. Nordihydroguaiaretic acid (NDGA) and BW755C have been demonstrated to inhibit islet 12-HETE synthesis and also to inhibit glucose-induced insulin secretion. Inhibition of insulin secretion and of 12-HETE synthesis exhibited similar dependence on the concentration of these compounds. Eicosa-5,8,11,14-tetrynoic acid (ETYA) also inhibited glucose-induced insulin secretion, as previously reported, at concentrations which inhibit islet 12-HETE synthesis. Exogenous 12-HETE partially reversed the suppression of glucose-induced insulin secretion by lipoxygenase inhibitors, but exogenous 12-hydroperoxyeicosatetraenoic acid (12-HPETE), 15-HPETE, 5-HPETE, 15-HETE, or 5-HETE did not reverse this suppression. These observations argue against the recently suggested hypothesis that islet synthesis of 5-HETE modulates insulin secretion. Suppression of glucose-induced insulin secretion by ETYA, BW755C and NDGA may be due to inhibition of the islet 12-lipoxygenase by these compounds. The possibility that other processes involved in glucose-induced insulin secretion are inhibited by ETYA, BW755C and NDGA cannot yet be excluded.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
Wolff-Parkinson-White syndrome type B and left bundle-branch block: electrophysiologic and radionuclide study.
Coinciding left bundle-branch block and Wolff-Parkinson-White syndrome type B, a very rare electrocardiographic occurrence, was found in a patient with dilated cardiomyopathy. Electrophysiologic study revealed eccentric retrograde atrial activation during ventricular pacing, suggesting right-sided accessory pathway. At programmed atrial pacing, effective refractory period of the accessory pathway was 310 ms; at shorter pacing coupling intervals, normal atrioventricular conduction with left bundle-branch block was seen. Left bundle-branch block was seen also with His bundle pacing. Radionuclide phase imaging demonstrated right ventricular phase advance and left ventricular phase delay; both right and left ventricular phase images revealed broad phase distribution histograms. Combined electrophysiologic and radionuclide investigations are useful to disclose complex conduction abnormalities and their mechanical correlates.
Aged↗
Arachidonic acid metabolism in isolated pancreatic islets. I. Identification and quantitation of lipoxygenase and cyclooxygenase products.
The metabolism of arachidonic acid by pancreatic islets has been studied with purified populations of large numbers of islets isolated from the rat. Sequential high-performance liquid chromatographic analyses of islet-derived metabolites of 3H-labeled arachidonate in both reversed and normal phases with 14C-labeled internal standards have demonstrated synthesis by the islets of the cyclooxygenase products prostaglandin E2, prostaglandin F2 alpha, thromboxane B2 and 12- hydroxyheptadecatrienoic acid as well as the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE). Islet synthesis of these compounds was suppressed with appropriate inhibitors of arachidonate metabolism. Synthesis of the identified metabolites from endogenous arachidonate has also been quantitated with the use of deuterated internal standards, capillary column gas chromatographic analyses, and negative ion-chemical ionization mass spectrometric measurements. The relative abundances of metabolites derived from exogenous, radiolabeled arachidonate versus endogenous precursor differed considerably, and 12-HETE was by far the most abundant of these metabolites synthesized from endogenous arachidonate. Platelets contaminating the isolated islet preparations have been excluded as the source of the identified arachidonate metabolites. These studies establish that cells intrinsic to pancreatic islets synthesize a clearly characterized profile of arachidonate lipoxygenase and cyclooxygenase products. The sensitive and specific mass spectrometric methods for quantitation of these compounds permit detailed evaluation of their possible participation in insulin secretion from isolated islets.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Arachidonic acid metabolism in isolated pancreatic islets. II. The effects of glucose and of inhibitors of arachidonate metabolism on insulin secretion and metabolite synthesis.
Isolated pancreatic islets from the rat incubated with 28 mM glucose have been found to secrete more insulin and to synthesize greater amounts of arachidonate lipoxygenase and cyclooxygenase products than islets incubated with 3 mM glucose. This effect was not apparent in studies examining metabolism of radiolabeled arachidonate and was revealed only when the metabolites were quantitated with mass spectrometric measurements. That the glucose-induced synthesis of arachidonate metabolites may participate in insulin secretion was suggested by studies with inhibitors of arachidonate metabolism. Eicosa 5,8,11,14 tetrynoic acid (ETYA) suppressed glucose-induced insulin secretion by 63-74% at a concentration (20 microM) which inhibited the synthesis of arachidonate lipoxygenase and cyclooxygenase products by 90%. Indomethacin (10 microM) completely prevented islet synthesis of cyclooxygenase products but did not influence glucose-induced insulin secretion. Although indomethacin did not inhibit the conversion of exogenous, 3H-labeled arachidonate to [3H]12-HETE, it did significantly inhibit (41-72%) the synthesis of 12-HETE from endogenous precursor. This is presumed to reflect indirect effects of indomethacin on hydrolysis of arachidonate from phospholipids, as recently reported in platelets. These studies constitute the first demonstration that glucose stimulates the synthesis of a lipoxygenase product (12-HETE) from endogenous arachidonate by isolated islets, and that suppression of 12-HETE synthesis with ETYA reduces glucose-induced insulin secretion from isolated islets.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗