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PubMed1986

Alpha-thrombin-induced inositol phosphate formation in G0-arrested and cycling hamster lung fibroblasts: evidence for a protein kinase C-mediated desensitization response.

In resting Chinese hamster fibroblasts (CCL39) alpha-thrombin rapidly induces the breakdown of phosphoinositides. Accumulation of inositol phosphates (IP), measured in the presence of Li+, is detectable within 5s (seconds) of thrombin stimulation. Formation of inositol tris- and bisphosphates slightly precedes that of inositol monophosphate, indicating that thrombin activates primarily the phospholipase C-mediated generation of inositol trisphosphate from phosphatidylinositol 4,5-bisphosphate. Initial rates of IP production increase with thrombin concentration, with no apparent saturability over the range 10(-4)-10 U/ml. Thrombin-induced phosphoinositide hydrolysis rapidly desensitizes (t1/2 less than 5 min), but a residual activity, corresponding to about 10% of the initial stimulation is sustained for at least 9 h, in contrast with the undetectable activity of G0-arrested cells. This apparent desensitization may be due to a feedback regulation by protein kinase C, since pretreatment with the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) markedly inhibits (by up to 70%) subsequent thrombin-induced inositol phosphate formation. Conversely, growth factor deprivation of CCL39 cells results in a progressive increase of thrombin-induced phosphoinositide hydrolysis, from the very low level of exponentially growing cells to the maximal level of G0-arrested cells. This "up regulation" was found maximal in A51, a very well growth-arrested CCL39 derivative, and reduced or virtually abolished in two tumoral and growth factor-relaxed derivatives of CCL39. Although preliminary, this observation suggests that a persistent activation of phosphatidyl inositol breakdown might operate in variants selected for autonomous growth.

Animals↗
PubMed2005

1H chemical shifts in NMR: Part 22-Prediction of the 1H chemical shifts of alcohols, diols and inositols in solution, a conformational and solvation investigation.

The (1)H NMR spectra of a number of alcohols, diols and inositols are reported and assigned in CDCl(3), D(2)O and DMSO-d(6) (henceforth DMSO) solutions. These data were used to investigate the effects of the OH group on the (1)H chemical shifts in these molecules and also the effect of changing the solvent. Inspection of the (1)H chemical shifts of those alcohols which were soluble in both CDCl(3) and D(2)O shows that there is no difference in the chemical shifts in the two solvents, provided that the molecules exist in the same conformation in the two solvents. In contrast, DMSO gives rise to significant and specific solvation shifts. The (1)H chemical shifts of these compounds in the three solvents were analysed using the CHARGE model. This model incorporates the electric field, magnetic anisotropy and steric effects of the functional group for long-range protons together with functions for the calculation of the two- and three-bond effects. The long-range effect of the OH group was quantitatively explained without the inclusion of either the C--O bond anisotropy or the C--OH electric field. Differential beta and gamma effects for the 1,2-diol group needed to be included to obtain accurate chemical shift predictions. For DMSO solution the differential solvent shifts were calculated in CHARGE on the basis of a similar model, incorporating two-bond, three-bond and long-range effects. The analyses of the (1)H spectra of the inositols and their derivatives in D(2)O and DMSO solution also gave the ring (1)H,(1)H coupling constants and for DMSO solution the CH--OH couplings and OH chemical shifts. The (1)H,(1)H coupling constants were calculated in the CHARGE program by an extension of the cos(2)phi equation to include the orientation effects of electronegative atoms and the CH--OH couplings by a simple cos(2)phi equation. Comparison of the observed and calculated couplings confirmed the proposed conformations of myo-inositol, chiro-inositol, quebrachitol and allo-inositol. The OH chemical shifts were also calculated in the CHARGE program. Comparison of the observed and calculated OH chemical shifts and CH.OH couplings suggested the existence of intramolecular hydrogen bonding in a myo-inositol derivative.

Alcohols↗
PubMed1998

Identification of a high concentration of scyllo-inositol in the brain of a healthy human subject using 1H- and 13C-NMR.

The peak at 3.35 ppm in the 1H-NMR spectrum characteristic for scyllo-inositol may be a marker for cerebral pathology, although it has a well-known constant concentration relative to myo-inositol. Such a peak was observed with an intensity at least 300% above normal in the brain of a healthy volunteer. The scyllo-inositol signal was assigned based on the detection of a corresponding peak at 74.5 ppm in the 13C-NMR spectrum and on the demonstration of singlet characteristics of the proton signal. The presence of substantial brain concentrations of scyllo-inositol suggests that scyllo-inositol metabolism may be regulated independently from myo-inositol and that such concentrations are compatible with normal health.

Adult↗
PubMedDate not supplied

Identification of Scyllo-inositol in proton NMR spectra of human brain in vivo.

Scyllo-inositol has been identified in proton NMR spectra of mammalian brain in vitro and in vivo. In contrast to myo-inositol this isomer comprises six equivalent CH protons that yield a singlet resonance at a chemical shift of 3.35 ppm. 1-D and 2-D J-resolved proton NMR studies (7.0 T) of perchloric acid extracts of brain tissues revealed different amounts of scyllo-inositol in man, sheep, cow and rat. Absolute quantification of localized short-echo time proton NMR spectra (2.0 T) of human brain in vivo resulted in scyllo-inositol concentrations of 0.35 +/- 0.06 mM for white matter (n = 25), 0.43 +/- 0.11 mM for grey matter (n = 23) and 0.57 +/- 0.14 mM for cerebellum (n = 10). Evidence for a tight metabolic link to myo-inositol was supported by a simultaneous variation of myo- and scyllo-inositol in patients with various brain diseases.

Animals↗
PubMed2003

Purification, characterization and functional cloning of inositol oxygenase from Cryptococcus.

The enzyme inositol oxygenase (myo-inositol : oxygen oxidoreductase; E.C. 1.13.99.1) is a monooxygenase that converts inositol into glucuronic acid in the presence of molecular oxygen. This enzyme is integrated into a pathway leading to either degradation and energy production or the biosynthesis of precursors for polysaccharides. The enzyme was purified from the yeast Cryptococcus lactativorus by a five-step chromatography procedure. The purified enzyme shows a molecular mass of 37 kDa on SDS-PAGE, similar to the estimation of the size of the native enzyme determined by size exclusion chromatography. Peptides of the inositol oxygenase protein derived from a tryptic digest were sequenced de novo by nanoelectrospray tandem mass spectrometry. Using degenerate oligonucleotides, the corresponding gene was cloned from first strand cDNA. The open reading frame encodes a 315 amino acid polypeptide with a predicted molecular mass of 36.9 kDa. Inositol oxygenase is a single copy gene in C. lactativorus. It has close homologues in other fungi such as Cryptococcus neoformans and Neurospora crassa. Biochemical characterization of the enzyme showed a pH optimum of 6-6.5 and a temperature optimum of 30 degrees C. Myo-inositol is the only accepted substrate with a Km of ca. 5 mM. The enzyme contains a Fe-centre but the enzyme activity is resistant to KCN.

Amino Acid Sequence↗
PubMed1997

Inositol phosphate metabolism during myocardial ischemia.

Inositol phosphate release in intact heart in response to norepinephrine involves primarily release of inositol(1,4)bisphosphate (Ins(1,4)P2) rather than inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) but Ins(1,4,5)P3 release predominates under conditions of post-ischemic reperfusion. In the current study, effects of myocardial ischemia on inositol phosphate responses were examined. Global myocardial ischemia in rat ventricle caused a reduction in the content of [3H]Ins(1,4)P3 (70-90%) and [3H]Ins(1,4,5)P3 (46%) and altered the pattern of norepinephrine stimulation such that increases in [3H]Ins(1,4,5)P3 were observed. Simulated ischemia in isolated right atria or isolated ventricular myocytes (P alpha 2 16-20 mmHg. pH 6.7. KCl 10 mM) produced similar changes. Reduction in O2 in the absence of other changes reduced the content of [3H]Ins (1,4)P2 (79%) in right atria whereas hypoxia and reduced pH were required to alter the [3H]Ins(1,4,5)P3 response. Progressive reduction in atrial ATP content using metabolic inhibitors caused a parallel decrease in [3H]Ins(1,4,5)P3 content (r = 0.96) without affecting [3H]Ins(1,4)P2 or the isomers of InsP1, showing that levels of Ins(1,4)P2 and Ins(1,4,5)P3 are regulated differently in the heart. These findings show that effects of ischemia on inositol phosphates in heart are complex and multifactorial, with Ins(1,4)P2 being affected under more moderately ischemic conditions than required for alterations in Ins(1,4,5)P3. These studies also demonstrate that ischemia produces similar effects on the release and metabolism of inositol phosphates in heart regardless of the ischemic model or the myocardial preparation used.

Adenosine Triphosphate↗
PubMed1987

Effect of the tachykinin antagonist, [D-Pro4, D-Trp7,9,10] substance P-(4-11), on tachykinin- and histamine-induced inositol phosphate generation in intestinal smooth muscle.

The effect of the tachykinin antagonist, [D-Pro4, D-Trp7,9,10] substance P-(4-11), on inositol phosphate accumulation produced by tachykinins and by histamine in strips of longitudinal muscle from the guinea-pig small intestine was investigated in the presence of 12 mM Li+. The two tachykinins substance P (SP) and kassinin (20 nM-20 microM) caused an accumulation of inositol phosphates in a concentration-dependent manner. This was seen with an agonist contact time of only 30 s. SP and kassinin were roughly equipotent in inducing inositol phosphate accumulation, which is consistent with their relative potencies in causing muscle contraction. The tachykinin antagonist (20 microM) produced a shift to the right of the dose-response curves for inositol phosphate accumulation caused by SP and kassinin. However, the effect of kassinin was inhibited much more than that of SP, which is consistent with a similar differential antagonism of the contractions induced by these agonists. The tachykinin antagonist also depressed histamine-induced accumulation of inositol phosphates whereas histamine-induced contractions had previously been found unaffected by the antagonist. These findings show that the tachykinin antagonist is not totally selective with regard to agonist-induced accumulation of inositol phosphates in intestinal smooth muscle. This may suggest that the antagonist not only acts on tachykinin receptors but also has another site of cellular action.

Animals↗
PubMed1983

Prevention of defects of axonal transport and nerve conduction velocity by oral administration of myo-inositol or an aldose reductase inhibitor in streptozotocin-diabetic rats.

The effects of orally-administered myo-inositol have been compared with those of an aldose reductase inhibitor on acute neurological defects in experimentally diabetic rats. Three groups of streptozotocin-treated diabetic rats (50 mg/kg, IP) together with three groups of age-matched controls (saline, IP) were compared. One pair of groups (control and diabetic) were untreated for 3 weeks, another pair of groups received daily oral myo-inositol (667 mg/kg) and the third pair received an aldose reductase inhibitor (ICI 105 552; 50 mg . kg-1, day-1, orally). The untreated diabetic group showed statistically significant deficits in accumulation, proximal to 24 h sciatic nerve constrictions, of choline acetyltransferase activity by comparison with untreated controls (2.8 +/- 0.4 versus 5.1 +/- 0.4 nmol acetylcholine . h-1 . nerve-1; p less than 0.001). The untreated diabetic rats also showed a fall in motor nerve conduction velocity of 6.2 +/- 0.7 m/s which was statistically significant (p less than 0.001). Treatment of the diabetic group with myo-inositol prevented the development of both defects of axonal transport and conduction velocity; both measurements were similar to those of the myo-inositol treated control rats. Likewise the diabetic rats which received aldose reductase inhibitor showed prevention of both defects. Nerves from untreated diabetic rats showed marked sorbitol accumulation and a statistically significant reduction in myo-inositol content by comparison with the untreated controls (sorbitol, 1.56 +/- 0.22 versus 0.8 +/- 0.01 and myo-inositol, 1.47 +/- 0.10 versus 2.3 +/- 0.10 nmol/mg; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗
PubMed1991

D-3-deoxy-3-substituted myo-inositol analogues as inhibitors of cell growth.

A number of unnatural D-3-deoxy-3-substituted myo-inositols were synthesized and their effects on the growth of wild-type NIH 3T3 cells and oncogene-transformed NIH 3T3 cells were studied. The compounds were found to exhibit a diversity of growth-inhibitory activities and showed selectivity in inhibiting the growth of some transformed cells as compared with wild-type cells. Remarkably, D-3-deoxy-3-azido-myo-inositol exhibited potent growth-inhibitory effects toward v-sis-transformed NIH 3T3 cells but had little effect on the growth of wild-type cells. The growth-inhibitory effects of the myo-inositol analogues were antagonized by myo-inositol. Since [3H]-3-deoxy-3-fluoro-myo-inositol was shown to be taken up by cells and incorporated into cellular phospholipids, we suggest that these unnatural myo-inositol analogues may act as antimetabolites in the phosphatidylinositol intracellular signalling pathways. Because cells transformed by oncogenes often exhibit elevated phosphatidylinositol turnover, the inhibition of signalling pathways that mediate oncogene action could offer new opportunities for controlling the growth of cancer cells.

3T3 Cells↗
PubMed1994

Osmotic regulation of myo-inositol uptake in primary astrocyte cultures.

Uptake of myo-inositol by astrocytes in hypertonic medium (440 mosm/kg H2O) was increased near 3-fold after incubation for 24 hours, which continued for 72 hours, as compared with the uptake by cells cultured in isotonic medium (38 nmoles/mg protein). myo-Inositol uptake by astrocytes cultured in hypotonic medium (180 mosm/kg H2O) for periods up to 72 hours was reduced by 74% to 8 to 10 nmoles/mg protein. Astrocytes incubated in either hypotonic or hypertonic medium for 24 hours and then placed in isotonic medium reversed the initial down- or up-regulation of uptake. Activation of chronic RVD and RVI correlates with regulation of myo-inositol uptake. A 30 to 40 mosm/kg H2O deviation from physiological osmolality can influence myo-inositol homeostasis. The intracellular content of myo-inositol in astrocytes in isotonic medium was 25.6 +/- 1.3 micrograms/mg protein (28 mM). This level of myo-inositol is sufficient for this compound to function as an osmoregulator in primary astrocytes and it is likely to contribute to the maintenance of brain volume.

Animals↗
PubMed1995

Inhibition by veratridine of carbachol-stimulated inositol tetrakisphosphate accumulation in rat brain cortical slices.

The present studies examined the inhibitory effect of veratridine (a Na+ channel activator) on carbachol (a cholinergic agonist) stimulated inositol 1,3,4,5-tetrakisphosphate accumulation in rat brain cortical slices. Veratridine inhibited carbachol stimulation of inositol 1,3,4,5-tetrakisphosphate formation (after a delay of about 30 seconds) at 60 or 120 seconds when there was little inhibition of inositol 1,4,5 trisphosphate accumulation. The inhibitory effect of veratridine on carbachol stimulated inositol 1,3,4,5-tetrakisphosphate accumulation was abolished in the presence of ouabain or tetrodotoxin but was unaffected in low calcium conditions. Veratridine reduced the total ATP content and this effect was abolished by tetrodotoxin. The inhibitory effect of 10 but not 30 microM veratridine on inositol 1,3,4,5-tetrakisphosphate accumulation in the presence of carbachol was reversed by the presence of exogenous 8-bromo cyclic AMP or forskolin which activates adenylyl cyclase. However, the decrease in brain slice ATP seen in the presence of veratridine was unaffected by forskolin. Our results are compatible with the hypothesis that veratridine inhibition of carbachol-stimulated inositol 1,3,4,5-tetrakisphosphate formation is due to depletion of ATP at the site of Ins 1,3,4,5-P4 formation from Ins 1,4,5-P3.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

A correlation of the outcome of clinical in vitro fertilization with the inositol content and embryotrophic properties of human serum.

PURPOSE: This study was designed to investigate whether the level of myo-inositol (MI) in human serum is critical for embryotrophic activity. METHODS: The embryotrophic properties of human serum were evaluated by the development of postimplantation mouse embryos [in vitro assay of Tam et al. (Fertil Steril 48:834-839, 1987)]. An enzymatic spectrophotometric method using myo-inositol dehydrogenase was used for determination of serum MI. The level of MI detected in serum was compared with the embryotrophic properties and the pregnancy outcome. The effect of MI on the embryotrophic activity of human serum was studied by supplementing the suboptimal serum samples that were unsupportive of embryo growth with extra MI. RESULTS: Serum obtained from patients having successful IVF pregnancies generally supported better development of postimplantation mouse embryos and contained higher levels of inositol, particularly if the serum sample was collected during the IVF treatment cycle. Serum samples obtained from patients with aborted pregnancies, though supporting mouse embryo development, contained significantly lower concentrations of inositol. An improvement of the embryotrophic properties with exogenous inositol supplement was achieved in some but not all of the suboptimal serum samples studied. CONCLUSIONS: It is possible that other factors in addition to inositol are crucial in promoting better embryonic development.

Abortion, Spontaneous↗
PubMed2006

Inositol pyrophosphates: metabolism and signaling.

Inositol pyrophosphates belong to the diverse family of inositol polyphosphate species that have a range of signaling functions. Since the discovery of inositol pyrophosphates in the early 1990s, enormous progress has been achieved in characterising this class of molecules, linking their biological presence to a wide range of cellular functions, including vesicular trafficking, apoptosis, telomere maintenance and protein phosphorylation. The activity of inositol pyrophosphates appears to be related to their rapid turnover in cells and also to their pyrophosphate groups, which are considered to contain high-energy bonds. Together, these observations suggest that inositol pyrophosphates may represent a class of cellular messengers with basic and not yet fully characterised functions. This review aims at summarising the recent progress of our knowledge of this exciting class of molecules, from inositol pyrophosphate discovery to the description of their physiological functions.

Animals↗
PubMed2003

Immobilization of Candida krusei cells producing phytase in alginate gel beads: an application of the preparation of myo-inositol phosphates.

Cells of Candida krusei capable of producing phytase were immobilized in Ca-alginate gel beads and used for the preparation of myo-inositol phosphates. The immobilization yield was increased about 5-fold after the beads were treated for 96 h at pH 4.0, 4 degrees C. The increased yield was retained, even after 1 month, when the cells were kept at this temperature and pH. No shift in the pH optima of phytase of the immobilized cells was observed, compared with that of free cells. However, the optimum temperature for the enzyme of the immobilized cells was 55 degrees C, which was 15 degrees C higher than that of free cells. The degradation characteristics of the phytate in immobilized cells packed in a glass column (i.d. 1.2 cm, length 20 cm) were investigated. The variation in the composition of the products results from a change in the flow rate of phytate solution (5 mM). At a flow rate of 1.30 ml/min, a mixture of myo-inositol-2-monophosphate, myo-inositol-1,2,5-triphosphate and myo-inositol-1,2,5,6-tetrakisphosphate was produced, in which the latter two were physiologically active. Also, it was found by NMR analysis that the enzyme of this strain produced only one isomer of each of the inositol phosphates, with the exception of myo-inositol pentakisphosphate. Therefore, the pure isomers were easily isolated using ion-exchange chromatography.

6-Phytase↗
PubMed2006

RNAi-mediated silencing of the myo-inositol-1-phosphate synthase gene (GmMIPS1) in transgenic soybean inhibited seed development and reduced phytate content.

Inositol plays a role in membrane trafficking and signaling in addition to regulating cellular metabolism and controlling growth. In plants, the myo-inositol-1-phosphate is synthesized from glucose 6-phosphate in a reaction catalyzed by the enzyme myo-inositol-1-phosphate synthase (EC 5.5.1.4). Inositol can be converted into phytic acid (phytate), the most abundant form of phosphate in seeds. The path to phytate has been suggested to proceed via the sequential phosphorylation of inositol phosphates, and/or in part via phosphatidylinositol phosphate. Soybean [Glycine max (L.) Merrill] lines were produced using interfering RNA (RNAi) construct in order to silence the myo-inositol-1-phosphate (GmMIPS1) gene. We have observed an absence of seed development in lines in which the presence of GmMIPS1 transcripts was not detected. In addition, a drastic reduction of phytate (InsP6) content was achieved in transgenic lines (up to 94.5%). Our results demonstrated an important correlation between GmMIPS1 gene expression and seed development.

Cotyledon↗
PubMed2004

High cerebral scyllo-inositol: a new marker of brain metabolism disturbances induced by chronic alcoholism.

Cerebral metabolic changes that concur to motor and/or cognitive disorders in actively drinking alcoholics are not well established. We tested the hypothesis that chronic alcoholics exhibit profound alterations in the cerebral metabolism of scyllo-inositol. Brain metabolism was explored in nine actively drinking and 11 recently detoxified chronic alcoholics by in vivo brain (1)H-MRS and in vitro(1)H-MRS of blood serum and cerebrospinal fluid. The cohort was composed of individuals with acute, subacute or chronic encephalopathy or without any clinical encephalopathy. Chronic alcoholism is associated with a hitherto unrecognized accumulation of brain scyllo-inositol. Our results suggest that scyllo-inositol is produced within the central nervous system and shows a diffuse but heterogenous distribution in brain where it can persist several weeks after detoxification. Its highest levels were observed in subjects with a clinically symptomatic alcohol-related encephalopathy. When detected, brain scyllo-inositol takes part in a metabolic encephalopathy since it is associated with reduced N-acetylaspartate and increased creatine. High levels of cerebral scyllo-inositol are correlated with altered glial and neuronal metabolism. Our findings suggest that the accumulation of scyllo-inositol may precede and take part in the development of symptomatic alcoholic metabolic encephalopathy.

Adult↗
PubMed1988

Anion-exchange high-performance liquid chromatographic analysis of inositol phosphates.

The analysis of inositol phosphates by anion-exchange HPLC is described. The method employs a citrate buffer gradient to resolve several inositol phosphates including inositol 1-phosphate, inositol 1,4-bisphosphate (IP2), and inositol 1,4,5-trisphosphate (IP3), as well as some of the isomers of these compounds. Since the buffer system does not contain any phosphate, we can use a phosphate assay to examine the chromatographic behavior of phosphate-containing compounds. The method shows good resolution and recovery (greater than 95% for IP2 and IP3). Total analysis time, including reequilibration, is about 90 min. In addition, an isocratic system that can rapidly (less than 10 min) measure IP3 is described. The HPLC system was used to characterize inositol phosphate turnover in thrombin-stimulated platelets and formylmethionyl-leucyl-phenylalanine-stimulated HL-60 cells.

Animals↗
PubMed1990

Analysis of inositol by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method has been developed for identification and quantification of inositol isomers and monosaccharides in inositol-containing glycans. The method, which can determine 10 pmol of inositol, utilizes an Aminex HPX-87C column packed with an 8% crosslinked cation-exchange resin in the calcium form eluted with deionized water at 50 degrees C. NaOH solution is added to the column effluent through a postcolumn tee to increase the pH (pH greater than 11.6) before entering a pulsed amperometric detector which is highly sensitive for polyhydroxylated compounds. Samples in which inositol is linked to sugar through a glycosidic bond are hydrolyzed with 5.5 N trifluoroacetic acid, 100 degrees C, 4 h, and then reduced with NaBH4. Samples in which inositol is linked via a phosphate ester are hydrolyzed with 6 N HCl, 110 degrees C, 24 h. This method has been applied to the analysis of inositol in the hamster prion proteins (PrP) PrP27-30, and PrPSc.

Animals↗