SEARCH · Search PubMed

Results for “INOSITOL”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources

PubMed1986

Angiotensin-stimulated production of inositol trisphosphate isomers and rapid metabolism through inositol 4-monophosphate in adrenal glomerulosa cells.

The production and metabolism of inositol phosphates in rat adrenal glomerulosa cells prelabeled with [3H]inositol and stimulated with angiotensin II were analyzed by high-performance anion-exchange chromatography. Exposure to angiotensin II was accompanied by a rapid and substantial decrease in the phospholipid precursor, phosphatidylinositol (PtdIns) 4,5-bisphosphate with only a slight and transient increase in the level of the biologically active product, inositol 1,4,5-trisphosphate (Ins-1,4,5-P3), to a peak at about 5 sec. Inositol 1,3,4-trisphosphate (Ins-1,3,4-P3), the putative metabolite of Ins-1,4,5-P3, was also formed rapidly and maintained an elevated steady-state level during stimulation by angiotensin II. Inositol 1,4-bisphosphate (Ins-1,4-P2) exhibited a simultaneous and prominent increase that could not be accounted for solely by direct breakdown of PtdIns 4-phosphate, indicating that large amounts of Ins-1,4,5-P3 must also have been produced and metabolized. The rapid formation of a substantial amount of inositol 4-monophosphate (Ins-4-P), with no significant change in the level of inositol 1-monophosphate (Ins-1-P) during the first minute of stimulation, was a notable feature of the glomerulosa cell response to angiotensin II. These observations indicate that PtdIns-4,5-P2 catabolism in the angiotensin-stimulated glomerulosa cell initially proceeds via Ins-1,4,5-P3 through Ins-1,3,4-P3 and Ins-1,4-P2 to form Ins-4-P rather than Ins-1-P and that direct hydrolysis of PtdIns by phospholipase C does not occur during the initial phase of angiotensin action. In glomerulosa cells stimulated by angiotensin II in the presence of Li+, the progressive accumulation of both Ins-4-P, and after a short lag period, Ins-1-P indicated that dephosphorylation of both isomers was inhibited by Li+. The increase of Ins-P isomers in the presence of Li+ was associated with increased and progressive accumulation of Ins-1,4-P2 and Ins-1,3,4-P3 but not of Ins-1,4,5-P3. These data demonstrate that sustained and massive breakdown of PtdIns phosphates begins within seconds during cell activation by angiotensin II. The Ca2+-mobilizing metabolite, Ins-1,4,5-P3, is rapidly converted to Ins-1,3,4-P3 and degraded through Ins-1,4-P2 and Ins-4-P, in contrast to the previous view that conversion to Ins-1-P is the major route of PtdIns 4,5-bisphosphate metabolism.

Adrenal Glands↗

PubMed1995

Regulation of inositol transport in Saccharomyces cerevisiae involves inositol-induced changes in permease stability and endocytic degradation in the vacuole.

Uptake of inositol by Saccharomyces cerevisiae is mediated by a specific inositol permease encoded by the ITR1 gene. Removal of inositol from the growth medium results in an increase in ITR1 mRNA abundance. The increase in ITR1 mRNA is accompanied by an increase in de novo synthesis of the Itr1 permease leading to an increased capacity for uptake. When inositol is added to the growth medium inactivation of uptake activity occurs, and both transcription of ITR1 and uptake activity are repressed to a basal level of function. The transcriptional regulation of ITR1 depends on the INO2, INO4, and OPI1 genes. In addition, repression is also achieved by regulation of ITR1 expression at the post-translational level. In this study, we show that there is a change in the stability of the Itr1 permease after the addition of inositol to the growth medium. Immunoblot analysis using a monoclonal antibody against an epitope attached to the Itr1 permease showed that the addition of inositol causes a dramatic increase in the rate of degradation of the permease. After the repressed (basal) level is achieved, turnover continues to be rapid. The increased rate of degradation was also observed in strains with mutations that block conjugation to ubiquitin. Degradation was not observed in strains defective in the END3/END4 endocytic pathway or in the production of vacuolar proteases (PEP4). Thus, inactivation of the Itr1 permease is accompanied by endocytic internalization followed by degradation in the vacuole. Inactivation may be a separate process that precedes and signals endocytic degradation. Since the end3/end4 mutations did not affect uptake activity under derepressed conditions, endocytosis is not required for normal inositol uptake.

Base Sequence↗

PubMed1980

Myo-inositol content of common foods: development of a high-myo-inositol diet.

Since virtually no information is available concerning the myo-inositol content of dietary constituents, we have measured the amount of this material present in 487 foods by gas-liquid chromatography. We observed that the greatest amounts of myo-inositol were present in fruits, beans, grains, and nuts. Fresh vegetables and fruits were found to contain more myo-inositol than did frozen, canned, or salt-free products. The data provided in this report were used to develop diets that contained varying, but known amounts of myo-inositol. The myo-inositol intake that could be provided by such diets ranged from 225 to 1500 mg/day per 1800 kcal and within this range the agreement between the calculated and measured amounts of this material was excellent (r = 0.98). Since abnormalities in the metabolism of myo-inositol have been speculated to play a role in the pathogenesis of the polyneuropathies associated with diabetes mellitus and chronic renal failure, it is possible that the natural history of these neuropahties can be altered by modifying the amount of dietary myo-inositol that is ingested by patients with these diseases.

Bread↗

PubMed2003

Cancer inhibition by inositol hexaphosphate (IP6) and inositol: from laboratory to clinic.

Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that is present in substantial amounts in almost all plant and mammalian cells. It was recently recognized to possess multiple biological functions. A striking anticancer effect of IP6 was demonstrated in different experimental models. Inositol is also a natural constituent possessing moderate anticancer activity. The most consistent and best anticancer results were obtained from the combination of IP6 plus inositol. In addition to reducing cell proliferation, IP6 increases differentiation of malignant cells, often resulting in a reversion to normal phenotype. Exogenously administered IP6 is rapidly taken into the cells and dephosphorylated to lower-phosphate inositol phosphates, which further interfere with signal transduction pathways and cell cycle arrest. Enhanced immunity and antioxidant properties can also contribute to tumor cell destruction. However, the molecular mechanisms underlying this anticancer action are not fully understood. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP6 holds great promise in our strategies for the prevention and treatment of cancer. IP6 plus inositol enhances the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves the quality of life, as shown in a pilot clinical trial. The data strongly argue for the use of IP6 plus inositol in our strategies for cancer prevention and treatment. However, the effectiveness and safety of IP6 plus inositol at therapeutic doses needs to be determined in phase I and phase II clinical trials in humans.

1,2-Dimethylhydrazine↗

PubMed2006

Behavioural phenotyping of sodium-myo-inositol cotransporter heterozygous knockout mice with reduced brain inositol.

Inositol plays a key role in dopamine, serotonin, noradrenaline and acetylcholine neurotransmission, and inositol treatment is reported to have beneficial effects in depression and anxiety. Therefore, a reduction in brain intracellular inositol levels could be a cause of some psychiatric disorders, such as depression or anxiety. To determine the behavioural consequences of inositol depletion, we studied the behaviour of sodium-dependent myo-inositol cotransporter-1 heterozygous knockout mice. In heterozygous mice, free inositol levels were reduced by 15% in the frontal cortex and by 25% in the hippocampus, but they did not differ from their wild-type littermates in cholinergic-mediated lithium-pilocarpine seizures, in the apomorphine-induced stereotypic climbing model of dopaminergic system function, in the Porsolt forced-swimming test model of depression, in amphetamine-induced hyperactivity, or in the elevated plus-maze model of anxiety. Reduction of brain inositol by more than 25% may be required to elicit neurobehavioural effects.

Analysis of Variance↗

PubMed1972

Inositol phosphate phosphatases of microbiological origin: the inositol pentaphosphate products of Aspergillus ficuum phytases.

The fungus Aspergillus ficuum NRRL 3135 is known to produce an extracellular nonspecific orthophosphoric monoester phosphohydrolase (EC 3.1.3.2) with a pH optimum of 2.0, as well as an extracellular myo-inositol hexaphosphate phosphohydrolase (EC 3.1.3.8; phytase) with pH optima of 2.0 and 5.5. Both these enzymes are also known to hydrolyze myo-inositol hexaphosphate. The pentaphosphates liberated in the first step of this hydrolysis have been isolated and identified by ion-exchange chromatography and optical rotation. The nonspecific orthophosphoric monoester phosphohydrolase produces a single pentaphosphate, d-myo-inositol-1,2,4,5,6-pentaphosphate, whereas the phytase, at both pH 2.0 and 5.5, produces a mixture of two pentaphosphates. The major component of this mixture is d-myo-inositol-1,2,4,5,6-pentaphosphate and the other is d-myo-inositol-1,2,3,4,5-pentaphosphate. Thus the pathways of dephosphorylation of myo-inositol hexaphosphate by these two enzymes differ from that of wheat-bran phytase which forms l-myo-inositol-1,2,3,4,5-pentaphosphate.

6-Phytase↗

PubMed1991

Upregulation of inositol transport mediates inositol accumulation in hyperosmolar brain cells.

Attempts to understand brain volume regulation have been greatly hampered by the structural complexity of the mammalian central nervous system, indicating a need for the investigation of cultured brain cell lines whose behavior reflects that observed in situ. We demonstrate here that rat C6 glioma cells exhibit a pattern of hyperosmolar volume regulation qualitatively similar to that of the intact brain. Chronic (2-6 days) acclimation of C6 cells to high NaCl media (440 or 590 mosM) resulted in a 46-133 mM increase in cellular inositol, a known major brain osmolyte. C6 cells exposed acutely to 440 mosM medium shrank abruptly and then underwent a complete regulatory volume increase (RVI) within 4 h. Inositol levels began to increase after 10 h of hyperosmolar stress and reached maximal values by 24 h, suggesting that RVI is initially mediated by inorganic ion uptake. [3H]inositol uptake measurements revealed a sevenfold stimulation of phlorizin-inhibitable inositol transport in hyperosmotic cells. The enhancement of inositol transport paralleled the rise in cellular inositol content. Phlorizin reduced inositol accumulation in hyperosmolar cells by 44%. Our studies provide the first demonstration of RVI and organic osmolyte accumulation in a cultured brain cell line.

Animals↗

PubMed1988

Formation and metabolism of [3H]inositol phosphates in AR42J pancreatoma cells. Substance P-induced Ca2+ mobilization in the apparent absence of inositol 1,4,5-trisphosphate 3-kinase activity.

After 2 days of incubation of AR42J pancreatoma cells with 400 microM [3H]inositol, the specific radioactivity of [3H]phosphatidylinositol 4,5-bisphosphate and the specific radioactivity of [3H]inositol were similar, indicating that isotopic equilibrium had been achieved. The inositol 1,4,5-trisphosphate (1,4,5-IP3) level in cells was estimated to be approximately 2 microM and was increased by substance P receptor activation to about 25 microM. HPLC analysis of [3H]inositol phosphates indicated that only 1,4,5-IP3, inositol 1,4-bisphosphate, and inositol 4-monophosphate were increased upon receptor activation. There was no increase in inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4), or in any of its metabolites. Incubation of [3H]1,4,5-IP3 with a cell homogenate did not result in the formation of [3H]1,3,4,5-IP4. Therefore, it appears that 1,4,5-IP3 3-kinase is either not present or not functional under these assay conditions. Substance P increased cytosolic calcium levels in fura-2-loaded cells from about 600 nM to 2.5 microM. This increase in Ca2+ was partially attenuated in the absence of extracellular calcium, indicating that in AR42J cells, substance P stimulation appears to activate calcium signaling through both Ca2+ entry and intracellular Ca2+ release. These modes of Ca2+ mobilization occur without an increase in 1,3,4,5-IP4 or any of its metabolites.

Animals↗

PubMed1989

Structures and metabolism of inositol tetrakisphosphates and inositol pentakisphosphate in bovine adrenal glomerulosa cells.

In adrenal glomerulosa cells, angiotensin II stimulates rapid increases in inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) and inositol 1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4), followed by slower increases in two additional inositol tetrakisphosphate (InsP4) isomers. One of these InsP4 isomers was previously identified as Ins-1,3,4,6-P4 and shown to be a precursor of inositol pentakisphosphate (InsP5). Analysis of the third InsP4 isomer, purified from cultured bovine adrenal cells labeled with [3H]inositol and stimulated by angiotensin II, revealed that the polyol produced by periodate oxidation, borohydrate reduction, and dephosphorylation was [3H]iditol. This finding is consistent with precursor structures of either Ins-1,4,5,6-P4 or Ins-3,4,5,6-P4 (= L-Ins-1,4,5,6-P4) for the third InsP4 isomer. The [3H]iditol was readily converted to [3H]sorbose by the stereospecific enzyme, L-iditol dehydrogenase, indicating that it originated from Ins-3,4,5,6-P4. Chicken erythrocytes labeled with [3H]inositol also contained high levels of Ins-1,3,4,6-P4 and Ins-3,4,5,6-P4, as well as InsP5, but only small amounts of Ins-1,3,4,5-P4. Both [3H]Ins-1,3,4,6-P4 and [3H]Ins-3,4,5,6-P4, but not [3H]Ins-1,3,4,5-P4, were phosphorylated to form InsP5 in permeabilized bovine glomerulosa cells. In addition, InsP5 itself was slowly dephosphorylated to Ins-1,4,5,6-P4, indicating that its structure is Ins-1,3,4,5,6-P5. These results demonstrate that the higher inositol phosphates are metabolically interrelated and are linked to the receptor-regulated InsP3 response by the conversion of Ins-1,3,4-P3 through Ins-1,3,4,6-P4 to Ins-1,3,4,5,6-P5. The source of Ins-3,4,5,6-P4, the other precursor of InsP5, is not yet known but its elevation in angiotensin II-stimulated glomerulosa cells suggests that its formation is also influenced by agonist-regulated processes.

Animals↗

PubMed1996

Antagonistic effect of inositol pentakisphosphate on inositol triphosphate receptors.

We present evidence that inositol 1,3,4,5,6-pentakisphosphate acts as an antagonist of inositol triphosphate receptors in vitro by dampening the activity of Ca(2+)-mobilizing inositol phosphates. This antagonism bears physiological significance as cells maintain substantial quantities of this phosphoinositol in the cytosol, especially during cell differentiation or proliferation. Over a concentration range from 30 to 150 microM, this pentakisphosphate causes a two- to five-fold increase in the EC50 values of inositol 1,4,5-trisphosphate and other active phosphoinositols in effecting Ca2+ efflux from brain microsomes. This specific inhibition results from competitive receptor binding, and is not noted with inositol hexaphosphate or related metabolites at comparable concentrations. Thus, inositol 1,3,4,5,6-pentakisphosphate in concert with other allosteric modulators may constitute an integral component for the receptor regulation.

Animals↗

PubMed1992

Vanadate amplifies receptor-mediated accumulation of inositol trisphosphates and inhibits inositol tris- and tetrakis-phosphatase activities.

Lithium ion, which inhibits hydrolytic degradation of inositol monophosphates, is the most common therapeutic agent used in the control of bipolar disorder. There exists evidence that elevated elemental vanadium levels may play an etiological role in at least some forms of manic-depression. Here we demonstrate that vanadate treatment of intact cells from several different clonal lines synergistically induces substantial augmentation in neurotransmitter receptor-mediated or growth factor receptor-triggered inositol trisphosphate accumulation in situ. Furthermore, studies done using cellular extracts indicate that effects of vanadate treatment in situ may be due to its ability to inhibit hydrolysis of inositol 1,4,5-trisphosphate inositol 1,3,4-trisphosphate, and inositol 1,3,4,5-tetrakisphosphate in vitro. These results suggest that vanadate treatment may facilitate characterization of inositol phosphate metabolism and intracellular signaling.

Animals↗

PubMed1989

Inositol 1,2-cyclic 4,5-trisphosphate is an order of magnitude less potent than inositol 1,4,5-trisphosphate in mobilizing intracellular stores of calcium in mouse pancreatic acinar cells.

Semi-synthetic inositol 1,2-cyclic 4,5-trisphosphate is 1/16th as potent as inositol 1,4,5-trisphosphate in releasing Ca2+ from intracellular stores in permeabilized mouse pancreatic acinar cells. Competitive displacement studies in mouse pancreatic microsomes show that the affinity of inositol 1,2-cyclic 4,5-trisphosphate is 1/20th of that of inositol 1,4,5-trisphosphate at the latter's receptor, indicating that the lower potency of inositol 1,2-cyclic 4,5-trisphosphate in releasing Ca2+ can be accounted for by a weaker affinity at the receptor. These results suggest that inositol 1,2-cyclic 4,5-trisphosphate is unlikely to play any significant role in Ca2+ mobilization, at least in mouse pancreatic acinar cells.

Animals↗

PubMed1986

Effects of bombesin and insulin on inositol (1,4,5)trisphosphate and inositol (1,3,4)trisphosphate formation in Swiss 3T3 cells.

The effects of bombesin and insulin, separately and in combination, have been studied in Swiss mouse 3T3 cells. Bombesin caused a rapid transfer of 3H from the lipid inositol pool of prelabeled cells into inositol phosphates. Label in inositol tetrakisphosphate (InsP4) and in Ins1,4,5P3 and Ins1,3,4P3 rose within 10 sec of stimulation and that in Ins1,4P2, another InsP2 and InsP1, more slowly. Insulin, which had little effect on its own, increased the turnover of inositol lipids due to acute bombesin stimulation and also enhanced the DNA synthesis evoked by prolonged bombesin treatment. The results suggest that bombesin acting as a growth factor, uses inositol lipids as part of its transduction mechanism and that insulin acts synergistically to enhance both inositol phosphate formation and DNA synthesis.

Animals↗

PubMed1991

Accumulation of [3H]-inositol into inositol polyphosphates during development of Dictyostelium.

Inositol hexakisphosphate (InsP6) is present in large amounts during the development of Dictyostelium discoideum although its function is unknown. We have investigated the accumulation of [3H]-labelled inositol into both InsP6 and a more highly charged inositol species called InsPY during development of amoebae on filters. We report that the pattern of [3H]-labelled inositol incorporation into InsP6 and InsPY differs markedly from the pattern seen for inositol phospholipids and inositol(1,4,5)trisphosphate. Incorporation into PtdIns, PtdInsP, PtdInsP2 and Ins(1,4,5)P3 reached plateau values within 4 h. In contrast, incorporation into InsP6 continued in an approximately linear manner for the first eight hours of development. No incorporation into InsPY was seen during the first three hours of development at which time accumulation of [3H] continued linearly in a similar manner as for InsP6. Because the total cell concentration of InsP6 (measured by chemical assay) changes very little during development it seems probable that incorporation of label into InsPY after 3 h is due to a developmentally controlled metabolic switch rather than a requirement for a threshold level of its probable precursor, InsP6.

Animals↗

PubMed2000

Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain.

One of the mechanisms underlying lithium's efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI-cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myo-inositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myo-inositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myo-inositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI-cycle.

Animals↗

PubMed1994

Synthesis of 1L-chiro-inositol 2,3,5-trisphosphorothioate, the first partial agonist at the platelet myo-inositol 1,4,5-trisphosphate receptor.

The synthesis of L-chiro-inositol 2,3,5-trisphosphorothioate, a novel analogue of the second messenger D-myo-inositol 1,4,5-trisphosphate has been accomplished from the natural product L-quebrachitol. Phosphitylation of (-)-1L-1,4,6-tri-O-benzoyl-chiro-inositol obtained from L-quebrachitol followed by sulfoxidation of the products gave (-)-1L-1,4,6-tri-O-benzoyl-chiro-inositol 2,3,5-tris[di(2-cyanoethyl) phosphorothioate], which was deblocked using sodium in liquid ammonia to give 1L-(-)-chiro-inositol 2,3,5-trisphosphorothioate. 1L-chiro-Inositol 2,3,5-trisphosphorothioate is a partial agonist in the release of intracellular Ca2+ from saponin-permeabilised platelets and is both a key tool for pharmacological dissection of the polyphosphoinositide pathway of cellular signalling and a lead compound for the design of small molecule Ins(1,4,5)P3 receptor antagonists.

Animals↗

PubMed1990

Stepwise phosphorylation of myo-inositol leading to myo-inositol hexakisphosphate in Dictyostelium.

Although myo-inositol hexakisphosphate (InsP6; phytate) is the most abundant inositol phosphate in nature and probably has a wide variety of functions, neither the route of its synthesis from myo-inositol nor its metabolic relationships with other inositol-containing compounds (such as the second messenger inositol 1,4,5-trisphosphate, Ins(1,4,5)P3) are known. Here we report that the pathway by which InsP6 is synthesized in the cellular slime mould Dictyostelium, and in cell-free preparations derived from them, is catalysed by a series of soluble ATP-dependent kinases independently of the metabolism of both phosphatidylinositol and Ins(1,4,5)P3. The intermediates between myo-inositol and InsP6 are Ins3P, Ins(3,6)P2, Ins(3,4,6)P3, Ins(1,3,4,6)P4 and Ins(1,3,4,5,6)P5. The 3- and 5-phosphates of InsP6 take part in futile cycles in which Ins(1,2,4,5,6)P5 and Ins(1,2,3,4,6)P5 are rapidly formed by dephosphorylation of InsP6, only to be rephosphorylated to yield their precursor.

Dictyostelium↗

PubMed1979

Enzymes of myo-inositol and inositol lipid metabolism in rats with streptozotocin-induced diabetes.

Diabetes, with only mild ketosis, was induced in male rats by a single injection of streptozotocin. After 12 weeks the specific activities of enzymes concerned with the metabolism of inositol and of inositol lipids were measured in various tissues. Inositol 1-phosphate synthase (EC 5.5.1.4) was most active in testis and the activity was significantly less in diabetic rats than in controls on a similar diet. Inositol oxygenase (EC 1.13.99.1), which converts myo-inositol into glucuronic acid, was also less active in kidney from diabetic animals. CDP-diacylglycerol-inositol phosphatidyltransferase (EC 2.7.8.11) and phosphatidylinositol 4-phosphate kinase (EC 2.7.1.68) showed decreased specific activities in brain and sciatic nerve of diabetic rats. By contrast the diabetic state did not affect the specific activities of phosphatidylinositol kinase (EC 2.7.1.67) or phosphatidylinositol 4,5-bisphosphate phosphatase (EC 3.1.3.36) in these tissues. The results are discussed in relation to diabetic neuropathy.

Animals↗