Use Of Inositol Research Articles

7941 Comparison of Metformin with Inositol versus Metformin Alone in Women with Polycystic Ovarian Syndrome (PCOS): A Systematic Review and Meta Analysis of Randomized Controlled Trials

Abstract Disclosure: F.A. Kelly: None. A.D. Lôbo: None. I.B. Andrade: None. P.G. Lima: None. I.P. da Silva: None. M.C. Souza: None. V. Morbach: None. M.S. Barros: None. F.A. Moraes: None. M.B. Jardine: None. L.M. Lopes: None. M.P. Lima: None. M.G. Leite: None. R.Y. Ura Sudo: None. J.C. Cardoso: None. A.M. De Almeida: None. F.D. Pessôa: None. Metformin was the first medication targeting insulin resistance in PCOS, and it has been extensively studied as a metabolic treatment option. It addresses the chronic inflammatory state of PCOS and improves ovulation, metabolic parameters, and fertility.In recent years, inositols, specifically myo-inositol, and D-chiro-inositol, have emerged as potential treatment options for PCOS. These compounds act as a messenger for hormones, including insulin and follicle-stimulating hormones. Inositols effectively address insulin resistance and modulate the insulin signaling pathways.Although inositols have recently been included in the recommendations of the European Journal of Endocrinology's 2023 International evidence-based guideline for improvement in metabolic measures and considered with benefits in ovulation, hirsutism, and weight in patients with PCOS, the confidence in the available evidence supporting their use is considered to be limited. We aimed to perform a meta-analysis to understand the role of inositol, on glycemic control, LH/FSH ratio, hirsutism, HOMA-IR, and body mass index (BMI) in individuals with polycystic ovary syndrome (PCOS).PubMed, Embase, and Cochrane databases were systematically searched for RCTs comparing the use of metformin alone versus metformin and inositol in patients with polycystic ovary syndrome. Statistical analysis was performed in R software 4.3.1. A random-effects model was used to calculate the risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). A p-value of < 0.05 was considered statistically significant. Heterogeneity was examined with the Cochran Q test, prediction interval, and I² statistics. A total of 4 RCTs and 277 patients were included, of whom 138 were randomized to metformin alone and 139 to metformin plus myo-inositol. Compared with metformin alone, Myo-inositol plus Metformin significantly reduced hirsutism (MD -0.97; 95% CI -1.53; -0.40; p=0.0008) and LH/FSH ratio (MD -0.15; 95% CI -0.26, -0.03; p=0.02). There was no significant difference between groups for BMI (MD: 0.97; 95% CI -0.37, 2.32; p=0.16) and HOMA-IR (MD -0.17; 95% CI -0.35, 0.01; p=0.07).In this meta-analysis of RCTs of patients with polycystic ovary syndrome, inositol was associated with a reduction in hirsutism and LH/FSH ratio, compared with metformin monotherapy. Further studies are needed to clarify whether there are benefits for the use of inositol in PCOS treatment. Presentation: 6/3/2024

Comparison of metformin with inositol versus metformin alone in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.

Metformin was the first medication targeting insulin resistance in PCOS, and it has been extensively studied as a metabolic treatment option. In recent years, inositols have emerged as potential treatment options for PCOS, but confidence in the available evidence supporting their use is limited. We comprehensively searched PubMed, Embase, and Cochrane databases for RCTs comparing the use of combined metformin and inositol versus metformin alone in women with PCOS. A random-effects model was used to calculate the risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). A p-value of <0.05 was deemed as statistically significant. Six RCTs and 388 patients were included in the analysis, with follow-up ranging from 3 to 6 months. Combination therapy was significantly associated with improved menstrual cycle regularity (RR 1.56; 95% CI 1.01 to 2.41; p = 0.04), and lower values of modified Ferriman-Gallwey score (MD -0.97; 95% CI -1.53 to -0.40; p < 0.01) and LH/FSH ratios (MD -0.13; 95% CI -0.24 to -0.03; p = 0.01). Differences in acne (p = 0.58), body mass index (p = 0.13), fasting blood glucose (p = 0.07) and HOMA-IR (p = 0.25) were not statistically significant. In this meta-analysis of RCTs, combination therapy was associated with cycle regularization and reduction in hirsutism and LH/FSH ratio compared to metformin monotherapy. Further studies are needed to clarify the true benefits of the use of inositol in PCOS treatment.

Polycystic ovary syndrome: new and promising treatment methods

Polycystic Ovary Syndrome (PCOS) - is a polygenic endocrine disorder caused by genetic, hormonal, and epigenetic factors. The importance of addressing PCOS lies in its prevalence, affecting approximately 10 to 13% of women, as well as the associated health conditions that can have a negative impact on women's lives, including infertility, dermatological manifestations of hyperandrogenism (such as hirsutism and acne), cardiovascular pathologies, metabolic disorders, and psychoemotional disorders. Currently, many theories of the development of this disease have been proposed, and as a consequence of methods of influencing and treating it. According to the clinical recommendations of the Ministry of Health of the Russian Federation, modifying the patient's lifestyle forms the basis of comprehensive therapy. We have analyzed about 60 articles on various dietary approaches to the treatment of PCOS, sourced from PubMed, Nature Reviews, Oxford Academic, Clinical Nutrition, EJOG, ScienceDirect, and MDPI. The Mediterranean diet, the DASH diet, the ketogenic diet and the low-carb diet have proven themselves the best. Also, it's necessary to add vitamin D, E, folic acid, calcium, various pro- and prebiotics to a woman's diet. Currently, the use of inositol and GPP-1 is becoming a promising method of PCOS therapy. According to the results of the analysis, a positive effect of diet therapy on the anthropometric and biochemical parameters was noted. Based on the analysis, a positive effect of diet therapy on anthropometric and biochemical parameters has been observed. It is crucial to consider the individual characteristics of each patient and not rely solely on drug therapy when approaching the treatment of PCOS.

Inositols and female reproduction disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)-Women's Endocrinology.

To provide the latest scientific knowledge on the efficacy of inositols for improving reproductive disorders in women with and without polycystic ovary syndrome (PCOS) and to reach a consensus on their potential use through a Delphi-like process. A panel of 17 endocrinologists and 1 gynecologist discussed 4 key domains: menses irregularity and anovulation, fertility, pregnancy outcomes, and neonatal outcomes. A total of eight consensus statements were drafted. Myo-inositol (Myo) supplementation can be used to improve menses irregularities and anovulation in PCOS. Myo supplementation can be used in subfertile women with or without PCOS to reduce the dose of r-FSH for ovarian stimulation during IVF, but it should not be used to increase the clinical pregnancy rate or live birth rate. Myo supplementation can be used in the primary prevention of gestational diabetes mellitus (GDM), but should not be used to improve pregnancy outcomes in women with GDM. Myo can be preconceptionally added to folic acid in women with a previous neural tube defects (NTD)-complicated pregnancy to reduce the risk of NTDs in newborns. Myo can be used during pregnancy to reduce the risk of macrosomia and neonatal hypoglycemia in mothers at risk of GDM. This consensus statement provides recommendations aimed at guiding healthcare practitioners in the use of inositols for the treatment or prevention of female reproductive disorders. More evidence-based data are needed to definitively establish the usefulness of Myo, the appropriate dosage, and to support the use of D-chiro-inositol (DCI) or a definitive Myo/DCI ratio.

Inositol for Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis to Inform the 2023 Update of the International Evidence-based PCOS Guidelines.

Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Inositol may have insulin sensitizing effects; however, its efficacy in the management of PCOS remains indeterminate. To inform the 2023 international evidence-based guidelines in PCOS, this systematic review and meta-analysis evaluated the efficacy of inositol, alone or in combination with other therapies, in the management of PCOS. Medline, PsycInfo, EMBASE, All EBM, and CINAHL from inception until August 2022. Thirty trials (n = 2230; 1093 intervention, 1137 control), with 19 pooled in meta-analyses were included. Data were extracted for hormonal, metabolic, lipids, psychological, anthropometric, reproductive outcomes, and adverse effects by 1 reviewer, independently verified by a second. Thirteen comparisons were assessed, with 3 in meta-analyses. Evidence suggests benefits for myo-inositol or D-chiro-inositol (DCI) for some metabolic measures and potential benefits from DCI for ovulation, but inositol may have no effect on other outcomes. Metformin may improve waist-hip ratio and hirsutism compared to inositol, but there is likely no difference for reproductive outcomes, and the evidence is very uncertain for body mass indexI. Myo-inositol likely causes fewer gastrointestinal adverse events compared with metformin; however, these are typically mild and self-limited. The evidence supporting the use of inositol in the management of PCOS is limited and inconclusive. Clinicians and their patients should consider the uncertainty of the evidence together with individual values and preferences when engaging in shared decision-making regarding the use of inositol for PCOS.

D-Chiro-Inositol and Myo-Inositol Induce WAT/BAT Trans-Differentiation in Two Different Human Adipocyte Models (SGBS and LiSa-2).

White adipose tissue/brown adipose tissue trans-differentiation is one of the main study targets for therapies against obesity and metabolic diseases. In recent years, numerous molecules able to induce such trans-differentiation have been identified; however, their effect in obesity therapies has not been as expected. In the present study, we investigated whether myo-inositol and its stereoisomer D-chiro-inositol could be involved in the browning of white adipose tissue. Our preliminary results clearly indicate that both, at 60 μM concentration, induce the upregulation of uncoupling protein 1 mRNA expression, the main brown adipose tissue marker, and increase mitochondrial copy number as well as oxygen consumption ratio. These changes demonstrate an activation of cell metabolism. Therefore, our results show that human differentiated adipocytes (SGBS and LiSa-2), assume the features typical of brown adipose tissue after both treatments. Furthermore, in the cell lines examined, we proved that D-chiro-inositol and myo-Inositol induce an increase in the expression of estrogen receptor mRNAs, suggesting a possible modulation by these isomers. We also found an increase in the mRNA of peroxisome proliferator-activated receptor gamma, a very important target in lipid metabolism and metabolic diseases. Our results open new opportunities for the use of inositols in therapeutic strategies to counteract obesity and its metabolic complications.

Neurobiology and Applications of Inositol in Psychiatry: A Narrative Review

Inositol is a natural sugar-like compound, commonly present in many plants and foods. It is involved in several biochemical pathways, most of them controlling vital cellular mechanisms, such as cell development, signaling and nuclear processes, metabolic and endocrine modulation, cell growth, signal transduction, etc. In this narrative review, we focused on the role of inositol in human brain physiology and pathology, with the aim of providing an update on both potential applications and current limits in its use in psychiatric disorders. Overall, imaging and biomolecular studies have shown the role of inositol levels in the pathogenesis of mood disorders. However, when administered as monotherapy or in addition to conventional drugs, inositol did not seem to influence clinical outcomes in both mood and psychotic disorders. Conversely, more encouraging results have emerged for the treatment of panic disorders. We concluded that, despite its multifaceted neurobiological activities and some positive findings, to date, data on the efficacy of inositol in the treatment of psychiatric disorders are still controversial, partly due to the heterogeneity of supporting studies. Therefore, systematic use of inositol in routine clinical practice cannot be recommended yet, although further basic and translational research should be encouraged.

Inositol supplementation - known and possible applications

Introduction: Myo-inositol (MYO) and D-chiro-inositol are chemical compounds known to exert an impact on multiple signaling pathways of a human body. Due to its effects on insulin metabolism and ovaries’ hormone activity their use in polycystic ovary syndrome (PCOS) therapies has been highly recommended in the recent literature. In this article we aim to review the known and possible applications of inositol and its derivatives for treatment of various gynecological and endocrine disorders and to indicate possible directions of further investigations. Methods and materials: This article is based on the literature found in PubMed Database from the period of 2016-2022 with use of keywords such as “inositol”; “myoinositol”; “d-chiro-inositol”; “PCOS”; “insulin”. Results: The applications of myoinositol in the treatment of polycystic ovary syndrome (PCOS) are very well known in recent publications. It is reported that MYO supplementation improves the quality of oocytes, regulates the menstrual cycle and ovulation rates. Prevention of gestational diabetes (GDM) amongst the patients with risk factors is likely another use of inositols. Inositol takes part in phospholipase C pathway, thus its depletion may be the cause for hypothyroidism. Inositol inhibits the expression of aromatase, the enzyme which is responsible for the growth of endometrial tissue - it may constitute a targeting point in the treatment of endometriosis. So far, no adverse effects of inositol isomers have been reported. Conclusion: The use of inositol, its isomers and derivatives represents an interesting direction in the development of the treatment of many conditions associated with endocrine disorders. There is a need for further investigations and studies on larger groups of patients to exploit its potential.

P–686 &amp;lt;span&amp;gt;safety &amp;amp; efficacy of the combination therapy of inositols, antioxidants and vitamins in polycystic ovarian syndrome (PCOS): A multicentric, retrospective observational study (Trazer study)&amp;lt;/span&amp;gt;

Abstract Study question Does combinations therapy of insulin sensitizing agents, antioxidants and vitamins are safe and efficacious in PCOS patients. Summary answer Combination therapy of inositols, antioxidants and vitamins is safe and effective non-hormonal treatment option to manage PCOS. What is known already Monotherapy of insulin sensitising agents, antioxidants and vitamins is beneficial in the treatment of PCOS. Nutritional supplement containing inositols, N-acetylcysteine (NAC), lycopene, chromium picolinate, vitamin D3, biotin and folic acid treatment resulted in a significant improvement in menstrual cyclicity, acne and hirsutism. But there is no evidence pertaining to the hormonal parameters and ovarian morphology. Therefore, the present investigation was planned to evaluate the effects of combination therapy of inositols, antioxidants and vitamins on sign and symptoms, metabolic and hormonal parameters in women with PCOS. Study design, size, duration Multicentric, retrospective, observational cohort study was planned for the first time at thirty-six fertility clinics in different states of India from April 2019 to November 2020. Both lean and obese patients (16–39 years; n = 180) with confirmed diagnosis of PCOS as per the Rotterdam/ESHRE criteria were included in study. Participants/materials, setting, methods Patients were received a combination therapy of insulin sensitizers, antioxidants and vitamins in a marketed formulation (Trazer F ForteTM) twice daily as a tablet for 3 months and thereafter ovulation induction was done using letrozole (2.5–5 mg). Primary outcomes were improvements in signs of PCOS (menstrual cyclicity or ovulation restoration, acne and hirsutism), body weight, body mass index, waist circumference, ovarian cysts, pregnancy rate and hormonal balance. Secondary outcome was the evaluation of side effects. Main results and the role of chance Combination therapy of Trazer F ForteTM containing insulin sensitising agents (inositols, NAC and chromium), antioxidants (NAC and lycopene), and vitamins (vitamin D, biotin and folic acid) showed significant improvement in menstrual cyclicity by 54.3% and 88.2% in obese PCOS cases, and 48.7% and 79.5% in lean PCOS cases after 3- and 6-month of intervention respectively. Significant improvement was observed in acne, hirsutism and ovarian cysts post-intervention in both obese and lean PCOS women. After successful completion of the treatment, significant corrections were observed in metabolic (fasting glucose, fasting insulin and HOMA-IR) and hormonal profile (free testosterone, LH:FSH ratio, AMH and progesterone) in obese as well as lean PCOS cases. The clinical pregnancy rate was 16.2% and 34.1% in obese women, and 9.9% and 22.1% in lean cases after 3- and 6-month of intervention respectively. Limitations, reasons for caution Prevalent of PCOS is different in different population in India with diverse ethnic background. Hence, community-based intervention studies on larger population are needed to assess the efficacy and safety of such combinations amongst different age groups of women with PCOS. Wider implications of the findings: Since, PCOS is a multifactorial disorder, combined use of inositols, antioxidants and vitamins can be used as a promising and clinically relevant non-hormonal treatment option for the management of PCOS. Trial registration number NA

Використання інозитолу в комплексному лікуванні пацієнток з синдромом полікістозних яєчників

Стаття присвячена сучасному методу лікування синдрому полікістозних яєчників (СПКЯ) з використанням інозитолу. Показано, що застосування інозитолу при СПКЯ нормалізує не тільки метаболічні й гормональні показники, а й сприяє відновленню менструальної функції, покращенню роботи яєчників, функції гіпоталамо-гіпофізарної системи та досягненню вагітності

D-Chiro-Inositol Improves Sperm Mitochondrial Membrane Potential: In Vitro Evidence.

The use of inositols in endocrinological clinical practice is increasingly widespread. Most of the existing evidence concerns myoinositol (MYO), the most abundant form in nature, especially in women with polycystic ovarian syndrome. We have previously shown that MYO increases sperm motility in patients with asthenozoospermia by the increase of sperm mitochondrial membrane potential (MMP), a biofunctional sperm parameter closely associated to sperm motility. The aim of this study was to evaluate the effects of D-chiro-inositol (DCI), another biologically active isoform of inositols, on sperm MMP, as data on this matter has never been released so far. To accomplish this, semen samples from 15 patients with asthenozoospermia and 15 healthy normozoospermic men were incubated with increasing concentrations of DCI (0, 75, and 750 µg/mL) or phosphate buffer saline for 30 min. Incubation with DCI significantly improved sperm MMP at lower concentrations, and with shorter incubation length than those used in our similar MYO studies. In conclusion, these findings indicate that DCI positively impacts on sperm mitochondrial function in vitro. Studies aimed at assessing the role of DCI in the treatment of asthenozoospermia in-vivo are warranted.

Inositols' Importance in the Improvement of the Endocrine-Metabolic Profile in PCOS.

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility and metabolic problems among women of reproductive age. The mechanism of PCOS is associated with concurrent alterations at the hormonal level. The diagnosis assumes the occurrence of three interrelated symptoms of varying severity, namely ovulation disorders, androgen excess, or polycystic ovarian morphology (PCOM), which all require a proper therapeutic approach. The main symptom seems to be an increased androgen concentration, which in turn may contribute to different metabolic disorders. A number of papers have demonstrated the significant role of inositol therapy in PCOS. However, there is a lack of detailed discussion about the importance of myo-inositol (MI) and d-chiro-inositol (DCI) in reference to particular symptoms. Thus, the aim of this review is to present the effectiveness of MI and DCI treatment for PCOS symptoms. Moreover, the review is focused on analyzing the use of inositols, taking into account their physiological properties, together with the mechanism of individual PCOS symptom formation.

Inositols in Midlife.

This review describes the mechanistic, animal, and clinical data related to the use of inositols in midlife. It covers studies related to the mechanism of action of myo-inositol and D-chiro-inositol and randomized controlled trials conducted in postmenopausal women with metabolic syndrome and supports these data with the results of in vitro and animal studies on inositol in nephropathy and other related conditions. Recent advances related to biochemistry, pharmaceutical science, and genetics are discussed. It concludes that inositols have a potential role to play in maintaining metabolic health in postmenopausal women.

Improvement in quality of oocytes in polycystic ovarian syndrome in programs of in vitro fertilization

Inositol therapy is aimed at improving the quality of oocytes during preconception care in patients with polycystic ovarian syndrome (PCOS), a cause of infertility and reproductive dysfunction. The objectives of this observational comparative multicentre study were to evaluate the effectiveness of inositol in improving the quality of oocytes/embryos and IVF cycle outcome. Group 1 patients (N = 133) received inositol 1000 mg (Inofert or Nutrilinea) + folic acid 0.1 mg. Group 2 consisted of patients with preserved ovarian reserve without PCOS (N = 137), not administered inositol prior to pregnancy. Effectiveness criteria were numbers of mature oocytes and good quality embryos, pregnancy rates per ET, ‘take home baby’ index and miscarriage rates. Pregnancy rates per ET (87.0% vs. 87.4%), ‘take home baby’ index (79.6% vs. 89.4%) and miscarriage rates (14.3% vs. 10.6%) were comparable. Use of inositol in patients with PCOS during preconception care is an effective method allowing improvement of oocytes quality and positively affecting IVF cycle prognosis. High pregnancy rates per ET and ‘take home baby’ index after treatment are justifying inositol usage in patients with PCOS and infertility.

The influence of D-chiro-inositol and D-myo-inositol in pregnant women with glucose intolerance.

The aim of the present study was to demonstrate that the use of inositol and folic acid from the first trimester of pregnancy, counteracts the onset of gestational diabetes mellitus (GDM) in women at risk, preserving the infants from macrosomia, hypoglycemia and preterm delivery. The authors collected data from the pregnant women at the laboratory (Unit of Cytogenic and Molecular Genetics), from January 2014 to April 2016, all with first trimester fasting plasma glucose (FPG) >92 mg/dl. A total of 40 women were treated with 250 mg/day D-chiro-inositol, 1.75 g/day D-myo-inositol, 12.5 mg/day zinc, 10 mg/day methylsulfonylmethane, 400 µg/day 5-methyltetrahydrofolic acid. The other 43 women (control group) were treated with only 400 µg/day folic acid. The primary outcome measure was the incidence of maternal GDM. The secondary outcome measures were the incidence of fetal macrosomia, preterm delivery and neonatal hypoglycemia. At the 24th week of pregnancy, the incidence of maternal GDM was recorded in 18 women in the control group and in 5 women in the treated group [relative risk (RR)=3.35; 95% confidence interval (CI)=1.37-8.17; P=0.0028). A significant difference was observed between treated and control groups in terms of risk of macrosomia. A total of seven infants in the control group, and two in the treated group, weighed >4,000 g (RR=5,12; 95% CI=1.21-21.68; P=0.0099). No significant difference was identified between two groups, regarding the other two secondary outcomes, neonatal hypoglycemia (RR=4.650; 95% CI=0.57-38.11; P=0.1086) and preterm delivery (RR=1.74; 95% CI=0.83-3.66; P=0.1301). The current study demonstrated the potential benefit of supplementation with the association of D-chiro-inositol and D-myo-inositol in pregnant 'at risk' women, with first trimester FPG >92 mg/dl, in preventing the onset of maternal GDM and macrosomia in newborns.

Polycystic Ovary Syndrome: Insights into the Therapeutic Approach with Inositols.

Polycystic ovary syndrome (PCOS) is characterized by hormonal abnormalities that cause menstrual irregularity and reduce ovulation rate and fertility, associated to insulin resistance. Myo-inositol (cis-1,2,3,5-trans-4,6-cyclohexanehexol, MI) and D-chiro-inositol (cis-1,2,4-trans-3,5,6-cyclohexanehexol, DCI) represent promising treatments for PCOS, having shown some therapeutic benefits without substantial side effects. Because the use of inositols for treating PCOS is widespread, a deep understanding of this treatment option is needed, both in terms of potential mechanisms and efficacy. This review summarizes the current knowledge on the biological effects of MI and DCI and the results obtained from relevant intervention studies with inositols in PCOS. Based on the published results, both MI and DCI represent potential valid therapeutic approaches for the treatment of insulin resistance and its associated metabolic and reproductive disorders, such as those occurring in women affected by PCOS. Furthermore, the combination MI/DCI seems also effective and might be even superior to either inositol species alone. However, based on available data, a particular MI:DCI ratio to be administered to PCOS patients cannot be established. Further studies are then necessary to understand the real contents of MI or DCI uptaken by the ovary following oral administration in order to identify optimal doses and/or combination ratios.

The inositols and polycystic ovary syndrome.

This review describes the rationale, biochemical, and clinical data related to the use of inositols in polycystic ovary syndrome (PCOS). It covers studies related to the mechanism of action of myo-inositol and D-chiro-inositol (MDI), with randomized controlled trials conducted in women with PCOS, and utilizes these data to suggest pragmatic indications and methods for using MDI combination in PCOS. Rationally crafted inositol combinations have a potential role to play in maintaining metabolic, endocrine, and reproductive health in women with PCOS.

Abstract 4112: Inositol hexaphosphate (IP6) and inositol against large granular lymphocytic leukemia (LGLL)

Abstract Introduction: The anticancer activity of dietary IP6 and its parent compound inositol, either alone or in combination, has been shown in many different experimental models. Using rat leukemia RNK-16 cells, we investigated the in vitro efficacy of IP6 and inositol in large granular lymphocytic leukemia (LGLL) that develops spontaneously in male Fisher 344 rats and is very similar to human disease. RAS and ERK are constitutively active in LGLL in both humans and rats, and the PI3K/Akt pathway plays a major role in proliferation and survival of these leukemic cells. Therefore, we also investigated the effect of IP6 and inositol on these pathways. Methods: We have previously shown that after in vitro or in vivo administration, exogenous IP6 rapidly dephosphorylates to inositol. In this study, we first implemented the assay for the measurement of unlabeled intracellular myo-inositol by LC-MS/MS after in vitro exposure to IP6 and inositol. Cytotoxicity of IP6 and inositol against Fisher 344 RNK-16 cells alone and in combination with 4-OH-cyclophosphamide was measured by MTT cytotoxicity assay. Western blot analysis was used for protein expression. Results: Uptake of inositol increased more than 5-fold following exposure to 2 mM inositol, and no differences were observed between unsynchronized and synchronized cells. Inositol was relatively non-toxic (30% cytotoxicity at 100 mM), while IP6 had an IC50 of approximately 2 mM. 4-OH-cyclophosphamide had an IC50 of 180 µg/mL, and co-administration of either IP6 or inositol decreased its IC50 by 3-fold. While the expression and phosphorylation status of ERK1/2 were unaffected, p-Akt was completely inhibited between 5 and 60 min after 2 mM IP6 and between 15 and 60 min after inositol, by 2-fold. Furthermore, IP6 treatment caused a significant increase in the expression of the Cdk inhibitor p27Kip1 in RNK-16 cells (1.9-fold) 5 and 15 min. Conclusion: Our data data suggest the use of inositol and IP6 as chemopreventive agents in control of LGLL in humans or as adjuvant therapies. Further studies are justified and warranted. Support: P30-CA-47904 Citation Format: Ivana Vucenik, Jan H. Beumer, Julie L. Eiseman. Inositol hexaphosphate (IP6) and inositol against large granular lymphocytic leukemia (LGLL). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4112. doi:10.1158/1538-7445.AM2014-4112

Scientific Opinion on the safety and efficacy of inositol as a feed additive for fish, dogs and cats

Inositol is an essential micronutrient for salmon, carp, tilapia and shrimps, particularly juveniles. This conclusion is extended to all fish and crustaceans. The requirements differ among species and may be in the range of 250–500 mg/kg complete feed for fish. The use of inositol in feed for fish and crustaceans is considered safe at the recommended levels; setting a maximum content is not considered necessary. Based on the study provided in dogs, it was not possible to (i) demonstrate the essentiality of dietary inositol for dogs and (ii) conclude on the safety of dietary inositol at the recommended use levels of between 500 and 3 000 mg/kg. The FEEDAP Panel is not in the position to conclude on the efficacy and safety of inositol for cats. Supplementing feed for fish and crustaceans will not substantially increase the exposure of the consumer to inositol. Considering dietary exposure and endogenous synthesis of inositol, the additional exposure from fish fed an inositol-supplemented diet is of no concern for consumer safety. Considering the potential inhalation exposure upon handling the additive and the absence of data on inhalation toxicity, the FEEDAP Panel concludes that inhalation exposure from handling inositol could be hazardous. In the absence of data, inositol should be considered as irritant to skin and eyes and as a skin sensitiser. Inositol occurs naturally in the environment, particularly in plants. The use of inositol in fish nutrition is not expected to substantially increase the concentration in the environment. Consequently, the supplementation of fish feed with inositol does not pose a risk to the environment.

Optimisation of a biotechnological procedure for selective fractionation of bioactive inositols in edible legume extracts

Currently, disorders such as diabetes mellitus, obesity or atherosclerosis are recognised as major global health problems. The use of inositols for treating these illnesses has attracted considerable attention and their extraction from natural sources presents added value as they are considered bioactive ingredients in the food industry. Legumes are natural and rich sources of inositols; however, the co-existence of other low molecular weight carbohydrates (LMWCs) in their extracts, which interfere in their bioactivity, might constitute an important drawback, thereby making their removal essential. LMWCs, including inositols, methyl-inositols and glycosyl-inositols of different legume extracts, were determined by GC-MS; the presence of bornesitol (2.35 mg g(-1) ) and lathyritol (0.27 mg g(-1) ) were reported for the first time in grass peas. The use of Saccharomyces cerevisiae for the selective removal of interfering carbohydrates was optimised. Incubation time (3-40 h) was highly dependent on the composition of the legume considered; inositol contents were generally stable along the treatment. Removal of interfering LMWCs from inositol-enriched extracts was successfully achieved using a clean and easily scalable fractionation methodology. This biotechnological procedure not only represents high interest for the production of bioactive food ingredients but for applications in other research areas.