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Introduction: This research was conducted to assess the effect of myo-inositol (MYO) in the freezing extender on the semen quality and oxidative stress parameters of frozen–thawed bull sperm. Mater...

The inositol 1,4,5-trisphosphate receptor (InsP(3)R) is up-regulated in patients with atrial fibrillation (AF) and InsP(3)-induced Ca(2+) release (IICR) is linked to pro-arrhythmic spontaneous Ca(2+) release events. Nevertheless, knowledge of the physiological relevance and regulation of InsP(3)Rs in atrial muscle is still limited. We hypothesize that InsP(3)R and NADPH oxidase 2 (NOX2) form a functional signaling domain where NOX2 derived reactive oxygen species (ROS) regulate InsP(3)R agonist affinity and thereby Ca(2+) release. To quantitate the contribution of IICR to atrial excitation-contraction coupling (ECC) atrial myocytes (AMs) were isolated from wild type and NOX2 deficient (Nox2(−/−)) mice and changes in the cytoplasmic Ca(2+) concentration ([Ca(2+)](i); fluo-4/AM, indo-1) or ROS (2’,7’-dichlorofluorescein, DCF) were monitored by fluorescence microscopy. Superfusion of AMs with angiotensin II (AngII: 1 μmol/L) significantly increased diastolic [Ca(2+)](i) (F/F(0), Ctrl: 1.00±0.01, AngII: 1.20±0.03; n=7; p

BACKGROUND: Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. PURPOSE: To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. MATERIALS AND METHODS: In this prospective longitudinal study (2016–2020), spectroscopic data on mI—a glial marker and osmoregulator within the brain—normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. RESULTS: Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). CONCLUSION: Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article.

BACKGROUND Chronic lung disease (CLD) is the most common pulmonary morbidity in extremely preterm infants. It is unclear to what extent prenatal exposures influence the risk of CLD. Epigenetic variation in placenta DNA methylation may be associated with differential risk of CLD, and these associations may be dependent upon sex. METHODS Data were obtained from a multi-center cohort of infants born extremely preterm (

Review article is devoted to one of the most common polygenic endocrinopathies in women of reproductive age, polycystic ovarian syndrome (PCOS). We review the current criteria used to make a correct diagnosis based on four phenotypes of PCOS: Frank (phenotype A) – biochemical and/or clinical hyperandrogenism, oligo-/anovulation, polycystic ovarian morphology according to ultrasound; anovulatory (phenotype B) – oligo-/anovulation, biochemical and/or clinical hyperandrogenism; ovulatory (phenotype C) – biochemical and/or clinical hyperandrogenism, polycystic ovarian morphology according to ultrasound; non-androgenic (phenotype D) – oligo-/anovulation, polycystic ovarian morphology according to ultrasound. This article presents the main theories of PCOS pathogenesis: peripheral, central, insulin, genetic, and also considers epigenetic factors. PCOS is a multifactorial disease in which genes are responsible for the mechanisms of the process, and environmental factors through epigenetics affect the genetic material. PCOS phenotypes play an important role in clinical practice, as they allow an individualised approach to the selection of therapy in each case, taking into account the pathogenesis of the disease and predicting its course in the future. The main therapeutic options for treating patients with PCOS, taking into account the multifactorial nature of the disease and the patient's interest in pregnancy, are reviewed. The article presents modern methods for the correction of hyperandrogenism and anovulation, with special emphasis on the need for progesterone therapy.

1. The objective of this study was to investigate wheat genotypes bred for increased intrinsic phytase activity for InsP6 disappearance and the formation of lower inositol phosphates in such wheat-fed broiler chickens. The influence of monocalcium phosphate (MCP) supplementation on these characteristics and the utilisation of P and Ca were also determined. A three-step in vitro assay and a broiler trial were performed.2. In the 63 wheat genotypes tested in vitro, phytase activity varied from 1900 FTU/kg to 5200 FTU/kg, and InsP6 disappearance increased with higher phytase activity of wheat in a linear manner. The addition of MCP significantly reduced in vitro InsP6 disappearance by one-third, independent of the inclusion level of wheat in the feed. When exogenous phytase was added to wheat, in vitro InsP6 disappearance increased independently of the phytase activity of the wheat used.3. In the broiler trial, four wheat genotypes with phytase activities between 2400 and 3700 FTU/kg were included at 400 g/kg in diets with and without MCP. The diets were not pelleted. Separately, wheat 1, without MCP, was tested with the addition of exogenous phytase. Unsexed Ross 308 broiler chickens were allocated to 72 metabolic units of 10 birds each and assigned one of the nine diets. Mineral utilisation was measured based on excreta collection from 20 to 23 d of age. Digesta from the crop and terminal ileum were collected on d 24.4. In the crop and ileum, InsP6 disappearance was not affected by the wheat genotypes, but the addition of MCP significantly decreased InsP6 disappearance. Precaecal P disappearance was significantly reduced by the addition of MCP, with wheat genotypes also exerting an effect. Wheat genotypes and the addition of exogenous phytase significantly affected P utilisation. Exogenous phytase had no effect on InsP6 disappearance in the crop but did up to the terminal ileum, the precaecal InsP6 and P disappearance increased with the addition of exogenous phytase.5. Although the intrinsic wheat phytase activity exerted distinct effects on in vitro InsP6 disappearance, no such effect was found in the broiler trial. The addition of MCP significantly inhibited InsP6 degradation in vitro and in vivo.

Background Prognostic value of proton MR spectroscopy (H-MRS) in hypoxic–ischemic encephalopathy (HIE) is acknowledged; however, effects of gestational age (GA) and postnatal age (PA) on prediction and metabolite levels are unknown. Methods One hundred and sixty-nine newborns with moderate-to-severe HIE were studied, having ≥1 H-MRS scan during postnatal days 0–14 and known neurodevelopmental outcome (Bayley-II score/cerebral palsy/death). Initial scans were categorized by PA (day 1–3/4–6/≥7), and metabolite ratios were compared by predictive value. Metabolite dynamics were assessed in a total of 214 scans performed in the study population, using regression modeling, with predictors GA, PA, and outcome. Results N-acetyl-aspartate (NAA)/creatine (Cr) and myo-inositol (mI)/NAA height ratios were consistently associated with outcome throughout the first 14 days, with the highest predictive value in the late (≥7 days) period (AUC = 0.963 and 0.816, respectively). Neither GA nor PA had an overall effect on these metabolite ratios, which showed strongest association with outcome (p p = 0.0058 and 0.0002, respectively). However, this association disappeared in the poor outcome group. Conclusions In HIE, NAA/Cr and mI/NAA give most accurate outcome prediction throughout postnatal days 0–14. GA only affected metabolite levels in the good outcome group. Impact Proton MR spectroscopy metabolite ratios N-acetyl-aspartate/creatine and myo-inositol/N-acetyl-aspartate have persistently high predictive value throughout postnatal days 0–14 in newborns with hypoxic–ischemic encephalopathy, with the highest predictive power between postnatal days 7 and 14. Overall, neither metabolite ratio was affected by gestational age nor by postnatal age, while they showed the strongest association with neurological outcome. However, in newborns facing good outcome, metabolite ratios were associated with gestational age, whereas in cases facing poor outcome, this association disappeared. Proton MR spectroscopy provides valuable prognostic information in neonatal hypoxic–ischemic encephalopathy throughout the first 2 weeks of life, irrespective of the timing of MR scan.

1. Myo-inositol (MI) is an essential metabolite for cell function in animals and humans. The aim of this study was to characterise the transport mechanism of MI in the small intestine of laying hens as there is a lack of knowledge about the MI uptake mechanisms. The hypothesised secondary active, cation coupled transport of MI was assessed by electrophysiological measurements with Ussing chambers, and was compared to the electrophysiology of glucose transport. 2. Twenty-six laying hens were used. The potential ion-dependent transport was tested in tissue of the small intestine. Barrier function of the tissue was shown by determining the transepithelial resistance. During the experiments, mucosal and serosal buffers were sampled to measure time-dependent changes in MI concentrations. Samples from eight hens were further used for Western blot analyses of the jejunal apical membranes. 3. Active MI transport, indicated by changes in the short circuit current after MI addition, could not be demonstrated in the Ussing chambers experiments. MI was further not detectable in the serosal buffer, nor in the lysates of mucosal tissue cytoplasm nor lipids. Thus, there was no evidence for a MI transport or absorption. However, Western blot analyses of the jejunal apical membrane revealed signals indicated the expression of the MI transport proteins SMIT-1 and SMIT-2. 4. In conclusion, the MI transport process in the chicken intestine is more complex than it was presumed and is probably influenced by still unknown regulations or metabolic processes.

Ovulasyon bozukluklarına bağlı infertilite, tüm infertilite nedenlerinin %25'ini oluşturmaktadır. Ovulasyon bozukluklarının en sık nedeni, Dünya Sağlık Örgütü anovulasyon sınıflamasına göre grup II olan ve çoğunlukla üreme çağındaki kadınların %6-20'sini etkileyen polikistik over sendromlu hastalardan oluşan normogonadatropik normogonadizmli hastalardır. Oral ovulasyon indüksiyon ajanları sadece bu gruptaki hastalar için uygun bir seçenektir. Ovulasyon indüksiyonunun amacı, yumurtalıkları monofoliküler gelişim için uyarmaktır. Ovulasyon indüksiyonunda kullanılan oral ajanlar, birinci basamak ajanlar olarak selektif östrojen reseptör modülatörleri ve aromataz inhibitörleri ve ikinci basamak ajanlar olarak metformin ve inositoller olmak üzere iki gruba ayrılabilir. Bu derlemenin amacı, birincil oral ovulasyon indüksiyon ajanları olan klomifen sitrat ve letrozolün kullanım ve etkinliklerini karşılaştırmak ve ayrıca adjuvan ilaçlar olan metformin ve inositolün katkılarını ortaya koymaktır. Polikistik over sendromunda letrozolün klomifen sitrata göre daha üstün olduğu ve günümüzde dünya çapında ilk seçenek ilaç olarak tercih edildiği görülmektedir. Polikistik over sendromlu kadınlarda, tek başına metformin plaseboya kıyasla ovulasyon oranını arttırır, ancak anovulasyon için birinci basamak tedavi olarak kullanılmamalıdır. Benzer şekilde, inositol tek başına kullanıldığında gebelik oranını artırmamaktadır., Infertility due to ovulation disorders is 25% of all infertility causes. The most common cause of ovulation disorders is patients with normogonadatropic normogonadism, which is group II according to the World Health Organization anovulation classification and mostly consists of patients with polycystic ovary syndrome which affects 6-20% of women of reproductive age. Oral ovulation induction agents are a suitable option only for patients in this group. The purpose of the ovulation induction is to stimulate the ovaries for monofollicular development. Oral agents used in ovulation induction can be divided into two groups, selective estrogen receptor modulators and aromatase inhibitors as first-line agents, and metformin and inositols as second-line agents. The aim of this review is to compare the use and efficacy of the primary oral ovulation induction agents, clomiphene citrate and letrozole, and also to reveal the contributions of the adjuvant drugs metformin and inositol. It is seen that letrozole is superior to clomiphene citrate in polycystic ovary syndrome and is currently preferred as the first-choice drug worldwide. Metformin alone increases the ovulation rate compared to placebo in women with polycystic ovary syndrome, but should not be used as first-line therapy for anovulation. Similarly, when inositol is used alone, it does not increase the pregnancy rate.

AIM: This study aims to investigate the concentration of cyclic adenosine monophosphate (cAMP), inositol 1,4,5-trisphosphate (IP3), calcium (Ca2+), and the expression phosphorylated myosin light chain (MLC) in Rattus norvegicus scleral fibroblast cells. METHODOLOGY: This study utilized an in vitro experimental study by applying Rattus norvegicus scleral fibroblast cell culture. The cultured cells were divided into control and lens-induced myopia (LIM) groups. The control and LIM culture groups were each divided into five groups, namely, negative control, 0.1 μM acetylcholine, 0.1 μM himbacine, 0.1 μM methoctramine, and 0.1 μM 4-DAMP group. The cAMP, IP3, and Ca2+ concentration were analyzed in the 0th, 5th, 10th, 20th, and 30th. The phosphorylated MLC expression was analyzed using confocal microscope. RESULTS: In the LIM group, the highest cAMP concentration is visible at the 10th min on the himbacine group (0.304 ± 0; p = 0.043) and on the 4-DAMP group (0.346 ± 0; p = 0.043). The highest IP3 concentration is found on the LIM group at the 20th min in comparison to the control group (2503.6 ± 11 vs. 2039.2 ± 2.1; p = 0.046). The highest Ca2+ concentration belongs to the 4-DAMP treatment group from the 5th to the 30th min. The highest average phosphorylated MLC expression value in the LIM group is shown by the 0.1μM 4-DAMP treatment (184.2 ± 37.9c au). CONCLUSION: The regulation of cAMP, IP3, Ca2+, and phosphorylated MLC on the M2 and M3 muscarinic receptor of the scleral fibroblast cells of myopia animal models differs from normal animal models which may be due to interactions of M2 and M3 muscarinic receptor as compensation reaction or crosstalk on myopia induction.

Alterations in prolyl oligopeptidase (PREP) activity have been connected, for example, with bipolar and major depressive disorder, and several studies have reported that lack or inhibition of PREP blocks the effects of lithium on inositol 1,4,5-triphosphate (IP3) levels. However, the impact of PREP modulation on other intracellular targets of lithium, such as glycogen synthase kinase 3 beta (GSK3b) or protein kinase B (Akt), has not been studied. We recently found that PREP regulates protein phosphatase 2A (PP2A), and because GSK3b and Akt are PP2A substrates, we studied if PREP-related lithium insensitivity is dependent on PP2A. To assess this, HEK-293 and SH-SY5Y cells with PREP deletion or PREP inhibition (KYP-2047) were exposed to lithium, and thereafter, the phosphorylation levels of GSK3b and Akt were measured by Western blot. As expected, PREP deletion and inhibition blocked the lithium-induced phosphorylation on GSK3b and Akt in both cell lines. When lithium exposure was combined with okadaic acid, a PP2A inhibitor, KYP-2047 did not have effect on lithium-induced GSK3b and Akt phosphorylation. Therefore, we conclude that PREP deletion or inhibition blocks the intracellular effects of lithium on GSK3b and Akt via PP2A activation.

Bipolar disorder (BD) is a complex psychiatric disease characterized by mood swings that include episodes of mania and depression. Given its cyclical nature, BD is especially hard to model; however, the standard practice has been to mimic manic episodes in animal models. Despite scientific advances, the pathophysiology of BD is not fully understood, and treatment remains limited. In the last years, natural products have emerged as potential neuroprotective agents for the treatment of psychiatric diseases. Thus, the aim of this review was to explore the therapeutic potential of natural compounds and derivatives against BD, taking into account preclinical and clinical studies. Reliable articles indexed in databases such as PubMed, Web of Science and Science Direct were used. In clinical studies, treatment with herbal plants extracts, omega-3, inositol, n-acetylcysteine and vitamin D has been associated with a clinical improvement in symptoms of mania and depression in BD patients. In animal models, it has been shown that red fruits extracts, curcumin, quercetin, gallic acid, alpha-lipoic acid and carvone can modulate many neurochemical pathways involved in the pathophysiology of manic episodes. Thus, this review appointed the advances in the consumption of natural compounds and derivatives as an important therapeutic strategy to mitigate the symptoms of BD.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by widespread joint inflammation, which leads to joint damage, disability, and mortality. Among the several types of immune cells, myeloid cells such as macrophages are critical for controlling the pathogenesis of RA. Inositol phosphates are water-soluble signaling molecules, which are synthesized by a series of enzymes including inositol phosphate kinases. Previous studies revealed actions of inositol phosphates and their metabolic enzymes in the modulation of inflammation such as Toll-like receptor-triggered innate immunity. However, the physiological roles of inositol polyphosphate (IP) metabolism in the regulation of RA remain largely uncharacterized. Therefore, our study sought to determine the role of inositol polyphosphate multikinase (IPMK), a key enzyme for IP metabolism and various cellular signaling control mechanisms, in mediating RA. Using myeloid cell-specific IPMK knockout (KO) mice, arthritis was induced via intraperitoneal K/BxN serum injection, after which disease severity was evaluated. Both wild-type and IPMK KO mice developed similar RA phenotypes; however, conditional deletion of IPMK in myeloid cells led to elevated arthritis scores during the resolution phase, suggesting that IPMK deficiency in myeloid cells impairs the resolution of inflammation. Bone marrow-derived IPMK KO macrophages exhibited no apparent defects in immunoglobulin Fc receptor (FcR) activation, osteoclast differentiation, or resolvin signaling. Taken together, our findings suggest that myeloid IPMK is a key determinant of RA resolution.

Lithium (Li+) is the first-line therapy for bipolar disorder and a candidate drug for various diseases such as amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Despite being the captivating subject of many studies, the mechanism of lithium's therapeutic action remains unclear. To date, it has been shown that Li+ competes with Mg2+ and Na+ to normalize the activity of inositol and neurotransmitter-related signaling proteins, respectively. Furthermore, Li+ may co-bind with Mg2+-loaded adenosine or guanosine triphosphate to alter the complex's susceptibility to hydrolysis and mediate cellular signaling. Bipolar disorder patients exhibit abnormally high cytosolic Ca2+ levels and protein kinase C (PKC) hyperactivity that can be downregulated by long-term Li+ treatment. However, the possibility that monovalent Li+ could displace the bulkier divalent Ca2+ and inhibit PKC activity has not been considered. Here, using density functional theory calculations combined with continuum dielectric methods, we show that Li+ may displace the native dication from the positively charged trinuclear site in the C2 domain of cytosolic PKCα/γ. This would affect the membrane-docking ability of cytosolic PKCα/γ and reduce the abnormally high membrane-associated active PKCα/γ levels, thus downregulating the PKC hyperactivity found in bipolar patients.

Purpose: This study is striving to test the hypothesis that a low dosage of myo-inositol supplementation may decrease the likelihood of gestational diabetes in overweight, pregnant women. Methods: A randomized, double-blind, controlled trial was performed on 60 eligible overweight, pregnant women at 12-14 weeks of gestation at two Iranian obstetric clinics. The participants were divided into two groups based on blocked randomization. The myo-inositol group, receiving 2000 mg plus 200 μg folic acid daily and the control group, receiving 400 μg of folic acid daily from 14 - 24 gestational weeks. The occurrence of gestational diabetes was determined based on 75-g 2-hour oral glucose tolerance test (OGTT) at 24–28 gestational weeks, which was the primary outcome of the study. The secondary outcomes were: the evaluation of insulin therapy, insulin resistance, and lipid profile, gestational weight gain, as well as fetal and maternal outcomes. Results: The incidence of gestational diabetes in myo-inositol group was noticeably minimized compared with that of the control group (RR 0.29, 95% CI 0.09-0.94, p= 0.037). There were no differences between the two groups in terms of fasting blood sugar, fasting insulin, HOMA-IR, insulin therapy, and triglyceride. There was no report of severe adverse drug reactions, either.Conclusions: The absolute risk reduction and the ‘‘Number-Needed-to-Treat’’ for gestational diabetes were 26.8% (95% CI, 5.6–48) and 3.7 (95% CI, 2.1–18.0), respectively. Hence, it can be concluded that approximately one out of every four overweight pregnant women receiving myo-inositol benefitted from its daily intake.

Objective The purpose of this study was to investigate correlations between brain proton magnetic resonance spectroscopy (1H‐MRS) findings with serum biomarkers and heteroplasmy of mitochondrial DNA (mtDNA) mutations. This study enrolled patients carrying mtDNA mutations associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke‐like episodes (MELAS), and MELAS‐Spectrum Syndrome (MSS). Methods Consecutive patients carrying mtDNA mutations associated with MELAS and MSS were recruited and their serum concentrations of lactate, alanine, and heteroplasmic mtDNA mutant load were evaluated. The brain protocol included single‐voxel 1H‐MRS (1.5T) in the medial parieto‐occipital cortex (MPOC), left cerebellar hemisphere, parieto‐occipital white matter (POWM), and lateral ventricles. Relative metabolite concentrations of N‐acetyl‐aspartate (NAA), choline (Cho), and myo‐inositol (mI) were estimated relative to creatine (Cr), using LCModel 6.3. Results Six patients with MELAS (age 28 ± 13 years, 3 [50%] female) and 17 with MSS (age 45 ± 11 years, 7 [41%] female) and 39 sex‐ and age‐matched healthy controls (HC) were enrolled. These patients demonstrated a lower NAA/Cr ratio in MPOC compared to HC (p = 0.006), which inversely correlated with serum lactate (p = 0.021, rho = −0.68) and muscle mtDNA heteroplasmy (p

To compare efficacy of myoinositol as an adjuvant to dietary modification for treatment of gestational diabetes mellitus in Asian Indian women compared to controls.Setting: This pilot randomized open label trial was conducted in a single antenatal clinic in India.One hundred women with singleton pregnancy and gestational diabetes diagnosed between 14-28 weeks' gestation were included. Overt diabetes, twin pregnancy, pre-existing renal disease, heart disease and other chronic medical disorders were exclusions.Participants were randomized in two groups (1:1 ratio) by opaque envelope method. Individualized nutrition counseling with dietary modification and routine antenatal care was provided to all. Fifty women received myoinositol 1000 mg twice daily; 50 controls did not receive myoinositol. Fasting and postprandial glucose levels were assessed after two weeks. Women not achieving glycemic targets (fasting glucose95 and postprandial glucose120 mg/dL) were given pharmacologic therapy. Contributory factors in women requiring additional pharmacologic therapy, maternal and fetal outcomes were noted.Between group comparisons reported relative risk and mean difference. To assess predictive factors for need for pharmacologic therapy, univariate and multivariable logistic regression analysis were used.Baseline characteristics were comparable in both groups. Except one woman in the myoinositol group, all women provided glycaemia data throughout their pregnancy. Glycemic control was achieved in 44/ 49 (89.8 %) women in myoinositol group which was significantly higher than 34/50 (68 %) in the controls ((relative risk 0.31, 95 % confidence interval 0.13 to 0.80, p = 0.008). Mean duration of myoinositol treatment was 17.6 weeks (standard deviation 5.3). Additional treatment with metformin/insulin was needed in all women failing to achieve glycaemic control. The mean (range) dose of insulin was 25.3 units in myoinositol group compared to 14.27 units in controls (p = 0.058). Secondary outcomes were similar in two groups except baby weight which was higher in controls (p = 0.018).Oral supplementation with myoinositol in dose of 1 gm twice-daily, when started soon after the diagnosis of GDM, is effective in achieving glycemic control and decreasing the need for additional pharmacological therapy in Asian Indian women.

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model., BMI1 and CHD7 are chromatin remodelling genes with a role in medulloblastoma pathogenesis. Here, the authors demonstrate that the BMI1High/CHD7Low signature mediates metabolic adaptation in G4 MB and predicts response to inositol treatment either alone or in combination with chemotherapy.

OBJECTIVE: This study evaluates the 24 month follow up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial. STUDY DESIGN: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score

Acanthamoeba keratitis is a sight-endangering eye infection, and causative organism Acanthamoeba presents a significant concern to public health, given escalation of contact lens wearers. Contemporary therapy is burdensome, necessitating prompt diagnosis and aggressive treatment. None of the contact lens disinfectants (local and international) can eradicate Acanthamoeba effectively. Using a range of compounds targeting cellulose, ion channels, and biochemical pathways, we employed bioassay-guided testing to determine their anti-amoebic effects. The results indicated that acarbose, indaziflam, terbuthylazine, glimepiride, inositol, vildagliptin and repaglinide showed anti-amoebic effects. Compounds showed minimal toxicity on human cells. Therefore, effects of the evaluated compounds after conjugation with nanoparticles should certainly be the subject of future studies and will likely lead to promising leads for potential applications.

The use of supplement to prevent and ease gestational diabetes (GDM) progression has been examined in various studies, but the results were inconclusive, and studies evaluated dietary supplements separately. The present review aimed to evaluate the efficacy of various dietary supplementation on GDM risk and the surrogate markers for cardiometabolic risk of pregnant women with GDM. A comprehensive search on multiple databases were performed to identify randomized controlled trials. Random-effects model was used to pool the results in relative risk (RR) or mean difference. Fifty-three randomized controlled studies with 9443 pregnant women were included. Vitamin D (5 studies, RR 0.64; 95% CI 0.44, 0.94) and myo-inositol (4 studies, RR 0.34, 95% CI 0.20, 0.58) supplementation significantly reduced the risk of GDM. Myo-inositol, probiotics, and vitamin D showed significant intervention effect on surrogate markers related to glycemic control, lipid profile, inflammatory, and oxidative stress. However, the majority of included studies were clustered to Iran and Italy, which might convey a generalizability bias. Dietary supplementation including vitamin D and myoinositol supplementation has the potential in primary prevention and management of GDM, whereas probiotics demonstrated its ability in GDM management by improving the levels of surrogate markers for cardiometabolic risk. The potential for dietary supplement in preventing GDM or managing cardiometabolic risk of pregnant women should receive more attentions.

Objective: To determine the effects of Myo- inositol in young females with polycystic ovarian syndrome. Study Design and Setting: This was a quasi-experimental study and was conducted in United Medical and Dental College and Creek General Hospital from January 2017 to January 2018. Methodology: Total 100 patients were recruited based on the specific inclusion criteria of PCO diagnosed by symptoms (body mass index, menstrual irregularity, hirsutism, acne) biochemical markers (fasting insulin, random blood sugar) and ultrasound findings. Each subject in the study group was given sachet (Myo- inositol 2000mg and folic acid 400ug) once a day dissolved in glass of water for duration of 6 months. Improvement in symptoms, biochemical markers and ultrasound findings were reassessed after the completion of 6 months duration. The SPSS version 21 was used for data analysis. The paired T test was used to assess the effects of Myo-Inositol before treatment and after six months of treatment. Result: The significant relation (0.001) was observed between the intervention and PCO and its related symptoms. An evident effect was noticed in each individual after the intervention was provided to them. The relatable symptoms such as irregularities in menses, hirsutism,weight and insulin resistance were reduced by significant ratio. Conclusion: Myo – inositol has proven to be effective in reducing the PCO and its relatable symptoms in young females. Despite the limitations, enough evidence was collected that indicated a significant effect of the intervention

The deficit syndrome is thought to be a more homogenous clinical subgroup within the syndrome of schizophrenia that is characterized by enduring negative symptoms. It is hypothesized that distinct pathophysiological processes underlie the subtypes, where the deficit syndrome reflects an early onset nonprogressive developmental process, and the nondeficit form of the illness is characterized by attenuated neuroplasticity secondary to elevated glutamate levels. We used single-voxel magnetic resonance spectroscopy (PRESS; TE: 30 ms) to measure left frontal white matter neurometabolite levels in 61 antipsychotic-naïve first-episode psychosis patients (39 who did not display deficit features, 22 who did display deficit features, assessed with the Schedule for the Deficit Syndrome) and 59 healthy controls. Metabolite levels were quantified with the LCModel. We used a MANCOVA to determine neurometabolite differences between healthy controls, deficit syndrome patients, and nondeficit patients. We report a significant group difference when all metabolites were considered jointly (F[10,208] = 2.16; P = .02). Post hoc analyses showed that patients presenting without deficit features had higher glutamate levels than patients with deficit features and controls. Patients presenting without deficit features also had significantly higher myoinositol levels than controls; myoinositol levels were trend-level higher in patients presenting with deficit features compared to controls. Our data support the idea that the pathophysiology of patients presenting without deficit features may differ from those presenting with deficit features.

Chronic hyperglycemia induces activation of the polyol-sorbitol pathway, which is a major contributor to microvascular complications like stroke. The current study was designed to elucidate the therapeutic role of α-glucose inhibitor in chronic hyperglycemia-induced impaired polyol pathway and associated micro-complications. Male albino-Wistar rats (200-250 g) were treated with voglibose 10 mg kg-1 day-1 /p.o. for 2 weeks before middle cerebral artery occlusion; 72 hr after surgery, neurological score was evaluated and blood was collected for the assessment of various serum biochemical parameters like CRP, CK-MB, LDH, lipid profile, and blood glucose levels. In the end, brain samples were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity oxidative stress-related parameters, aldose reductase activity, and gene expression studies. Results from the present study indicate that pre-treatment with voglibose showed significant improvement in lipid parameters but did not impact glucose levels. Voglibose has shown a statistically significant (p

Rationale: The mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca 2+ regulates gene expression, but the nature and significance of nuclear Ca 2+ -changes in AF are largely unknown. Objective: To elucidate mechanisms by which AF alters atrial-cardiomyocyte nuclear Ca 2+ ([Ca 2+ ] Nuc ) and CaMKII (Ca 2+ /calmodulin-dependent protein kinase-II)-related signaling. Methods and Results: Atrial cardiomyocytes were isolated from control and AF dogs (kept in AF by atrial tachypacing [600 bpm × 1 week]). [Ca 2+ ] Nuc and cytosolic [Ca 2+ ] ([Ca 2+ ] Cyto ) were recorded via confocal microscopy. Diastolic [Ca 2+ ] Nuc was greater than [Ca 2+ ] Cyto under control conditions, while resting [Ca 2+ ] Nuc was similar to [Ca 2+ ] Cyto ; both diastolic and resting [Ca 2+ ] Nuc increased with AF. IP 3 R (Inositol-trisphosphate receptor) stimulation produced larger [Ca 2+ ] Nuc increases in AF versus control cardiomyocytes, and IP 3 R-blockade suppressed the AF-related [Ca 2+ ] Nuc differences. AF upregulated nuclear protein expression of IP 3 R1 (IP 3 R-type 1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot) while decreasing the nuclear/cytosolic expression ratio for HDAC4 (histone deacetylase type-4). Isolated atrial cardiomyocytes tachypaced at 3 Hz for 24 hours mimicked AF-type [Ca 2+ ] Nuc changes and L-type calcium current decreases versus 1-Hz-paced cardiomyocytes; these changes were prevented by IP 3 R knockdown with short-interfering RNA directed against IP 3 R1. Nuclear/cytosolic HDAC4 expression ratio was decreased by 3-Hz pacing, while nuclear CaMKII phosphorylation was increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IP 3 R-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial cardiomyocytes from AF patients, nuclear IP 3 R1-expression was significantly increased, with decreased nuclear/nonnuclear HDAC4 ratio. MicroRNA-26a was predicted to target ITPR1 (confirmed by luciferase assay) and was downregulated in AF atrial cardiomyocytes; microRNA-26a silencing reproduced AF-induced IP 3 R1 upregulation and nuclear diastolic Ca 2+ -loading. Conclusions: AF increases atrial-cardiomyocyte nucleoplasmic [Ca 2+ ] by IP 3 R1-upregulation involving miR-26a, leading to enhanced IP 3 R1-CaMKII-HDAC4 signaling and L-type calcium current downregulation. Graphic Abstract: A graphic abstract is available for this article.

The long-term imposition of pressure overload on the cardiac tissue causes left ventricular hypertrophy (LVH) and cardiac fibrosis. Pinitol has been reported to possess antioxidant potential. The aim was to evaluate the efficacy of pinitol against pressure overload–induced cardiac hypertrophy and fibrosis in the aortic stenosis (AS) rat model. Cardiac hypertrophy was produced in Sprague-Dawley rats by abdominal aortic constriction and treated with lisinopril (15 mg/kg) or pinitol (5, 10, and 20 mg/kg). Pressure overload–induced alterations in hemodynamic and left ventricular function tests, cardiac SOD, GSH, MDA, NO, Na-K-ATPase, and mitochondrial complex enzyme levels were significantly attenuated by pinitol. The upregulated mRNA expressions of cardiac ANP, BNP, cTn-I, TNF-α, IL-1β, IL-6, Bax, Caspase-3, collagen-I, and cardiac apoptosis were markedly downregulated by pinitol. In conclusion, pinitol ameliorated pressure overload–induced LVH and fibrosis via its anti-inflammatory, antioxidant, antifibrotic, and antiapoptotic potential in experimental AS.

Calcium (Ca2+) homeostasis is a crucial determinant of cellular function and survival. Endoplasmic reticulum (ER) acts as the largest intracellular Ca2+ store that maintains Ca2+ homeostasis through the ER Ca2+ uptake pump, sarco/ER Ca2+ ATPase, ER Ca2+ release channels, inositol 1,4,5-trisphosphate receptor channel, ryanodine receptor, and Ca2+-binding proteins inside of the ER lumen. Alterations in ER homeostasis trigger ER Ca2+ depletion and ER stress, which have been associated with the development of a variety of diseases. In addition, recent studies have highlighted the role of ER Ca2+ imbalance caused by dysfunction of sarco/ER Ca2+ ATPase, ryanodine receptor, and inositol 1,4,5-trisphosphate receptor channel in various kidney diseases. Despite progress in the understanding of the importance of these ER Ca2+ channels, pumps, and binding proteins in the pathogenesis of kidney disease, treatment is still lacking. This mini-review is focused on: i) Ca2+ homeostasis in the ER, ii) ER Ca2+ dyshomeostasis and apoptosis, and iii) altered ER Ca2+ homeostasis in kidney disease, including podocytopathy, diabetic nephropathy, albuminuria, autosomal dominant polycystic kidney disease, and ischemia/reperfusion-induced acute kidney injury.

BACKGROUND Inositol is a hexa-carbon polyol, a naturally soluble vitamin, often found in various foods. AIM To discuss the impact of different stereoisomers of inositol on insulin sensitivity of gestational diabetes mellitus (GDM) patients. METHODS Eighty GDM pregnant women were divided into four groups according to their treatment received: A group (placebo folic acid 400 μg/d), B group [myo-inositol (MI) 1500 mg, twice a day], C group [D-chiro-inositol (DCI) 250 mg, twice a day], and D group (inositol MI and inositol DCI 1500 mg/250 mg, twice a day). Each patient routinely used dietary guidance adjustments and did some safe and effective aerobic exercise in addition to receiving placebo or inositol from GDM diagnosis to delivery. Triglyceride, total cholesterol, fasting plasma glucose, oral glucose tolerance test postprandial glucose (2 h postprandial blood glucose), fasting insulin, fasting plasma glucose, and glycosylated hemoglobin levels and Homeostasis Model Assessment-insulin resistance (HOMA-IR) and Homeostasis Model Assessment-insulin sensitivity index (HOMA-ISI) scores were determined before treatment and 8 wk after treatment onset. Adverse maternal and infant outcomes, including hypoglycemia, excessive amniotic fluid, premature infants, macrosomia, fetal distress etc., were also recorded. RESULTS There was no statistical difference in the baseline data of each group. The levels of 2 h blood glucose, glycosylated hemoglobin, fasting insulin, total cholesterol, and triglyceride in the B, C, and D groups were significantly lower than those in the control group (A group) after treatment (P < 0.05). Moreover, compared with the B group, the level of the above indexes in the C and D groups decreased more significantly, and the differences were statistically significant (P < 0.05). The HOMA-IR of B, C, and D groups decreased significantly, and the HOMA-ISI increased significantly compared with the A group, and the differences were statistically significant (P < 0.05), among which the decrease of HOMA-IR and the increase of HOMA-ISI were more significant in the C and D group compared with the B group (P < 0.05). The occurrence rate of adverse maternal and infant outcomes in the C and D group was significantly lower than that in the control group (A group), and the differences were statistically significant (P < 0.05). CONCLUSION Treatment with different inositol stereoisomers (inositol MI and inositol DCI) can improve insulin sensitivity and reduce insulin resistance in diabetic patients, and inositol DCI has a better curative effect than inositol MI.

Background and Purpose: Coordinated endothelial control of cardiovascular function is proposed to occur by endothelial cell communication via gap junctions and connexins. To study intercellular communication, the pharmacological agents carbenoxolone (CBX) and 18β-glycyrrhetinic acid (18βGA) are used widely as connexin inhibitors and gap junction blockers. Experimental Approach: We investigated the effects of CBX and 18βGA on intercellular Ca 2+ waves, evoked by inositol 1,4,5-trisphosphate (IP 3) in the endothelium of intact mesenteric resistance arteries. Key Results: Acetycholine-evoked IP 3-mediated Ca 2+ release and propagated waves were inhibited by CBX (100 μM) and 18βGA (40 μM). Unexpectedly, the Ca 2+ signals were inhibited uniformly in all cells, suggesting that CBX and 18βGA reduced Ca 2+ release. Localised photolysis of caged IP 3 (cIP 3) was used to provide precise spatiotemporal control of site of cell activation. Local cIP 3 photolysis generated reproducible Ca 2+ increases and Ca 2+ waves that propagated across cells distant to the photolysis site. CBX and 18βGA each blocked Ca 2+ waves in a time-dependent manner by inhibiting the initiating IP 3-evoked Ca 2+ release event rather than block of gap junctions. This effect was reversed on drug washout and was unaffected by small or intermediate K +-channel blockers. Furthermore, CBX and 18βGA each rapidly and reversibly collapsed the mitochondrial membrane potential. Conclusion and Implications: CBX and 18βGA inhibit IP 3-mediated Ca 2+ release and depolarise the mitochondrial membrane potential. These results suggest that CBX and 18βGA may block cell–cell communication by acting at sites that are unrelated to gap junctions.

Oxidative damage to cells from metabolites at a wound site is one of the trickiest factors inhibiting tissue regeneration, especially with bulk damage. In addition, an excessive inflammatory reaction by the body at the wound site can make it even worse. How to scavenge the reactive oxygen species (ROS) produced from metabolism and inflammatory reactions has become a critical issue in tissue engineering. Here, we utilize the natural bioactive small molecules l-arginine and l-phenylalanine and the growth factor inositol to synthesize a branched poly(ester amide) (BPEA) to fabricate BPEA nanocapsules for vitamin E delivery at wound sites. BPEA nanocapsules loaded with vitamin E (BPEA@VE NCs) could protect cells from both extracellular and intracellular damage by scavenging ROS. Simultaneously, the inflammatory reaction could also be downregulated, benefiting from the introduction of l-arginine. Furthermore, the biodegradation products of BPEA are natural metabolites of the body, such as amino acids and growth factors, guaranteeing the biocompatibility of the BPEA@VE NCs. The protective ability of the BPEA@VE NCs was also investigated in vivo for accelerated wound healing. All the results indicate that the BPEA@VE NCs have promising potential for the modulation of the local microenvironment in tissue engineering for excellent antioxidative and anti-inflammatory properties.

Background: Acute pancreatitis caused by hyperlipidemia is a severe life-threatening condition. Therefore, it is urgent to develop new therapeutic methods to treat this disease. Methods: Cell viability was determined by the Cell Counting Kit-8 (CCK-8) assay. Western blotting (WB) was used to detect the expression levels of apoptotic and endoribonuclease inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP-1) pathway-associated proteins. The induction of cell apoptosis was determined using flow cytometry. The expression levels of the oxidative stress indicators were measured by an enzyme-linked immunosorbent assay. Results: WB analysis and the CCK-8 assay demonstrated that trimethylamine-N-oxide (TMAO) decreased cell viability and facilitated apoptosis of MPC-83 cells in a dose-dependent manner. Furthermore, the induction of oxidative stress was assessed by evaluating the levels of specific markers, including hydrogen peroxide, reactive oxygen species, nitric oxide, and superoxide dismutase. The levels of the aforementioned markers were increased in the TMAO-treated group. Subsequently, the IRE1α/XBP-1 pathway-associated proteins were analyzed by WB analysis and the data demonstrated that the regulatory effects of TMAO on MPC-83 cells were meditated by the IRE1α/XBP-1 signaling pathway. Subsequently, rescue experiments were performed to further assess the effects of TMAO. Conclusion: The present study provides evidence on the application of TMAO as a potential diagnostic and therapeutic strategy for the therapeutic intervention of hyperlipidemic acute pancreatitis.

Isocitrate dehydrogenase (IDH) wild-type diffuse astrocytic tumors tend to be pathologically diagnosed as glioblastomas (GBMs). We previously reported that myoinositol to total choline (Ins/Cho) ratio in GBMs on magnetic resonance (MR) spectroscopy was significantly lower than that in IDH-mutant gliomas. We then hypothesized that a low Ins/Cho ratio is a poor prognosis factor in patients with GBMs, IDH-wild-type. In the present study, we calculated the Ins/Cho ratios of patients with GBMs and investigated their progression-free survival (PFS) and overall survival (OS) to determine their utility as prognostic marker. We classified patients with GBMs harboring wild-type IDH (n = 27) into two groups based on the Ins/Cho ratio, and compared patient backgrounds, pathological findings, PFS, OS, and copy number aberrations between the high and low Ins/Cho groups. Patients with GBMs in the low Ins/Cho ratio group indicated shorter PFS (P = 0.021) and OS (P = 0.048) than those in the high Ins/Cho group. Multivariate analysis demonstrated that the Ins/Cho ratio was significantly correlated with PFS (hazard ratio 0.24, P = 0.028). In conclusion, the preoperative Ins/Cho ratio can be used as a novel potential prognostic factor for GBM, IDH-wild-type.

Ulcerative colitis is a recrudescent intestinal inflammation coupled with diarrhea, weight loss, pus, and blood stool, which seriously impacts the quality of patient life. d-Pinitol, which can be a food supplement isolated from the food plant-like soybeans, Ceratonia siliqua Linn and Bruguiera gymnorrhiza, has been proved to show anti-oxidative and anti-inflammatory effects. However, the potential mechanism of d-pinitol still remains ill-defined contemporarily. In the current study, the therapeutic effect and potential mechanisms of d-pinitol against colitis were investigated. Oxidative stress and inflammation of experimental colitis were caused by 3% DSS treatment once daily for 7 days. During DSS treatment, the mice of the positive drug group and three other groups were orally administered SASP or d-pinitol once daily. Clinical symptoms were analyzed, and macroscopic scores were calculated. The levels of oxidative and inflammatory cytokines were measured using assay kits and RT-PCR. Additionally, the protein expression of the Nrf2/ARE pathway and PPAR-γ was measured by Western blot. Results showed that d-pinitol enormously alleviated DSS-induced bodyweight loss, colon shortening, and histological injuries, achieving a therapeutic efficacy superior to SASP. Moreover, the oxidative stress and colonic inflammatory response were mitigated. d-pinitol not only significantly activated the Nrf2/ARE signaling pathway via facilitating the translocation of Nrf2 from sitoplazma to cytoblast, upregulating the protein expression levels of GCLC, GCLM, HO-1, and NQO1, but also improved the PPAR-γ level by binding to the active site of PPAR-γ, when suppressing NF-κB p65 and IκBα phosphorylation. In conclusion, d-pinitol exhibited a dramatic anti-colitis efficacy by activating the Nrf2/ARE pathway and PPAR-γ. Hence, d-pinitol may be a promising therapeutic drug against UC in the future.

This case report is the first to describe the detection of antibodies against inositol 1,4,5-trisphosphate receptor 1 (ITPR1, I3PR) in a patient diagnosed with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. ITPR1 is known as one of the Purkinje cell antibodies present in autoimmune cerebellar ataxia (ACA). Here, we described the association between autoimmune GFAP astrocytopathy and autoimmune cerebellar disease (ACD).Demographic features, clinical characteristics, cerebrospinal fluid (CSF) parameters and neuroimaging findings were collected from this patient. Specifically, antibodies against GFAP and other proteins associated with neurological disorders were measured by immunofluorescence staining in both serum and CSF samples.A 52-year-old woman was diagnosed with autoimmune inflammatory meningoencephalitis. She presented with cognitive dysfunction, psychiatric/behavioral abnormalities and serious insomnia with subacute onset. Brain magnetic resonance imaging (MRI) showed bilateral hyperintensity in the semioval centers on axial images and perivascular linear enhancement oriented radially to the ventricles on sagittal images. GFAP-IgG, oligoclonal bands (OBs), N-methyl-D-aspartate receptor (NMDAR)-IgG and ITPR1-IgG co-existed in her CSF. She responded well to immunoglobulin and steroid treatments.Here, we describe the case of a patient with autoimmune GFAP astrocytopathy whose CSF was positive for ITPR1-IgG; however, she did not show typical ataxia manifestations or cerebellar lesions on her MRI scan. This suggests that ITPR1-IgG is not pathogenic, and the positivity of this antibody in CSF is probably associated with the presence of autoimmune inflammation.

The article presents literature data on the role of inositol and its derivatives in human body, results of the myo-inositol (MI) use in gynecological diseases, treatment of female and male infertility, including in cycles of assisted reproductive technologies, in the prevention of gestational and perinatal complications. It has been shown that the inability to adequately synthesize or metabolize inositol can contribute to disturbances in the transmission of intracellular signals, disturbances in the activity of insulin signaling cascades, development of insulin resistance and hyperinsulinemia, which cause abnormal steroidogenesis in the gonads and metabolic disorders. The concept of “D-chiro-inositol paradox” is highlighted, according to which women with polycystic ovary syndrome are characterized by increased epimerization of MI to D-chiro-inositol, depletion of MI reserves and low oocyte quality. Prescribing biologically active supplements with MI and folic acid for pregnant women reduces the likelihood of threatened abortion, preeclampsia, placental dysfunction, gestational diabetes mellitus, diabetic fetopathy, malformations, oxidative stress in the fetus. Experience has also been accumulated about myo-inositol use in andrology: it plays a decisive role in osmoregulation of seminal fluid and, as a consequence, increasing the progressive sperm motility and speed, increasing the mitochondrial sperm potential, improves libido and potency, helps to increase the endogenous testosterone, and normalizes the men’s hormonal balance. Inositol is a synergist of folates and other B vitamins and significantly potentiates their effect on the human body; it is the basis for the advantages of using combined biological supplements such as Miofolic® and Miofolic® MEN in the clinic for female and male reproduction. Harmonious use of all possible reserves of micronutrient support for the preconception and gestational period with the use of biologically active supplements of MI in combination with folic acid and vitamin B12 is a promising preventive and therapeutic agent in supporting of reproductive system, embryo development, neuroprotection of the fetal brain, ensuring the activity of signaling cascades insulin.