Role Of Inositol Research Articles

The Role of Inositols in Endocrine and Neuroendocrine Tumors.

Inositols have demonstrated a role in cancer prevention and treatment in many kinds of neoplasms. Their molecular mechanisms vary from the regulation of survival and proliferative pathways to the modulation of immunity and oxidative stress. The dysregulation of many pathways and mechanisms regulated by inositols has been demonstrated in endocrine and neuroendocrine tumors but the role of inositol supplementation in this context has not been clarified. The aim of this review is to summarize the molecular basis of the possible role of inositols in endocrine and neuroendocrine tumors, proposing it as an adjuvant therapy.

The role of inositol in improving fertility in patients with PCOS

Introduction and purpose
 Polycystic ovary syndrome is a common reproductive disorder, accompanied primarily by hyperandrogenism and insulin resistance. Myo-inositol (MI) and D-chiro-inositol (DCI), have emerged as potential therapeutic agents due to their role as insulin sensitizers. This article examines the effects of inositol therapy on fertility in women with PCOS and its role in assisted reproductive technology (ART). Studies suggest that inositols alleviate irregular menstruation, reduce androgen levels and positively affect ovulation rates. MI supplementation has also shown positive effects during controlled ovarian hyperstimulation and IVF procedures, reducing the required FSH dose and cycle length. However, despite positive results on ovulation and menstrual regularity, the article indicates the need for further studies to establish inositol as standard ART therapy in patients with PCOS.
 Material and methods
 The following review was based on articles from the PubMed and Google Scholar databases. Key search terms included polycystic ovary syndrome; assisted reproductive treatment, insulin resistance, inositols, Myo-inositol, D-chiro-inositol.
 Conclusions 
 Inositols are a promising therapeutic option for women with PCOS. They have been shown to have positive effects on improving insulin sensitivity and fertility. However, despite inositol's safety and easy availability, the ideal dose and timing of use, the appropriate MI/DCI ratio, as well as the potential side effects of excess DCI and the problem of inositol resistance, require further comprehensive studies.

Маски синдрома поликистоза яичников: роль инозитолов

Aim: to evaluate the effect of the complex of myo-inositol and D-chiroinositol (MI/DCI) 40:1 in combination with alpha-lipoic acid (ALA) on endocrine and metabolic parameters, body weight, menstrual cycle duration, and pregnancy rate in women with polycystic ovary syndrome (PCOS). Patients and Methods: 50 women aged 18–35 years who were planning to become pregnant were studied. Group 1 included 30 women who received MI/DCI 40:1 and ALA, folic acid, vitamin D3, and manganese (Diferton supplement) 1 tablet twice daily for 180 days. Group 2 (controls) included 20 women who also received the preconception nutrient complex (docosahexaenoic acid, vitamin D3, folic acid, vitamin E, potassium iodide) for 180 days. All women signed a voluntary informed consent prior to enrollment. Hormonal status, fasting glucose, HOMA- IR, insulin, lipid profile, body weight, body mass index (BMI), waist circumference, menstrual cycle duration at baseline, after 90 and 180 days, and pregnancy rate in both groups were evaluated. Results: in group 1, Diferton contributed to a significant decrease in total cholesterol and low-density lipoprotein levels and an increase in high- density lipoprotein levels. In group 2, changes in these parameters were also observed, but they were not significant. A decrease in fasting plasma glucose was also observed in group 1 (p<0.01), indicating a significant effect of the studied dietary supplement on carbohydrate metabolism. Women in group 1 lost 3±1.19 kg of body weight in 6 months and waist circumference decreased by an average of 3.1±1.5 cm. Meanwhile, women in group 2 did not lose weight and waist circumference changed insignificantly. In group 1, the menstrual cycle duration decreased to 40±1.9 days, while in group 2, the cycle duration decreased by an average of 4 days. Pregnancy occurred in 6 women in group 1 and in 1 woman in group 2. Conclusion: Diferton improved not only hormonal and metabolic parameters but also ovarian dysfunction in women with PCOS. It is reasonable to use it for pregravidaral preparation in women with PCOS. Significant decrease in BMI, body weight and waist circumference in group 1 during the treatment is an additional marker of the positive effect of the dietary supplement Diferton on the somatic status of women with metabolic disorders. KEYWORDS: polycystic ovary syndrome, complex of myo-inositol and D-chiroinositol, alphalipoic acid, metabolic disorders, infertility. FOR CITATION: Dub N.V., Kruchinina E.V. Masks of polycystic ovary syndrome: the role of inositols. Russian Journal of Woman and Child Health. 2024;7(3):205–213 (in Russ.). DOI: 10.32364/2618-8430-2024-7-3-8.

Role of inositol polyphosphate-4-phosphatase type II in oncogenesis of digestive system tumors.

Inositol polyphosphate-4-phosphatase type II (INPP4B) is a newly discovered PI(3,4,5)P3 phosphatase. Many studies have revealed that INPP4B is upregulated or downregulated in tumors of the digestive system, and the abnormal expression of INPP4B may be attributed to the occurrence, development, and prognosis of tumors of the digestive system. This paper reviews studies on the correlations between INPP4B and digestive system tumors and the roles of INPP4B in the development of different tumors to provide a theoretical basis for further research on its molecular mechanism and clinical application. "INPP4B" and "tumor" were searched as key words in PubMed and in the CNKI series full text database retrieval system from January 2000 to August 2023. A total of 153 English-language studies and 30 Chinese-language studies were retrieved. The following enrollment criteria were applied: (1) Studies contained information on the biological structure and functions of INPP4B; (2) studies covered the influence of abnormal expression of INPP4B in digestive system tumors; and (3) studies covered the role of INPP4B in the diagnosis, treatment, and prognosis of digestive system tumors. After excluding the literature irrelevant to this study, 61 papers were finally included in the analysis. INPP4B expression is low in gastric cancer, colon cancer, pancreatic cancer, and liver cancer but it has high expression in esophageal cancer, colon cancer, pancreatic cancer, and gallbladder cancer. INPP4B is involved in the occurrence and development of digestive system tumors through the regulation of gene expression and signal transduction. The abnormal expression of INPP4B plays an important role in the development of digestive system tumors. Studies on INPP4B provide new molecular insights for the diagnosis, treatment, and prognosis evaluation of digestive system tumors.

The Role of Inositols in the Hyperandrogenic Phenotypes of PCOS: A Re-Reading of Larner's Results.

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers-myo-Inositol and D-Chiro-Inositol-have recently been pharmacologically effective in managing many PCOS symptoms while rescuing ovarian fertility. However, some disappointing clinical results prompted the reconsideration of their specific biological functions. Surprisingly, D-Chiro-Ins stimulates androgen synthesis and decreases the ovarian estrogen pathway; on the contrary, myo-Ins activates FSH response and aromatase activity, finally mitigating ovarian hyperandrogenism. However, when the two isomers are given in association-according to the physiological ratio of 40:1-patients could benefit from myo-Ins enhanced FSH and estrogen responsiveness, while taking advantage of the insulin-sensitizing effects displayed mostly by D-Chiro-Ins. We need not postulate insulin resistance to explain PCOS pathogenesis, given that insulin hypersensitivity is likely a shared feature of PCOS ovaries. Indeed, even in the presence of physiological insulin stimulation, the PCOS ovary synthesizes D-Chiro-Ins four times more than that measured in control theca cells. The increased D-Chiro-Ins within the ovary is detrimental in preserving steroidogenic control, and this failure can easily explain why treatment strategies based upon high D-Chiro-Ins have been recognized as poorly effective. Within this perspective, two factors emerge as major determinants in PCOS: hyperandrogenism and reduced aromatase expression. Therefore, PCOS could no longer be considered a disease only due to increased androgen synthesis without considering the contemporary downregulation of aromatase and FSH receptors. Furthermore, these findings suggest that inositols can be specifically effective only for those PCOS phenotypes featured by hyperandrogenism.

Role of inositol and its isomers in glucose metabolism

Despite the chemical similarities between myo-inositol and D-chiro-inositol and their synergistic effects on insulin sensitivity, they serve different functions. Insulin resistance is one of the etiological factors in the development of polycystic ovary syndrome (PCOS), diabetes mellitus, metabolic syndrome, infertility, menstrual irregularities and ovulation disorders, pregnancy complications, in particular, gestational diabetes. Myo-inositol plays an important role in the insulin transfer and hormone synthesis in the ovaries, in oocyte maturation, fertilization, implantation and post-implantation development.Many studies confirm the positive effect of inositol isomers on metabolic, hormonal and reproductive disorders, both in the form of monotherapy and in combination with other drugs to enhance the therapeutic effect and bioavailability. Myo-inositol has a favorable safety profile. Studies have shown that in patients with PCOS myo-inositol improves ovarian function and fertility, reduces the manifestations of hyperandrogenism, insulin resistance and normalizes weight.Myo-inositol and D-chiro-inositol have different mechanisms of action on insulin sensitivity and have different functions. The balance of the two isomers ensures the normal secretion of hormones and ovarian functioning, but it is currently unknown what the optimal ratio of these two isomers due to the small number of high quality studies and the difficulty of studying their isolated action.There are currently different combinations of myo- and D-chiro-inisotol, but they also have not been supported by enough high quality studies. When prescribing various isomers of inositol, it should be remembered that doses above 4000 mg are the most studied in patients with PCOS, but D-chiro-inositol concentration above 1200 mg/day has undesirable effects. Most studies indicate that D-chiro-inositol value is increased in PCOS, therefore oocytes are more sensitive to its overdose, and combination drugs require more study. Currently, there is no consensus in the literature on the advantage of combined supplements of myo- and D-chiro-inositol compared to monotherapy with myo-inositol. Today, myo-inositol monotherapy is more researched and safer.

PCOS and Assisted Reproduction Technique: Role and Relevance of Inositols

Polycystic ovary syndrome is an endocrine disorder often characterized by insulin resistance and hyperinsulinemia, especially in overweight/obese women. Among insulin sensitizers, the positive role of inositols has been increasingly established in recent years. The action of inositols not only concerns the metabolic parameters of these patients, but also the hormonal profile, resulting in beneficial effects on ovarian function. For this reason, many studies have tried to recognize their role in PCOS infertile women who underwent in vitro fertilization (IVF) procedures.

The relevance of inositols treatment for PCOS before and during ART.

Polycystic ovary syndrome (PCOS) is an endo-crine disorder that occurs in 8-10% of women of reproduc-tive age. It is characterized by oligo or anovulation, hyperandrogenism and/or polycystic ovaries, but also by an increased insulin plasma level especially in overweight/obese women or in those with familial diabetes. In the last years, among the insulin sensitizers, the use of the two active isoforms of inositols (myo-inositol and d-chiro-inositol) has been spreading for the treatment of PCOS insulin resistance. Several studies have shown a positive role of inositols both on the metabolic profile of PCOS patients, but also on hormonal parameters. Hence, inositols can positively affect the infertility that characterizes many PCOS patients, acting both on ovarian function and spontaneous ovulation and during IVF procedures, in terms of oocyte quality and pregnancy rate.

Inositols in reproductive medicine

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.

Role of Inositols and Inositol Phosphates in Energy Metabolism.

Recently, inositols, especially myo-inositol and inositol hexakisphosphate, also known as phytic acid or IP6, with their biological activities received much attention for their role in multiple health beneficial effects. Although their roles in cancer treatment and prevention have been extensively reported, interestingly, they may also have distinctive properties in energy metabolism and metabolic disorders. We review inositols and inositol phosphate metabolism in mammalian cells to establish their biological activities and highlight their potential roles in energy metabolism. These molecules are known to decrease insulin resistance, increase insulin sensitivity, and have diverse properties with importance from cell signaling to metabolism. Evidence showed that inositol phosphates might enhance the browning of white adipocytes and directly improve insulin sensitivity through adipocytes. In addition, inositol pyrophosphates containing high-energy phosphate bonds are considered in increasing cellular energetics. Despite all recent advances, many aspects of the bioactivity of inositol phosphates are still not clear, especially their effects on insulin resistance and alteration of metabolism, so more research is needed.

The Role of IP3 in NO-Enhanced Chilling Tolerance in Peach Fruit.

The role of inositol 1,4,5-trisphosphate (IP3) in nitric oxide (NO)-reduced chilling injury (CI) in peach fruit was investigated. The fruit were immersed in sodium nitroprusside (SNP) (NO donor) and neomycin (IP3 inhibitor). Results showed that chilling tolerance was enhanced upon exogenous SNP in postharvest peach fruit. Further, GABA accumulation was stimulated by SNP. The increase in protein expression and activity for enzymes in GABA biosynthesis, including glutamate decarboxylase (GAD), polyamine oxidase (PAO), and amino aldehyde dehydrogenase (AMADH), upon SNP treatment was also observed. Also, the up-regulation of Δ1-pyrroline-5-carboxylate synthetase (P5CS) and ornithine d-aminotransferase (OAT) and the down-regulation of proline dehydrogenase (PDH) were induced by SNP treatment, thereby accelating proline production. Additionally, SNP treatment elevated protein expression and activity of alternative oxidase (AOX). The above effects induced upon SNP were partly weakened by neomycin. Therefore, IP3 mediated NO-activated GABA and proline accumulation as well as AOX, thus inducing chilling tolerance in postharvest peach fruit.

Overview of systematic reviews of non-pharmacological interventions in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a major contributor to subfertility, diabetes and cardiovascular disease in women. The role of non-pharmacological interventions to prevent these outcomes has been reported in many systematic reviews, but robust conclusions have not been made due to variations in the scope, quality and findings of these reviews. Our aim was to provide an overview of existing evidence on the effects of non-pharmacological interventions in women with PCOS on fertility and non-fertility outcomes by a review of existing systematic reviews. We reviewed systematic reviews of randomized trials that have evaluated the effects of non-pharmacological interventions, such as lifestyle interventions, nutritional supplements or alternative medicine therapies in women with PCOS on fertility, endocrine, glycaemic and weight-related outcomes. We assessed the quality of systematic reviews with the AMSTAR tool, and reported the outcomes with regard to: fertility (live birth, clinical pregnancy, ovulation and menstrual cycle regularization); endocrine outcomes (Ferriman-Gallwey score, free androgen index, free testosterone and total testosterone levels); and glycaemic (fasting blood insulin, fasting blood glucose, homoeostatic model assessment) and weight-related (BMI) outcomes. We assessed the strength of evidence for significant outcomes as per the grading of recommendations assessment, development and evaluation (GRADE) system. We found twelve eligible systematic reviews which included between three (143 women) and 27 randomized trials (2093 women). Four reviews assessed the effects of lifestyle interventions (diet, physical activity and/or behavioural interventions); four evaluated nutritional supplements (one each on n-acetylcysteine, omega-3 fatty acids, inositol and vitamin D); and four studied alternative medical therapies (Chinese herbal medicine and acupuncture). All of the included reviews were of high quality and scored between 8 and 11 with the AMSTAR tool (with a maximum score of 11).Randomized evidence is lacking for live birth rate. N-acetylcysteine, inositol and the addition of alternative medicine to ovulation induction agents show preliminary potential to improve fertility (odds ratios (OR) for clinical pregnancy rate range from 1.99 to 4.83). Lifestyle interventions show benefits in improving hirsutism (mean difference (MD): -1.01 to -1.19). Lifestyle interventions (MD: -1.10 to -2.02), inositol (MD: -2.1) and acupuncture (MD: -1.90 to -3.43) all show some evidence of improvement in glycaemic outcomes and there is some evidence of reduced BMI with lifestyle interventions (MD: -0.15 to -1.12). All of these outcomes scored either low or very low quality of evidence on the GRADE score. Lifestyle interventions in women with PCOS appear to improve glycaemic results, androgenic symptoms and anthropometric outcomes. The role of inositol and N-acetylcysteine in women with PCOS needs further evaluation. Large primary trials on all interventions are needed for an agreed set of core outcomes.

Role of inositol 1,4,5-trisphosphate receptor type 1 in ATP-induced nuclear Ca2+ signal and hypertrophy in atrial myocytes

Inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is expressed in atrial muscle, but not in ventricle, and they are abundant in the perinucleus. We investigated the role of IP3R1 in the regulations of local Ca2+ signal and cell size in HL-1 atrial myocytes under stimulation by IP3-generating chemical messenger, ATP. Assessment of nuclear and cytosolic Ca2+ signal using confocal Ca2+ imaging revealed that IP3 generation by ATP (1 mM) induced monophasic nuclear Ca2+ increase, followed by cytosolic Ca2+ oscillation. Genetic knock-down (KD) of IP3R1 eliminated the monophasic nuclear Ca2+ signal and slowed the cytosolic Ca2+ oscillation upon ATP exposure. Prolonged application of ATP as well as other known hypertrophic agonists (endothelin-1 and phenylephrine) increased cell size in wild-type cells, but not in IP3R1 KD cells. Our data indicate that IP3R1 mediates sustained elevation in nuclear Ca2+ level and facilitates cytosolic Ca2+ oscillation upon external ATP increase, and further suggests possible role of nuclear IP3R1 in atrial hypertrophy.

Downregulation of type 3 inositol (1,4,5)-trisphosphate receptor decreases breast cancer cell migration through an oscillatory Ca2+ signal.

Breast cancer remains a research priority due to its invasive phenotype. Although the role of ion channels in cancer is now well established, the role of inositol (1,4,5)-trisphosphate (IP3) receptors (IP3Rs) remains enigmatic. If the three IP3Rs subtypes expression have been identified in various cancers, little is known about their physiological role. Here, we investigated the involvement of IP3R type 3 (IP3R3) in the migration processes of three human breast cancer cell lines showing different migration velocities: the low-migrating MCF-7 and the highly migrating and invasive MDA-MB-231 and MDA-MB-435S cell lines. We show that a higher IP3R3 expression level, but not IP3R1 nor IP3R2, is correlated to a stronger cell line migration capacity and a sustained calcium signal. Interestingly, silencing of IP3R3 highlights an oscillating calcium signaling profile and leads to a significant decrease of cell migration capacities of the three breast cancer cell lines. Conversely, stable overexpression of IP3R3 in MCF-7 cells significantly increases their migration capacities. This effect is completely reversed by IP3R3 silencing. In conclusion, we demonstrate that IP3R3 expression level increases the migration capacity of human breast cancer cells by changing the calcium signature.

Signaling Pathway for Endothelin-1- and Phenylephrine-Induced cAMP Response Element Binding Protein Activation in Rat Ventricular Myocytes: Role of Inositol 1,4,5-Trisphosphate Receptors and CaMKII

Background/Aims: Endothelin-1 (ET-1) and the α<Sub>1</Sub>-adrenoceptor agonist phenylephrine (PE) activate cAMP response element binding protein (CREB), a transcription factor implicated in cardiac hypertrophy. The signaling pathway involved in CREB activation by these hypertrophic stimuli is poorly understood. We examined signaling pathways for ET-1- or PE-induced cardiac CREB activation. Methods: Western blotting was performed with pharmacological and genetic interventions in rat ventricular myocytes. Results: ET-1 and PE increased CREB phosphorylation, which was inhibited by blockade of phospholipase C, the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway, protein kinase C (PKC) or Ca²⁺-calmodulin-dependent protein kinase II (CaMKII). Intracellular Ca²⁺ buffering decreased ET-1- and PE-induced CREB phosphorylation by ≥80%. Sarcoplasmic reticulum Ca²⁺ pump inhibitor, inositol 1,4,5-trisphosphate receptor (IP<Sub>3</Sub>R) blockers, or type 2 IP<Sub>3</Sub>R (IP<Sub>3</Sub>R2) knock-out abolished ET-1- or PE-induced CREB phosphorylation. ET-1 and PE increased phosphorylation of CaMKII and ERK1/2, which was eliminated by IP<Sub>3</Sub>R blockade/knock-out or PKC inhibition. Activation of CaMKII, but not ERK1/2, by these agonists was sensitive to Ca²⁺ buffering or to Gö6976, the inhibitor of Ca²⁺-dependent PKC and protein kinase D (PKD). Conclusion: CREB phosphorylation by ET-1 and PE may be mainly mediated by IP<Sub>3</Sub>R2/Ca²⁺-PKC-PKD-CaMKII signaling with a minor contribution by ERK1/2, linked to IP<Sub>3</Sub>R2 and Ca²⁺-independent PKC, in ventricular myocytes.

A mutation in β-amyloid precursor protein renders SH‑SY5Y cells vulnerable to isoflurane toxicity: The role of inositol 1,4,5‑trisphosphate receptors.

Isoflurane is a commonly used inhaled anesthetic, which induces apoptosis of SH-SY5Y cells in a dose- and time-dependent manner; however, the underlying mechanisms remain unknown. The authors of the present study hypothesized that a mutation in β-amyloid precursor protein (APP), which is a gene associated with familial Alzheimer's disease, may render cells vulnerable to isoflurane-induced cytotoxicity via activation of inositol 1,4,5-trisphosphate receptors (IP3R). In the present study, SH-SY5Y cells were transfected with a vector or with mutated APP, and were treated with the equivalent of 1 minimum alveolar concentration (MAC) isoflurane for 8 h. Cell apoptosis rate, alterations to cytosolic calcium concentrations ([Ca2+]c), and protein levels of IP3R were determined following exposure of cells to isoflurane. In addition, the effects of the IP3R antagonist xestospongin C were determined on isoflurane-induced cytotoxicity and calcium release from the endoplasmic reticulum (ER) of mutated APP- and vector-transfected SH-SY5Y cells. Treatment with isoflurane (1 MAC) for 8 h induced a higher degree of cytotoxicity, and a marked increase in [Ca2+]c and IP3R protein levels in mutated APP-transfected SH-SY5Y cells compared with vector-transfected SH-SY5Y cells. Xestospongin C significantly attenuated isoflurane-mediated cytotoxicity and inhibited calcium release from the ER of SH-SY5Y cells. These results indicated that the APP mutation may render SH-SY5Y cells vulnerable to isoflurane neurotoxicity, and the underlying mechanism may be associated with Ca2+ dysregulation via overactivation of IP3R.

A review on the role of inositol in aquaculture

Inositol is usually classified as an essential vitamin for most animals, and is recognised as a part of the B-complex vitamins. Among all other inositol isomer forms, myo-inositol possesses biological activity. It is found in the brain, skeletal, heart, and main reproductive tissues and exists as a structural component of phosphatidylinositol in biological cell membranes. Myo-inositol, also acts as a growth factor and affects the antioxidant capacity and oxidative status of cells. It is a major intracellular osmolyte that can be accumulated to protect cells from a variety of stresses and can also participate in transmembrane signal transfer. Myo-inositol is synthesised by various animal tissues and microorganisms in gut and fulfils the requirement for a few fish species. However, the supply of inositol by exogenous source (the diet) is required in most fish and shrimp for preventing deficiency signs such as inefficiency in digestion and food utilization, poor growth, fin erosion, dark skin colouration, and high accumulation of lipid in liver and muscle. The current paper aimed to provide a review on the published studies on the role of inositol in aquaculture.

Type 1 and 3 inositol trisphosphate receptors are required for extra-embryonic vascular development

The embryonic-maternal interface of the placental labyrinth, allantois, and yolk sac are vital during embryogenesis; however, the precise mechanism underlying the vascularization of these structures remains unknown. Herein we focus on the role of inositol 1,4,5-trisphosphate (IP3) receptors (IP3R), which are intracellular Ca2+ release channels, in placentation. Double knockout (DKO) of type 1 and 3 IP3Rs (IP3R1 and IP3R3, respectively) in mice resulted in embryonic lethality around embryonic day (E) 11.5. Because IP3R1 and IP3R3 were co-expressed in endothelial cells in the labyrinth, allantois, and yolk sac, we investigated extra-embryonic vascular development in IP3R1- and IP3R3-DKO mice. The formation of chorionic plates and yolk sac vessels seemed dysregulated around the timing of the chorio-allantoic attachment, immediately followed by the disorganization of allantoic vessels, the decreased expression of the spongiotrophoblast cell marker Tpbpa and the growth retardation of the embryos in DKO mice. Fluorescent immunohistochemistry demonstrated downregulation of a vascular endothelial marker, CD31, in labyrinth embryonic vessels and poor elongation of extra-embryonic mesoderm into the labyrinth layer in DKO placenta, whereas the branching of the DKO chorionic trophoblast was initiated. In addition, allantoic and yolk sac vessels in extra-embryonic tissues were less remodeled in DKO mice. In vitro endothelial cord formation and migration activities of cultured vascular endothelial cells derived from human umbilical vein were downregulated under the inhibition of IP3R. Our results suggest that IP3R1 and IP3R3 are required for extra-embryonic vascularization in the placenta, allantois, and yolk sac. This is the first demonstration of the essential role of IP3/IP3Rs signaling in the development of the vasculature at the embryonic-maternal interface.

Abstract 388: Functional Role of Inositol 1,4,5-Trisphosphate Receptors in Cardiac Hypertrophy

Calcium is a second messenger that is essential for the control of a variety of cellular functions. In the heart, calcium plays an integral role in many cellular processes including energy metabolism, contraction, gene expression, and cell death. The inositol 1,4,5-trisphosphate receptor (IP 3 R) is a calcium channel that is ubiquitously expressed throughout the body. There are three IP 3 R isoforms encoded by separate genes. In the heart, the IP 3 R-2 isoform is reported to being most predominant with regards to both expression levels and functional significance. Several groups have shown that perinuclear IP 3 R-2 may play a key role in the progression of hypertrophy by mediating nuclear calcium release in response to endothelin-1 (ET-1) and angiotensin II. However, the functional roles of IP 3 R-1 and IP 3 R-3 in the heart are essentially unexplored despite measureable expression levels. We hypothesize that all three IP 3 R isoforms can contribute to cytosolic calcium transients and cardiac stress induced by ET-1. As our model we used dissociated neonatal and adult rat ventricular cardiomyocytes. We found readily detectable levels of expression of all three IP 3 Rs in both neonatal and adult rat ventricular cardiomyocytes. We found that in addition to the perinuclear area, all three IP 3 R isoforms were expressed throughout the cardiomyocyte including the sarcoplasmic reticulum. Using isoform specific siRNA, we found that knocking down individual IP 3 Rs did not alter ET-1 induced calcium responses in neonatal cardiomyocytes. However, knocking down all three isoforms abolished the effects of ET-1 on calcium homeostasis. We next tested whether IP 3 Rs mediate nuclear-specific calcium elevations. Using a genetically encoded calcium indicator targeted to the nucleus we were able to specifically discriminate nuclear versus cytosolic calcium transients after ET-1 treatment. Contrary to previous reports, we found no evidence that IP 3 R-mediated calcium release is confined to the nucleus. Our findings that IP 3 R isoforms are functionally redundant in the heart have significant implications for animal models of hypertrophy and human disease.

Myeloid cell-specific inositol polyphosphate-4-phosphatase type I knockout mice impair bacteria clearance in a murine peritonitis model

Phosphatidylinositol 3-kinase (PI3K)/Akt signaling has been implicated in the anti-inflammatory response in a mouse model of endotoxemia and sepsis. The present study focused on the role of inositol polyphosphate-4-phosphatase type I (Inpp4a), which dephosphorylates PtdIns(3,4)P2 to PtdIns(3)P, in bacterial infections. We prepared myeloid cell-specific Inpp4a-conditional knockout mice. Macrophages from these mice showed increased Akt phosphorylation and reduced production of inflammatory cytokines in response to LPS or Escherichia coli invitro The Inpp4a knockout mice survived for a shorter time than wild type mice after i.p. infection with E. coli, with less production of inflammatory cytokines. Additionally, E. coli clearance from blood and lung was significantly impaired in the knockout mice. A likely mechanism is that the Inpp4a-catalyzed dephosphorylation of PtdIns(3,4)P2 down-regulates Akt pathways, which, in turn, increases the production of inflammatory mediators. This mechanism at least fits the decreased E. coli clearance and short survival in the Inpp4a knockout mice.