Inositol

i-Inositol is a chemical compound, associated lipids are found in many foods, in particular fruit, especially cantaloupe and oranges.

Effect of phytase superdosing, myo-inositol and available phosphorus concentrations on performance and bone mineralisation in broilers.[Pubmed:29767153]

Anim Nutr. 2017 Sep;3(3):247-251.

A total of 2,376 one-day-old Ross broiler chickens were used to investigate the effect of myo-Inositol (MYO) and phytase supplementation on performance and bone mineralization variables in broilers fed diets formulated to have varying concentrations of available phosphorus (P). The trial was designed as a 2 x 2 x 3 factorial; with and without phytase superdosing (0 or 1,500 FTU/kg), MYO (0 or 3 g/kg), and dietary P (low, moderate or high). At 21 d, dietary phytase and MYO had no consistent benefit on bone mineralization variables. Bone ash reduced by 4.7% from the medium to low P diet (P < 0.01), with no effect of phytase supplementation. Superdosing improved bone P content by 6% in birds fed the low P diet, signifying an interaction between dietary P concentrations and phytase (P < 0.05). Dietary MYO addition resulted in a numerical reduction in bone ash and a significant reduction in bone strength (P < 0.05). At 42 d, the beneficial effect of phytase superdosing on feed intake and body weight gain was evident in the low P diet. Superdosing reduced feed conversion rate (FCR) at all P levels (P < 0.05), although this effect was more pronounced on the low P diet, suggesting that sufficient P being released from the phytase itself to re-phosphorylate MYO and hence improve FCR. The significant improvement in FCR was greater with superdosing than with MYO alone, and the combination led to no further improvement in FCR compared with superdosing alone, signifying a phytase and MYO interaction (P < 0.05). From these results, it can be estimated that MYO is providing around 30% to 35% of the total response to superdosing.

SINGLE-CHANNEL ION CURRENTS IN THE NUCLEAR ENVELOPE OF RAT CARDIOMYOCYTES.[Pubmed:29762965]

Fiziol Zh. 2016;62(6):3-8.

Using the patch clamp technique in nucleus attached configuration we have found that the nuclear membrane of rat cardiomyocytes contains different types of ion channels with conductances in the range from 10 to 400 pS. In particular, we recorded Inositol 1,4,5-trisphosphate receptors with conductance of 384 +/- 5 pS and 209 +/- 13 pS cation channels similar to LCC-channels, previously reported in neurons. In addition, we found at least two types of ion channels with significantly higher conductance than that of LCC-channels and several types of ion channels with lower conductance (10-90 pS).

IRE1alpha prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.[Pubmed:29764990]

Sci Signal. 2018 May 15;11(530). pii: 11/530/eaao4617.

Obesity or a high-fat diet represses the endoribonuclease activity of Inositol-requiring enzyme 1alpha (IRE1alpha), a transducer of the unfolded protein response (UPR) in cells under endoplasmic reticulum (ER) stress. An impaired UPR is associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD), which is caused by lipid accumulation in the liver. We found that IRE1alpha was critical to maintaining lipid homeostasis in the liver by repressing the biogenesis of microRNAs (miRNAs) that regulate lipid mobilization. In mice fed normal chow, the endoribonuclease function of IRE1alpha processed a subset of precursor miRNAs in the liver, including those of the miR-200 and miR-34 families, such that IRE1alpha promoted their degradation through the process of regulated IRE1-dependent decay (RIDD). A high-fat diet in mice or hepatic steatosis in patients was associated with the S-nitrosylation of IRE1alpha and inactivation of its endoribonuclease activity. This resulted in an increased abundance of these miRNA families in the liver and, consequently, a decreased abundance of their targets, which included peroxisome proliferator-activated receptor alpha (PPARalpha) and the deacetylase sirtuin 1 (SIRT1), regulators of fatty acid oxidation and triglyceride lipolysis. IRE1alpha deficiency exacerbated hepatic steatosis in mice. The abundance of the miR-200 and miR-34 families was also increased in cultured, lipid-overloaded hepatocytes and in the livers of patients with hepatic steatosis. Our findings reveal a mechanism by which IRE1alpha maintains lipid homeostasis through its regulation of miRNAs, a regulatory pathway distinct from the canonical IRE1alpha-UPR pathway under acute ER stress.

Glucocorticoid-activated IRE1alpha/XBP-1s signaling: an autophagy-associated protective pathway against endotheliocyte damage.[Pubmed:29768047]

Am J Physiol Cell Physiol. 2018 Sep 1;315(3):C300-C309.

Glucocorticoid-induced endothelial injury has been reported in several diseases. Although there are several theories, the exact mechanism underlying the role of glucocorticoids in this process remains unclear. Autophagy has been reported to occur as a response to different stimuli and can affect cell survival and function. In this study, we found that glucocorticoids induced apoptosis and endoplasmic reticulum (ER) stress in endotheliocytes. Furthermore, we discovered that glucocorticoids induced autophagy in these cells and the Inositol requiring protein 1 (IRE1alpha)/X-box binding protein 1s (XBP-1s) axis, one of the downstream signaling pathways of ER stress, was associated with the glucocorticoid-induced autophagy. The autophagy partly protected endotheliocytes from glucocorticoid-induced apoptosis and inhibition of proliferation. In conclusion, glucocorticoid-induced endoplasmic reticulum stress activated the IRE1alpha/XBP-1s signaling and induced autophagy, which, in turn, played a protective role in endotheliocyte survival and proliferation, avoiding further cellular damage caused by glucocorticoids.

Myristate-induced endoplasmic reticulum stress requires ceramide synthases 5/6 and generation of C14-ceramide in intestinal epithelial cells.[Pubmed:29768040]

FASEB J. 2018 Oct;32(10):5724-5736.

Saturated fatty acids (SFAs) have been shown to induce endoplasmic reticulum (ER) stress and chronic inflammatory responses, as well as alter sphingolipid metabolism. Disruptions in ER stress and sphingolipid metabolism have also been implicated in intestinal inflammation. Therefore, to elucidate the roles of SFAs in ER stress and inflammation in intestinal epithelial cells, we examined myristate (C14:0) and palmitate (C16:0). Myristate, but not palmitate, induced ER stress signaling, including activation of Inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP1) signaling. Myristate significantly increased C14-ceramide levels, whereas palmitate increased several long-chain ceramides. To define the role of ceramide synthases (CerSs) in myristate-induced ER stress, we used the pharmacologic inhibitor, fumonisin B1 (FB1), and small interfering RNA (siRNA) for CerS5 and 6, the primary isoforms that are involved in C14-ceramide generation. FB1 and siRNA for CerS5 or 6 suppressed myristate-induced C14-ceramide generation and XBP1 splicing (XBP1s). Moreover, increased XBP1s induced the downstream expression of IL-6 in a CerS5/6-dependent manner. In addition, a myristate-enriched milk fat-based diet, but not a lard-based diet, increased C14-ceramide, XBP1s, and IL-6 expression in vivo. Taken together, our data suggest that myristate modulates ER stress and cytokine production in the intestinal epithelium via CerS5/6 and C14-ceramide generation.-Choi, S., Snider, J. M., Olakkengil, N., Lambert, J. M., Anderson, A. K., Ross-Evans, J. S., Cowart, L. A., Snider, A. J. Myristate-induced endoplasmic reticulum stress requires ceramide synthases 5/6 and generation of C14-ceramide in intestinal epithelial cells.

Biological Roles Played by Sphingolipids in Dimorphic and Filamentous Fungi.[Pubmed:29764947]

MBio. 2018 May 15;9(3). pii: mBio.00642-18.

Filamentous and dimorphic fungi cause invasive mycoses associated with high mortality rates. Among the fungal determinants involved in the establishment of infection, glycosphingolipids (GSLs) have gained increased interest in the last few decades. GSLs are ubiquitous membrane components that have been isolated from both filamentous and dimorphic species and play a crucial role in polarized growth as well as hypha-to-yeast transition. In fungi, two major classes of GSLs are found: neutral and acidic GSLs. Neutral GSLs comprise glucosylceramide and galactosylceramide, which utilize Delta4-Delta8-9-methyl-sphingadienine as a sphingoid base, linked to a C16-18 fatty acid chain, forming ceramide, and to a sugar residue, such as glucose or galactose. In contrast, acidic GSLs include glycosylInositol phosphorylceramides (GIPCs), composed of phytosphingosine attached to a long or very long fatty acid chain (C18-26) and to diverse and complex glycan groups via an Inositol-phosphate linker. GIPCs are absent in mammalian cells, while fungal glucosylceramide and galactosylceramide are present but diverge structurally from their counterparts. Therefore, these compounds and their biosynthetic pathways represent potential targets for the development of selective therapeutic strategies. In this minireview, we discuss the enzymatic steps involved in the production of fungal GSLs, analyze their structure, and address the role of the currently characterized genes in the biology and pathogenesis of filamentous and dimorphic fungi.

Brain Lipopolysaccharide Preconditioning-Induced Gene Reprogramming Mediates a Tolerance State in Electroconvulsive Shock Model of Epilepsy.[Pubmed:29765321]

Front Pharmacol. 2018 May 1;9:416.

There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS). A total of 60 male Sprague Dawley rats were randomly assigned to five groups: control, vehicle (single and chronic), and LPS PC (single and chronic). We first recorded the data regarding the behavioral and histological changes. We further investigated the alterations of gene and protein expression of important mediators in relation to TLR4 and inflammatory signaling pathways. Interestingly, significant increased presence of NFkappaB inhibitors [Src homology 2-containing Inositol phosphatase-1 (SHIP1) and Toll interacting protein (TOLLIP)] was observed in LPS-preconditioned animals. This result was also associated with over-expression of IRF3 activity and anti-inflammatory markers, along with down-regulation of pro-inflammatory mediators. Summarizing, the analysis revealed that PC with LPS prior to seizure induction may have a neuroprotective effect possibly by reprogramming the signaling response to injury.

i-Inositol is a chemical compound, associated lipids are found in many foods, in particular fruit, especially cantaloupe and oranges.

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