Inositol Research Articles

D-Pinitol Ameliorated Osteoporosis via Elevating D-chiro-Inositol Level in Ovariectomized Mice.

A natural sugar alcohol, D-pinitol, has been reported to be a potential compound for osteoporosis treatment via inhibiting osteoclastgenesis. However, research on the effects of pinitol on osteoporosis in vivo is still limited. The present study investigated the protective effects of pinitol on ovariectomized mice and attempted to elucidate this mechanism in vivo. Four-week-old female ovariectomized ICR mice were employed as a postmenopausal osteoporosis model and treated with pinitol or estradiol (E2) for 7 wk. Thereafter, serum calcium content, phosphorus content, tartrate-resistant acid phosphatase (TRAcP) and bone-specific alkaline phosphatase activity (BALP) were measured. Bilateral femurs were isolated, and bone marrow protein was collected through centrifuge. Dry femurs were weighed, while femur length, cellular bones, and bone mineral content were measured. D-chiro-Inositol (DCI) and myo-inositol (MI) content in serum and bone marrow was measured by GC-MS. At the end of experiment, the serum BALP and TRAcP activities of the OVX mice were suppressed significantly by treatment with either pinitol or E2. Femur weight, cellular bone rate, Ca and P content were improved by pinitol or E2. The DCI content of the serum of OVX decreased significantly, although it recovered to some extent after pinitol treatment. Pinitol significantly increased the ratio of DCI to MI in serum or bone marrow protein in the observed OVX mice. Besides, pinitol had no significant effects on osteoblast viability and differentiation. The present results showed that continuous pinitol intake exerts potent anti-osteoporosis activity via elevating DCI content in serum and bone marrow in OVX mice.

The effect of Daflon on Polycystic Ovary Syndrome Induced by Letrozole in the Rat model

Background: Polycystic ovary syndrome (PCOS) is a condition in which the ovaries produce an abnormal amount of androgens, male sex hormones that are usually present in women in small amounts. The name polycystic ovary syndrome describes the numerous small cysts (fluid-filled sacs) that form in the ovaries. Objective: This study aimed to evaluate the therapeutic role of Daflon versus myoinositol (MI) in improving the reproductive function in the rat model of PCOS. Methods: Oral letrozole(LTZ) combined with a high-fat diet for 21 days was used to induce the PCOS in Wister rats, group 1: 8 female Wister rats received only the vehicle C.M.C (carboxy methyl cellulose) for 21 days, group 2: received LTZ solution orally for 21days on daily bases(induction group) group 3: received LTZ for 21 days for PCOS induction than after that, Daflon 100mg/kg (DAF-H) for the next 21 days, group 4: recived LTA for 21 days for PCOS induction then received Daflon 50mg/kg (DAF-L) for the next 21 days, and group 5: recived LTZ for 21 days for PCOS induction then MI were administered for the following 21 days. Results: The LTZ-induced PCOS rats have lost their estrous cyclicity and become fixed at the diestrus phase, developed, abnormal sex and gonadotrophin hormone serum levels, increased cystic follicles, decreased number of the growing follicles, and very little or no corpora lutea on microscopic examination, which were reversed by the three drugs, DAF-H, DAF-L, and myoinositol.DAF-H and myoinositol were mostly equally effective in improving the reproductive manifestations of the disease. However, DAF-L was effective in returning the estrus cycle regulatory but yet not as effective in improving the condition compared to DAF-H and MI in this LTZ-induced model of PCOS. Conclusion: Daflon had the potential to ameliorate polycystic ovarian syndrome at the dose of 100mg/kg which is statistically comparable with myo-inositol. This property might be attributed to antioxidant activity of Daflon.

MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS

Abstract Medulloblastoma (MB) is the most common paediatric malignant brain tumour and is classified into four distinct molecular subgroups (WNT, SHH, G3 and G4), each of them further divided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes play an essential role in MB, particularly in the G4 subgroup. A BMI1High;CHD7Low molecular signature identifies patients with poor survival. We have shown that BMI1High;CHD7Low sustains MB growth through regulation of MAPK/ERK signalling and via epigenetic regulation of inositol metabolism in both G4 MB cells and patients. These tumours display over-activation of MAPK/ERK and AKT/mTOR pathways leading to energetic rewiring characterised by enhanced glycolytic capacity and reduced mitochondrial function. We demonstrate that inositol administration counteracts this metabolic alteration and significantly extends survival in an in vivo pre-clinical model. Additionally, we identify a synergistic vulnerability of G4 MB to a combination treatment with BMI1 and MAPK/ERK inhibitors that overcomes the acquired resistance induced by single drug therapies. Importantly, we have now analysed recurrent G4 MB and found that the BMI1High;CHD7Low signature is maintained at recurrence and it continues to predict the pharmacological vulnerabilities we previously described. Finally, we extended the analysis to other paediatric brain tumours, including histone mutant gliomas and ependymomas, and identified molecularly defined subgroups that exhibit differential response to the compounds predicted to be effective by the BMI1High;CHD7Low signature, hence expanding the spectrum of tumour potentially amenable to these novel pharmacological approaches.

Impact of carbocyclic sugar-based myo-inositol on conventional surfactants

Surfactants and inositol are examples of eco-friendly components that seem to be sustainable in chemistry. The hydrophilic portion of myo-inositol (MI) may be effective in increasing the superficial activity of the micellar systems. It is possible to modify and enhance the aggregation properties of surfactants by selecting suitable additives such as MI. The impact of carbocyclic sugar-based MI on conventional surfactants such as Triton X-100 (TX-100), cetyltrimethylammonium bromide (CTAB), and sodium dodecyl sulfate (SDS) was performed by electrical conductivity, viscometer, colorimetry, stalagmometer, dynamic light scattering (DLS) and FTIR methods. The main focus of this paper was to determine the critical micelle concentration (CMC), hydrodynamic radii (Rh), zeta potential (ζ), various interfacial parameters viz., the surface tension at CMC (γCMC), the surface pressure at CMC (πCMC), the efficiency of adsorption pC20, the minimum surface area per molecule (Amin), the maximum surface excess concentration (Гmax), and thermodynamic parameters i.e., the standard Gibbs free energy of adsorption (ΔG°ads), the standard Gibbs free energy of transfer (ΔG°trans), the standard Gibbs free energy of air–water interface (ΔGsmin), the standard Gibbs free energy of micellization (ΔGom), the standard Gibbs free energy of micellization per alkyl tail (ΔG°tail). A significant decrease in the CMC values of all conventional surfactants was reported with the addition of different concentrations of MI (mM) and its conformational study by colorimetric method. The higher negative values of ΔG°m and ΔG°ads have been shown the micellization and adsorption properties became more spontaneous. Relative viscosity-based rheological behaviour was calculated for various surfactant-MI systems. The DLS and FTIR spectra were used to reveal the improved micellization behaviour of conventional surfactant-MI systems. The FTIR data showed that the CTAB-MI and SDS-MI systems have significantly influenced the stretching frequency as compared to the TX-100-MI system. The present works will apply to drug delivery, agrochemical, molecular biology, and pharmaceutical sciences.

Myo-Inositol Attenuates Renal Interstitial Fibrosis in Obstructive Nephropathy by Inhibiting PI3K/AKT Activation.

Emerging evidence suggests that myo-inositol (MI) has a critical role in reducing renal inflammatory processes and improving podocyte function and preventing diabetes-related renal damage. We aimed to explore the function and underlying workings of MI in renal interstitial fibrosis (RIF). Based on a mouse model, we explored the effect of MI in unilateral ureteral obstruction (UUO) and in transforming growth factor-β1 (TGF-β1)-treated HK-2 cells. Pathological changes of the kidney tissues were examined following staining of the tissues with hematoxylin, eosin, and Masson's trichrome. The mRNA quantities of fibrosis markers, fibronectin, α-smooth muscle actin (α-SMA), and collagen I, were analyzed by means of real-time polymerase chain reaction, whereas those of protein levels were assessed with Western blotting. We also determined the expression of collagen I by immunofluorescence, and the levels of phosphorylated phosphotidylinositol-3-kinase and protein kinase B (PI3K/AKT) by Western blot. In vivo, histopathological examination in the UUO mice revealed renal tubular epithelial cell necrosis, inflammatory cell infiltration, and RIF. UUO mice showed higher expression levels of collagen I, fibronectin, α-SMA, pPI3K, and pAKT compared with sham-operated mice. However, MI treatment diminished the pathological alterations of RIF in UUO mice and downregulated the expression of fibrosis markers and phosphorylated PI3K/AKT. In vitro, TGF-β1 positively influenced the propagation and differentiation of HK-2 cells and upregulated the levels of α-SMA, fibronectin, collagen I, pPI3K, and pAKT, but these became significantly reversed by MI treatment. In conclusion, MI ameliorates RIF, possibly by negatively regulating TGF-β1-induced epithelial transdifferentiation and PI3K/AKT activation.

Effects of myo-inositol vs. metformin on hormonal and metabolic parameters in women with PCOS: a meta-analysis.

Polycystic Ovary Syndrome is the most prevalent hormonal disorder in females. Over the years, metformin (MET) has become the first-line choice of treatment; however, due to its gastrointestinal side effects, a more recent drug, myo-inositol (MI), has been introduced. We aim to conduct a systematic review and meta-analysis to compare the effects of MET and MI on hormonal and metabolic parameters. Authors extensively searched PubMed, Scopus, Cochrane Library, Google Scholar, and Web of Science for randomized clinical trials (RCTs) until August 2021. Eight (n = 8) articles were included, with a total sample size of 1088, of which 460 patients received MET, 436 received MI, and 192 received a combination of both. Standard mean differences (SMDs) and Confidence Intervals (CIs) were used for data synthesis, and forest plots were made using Review Manager 5.4 for Statistical Analysis using the random-effect model. The meta-analysis indicates that there is no significant difference between MET and MI in terms of their effects on BMI (SMD = 0.16, 95% CI: - 0.11 to 0.43, p = 0.24), fasting insulin (SMD = 0.00, 95% CI: - 0.26 to 0.27, p = 0.97), fasting blood sugar (SMD = 0.11, 95% CI: - 0.31to 0.53, p = 0.60), HOMA index (SMD = 0.09, 95% CI: - 0.20 to 0.39, p = 0.50), and LH/FSH (SMD = 0.20, 95% CI: - 0.24 to 0.64, p = 0.37). BMI, fasting blood sugar, and LH/FSH ratio reported moderate heterogeneity because of the varying number of study participants. Our meta-analysis comparing hormonal and metabolic parameters between MET and MI did not show much significant difference, indicating both drugs are equally beneficial in improving metabolic and hormonal parameters in patients with PCOS.

Alternative routes for production of the drug candidate d-chiro-inositol with Corynebacterium glutamicum using endogenous or promiscuous plant enzymes

d-chiro-Inositol (DCI) is a promising drug candidate for treating insulin resistance and associated diseases such as type 2 diabetes or polycystic ovary syndrome. In this study, we developed two production processes for DCI using Corynebacterium glutamicum as host. In the first process, myo-inositol (MI) is oxidized to 2-keto-myo-inositol (2KMI) by the inositol dehydrogenase (IDH) IolG and then isomerized to 1-keto-d-chiro-inositol (1KDCI) by the isomerases Cg0212 or Cg2312, both of which were identified in this work. 1KDCI is then reduced to DCI by IolG. Overproduction of IolG and Cg0212 in a chassis strain unable to degrade inositols allowed the production of 1.1 g/L DCI from 10 g/L MI. As both reactions involved are reversible, only a partial conversion of MI to DCI can be achieved. To enable higher conversion ratios, a novel route towards DCI was established by utilizing the promiscuous activity of two plant-derived enzymes, the NAD+-dependent d-ononitol dehydrogenase MtOEPa and the NADPH-dependent d-pinitol dehydrogenase MtOEPb from Medicago truncatula (barrelclover). Heterologous production of these enzymes in the chassis strain led to the production of 1.6 g/L DCI from 10 g/L MI. For replacing the substrate MI by glucose, the two plant genes were co-expressed with the endogenous myo-inositol-1-phosphate synthase gene ino1 either as a synthetic operon or using a novel, bicistronic T7-based expression vector. With the single operon construct, 0.75 g/L DCI was formed from 20 g/L glucose, whereas with the bicistronic construct 1.2 g/L DCI was obtained, disclosing C. glutamicum as an attractive host for of d-chiro-inositol production.

The Relationship of Coenzyme Q10, Myo Inositol, Astaxanthin and L-Arginine Values in Serum and Follicular Fluid with Icsi+Et and Pregnancy Outcomes

ÖZET Serum ve Foliküler Sıvıdaki Koenzim Q10, Myoinositol, Asta Ksantin ve L-Arginin Değerlerinin Icsı+Et ve Gebelik Sonuçları ile İlişkisi Amaç: Bu çalışmada, serumda ve oosit toplanması sırasında elde edilen folikül sıvısında Koenzim Q10, Myoinositol, Asta Ksantin ve L-Arginin değerlerinin oosit maturasyonu, fertilizasyon ve gebelik sonuçları üzerine etkilerini değerlendirmeyi, ayrıca eş zamanlı olarak serum ve foliküler sıvıdaki seviyeler ve diğer parametreler arasındaki korelasyonun değerlendirilmesi amaçlanmıştır. Bu değerlendirmede önemli sonuçlar elde edilir ise, yardımcı üreme teknolojisinin başarısını öngören uygun fiyatlı ve kolay erişilebilir bir test bulunacak, sağlıklı bir gebelikle sonuçlanan tedavi başarı oranları artacaktır. Gereç ve Yöntem: Ekim 2021 - Ekim 2022 tarihleri arasında kliniğimizde IVF protokolüne alınan 60 hastanın Gün-3 ile OPU günü alınan serumlarında ve toplanan folliküler sıvılarında Koenzim Q10, Myoinositol, Asta Ksantin ve L-Arginin değerleri çalışıldı. Koenzim Q10, Myoinositol, Asta Ksantin ve L-Arginin seviyelerinin oosit maturasyonu, fertilizasyon ve gebelik sonuçları ile ilişkisi istatiksel olarak değerlendirilmiştir. Bulgular: Matür oosit ve fertilize olan oosit sayıları ile serumdan ve folikülden bakılan Koenzim Q10, Myoinositol, Asta ksantin ve L-arginin değerleri arasında korelasyon saptanmamıştır( p<0.05). Toplam gonadotropin dozları ile toplanan oosit, matür oosit ve fertilize oosit sayıları arasında negatif koralasyon izlenmiştir ( p<0.05). Folliküler fazın 3. Günü alınan serumda, oosit toplama günü serumda ve folikülden bakılan Koenzim Q1O, Myoinositol ve L-arginin değerleri gebe kalan ve gebe kalmayanlar arasında anlamlı bir farklılık saptanmamıştır ( p<0.05). Folliküler fazın 3. Günü serumda bakılan Asta ksantin değeri ≤ 0,3035 olduğunda gebelik olasılığı daha yüksek bulunmuştur. Folliküler fazın 3. Günü alınan serumda, oosit toplama günü serumda ve folikülden bakılan Koenzim Q1O, Asta ksantin ve L-arginin değerlerinde klinik gebelik ve biyokimyasal gebelik geçirenler arasında anlamlı bir farklılık saptanmamıştır ( p<0.05). Oosit toplama günü serumda bakılan Myoinositol değeri ≥ 1,6555 olduğunda biyokimyasal gebelik olasılığı daha yüksek bulunmuştur. Sonuç: Araştırma hipotezimizin daha güçlü sonuçları için daha geniş hasta popülasyonları ile çalışmalara ihtiyaç vardır. Anahtar kelimeler: Folikül sıvısı, Serum, İnfertilite, İVF, Koenzim Q10, Myoinositol, Asta Ksantin, L-Arginin

Cyclitols: From Basic Understanding to Their Association with Neurodegeneration

One of the most common cyclitols found in eukaryotic cells—Myo-inositol (MI) and its derivatives play a key role in many cellular processes such as ion channel physiology, signal transduction, phosphate storage, cell wall formation, membrane biogenesis and osmoregulation. The aim of this paper is to characterize the possibility of neurodegenerative disorders treatment using MI and the research of other therapeutic methods linked to MI’s derivatives. Based on the reviewed literature the researchers focus on the most common neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Spinocerebellar ataxias, but there are also works describing other seldom encountered diseases. The use of MI, d-pinitol and other methods altering MI’s metabolism, although research on this topic has been conducted for years, still needs much closer examination. The dietary supplementation of MI shows a promising effect on the treatment of neurodegenerative disorders and can be of great help in alleviating the accompanying depressive symptoms.

Metabolic dysfunction correction as a method of restoring the function of the reproductive system in women

Insulin resistance is the main pathogenetic component of many metabolic diseases, including obesity, type 2 diabetes mellitus, gestational diabetes mellitus, and polycystic ovary syndrome (PCOS). Despite the fact that to date the mechanisms of insulin resistance formation have not been established, one of the promising directions at present is the search for potential therapeutic strategies for its correction, due to the fact that this also improves the course of the concomitant underlying disease. Insulin sensitizers are a generally recognized method of PCOS therapy due to their safety and effectiveness in normalizing the metabolic and endocrine profile of patients with polycystic ovary syndrome. The leading position in this direction is occupied by the combination of myo-inositol (MI) with D-chiro-inositol (DHI) in a ratio of 40:1, which, according to the conducted studies, is comparable to the concentration of inositols in the blood plasma of healthy women. This ratio of MI/DHI is effective both for normalization of the metabolic profile, and for regulation of the menstrual cycle and overcoming anovulatory infertility. An analysis of the literature has shown that a number of biologically active substances, such as folic acid, vitamin D and alpha-lipoic acid, in combination with insulin sensitizers, have additional advantages, which gives grounds for continuing research on their significance as components of combined treatment, as well as in the search for the optimal dose and duration of such therapy.

Target therapy of polycystic ovary syndrome

Due to the complexity of the diagnosis and treatment of polycystic ovary syndrome (PCOS) in adolescents, studies are currently underway to select targeted therapy to normalize the metabolic and reproductive status of girls, including those at risk for PCOS. There are a lot of researches, that evaluate the effectiveness of inositol therapy in PCOS, ovarian dysfunction, insulin resistance (IR), ovarian hyperandrogenism in both adolescents and adult women, including those in IVF cycles. Currently, the choice of determining the ratio of myo-inositol (MI) and d-chiro-inositol (DCI) for the treatment of PCOS often leads to the physiological proportion of inositols in plasma (40:1), since research results are insufficient to unambiguously confirm it. In this connection, there is a large number of pharmaceuticals without or with a low dosage of DCI, that can’t bypass the defective epimerase activity and achieve an adequate level of DCI in the ovaries. Determination of a fair assessment and dosage of MI/DCI is required for long-term correction of metabolic, endocrinological and clinical manifestations of various PCOS phenotypes. Inositols are promising and safe treatment of hyperandrogenism, obesity, insulin resistance in women of various age groups and can also effectively complement a therapeutic effect of metformin and combined oral contraceptives.

Abnormal immune system response in the brain of women with Fibromyalgia after experimental endotoxin challenge

BackgroundThe pathophysiology of fibromyalgia (FM) is thought to include an overactive immune system, leading to central nervous system sensitization, allodynia, and hyperalgesia. We aimed to test this theory using an experimental immune system activation procedure and neuroimaging with magnetic resonance spectroscopic imaging (MRSI). MethodsTwelve women with FM and 13 healthy women (healthy controls; HC) received 0.3 or 0.4 ng/kg endotoxin and underwent MRSI before and after the infusion. Changes in brain levels of choline (CHO), myo-inositol (MI), N-Acetylaspartate (NAA), and MRSI-derived brain temperature were compared between groups and dosage levels using mixed analyses of variance. ResultsSignificant group-by-time interactions in brain temperature were found in the right thalamus. Post-hoc testing revealed that brain temperature increased by 0.55 °C in the right thalamus in FM (t(10) = -3.483, p = 0.006), but not in HCs (p > 0.05). Dose-by-time interactions revealed brain temperature increases in the right insula after 0.4 ng/kg (t(12) = -4.074, p = 0.002), but not after 0.3 ng/kg (p > 0.05). Dose-by-time interactions revealed decreased CHO in the right Rolandic operculum after 0.4 ng/kg endotoxin (t(13) = 3.242, p = 0.006) but not 0.3 ng/kg. In the left paracentral lobule, CHO decreased after 0.3 ng/kg (t(9) = 2.574, p = 0.030) but not 0.4 ng/kg. Dose-by-time interactions affected MI in several brain regions. MI increased after 0.3 ng/kg in the right Rolandic operculum (t(10) = -2.374, p = 0.039), left supplementary motor area (t(9) = -2.303, p = 0.047), and left occipital lobe (t(10) = -3.757, p = 0.004), with no changes after 0.4 ng/kg (p > 0.05). Group-by time interactions revealed decreased NAA in the left Rolandic operculum in FM (t(13) = 2.664, p = 0.019), but not in HCs (p > 0.05). A dose-by-time interaction showed decreased NAA in the left paracentral lobule after 0.3 ng/kg (t(9) = 3.071, p = 0.013) but not after 0.4 ng/kg (p > 0.05). In the combined sample, there was a main effect of time whereby NAA decreased in the left anterior cingulate (F[1,21] = 4.458, p = 0.047) and right parietal lobe (F[1,21] = 5.457, p = 0.029). ConclusionWe found temperature increases and NAA decreases in FM that were not seen in HCs, suggesting that FM patients may have abnormal immune responses in the brain. The 0.3 and 0.4 ng/kg had differential effects on brain temperature and metabolites, with neither dose effecting a stronger response overall. There is insufficient evidence provided by the study to determine whether FM involves abnormal central responses to low-level immune challenges.

Phenotypic damage and transcriptomic responses of flower buds in rapeseed (Brassica napus L.) under low-temperature stress

Low temperature occurs frequently in the early spring during the flowering period of rapeseed (Brassica napus L.), which always results in yield loss of rapeseed. However, very little is known about the effects of cold on rapeseed during the early flowering stage. This study investigated the phenotypes and transcriptome profiles of two B. napus inbred lines (10B and GZH) in the early flowering stage. The ratio of pollen viability and stigma receptivity of cold-treated buds were detected on the flowering day, which were dramatically decreased before the binucleate period. Pollination experiments ascertained the same contributions to yield loss between cold damaged male and female parts. Furthermore, a total of 1396 differentially expressed genes (DEGs) were identified in flower buds under different cold treatments via RNA-seq. These genes were significantly enriched in biological processes related to photosynthesis, circadian rhythm, inositol metabolism, phenylpropanoid biosynthesis, response to temperature stimulus. According to gene expression patterns, functional annotations, and nucleotide variations, 104 DEGs were predicted as conservative genes responding to cold stresses in the buds of rapeseed, which were associated with abiotic stress response, photosynthesis, circadian rhythm, metabolisms (phenylpropanoid, polyamine, sugar, and lipid metabolisms), and gamete cell development. Based on these findings, a hypothetical model of rapeseed buds under low temperature conditions is proposed, in which rapeseed bud responds to low temperature through the CBF-dependent pathways and disordered biological metabolisms. This study will be useful for elucidating the molecular basis of the cold responsive mechanism of young buds in B. napus.

Expression of inflammatory genes, WBC-derived inflammatory biomarkers and liver function indices: Effects of myo-inositol supplementation in obese patients with NAFLD

Myo-inositol (MI) has known to exert anti-diabetic, anti-oxidative and anti-inflammatory properties. The present study examined the effects of MI supplementation on the expression of some inflammatory genes, serum high-sensitivity C-reactive protein (hs-CRP), WBC-derived inflammatory biomarkers, body composition and liver function in obese patients with non-alcoholic fatty liver disease (NAFLD). Forty-eight obese patients with NAFLD were randomly allocated into either MI (4 g/day) or placebo (maltodextrin 4 g/day) group along with dietary recommendations for 8 weeks. At the end of the study, reduction in fat mass and an increase in fat free mass were statistically greater in the MI group compared with placebo group. Moreover, MI supplementation resulted in a significant reduction in TNF-α mRNA expression, compared with placebo. Despite the decrease in systemic inflammation response index (SIRI) and monocytes to lymphocyte ratio (MLR) in the MI group, no differences were observed in other WBC-derived inflammatory markers as well as serum hs-CRP.

Protective Effects of Quercetin and Phytic Acid (Myo Inositol) on Cadmium Toxicity in Thyroid Gland of Albino Rats

Protective Effects of Quercetin and Phytic Acid (Myo Inositol) on Cadmium Toxicity in Thyroid Gland of Albino Rats

The Attenuation of Insulin/IGF-1 Signaling Pathway Plays a Crucial Role in the Myo-Inositol-Alleviated Aging in Caenorhabditis elegans.

Myo-Inositol (MI) has been shown to alleviate aging in Caenorhabditis (C). elegans. However, the mechanism by which MI alleviates aging remains unclear. In this study, we investigate whether MI can modulate the PI3K so as to attenuate the insulin/IGF-1 signaling (IIS) pathway and exert the longevity effect. The wild-type C. elegans and two mutants of AKT-1 and DAF-16 were used to explore the mechanism of MI so as to extend the lifespan, as well as to improve the health indexes of pharyngeal pumping and body bend, and an aging marker of autofluorescence in the C. elegans. We confirmed that MI could significantly extend the lifespan of C. elegans. MI also ameliorated the pharyngeal pumping and body bend and decreased autofluorescence. We further adopted the approach to reveal the loss-of-function mutants to find the signaling mechanism of MI. The functions of the lifespan-extending, health-improving, and autofluorescence-decreasing effects of MI disappeared in the AKT-1 and DAF-16 mutants. MI could also induce the nuclear localization of the DAF-16. Importantly, we found that MI could dramatically inhibit the phosphoinositide 3-kinase (PI3K) activity in a dose-dependent manner with an IC50 of 90.2 μM for the p110α isoform of the PI3K and 21.7 μM for the p110β. In addition, the downregulation of the PI3K expression and the inhibition of the AKT phosphorylation by MI was also obtained. All these results demonstrate that MI can inhibit the PI3K activity and downregulate the PI3K expression, and the attenuation of the IIS pathway plays a crucial role for MI in alleviating aging in C. elegans.

Optimal LC-MS metabolomic profiling reveals emergent changes to monocyte metabolism in response to lipopolysaccharide.

Immunometabolism examines the links between immune cell function and metabolism. Dysregulation of immune cell metabolism is now an established feature of innate immune cell activation. Advances in liquid chromatography mass spectrometry (LC-MS) technologies have allowed discovery of unique insights into cellular metabolomics. Here we have studied and compared different sample preparation techniques and data normalisation methods described in the literature when applied to metabolomic profiling of human monocytes. Primary monocytes stimulated with lipopolysaccharide (LPS) for four hours was used as a study model. Monocytes (n=24) were freshly isolated from whole blood and stimulated for four hours with lipopolysaccharide (LPS). A methanol-based extraction protocol was developed and metabolomic profiling carried out using a Hydrophilic Interaction Liquid Chromatography (HILIC) LC-MS method. Data analysis pipelines used both targeted and untargeted approaches, and over 40 different data normalisation techniques to account for technical and biological variation were examined. Cytokine levels in supernatants were measured by ELISA. This method provided broad coverage of the monocyte metabolome. The most efficient and consistent normalisation method was measurement of residual protein in the metabolite fraction, which was further validated and optimised using a commercial kit. Alterations to the monocyte metabolome in response to LPS can be detected as early as four hours post stimulation. Broad and profound changes in monocyte metabolism were seen, in line with increased cytokine production. Elevated levels of amino acids and Krebs cycle metabolites were noted and decreases in aspartate and β-alanine are also reported for the first time. In the untargeted analysis, 154 metabolite entities were significantly altered compared to unstimulated cells. Pathway analysis revealed the most prominent changes occurred to (phospho-) inositol metabolism, glycolysis, and the pentose phosphate pathway. These data report the emergent changes to monocyte metabolism in response to LPS, in line with reports from later time points. A number of these metabolites are reported to alter inflammatory gene expression, which may facilitate the increases in cytokine production. Further validation is needed to confirm the link between metabolic activation and upregulation of inflammatory responses.

Diet Control and Swimming Exercise Ameliorate HFD-Induced Cognitive Impairment Related to the SIRT1-NF-κB/PGC-1α Pathways in ApoE-/- Mice.

High-fat diet- (HFD-) induced neuroinflammation may ultimately lead to an increased risk of cognitive impairment. Here, we evaluate the effects of diet control and swimming or both on the prevention of cognitive impairment by enhancing SIRT1 activity. Twenty-week-old ApoE-/- mice were fed a HFD for 8 weeks and then were treated with diet control and/or swimming for 8 weeks. Cognitive function was assessed using the novel object recognition test (NORT) and Y-maze test. The expression of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), brain-derived neurotrophic factor (BDNF), nuclear factor kappa B p65 (NF-κB p65), interleukin-1β (IL-1β), and tumour necrosis factor-α (TNF-α) in the hippocampus was measured by western blotting. The levels of fractional anisotropy (FA), N-acetylaspartate (NAA)/creatine (Cr) ratio, choline (Cho)/Cr ratio, and myo-inositol (MI)/Cr ratio in the hippocampus were evaluated by diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) using 7.0-T magnetic resonance imaging (MRI). Our results showed that cognitive dysfunction and hippocampal neuroinflammation appeared to be remarkably observed in apolipoprotein E (ApoE)-/- mice fed with HFD. Diet control plus swimming significantly reversed HFD-induced cognitive decline, reduced the time spent exploring the novel object, and ameliorated spontaneous alternation in the Y-maze test. Compared with the HFD group, ApoE-/- mice fed diet control and/or subjected to swimming had an increase in FA, NAA/Cr, and Cho/Cr; a drop in MI/Cr; elevated expression levels of SIRT1, PGC-1α, and BDNF; and inhibited production of proinflammatory cytokines, including NF-κB p65, IL-1β, and TNF-α. SIRT1, an NAD+-dependent class III histone enzyme, deacetylases and regulates the activity of PGC-1α and NF-κB. These data indicated that diet control and/or swimming ameliorate cognitive deficits through the inhibitory effect of neuroinflammation via SIRT1-mediated pathways, strongly suggesting that swimming and/or diet control could be potentially effective nonpharmacological treatments for cognitive impairment.

Clinical effectiveness of α-lipoic acid, myo-inositol and propolis supplementation on metabolic profiles and liver function in obese patients with NAFLD: A randomized controlled clinical trial

To compare the effects of α-lipoic acid (ALA), myo-inositol (MI) and propolis supplementation on metabolic parameters and liver function in obese patients with non-alcoholic fatty liver disease (NAFLD) METHODS: Ninety-two obese patients with NAFLD were randomly allocated into one of the four groups (ALA, MI, propolis, and control groups) for 8 weeks. At pre-and post-intervention, anthropometric measures, metabolic parameters and liver function were assessed. Clinical effectiveness was assessed using Absolute Risk Reduction (ARR) and Number Needed to Treat (NNT). After 8 weeks, apart from waist-to-hip ratio, all studied anthropometric measures decreased significantly in each of the groups over the trial. Although the greatest improvements in glycemic indices were observed in MI group (p<0.05), the differences among the groups were not significant. Control group showed the greatest reduction in serum triglyceride level (p=0.026) while the greatest improvements in serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were observed in MI group (p=0.043, p=0.019 and p=0.041, respectively). Alanine aminotransferase (ALT) levels reduced significantly in all groups, particularly in propolis group (p=0.012). The greatest reduction in serum aspartate transaminase (AST) level was observed in control group (p<0.001), however, the difference among the groups was statistically marginal (p=0.058). The estimated NNTs for one grade reduction in liver steatosis for MI, ALA and propolis supplementation compared with control group were 1.5, 2.2 and 3, respectively. Dietary recommendation for weight loss accompanied by MI and then ALA supplementation improved metabolic parameters and liver steatosis. "Registered under ClinicalTrials.gov Identifier no: IRCT20100209003320N22".

Effect of aqueous solutions of KCl, MgCl2, Dextrose and Urea on solvation behavior of aqueous myo-Inositol

Owing to the indispensable role of myo-Inositol (MI), a cyclic polyol, in biological, pharmaceutical and food industries, in this investigation, we herewith report the systematic data of densities (ρ) and speed of sound (u) of MI in water, aqueous electrolytic (0.06 mol∙kg−1 KCl/MgCl2) and non-electrolytic (0.06 mol∙kg−1 Dextrose/Urea) solutions at seven different temperatures T/K (=288.15–318.15) and ambient pressure over the dilute concentration range of (0.03–0.2) mol∙kg−1. The experimental data of density (ρ) and speed of sound (u) were further processed to obtain respective derived parameters, such as apparent molar volume of solute Vϕ, isentropic compressibility of solution κs and apparent molar isentropic compression of the solute Ks,ϕ. The limiting values of apparent molar volume Vϕ0, apparent molar isentropic compression Ksϕ0 and apparent molar expansibility Eϕ0 of solute have been computed. Further, the coefficient of thermal expansion α∗, second order derivative of limiting apparent molal volume ∂2Vϕ0/∂T2, hydration number (nH) and transfer properties (ΔtrVϕ0andΔtrKs,ϕ0) of MI have also been obtained. An attempt has been made to analyse the molecular interactions through the coulomb attenuated hybrid exchange–correlation density functional theory (DFT) by gaussian tool. The effect of temperature and the studied electrolytic and non-electrolytic moieties (i.e., KCl, MgCl2, Dextrose and Urea) have been discussed in the light of prevailing interactions between solute-co-solute and solvent molecules on the basis of co-sphere overlap model.