Identification of inositol monophosphatase as a broad-spectrum antiviral target of ivermectin.

Ivermectin has broad-spectrum antiviral activities. Despite the failure in clinical application of COVID-19, it can serve as a lead compound for the development of more effective broad-spectrum antivirals, for which a better understanding of its antiviral mechanisms is essential. We thus searched for potential novel targets of ivermectin in host cells by label-free thermal proteomic profiling using Huh-7 cells. Inositol monophosphatase (IMPase) was found among the proteins with shifted thermal stability by ivermectin. Ivermectin could inhibit IMPase activity and reduce cellular myo-inositol and phosphatidylinositol-4-phosphate levels. On the other hand, inositol could impair the antiviral activity of ivermectin and lithium, an IMPase inhibitor with known antiviral activity. As phosphatidylinositol phosphate is crucial for the replication of many RNA viruses, inhibition of cellular myo-inositol biosynthesis may be an important antiviral mechanism of ivermectin. Hence, inhibition of IMPase could serve as a potential target for broad-spectrum antiviral development.

Inositol-Exchange Activity in Human Primordial Placenta.

Human placenta is an intensively growing tissue. Phosphatidylinositol (PI) and its derivatives are part of the signaling pathway in the regulation of trophoblast cell differentiation. There are two different enzymes that take part in the direct PI synthesis: phosphatidylinositol synthase (PIS) and inositol exchange enzyme (IE). The presence of PIS is known in the human placenta, but IE activity has not been documented before. In our study, we describe the physiological properties of the two enzymes in vitro. PIS and IE were studied in different Mn2+ and Mg2+ concentrations that enabled us to separate the individual enzyme activities. Enzyme activity was measured by incorporation of 3[H]inositol in human primordial placenta tissue or microsomes. Optimal PIS activity was achieved between 0.5 and 2.0 mM Mn2+ concentration, but higher concentrations inhibit enzyme activity. In the presence of Mg2+, the enzyme activity increases continuously up to a concentration of 100 mM. PIS was inhibited by nucleoside di- and tri-phosphates. PI production increases between 0.1 and 10 mM Mn2+ concentration. The incorporation of [3H]inositol into PI increased by 57% when adding stabile GTP analog. The described novel pathway of inositol synthesis may provide an additional therapeutic approach of inositol supplementation before and during pregnancy.

Deficiency of immunoglobulin IgSF6 enhances antibacterial effects by promoting endoplasmic reticulum stress and the inflammatory response in intestinal macrophages.

Immunoglobulin superfamily (IgSF) members are known for their role as glycoproteins expressed on the surface of immune cells, enabling protein-protein interactions to sense external signals during immune responses. However, the functions of immunoglobulins localized within subcellular compartments have been less explored. In this study, we identified an endoplasmic reticulum (ER)-localized immunoglobulin, IgSF member 6 (IgSF6), that regulates ER stress and the inflammatory response in intestinal macrophages. Igsf6 expression is sustained by microbiota and significantly upregulated upon bacterial infection. Mice lacking Igsf6 displayed resistance to Salmonella typhimurium challenge but increased susceptibility to dextran sulfate sodium-induced colitis. Mechanistically, deficiency of Igsf6 enhanced inositol-requiring enzyme 1α/-X-box binding protein 1 pathway, inflammatory response, and reactive oxygen species production leading to increased bactericidal activity of intestinal macrophages. Inhibition of reactive oxygen species or inositol-requiring enzyme 1α-X-box binding protein 1 pathway reduced the advantage of Igsf6 deficiency in bactericidal capacity. Together, our findings provide insight into the role of IgSF6 in intestinal macrophages that modulate the ER stress response and maintain intestinal homeostasis.

Activated Inositol Phosphate, Substrate for Synthesis of Prostaglandylinositol Cyclic Phosphate (Cyclic PIP)-The Key for the Effectiveness of Inositol-Feeding.

The natural cyclic AMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP), is biosynthesized from prostaglandin E (PGE) and activated inositol phosphate (n-Ins-P), which is synthesized by a particulate rat-liver-enzyme from GTP and a precursor named inositol phosphate (pr-Ins-P), whose 5-ring phosphodiester structure is essential for n-Ins-P synthesis. Aortic myocytes, preincubated with [3H] myo-inositol, synthesize after angiotensin II stimulation (30 s) [3H] pr-Ins-P (65% yield), which is converted to [3H] n-Ins-P and [3H] cyclic PIP. Acid-treated (1 min) [3H] pr-Ins-P co-elutes with inositol (1,4)-bisphosphate in high performance ion chromatography, indicating that pr-Ins-P is inositol (1:2-cyclic,4)-bisphosphate. Incubation of [3H]-GTP with unlabeled pr-Ins-P gave [3H]-guanosine-labeled n-Ins-P. Cyclic PIP synthase binds the inositol (1:2-cyclic)-phosphate part of n-Ins-P to PGE and releases the [3H]-labeled guanosine as [3H]-GDP. Thus, n-Ins-P is most likely guanosine diphospho-4-inositol (1:2-cyclic)-phosphate. Inositol feeding helps patients with metabolic conditions related to insulin resistance, but explanations for this finding are missing. Cyclic PIP appears to be the key for explaining the curative effect of inositol supplementation: (1) inositol is a molecular constituent of cyclic PIP; (2) cyclic PIP triggers many of insulin's actions intracellularly; and (3) the synthesis of cyclic PIP is decreased in diabetes as shown in rodents.

Effect of type and concentration of antioxidant on sperm motility, viability, and DNA integrity of climbing perch Anabas testudineus Bloch, 1792 (Pisces: Anabantidae) post-cryopreservation.

Sperm quality is preserved through the crucial involvement of antioxidants, which play a vital role in minimizing the occurrence of reactive oxygen species (ROS) during the cryopreservation process. The suitability of the type and concentration of antioxidants are species-dependent, and this study is crucial in order to improve the quality of the climbing perch sperm post-cryopreservation. Therefore, this study aimed to determine the best type and concentration of antioxidants for cryopreservation of climbing perch Anabas testudineus sperm. To achieve this, 6 types of antioxidants, namely, ascorbic acid, beta-carotene, glutathione, butylated hydroxytoluene (BHT), myo-inositol, and alpha-tocopherol, with inclusion of a control were tested in 3 replications at three concentration levels of 0 mg/L (control), 20 mg/L, 40 mg/L, and 60 mg/L. Sperm was diluted in a glucose-base extender at a ratio of 1:60 (sperm: glucose base), then 10 % DMSO and 5 % egg yolk was added before cryopreservation for two weeks. The results showed that the type and concentration of antioxidants had a significant effect on the motility and viability of cryopreserved climbing perch sperm (P < 0.05), where the best results for ascorbic acid, beta-carotene, glutathione, myo-inositol, and alpha-tocopherol were obtained at a concentration of 60 mg/L, while BHT was at a concentration of 20 mg/L. The best results for glutathione, myo-inositol, and alpha-tocopherol were significantly different from other treatments, while the best results for ascorbic acid and beta-carotene (60 mg/L) were not significantly different from the 40 mg/L concentration, while the best results for BHT were not significantly different from the control treatments. Therefore, the best concentration of glutathione, myo-inositol, and alpha-tocopherol was 60 mg/L, while for ascorbic acid and beta-carotene it was 40 mg/L, and BHT was not recommended. DNA integrity analysis indicated the absence of fragmentation in all samples, including fresh, control, and treated sperm. Based on practical and economic considerations, myo-inositol at 60 mg/L was recommended for cryopreservation of climbing perch A. testudineus sperm.

The Effects of Myo-Inositol and D-Chiro-Inositol in a Ratio 40:1 on Hormonal and Metabolic Profile in Women with Polycystic Ovary Syndrome Classified as Phenotype A by the Rotterdam Criteria and EMS-Type 1 by the EGOI Criteria.

SETTING: Insulin resistance (IR) and compensatory hyperinsulinemia are considered contributing factors toward polycystic ovary syndrome (PCOS). OBJECTIVES: This study evaluates the frequency of metabolic abnormalities in PCOS patients and the effects of myo-inositol (MI) and D-chiro-inositol (DCI), in a 40:1 ratio on hormonal and metabolic parameters. PARTICIPANTS: Thirty-four women with PCOS phenotype A (endocrine-metabolic syndrome [EMS-type 1]) between the ages of 20-40. DESIGN: Open prospective study with phenotype A (EMS-type I, n = 34) supplemented with 2,255 mg/day of inositol (MI and DCI in a 40:1 ratio) for 3 months. METHODS: The following were measured before and after treatment: serum levels of follicular stimulating hormone, luteinizing hormone (LH), estradiol, total and free testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), anti-Müllerian hormone, glucose, insulin, HOMA-IR, and body mass index (BMI). RESULTS: 55.9% of the enrolled patients were overweight or obese, 50% affected by IR, 17.6% with a history of gestational diabetes mellitus, and 61.8% had familial diabetes mellitus. At the conclusion of the study, BMI (p = 0.0029), HOMA-IR (p < 0.001) significantly decreased, along with decreased numbers of patients with elevated insulin levels. The supplementation resulted in decreased total testosterone (p < 0.001), free testosterone (p < 0.001), FAI (p < 0.001), and LH (p < 0.001); increased SHBG (p < 0.001) and estradiol (p < 0.001). LIMITATIONS: The present analysis was limited to a 12-week follow-up, which precluded a long-term evaluation of the effects of MI and DCI combination. Also, this period was insufficient to achieve and analyze clinical changes such as restoration of the menstrual cycle, restoration of reproductive function, and clinical manifestations of hyperandrogenism. CONCLUSIONS: Supplementation improved metabolic and hormonal profile in PCOS phenotype A (EMS-type I) patients. This builds upon previous work that demonstrated that combined inositol treatment may be effective in PCOS. The study presented herein, used a reduced concentration than in prior literature; however, a significant change in hormonal and metabolic parameters was still observed.

Antioxidant and Antidiabetic Potential of Ormocarpum cochinchinense (Lour.) Merr. Leaf: An Integrated In vitro and In silico Approach.

Diabetes is a prevalent metabolic disorder associated with various complications. Inhibition of α-glucosidase and α-amylase enzymes is an effective strategy for managing non-insulin-dependent diabetes mellitus. This study aimed to investigate the antioxidant and antidiabetic potential of Ormocarpum cochinchinense leaf through in vitro and in silico approaches. The methanol extract exhibited the highest phenolic and flavonoid content over solvent extracts aqueous, acetone, hexane, and chloroform, the same has been correlating with strong antioxidant activity. Furthermore, the methanol extract demonstrated significant inhibitory effects on α-amylase and α-glucosidase enzymes, indicating its potential as an antidiabetic agent. Molecular docking analysis identified compounds, including myo-inositol, with favorable binding energies comparable to the standard drug metformin. The selected compounds displayed strong binding affinity towards α-amylase and α-glucosidase enzymes. Structural dynamics analysis revealed that myo-inositol formed a more stable complex with the enzymes. These findings suggest that O. cochinchinense leaf possesses antioxidant and antidiabetic properties, making it a potential source for developing therapeutic agents.

Inositols in treating polycystic ovary syndrome and non-insulin dependent diabetes mellitus: now and the future.

INTRODUCTION: This Expert Opinion covers recent updates in the use of Inositol in polycystic ovary syndrome (PCOS) and type II diabetes and gives support to researchers and clinicians. AREAS COVERED: This article discusses the role of Myo-Inositol (MI) and D-Chiro-Inositol (DCI) in physiological function, the use of MI in PCOS, the risks of using DCI in reproductive conditions, the 40:1 combination of MI/DCI in PCOS. Furthermore, we discuss the issues of insulin resistance and how α-lactalbumin may increase the intestinal bioavailability of MI. The paper then transitions to talk about the use of inositols in diabetes, including type II diabetes, Gestational Diabetes Mellitus (GDM), and double diabetes. Literature searches were performed with the use of PubMed, Google Scholar, and Web of Science between July and October 2023. EXPERT OPINION: Inositol therapy has grown in the clinical field of PCOS, with it demonstrating an efficacy like that of metformin. The use of α-lactalbumin has further supported the use of MI, as issues with intestinal bioavailability have been largely overcome. In contrast, the effect of inositol treatment on the different PCOS phenotypes remains an outstanding question. The use of inositols in type II diabetes requires further study despite promising analogous data from GDM.

Acute and sub-acute metabolic change in different brain regions induced by moderate blunt traumatic brain injury.

The objective of the study was to observe the effect of moderate closed-head injury on hippocampal, thalamic, and striatal tissue metabolism with time. Closed head injury is responsible for metabolic changes. These changes can be permanent or temporary, depending on the injury's impact. For the experiment, 20 rats were randomly divided into four groups, each containing five animals. Animals were subjected to injury using a modified Marmarou's weight drop device; hippocampal, thalamic, and striatal tissue samples were collected after 1 day, 3 days, and 7 days of injury. NMR spectra were acquired following sample processing. Changes in myo-inositol, creatine, glutamate, succinate, lactate, and N-acetyl aspartic acid in hippocampal tissues were observed at day 3 PI. The tyrosine level in the hippocampus was altered at day 7 PI. While thalamic and striatal tissue samples showed altered levels of branched-chain amino acids and myo-inositol at day 1PI. Taurine, gamma amino butyric acid (GABA), choline, and alpha keto-glutarate levels were found to be significantly altered in striatal tissues at days 1 and 3PI. Acetate and GABA levels were altered in the thalamus on day 1 PI. The choline level in the thalamus was found to alter at all-time points after injury. The alteration in these metabolites may be due to the alteration in their respective pathways. Neurotransmitter and energy metabolism pathways were found to be altered in all three brain regions after TBI. This study may help better understand the effect of injury on the metabolic balance of a specific brain region and recovery.

The Jinggangmycin-induced Mthl2 gene regulates the development and stress resistance in Nilaparvata lugens Stål (Hemiptera: Delphacidae).

Methuselah (Mth) belongs to the GPCR family B, which regulates various biological processes and stress responses. The previous transcriptome data showed jinggangmycin (JGM)-induced Mthl2 expression. However, its detailed functional role remained unclear in brown planthopper, Nilaparvata lugens Stål. In adult N. lugens, the Mthl2 gene showed dominant expressions, notably in ovaries and fat body tissues. The 3rd instar nymphs treated with JGM increased starvation, oxidative stress, and high temperature (34 °C) tolerance of the adults. On the contrary, under dsMthl2 treatment, completely opposite phenotypes were observed. The lipid synthesis genes (DGAT1and PNPLA3) of both females and males treated with JGM in the nymphal stage were observed with high expressions, while the lipolysis of the Lipase 3 gene was observed with low expressions. The JGM increased triglyceride (TG) content, fat body droplet size, and the number of fat body droplets. The same treatment also increased the Glutathione S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) activities. An increase in the heat shock protein (HSP70 and HSP90) expression levels was also observed under JGM treatment but not dsMthl2. The current study demonstrated the influential role of the Mthl genes, particularly the Mthl2 gene, in modulating the growth and development and stress-responsiveness in N. lugens. Thus, providing a platform for future applied research programs controlling N. lugens population in rice fields.

Disruption of the inositol phosphorylceramide synthase gene affects Trypanosoma cruzi differentiation and infection capacity.

Sphingolipids (SLs) are essential components of all eukaryotic cellular membranes. In fungi, plants and many protozoa, the primary SL is inositol-phosphorylceramide (IPC). Trypanosoma cruzi is a protozoan parasite that causes Chagas disease (CD), a chronic illness for which no vaccines or effective treatments are available. IPC synthase (IPCS) has been considered an ideal target enzyme for drug development because phosphoinositol-containing SL is absent in mammalian cells and the enzyme activity has been described in all parasite forms of T. cruzi. Furthermore, IPCS is an integral membrane protein conserved amongst other kinetoplastids, including Leishmania major, for which specific inhibitors have been identified. Using a CRISPR-Cas9 protocol, we generated T. cruzi knockout (KO) mutants in which both alleles of the IPCS gene were disrupted. We demonstrated that the lack of IPCS activity does not affect epimastigote proliferation or its susceptibility to compounds that have been identified as inhibitors of the L. major IPCS. However, disruption of the T. cruzi IPCS gene negatively affected epimastigote differentiation into metacyclic trypomastigotes as well as proliferation of intracellular amastigotes and differentiation of amastigotes into tissue culture-derived trypomastigotes. In accordance with previous studies suggesting that IPC is a membrane component essential for parasite survival in the mammalian host, we showed that T. cruzi IPCS null mutants are unable to establish an infection in vivo, even in immune deficient mice.

Jinggangmycin stimulates reproduction and increases CHCs-dependent desiccation tolerance in Drosophila melanogaster.

Jinggangmycin (JGM), an agricultural antibiotic compound, is mainly used against the rice sheath blight (RSB) Rhizoctonia solani. However, its application may lead to unexpected consequences in insects. In this study, the effects of JGM on the physiological parameters of Drosophila melanogaster were investigated. The results showed that 0.005 g/ml JGM exposure increased female daily egg production and extended the oviposition period, while there was no significant effect on reproduction at 0.016 g/ml. At the same time, desiccation tolerance increased in flies fed 0.005 g/ml JGM. The RT-qPCR results revealed that FAS1 and FAS3 expression were upregulated in 0.005 g/ml JGM treated flies. Consistently, the amount of CHCs accumulated on the cuticle surface increased upon JGM treatment at 0.005 g/ml. Moreover, RNAi for FAS3 decreased desiccation tolerance of JGM-treated flies. These results suggest that JGM affects fatty acid biosynthesis, which in turn enhances reproduction and desiccation tolerance in Drosophila.

Effects of Dietary Supplementation of Arginine-Silicate- Inositol and Phytase Complex on Performance and Blood Biochemical Traits of Laying Hens.

Arginine silicate inositol complex (ASI; Arg = 49.47%, silicone = 8.2%, inositol = 25%) is a novel, bioavailable source of Si and Arg and may offer potential benefits for laying hens' performance. The aim of this study was to evaluate the effect of Arginine-Silicate and inositol/phytase on the performance of laying hens. A total of 90 laying hens, 25 weeks old, were randomly assigned to 6 treatments with 3 replicates (5 birds per replicate). The treatments were as follows: 1ST treatment PC: positive Control group (basal diet without additives (, 2nd treatment: basal diet +1000 mg/kg arginine-silicate complex (49.5±8.2 % respectively), 3d treatment: basal diet +1000 mg/kg arginine-silicate- inositol (ASI) complex (49.5, 8.2 , 25 % respectively) , 4th treatment: T 2 +500 FTU/kg , 5th treatment: T2 +1000 FTU/kg and 6th treatment: T2+2000 FTU/kg . Results indicate a significant increase (P<0.05) in hen house production (H.H. pro.%) of T5 (95.06 %)compared with T1(91.67%) and no significant differences between T2, T3, T4, T6 (91.84, 93.21, 93.46, 92.98%) and compared with T1 and T5. were no significant difference observed in average egg weight and egg mass between the experimental treatments all over the period. Daily feed intake (DFI) significantly decreased (P<0.05) with supplementing diets with deferent levels of phytase with arginine-silicate mixture T4, T5, andT6 (113.56،113.06، 112.10 g) compared with T1 (114.34 g ) which has no significant differences compared with T2 and T3 (113.96, 113.92 g). Phytase supplementation significantly (P<0.05) improved FCR g feed/egg in T5 (119.02) compared with T1 and T2 (124.89, 124.32), while no significant differences between T3.T4.T6 treatments (122.39, 121.80, 120.69) respectively and compared with other treatments. The experimental treatments observed no significant difference in g feed/ g egg.

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 human milk component myo-inositol promotes neuronal connectivity.

Effects of micronutrients on brain connectivity are incompletely understood. Analyzing human milk samples across global populations, we identified the carbocyclic sugar myo-inositol as a component that promotes brain development. We determined that it is most abundant in human milk during early lactation when neuronal connections rapidly form in the infant brain. Myo-inositol promoted synapse abundance in human excitatory neurons as well as cultured rat neurons and acted in a dose-dependent manner. Mechanistically, myo-inositol enhanced the ability of neurons to respond to transsynaptic interactions that induce synapses. Effects of myo-inositol in the developing brain were tested in mice, and its dietary supplementation enlarged excitatory postsynaptic sites in the maturing cortex. Utilizing an organotypic slice culture system, we additionally determined that myo-inositol is bioactive in mature brain tissue, and treatment of organotypic slices with this carbocyclic sugar increased the number and size of postsynaptic specializations and excitatory synapse density. This study advances our understanding of the impact of human milk on the infant brain and identifies myo-inositol as a breast milk component that promotes the formation of neuronal connections.

Opi1-mediated transcriptional modulation orchestrates genotoxic stress response in budding yeast.

In budding yeast, the transcriptional repressor Opi1 regulates phospholipid biosynthesis by repressing expression of genes containing inositol-sensitive upstream activation sequences. Upon genotoxic stress, cells activate the DNA damage response to coordinate a complex network of signaling pathways aimed at preserving genomic integrity. Here, we reveal that Opi1 is important to modulate transcription in response to genotoxic stress. We find that cells lacking Opi1 exhibit hypersensitivity to genotoxins, along with a delayed G1-to-S-phase transition and decreased gamma-H2A levels. Transcriptome analysis using RNA sequencing reveals that Opi1 plays a central role in modulating essential biological processes during methyl methanesulfonate (MMS)-associated stress, including repression of phospholipid biosynthesis and transduction of mating signaling. Moreover, Opi1 induces sulfate assimilation and amino acid metabolic processes, such as arginine and histidine biosynthesis and glycine catabolism. Furthermore, we observe increased mitochondrial DNA instability in opi1Δ cells upon MMS treatment. Notably, we show that constitutive activation of the transcription factor Ino2-Ino4 is responsible for genotoxin sensitivity in Opi1-deficient cells, and the production of inositol pyrophosphates by Kcs1 counteracts Opi1 function specifically during MMS-induced stress. Overall, our findings highlight Opi1 as a critical sensor of genotoxic stress in budding yeast, orchestrating gene expression to facilitate appropriate stress responses.

The Combination of Inositol Hexaphosphate and Inositol Inhibits Metastasis of Colorectal Cancer Cells by Upregulating Claudin 7.

Inositol hexaphosphate (IP6), a widely found natural bioactive substance in grains, effectively inhibits the progression of colorectal cancer (CRC) when used in combination with inositol (INS). We previously showed that supplementation of IP6 and INS upregulated the claudin 7 gene in orthotropic CRC xenografts in mice. The aim of this study was to elucidate the role of claudin 7 in the inhibition of CRC metastasis by IP6 and INS, and explore the underlying mechanisms. We found that IP6, INS and their combination inhibited the epithelial-mesenchymal transition (EMT) of colon cancer cell lines (SW480 and SW620), as indicated by upregulation of claudin 7 and E-cadherin, and downregulation of N-cadherin. The effect of IP6 and INS was stronger compared to either agent alone (combination index < 1). Furthermore, the silencing of the claudin 7 gene diminished the anti-metastatic effects of IP6 and INS on SW480 and SW620 cells. Consistent with in vitro findings, the combination of IP6 and INS suppressed CRC xenograft growth in a mouse model, which was neutralized by claudin 7. Taken together, the combination of IP6 and INS can inhibit CRC metastasis by blocking EMT of tumor cells through upregulation of claudin 7.

Application of Inositol Hexaphosphate and Inositol in Dental Medicine: An Overview.

Phosphorylated inositol hexaphosphate (IP6) is a naturally occurring carbohydrate, and its parent compound, myoinositol (Ins), is abundantly present in plants, particularly in certain high-fiber diets, but also in mammalian cells, where they regulate essential cellular functions. IP6 has profound modulation effects on macrophages, which warrants further research on the therapeutic benefits of IP6 for inflammatory diseases. Here, we review IP6 as a promising compound that has the potential to be used in various areas of dentistry, including endodontics, restorative dentistry, implantology, and oral hygiene products, due to its unique structure and characteristic properties. Available as a dietary supplement, IP6 + Ins has been shown to enhance the anti-inflammatory effect associated with preventing and suppressing the progression of chronic dental inflammatory diseases. IP6 in dentistry is now substantial, and this narrative review presents and discusses the different applications proposed in the literature and gives insights into future use of IP6 in the fields of orthodontics, periodontics, implants, and pediatric dentistry.

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

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Inositol possesses antifibrotic activity and mitigates pulmonary fibrosis.

BACKGROUND: Myo-inositol (or inositol) and its derivatives not only function as important metabolites for multiple cellular processes but also act as co-factors and second messengers in signaling pathways. Although inositol supplementation has been widely studied in various clinical trials, little is known about its effect on idiopathic pulmonary fibrosis (IPF). Recent studies have demonstrated that IPF lung fibroblasts display arginine dependency due to loss of argininosuccinate synthase 1 (ASS1). However, the metabolic mechanisms underlying ASS1 deficiency and its functional consequence in fibrogenic processes are yet to be elucidated. METHODS: Metabolites extracted from primary lung fibroblasts with different ASS1 status were subjected to untargeted metabolomics analysis. An association of ASS1 deficiency with inositol and its signaling in lung fibroblasts was assessed using molecular biology assays. The therapeutic potential of inositol supplementation in fibroblast phenotypes and lung fibrosis was evaluated in cell-based studies and a bleomycin animal model, respectively. RESULTS: Our metabolomics studies showed that ASS1-deficient lung fibroblasts derived from IPF patients had significantly altered inositol phosphate metabolism. We observed that decreased inositol-4-monophosphate abundance and increased inositol abundance were associated with ASS1 expression in fibroblasts. Furthermore, genetic knockdown of ASS1 expression in primary normal lung fibroblasts led to the activation of inositol-mediated signalosomes, including EGFR and PKC signaling. Treatment with inositol significantly downregulated ASS1 deficiency-mediated signaling pathways and reduced cell invasiveness in IPF lung fibroblasts. Notably, inositol supplementation also mitigated bleomycin-induced fibrotic lesions and collagen deposition in mice. CONCLUSION: These findings taken together demonstrate a novel function of inositol in fibrometabolism and pulmonary fibrosis. Our study provides new evidence for the antifibrotic activity of this metabolite and suggests that inositol supplementation may be a promising therapeutic strategy for IPF.