Design and Evaluation of a Potential Non-Invasive Neurostimulation Strategy for Treating Persistent Anosmia in Post-COVID-19 Patients.

A new pandemic was declared at the end of 2019 because of coronavirus disease 2019 (COVID-19). One of the effects of COVID-19 infection is anosmia (i.e., a loss of smell). Unfortunately, this olfactory dysfunction is persistent in around 5% of the world's population, and there is not an effective treatment for it yet. The aim of this paper is to describe a potential non-invasive neurostimulation strategy for treating persistent anosmia in post-COVID-19 patients. In order to design the neurostimulation strategy, 25 subjects who experienced anosmia due to COVID-19 infection underwent an olfactory assessment while their electroencephalographic (EEG) signals were recorded. These signals were used to investigate the activation of brain regions during the olfactory process and identify which regions would be suitable for neurostimulation. Afterwards, 15 subjects participated in the evaluation of the neurostimulation strategy, which was based on applying transcranial direct current stimulation (tDCS) in selected brain regions related to olfactory function. The results showed that subjects with lower scores in the olfactory assessment obtained greater improvement than the other subjects. Thus, tDCS could be a promising option for people who have not fully regained their sense of smell following COVID-19 infection.

ChREBP-driven DNL and PNPLA3 Expression Induced by Liquid Fructose are Essential in the Production of Fatty Liver and Hypertriglyceridemia in a High-Fat Diet-Fed Rat Model.

SCOPE: The aim of this study is to delineate the contribution of dietary saturated fatty acids (FA) versus liquid fructose to fatty liver and hypertriglyceridemia. METHODS AND RESULTS: Three groups of female rats are maintained for 3 months in standard chow (CT); High-fat diet (46.9% of fat-derived calories, rich in palmitic and stearic FA, HFD); and HFD with 10% w/v fructose in drinking water (HFHFr). Zoometric parameters, plasma biochemistry, and liver Oil-Red O (ORO) staining, lipidomics, and expression of proteins involved in FA metabolism are analyzed. Both diets increase ingested calories without modifying body weight. Only the HFHFr diet increases liver triglycerides (x11.0), with hypertriglyceridemia (x1.7) and reduces FA ß-oxidation (x0.7), and increases liver FA markers of DNL (de novo lipogenesis). Whereas HFD livers show a high content of ceramides, HFHFr samples show unchanged ceramides, and an increase in diacylglycerols. Only the HFHFr diet leads to a marked increase in the expression of enzymes involved in DNL and triglyceride metabolism, such as carbohydrate response element binding protein ß (ChREBPß, x3.2), a transcription factor that regulates DNL, and patatin-like phospholipase domain-containing 3 (PNPLA3, x2.6), a lipase that mobilizes stored triglycerides for VLDL secretion. CONCLUSION: The addition of liquid-fructose to dietary FA is determinant in liver steatosis and hypertriglyceridemia production, through increased DNL and PNPLA3 expression, and reduced FA catabolism.

Arsenate removal from aqueous solution by montmorillonite and organo-montmorillonite magnetic materials.

Magnetic-clay (MtMag) and magnetic-organoclay (O100MtMag) nanocomposites were synthesized, characterized and evaluated for arsenic adsorption. Batch arsenic adsorption experiments were performed varying pH conditions and initial As(V) concentration, while successive adsorption cycles were made in order to evaluate the materials reuse. The highest As(V) removal efficiency (9 ± 1 mg g-1 and 7.8 ± 0.8 mg g-1 for MtMag and O100MtMag, respectively) was found at pH 4.0, decreasing at neutral and alkaline conditions. From As(V) adsorption isotherm, two adsorption processes or two different surface sites were distinguished. Nanocomposites resulted composed by montmorillonite or organo-montmorillonite and magnetite as the principal iron oxide, with saturation magnetization of 8.5 ± 0.5 Am2 Kg-1 (MtMag) and 20.3 ± 0.5 Am2 Kg-1 (O100MtMag). Thus, both materials could be separated and recovered from aqueous solutions using external magnetic fields. Both materials allowed achieving arsenic concentrations lower than the World Health Organization (WHO) recommended concentration limit after two consecutive adsorption cycles (2.25 and 4.5 µg L-1 for MtMag and O100MtMag, respectively).

Norfloxacin adsorption on montmorillonite and carbon/montmorillonite hybrids: pH effects on the adsorption mechanism, and column assays.

The presence of norfloxacin antibiotic (NFX) in drinking water raises significant scientific concern due to the health and environmental problems that may cause. This study aimed to evaluate the NFX removal: 1) in batch adsorption at different pH values on montmorillonite (M) and montmorillonite-carbon hybrids (M-HC); 2) in continuous columns experiments, to assess the technological application of these hybrids as domestic filters, using one M-HC as adsorbent material ranging from 1% to 5%. Batch experiments showed that adsorption occurred in all the samples, being M the material with the highest adsorption capacity (95% of adsorption for cationic NFX). For the M-HC the adsorption seemed to be not strongly dependent of the pH (20%- 41% of adsorption). The characterization of adsorbents and NFX adsorption products (FTIR, XRD, and zeta potential analysis) disclosed that adsorption occurs at both the external surface and the interlayer space of M. For the M-HC synthesized without activation, the interlayer space seemed to be predominantly responsible; while for the activated M-HC the adsorption occurred at the external surface (its interlayer was destroyed). The column experiments revealed that the best adsorption capacity and highest flow were attained using 1% of adsorbent material in the column packing.

Antimicrobial activities of bacterial cellulose - Silver montmorillonite nanocomposites for wound healing.

A nanocomposite based on bacterial cellulose (BC) containing montmorillonite (MMT) modified with silver (BC-MMT-Ag) was developed to be used as potential scaffold for wound healing. Montmorillonite was suspended in silver nitrate solution to incorporate silver in the matrix by ion exchange. The derivative silver clay suspension was used to modify bacterial cellulose membranes by ex situ technique. The BC nanocomposite was analyzed by thermal analysis, scanning electron microscopy, Fourier transform infrared and electron dispersion spectroscopies, X-ray diffraction, and rehydration capacity. The antimicrobial activity of the silver montmorillonite-bacterial cellulose nanocomposite was challenged in cultures of Gram(+) Staphylococcus aureus and Gram(-) Pseudomonas aeruginosa, and showed inhibition of growth in agar plates and biofilm formation as revealed by live-dead assay. Cytotoxicity of BC nanocomposites containing 1% to 25% of MMT-Ag showed good in vitro biocompatibility with L929 fibroblast cells.

Adsorption of picloram on clays nontronite, illite and kaolinite: equilibrium and herbicide-clays surface complexes.

The picloram (PCM) adsorption on nontronite, illite and kaolinite was studied at pH 3, 5 and 7. The adsorption isotherms had well-fitted to Langmuir and Freundlich models equations. The interactions of PCM with the clay mineral surfaces exhibited an anionic profile adsorption, with a decrease in adsorption when the pH increases. The PCM adsorption capacity increases in the following order: kaolinite < illite < nontronite. The X-ray diffraction (XRD) analysis of PCM-clay samples revealed that the picloram molecule does not enter into the clays basal space. The interaction of PCM with clays surface sites through nitrogen of the pyridine ring was confirmed by X-ray photoelectron spectroscopy (XPS). Due to the anionic form of PCM, the adsorption onto the external and edges surface sites of the clay minerals was proposed.

Kinetic and equilibrium adsorption of two post-harvest fungicides onto copper-exchanged montmorillonite: synergic and antagonistic effects of both fungicides' presence.

The simultaneous adsorption of both imazalil (IMZ) and thiabendazole (TBZ) fungicides in a Cu2+-exchanged Mt was studied in this work. Kinetic studies were used to determine the rate law which describes the adsorption of individual fungicides onto the adsorbent. Adsorption isotherm of individual and combined fungicides was done to evaluate synergic or antagonistic effects. The Mt-Cu material considerably improved TBZ and/or IMZ adsorption from aqueous suspensions with respect to raw Mt, leading to removal efficiencies higher than 99% after 10 min of contact time for TBZ and IMZ Ci = 15 and 40 mg/L, respectively, when a solid dosage = 1 g/L was used. The adsorption sites involved were determined by a combination of X-ray diffraction (XRD) determinations and electron paramagnetic resonance (EPR), indicating that fungicides were bonded to Cu2+ cations, while the rate limiting step was the formation of coordination bonds. The adsorption mechanism proposed is that of ligand exchange between water and fungicide molecules in the metal coordination sphere. The single-crystal structure for the IMZ-Cu2+ complex indicated that four molecules were bounded to the copper centers, while two molecules of TBZ are bounded to copper explaining the higher IMZ uptake capacity for the Mt-Cu material. Graphical abstract.

Some aspects of the adsorption of glyphosate and its degradation products on montmorillonite.

The most worldwide used herbicide is glyphosate, phosphonomethylglycine (PMG). Consequently, a significant amount of PMG, its metabolites (sarcosine, SAR, and aminomethylphosphonic acid, AMPA) and the degradation product, methylphosphonic acid (MPA), reaches the soil, which acts as final sink. Because clays are one of the most reactive components of soils, expansive clays such as montmorillonite (Mt) are used to retain agriculture contaminants with some success. In this work, as a preliminary step for the evaluation of the risk that PMG, SAR, AMPA, and MPA occurrence could have on the environment, their adsorption on Mt surface was performed. The adsorption process was analyzed at constant adsorbate concentrations and two pH values to take into account the different protonation states of the amino group. DTA, XRD, zeta potential measurements, and XPS were used to identify the interactions or association mechanisms with the clay surface, the entry of adsorbates into the Mt interlayer, and electric charge changes on the Mt surface, and evaluate the acid-base surface complex constants, respectively. The interlayer thickness in acid media indicated that adsorbates are able to enter the interlayer in planar form. Besides, for the Mt-PMG sample, some PMG molecules could be also inserted as a bilayer or with a tilt angle of 52.4° in the interlayer. However, in alkaline media, the interlayer thickness indicated that the adsorbate arrangement differed from that of acidic media where PMG and MPA could have more than one orientation. The surface complex deprotonation constants were determined for the =NH+2 â‡† =NH+H+ process, being 3.0, 5.0, and 7.3 for PMG, AMPA, and SAR, respectively.

Technological applications of organo-montmorillonites in the removal of pyrimethanil from water: adsorption/desorption and flocculation studies.

Pyrimethanil (2-aniline-4, 6-dimethylpyrimidine, PRM) is used in fruit packing plants to control fungal infections and diseases. The effluents greatly polluted with this fungicide, as a point source contamination, need to be technologically treated for their regeneration before they reach water bodies. This work evaluates the use of organo-montmorillonites, synthetized in our laboratory, for their application in adsorption and coagulation/flocculation processes for the removal of PRM from water. The adsorption-desorption performance of PRM in a raw montmorillonite (Mt) and several organo-montmorillonites (organo-Mt) obtained by different amounts and types of exchanged surfactants (octadecyltrimethylammonium (ODTMA) and didodecyldimethylammonium (DDAB) bromides and benzyltrimethylammonium chloride (BTMA)) was studied. The PRM adsorption on raw Mt was assigned mainly to an interlayer occupancy, while hydrophobic interactions between PRM and the surfactants in the exchanged samples increased PRM adsorption, which was correlated with the surfactant loading. PRM desorption showed irreversible behavior in raw Mt, which changed to reversible for organo-Mt samples, and was also correlated with the increase of surfactant loading.Two of the organo-Mt with high surfactant loading (twice the CEC) were assayed for the removal of commercial PRM in coagulation/flocculation tests, and their performance was compared to that of the native clay (Mt). The use of the organo-Mt produced flocculation at a very low ratio (0.5 g L-1), whereas no flocculation was observed with Mt. These results proved the feasibility of the use of organo-Mt for the treatment of wastewater contaminated with PRM using a low organo-Mt/liquid ratio.

Slow-release formulations of the herbicide picloram by using Fe-Al pillared montmorillonite.

Slow-release formulations of the herbicide picloram (PCM, 4-amino-3,5,6-trichloropyridine-2-carboxylic acid) were designed based on its adsorption on pillared clays (pillared clays (PILCs)) for reducing the water-polluting risk derived from its use in conventional formulations. Fe-Al PILCs were synthesized by the reaction of Na+-montmorillonite (SWy-2) with base-hydrolyzed solutions of Fe and Al. The Fe/(Fe + Al) ratios used were 0.15 and 0.50. The PCM adsorption isotherms on Fe-Al PILCs were well fitted to Langmuir and Freundlich models. The PCM adsorption capacity depended on the Fe content in the PILCs. Slow-release formulations were prepared by enhanced adsorption of the herbicide from PCM-cyclodextrin (CD) complexes in solution. CDs were able to enhance up to 2.5-fold the solubility of PCM by the formation of inclusion complexes where the ring moiety of the herbicide was partially trapped within the CD cavity. Competitive adsorption of anions such as sulfate, phosphate, and chloride as well as the FTIR analysis of PCM-PILC complexes provided evidence of formation of inner sphere complexes of PCM-CD on Fe-Al PILCs. Release of the herbicide in a sandy soil was lower from Fe-Al PILC formulations relative to a PCM commercial formulation.

Adsorption and characterization of MCPA on DDTMA- and raw-montmorillonite: Surface sites involved.

The 4-chloro-2-methylphenoxy acid (MCPA) is an herbicide widely used in agriculture, which generates a great concern about contamination of surface water and serious consequences for human health and the environment. In this work, the adsorption of MCPA on an Argentine montmorillonite (MMT) and its organo-montmorillonite product (OMMT) with different dodecyl trimethyl ammonium loading was investigated. MCPA adsorption on OMMT increases at least 3 times, with respect to the amount determined for MMT. X-ray diffraction and zeta potential analyses indicated the inner (interlayer) and outer surface participate as adsorption sites. Changes in surface electric charge and also interlayer expansion suggest that dimethyl amine (MCPA counterion) was also surface-adsorbed. The larger aggregates of OMMT, without and with MCPA, obtained compared to those of MMT samples, generate an improvement in the coagulation efficiency. This property, particularly after MCPA retention, allows an easier separation of the solids from the solution and enables a simple technological process application.

New insights on the structure of the picloram-montmorillonite surface complexes.

HYPOTHESIS: The environmental mobility and bioavailability of Picloram (PCM) are determined by the amine and carboxylate chemical groups interaction with the soils mineral phases. Clay particles, such as montmorillonite (Mt), and the pH value of the media could play an important role in adsorption processes. Thus, the study of the role of soil components other than organic matter deserves further investigation for a more accurate assessment of the risk of groundwater contamination. EXPERIMENTS: Samples with PCM adsorbed on Mt dispersions were prepared at pH 3-9. Subsequently, the dispersions were separated, washed, centrifuged and stored at room temperature. Picloram (PCM) herbicide interaction with surface groups of montmorillonite (Mt) was studied using XRD, DTA, FTIR and XPS techniques. FINDINGS: The entrance of PCM into the Mt basal space, in two different arrangements, perpendicular and planar, is proposed and the final arrangement depends on PCM concentration. The interaction of PCM with Mt surface sites through the nitrogen of the pyridine ring and carboxylic group of PCM, forming bidentate and bridge inner-sphere complexes was confirmed by FTIR and XPS analysis. The acidity constant of the PCM adsorbed on the Mt surface was calculated.

Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress.

Supplementation with 10% liquid fructose to female rats for 2weeks caused hepatic steatosis through increased lipogenesis and reduced peroxisome proliferator activated receptor (PPAR) α activity and fatty acid catabolism, together with increased expression of the spliced form of X-binding protein-1 (Rebollo et al., 2014). In the present study, we show that some of these effects are preserved after sub-chronic (8weeks) fructose supplementation, specifically increased hepatic expression of lipid synthesis-related genes (stearoyl-CoA desaturase, ×6.7-fold; acetyl-CoA carboxylase, ×1.6-fold; glycerol-3-phosphate acyltransferase, ×1.65-fold), and reduced fatty acid ß-oxidation (×0.77-fold), resulting in increased liver triglyceride content (×1.69-fold) and hepatic steatosis. However, hepatic expression of PPARα and its target genes was not modified and, further, livers of 8-week fructose-supplemented rats showed no sign of unfolded protein response activation, except for an increase in p-IRE1 levels. Hepatic mTOR phosphorylation was enhanced (×1.74-fold), causing an increase in the phosphorylation of UNC-51-like kinase 1 (ULK-1) (×2.8-fold), leading to a decrease in the ratio of LC3B-II/LC3B-I protein expression (×0.39-fold) and an increase in the amount of the autophagic substrate p62, indicative of decreased autophagy activity. A harmful cycle may be established in the liver of 8-week fructose-supplemented rats where lipid accumulation may cause defective autophagy, and reduced autophagy may result in decreased free fatty acid formation from triglyceride depots, thus reducing the substrates for ß-oxidation and further increasing hepatic steatosis. In summary, the length of supplementation is a key factor in the metabolic disturbances induced by fructose: in short-term studies, PPARα inhibition and ER stress induction are critical events, whereas after sub-chronic supplementation, mTOR activation and autophagy inhibition are crucial.

Liquid fructose downregulates Sirt1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells.

Fructose ingestion is associated with the production of hepatic steatosis and hypertriglyceridemia. For fructose to attain these effects in rats, simultaneous induction of fatty acid synthesis and inhibition of fatty acid oxidation is required. We aimed to determine the mechanism involved in the inhibition of fatty acid oxidation by fructose and whether this effect occurs also in human liver cells. Female rats were supplemented or not with liquid fructose (10% w/v) for 7 or 14 days; rat (FaO) and human (HepG2) hepatoma cells, and human hepatocytes were incubated with fructose 25mM for 24h. The expression and activity of the enzymes and transcription factors relating to fatty acid ß-oxidation were evaluated. Fructose inhibited the activity of fatty acid ß-oxidation only in livers of 14-day fructose-supplemented rats, as well as the expression and activity of peroxisome proliferator activated receptor α (PPARα). Similar results were observed in FaO and HepG2 cells and human hepatocytes. PPARα downregulation was not due to an osmotic effect or to an increase in protein-phosphatase 2A activity caused by fructose. Rather, it was related to increased content in liver of inactive and acetylated peroxisome proliferator activated receptor gamma coactivator 1α, due to a reduction in sirtuin 1 expression and activity. In conclusion, fructose inhibits liver fatty acid oxidation by reducing PPARα expression and activity, both in rat and human liver cells, by a mechanism involving sirtuin 1 down-regulation.

Liquid fructose down-regulates liver insulin receptor substrate 2 and gluconeogenic enzymes by modifying nutrient sensing factors in rats.

High consumption of fructose-sweetened beverages has been linked to a high prevalence of chronic metabolic diseases. We have previously shown that a short course of fructose supplementation as a liquid solution induces glucose intolerance in female rats. In the present work, we characterized the fructose-driven changes in the liver and the molecular pathways involved. To this end, female rats were supplemented or not with liquid fructose (10%, w/v) for 7 or 14 days. Glucose and pyruvate tolerance tests were performed, and the expression of genes related to insulin signaling, gluconeogenesis and nutrient sensing pathways was evaluated. Fructose-supplemented rats showed increased plasma glucose excursions in glucose and pyruvate tolerance tests and reduced hepatic expression of several genes related to insulin signaling, including insulin receptor substrate 2 (IRS-2). However, the expression of key gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, was reduced. These effects were caused by an inactivation of hepatic forkhead box O1 (FoxO1) due to an increase in its acetylation state driven by a reduced expression and activity of sirtuin 1 (SIRT1). Further contributing to FoxO1 inactivation, fructose consumption elevated liver expression of the spliced form of X-box-binding-protein-1 as a consequence of an increase in the activity of the mammalian target of rapamycin 1 and protein 38-mitogen activated protein kinase (p38-MAPK). Liquid fructose affects both insulin signaling (IRS-2 and FoxO1) and nutrient sensing pathways (p38-MAPK, mTOR and SIRT1), thus disrupting hepatic insulin signaling without increasing the expression of key gluconeogenic enzymes.

Chromium removal by zeolite-rich materials obtained from an exhausted FCC catalyst: Influence of chromium incorporation on the sorbent structure.

A spent FCC catalyst was converted into a zeolitic mixture, and the product obtained was afterward used as trapping material for Cr(III) species frequently found in aqueous solutions. Eventual changes in the sorbent structure produced by Cr incorporation were studied by different characterization techniques such as point of zero charge determinations (PZC), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), and infrared absorption (FTIR). The XRD and FTIR analyses indicated that chromium incorporation produces an amorphization of the material, and PZC measurements show no surface adsorption of charged chromium species. SEM and EDX analyses clearly show that after chromium sorption, the initial microspheroidal catalyst morphology was maintained, and the presence of chromium species was mainly detected in the outer microsphere surface, where the zeolite crystals were hydrothermally grown.

Liver AMP/ATP ratio and fructokinase expression are related to gender differences in AMPK activity and glucose intolerance in rats ingesting liquid fructose.

Women, but not men, show an association between fructose consumption and an increased risk of Type 2 diabetes mellitus. As rats are considered a model for human fructose metabolism, we sought to determine whether such a gender-related difference is present in Sprague-Dawley rats and to analyze the molecular mechanism behind. Male and female Sprague-Dawley rats had free access to water or to a 10% w/v fructose solution for 14 days. Plasma analytes, liver triglycerides and enzyme activities and the expression of enzymes and transcription factors related to fatty acid metabolism, insulin signaling and glucose tolerance were determined. Fructose-fed rats had hypertriglyceridemia, steatosis and reduced fatty acid oxidation activity, although the metabolic pattern of fructose-fed female rats was different to that observed for male rats. Fructose-fed female, but not male rats, showed no change in plasma leptin; they had hyperinsulinemia, an altered glucose tolerance test and less liver insulin receptor substrate-2. Further, only fructose-fed female rats had increased adenosine 5'-monophosphate (AMP)-activated protein kinase activity, resulting in a decreased expression of hepatic nuclear factor 4 and sterol response element binding protein 1. These differences were related to the fact that liver expression of the enzyme fructokinase, controlling fructose metabolism, was markedly induced by fructose ingestion in female, but not in male rats, resulting in a significant increase in the AMP/adenosine 5'-triphosphate (ATP) ratio and, thus, AMP-activated protein kinase activation, in female rats only. The difference in fructokinase induction could explain the higher metabolic burden produced by fructose ingestion in the livers of female Sprague-Dawley rats.

TGF-ß Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma.

Glioma-initiating cells (GICs), also called glioma stem cells, are responsible for tumor initiation, relapse, and therapeutic resistance. Here, we show that TGF-ß inhibitors, currently under clinical development, target the GIC compartment in human glioblastoma (GBM) patients. Using patient-derived specimens, we have determined the gene responses to TGF-ß inhibition, which include inhibitors of DNA-binding protein (Id)-1 and -3 transcription factors. We have identified a cell population enriched for GICs that expresses high levels of CD44 and Id1 and tend to be located in a perivascular niche. The inhibition of the TGF-ß pathway decreases the CD44(high)/Id1(high) GIC population through the repression of Id1 and Id3 levels, therefore inhibiting the capacity of cells to initiate tumors. High CD44 and Id1 levels confer poor prognosis in GBM patients.

Cyclooxygenase 2 inhibition exacerbates palmitate-induced inflammation and insulin resistance in skeletal muscle cells.

Palmitate-induced inflammation is involved in the development of insulin resistance in skeletal muscle cells. Here we evaluated the effect of the saturated fatty acid palmitate and the monounsaturated fatty acid oleate on Toll-like receptors (TLR)-2 and -4 and cyclooxygenase 2 (COX-2) expression and examined whether the inhibition of this enzyme modulates fatty acid-induced inflammation. Skeletal muscle cells exposed to palmitate showed enhanced TLR-2 and COX-2 mRNA levels, whereas oleate did not modify their expression. Palmitate-induced expression of these genes was dependent on nuclear factor (NF)-kappaB activation, because expression was reduced in the presence of the NF-kappaB inhibitor parthenolide. Coincubation of palmitate-exposed cells with oleate also prevented the increase in the expression of TLR-2 and COX-2, through a mechanism that may involve activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) by this monounsaturated fatty acid. COX-2 inhibition by NS-398 enhanced IL-6 and TNF-alpha expression and IL-6 protein secretion induced by palmitate. NF-kappaB binding activity and TNF-alpha mRNA levels were enhanced in palmitate-exposed cells in the absence or in the presence of NS-398, whereas coincubation of palmitate-exposed cells with NS-398 and prostaglandin E(2) (PGE(2)) prevented these changes. In contrast, 12-lypoxygenase and cytochrome P450 hydroxylase pathways were not involved in these changes. Similarly, COX-2 inhibition impaired insulin-stimulated Akt phosphorylation and 2-deoxy-D-[(14)C]glucose uptake in palmitate-exposed skeletal muscle cells, and this effect was abolished in the presence of PGE(2). These findings indicate that COX-2 activity, through the production of PGE(2), attenuates the fatty acid-induced inflammatory process and insulin resistance.

TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma.

Glioma-initiating cells (GICs) are responsible for the initiation and recurrence of gliomas. Here, we identify a molecular mechanism that regulates the self-renewal capacity of patient-derived GICs. We show that TGF-beta and LIF induce the self-renewal capacity and prevent the differentiation of GICs. TGF-beta induces the self-renewal capacity of GICs, but not of normal human neuroprogenitors, through the Smad-dependent induction of LIF and the subsequent activation of the JAK-STAT pathway. The effect of TGF-beta and LIF on GICs promotes oncogenesis in vivo. Some human gliomas express high levels of LIF that correlate with high expression of TGF-beta2 and neuroprogenitor cell markers. Our results show that TGF-beta and LIF have an essential role in the regulation of GICs in human glioblastoma.