Inter- and Intramolecular RNA-RNA Interactions Modulate the Regulation of Translation Mediated by the 3' UTR in West Nile Virus.

RNA viruses rely on genomic structural elements to accomplish the functions necessary to complete the viral cycle. These elements participate in a dynamic network of RNA-RNA interactions that determine the overall folding of the RNA genome and may be responsible for the fine regulation of viral replication and translation as well as the transition between them. The genomes of members of the genus Flavivirus are characterized by a complexly folded 3' UTR with a number of RNA structural elements that are conserved across isolates of each species. The present work provides evidence of intra- and intermolecular RNA-RNA interactions involving RNA structural elements in the 3' UTR of the West Nile virus genome. The intermolecular interactions can be visualized in vitro by the formation of molecular dimers involving the participation of at least the SLI and 3'DB elements. Certainly, the 3' UTR of dengue virus, which lacks the SLI element, forms molecular dimers in lower quantities via a single interaction site, probably 3'DB. The functional analysis of sequence or deletion mutants revealed an inverse relationship between 3' UTR dimerization and viral translation efficiency in cell cultures. A network of RNA-RNA interactions involving 3' UTR structural elements might therefore exist, helping to regulate viral translation.

Structure and function analysis of the essential 3'X domain of hepatitis C virus.

The 3'X domain of hepatitis C virus has been reported to control viral replication and translation by modulating the exposure of a nucleotide segment involved in a distal base-pairing interaction with an upstream 5BSL3.2 domain. To study the mechanism of this molecular switch, we have analyzed the structure of 3'X mutants that favor one of the two previously proposed conformations comprising either two or three stem-loops. Only the two-stem conformation was found to be stable and to allow the establishment of the distal contact with 5BSL3.2, and also the formation of 3'X domain homodimers by means of a universally conserved palindromic sequence. Nucleotide changes disturbing the two-stem conformation resulted in poorer replication and translation levels, explaining the high degree of conservation detected for this sequence. The switch function attributed to the 3'X domain does not occur as a result of a transition between two- and three-stem conformations, but likely through the sequestration of the 5BSL3.2-binding sequence by formation of 3'X homodimers.

The Genomic 3' UTR of Flaviviruses Is a Translation Initiation Enhancer.

Viruses rely on the cellular machinery of host cells to synthesize their proteins, and have developed different mechanisms enabling them to compete with cellular mRNAs for access to it. The genus Flavivirus is a large group of positive, single-stranded RNA viruses that includes several important human pathogens, such as West Nile, Dengue and Zika virus. The genome of flaviviruses bears a type 1 cap structure at its 5' end, needed for the main translation initiation mechanism. Several members of the genus also use a cap-independent translation mechanism. The present work provides evidence that the WNV 5' end also promotes a cap-independent translation initiation mechanism in mammalian and insect cells, reinforcing the hypothesis that this might be a general strategy of flaviviruses. In agreement with previous reports, we show that this mechanism depends on the presence of the viral genomic 3' UTR. The results also show that the 3' UTR of the WNV genome enhances translation of the cap-dependent mechanism. Interestingly, WNV 3' UTR can be replaced by the 3' UTR of other flaviviruses and the translation enhancing effect is maintained, suggesting a molecular mechanism that does not involve direct RNA-RNA interactions to be at work. In addition, the deletion of specific structural elements of the WNV 3' UTR leads to increased cap-dependent and cap-independent translation. These findings suggest the 3' UTR to be involved in a fine-tuned translation regulation mechanism.

Acute supplementation with grapes in obese subjects did not affect postprandial metabolism: a randomized, double-blind, crossover clinical trial.

PURPOSE: The aim of this study was to determine whether grape polyphenols have a "second-meal effect", modulating glucose and lipid elevations in the postprandial period after two successive meals in subjects with obesity. METHODS: A randomized, double-blind, placebo-controlled, acute clinical trial was conducted. Twenty-five obese subjects (BMI = ≥ 30 and < 40 kg/m2) were randomly divided into two groups. At an initial visit, blood was collected in a fasting state and the subjects received breakfast and 46 g of either grape powder (equivalent to 252 g fresh grapes) or placebo, both solved in water. Lunch was provided 5 h later and then blood was collected after 0, 30, 60, 120, 180, 240, 300, 330, 360, and 420 min since arrival. Two weeks later, at a second visit, the subjects received the other powder. The following were determined: glucose, insulin, triglycerides, uric acid, blood count, hemoglobin, viscosity, antioxidant capacity, and satiety perception. RESULTS: Postprandial increases were observed as expected in, for example, glucose and triglycerides after breakfast and lunch. The grape powder supplementation did not cause any significant modification compared to placebo, in these parameters; nor did it significantly modify plasma antioxidant capacity in the 6 h postprandial period. DISCUSSION: Single grape powder supplementation did not modify postprandial responses in obese subjects, probably because the polyphenol dose was insufficient to induce such an effect. The result of a combination of grape with other polyphenol-rich products or chronic supplementation with grape powder on postprandial responses remains to be elucidated. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov , NCT03741218.

Development of Optimized Inhibitor RNAs Allowing Multisite-Targeting of the HCV Genome.

Engineered multivalent drugs are promising candidates for fighting infection by highly variable viruses, such as HCV. The combination into a single molecule of more than one inhibitory domain, each with its own target specificity and even a different mechanism of action, results in drugs with potentially enhanced therapeutic properties. In the present work, the anti-HCV chimeric inhibitor RNA HH363-10, which has a hammerhead catalytic domain and an aptamer RNA domain, was subjected to an in vitro selection strategy to isolate ten different optimised chimeric inhibitor RNAs. The catalytic domain was preserved while the aptamer RNA domain was evolved to contain two binding sites, one mapping to the highly conserved IIIf domain of the HCV genome's internal ribosome entry site (IRES), and the other either to IRES domain IV (which contains the translation start codon) or the essential linker region between domains I and II. These chimeric molecules efficiently and specifically interfered with HCV IRES-dependent translation in vitro (with IC50 values in the low µM range). They also inhibited both viral translation and replication in cell culture. These findings highlight the feasibility of using in vitro selection strategies for obtaining improved RNA molecules with potential clinical applications.

New Alternatives in Seafood Restructured Products.

A general overview, focusing on new trends in the different techniques used in restructured seafood product processing has been described in this work. Heat-induced gelation has been more widely studied in scientific literature than cold gelation technology. This latter technology includes the use of hydrocolloids (alginates and glucomannan) or enzymes (microbial transglutaminase) for making both raw and cooked restructured products. In restructuration processes, fortification processing with some functional ingredients is studied, giving as a result extra value to the products as well as increasing the variety of new seafood products. The process of alleviating heavy metals and organic pollutants from the raw material used has also been reviewed in the present paper.

RNA Aptamers as Molecular Tools to Study the Functionality of the Hepatitis C Virus CRE Region.

BACKGROUND: Hepatitis C virus (HCV) contains a (+) ssRNA genome with highly conserved structural, functional RNA domains, many of them with unknown roles for the consecution of the viral cycle. Such genomic domains are candidate therapeutic targets. This study reports the functional characterization of a set of aptamers targeting the cis-acting replication element (CRE) of the HCV genome, an essential partner for viral replication and also involved in the regulation of protein synthesis. METHODS: Forty-four aptamers were tested for their ability to interfere with viral RNA synthesis in a subgenomic replicon system. Some of the most efficient inhibitors were further evaluated for their potential to affect the recruitment of the HCV RNA-dependent RNA polymerase (NS5B) and the viral translation in cell culture. RESULTS: Four aptamers emerged as potent inhibitors of HCV replication by direct interaction with functional RNA domains of the CRE, yielding a decrease in the HCV RNA levels higher than 90%. Concomitantly, one of them also induced a significant increase in viral translation (>50%). The three remaining aptamers efficiently competed with the binding of the NS5B protein to the CRE. CONCLUSIONS: Present findings confirm the potential of the CRE as an anti-HCV target and support the use of aptamers as molecular tools for investigating the functionality of RNA domains in viral genomes.

Integrin-linked kinase regulates vasomotor function by preventing endothelial nitric oxide synthase uncoupling: role in atherosclerosis.

RATIONALE: Atherosclerotic lesions develop in regions of disturbed flow, whereas laminar flow protects from atherogenesis; however, the mechanisms involved are not completely elucidated. Integrins are mechanosensors of shear stress in endothelial cells, and integrin-linked kinase (ILK) is important for blood vessel integrity and cardiovascular development. OBJECTIVES: To explore the role of ILK in vascular function by studying conditionally ILK-deficient (cKO) mice and human atherosclerotic arteries. RESULTS: ILK expression was detected in the endothelial cell layer of nonatherosclerotic vessels but was absent from the endothelium of atherosclerotic arteries. Live ultrasound imaging revealed that acetylcholine-mediated vasodilatation was impaired in cKO mice. These mice exhibited lowered agonist-induced nitric oxide synthase (NOS) activity and decreased cyclic guanosine monophosphate and nitrite production. ILK deletion caused endothelial NOS (eNOS) uncoupling, reflected in reduced tetrahydrobiopterin (BH4) levels, increased BH2 levels, decreased dihydrofolate reductase expression, and increased eNOS-dependent generation of superoxide accompanied by extensive vascular protein nitration. ILK reexpression prevented eNOS uncoupling in cKO cells, whereas superoxide formation was unaffected by ILK depletion in eNOS-KO cells, indicating eNOS as a primary source of superoxide anion. eNOS and ILK coimmunoprecipitated in aortic lysates from control animals, and eNOS-ILK-shock protein 90 interaction was detected in human normal mammary arteries but was absent from human atherosclerotic carotid arteries. eNOS-ILK interaction in endothelial cells was prevented by geldanamycin, suggesting heat shock protein 90 as a binding partner. CONCLUSIONS: Our results identify ILK as a regulatory partner of eNOS in vivo that prevents eNOS uncoupling, and suggest ILK as a therapeutic target for prevention of endothelial dysfunction related to shear stress-induced vascular diseases.

Olive Pomace Oil Structuring for the Development of Healthy Puff Pastry Laminating Fats: The Effect of Chilling Storage on the Quality of Baked Products.

Developing puff pastry (PP) laminating fats (LFs) with sustainable structured olive pomace oil (OPO) could contribute to its increased valorization. This study evaluated the physicochemical stability of four OPO-based LFs or margarines and the performance of their baked PP counterparts during two months of chilling storage at 4 °C. LF samples, developed at the laboratory scale, contained 41% (LF1 and LF2) OPO and 31% (LF3 and LF4) OPO together with 10% cocoa butter when using two static initial crystallization conditions (room temperature for LF1 and LF3, freezer for LF2 and LF4) before storage. During the storage period, the proximate composition, thermal and dynamic rheological properties, firmness and spreadability, oil-binding capacity, color, and lipid oxidation of the four LF samples were examined, along with the baking performance and textural properties of the PP counterparts. The initial cooling rate had minimal significance. Cocoa butter negatively influenced post-crystallization processes occurring in OPO-based LF3 and LF4, resulting in increased hardness and reduced performance after 18 days of storage, attributed, at least partially, to a high amount of 1,3-dipalmitoyl-2-oleoyl-glycerol (POP), mainly from cocoa butter. Conversely, OPO-based LF1 and LF2 maintained their quality and were stable for two months without apparent granular crystal formation.

Enriching Eggs with Bioactive Compounds through the Inclusion of Grape Pomace in Laying Hens Diet: Effect on Internal and External Egg Quality Parameters.

(1) Background: Grapes and their associated by-products (such as grape pomace, GP) stand out for their polyphenol content, which makes them a source of bioactive compounds with antioxidant capacity. The aim of this research was to determine if the inclusion of 50 g/kg of GP in the diet of hens could enrich eggs with antioxidants and to study its effect on internal and external egg quality parameters. (2) Methods: A trial was conducted with two genetic lines of hens, which were fed either a control diet or a diet containing 50 g/kg of GP. Performance, internal and external egg quality, and egg yolk content of vitamins E and A and gallic acid were determined. (3) Results: In eggs laid by hens fed a GP diet, Haugh units and yolk color scores were enhanced, and eggshells became thinner, but without affecting the breaking strength. No dietary effect was observed on the vitamin contents of the yolk. A higher gallic acid content was observed in the yolks of eggs laid by hens fed the GP diet, suggesting that some dietary phenolic compounds could be transferred to the eggs. Hen genetics influenced egg weight, albumen Haugh units, shell thickness, and α- and γ-tocopherol concentration in yolks. (4) Conclusions: Dietary inclusion of GP improved the internal quality of eggs, enriching yolks with a phenolic compound but reducing shell thickness.

Recruitment of the 40S ribosomal subunit by the West Nile virus 3' UTR promotes the cross-talk between the viral genomic ends for translation regulation.

Flaviviral RNA genomes are composed of discrete RNA structural units arranged in an ordered fashion and grouped into complex folded domains that regulate essential viral functions, e.g. replication and translation. This is achieved by adjusting the overall structure of the RNA genome via the establishment of inter- and intramolecular interactions. Translation regulation is likely the main process controlling flaviviral gene expression. Although the genomic 3' UTR is a key player in this regulation, little is known about the molecular mechanisms underlying this role. The present work provides evidence for the specific recruitment of the 40S ribosomal subunit by the 3' UTR of the West Nile virus RNA genome, showing that the joint action of both genomic ends contributes the positioning of the 40S subunit at the 5' end. The combination of structural mapping techniques revealed specific conformational requirements at the 3' UTR for 40S binding, involving the highly conserved SL-III, 5'DB, 3'DB and 3'SL elements, all involved in the translation regulation. These results point to the 40S subunit as a bridge to ensure cross-talk between both genomic ends during viral translation and support a link between 40S recruitment by the 3' UTR and translation control.

Functionality of Puff Pastry Olive Pomace Oil-Based Margarines and Their Baking Performance.

Designing healthier lipids is a current approach to developing potential functional foods. Olive pomace oil (OPO) has beneficial effects on human health, attributed to its high oleic acid content and unique bioactive compounds. Four puff pastry margarines (PP-M), based on OPO (M1, M2 at 40.8%, and M3, M4 at 30.8%, and cocoa butter at 10%) combined with low molecular weight organogelators, were prepared using two initial cooling rates (M1, M3 at 0.144 °C/min and M2, M4 at 0.380 °C/min) and compared to both commercial puff pastry (PP) butter (CB) and fatty preparation (CFP). Subsequently, six baked PP counterparts were elaborated. Physical-chemical, mechanical properties, and lipid profiles were analyzed in M1-M4 and PP, while thermal properties were determined in M1-M4. Sensory analysis was carried out in PP-M1 and PP-M3 counterparts. Elasticity (G') of M1-M4 samples was between that of controls CB and CFP, although a higher OPO content reduced viscous modulus (G″). The initial cooling rate did not affect the melting behavior of M1-M4. The firmness of PP-M1 was similar to that of PP-CB and PP-CFP, and the better spreadability and plasticity of M1 positively favored PP puffing. In addition, PP-M1 had 36.8% less SFA content than baked PP-CB, and its overall acceptability was similar. For the first time, a new margarine with high OPO content, showing adequate firmness, spreadability, and plasticity, was formulated, which gave rise to PP with appropriate performance and sensory quality and a healthy lipid profile.

Development and Physico-Chemical Characterization of Healthy Puff Pastry Margarines Made from Olive-Pomace Oil.

Due to its characteristic aroma and flavor, puff pastry (PP) prepared with butter is more accepted than that made with margarine, yet a high saturated fat consumption is associated with cardiovascular disease. This work studies the potential of olive-pomace oil (OPO) as main ingredient of PP margarines together with different organogelator agents to imitate the technological properties of a commercial fatty preparation (CFP). Rheological and textural properties were measured in all formulated margarines (FM) and, additionally, thermal and microstructural properties, and fatty acid (FA) profiles were analyzed in some selected FM. The different FM had viscous modulus (G″) and loss factor (tan δ) values lower than those of CFP, thus reflecting a different viscoelasticity and plasticity. The crystallization and melting temperatures of FM were also different from those of CFP, indicating the presence of a dissimilar polymorphic fat-crystal structure. Nevertheless, the FM containing an oleogel prepared with 5% beeswax and OPO was more similar to CFP. The FA profile of CFP and FM, with 80% polyunsaturated fatty acids (PUFA) and 60% oleic acid, is healthier than that of a PP commercial butter (CB), evidencing that, although improvements in margarine plasticity are still necessary, OPO is technologically viable to produce healthier PP margarines.

Insights on the effect of age and gender on in-mouth volatile release during wine tasting.

This study focus for the first time, in looking for age-gender effects on in vivo volatile release during wine consumption, also considering oral physiological differences (e.g. saliva composition). To do so, the in-mouth Head Space Sorptive Extraction technique was used, which allowed monitoring the oral release of twenty-four different types of volatile compounds from white and red wines. Thirty-two individuals (n = 32) males and females, belonging to two different age groups: young (18-35 y.o) and senior (>55 y.o.) participated in this analytical in vivo study. Results showed differences in volatile release among age-gender groups, which also depended on the volatile compound and wine type. Senior groups (SM, SF) showed a similar release behaviour among them. Contrarily, young males showed a higher release (between 10 and 29%) of alcohols and esters indistinctly of the wine type, while young females showed the lowest oral volatile release among the four age-gender groups. Gender differences in volatile release were more evident in young than in seniors. A higher release of furanic compounds (furfural and 5-methyl furfural) in seniors was likely related to differences in their saliva composition (total protein content, minerals (Mg, Zn) and α-amylase activity).

Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas.

The extraordinary plasticity of glioma cells allows them to contribute to different cellular compartments in tumor vessels, reinforcing the vascular architecture. It was recently revealed that targeting glioma-derived pericytes, which represent a big percentage of the mural cell population in aggressive tumors, increases the permeability of the vessels and improves the efficiency of chemotherapy. However, the molecular determinants of this transdifferentiation process have not been elucidated. Here we show that mutations in EGFR stimulate the capacity of glioma cells to function as pericytes in a BMX- (bone marrow and X-linked) and SOX9-dependent manner. Subsequent activation of platelet-derived growth factor receptor beta in the vessel walls of EGFR-mutant gliomas stabilized the vasculature and facilitated the recruitment of immune cells. These changes in the tumor microenvironment conferred a growth advantage to the tumors but also rendered them sensitive to pericyte-targeting molecules such as ibrutinib or sunitinib. In the absence of EGFR mutations, high-grade gliomas were enriched in blood vessels, but showed a highly disrupted blood-brain barrier due to the decreased BMX/SOX9 activation and pericyte coverage, which led to poor oxygenation, necrosis, and hypoxia. Overall, these findings identify EGFR mutations as key regulators of the glioma-to-pericyte transdifferentiation, highlighting the intricate relationship between the tumor cells and their vascular and immune milieu. Our results lay the foundations for a vascular-dependent stratification of gliomas and suggest different therapeutic vulnerabilities determined by the genetic status of EGFR. SIGNIFICANCE: This study identifies the EGFR-related mechanisms that govern the capacity of glioma cells to transdifferentiate into pericytes, regulating the vascular and immune phenotypes of the tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2142/F1.large.jpg.

Assessment of the Miniature Kramer Shear Cell to Measure Both Solid Food and Bolus Mechanical Properties and Their Interplay with Oral Processing Behavior.

This study assessed the usefulness of the miniature Kramer shear cell to determine relevant instrumental parameters of solid foods and bolus counterparts, examining their relationships with oral processing behaviors to obtain greater knowledge about the texture perception process. Six solid foods with different textural properties were tested. Bolus mechanical properties were also determined by means of cone penetration tests and rheological measurements, and their particle size distributions by sieving. Oral processing behavior (chewing time, number of chews, chewing rate, eating rate) and food saliva uptake (SU) of a young volunteer and a panel of 39 untrained participants were analyzed. The Kramer mechanical properties were very suitable for detecting different levels of food and bolus textural hardness and fracturability and the associated degrees of fragmentation achieved during mastication. Chewing time and number of chews were highly correlated with Kramer food and bolus mechanical properties for the single subject and for the panel's oral processing behaviors. For the single subject, SU and eating rate also showed strong correlations with food and bolus mechanical properties, unlike chewing rate and food moisture content (FMC). In contrast, eating rate, FMC, and SU did not vary with the oral activities of the panel.

Understanding the crispy-crunchy texture of raw red pepper and its change with storage time.

Red sweet peppers held in cold storage were periodically sampled at 1-week intervals over a 3-weeks period using three-point bending, puncture, cutting, and Volodkevich (coupled with acoustic emission) tests, confocal laser scanning microscopy (CLSM) and other physicochemical measurements. At each sampling, tissue specimens were soaked in mannitol solutions (0.0-0.9M) and puncture test, dimension changes and CLSM were used to identify degrees of turgidity present in osmotically manipulated pepper tissue. Pepper texture became crumbly with increased storage time due to softening and wilting processes. The Young's modulus, derived from the bending test using the single-edge notched bend geometry without notches decreased progressively during cold storage and resulted as the best mechanical parameter for measuring the loss of whole-tissue stiffness by both decreased cell wall stiffness and turgor pressure. Osmotic adjustment indicated that the pepper structure is extremely anisotropic, with the specimen's "average" relative thickness (RT) being the dimension change more affected. Incipient plasmolysis was evident in the highest mannitol concentration (0.9M), therefore, the turgor pressure of nonsoaked tissue could not be inferred. However, significant correlations were found between RT and puncture parameters such as initial slope, initial and final distances, and the number of flesh and skin force peaks, which depended on the dilation or shrinkage caused by the osmotic adjustment. During storage, soaked tissues had lower crunchy texture than nonsoaked, reflecting that cell wall stiffness plays a more significant role in determining pepper crunchiness than cell turgor pressure.

The Effect of Emulsifying Protein and Addition of Condensed Tannins on n-3 PUFA Enriched Emulsions for Functional Foods.

This paper examines the effect of the type of the emulsifying protein (EP) (sodium caseinate (SC) and whey protein isolate (WPI)) on both oil-in-water liquid-like emulsions (Es) and the corresponding cold gelled emulsions (GEs), and also the effect of addition of carob extract rich in condensed tannins (T). The systems, intended as functional food ingredients, were studied in various different respects, including rheological behaviour, in vitro gastrointestinal digestion with determination of the release of non-extractable proanthocyanidins (NEPA) from T, antioxidant activity and lipolysis. EP significantly affects the rheological behaviour of both Es and GEs. T incorporation produced a structural reinforcement of GEs, especially in the case of SC. The digests from Es displayed a higher antioxidant activity than those from GEs. T lipase inhibition was observed only in the formulations with WPI. Our results highlight the importance, in the design of functional foods, of analyzing different variables when incorporating a bioactive compound into a food or emulsion in order to select the better combination for the desired objective, owing to the complex interplay of the various components.

Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype.

BACKGROUND: Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors. METHODS: We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in syngeneic mouse models. RESULTS: We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic allografts of GL261 cells, delaying tumor growth. CONCLUSIONS: We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.

The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas.

Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (MAPT), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, MAPT was almost absent from tumors with epidermal growth factor receptor (EGFR) mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) EGFR We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy.