Background:Eosinophilic esophagitis (EoE) and atopy are associated with several genetic variants; however, their relationship with clinical features has been scarcely investigated. Objective:We sought to characterize the distribution of such variants and evaluate the association with endoscopic and histologic presentation of EoE and concomitant atopies. Methods:Thirty-eight single nucleotide polymorphisms (SNPs), previously linked to EoE risk, were analyzed in a large cohort of Spanish patients. An observational study was performed in patients with EoE recruited at 4 sites. SNP genotyping was performed using the OpenArray platform (Thermo Fisher Scientific) from DNA samples extracted from peripheral blood. To enhance the robustness and reliability of the identified genetic associations, patients were divided into discovery (70%) and validation (30%) cohorts. Results:Overall, 628 patients with EoE (74% male; mean age, 32 ± 15 years) were recruited. An association between EoE and SNPs located at the 5q22 locus was confirmed in our cohort; in addition, 2 new SNPs not previously associated with EoE in which the alternative allele distributed differently were identified. A multivariate model identified 4 SNPs (ABCB1 rs1128503, KCNJ2 rs312691, STAT6 rs841718, and TGFB1 rs8179181) predicting a mixed/stricturing phenotype. CAPN14 rs74732520-CG/GG and rs77569859-TC/CC genotypes were associated with lower peak eosinophil counts at diagnosis. Regarding concomitant atopies, IL13 rs1800925-TT was associated with increased risk for asthma and conjunctivitis, whereas ABCB1 rs2032582-TT was linked to a reduced risk of dermatitis. Conclusions:The analysis of genetic variants in a Spanish population with EoE showed novel associations between specific SNPs and clinical characteristics of this disease.

Endoluminal functional lumen impedance planimetry (EndoFLIPTM) has become the gold standard to evaluate esophageal distensibility, although the study itself and its analysis present challenges. We propose here a new method to assess lower esophageal distension capacity that overcomes several limitations of prior approaches, including incomplete and corrupted EndoFLIPTM recordings. Esophageal distension capacity was evaluated with a 16-channel EndoFLIPTM in 10 controls and 14 patients with eosinophilic esophagitis (EoE). Controls were evaluated once. EoE patients were evaluated at baseline and after at least six weeks of treatment with orodispersible budesonide tablets, 1 mg bd. Balloon volumes were increased by 5 mL stepwise, either reaching a maximum volume of 60 mL or a maximum balloon pressure of 60 mmHg. Recordings were analyzed with a homemade R script. The mean esophageal diameter at 60 mL, D (60 mL), was calculated or extrapolated depending on whether the 60 mL volume was reached. By fitting a Michaelis-Menten curve across all measured diameters throughout all constant volume steps, the mean D (60 mL) was estimated. For control subjects, the mean ± SD value of D (60 mL) was 17.08 ± 1.69 mm, and for EoE patients at baseline, D (60 mL) was 14.51 ± 2.68 mm. After six weeks of treatment of EoE patients, D (60 mL) significantly increased to 16.22 ± 1.86 mm (paired Wilcoxon signed test: p = 0.0052), although the values for control subjects were not reached. The estimated mean esophageal diameter at 60 mL is a good proxy for esophageal distension capacity, which correlates with clinical outcomes in EoE. The method presented in this study overcomes difficulties encountered during the standard measurement protocol, allowing the analysis of recordings from incomplete and corrupted registries.

Proton pump inhibitors (PPIs) are the first-line drug for eosinophilic esophagitis (EoE), although it is estimated that there is a lack of histological remission in 50% of patients. This research aimed to identify pharmacogenetic biomarkers predictive of PPI effectiveness and to study their association with disease features. Peak eosinophil count (PEC) and the endoscopic reference score (EREFS) were determined before and after an eight-week PPI course in 28 EoE patients. The impact of the signal transducer and activator of transcription 6 (STAT6), CYP2C19, CYP3A4, CYP3A5, and ABCB1 genetic variations on baseline PEC and EREFS, their reduction and histological response, and on EoE symptoms and comorbidities was analyzed. PEC reduction was higher in omeprazole-treated patients (92.5%) compared to other PPIs (57.9%, p = 0.003). STAT6 rs12368672 (g.18453G>C) G/G genotype showed higher baseline PEC values compared to G/C and C/C genotypes (83.2 vs. 52.9, p = 0.027). EREFS reduction in STAT6 rs12368672 G/G and G/C genotypes was higher than in the C/C genotype (36.7% vs. −75.0% p = 0.011). However, significance was lost after Bonferroni correction. Heartburn incidence was higher in STAT6 rs167769 (g.27148G>A) G/G patients compared to G/A (54.55% vs. 11.77%, p = 0.030). STAT6 rs12368672G>C and rs167769G>A variants might have a relevant impact on EoE status and PPI response. Further research is warranted to clarify the clinical relevance of these variants.

ABSTRACT Background Recently, we have identified a dysregulated protein signature in the esophageal epithelium of eosinophilic esophagitis (EoE) patients; however, the effect of proton pump inhibitor (PPI) treatment on this signature is unknown. Herein, we used a proteomic approach to investigate: (1) whether PPI treatment alters the esophageal epithelium protein profile observed in EoE patients and (2) whether the protein signature at baseline predicts PPI response. Methods We evaluated the protein signature of esophageal biopsies using a cohort of adult EoE (n=25) patients and healthy controls (C) (n=10). In EoE patients, esophageal biopsies were taken before (Pre) and after (Post) an 8-week PPI treatment, determining the histologic response. Eosinophil count PostPPI was used to classify the patients: ≥15 eosinophils/hpf as non-responders (NR) and <15 eosinophils/hpf as responders (R). Protein signature was determined and differentially accumulated proteins (DAP) were characterized to identify altered biological processes and signaling pathways. Results High dimensional analysis of DAP between groups revealed common signatures between three groups of patients with inflammation (R-PrePPI, NR-PrePPI and NR-PostPPI) and without inflammation (C and R- PostPPI). PPI therapy almost reversed the EoE specific esophageal protein signature, which is enriched in pathways associated with inflammation and epithelial barrier function, in R-PostPPI. Furthermore, we identified a set of candidate proteins to differentiate R-PrePPI and NR-PrePPI EoE patients before treatment. Conclusion These findings provide evidence that PPI therapy reverses the alterations in the protein profile associated with EoE. Interestingly, our results also suggest that PPI response could be predicted at baseline in EoE.

Epithelial intercellular adhesion molecule (ICAM)-1 is apically polarized, interacts with, and guides leukocytes across epithelial barriers. Polarized hepatic epithelia organize their apical membrane domain into bile canaliculi and ducts, which are not accessible to circulating immune cells but that nevertheless confine most of ICAM-1. Here, by analyzing ICAM-1_KO human hepatic cells, liver organoids from ICAM-1_KO mice and rescue-of-function experiments, we show that ICAM-1 regulates epithelial apicobasal polarity in a leukocyte adhesion-independent manner. ICAM-1 signals to an actomyosin network at the base of canalicular microvilli, thereby controlling the dynamics and size of bile canalicular-like structures. We identified the scaffolding protein EBP50/NHERF1/SLC9A3R1, which connects membrane proteins with the underlying actin cytoskeleton, in the proximity interactome of ICAM-1. EBP50 and ICAM-1 form nano-scale domains that overlap in microvilli, from which ICAM-1 regulates EBP50 nano-organization. Indeed, EBP50 expression is required for ICAM-1-mediated control of BC morphogenesis and actomyosin. Our findings indicate that ICAM-1 regulates the dynamics of epithelial apical membrane domains beyond its role as a heterotypic cell–cell adhesion molecule and reveal potential therapeutic strategies for preserving epithelial architecture during inflammatory stress.

ObjectivesThe aim of the study was to characterize the circulating immunome of patients with EoE before and after proton pump inhibitor (PPI) treatment in order to identify potential non-invasive biomarkers of treatment response.MethodsPBMCs from 19 healthy controls and 24 EoE patients were studied using a 39-plex spectral cytometry panel. The plasmacytoid dendritic cell (pDC) population was differentially characterized by spectral cytometry analysis and immunofluorescence assays in esophageal biopsies from 7 healthy controls and 13 EoE patients.ResultsInterestingly, EoE patients at baseline had lower levels of circulating pDC compared with controls. Before treatment, patients with EoE who responded to PPI therapy had higher levels of circulating pDC and classical monocytes, compared with non-responders. Moreover, following PPI therapy pDC levels were increased in all EoE patients, while normal levels were only restored in PPI-responding patients. Finally, circulating pDC levels inversely correlated with peak eosinophil count and pDC count in esophageal biopsies. The number of tissue pDCs significantly increased during active EoE, being even higher in non-responder patients when compared to responder patients pre-PPI. pDC levels decreased after PPI intake, being further restored almost to control levels in responder patients post-PPI.ConclusionsWe hereby describe a unique immune fingerprint of EoE patients at diagnosis. Moreover, circulating pDC may be also used as a novel non-invasive biomarker to predict subsequent response to PPI treatment.

BACKGROUND:Eosinophilic esophagitis (EoE) is a chronic non-IgE-mediated allergic disease of the esophagus. An unbiased proteomics approach was performed to investigate pathophysiological changes in esophageal epithelium. Additionally, an RNAseq-based transcriptomic analysis in paired samples was also carried out.METHODS:Total proteins were purified from esophageal endoscopic biopsies in a cohort of adult EoE patients (n = 25) and healthy esophagus controls (n = 10). Differentially accumulated (DA) proteins in EoE patients compared to control tissues were characterized to identify altered biological processes and signaling pathways. Results were also compared with a quantitative proteome dataset of the human esophageal mucosa. Next, results were contrasted with those obtained after RNAseq analysis in paired samples. Finally, we matched up protein expression with two EoE-specific mRNA panels (EDP and Eso-EoE panel).RESULTS:A total of 1667 proteins were identified, of which 363 were DA in EoE. RNA sequencing in paired samples identified 1993 differentially expressed (DE) genes. Total RNA and protein levels positively correlated, especially in DE mRNA-proteins pairs. Pathway analysis of these proteins in EoE showed alterations in immune and inflammatory responses for the upregulated proteins, and in epithelial differentiation, cornification and keratinization in those downregulated. Interestingly, a set of DA proteins, including eosinophil-related and secreted proteins, were not detected at the mRNA level. Protein expression positively correlated with EDP and Eso-EoE, and corresponded with the most abundant proteins of the human esophageal proteome.CONCLUSIONS:We unraveled for the first time key proteomic features involved in EoE pathogenesis. An integrative analysis of transcriptomic and proteomic datasets provides a deeper insight than transcriptomic alone into understanding complex disease mechanisms.

Background: active eosinophilic esophagitis is associated with esophageal caliber, distensibility and motility changes that may be reversed with treatment.Objectives: to study esophageal diameter, distensibility and contractility in healthy subjects compared to patients with eosinophilic esophagitis, both before and after treatment.Methods: a quasi-experimental study, EndoFLIPTM, was used to analyze the esophageal body and esophago-gastric junction (EGJ) in all three groups, and a program was designed to obtain esophageal diameter, distensibility and contractility values.Results: ten healthy volunteers (24-61 years, six men) and nine patients with eosinophilic esophagitis (21-52 years, seven men) were included. The esophagogastric junction distensibility index was 5.07 mm(2)/Hg in the control subjects, 2.40 mm(2/)Hg in the subjects with eosinophilic esophagitis before treatment and 2.46 mm(2)/Hg after treatment. The distensibility plateau was 20.02 mm, 15.43 mm and 17.41 mm, respectively, and the diameter was 21.90 mm, 17.73 mm and 18.30 mm, showing significant differences (p < 0.05), except between control subjects and patients after treatment (p = 0.079). Repetitive antegrade contractions developed in 90 % of control subjects, 66.7 % of eosinophilic esophagitis patients before treatment and 88.9 % of the latter after treatment (p > 0.05).Conclusions: esophago-gastric junction distensibility index, distensibility plateau and diameter values were higher in controls than in patients, although six weeks of treatment seems a short period to observe significant changes in esophageal biomechanics. Repetitive antegrade contractions are the predominant pattern in healthy subjects and eosinophilic esophagitis. We provide normality values for esophageal biomechanics, measured by impedance planimetry in our setting.

In the present study, we have demonstrated that sofosbuvir (SOF) treatment improves systemic insulin resistance in hepatitis C virus (HCV)-patients, and, for the first time, revealed which molecular mechanisms are involved in SOF effects on the impaired insulin response induced by HCV in hepatocytes. One of the major concerns in the health care field is the huge number of people affected by chronic HCV infection and its associated complications.1 In this regard, chronic HCV infection is associated with hepatic insulin resistance, and an increased risk of diabetes in HCV-infected patients has been well described.2 In fact, the development of these HCV-related metabolic complications affects the health quality of patients and causes an important burden on medical care. In the last years, the introduction of anti-HCV regimens based on direct antiviral agents (DAAs) has become a revolutionary advance in the treatment of HCV infection. Among them, SOF, a nucleotide analogue HCV NS5B polymerase inhibitor, was approved by the Food and Drug Administration for the treatment of chronic HCV infection in combination with other antiviral agents since December 2013.3 Chronic HCV infection seems to be decreasing with the advent of these new therapies, which is manifesting as a lower burden of cirrhosis and chronic liver failure among waitinglist additions and new transplant recipients. The obtained results from this study showed that insulin-resistant HCV-patients treated with SOF-based regimens (Table 1) were responders at the end of the treatment, regardless of genotype or degree of liver fibrosis. As expected, a significant decline of serum liver damage markers - AST, ALT, GGT, and bilirubin - concentration was detected in patients at the end of the treatment that remained 1 year later in parallel with a reduction of FIB4 score throughout the study (P < .001) (Figure 1A). Moreover, we addressed that SOF-based treatments could effectively improve the insulin-resistant state of HCV-patients. Particularly, a significant reduction of the insulin resistance index HOMA was observed since the end of the treatment (P = .0048), being more pronounced 1 year later (P < .001), compared with the baseline data (Figure 1B and Figure S1A). Our findings are in agreement with previous data that showed that interferon (IFN)-free all-oral DAA regimens improved systemic insulin resistance and blood glucose levels in patients who cleared HCV.2 On the other hand, HCV itself may also impair lipid metabolism since several studies have documented hypocholesterolemia and hypolipidemia, particularly lower levels of total cholesterol (Tc), low density lipoprotein cholesterol (LDLc) and apolipoprotein B (ApoB), the main protein constituent of LDLc and very low density lipoprotein cholesterol (VLDLc), in patients with chronic HCV infection.2 Although our study was not designed to clarify the effects of HCV on lipid profile, it has demonstrated that successful HCV clearance resulted in a rebound of circulating Tc, LDLc, and ApoB levels (P < .005) (Figure 1C and Figure S1B), according to observations in patients who achieved sustained virologic response with IFN-based or IFN-free DAA regimens.2, 4 In order to explore the possible molecular mechanisms involved in SOF effects on the improvement of insulin resistance observed in patients, we performed an in vitro experimental model: HCV replicon-carrying cells treated with SOF for HCV clearance (Figure 2A and Figure S2) and further stimulated with different doses of insulin. Results obtained from this experimental study have demonstrated that SOF improves the hepatic insulin resistance induced by HCV infection (Figure 2B and Figure S3A). In this regard, it is well known that HCV interferes with the early steps of the insulin signalling cascade, particularly by reducing the expression of the insulin receptor substrates (IRSs), IRS1 and IRS2.5 Inactivation of these docking proteins by different mechanisms, such as proteasome-mediated degradation, has been highly associated with insulin resistance.6 Importantly, we observed that HCV induced a reduction of IRS1 protein content in hepatocytes (Figure 2C and Figure S3B), according to previous studies in different cell-based systems for studying HCV,5 and SOF challenge balanced the low protein levels of IRS1 in HCV-cells (Figure 2C and Figure S3B). Indeed, we found that serine phosphorylation levels were reduced in HCV-cells treated with SOF as compared to untreated HCV-cells (Figure 2D and Figure S3B), which might explain the recovery of IRS1 total protein content after SOF treatment. In this sense, it is well established that HCV core protein induces serine phosphorylation of IRS1 blocking its tyrosine phosphorylation and targets IRS1 for proteasomal degradation.7, 8 As IRS1 is a critical molecule involved in the transduction of insulin signal from the insulin receptor, its degradation impairs the downstream AKT signalling pathway leading to insulin resistance.7 In our study, we observed that SOF treatment greatly improved the response to insulin in AKT phosphorylation and its targets (Foxo1 and GSK3β) in HCV-hepatocytes compared to DMSO condition (Figure 2B and Figure S3A), reversing the insulin resistance state and, accordingly, the elevated expression of gluconeogenic genes (Figure 2E), the increased glucose production (Figure 2F), and the impairment of glycogen synthesis (Figure 2G) induced by HCV. Other studies have also shown that curing infected cells with IFN treatment partly modifies surrogate markers of insulin resistance such as the upregulated gluconeogenesis.8, 9 However, to our knowledge, this is the first study showing a reversion of the impaired insulin-stimulated IR/IRS1/AKT signalling pathway in cured HCV-cells, which is reflected in a decreased gluconeogenesis and a recover of the glycogen synthesis, giving SOF a key role in the regulation of this pathway that is responsible for its insulin metabolic effects. Taken together, the results derived from this investigation indicate that SOF improves the impaired insulin response induced by HCV infection. Indeed, this study is especially relevant as it is the first one demonstrating the molecular mechanisms involved in the hepatic insulin sensitization induced by SOF treatment, involving the recovery of IRS1 protein levels as a hallmark of SOF effects, and providing a better understanding of the signalling pathways targeted by SOF in hepatocytes which may offer new insights on the benefits of this DAA. Águeda González-Rodríguez is supported by CP14/00181 and PI16/00823 grants, Carmelo García-Monzón is supported by PI17/0535 grant, and Pedro Majano is supported by PI17/0008 grant. All are funded by Instituto de Salud Carlos III (ISCIII, Spain) and co-funded by Fondo Europeo de Desarrollo Regional (FEDER). The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background: Long-standing inflammation leads to esophageal remodeling with stricture formation in patients with eosinophilic esophagitis (EoE). The ability of proton pump inhibitors (PPI) to reverse endoscopic features of fibrosis is still unknown. Objective: To investigate the effect of a short course of PPI treatment in reducing endoscopic findings indicative of esophageal fibrosis in EoE patients. Methods: Cross-sectional analysis of the EoE CONNECT registry. Patients who received PPI to induce EoE remission were evaluated. Endoscopic features were graded using the EoE Endoscopic Reference Score (EREFS), with rings and strictures indicating fibrosis. Results were compared to those from patients treated with swallowed topic corticosteroids (STC). Results: Clinico-histological remission was achieved in 83/166 adult patients treated with PPI (50%) and in 65/79 (82%) treated with STC; among responders, 60 (36%) and 57 (72%) patients respectively achieved deep histological remission (<5 eosinophils/hpf). At baseline, mean +/- SD EREFS was lower in patients treated with PPI compared to those who received STC (p < 0.001). Short term treatment significantly reduced EREFS scores in patients treated either with PPI or STC as well as rings and strictures. Among patients treated with PPI, deep histological remission (<5 eosinophils/hpf) provided further reduction in total EREFS score. Conclusion: Effective PPI therapy for EoE significantly reduced endoscopic esophageal fibrosis in the short term. (C) 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

A lifelong gluten-free diet (GFD) is the only current treatment for celiac disease (CD), but strict compliance is complicated. Duodenal biopsies are the “gold standard” method for diagnosing CD, but they are not generally recommended for disease monitoring. We evaluated the sensitivity and specificity of fecal gluten immunogenic peptides (GIPs) to detect duodenal lesions in CD patients on a GFD and compared them with serum anti-tissue transglutaminase (tTG) IgA antibodies. A prospective study was conducted at two tertiary centers in Spain on a consecutive series of adolescents and adults with CD who maintained a long-lasting GFD. Adherence to a GFD and health-related quality of life were scored with validated questionnaires. Mucosal damage graded according to the Marsh–Oberhüber classification (Marsh 1/2/3) was used as the reference standard. Of the 97 patients included, 27 presented duodenal mucosal damage and 70 had normal biopsies (Marsh 0). The sensitivity (33%) and specificity (81%) of GIPs were similar to those provided by the two assays used to measure anti-tTG antibodies. Scores in questionnaires showed no association with GIP, but an association between GIPs and patients’ self-reported gluten consumption was found (p = 0.003). GIP displayed low sensitivity but acceptable specificity for the detection of mucosal damage in CD.

Epithelial-to-mesenchymal transition (EMT) is a self-regulated physiological process required for tissue repair that, in non-controled conditions may lead to fibrosis, angiogenesis, loss of normal organ function or cancer. Although several molecular pathways involved in EMT regulation have been described, this process does not have any specific treatment. This article introduces a systematic review of effective natural plant compounds and their extract that modulates the pathological EMT or its deleterious effects, through acting on different cellular signal transduction pathways both in vivo and in vitro. Thereby, cryptotanshinone, resveratrol, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, curcumin, genistein, paeoniflorin, gambogic acid and Cinnamomum cassia extracts inhibit EMT acting on transforming growth factor-β (TGF-β)/Smads signaling pathways. Gedunin, carnosol, celastrol, black rice anthocyanins, Duchesnea indica, cordycepin and Celastrus orbiculatus extract downregulate vimectin, fibronectin and N-cadherin. Sulforaphane, luteolin, celastrol, curcumin, arctigenin inhibit β-catenin signaling pathways. Salvianolic acid-A and plumbagin block oxidative stress, while honokiol, gallic acid, piperlongumine, brusatol and paeoniflorin inhibit EMT transcription factors such as SNAIL, TWIST and ZEB. Plectranthoic acid, resveratrol, genistein, baicalin, polyphyllin I, cairicoside E, luteolin, berberine, nimbolide, curcumin, withaferin-A, jatrophone, ginsenoside-Rb1, honokiol, parthenolide, phoyunnanin-E, epicatechin-3-gallate, gigantol, eupatolide, baicalin and baicalein and nitidine chloride inhibit EMT acting on other signaling pathways (SIRT1, p38 MAPK, NFAT1, SMAD, IL-6, STAT3, AQP5, notch 1, PI3K/Akt, Wnt/β-catenin, NF-κB, FAK/AKT, Hh). Despite the huge amount of preclinical data regarding EMT modulation by the natural compounds of plant, clinical translation is poor. Additionally, this review highlights some relevant examples of clinical trials using natural plant compounds to modulate EMT and its deleterious effects. Overall, this opens up new therapeutic alternatives in cancer, inflammatory and fibrosing diseases through the control of EMT process.

Alphaviruses are insect-borne viruses that alternate between replication in mosquitoes and vertebrate species. Adaptation of some alphaviruses to vertebrate hosts has involved the acquisition of an RNA structure (downstream loop [DLP]) in viral subgenomic mRNAs that confers translational resistance to protein kinase (PKR)-mediated eIF2α phosphorylation. Here, we found that, in addition to promoting eIF2-independent translation of viral subgenomic mRNAs, presence of the DLP structure also increased the resistance of alphavirus to type I interferon (IFN). Aura virus (AURAV), an ecologically isolated relative of Sindbis virus (SV) that is poorly adapted to replication in vertebrate cells, displayed a nonfunctional DLP structure and dramatic sensitivity to type I IFN. Our data suggest that an increased resistance to IFN emerged during translational adaptation of alphavirus mRNA to vertebrate hosts, reinforcing the role that double-stranded RNA (dsRNA)-activated protein kinase (PKR) plays as both a constitutive and IFN-induced antiviral effector. Interestingly, a mutant SV lacking the DLP structure (SV-ΔDLP) and AURAV both showed a marked oncotropism for certain tumor cell lines that have defects in PKR expression and/or activation. AURAV selectively replicated in and killed some cell lines derived from human hepatocarcinoma (HCC) that lacked PKR response to infection or poly(I·C) transfection. The oncolytic activities of SV-ΔDLP and AURAV were also confirmed using tumor xenografts in mice, showing tumor regression activities comparable to wild-type SV. Our data show that translation of alphavirus subgenomic mRNAs plays a central role in IFN susceptibility and cell tropism, suggesting an unanticipated oncolytic potential that some naive arboviruses may have in virotherapy.IMPORTANCE Interferons (IFNs) induce the expression of a number of antiviral genes that protect the cells of vertebrates against viruses and other microbes. The susceptibility of cells to viruses greatly depends on the level and activity of these antiviral effectors but also on the ability of viruses to counteract this antiviral response. Here, we found that the level of one of the main IFN effectors in the cell, the dsRNA-activated protein kinase (PKR), greatly determines the permissiveness of cells to alphaviruses that lack mechanisms to counteract its activation. These naive viruses also showed a hypersensitivity to IFN, suggesting that acquisition of IFN resistance (even partial) has probably been involved in expanding the host range of alphaviruses in the past. Interestingly, some of these naive viruses showed a marked oncotropism for some tumor cell lines derived from human hepatocarcinoma (HCC), opening the possibility of their use in oncolytic therapy to treat human tumors.

Hepatitis C virus (HCV) infection is a major biomedical problem worldwide. Although new direct antiviral agents (DAAs) have been developed for the treatment of chronic HCV infection, the potential emergence of resistant virus variants and the difficulties to implement their administration worldwide make the development of novel antiviral agents an urgent need. Moreover, no effective vaccine is available against HCV and transmission of the virus still occurs particularly when prophylactic measures are not taken. We used a cell-based system to screen a battery of polyanionic carbosilane dendrimers (PCDs) to identify compounds with antiviral activity against HCV and show that they inhibit effective virus adsorption of major HCV genotypes. Interestingly, one of the PCDs irreversibly destabilized infectious virions. This compound displays additive effect in combination with a clinically relevant DAA, sofosbuvir. Our results support further characterization of these molecules as nanotools for the control of hepatitis C virus spread.

Background: Ulcerative colitis is an inflammatory condition limited to the colon in the gastrointestinal system.Currently the most potent medications used for medical treatment of ulcerative colitis produce no response in 20%-30% of cases, in spite of a high side-effect profile.There is a need for more efficient and reliable medications.Tyrosine kinase inhibitors have shown efficacy in some inflammatory diseases and in experimental colitis models.Even though dasatinib, a tyrosine kinase inhibitor, suppresses proinflammatory cytokines in colonic tissue, there are a few case reports of haemorrhagic colitis with use of the medication.There is no study investigating the effect of dasatinib on experimental colitis.We aimed to investigate the effect of dasatinib in a colitis model induced with acetic acid in our study.Methods: In the study, 24 male Sprague-Dawley rats distributed into 4 groups of 6 rats each as control, dasatinib, colitis, and dasatinib+colitis groups randomly.For colitis induction, 4% acetic acid was used.Sacrificing of the rats was performed on the seventh day.Disease activity; morphologic and histological injury; superoxide dismutase, myeloperoxidase, and malondialdehyde activity; and TNFα and CD3 expression were assessed in colonic tissue.