Esophageal food bolus impaction in pediatric age.

OBJECTIVES: Esophageal food impaction (EFI) is the sudden onset of dysphagia that occurs when a food bolus becomes lodged in the esophagus, requiring endoscopic removal. Scientific data on the prevalence and causes of EFI in children is lacking. The aim of this study was to provide further insights into EFI episodes in children. METHODS: We have prospectively enrolled all children admitted for a first episode of EFI between March 2018 and March 2023. A fluoroscopic contrast study was performed in all patients to confirm the boluses and assess their position. Boluses were extracted by esophagogastroduodenoscopies, and esophageal biopsies were routinely obtained for histologic evaluation. RESULTS: Over the study period, 41 children were admitted for a first episode of food impaction. Drooling was the most commonly reported symptom. Half children experiencing a first episode of food bolus were diagnosed with EoE (20/41, 48.8%). Almost a fourth of the episodes subtended a different condition, such as esophageal anastomotic, peptic or congenital strictures, stricturing caustic esophagitis, esophageal duplication, and achalasia. In the last fourth of patients the cause of EFI was not identified and thus probably related to quick eating and inadequate chewing of food. DISCUSSION: Our study represents the largest known series of pediatric patients evaluated for food bolus impaction. Our main finding is the high frequency of EoE, which accounts for a half of EFI episodes in pediatric age, especially in older children. This finding highlights the importance of obtaining esophageal biopsies after the endoscopic bolus removal in children with EFI to provide a complete diagnostic evaluation.

Plasma and dried blood spot lysosphingolipids for the diagnosis of different sphingolipidoses: a comparative study.

Background Lysosphingolipids, the N-deacylated forms of sphingolipids, have been identified as potential biomarkers of several sphingolipidoses, such as Gaucher, Fabry, Krabbe and Niemann-Pick diseases and in GM1 and GM2 gangliosidoses. To date, different methods have been developed to measure various lysosphingolipids (LysoSLs) in plasma. Here, we present a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for a simultaneous quantification of LysoSLs (HexSph, LysoGb3, LysoGM1, LysoGM2, LysoSM and LysoSM509) in dried blood spot (DBS). This LC-MS/MS method was used to compare the levels of LysoSLs in DBS and plasma in both affected patients and healthy controls. Methods Lysosphingolipids were extracted from a 3.2 mm diameter DBS with a mixture of methanol:acetonitrile:water (80:15:5, v/v) containing internal stable isotope standards. Chromatographic separation was performed using a C18 column with a gradient of water and acetonitrile both with 0.1% formic acid in a total run time of 4 min. The compounds were detected in the positive ion mode electrospray ionization (ESI)-MS/MS by multiple reaction monitoring (MRM). Results The method was validated on DBS to demonstrate specificity, linearity, lowest limit of quantification, accuracy and precision. The reference ranges were determined in pediatric and adult populations. The elevated levels of LysoSLs were identified in Gaucher disease (HexSph), Fabry disease (LysoGb3), prosaposin deficiency (HexSph and LysoGb3) and Niemann-Pick disease types A/B and C (LysoSM and LysoSM509). The correlation in the levels between DBS and plasma was excellent for LysoGb3 and HexSph but poor for LysoSM and LysoSM509. Conclusions Despite the fact that plasma LysoSLs determination remains the gold standard, our LC-MS/MS method allows a rapid and reliable quantification of lysosphingolipids in DBS. The method is a useful tool for the diagnosis of different sphingolipidoses except for Niemann-Pick type C.

Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome.

BACKGROUND: The pathogenesis of macrophage activation syndrome (MAS) is not clearly understood: a large body of evidence supports the involvement of mechanisms similar to those implicated in the setting of primary hemophagocytic lymphohistiocytosis. OBJECTIVE: We sought to investigate the pathogenic role of IFN-γ and the therapeutic efficacy of IFN-γ neutralization in an animal model of MAS. METHODS: We used an MAS model established in mice transgenic for human IL-6 (IL-6TG mice) challenged with LPS (MAS mice). Levels of IFN-γ and IFN-γ-inducible chemokines were evaluated by using real-time PCR in the liver and spleen and by means of ELISA in plasma. IFN-γ neutralization was achieved by using the anti-IFN-γ antibody XMG1.2 in vivo. RESULTS: Mice with MAS showed a significant upregulation of the IFN-γ pathway, as demonstrated by increased mRNA levels of Ifng and higher levels of phospho-signal transducer and activator of transcription 1 in the liver and spleen and increased expression of the IFN-γ-inducible chemokines Cxcl9 and Cxcl10 in the liver and spleen, as well as in plasma. A marked increase in Il12a and Il12b expression was also found in livers and spleens of mice with MAS. In addition, mice with MAS had a significant increase in numbers of liver CD68+ macrophages. Mice with MAS treated with an anti-IFN-γ antibody showed a significant improvement in survival and body weight recovery associated with a significant amelioration of ferritin, fibrinogen, and alanine aminotransferase levels. In mice with MAS, treatment with the anti-IFN-γ antibody significantly decreased circulating levels of CXCL9, CXCL10, and downstream proinflammatory cytokines. The decrease in CXCL9 and CXCL10 levels paralleled the decrease in serum levels of proinflammatory cytokines and ferritin. CONCLUSION: These results provide evidence for a pathogenic role of IFN-γ in the setting of MAS.

Modulatory effects of 1,25-dihydroxyvitamin D3 on eye disorders: A critical review.

Many studies have shown that the presence of 1,25-dihydroxyvitamin D3 in the eye is able to modulate inflammatory responses. In fact, it has been demonstrated that topical administration of vitamin D3 inhibits Langerhans cells migration from the central cornea, corneal neovascularization, and production of cytokines (i.e., interleukin-1-6-8) in experimental animals. Moreover, both in vitro and in vivo studies have demonstrated that vitamin D is a potent inhibitor of retinal neovascularization. It has been shown that calcitriol, the biologically active form of vitamin D, inhibits angiogenesis both in cultured endothelial cells and in retinas from guinea pigs with retinoblastoma or oxygen-induced ischemic retinopathy. In addition, it seems that this compound is able to prevent the progression from early to neovascular age-related macular degeneration (AMD) and, at the same time, to down-regulate the characteristic inflammatory cascade at the retinal pigment epithelium-choroid interface due to its anti-inflammatory and immunomodulatory capabilities. Furthermore, 1,25-dihydroxyvitamin D3 and its analogue, 2-methylene-19-nor-1,25-dihydroxyvitamin D3, are able to modulate intraocular pressure (IOP) through gene expression. Several studies have suggested a role in glaucoma and diabetic retinopathy therapies for vitamin D3. In conclusion, this review summarizes our current knowledge on the potential use of vitamin D3 in the protection and treatment of ocular diseases in ophthalmology.

Curcumin: therapeutical potential in ophthalmology.

Curcumin (diferuloylmethane) is the main curcuminoid of the popular Indian spice turmeric (Curcuma longa). In the last 50 years, in vitro and in vivo experiments supported the main role of polyphenols and curcumin for the prevention and treatment of many different inflammatory diseases and tumors.The anti-inflammatory, antioxidant, and antitumor properties of curcumin are due to different cellular mechanisms: this compound, in fact, produces different responses in different cell types. Unfortunately, because of its low solubility and oral bioavailability, the biomedical potential of curcumin is not easy to exploit; for this reason more attention has been given to nanoparticles and liposomes, which are able to improve curcumin's bioavailability. Pharmacologically, curcumin does not show any dose-limiting toxicity when it is administered at doses of up to 8 g/day for three months. It has been demonstrated that curcumin has beneficial effects on several ocular diseases, such as chronic anterior uveitis, diabetic retinopathy, glaucoma, age-related macular degeneration, and dry eye syndrome. The purpose of this review is to report what has so far been elucidated about curcumin properties and its potential use in ophthalmology.

Role of Protease-Inhibitors in Ocular Diseases.

It has been demonstrated that the balance between proteases and protease-inhibitors system plays a key role in maintaining cellular and tissue homeostasis. Indeed, its alteration has been involved in many ocular and systemic diseases. In particular, research has focused on keratoconus, corneal wounds and ulcers, keratitis, endophthalmitis, age-related macular degeneration, Sorsby fundus dystrophy, loss of nerve cells and photoreceptors during optic neuritis both in vivo and in vitro models. Protease-inhibitors have been extensively studied, rather than proteases, because they may represent a therapeutic approach for some ocular diseases. The protease-inhibitors mainly involved in the onset of the above-mentioned ocular pathologies are: α2-macroglobulin, α1-proteinase inhibitor (α1-PI), metalloproteinase inhibitor (TIMP), maspin, SERPINA3K, SERPINB13, secretory leukocyte protease inhibitor (SLPI), and calpeptin. This review is focused on the several characteristics of dysregulation of this system and, particularly, on a possible role of proteases and protease-inhibitors in molecular remodeling that may lead to some ocular diseases. Recently, researchers have even hypothesized a possible therapeutic effect of the protease-inhibitors in the treatment of injured eye in animal models.

Monoamine oxidase enzymes and oxidative stress in the rat optic nerve: age-related changes.

In this study, age-related changes in the monoamine oxidases (MAO) were studied in the optic nerve (ON) of both young and aged male rats. The aim of the study was to assess the role of MAO in age-related changes in the rat ON and explain the mechanisms of neuroprotection mediated by MAO-B-specific inhibitors. Fifteen three month old and fifteen 26 month old Sprague-Dawley rats were used. The animals were killed by terminal anaesthesia. Staining of MAO, quantitative analysis of images, biochemical assays and statistical analysis of data were carried out. Samples of the ON were washed in water, fixed in Bowen fluid, dehydrated and embedded in Entellan. Histological sections were stained for MAO-enzymatic activities. The specificity of the reaction was evaluated by incubating control sections in a medium either without substrate or without dye. The quantitative analysis of images was carried out at the same magnification and the same lighting using a Zeiss photomicroscope. The histochemical findings were compared with the biochemical results. After enzymatic staining, MAO could be demonstrated in the ON fibres of both young and aged animals; however, MAO were increased in the nerve fibres of the elderly rats. These morphological findings were confirmed biochemically. The possibility that age-related changes in MAO levels may be attributed to impaired energy production mechanisms and/or represent the consequence of reduced energy needs is discussed.

Changing Epidemiology of Acute Viral Respiratory Infections in Hospitalized Children: The Post-Lockdown Effect.

Several reports highlighted how public health measures aimed at limiting severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) circulation have likely contributed to reducing the circulation of other respiratory viruses, particularly during the first year of the COVID-19 pandemic. We evaluated the epidemiology of acute respiratory infections in a large cohort of hospitalized children during the third year of the pandemic (2021−2022). We retrospectively analyzed data from the health records of children (<14 years) hospitalized for acute respiratory infections between 1 July 2021 and 31 March 2022. A total of 1763 respiratory panels were collected. Overall, 1269 (72%) panels hadpositive results for at least one pathogen. Most positive panels (53.8%) belonged to patients aged 1−12 months. The most detected pathogen was respiratory syncytial virus (RSV) (57.8% of positive panels). The RSV peak occurred in November 2021. Nine hundred and forty-five (74.5%) panels were positive for one pathogen while three hundred and twenty-four (25.5%) showed multiple infections. Patients with multiple infections were significantly older than those with a single infection. The 2021−2022 peak of RSV infection in Italy occurred earlier than in the previous pre-pandemic seasons. A high number of children have been hospitalized because of acute viral infections also due to less aggressive viruses.

Seizures in Children with SARS-CoV-2 Infection: Epidemiological, Clinical and Neurophysiological Characterization.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may present with a wide variety of symptoms, including neurological manifestations. We investigated clinical, demographic, laboratory, neurophysiological and imaging characteristics of SARS-CoV-2-positive children with seizures and analyzed differences between children admitted during the periods with prevalent circulation of the Alpha/Delta and Omicron variants, respectively. Patients' characteristics were analyzed according to the presence or absence of seizures and then according to the SARS-CoV-2 variants. Five-hundred and four SARS-CoV-2-positive patients were included: 93 (18.4%) with seizures and 411 (81.6%) without. Patients with seizures were older, had more commonly an underlying epilepsy and had more frequently altered C-reactive protein than those without seizures. Electroencephalography was abnormal in 5/38 cases. According to the SARS-CoV-2 variant, seizures were recorded in 4.7% of the total number of hospitalized patients during the Alpha/Delta period, and in 16.9% of patients admitted during the Omicron period. During the Alpha/Delta variants, seizures were more commonly observed in patients with epilepsy compared to those observed during the Omicron period. Our findings suggest that although SARS-CoV-2 may potentially trigger seizures, they are generally not severe and do not require intensive care admission.

Immune responses to alglucosidase in infantile Pompe disease: recommendations from an Italian pediatric expert panel.

BACKGROUND: Classic infantile onset of Pompe disease (c-IOPD) leads to hypotonia and hypertrophic cardiomyopathy within the first days to weeks of life and, without treatment, patients die of cardiorespiratory failure in their first 1-2 years of life. Enzymatic replacement therapy (ERT) with alglucosidase alfa is the only available treatment, but adverse immune reactions can reduce ERT's effectiveness and safety. It is therefore very important to identify strategies to prevent and manage these complications. Several articles have been written on this disease over the last 10 years, but no univocal indications have been established. METHODS: Our study presents a review of the current literature on management of immune responses to ERT in c-IOPD as considered by an Italian study group of pediatric metabolists and immunologists in light of our shared patient experience. RESULTS: We summarize the protocols for the management of adverse reactions to ERT, analyzing their advantages and disadvantages, and provide expert recommendations for their optimal management, to the best of current knowledge. However, further studies are needed to improve actual management protocols, which still have several limitations.

Monocytes From Patients With Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis Are Hyperresponsive to Interferon Gamma.

Objective: To investigate the activation of the IFNγ signaling pathway in monocytes of patients with secondary hemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) and to evaluate whether levels of phosphorylated STAT1 represent a biomarker for the identification of patients at early stages of the disease. Methods: Fresh whole blood samples from pediatric patients with active sHLH/MAS, not receiving (n=10) and receiving glucocorticoids (n=14) at time of sampling, were prospectively collected. As disease control groups, patients with active systemic juvenile idiopathic arthritis (sJIA) without MAS, patients with sHLH/MAS in remission and patients with other rheumatic diseases were also sampled. Whole blood cells were left unstimulated or stimulated with increasing concentrations of IFNγ for 10 minutes and the intracellular Tyrosine (701)-phosphorylated STAT1 (pSTAT1) levels were evaluated in monocytes by flow cytometry. Results: Monocytes from untreated sHLH/MAS patients showed significantly higher basal levels of pSTAT1 compared to those observed in monocytes from glucocorticoid-treated sHLH/MAS patients and from all the other disease controls. In addition, a significant increase in responsiveness to IFNγ, as assessed by increased levels of pSTAT1 following ex vivo stimulation, was observed in monocytes from untreated sHLH/MAS patients. pSTAT1 levels in monocytes distinguished patients with sHLH/MAS not treated with glucocorticoids from patients with active sJIA or with other rheumatic diseases [AUC, 0.93; 95% confidence interval 0.85-1.00, p<0.001]. Statistically significant correlations between IFNG mRNA levels in whole blood cells, circulating IFNγ levels and pSTAT1 levels in sHLH/MAS monocytes were found. Conclusion: Our data demonstrating higher basal levels of pSTAT1 as well as a hyperreactivity to IFNγ stimulation in monocytes from patients with sHLH/MAS point to perturbations in the activation of downstream IFNγ signaling pathway as a contributor to the hyperinflammation occurring in these patients. Finally, the observation that glucocorticoids affect pSTAT1 levels in vivo, makes it difficult to consider the measurement of pSTAT1 levels as a biomarker to identify patients at early stages of sHLH/MAS in clinical practice.

DEHP effects on retinal vessels in newborn rats: a qualitative and quantitative analysis.

Di-(2-ethylhexyl)-phthalate (DEHP), employed in polyvinyl chloride fabrication and released by endotracheal tubes, is known to cause alterations to several mammalian tissues, markedly in immature animals. The high incidence and severity of bronchopulmonary dysplasia and retinopathy in preterm babies submitted to endotracheal intubation prompted us to investigate the effects of DEHP in lung and retina perinatal development. We previously demonstrated that in rats delivered and breast-fed by DEHP-treated mothers lung alveolarisation is severely impaired. In the present research, the maturation of retinal vessels was studied in (a) flat-mounted retinas obtained after intracardiac injection of FITC-conjugated dextran, (b) flat-mounted retinas incubated with FITC-conjugated Bandeira simplicifolia isolectin B4, marker of vascular endothelial cells, and (c) eyecup sections incubated with biotinylated IB4 and revealed by ABC. DEHP-induced vascular alterations mainly affected the superficial plexus, where the radial vessels showed non-perfused as well as remarkably dilated and branched segments, capillary net appeared coarsely arranged and locally absent; periarteriolar capillary-free regions were still found in 14-day-old animals. This extensive vascular remodelling and generally the high responsiveness to DEHP shown by the immature rat retina confirm previous hypothesis that the phthalate released by PVC medical devices remarkably affects perinatal development of several tissues in different body districts.

NLRP2 Regulates Proinflammatory and Antiapoptotic Responses in Proximal Tubular Epithelial Cells.

Nod-like Receptor Pyrin domain containing proteins (NLRPs) expressed by resident renal cells may contribute to the pathogenesis of multiple renal diseases. Cystinosis is a genetic disorder that affects kidney and particularly proximal tubular epithelial cells (PTEC). Here, we investigated the expression of NLRP family members in human control and cystinotic conditionally immortalized PTEC. Among all the NLRPs tested, we found that NLRP2 is highly expressed in cystinostic PTEC, but not in PTEC from healthy subjects. The NLRP2 overexpression was confirmed in primary PTEC and in kidney biopsies from cystinotic patients. In order to elucidate the role of NLRP2 in PTEC, we stably transfected control PTEC with an NLRP2-containing plasmid. We showed that NLRP2 markedly increases the production of several NF-κB regulated cytokines and chemokines. Accordingly, we demonstrated that NLRP2 interacts with IKKa and positively regulates the DNA-binding activity of p50 and p65 NF-κB, by modulating the p65 NF-κB phosphorylation status in Serine 536. Transcriptome analysis revealed that NLRP2 also upregulates the expression of profibrotic mediators and reduces that of several interferon-inducible genes. Finally, NLRP2 overexpression decreased the apoptotic cell rate. Consistently, silencing of NLRP2 by small-interfering RNA in cystinotic PTEC resulted in a significant decrease in cytokine and chemokine production as well as in an increase in the apoptosis rate. Altogether, our data reveals a previously unrecognized role for NLRP2 in regulating proinflammatory, profibrotic and antiapoptotic responses in PTEC, through NF-κB activation. Moreover, our findings unveil a novel potential mechanism involving NLRP2 overexpression in the pathogenesis of cystinosis.

The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis.

Aim of this study was to investigate the activation of the IFNγ pathway in the affected liver and in the blood of patients with secondary hemophagocytic lymphohistiocytosis (sHLH). To this purpose, the mRNA expression levels of IFNG and IFNγ-inducible genes as well as Tyrosine (701)-phosphorylated signal transducer and activator of transcription 1 (STAT1) protein levels were evaluated in the liver and in peripheral blood mononuclear cells (PBMCs) of three patients with sHLH with predominant liver involvement. The mRNA expression levels of IFNG and IFNγ-inducible genes were markedly higher in patient livers compared to control livers and to one disease control liver. Conversely, slight differences in the expression levels of Type I IFN-inducible genes and other classical inflammatory cytokine genes were found. Further supporting the activation of the IFNγ pathway, higher protein levels of phosphorylated and total STAT1 were detected in patient livers compared to control livers. When the expression of the same genes analysed in liver tissues was evaluated in PBMCs collected from 2 out of 3 patients before the liver biopsy, we found that mRNA levels of IFNγ-inducible genes were markedly increased. Accordingly, high circulating levels of IFNγ-inducible CXCL9 were observed in patients. Altogether, these data demonstrate the selective and marked up-regulation of the IFNγ pathway in the liver tissue and blood of patients with active sHLH. Finally, we show that measurement of circulating CXCL9 levels and evaluation of IFNγ-inducible gene expression levels in PBMCs may represent a new valid tool to better identify patients with suspected HLH with predominant liver involvement.

A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.

Clinical efficacy of enzyme replacement therapy in paediatric Hunter patients, an independent study of 3.5 years.

BACKGROUND: Hunter Syndrome is an X-linked lysosomal storage disorder due to the deficit of iduronate 2-sulfatase, an enzyme catalysing the degradation of the glycosaminoglycans (GAG) dermatan- and heparan-sulfate. Treatment of the disease is mainly performed by Enzyme Replacement Therapy (ERT) with idursulfase, in use since 2006. Clinical efficacy of ERT has been monitored mainly by the Hunter Outcome Survey (HOS) while very few independent studies have been so far conducted. The present study is a 3.5-years independent follow-up of 27 Hunter patients, starting ERT between 1.6 and 27 years of age, with the primary aim to evaluate efficacy of the therapy started at an early age (<12 years). METHODS: In this study, we evaluated: urinary GAG content, hepato/splenomegaly, heart valvulopathies, otorinolaryngological symptoms, joint range of motion, growth, distance covered in the 6-minute walk test, neurological involvement. For data analysis, the 27 patients were divided into three groups according to the age at start of ERT: ≤5 years, >5 and ≤ 12 years and > 12 years. Patients were analysed both as 3 separate groups and also as one group; in addition, the 20 patients who started ERT up to 12 years of age were analysed as one group. Finally, patients presenting a "severe" phenotype were compared with "attenuated" ones. RESULTS: Data analysis revealed a statistically significant reduction of the urinary GAG in patients ≤5 years and ≤ 12 years and of the hepatomegaly in the group aged >5 and ≤ 12 years. Although other clinical signs improved in some of the patients monitored, statistical analysis of their variation did not reveal any significant changes following enzyme administration. The evaluation of ERT efficacy in relation to the severity of the disease evidenced slightly higher improvements as for hepatomegaly, splenomegaly, otological disorders and adenotonsillar hypertrophy in severe vs attenuated patients. CONCLUSIONS: Although the present protocol of idursulfase administration may result efficacious in delaying the MPS II somatic disease progression at some extent, in this study we observed that several signs and symptoms did not improve during the therapy. Therefore, a strict monitoring of the efficacy obtained in the patients under ERT is becoming mandatory for clinical, ethical and economic reasons.

Resveratrol enhances solar UV-induced responses in normal human epidermal keratinocytes.

Resveratrol (RV) differentially affects UV-induced death/pro-survival pathways in normal and tumor cells. On these grounds, RV-containing topical products have been developed to prevent UV-associated tumorigenesis/damage to human skin. In this study, we evaluated mechanisms of combined effects of RV and low-dose solar simulated UVA+UVB or 6-formylindo[3,2-b]carbazole (FICZ), a product of tryptophan photo-oxidation known to mediate UV effects, on the inflammatory, metabolic and proliferative responses of cultured normal human epidermal keratinocytes (HEK). Applied alone, RV, UV and FICZ induced time- and dose-dependent activation of aryl hydrocarbon receptor (AhR) pathway followed by over-expression of Cyp1A1 (metabolic response), UV and RV induced IL-8 expression (inflammatory response), while RV enhanced also HEK proliferation revealed by MTT assay and (3)H-thymidine incorporation. In the combined treatment, RV synergized with both UV and FICZ, leading to further activation of AhR machine, Cyp1A1 transcription and IL-8 expression, the latter partly AhR-dependent as assessed by AhR silencing. RV enhanced UV-induced NFkappaB activation and nuclear translocation of epidermal growth factor receptor. By contrast, proliferative effect of RV was abolished in the presence of UV, whereas synergic anti-proliferative action of RV+UV was observed in the Nrf2-silenced HEK. Our data suggest cooperative effects of RV-specific and UV-/FICZ-activated transcription factors leading to deregulated inflammatory, metabolic and proliferative responses of HEK.