Silvia Dossena

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Verified

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• PhD
• Interim Director at Paracelsus Medical University

Pendrin is a transport protein exchanging chloride for other anions, such as iodide in the thyroid gland or bicarbonate in the inner ear. Mutations in the SLC26A4 gene encoding for pendrin are responsible for both syndromic (Pendred syndrome) and non-syndromic (non-syndromic enlarged vestibular aqueduct, EVA) hearing loss. Besides clinical and radi...

The SLC26A4 gene, which encodes the anion exchanger pendrin, is involved in determining syndromic (Pendred syndrome) and non-syndromic (DFNB4) autosomal recessive hearing loss. SLC26A4 c.349C>T, p.L117F is a relatively common allele in the Ashkenazi Jewish community, where its minor allele frequency is increased compared to other populations. Altho...

The prevalence and spectrum of sequence alterations in the SLC26A4 gene, which codes for the anion exchanger pendrin, are population-specific and account for at least 50% of cases of non-syndromic hearing loss associated with an enlarged vestibular aqueduct. A cohort of nineteen patients from Austria with hearing loss and a radiological alteration...

Purpose Hearing loss (HL) is often monogenic. The clinical importance of genetic testing in HL may further increase when gene therapy products become available. Diagnoses are, however, complicated by a high genetic and allelic heterogeneity, particularly of autosomal dominant (AD) HL. This work aimed to characterize the mutational spectrum of AD HL...

Type II diabetes mellitus (T2D) is a metabolic disorder. Childhood overweight or obesity raises the risk for developing T2D later in life. Early identification of at-risk individuals is fundamental for disease prevention and patient management. The scope of this pilot study was to explore whether leukocyte protein O-GlcNAc modification is elevated...

Background The enlarged vestibular aqueduct (EVA) is the most commonly detected inner ear malformation. Biallelic pathogenic variants in the SLC26A4 gene, coding for the anion exchanger pendrin, are frequently involved in determining Pendred syndrome and nonsyndromic autosomal recessive hearing loss DFNB4 in EVA patients. In Caucasian cohorts, the...

Pendrin (SLC26A4) is an anion exchanger abundantly expressed in the inner ear, kidney and thyroid, and its malfunction resulting from genetic mutation leads to Pendred syndrome and non-syndromic deafness DFNB4. Pathogenic variants of the pendrin protein are less expressed than the wild-type, but the mechanism underlying this phenomenon is unknown....

β-thalassemia, a hereditary hemoglobinopathy, is caused by reduced or absent synthesis of the β-globin chains of hemoglobin. Three clinical conditions are recognized: β-thalassemia major, β-thalassemia intermedia, and β-thalassemia minor (β-Thal⁺). This latter condition occurs when an individual inherits a mutated β-globin gene from one parent. In...

Cisplatin is an established component of treatment protocols for various solid malignancies but carries a significant potential for serious adverse effects. Ototoxicity from cisplatin treatment is an important dose-limiting toxicity that manifests as bilateral, progressive, irreversible, dose-dependent sensorineural hearing loss, ear pain, tinnitus...

Global aging represents a challenge for social health [...]

Prediabetes is a risk state that defines a high chance of developing diabetes and cardiovascular disease. Oxidative stress mediated by hyperglycemia‐induced production of reactive species could play a crucial role in this context. In the present study, we investigated whether the anion exchange capability mediated by AE1 ( SLC4A1 ), which is sensit...

The voltage‐gated Kv3.1/KCNC1 channel is abundantly expressed in fast‐spiking principal neurons and GABAergic inhibitory interneurons throughout the ascending auditory pathway and in various brain regions. Inactivating mutations in the KCNC1 gene lead to forms of epilepsy and a decline in the expression of the Kv3.1 channel is involved in age‐relat...

Melatonin is a pleiotropic biofactor and an effective antioxidant and free radical scavenger and, as such, can be protective in oxidative stress‐related brain conditions including epilepsy and aging. To test the potential protective effect of melatonin on brain homeostasis and identify the corresponding molecular targets, we established a new model...

Introduction: During their lifespan in the bloodstream, red blood cells (RBCs) are exposed to multiple stressors, including increased oxidative stress, which can affect their morphology and function, thereby contributing to disease. Aim: This investigation aimed to explore the cellular and molecular mechanisms related to oxidative stress underlying...

Introduction: Aging is a process characterised by a decline in physiological functions. Reactive species play a crucial role in the aging rate. Due to the close relationship between aging and oxidative stress, functional foods rich in phytochemicals are excellent candidates to neutralise age-related changes. Aim: This investigation aims to verify t...

X-linked deafness (DFNX) is estimated to account for up to 2% of cases of hereditary hearing loss and occurs in both syndromic and non-syndromic forms. POU3F4 is the gene most commonly associated with X-linked deafness (DFNX2, DFN3) and accounts for about 50% of the cases of X-linked non-syndromic hearing loss. This gene codes for a transcription f...

The cause of childhood hearing impairment (excluding infectious pathology of the middle ear) can be extrinsic (embryofoetopathy, meningitis, trauma, drug ototoxicity, noise trauma, etc [...]

Volume-regulated anion channels (VRAC) are mainly involved in the regulated transport of osmolytes such as ions or small organic compounds across the plasma membrane during anisosmotic cell swelling. However, they also play additional roles in various pathophysiological processes, such as the transport of metabolites and drugs, extracellular signal...

Oxidative stress and immune response play an important role in the development of several cancers, including melanoma. Ion channels are aberrantly expressed in tumour cells and regulate neoplastic transformation, malignant progression, and resistance to therapy. Ion channels are localized in the plasma membrane or other cellular membranes and are t...

Editorial on the Research Topic: Ion transporters and Channels in Cellular Pathophysiology

Hearing loss (HL) is the most common sensory defect and affects 450 million people worldwide in a disabling form. Pathogenic sequence alterations in the POU3F4 gene, which encodes a transcription factor, are causative of the most common type of X-linked deafness (X-linked deafness type 3, DFN3, DFNX2). POU3F4-related deafness is characterized by a...

During their lifespan, red blood cells (RBCs) are exposed to a large number of stressors and are therefore considered as a suitable model to investigate cell response to oxidative stress (OS). This study was conducted to evaluate the potential beneficial effects of the natural antioxidant quercetin (Q) on an OS model represented by human RBCs treat...

Aging is a process characterised by a general decline in physiological functions. The high bioavailability of reactive oxygen species (ROS) plays an important role in the aging rate. Due to the close relationship between aging and oxidative stress (OS), functional foods rich in flavonoids are excellent candidates to counteract age-related changes....

Aging is a multi-factorial process developing through a complex net of interactions between biological and cellular mechanisms and it involves oxidative stress (OS) as well as protein glycation. The aim of the present work was to verify the protective role of Quercetin (Q), a polyphenolic flavonoid compound, in a d-Galactose (d-Gal)-induced model o...

Oxidative stress (OS) has a main role in the pathogenesis of central nervous system disorders. In this regard, epilepsy is a highly prevalent serious brain disease and its prevalence increases with age. Strikingly, about 50% of all epilepsy cases diagnosed in elderly patients (>65 years) are idiopathic. Metabolic changes, including the production o...

D‐Galactose (D‐Gal) is a reducing sugar whose concentration in the blood is very low (between 0.00008 and 0.00018 mmol/L). An abnormal accumulation of D‐Gal, which occurs in pathological conditions such as galactosemia or to reproduce experimental models such as aging, leads to an increase in oxidative events and the formation of advanced glycation...

The transport of chloride and bicarbonate across epithelia controls the pH and volume of the intracellular and luminal fluids, as well as the systemic pH and vascular volume. The anion exchanger pendrin (SLC26A4) and the cystic fibrosis transmembrane conductance regulator (CFTR) channel are expressed in the apical membrane of epithelial cells of va...

Bicarbonate is one of the major anions in mammalian tissues and fluids, is utilized by various exchangers to transport other ions and organic substrates across cell membranes and plays a critical role in cell and systemic pH homeostasis. Chloride/bicarbonate (Cl−/HCO3−) exchangers are abundantly expressed in erythrocytes and epithelial cells and, a...

Aging, a time-dependent multifaceted process, affects both cell structure and function and involves oxidative stress as well as glycation. The present investigation focuses on the role of the band 3 protein (B3p), an anion exchanger essential to red cells homeostasis, in a d-galactose ( d-Gal)-induced aging model. Anion exchange capability, measure...

Hearing loss is the most common sensorial deficit in humans and one of the most common birth defects. In developed countries, at least 60% of cases of hearing loss are of genetic origin and may arise from pathogenic sequence alterations in one of more than 300 genes known to be involved in the hearing function. Hearing loss of genetic origin is fre...

The transcriptional regulator peroxisome proliferator activated receptor gamma coactivator 1A (PGC-1α), encoded by PPARGC1A, has been linked to neurodegenerative diseases. Recently discovered CNS-specific PPARGC1A transcripts are initiated far upstream of the reference promoter, spliced to exon 2 of the reference gene, and are more abundant than re...

Oxidative stress on a cellular level affects the function of tissues and organs and eventually of the whole body [...]

Zusammenfassung Die in den vergangenen Jahren zunehmende Verfügbarkeit molekularer Untersuchungstechniken führt zu einer steigenden Anzahl diagnostizierter genetischer Varianten im Genom untersuchter Patienten. Am Beispiel der hereditären Innenohrschwerhörigkeit wird bei Betrachtung der Vielzahl publizierter Berichte über die mögliche Beteiligung e...

O-GlcNAcylation is a post-translational modification of proteins that controls a variety of cellular processes, is chronically elevated in diabetes mellitus, and may contribute to the progression of diabetic complications, including diabetic nephropathy. Our previous work showed that increases in the O-GlcNAcylation of cellular proteins impair the...

d-Galactose (d-Gal), when abnormally accumulated in the plasma, results in oxidative stress production, and may alter the homeostasis of erythrocytes, which are particularly exposed to oxidants driven by the blood stream. In the present investigation, the effect of d-Gal (0.1 and 10 mM, for 3 and 24 h incubation), known to induce oxidative stress,...

Objective: The impact of acute inflammation, revealed by C-reactive protein (CRP) plasma levels, has been studied on the erythrocytes anion exchanger Band 3 protein. Methods: Anion exchange capability through Band 3 protein, lipid peroxidation, -SH membrane groups and intracellular GSH levels have been measured on erythrocytes from patients with CR...

Diabetes mellitus leads to a number of complications involving brain function, including cognitive decline and depression. Depression is linked to impaired adult neurogenesis in the gyrus dentatus of the hippocampus, but the underlying molecular mechanisms are incompletely understood. The process of neurogenesis consists of the proliferation of neu...

Metabolic dysfunctions continuously expose human erythrocytes to sugars present in plasma during their circulatory life span of 120 days. Hyperglycemia in diabetes mellitus causes glycation of proteins along with oxidative stress in erythrocytes. Moreover, acute systemic administration of D‐galactose was used to artificially induce blood senescence...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

IClswell is the chloride current induced by cell swelling, and plays a fundamental role in several biological processes, including the regulatory volume decrease (RVD). ICln is a highly conserved, ubiquitously expressed and multifunctional protein involved in the activation of IClswell. In platelets, ICln binds to the intracellular domain of the in...

Clswell is the chloride current induced by cell swelling, and plays a fundamental role in several biological processes, including the regulatory volume decrease (RVD). ICln is a highly conserved, ubiquitously expressed and multifunctional protein involved in the activation of IClswell. In platelets, ICln binds to the intracellular domain of the int...

O‐GlcNacylation (O‐GlcNAc) is a post‐translational modification of serine or threonine residues of nuclear and cytoplasmic proteins and occurs via conjugation to a single monosaccharide, the N‐acetylglucosamine. O‐GlcNAc modification intervenes in a wide variety of physiological and pathological processes, and negatively affects the regulation of c...

C‐reactive protein (CRP) has a functional role in the inflammatory process and its concentration increases in circulation during inflammatory events. Transcriptional induction of the CRP gene mainly occurs in hepatocytes in the liver in response to increased levels of inflammatory cytokines, especially interleukin‐6 (IL‐6), therefore CRP is used as...

Pendrin (SLC26A4), a Cl⁻/anion exchanger, is expressed at high levels in kidney, thyroid, and inner ear epithelia, where it has an essential role in bicarbonate secretion/chloride reabsorption, iodide accumulation, and endolymph ion balance, respectively. Pendrin is expressed at lower levels in other tissues, such as airways and esophageal epitheli...

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. PGC-1α, encoded by PPARGC1A, is a transcriptional co-activator that has been implicated in the pathogenesis of neurodegenerative disorders. We recently discovered multiple new PPARGC1A transcripts that initiate from a novel promoter located far upstream of the r...

O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic post-translational modification of serine and threonine residues on nuclear and cytoplasmic proteins. O-GlcNAc modification influences many cellular mechanisms, including carbohydrate metabolism, signal transduction and protein degradation. Multiple studies also showed that cell cycle might be mo...

Cnidaria include the most venomous animals of the world. Among Cnidaria, Scyphozoa (true jellyfish) are ubiquitous, abundant, and often come into accidental contact with humans and, therefore, represent a threat for public health and safety. The venom of Scyphozoa is a complex mixture of bioactive substances—including thermolabile enzymes such as p...

Background/Aims: In the human genome, more than 400 genes encode ion channels, which are ubiquitously expressed and often coexist and participate in almost all physiological processes. Therefore, ion channel blockers represent fundamental tools in discriminating the contribution of individual channel types to a physiological phenomenon. However, un...

Background/aim: Accurate genotyping of CYP2D6 is challenging due to its inherent genetic variation, copy number variation (duplications and deletions) and hybrid formation with highly homologous pseudogenes. Because a relatively high percentage (∼25%) of clinically prescribed drugs are substrates for this enzyme, accurate determination of its geno...

Interleukin-13 (IL13) is a major player in the development of airway hyperresponsiveness in several respiratory disorders. Emerging data suggest that an increased expression of pendrin in airway epithelia is associated with elevated airway hyperreactivity in asthma. Here, we investigate the effect of IL13 on pendrin localization and function using...

Lipoyl(Octanoyl) Transferase 2 (LIPT2) is a protein involved in the post-translational modification of key energy metabolism enzymes in humans. Defects of lipoic acid synthesis and transfer start to emerge as causes of fatal or severe early-onset disease. We show that the first 31 amino acids of the N-terminus of LIPT2 represent a mitochondrial tar...

Oxygen consumption in intact HEK 293 Phoenix cells determined by O2k high-resolution respirometry. (A) Representative traces of the respiration in intact cells. The blue line represents the oxygen concentration, the red line the oxygen flux. A coupling control protocol was applied after adding the cells into the O2k-chambers. (B) ROUTINE respiratio...

Whole-field determination of mitochondrial membrane potential and measurements of mitochondrial function (oxygen consumption) in intact cells. (DOCX)

LIPT2-EYFP targets the mitochondrion. Pearson’s correlation coefficient, overlap coefficient and co-localization rate (%) referred to the co-localization of EYFP, EYFP-LIPT2 or LIPT2-EYFP and the mitochondrion determined in HEK 293 Phoenix cells (A), 24, (B), 48 and (C), 72 hours after transfection. (n) indicates the number of cells. *: p<0.05, **:...

The mitochondrial targeting sequence of LIPT2 can generate an amphipathic α helix. (A) Amino acid sequence of LIPT2. The mitochondrial targeting sequence (amino acids 1–31) is highlighted in yellow. (B) Helical wheel projection of the mitochondrial targeting sequence of LIPT2, with the first (M1) and the last (Q31) amino acids in grey circles. In (...

Whole-field determination of mitochondrial membrane potential. (A) From left to right: fluorescent signal of Hoechst (nucleus), EYFP, Mito Tracker Deep Red (mitochondrial potential) and corresponding merge image of HEK 293 Phoenix cells transfected for 48 hours with the indicated constructs. Scale bar: 30 μm. (B) From left to right: fluorescent sig...

LIPT2-induced apoptosis is not dependent on endoplasmic reticulum stress and LIPT2 is not released from the mitochondrion following induction of apoptosis. (A) HEK 293 Phoenix cells were transfected for 48 hours with the indicated constructs or left untransfected (native). Caspase-12 was immunodetected in whole cell lysates. Cleaved caspase-12 was...

Methods: Real-time PCR and pyrosequencing were used to respectively quantify pendrin mRNA levels and methylation of pendrin promoter, with and without IL-4 stimulation, in healthy and diseased primary HBE cells, as well as NCI-H292 cells. Results: Increases in pendrin mRNA after IL-4 stimulation was more robust in NCI-H292 cells than in primary...

Pendrin (SLC26A4) is an electroneutral anion exchanger in which function-altering mutations cause inherited forms of non-syndromic (DFNB4) and syndromic deafness (Pendred syndrome) characterized by inner ear malformations. Elevated pendrin expression has also been identified as a risk modifier for inflammatory and infectious lung diseases. In addit...

This book reviews the current state of knowledge on the genetics, molecular biology and physiology of pendrin, with a particular focus on pendrin dysfunction and the consequences for human health. Pendrin is a membrane transport protein expressed in the thyroid, inner ear, kidney and airways, and was recently found in a variety of other tissues a...

Cnidarians may negatively impact human activities and public health but concomitantly their venom represents a rich source of bioactive substances. Pelagia noctiluca is the most venomous and abundant jellyfish of the Mediterranean Sea and possesses a venom with hemolytic and cytolytic activity for which the mechanism is largely unknown. Here we sho...

The present investigation aims to verify whether cadmium (Cd2+), a metal possibly accumulated in body tissues from air and food, affects cell volume regulation capability in cultured human embryonic kidney (HEK 293 Phoenix) cells. The osmotic phase (OP), which is the expected cell swelling due to aquaporins involvement after hyposmotic challenge, a...

Background/aims: Pendrin is a Cl-/I-/HCO3- exchanger playing a fundamental role in controlling blood pressure and airway function, therefore representing an attractive target for the treatment of hypertensive states and respiratory distresses. A review of the literature regarding the ability of some compounds (namely several known inhibitors of io...

Sequence alterations in the pendrin gene (SLC26A4) leading to functionally affected protein variants are frequently involved in the pathogenesis of syndromic and non-syndromic deafness. Considering the high number of SLC26A4 sequence alterations reported up to date, discriminating between functionally affected and unaffected pendrin protein variant...

Over the past few decades, mortality resulting from cardiovascular disease (CVD) steadily decreased in western countries; however, in recent years, the decline has become offset by the increase in obesity. Obesity is strongly associated with the metabolic syndrome and its atherogenic dyslipidemia resulting from insulin resistance. While lifestyle t...

The genomic region ~500 kb upstream of IRS1 has been implicated in insulin resistance, type 2 diabetes, adverse lipid profile, and cardiovascular risk. To gain further insight into this chromosomal region, we typed four SNPs in a cross-sectional cohort and subjects with type 2 diabetes recruited from the same geographic region. From 16 possible hap...

Supplementary Material contains 17 Supplementary Tables showing additional clinical data of study subjects, sequences of primers used for PCR and generation of in vitro translation and eGFP constructs, genotypes by SNPs and sex, pairwise linkage disequilibria between SNPs and associations of haplotypes with traits by sex.

Crude venom from nematocysts of the Scyphozoan Pelagia noctiluca possesses hemolytic and cytotoxic power on cultured cells and elicits local and systemic inflammation reactions in vivo. The ability of regulating their volume after exposure to an anisosmotic solution is a fundamental feature common to cells from vertebrates and invertebrates, includ...

Oxidative stress plays a critical role in the pathophysiology of several kidney diseases and is the consequence of alterations like ischemic events. The regulatory volume decrease (RVD) is an homeostatic response essential to many cells, including renal cells, to counteract changes in the osmolarity of the external medium. The aim of the present wo...

The small hydrophobic (SH) protein is a 64-amino acid polypeptide encoded by the human respiratory syncytial virus (hRSV). SH protein has a single α-helical transmembrane (TM) domain that forms pentameric ion channels. Herein, we report the first inhibitor of the SH protein channel, pyronin B, and we have mapped its binding site to a conserved surf...

Background: Pollution of marine ecosystems and, specifically, heavy metals contamination may compromise the physiology of marine animals with events occurring on a cellular and molecular level. The present study focuses on the effect of short-term exposure to heavy metals like Zinc, Cadmium, Cobalt and Lanthanum (2-10 mM) on the homeostasis of Pela...

Nematocyst discharge and concomitant delivery of toxins is triggered to perform both defence and predation strategies in Cnidarians, and may lead to serious local and systemic reactions in humans. Pelagia noctiluca (Cnidaria, Scyphozoa) is a jellyfish particularly abundant in the Strait of Messina (Italy). After accidental contact with this jellyfi...

Background: We recently reported that aquaporin 5 (AQP5), a water channel never identified in the kidney before, co-localizes with pendrin at the apical membrane of type-B intercalated cells in the kidney cortex. Since co-expression of AQP5 and pendrin in the apical membrane domain is a common feature of several other epithelia such as cochlear and...