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Article ; Online: Functional interplay between CFTR and pendrin

Grazia Tamma / Silvia Dossena

Frontiers in Bioscience-Landmark, Vol 27, Iss 2, p

physiological and pathophysiological relevance

2022 Volume 075

Abstract: 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 ... ...

Abstract	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 various organs and tissues, including the airways, kidney, thyroid, and inner ear. While pendrin drives chloride reabsorption and bicarbonate, thiocyanate or iodide secretion within the apical compartment, CFTR represents a pathway for the apical efflux of chloride, bicarbonate, and possibly iodide. In the airways, pendrin and CFTR seems to be involved in alkalinization of the apical fluid via bicarbonate secretion, especially during inflammation, while CFTR also controls the volume of the apical fluid via a cAMP-dependent chloride secretion, which is stimulated by pendrin. In the kidney, pendrin is expressed in the cortical collecting duct and connecting tubule and co-localizes with CFTR in the apical membrane of β intercalated cells. Bicarbonate secretion occurs via pendrin, which also drives chloride reabsorption. A functional CFTR is required for pendrin activity. Whether CFTR stimulates pendrin via a direct molecular interaction or other mechanisms, or simply provides a pathway for chloride recycling across the apical membrane remains to be established. In the thyroid, CFTR and pendrin might have overlapping functions in driving the apical flux of iodide within the follicular lumen. In other organs, including the inner ear, the possible functional interplay between pendrin and CFTR needs to be explored.
Keywords	cftr ; pendrin/slc26a4 ; lung ; kidney ; thyroid ; inner ear ; review ; Biochemistry ; QD415-436 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	IMR Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Clinical and Molecular Aspects Associated with Defects in the Transcription Factor POU3F4

Emanuele Bernardinelli / Florian Huber / Sebastian Roesch / Silvia Dossena

Biomedicines, Vol 11, Iss 1695, p

A Review

2023 Volume 1695

Abstract: 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 ... ...

Abstract	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 factor of the POU family that plays a major role in the development of the middle and inner ear. The clinical features of POU3F4-related hearing loss include a pathognomonic malformation of the inner ear defined as incomplete partition of the cochlea type 3 (IP-III). Often, a perilymphatic gusher is observed upon stapedectomy during surgery, possibly as a consequence of an incomplete separation of the cochlea from the internal auditory canal. Here we present an overview of the pathogenic gene variants of POU3F4 reported in the literature and discuss the associated clinical features, including hearing loss combined with additional phenotypes such as cognitive and motor developmental delays. Research on the transcriptional targets of POU3F4 in the ear and brain is in its early stages and is expected to greatly advance our understanding of the pathophysiology of POU3F4-linked hearing loss.
Keywords	POU3F4 ; X-linked deafness ; transcription factor ; hearing loss ; gene variants ; Biology (General) ; QH301-705.5
Subject code	390
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Oxidative Stress and Immune Response in Melanoma

Alessia Remigante / Sara Spinelli / Angela Marino / Michael Pusch / Rossana Morabito / Silvia Dossena

International Journal of Molecular Sciences, Vol 24, Iss 1, p

Ion Channels as Targets of Therapy

2023 Volume 887

Abstract: 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 ... ...

Abstract	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 targets of oxidative stress, which is particularly elevated in melanoma. At the same time, ion channels are crucial for normal and cancer cell physiology and are subject to multiple layers of regulation, and therefore represent promising targets for therapeutic intervention. In this review, we analyzed the effects of oxidative stress on ion channels on a molecular and cellular level and in the context of melanoma progression and immune evasion. The possible role of ion channels as targets of alternative therapeutic strategies in melanoma was discussed.
Keywords	oxidative stress ; immune response ; cancer ; melanoma ; ion channels ; Ca 2+ signaling ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	571 ; 572
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Açaì ( Euterpe oleracea ) Extract Protects Human Erythrocytes from Age-Related Oxidative Stress

Alessia Remigante / Sara Spinelli / Elisabetta Straface / Lucrezia Gambardella / Daniele Caruso / Giuseppe Falliti / Silvia Dossena / Angela Marino / Rossana Morabito

Cells, Vol 11, Iss 2391, p

2022 Volume 2391

Abstract: 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), ... ...

Abstract	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. This study aimed to verify the protective role of Açaì extract in a d -Galactose ( d -Gal)-induced model of aging in human erythrocytes. Markers of OS, including ROS production, thiobarbituric acid reactive substances (TBARS) levels, oxidation of protein sulfhydryl groups, as well as the anion exchange capability through Band 3 protein (B3p) and glycated haemoglobin (A1c) have been analysed in erythrocytes treated with d -Gal for 24 h, with or without pre-incubation for 1 h with 0.5–10 µg/mL Açaì extract. Our results show that the extract avoided the formation of acanthocytes and leptocytes observed after exposure to 50 and 100 mM d -Gal, respectively, prevented d -Gal-induced OS damage, and restored alterations in the distribution of B3p and CD47 proteins. Interestingly, d -Gal exposure was associated with an acceleration of the rate constant of SO 4 2− uptake through B3p, as well as A1c formation. Both alterations have been attenuated by pre-treatment with the Açaì extract. These findings contribute to clarify the aging mechanisms in human erythrocytes and propose functional foods rich in flavonoids as natural antioxidants for the treatment and prevention of OS-related disease conditions.
Keywords	Açaí berry ; d -Galactose ; aging ; oxidative stress ; glycation ; plasma membrane ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Interleukin-Mediated Pendrin Transcriptional Regulation in Airway and Esophageal Epithelia

Simone Vanoni / Giada Scantamburlo / Silvia Dossena / Markus Paulmichl / Charity Nofziger

International Journal of Molecular Sciences, Vol 20, Iss 3, p

2019 Volume 731

Abstract: 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, ... ...

Abstract	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 epithelia, where it is transcriptionally regulated by the inflammatory cytokines interleukin (IL)-4 and IL-13 through a signal transducer and activator of transcription 6 (STAT6)-mediated pathway. In the airway epithelium, increased pendrin expression during inflammatory diseases leads to imbalances in airway surface liquid thickness and mucin release, while, in the esophageal epithelium, dysregulated pendrin expression is supposed to impact the intracellular pH regulation system. In this review, we discuss some of the recent findings on interleukin-mediated transcriptional regulation of pendrin and how this dysregulation impacts airway and esophagus epithelial homeostasis during inflammatory diseases.
Keywords	pendrin ; interleukins ; airway epithelium ; esophageal epithelium ; asthma ; eosinophilic esophagitis ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2019-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: O-Linked N-Acetylglucosamine Transiently Elevates in HeLa Cells during Mitosis

Viktória Fisi / Emese Kátai / József Orbán / Silvia Dossena / Attila Miseta / Tamás Nagy

Molecules, Vol 23, Iss 6, p

2018 Volume 1275

Abstract: 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, ... ...

Abstract	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 modulated by O-GlcNAc. Although the role of O-GlcNAc in the regulation of some cell cycle processes such as mitotic spindle organization or histone phosphorylation is well established, the general behaviour of O-GlcNAc regulation during cell cycle is still controversial. In this study, we analysed the dynamic changes of overall O-GlcNAc levels in HeLa cells using double thymidine block. O-GlcNAc levels in G1, S, G2 and M phase were measured. We observed that O-GlcNAc levels are significantly increased during mitosis in comparison to the other cell cycle phases. However, this change could only be detected when mitotic cells were enriched by harvesting round shaped cells from the G2/M fraction of the synchronized cells. Our data verify that O-GlcNAc is elevated during mitosis, but also emphasize that O-GlcNAc levels can significantly change in a short period of time. Thus, selection and collection of cells at specific cell-cycle checkpoints is a challenging, but necessary requirement for O-GlcNAc studies.
Keywords	cell cycle ; cell synchronization ; mitosis ; O-GlcNAc ; post-translational modifications ; Organic chemistry ; QD241-441
Subject code	571
Language	English
Publishing date	2018-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases

Markus Kwik / Stefan Hainzl / Jan Oppelt / Boris Tichy / Ulrich Koller / Emanuele Bernardinelli / Markus Steiner / Greta Zara / Charity Nofziger / Serge Weis / Markus Paulmichl / Silvia Dossena / Wolfgang Patsch / Selma M. Soyal

International Journal of Molecular Sciences, Vol 22, Iss 3296, p

2021 Volume 3296

Abstract: 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 ... ...

Abstract	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 reference gene transcripts in post-mortem human brain samples. The proteins translated from the CNS and reference transcripts differ only at their N-terminal regions. To dissect functional differences between CNS-specific isoforms and reference proteins, we used clustered regularly interspaced short palindromic repeats transcriptional activation (CRISPRa) for selective endogenous activation of the CNS or the reference promoters in SH-SY5Y cells. Expression and/or exon usage of the targets was ascertained by RNA sequencing. Compared to controls, more differentially expressed genes were observed after activation of the CNS than the reference gene promoter, while the magnitude of alternative exon usage was comparable between activation of the two promoters. Promoter-selective associations were observed with canonical signaling pathways, mitochondrial and nervous system functions and neurological diseases. The distinct N-terminal as well as the shared downstream regions of PGC-1α isoforms affect the exon usage of numerous genes. Furthermore, associations of risk genes of amyotrophic lateral sclerosis and Parkinson’s disease were noted with differentially expressed genes resulting from the activation of the CNS and reference gene promoter, respectively. Thus, CNS-specific isoforms markedly amplify the biological functions of PPARGC1A and CNS-specific isoforms and reference proteins have common, complementary and selective functions relevant for neurodegenerative diseases.
Keywords	PPARGC1A ; PGC-1α ; CNS-specific transcripts and isoforms ; CRISPR ; RNA sequencing ; RNA expression ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Oxidative stress affects responsiveness to hypotonicity of renal cells

Rossana Morabito / Giuseppa La Spada / Silvia Dossena / Angela Marino

Journal of Biological Research, Vol 87, Iss

2014 Volume 2

Abstract: 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 ... ...

Abstract	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 work is to verify whether oxidative stress affects RVD in a model of renal cells (human embryonic kidney cells, HEK 293 Phoenix). To accomplish this aim, the experimental procedure consisted in: i) cell culture preparation and treatment with 200 μM H 2 O 2 and ii) measurement of cell volume changes in isotonic conditions or following hypotonic stress. H 2 O 2 added to the extracellular isotonic solution induced a significant reduction in cell volume, and added to the extracellular hypotonic solution dramatically impaired the expected osmotic cell swelling. Pre-incubation of cells in an extracellular isotonic solution containing H 2 O 2 prevented cell from swelling after hypotonic stress application. In conclusion, H 2 O 2 leads to cell shrinkage in isotonic conditions, inhibits the hypotonicity-induced cell swelling and consequently prevents RVD, hypothetically due to an activation of transport pathways determining ion loss and, in turn, water efflux. Cell shrinkage in isotonic conditions is a hallmark of apoptosis and is known as the apoptotic volume decrease.
Keywords	cell volume regulation ; RVD ; oxidative stress ; kidney cells ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2014-11-01T00:00:00Z
Publisher	PAGEPress Publications
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Regulatory volume decrease in isolated nematocytes is affected by crude venom from the jellyfish Pelagia noctiluca

Rossana Morabito / Silvia Dossena / Giuseppa La Spada / Angela Marino

Journal of Biological Research, Vol 87, Iss

2014 Volume 2

Abstract: 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 ... ...

Abstract	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, including Cnidarians. The aim of the present work i s to assay whether crude venom from Pelagia noctiluca may affect the regulatory volume decrease (RVD) of nematocytes isolated from the Anthozoan Aiptasia mutabilis , here employed as a cell model. For this purpose, nematocytes were isolated by 605 mM NaSCN plus 0.01 mM Ca2+ application on acontia of Aiptasia mutabilis , while crude venom was obtained by sonication of a population of, respectively, 10, 25 and 50 nematocysts/µL (n/µL). Isolated nematocytes were pre-treated for 30 min with crude venom, submitted to hypotonic stress and their osmotic response and RVD were measured optically. Our results show that, after exposure to crude venom, nematocytes were morphologically intact, as shown by the Trypan blue exclusion test, but did not exhibit RVD. This effect was dose-dependent and reversed by the ionopho re gramicidin. The last observation suggests an inhibitory effect of venom on cell membrane ion transport mechanisms involved in RVD. Further studies are needed to verify this hypothesis and ascertain if a similar effect could be observed in human cells.
Keywords	crude venom ; RVD ; nematocytes ; Pelagia noctiluca ; Aiptasia mutabilis ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2014-11-01T00:00:00Z
Publisher	PAGEPress Publications
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cadmium affects osmotic phase and regulatory volume decrease in cultured human embryonic kidney cells

Rossana Morabito / Alessia Remigante / Roberta Costa / Silvia Dossena / Giuseppa La Spada / Angela Marino

Journal of Biological Research, Vol 89, Iss

2016 Volume 1

Abstract: The present investigation aims to verify whether cadmium (Cd 2+ ), 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) ...

Abstract	The present investigation aims to verify whether cadmium (Cd 2+ ), 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, and regulatory volume decrease (RVD), bringing cell volume back to control values through Ca 2+ -dependent ion efflux (K+ and Cl–), have been monitored in HEK 293 cells treated with Cd 2+ (1-10-100 μM) for different time intervals (30 min, 3 h, overnight) and then submitted to 15 % hyposmotic shock. The results show that both 1 and 10 μM Cd 2+ significantly reduced OP, whereas 100 μM impaired Cd 2+ RVD mechanisms. The use of glutathione (GSH, 200 μM) confirmed that Cd 2+ elicited its effect via oxidative damage, being RVD inhibition after Cd 2+ treatment prevented by this antioxidant compound. Our findings show that: i) HEK 293 cells are a suitable model to assay the effect of xenobiotics on cell homeostasis; ii) Cd 2+ , depending on its concentration, affects cell homeostasis at different levels, i.e. water and ion permeability, responsible for, respectively, OP and RVD mechanism, adding thus more information to the knowledge of Cd 2+ toxicology.
Keywords	Cd2+ ; HEK 293 Phoenix cells ; Osmotic phase ; Regulatory volume decrease ; GSH ; Biology (General) ; QH301-705.5
Subject code	333
Language	English
Publishing date	2016-06-01T00:00:00Z
Publisher	PAGEPress Publications
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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