Papers by Israel Hanukoglu
Current Problems in Dermatology
and abnormal epidermal dlfferentlatlon/ volume editors, Makoto Sel]l, I A Bernstein.-Basel, New Y... more and abnormal epidermal dlfferentlatlon/ volume editors, Makoto Sel]l, I A Bernstein.-Basel, New York: Karger, 1983. (Current problems In dermatology: v. II) I Epidermis-cytology 2 Epidermis-physiology 3 Keratin-biosynthesIs 4. Keratin-physiology 5. Skin-anatomy & histology I. Bernstein, I. A II Sel]l, Makoto Ill. SerIes ISBN 3-8055-3752-2 WI CU804L v. II [WR 101 N842] © UNIVERSITY OF TOKYO PRESS, 1983 UTP 3047-68292-5149 Prin ted in Japan. All rights reserved No part of this pUblication may be translated into other languages, reproduced or ut!lized In any from or by any means, electronic or mechamcal, Including photocopymg, recording, microcopying, or by any informatIOn storage and retrIeval system, without permiSSIOn in wrItmg from the publisher. S. Karger AG, P.O. Box, CH-4009 Basel(Swltzerland)has the sale distribution nghts for all countries, with the exception of Japan.
The FASEB Journal, 2011
This study was designed to evaluate the changes number of cells of the two selected probiotic bac... more This study was designed to evaluate the changes number of cells of the two selected probiotic bacteria, B. longum TISTR2195 and L. plantarum TISTR1465, and yeast S. cerevisiae TISTR8656. The microorganisms were cultured in two types of media, namely selective media and protein base model. Selective media were divided into 4 subgroups: with 2% glucose added as a positive control (i), inulin (ii), fructo-oligosaccharide (FOS) (iii), and without added carbon source as negative control (iv). Protein base media had chicken egg and coconut juice, baker's yeast and potassium chloride (i), with 9% FOS (ii), or inulin (iii), or 7.34% whey protein (iv) to verify growth. All the probiotics were able to utilize inulin and FOS to growth. The numbers of cells increased with incubation time. However, L. plantarum produced an acidic in the selective culture medium significantly. Protein based with FOS and inulin added supported all probiotics growth. In addition, acetic acid content was the highest among short-chain fatty acids (SCFAs) produced. B. longum produced acetic acid very fast within 24 h. L. plantarum cultured in inulin added provided the peak level of acetic acid at 72 h. However, S. cerevisiae tended to decrease the SCFAs with incubation time.
Journal of molecular evolution, 2017
FAD and NAD(P) together represent an ideal pair for coupled redox reactions in their capacity to ... more FAD and NAD(P) together represent an ideal pair for coupled redox reactions in their capacity to accept two electrons and their redox potentials. Enzymes that bind both NAD(P) and FAD represent large superfamilies that fulfill essential roles in numerous metabolic pathways. Adrenodoxin reductase (AdxR) shares Rossmann fold features with some of these superfamilies but remains in a group of its own in the absence of sequence homology. This article documents the phylogenetic distribution of AdxR by examining whole genome databases for Metazoa, Plantae, Fungi, and Protista, and determines the conserved structural features of AdxR. Scanning these databases showed that most organisms have a single gene coding for an AdxR ortholog. The sequence identity between AdxR orthologs is correlated with the phylogenetic distance among metazoan species. The NADP binding site of all AdxR orthologs showed a modified Rossmann fold motif with a GxGxxA consensus instead of the classical GxGxxG at the ed...
Histochemistry and cell biology, Jan 27, 2017
A major function of the skin is the regulation of body temperature by sweat secretions. Sweat gla... more A major function of the skin is the regulation of body temperature by sweat secretions. Sweat glands secrete water and salt, especially NaCl. Excreted water evaporates, cooling the skin surface, and Na(+) ions are reabsorbed by the epithelial sodium channels (ENaC). Mutations in ENaC subunit genes lead to a severe multi-system (systemic) form of pseudohypoaldosteronism (PHA) type I, characterized by salt loss from aldosterone target organs, including sweat glands in the skin. In this study, we mapped the sites of localization of ENaC in the human skin by confocal microscopy using polyclonal antibodies generated against human αENaC. Our results reveal that ENaC is expressed strongly in all epidermal layers except stratum corneum, and also in the sebaceous glands, eccrine glands, arrector pili smooth muscle cells, and intra-dermal adipocytes. In smooth muscle cells and adipocytes, ENaC is co-localized with F-actin. No expression of ENaC was detected in the dermis. CFTR is strongly exp...
Gene, 2016
The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow... more The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na + ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na + in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. In multi-ciliated cells, ENaC is located in cilia and plays an essential role in the regulation of epithelial surface liquid volume necessary for cilial transport of mucus and gametes in the respiratory and reproductive tracts respectively. The subunits that form ENaC (named as alpha, beta, gamma and delta, encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D) are members of the ENaC/Degenerin superfamily. The earliest appearance of ENaC orthologs is in the genomes of the most ancient vertebrate taxon, Cyclostomata (jawless vertebrates) including lampreys, followed by earliest representatives of Gnathostomata (jawed vertebrates) including cartilaginous sharks. Among Euteleostomi (bony vertebrates), Actinopterygii (ray finned-fishes) branch has lost ENaC genes. Yet, most animals in the Sarcopterygii (lobe-finned fish) branch including Tetrapoda, amphibians and amniotes (lizards, crocodiles, birds, and mammals), have four ENaC paralogs. We compared the sequences of ENaC orthologs from 20 species and established criteria for the identification of ENaC orthologs and paralogs, and their distinction from other members of the ENaC/Degenerin superfamily, especially ASIC family. Differences between ENaCs and ASICs are summarized in view of their physiological functions and tissue distributions. Structural motifs that are conserved throughout vertebrate ENaCs are highlighted. We also present a comparative overview of the genotype-phenotype relationships in inherited diseases associated with ENaC mutations, including multisystem pseudohypoaldosteronism (PHA1B), Liddle syndrome, cystic fibrosis-like disease and essential hypertension.
Biochemistry and molecular biology education : a bimonthly publication of the International Union of Biochemistry and Molecular Biology, Jan 20, 2015
The Rossmann fold is one of the most common and widely distributed super-secondary structures. It... more The Rossmann fold is one of the most common and widely distributed super-secondary structures. It is composed of a series of alternating beta strand (β) and alpha helical (α) segments wherein the β-strands are hydrogen bonded forming a β-sheet. The initial beta-alpha-beta (βαβ) fold is the most conserved segment of Rossmann folds. As this segment is in contact with the ADP portion of dinucleotides such as FAD, NAD, and NADP it is also called as an "ADP-binding βαβ fold". The Proteopedia entry on the Rossmann fold (Available at: http://proteopedia.org/w/Rossmann_fold) was generated to illustrate several structural aspects of super families of FAD and NAD(P) binding proteins: (1) The coenzymes FAD and NAD(P) share the basic adenosine diphosphate (ADP) structure. (2) The βαβ fold motif that is common to both FAD and NAD(P) binding enzymes accommodates the common ADP component of these two coenzymes. (3) In both FAD and NAD(P) binding sites, the tight turn between the first β-...
Journal of Cell Biology, 1990
Advances in Molecular and Cell Biology, 1996
IUPHAR/BPS Guide to Pharmacology CITE, 2021
The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in t... more The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and some other organs [9, 13, 22, 21, 42]. In these epithelia, Na+ ions flow from the extracellular fluid into the cytoplasm of epithelial cells via ENaC. The Na+ ions are then pumped out of the cytoplasm into the interstitial fluid by the Na+/K+ ATPase located on the basolateral membrane [36]. As Na+ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na+ flow is accompanied by a flow of water accompanying Na+ ions [6]. Thus, ENaC has a central role in regulating ECF volume and blood pressure, primarily via its function in the kidney [37]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angiotensin-aldosterone system, and other factors involved in electrolyte homeostasis [37, 30]. In ...
The FEBS Journal, 2016
The acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) are members of a supe... more The acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) are members of a superfamily of channels that play critical roles in mechanosensation, chemosensation, nociception, and regulation of blood volume and pressure. These channels look and function like a tripartite funnel that directs the flow of Na + ions into the cytoplasm via the channel pore in the membrane. The subunits that form these channels share a common structure with two transmembrane segments (TM1 and TM2) and a large extracellular part. In most vertebrates, there are five paralogous genes that code for ASICs (ASIC1-ASIC5), and four for ENaC subunits alpha, beta, gamma, and delta (a, b, c, and d). While ASICs can form functional channels as a homo-or heterotrimer, ENaC functions as an obligate heterotrimer composed of a-b-c or b-c-d subunits. The structure of ASIC has been determined in several conformations, including desensitized and open states. This review presents a comparison of the structures of these states using easy-to-understand molecular models of the full complex, the central tunnel that includes an outer vestibule, the channel pore, and ion selectivity filter. The differences in the secondary, tertiary, and quaternary structures of the states are summarized to pinpoint the conformational changes responsible for channel opening. Results of site-directed mutagenesis studies of ENaC subunits are examined in light of ASIC1 models. Based on these comparisons, a molecular model for the selectivity filter of ENaC is built by in silico mutagenesis of an ASIC1 structure. These models suggest that Na + ions pass through the filter in a hydrated state.
British Journal of Pharmacology
IUPHAR/BPS Guide to Pharmacology CITE
The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in t... more The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the distal kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon and some other organs [20, 11, 7]. In these epithelia, ENaC allows flow of Na+ ions from the extracellular fluid in the lumen into the epithelial cell. Na+ ions are then pumped out of the cytoplasm into the interstitial fluid by the Na+/K+ ATPase located on the basolateral membrane [39]. As Na+ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na+ flow is accompanied by a flow of water accompanying Na+ ions [6]. Thus, ENaC has a central role in the regulation of ECF volume and blood pressure, especially via its function in the kidney [25, 30]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angotensin-aldosterone system, and other factors that are involved in electrolyte homeos...
The FEBS Journal
The basic functional unit in a kidney is the nephron, which is a long and morphologically segment... more The basic functional unit in a kidney is the nephron, which is a long and morphologically segmented tubule. The nephron begins with a cluster of capillaries called glomerulus through which the blood is filtered into the Bowman's space. The filtrate flows through the nephron segments. During this flow, electrolytes and solutes are reabsorbed by channels and transport systems into the capillaries wrapped around the nephron. Many questions related to renal function focus on identifying the sites of expression of these systems. In this study, we mapped whole kidney sections by confocal microscopic imaging of fluorescent phalloidin, which binds to actin filaments. In tile‐scans (composed of hundreds of images) of these sections, the cortex and the medullary regions (outer and inner stripes of the outer medulla, and inner medulla) could be easily identified by their cytoskeletal patterns. At a higher resolution, we identified distinct features of the actin cytoskeleton in the apical, basal, and lateral borders of the cells. These features could be used to identify segments of a nephron (the proximal tubule, thin and thick segments of Henle's loop, and distal tubule), the collecting duct system, the papillary ducts in the papilla and the urothelium that covers the pelvis. To verify our findings, we used additional markers, including aquaporin isoforms, cytokeratin 8‐18, and WGA lectin. This study highlights the power of high‐resolution confocal microscopy for identifying specific cell types using the simple probe of F‐actin‐binding phalloidin.
Clinical endocrinology, Jan 27, 2018
The Journal of steroid biochemistry and molecular biology, Jan 6, 2018
Pseudohypoaldosteronism type 1 (PHA) is a syndrome of unresponsiveness to aldosterone. The severe... more Pseudohypoaldosteronism type 1 (PHA) is a syndrome of unresponsiveness to aldosterone. The severe form of this disease results from mutations in the genes that encode for the epithelial sodium channel subunits, SCNN1A, SCNN1B, and SCNN1G. A PHA patient under our care failed to conceive after many years and IVF trials. Our earlier studies had shown that ENaC is expressed in the female reproductive tract. We hypothesized that a defective ENaC expression may be responsible for the infertility of the patient. To test this hypothesis we examined ENaC expression in endometrial Pipelle biopsy samples from three healthy women and the PHA patient with an Arg508X mutation in the SCNN1A gene. The formalin fixed samples were reacted with anti-ENaCA (alpha subunit) antisera, followed by secondary antibodies to visualize ENaC expression by immunofluorescence. Confocal microscopy imaging of the samples showed strong ENaC immunofluorescence along the luminal border (apical membrane) of the epitheli...
Gene, Jan 2, 2016
Wikipedia and other openly available resources are increasingly becoming commonly used sources of... more Wikipedia and other openly available resources are increasingly becoming commonly used sources of information not just among the lay public but even in academic circles including undergraduate students and postgraduate trainees. To enhance the quality of the Wikipedia articles, in 2013, we initiated the Gene Wiki Reviews on genes and proteins as a series of invited reviews that stipulated editing the corresponding Wikipedia article(s) that would be also subject to peer-review. Thus, while the review article serves as an authoritative snapshot of the field, the "living article" can continue to evolve with the crowdsourcing model of Wikipedia. After publication of over 50 articles, we surveyed the authors to assess the impact of the project. The author survey results revealed that the Gene Wiki project is achieving its major objectives to increase the involvement of scientists in authoring Wikipedia articles and to enhance the quantity and quality of the information about ge...
Pnas, 1988
Adrenodoxin reductase is a mitochondrial flavoprotein that receives electrons from NADPH, thus in... more Adrenodoxin reductase is a mitochondrial flavoprotein that receives electrons from NADPH, thus initiating the electron-transport chain serving mitochondrial cytochromes P450. We have cloned and sequenced two human adrenodoxin reductase cDNAs that differ by the presence of six additional codons in the middle of one clone. The sequence in this region indicates that these six extra codons arise by alternative splicing of the pre-mRNA. Southern blot hybridization patterns of human genomic DNA cut with four restriction enzymes indicate that the human genome has only one gene for adrenodoxin reductase. Analysis of a panel of mouse-human somatic cell hybrids localized this gene to chromosome 17cen----q25. The alternatively spliced mRNA containing the six extra codons represents 10-20% of all adrenodoxin reductase mRNA. The expression of the adrenodoxin reductase gene may be stimulated by pituitary tropic hormones acting through cAMP, but its response is quantitatively much less than the responses of P450scc and adrenodoxin.
Journal of Clinical Endocrinology Amp Metabolism, Jul 1, 2002
Multisystem pseudohypoaldosteronism (PHA), is a syndrome of unresponsiveness to aldosterone with ... more Multisystem pseudohypoaldosteronism (PHA), is a syndrome of unresponsiveness to aldosterone with autosomal recessive inheritance. Previously we showed that mutations in the epithelial sodium channel (ENaC) ␣-, -, and ␥-subunits are responsible for PHA. In this study we examined four independent probands with multisystem PHA, three of whom were born to consanguineous parents. In our search for mutations we also determined the complete coding sequences of each of the three genes encoding ␣-, -, and ␥-subunits in individuals representing different ethnic groups. Our analyses revealed the following homozygous mutations in three probands: 1) insertion of a T in exon 8 of the ␣ ENaC gene that causes a frameshift error at Tyr 447 and leads to a premature stop codon at K459 in a Pakistani patient; 2) R508stop mutation in exon 11 of the ␣ ENaC gene in an Indian patient; and 3) a splice site mutation in intron 12 of the  ENaC gene (1669 ؉ 1 g3a) in a Scottish patient. The parents were heterozygous for the latter two mutations.
Molecular and Applied Aspects of Oxidative Drug Metabolizing Enzymes, 1999
The Journal of Steroid Biochemistry and Molecular Biology, 1992
Sununary--Highly steroidogenic granulosa cell lines were established by transfection of primary g... more Sununary--Highly steroidogenic granulosa cell lines were established by transfection of primary granulosa cells from preovulatory follicles with SV40 DNA and Ha-ras oncogene. Progesterone production in these cells was enhanced to levels comparable to normal steroidogenic cells, by prolonged (> 12 h) stimulation with 8-Br-cAMP, forskolin and cholera toxin, which elevate intracellular cAMP. The steroidogenic capacity of individual lines correlated with the expression of the ras oncogene product (p21) and the morphology of the cells. Formation of the steroid hormones was associated with de novo synthesis of the mitochondrial cytochrome P450scc system proteins. Since cholesterol import into mitochondria is essential for steroidogenesis, the expression of the peripheral benzodiazepine receptor (PBR) and the steroi carrier protein 2 was characterized in these cells. The induction of the expression of the genes coding for both proteins appeared to be mediated, at least in part, by cAMP. Stimulation of the PBR by specific agonists enhanced progesterone production in these cells. The phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) dramatically suppressed the cAMP-induced steroidogenesis, in spite of enhanced intracellular cAMP levels, suggesting that TPA can modify the effects of cAMP. cAMP stimulation suppressed growth of transformed cells concomitantly with induction of steroidogenesis. The transformed cells lacked receptors for the native stimulants, the gonadotropic hormones. After transfection of the cells with a lutropin (LH) receptor expression plasmid, the LH and hCG response was reconstituted. In these newly established cell lines gonadotropins were able to stimulate the formation of cAMP and progesterone in a dose-dependent manner with an EDs0 characteristic of the native receptor. High doses caused desensitization to gonadotropins as observed in normal cells. These newly established oncogene-transformed granulosa cell lines can serve as a useful model to study inducible steroidogenesis and the effect of oncogene expression on this process.
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Papers by Israel Hanukoglu