Publications by authors named "Sunil K Saxena"

10 Publications

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Malignant Chondroid Syringoma With Nose and Paranasal Sinus Extension: A Case Report.

Allergy Rhinol (Providence) 2019 Jan-Dec;10:2152656719893367. Epub 2019 Dec 3.

Department of ENT, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India.

Chondroid syringoma is a rare, skin appendageal tumor. It is also known as mixed tumor of skin, as it histologically resembles mixed tumor of salivary gland (pleomorphic adenoma). It is most commonly a benign tumor, but a few malignant counterparts have been described in history. It usually presents as a solid, slow-growing, solitary, and painless nodule in the head and neck region. Malignant counterpart is rare and commonly affects trunk and extremities. Early diagnosis and surgery by wide local excision are the most reliable treatments to date. Recurrences are common and hence close follow-up is advised. In this study, we present a case of malignant chondroid syringoma of face with extensive extension into nose and paranasal sinuses, which was recurrent and managed by surgical excision and radiotherapy. To the best of our knowledge, this is the first reported case with extension and bone destruction into nose and sinuses.
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http://dx.doi.org/10.1177/2152656719893367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893930PMC
December 2019

Laryngotracheal rhinosporidiosis.

Ear Nose Throat J 2013 Jul;92(7):E27-30

Division of Head and Neck Oncology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.

Rhinosporidiosis is a chronic granulomatous disease caused by Rhinosporidium seeberi. It usually affects mucous membranes of the nose, nasopharynx, and ocular conjunctiva. Cutaneous, laryngeal, tracheal, genital, and bony dissemination is rare. Laryngotracheal involvement poses many diagnostic and therapeutic challenges. A 45-year-old South Indian man presented with complaints of a mass in both nostrils for 2 years, associated with progressive hoarseness of voice and difficulty in breathing for 6 months. Rhinosporidial lesions were seen bilaterally in the nasal cavity. Telescopic and fiberoptic laryngoscopic examinations showed reddish, strawberry-like masses with whitish spots on their surface involving the larynx and trachea. Computed tomography of the head and neck revealed soft-tissue mass lesions involving the bilateral nasal cavities and nasopharynx, extending to the oropharynx and involving the larynx and trachea. A preliminary tracheostomy was performed, followed by direct laryngoscopic excision of the laryngeal lesions and rigid-bronchoscopy-guided excision of the tracheal lesions. The patient was prescribed dapsone and advised to take it for 2 years. At 2 years of follow-up, there was no recurrence.
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http://dx.doi.org/10.1177/014556131309200718DOI Listing
July 2013

Longstanding malformation of right sided pinna in an elderly man.

Congenit Anom (Kyoto) 2010 Mar;50(1):68-70

Department of Otorhinolaryngology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India.

The pinna is the second most common site for external ear vascular malformation in the head and neck. These malformations are relatively uncommon in adults and can pose difficult therapeutic challenges. We hereby present a case of a 69-year-old man with a congenital lesion in the right pinna consistent with an arteriovenous malformation. The lesion was complicated by ulceration and bleeding for 6 months prior to presentation. Resection of pinna was carried out, and satisfactory functional and esthetic results were obtained. There was no recurrence at 22 months of regular follow up.
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http://dx.doi.org/10.1111/j.1741-4520.2009.00262.xDOI Listing
March 2010

Distinct domain-dependent effect of syntaxin1A on amiloride-sensitive sodium channel (ENaC) currents in HT-29 colonic epithelial cells.

Int J Biol Sci 2006 Nov 6;3(1):47-56. Epub 2006 Nov 6.

Center for Cell and Molecular Biology, Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA.

The amiloride-sensitive epithelial sodium channel (ENaC), a plasma membrane protein mediates sodium reabsorption in epithelial tissues, including the distal nephron and colon. Syntaxin1A, a trafficking protein of the t-SNARE family has been reported to inhibit ENaC in the Xenopus oocyte expression and artificial lipid bilayer systems. The present report describes the regulation of the epithelial sodium channel by syntaxin1A in a human cell line that is physiologically relevant as it expresses both components and also responds to aldosterone stimulation. In order to evaluate the physiological significance of syntaxin1A interaction with natively expressed ENaC, we over-expressed HT-29 with syntaxin1A constructs comprising various motifs. Unexpectedly, we observed the augmentation of amiloride-sensitive currents with wild-type syntaxin1A full-length construct (1-288) in this cell line. Both gammaENaC and neutralizing syntaxin1A antibodies blocked native expression as amiloride-sensitive sodium currents were inhibited while munc18-1 antibody reversed this effect. The coiled-coiled domain H3 (194-266) of syntaxin1A inhibited, however the inclusion of the transmembrane domain to this motif (194-288) augmented amiloride sensitive currents. More so, data suggest that ENaC interacts with multiple syntaxin1A domains, which differentially regulate channel function. This functional modulation is the consequence of the physical enhancement of ENaC at the cell surface in cells over-expressed with syntaxin(s). Our data further suggest that syntaxin1A up-regulates ENaC function by multiple mechanisms that include PKA, PLC, PI3 and MAP Kinase (p42/44) signaling systems. We propose that syntaxin1A possesses distinct inhibitory and stimulatory domains that interact with ENaC subunits, which critically determines the overall ENaC functionality/regulation under distinct physiological conditions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1657084PMC
http://dx.doi.org/10.7150/ijbs.3.47DOI Listing
November 2006

Regulation of epithelial ion channels by Rab GTPases.

Biochem Biophys Res Commun 2006 Dec 27;351(3):582-7. Epub 2006 Oct 27.

Center for Cell and Molecular Biology, Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA.

Epithelial ion channels are crucial to many of life's processes and disruption of their functions can lead to several disorders. Cystic fibrosis, an autosomal recessive disorder, is caused by defects in the biosynthesis or function of the CFTR chloride channel. Similarly, mutations in certain ENaC genes leading to increased or reduced channel activity cause diseases such as Liddle's syndrome or PHA. In order for ion channel proteins to be functional they need to be expressed on the plasma membrane. Thus, molecules that modulate the trafficking of ion channels to and from the membrane are of utmost significance. Among the numerous factors that regulate their functioning is a family of small GTPases known as Rab proteins. While Rabs have always played a pivotal role in membrane trafficking, their diversity of functions and plethora of interacting partners have lately been brought to light. Recent studies reveal that multiple Rab isoforms physically interact with and/or modulate the activity of several ion channels. Rab proteins have the ability to serve as molecular switches and many of the ion channels are regulated differentially by the GTP- or GDP-bound Rab isoforms. This review examines the role of Rab GTPases in the trafficking of ion channels, including CFTR, ENaC, TRPV5/6, and aquaporins, based on recent evidence.
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http://dx.doi.org/10.1016/j.bbrc.2006.10.087DOI Listing
December 2006

Rab27a negatively regulates CFTR chloride channel function in colonic epithelia: involvement of the effector proteins in the regulatory mechanism.

Biochem Biophys Res Commun 2006 Jul 24;346(1):259-67. Epub 2006 May 24.

Center for Cell and Molecular Biology, Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA.

Cystic fibrosis, an autosomal recessive disorder, is caused by the disruption of biosynthesis or function of CFTR. CFTR regulatory mechanisms include channel transport to plasma membrane and protein-protein interactions. Rab proteins are small GTPases involved in vesicle transport, docking, and fusion. The colorectal epithelial HT-29 cells natively express CFTR and respond to cAMP with an increase in CFTR-mediated currents. DPC-inhibited currents could be completely eliminated with CFTR-specific SiRNA. Over-expression of Rab27a inhibited, while isoform specific SiRNA and Rab27a antibody stimulated CFTR-mediated currents in HT-29 cells. CFTR activity is inhibited both by Rab27a (Q78L) (constitutive active GTP-bound form of Rab27a) and Rab27a (T23N) (constitutive negative form that mimics the GDP-bound form). Rab27a mediated effects could be reversed by Rab27a-binding proteins, the synaptotagmin-like protein (SLP-5) and Munc13-4 accessory protein (a putative priming factor for exocytosis). The SLP reversal of Rab27a effect was restricted to C2A/C2B domains while the SHD motif imparted little more inhibition. The CFTR-mediated currents remain unaffected by Rab3 though SLP-5 appears to weakly bind it. The immunoprecipitation experiments suggest protein-protein interactions between Rab27a and CFTR. Rab27a appears to impair CFTR appearance at the cell surface by trapping CFTR in the intracellular compartments. Munc13-4 and SLP-5, on the other hand, limit Rab27a availability to CFTR, thus minimizing its effect on channel function. These observations decisively prove that Rab27a is involved in CFTR channel regulation through protein-protein interactions involving Munc13-4 and SLP-5 effector proteins, and thus could be a potential target for cystic fibrosis therapy.
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http://dx.doi.org/10.1016/j.bbrc.2006.05.102DOI Listing
July 2006

Rab27a regulates epithelial sodium channel (ENaC) activity through synaptotagmin-like protein (SLP-5) and Munc13-4 effector mechanism.

Biochem Biophys Res Commun 2006 Jun 7;344(2):651-7. Epub 2006 Apr 7.

Center for Cell and Molecular Biology, Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA.

Liddle's syndrome (excessive absorption of sodium ions) and PHA-1 (pseudohypoaldosteronism type 1) with decreased sodium absorption are caused by the mutations in the amiloride-sensitive epithelial sodium channel ENaC. Rab proteins are small GTPases involved in vesicle transport, docking, and fusion. Earlier, we reported that Rab27a inhibits ENaC-mediated currents through protein-protein interaction in HT-29 cells. We hereby report that Rab27a-dependent inhibition is associated with the GTP/GDP status as constitutively active or GTPase-deficient mutant Q78L inhibits amiloride-sensitive currents whereas GDP-locked inactive mutant T23N showed no effect. In order to further explore the molecular mechanism of this regulation, we performed competitive assays with two Rab27a-binding proteins: synaptotagmin-like protein (SLP-5) and Munc13-4 (a putative priming factor for exocytosis). Both proteins eliminate negative modulation of Rab27a on ENaC function. The SLP-5 reversal of Rab27a effect was restricted to C-terminal C2A/C2B domains assigned for putative phospholipids-binding function while the Rab27a-binding SHD motif imparted higher inhibition. The ENaC-mediated currents remain unaffected by Rab27a though SLP-5 appears to strongly bind it. The immunoprecipitation experiments suggest that in the presence of excessive Munc13-4 and SLP-5 proteins, Rab27a interaction with ENaC is diminished. Munc13-4 and SLP-5 limit the Rab27a availability to ENaC, thus minimizing its effect on channel function. These observations decisively prove that Rab27a inhibits ENaC function through a complex mechanism that involves GTP/GDP status, and protein-protein interactions involving Munc13-4 and SLP-5 effector proteins.
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http://dx.doi.org/10.1016/j.bbrc.2006.03.160DOI Listing
June 2006

Epithelial sodium channel is regulated by SNAP-23/syntaxin 1A interplay.

Biochem Biophys Res Commun 2006 May 24;343(4):1279-85. Epub 2006 Mar 24.

Center for Cell and Molecular Biology, Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA.

Sodium-selective amiloride-sensitive epithelial channel (ENaC) located in the apical membrane is involved in the reabsorption of sodium in tight epithelia. The soluble N-ethylmaleimide-sensitive attachment receptors (SNAREs) mediate vesicle trafficking in a variety of cell systems. Syntaxin (a t-SNARE) has been shown to interact with and functionally regulate a number of ion channels including ENaC. In this study, we investigated the role of SNAP-23, another SNARE protein, on ENaC activity in the HT-29 colonic epithelial cell system and Xenopus oocytes. Recording of amiloride-sensitive currents in both systems suggest that SNAP-23 modulates channel function, though a much higher concentration is required to inhibit ENaC in Xenopus oocytes. The introduction of Botulinum toxin A (a neurotoxin which cleaves SNAP-23), but not Botulinum toxin B or heat-inactivated Botulinum toxin A, reversed the inhibitory effect of SNAP-23 on amiloride-sensitive currents. However, syntaxin 1A and SNAP-23 combined portray a complex scenario that suggests that this channel interacts within a quaternary complex. Synaptotagmin expression neither interacts with, nor showed any effect on amiloride-sensitive currents when co-expressed with ENaC. Pull down assays suggest mild interaction between ENaC and SNAP-23, which gets stronger in the presence of syntaxin 1A. Data further suggest that SNAP-23 possibly interacts with the N-terminal alphaENaC. These functional and biochemical approaches provide evidence for a complex relationship between ENaC and the exocytotic machinery. Our data suggest that SNARE protein interplay defines the fine regulation of sodium channel function.
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http://dx.doi.org/10.1016/j.bbrc.2006.03.093DOI Listing
May 2006

Rab4GTPase modulates CFTR function by impairing channel expression at plasma membrane.

Biochem Biophys Res Commun 2006 Mar 6;341(1):184-91. Epub 2006 Jan 6.

Center for Cell and Molecular Biology, Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA.

Cystic fibrosis (CF), an autosomal recessive disorder, is caused by the disruption of biosynthesis or the function of a membrane cAMP-activated chloride channel, CFTR. CFTR regulatory mechanisms include recruitment of channel proteins to the cell surface from intracellular pools and by protein-protein interactions. Rab proteins are small GTPases involved in regulated trafficking controlling vesicle docking and fusion. Rab4 controls recycling events from endosome to the plasma membrane, fusion, and degradation. The colorectal cell line HT-29 natively expresses CFTR and responds to cAMP stimulation with an increase in CFTR-mediated currents. Rab4 over-expression in HT-29 cells inhibits both basal and cAMP-stimulated CFTR-mediated currents. GTPase-deficient Rab4Q67L and GDP locked Rab4S22N both inhibit channel activity, which appears characteristically different. Active status of Rab4 was confirmed by GTP overlay assay, while its expression was verified by Western blotting. The pull-down and immunoprecipitation experiments suggest that Rab4 physically interacts with CFTR through protein-protein interaction. Biotinylation with cell impermeant NHS-Sulfo-SS-Biotin implies that Rab4 impairs CFTR expression at cell surface. The enhanced cytosolic CFTR indicates that Rab4 expression restrains CFTR appearance at the cell membrane. The study suggests that Rab4 regulates the channel through multiple mechanisms that include protein-protein interaction, GTP/GDP exchange, and channel protein trafficking. We propose that Rab4 is a dynamic molecule with a significant role in CFTR function.
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http://dx.doi.org/10.1016/j.bbrc.2005.12.170DOI Listing
March 2006

Rab4 GTP/GDP modulates amiloride-sensitive sodium channel (ENaC) function in colonic epithelia.

Biochem Biophys Res Commun 2006 Feb 27;340(2):726-33. Epub 2005 Dec 27.

Center for Cell and Molecular Biology, Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA.

The sodium-selective amiloride-sensitive epithelial sodium channel (ENaC) mediates electrogenic sodium re-absorption in tight epithelia. ENaC expression at the plasma membrane requires regulated transport, processing, and macromolecular assembly of subunit proteins in a defined and highly compartmentalized manner. Ras-related Rab GTPases monitor these processes in a highly regulated sequence of events. In order to evaluate the role of Rab proteins in ENaC function, Rab4 wild-type (WT), the GTPase-deficient mutant Rab4Q67L, and the dominant negative GDP-locked mutant Rab4S22N were over-expressed in the colon cancer cell line, HT-29 and amiloride-sensitive currents were recorded. Rab4 over-expression inhibited amiloride-sensitive currents. The effect was reversed by introducing Rab4-neutralizing antibody and Rab4 specific SiRNA. The GDP-locked Rab4 mutant inhibited, while GTPase-deficient mutant moderately stimulated amiloride-sensitive currents. Active status of Rab4 was confirmed by GTP overlay assay, while its expression was verified by Western blotting. Immunoprecipitation and pull-down assay suggest protein-protein interaction between Rab4 and ENaC. In addition, the functional modulation coincides with concomitant changes in ENaC expression at the cell surface and in intracellular pool. We propose that Rab4 is a critical element that regulates ENaC function by mechanisms that include GTP-GDP status, recycling, and expression level. Our observations imply that channel expression in apical membranes of epithelial cell system incorporates RabGTPase as an essential determinant of channel function and adds an exciting paradigm to ENaC therapeutics.
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http://dx.doi.org/10.1016/j.bbrc.2005.12.036DOI Listing
February 2006