Biomarkers and laryngopharyngeal reflux

AbstractLaryngopharyngeal reflux is a controversial but increasingly made diagnosis used in patients with a collection of often non-specific laryngeal symptoms. It is a clinical diagnosis, and its pathophysiology is currently poorly understood.Previous reflux research has focused on injurious agents, acid, pepsin and biomarker expression. Failure of intrinsic defences in the larynx may cause changes in laryngeal epithelia, particularly alterations in carbonic anhydrases and E-cadherin. Carbonic anhydrase III levels vary in the larynx in response to laryngopharyngeal reflux, depending on location. Expression of E-cadherin, a known tumour suppressor, is reduced in the presence of reflux. Mucin expression also varies according to the severity of reflux.Further research is required to define the clinical entity of laryngopharyngeal reflux, and to identify a definitive mechanism for mucosal injury. Understanding this mechanism should allow the development of a comprehensive model, which would enable future diagnostic and therapeutic interventions to be developed.

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Laryngeal Epithelial Defenses against Laryngopharyngeal Reflux: Investigations of E-Cadherin, Carbonic Anhydrase Isoenzyme III, and Pepsin

Annals of Otology Rhinology & Laryngology ◽

10.1177/000348940511401204 ◽

2005 ◽

Vol 114 (12) ◽

pp. 913-921 ◽

Cited By ~ 71

Author(s):

Gulnaz A. Gill ◽

Nikki Johnston ◽

Andrea Buda ◽

Massimo Pignatelli ◽

Jeffrey Pearson ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Research Study ◽

Annual Report ◽

Laryngopharyngeal Reflux ◽

Research Network ◽

Junctional Complex ◽

Carbonic Anhydrase Iii ◽

Biopsy Specimens ◽

Complex Protein ◽

E Cadherin

Objectives: This is the third annual report of an international research network studying the cellular impact of laryngopharyngeal reflux (LPR) on laryngeal epithelium. The objective of this study was to investigate the presence of E-cadherin (epithelial cadherin; the intercellular junctional complex protein) in relation to the presence of (intracellular) pepsin and carbonic anhydrase isoenzyme III (CAIII). Methods: Fifty-four laryngeal biopsy specimens from 18 LPR patients were studied by immunohistochemistry and Western blotting for pepsin, E-cadherin, and CAIII. These data were compared to those from normal control subjects analyzed in another research study. Results: Intracellular pepsin was detected in LPR patients, but not in controls. E-cadherin expression was reduced in patients with LPR. Carbonic anhydrase III expression was not found in the vocal fold or in the majority of samples taken from the ventricle of LPR patients and was inversely associated with E-cadherin membranous expression. Conclusions: The findings of depleted E-cadherin and CAIII and the presence of pepsin appear to correlate with LPR. The reduced protective response indicated by the reduced expression of CAIII may play an important role in the disruption of the intercellular barrier associated with the down-regulation of E-cadherin.

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Transgenic expression of carbonic anhydrase III in cardiac muscle demonstrates a mechanism to tolerate acidosis

AJP Cell Physiology ◽

10.1152/ajpcell.00130.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. C922-C931 ◽

Cited By ~ 2

Author(s):

Han-Zhong Feng ◽

J.-P. Jin

Keyword(s):

Carbonic Anhydrase ◽

Transgenic Mice ◽

Intracellular Ph ◽

Skeletal Muscles ◽

Ex Vivo ◽

Physiological Role ◽

Wild Type Mouse ◽

Carbonic Anhydrases ◽

Wild Type ◽

Carbonic Anhydrase Iii

Carbonic anhydrase III (CAIII) is abundant in liver, adipocytes, and skeletal muscles, but not heart. A cytosolic enzyme that catalyzes conversions between CO2 and [Formula: see text] in the regulation of intracellular pH, its physiological role in myocytes is not fully understood. Mouse skeletal muscles lacking CAIII showed lower intracellular pH during fatigue, suggesting its function in stress tolerance. We created transgenic mice expressing CAIII in cardiomyocytes that lack endogenous CAIII. The transgenic mice showed normal cardiac development and life span under nonstress conditions. Studies of ex vivo working hearts under normal and acidotic conditions demonstrated that the transgenic and wild-type mouse hearts had similar pumping functions under normal pH. At acidotic pH, however, CAIII transgenic mouse hearts showed significantly less decrease in cardiac function than that of wild-type control as shown by higher ventricular pressure development, systolic and diastolic velocities, and stroke volume via elongating the time of diastolic ejection. In addition to the effect of introducing CAIII into cardiomyocytes on maintaining homeostasis to counter acidotic stress, the results demonstrate the role of carbonic anhydrases in maintaining intracellular pH in muscle cells as a potential mechanism to treat heart failure.

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Are Carbonic Anhydrases Suitable Targets to Fight Protozoan Parasitic Diseases?

Current Medicinal Chemistry ◽

10.2174/0929867325666180326160121 ◽

2019 ◽

Vol 25 (39) ◽

pp. 5266-5278 ◽

Cited By ~ 9

Author(s):

Katia D'Ambrosio ◽

Claudiu T. Supuran ◽

Giuseppina De Simone

Keyword(s):

Drug Resistance ◽

Animal Models ◽

Carbonic Anhydrase ◽

Drug Target ◽

Treatment Options ◽

Parasitic Diseases ◽

Carbonic Anhydrases ◽

Extensive Drug Resistance ◽

Protozoan Infections

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

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Anticonvulsant Effects of Carbonic Anhydrase Inhibitors: The Enigmatic Link Between Carbonic Anhydrases and Electrical Activity of the Brain

Neurochemical Research ◽

10.1007/s11064-021-03390-2 ◽

2021 ◽

Author(s):

Hatice Zehra Ozsoy

Keyword(s):

Carbonic Anhydrase ◽

Electrical Activity ◽

Carbonic Anhydrases ◽

Carbonic Anhydrase Inhibitors ◽

The Brain ◽

Anticonvulsant Effects

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Synthesis and Human Carbonic Anhydrase I, II, IX, and XII Inhibition Studies of Sulphonamides Incorporating Mono-, Bi- and Tricyclic Imide Moieties

Pharmaceuticals ◽

10.3390/ph14070693 ◽

2021 ◽

Vol 14 (7) ◽

pp. 693

Author(s):

Kalyan K. Sethi ◽

KM Abha Mishra ◽

Saurabh M. Verma ◽

Daniela Vullo ◽

Fabrizio Carta ◽

...

Keyword(s):

Molecular Docking ◽

Carbonic Anhydrase ◽

Docking Studies ◽

Carbonic Anhydrases ◽

Molecular Docking Studies ◽

Structure Activity Relationships ◽

Structure Activity ◽

Carbonic Anhydrase I ◽

Human Carbonic Anhydrase ◽

Inhibition Studies

New derivatives were synthesised by reaction of amino-containing aromatic sulphonamides with mono-, bi-, and tricyclic anhydrides. These sulphonamides were investigated as human carbonic anhydrases (hCAs, EC 4.2.1.1) I, II, IX, and XII inhibitors. hCA I was inhibited with inhibition constants (Kis) ranging from 49 to >10,000 nM. The physiologically dominant hCA II was significantly inhibited by most of the sulphonamide with the Kis ranging between 2.4 and 4515 nM. hCA IX and hCA XII were inhibited by these sulphonamides in the range of 9.7 to 7766 nM and 14 to 316 nM, respectively. The structure–activity relationships (SAR) are rationalised with the help of molecular docking studies.

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Polypharmacology of epacadostat: a potent and selective inhibitor of the tumor associated carbonic anhydrases IX and XII

Chemical Communications ◽

10.1039/c8cc09568j ◽

2019 ◽

Vol 55 (40) ◽

pp. 5720-5723 ◽

Cited By ~ 9

Author(s):

Andrea Angeli ◽

Marta Ferraroni ◽

Alessio Nocentini ◽

Silvia Selleri ◽

Paola Gratteri ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Selective Inhibitor ◽

Carbonic Anhydrase Inhibitor ◽

Carbonic Anhydrases ◽

Indoleamine 2,3 Dioxygenase

Epacadostat (EPA), a selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, has been investigatedin vitroas a human (h) Carbonic Anhydrase Inhibitor (CAI).

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Carbonic Anhydrases in Photosynthesizing Cells of C3 Higher Plants

Metabolites ◽

10.3390/metabo9040073 ◽

2019 ◽

Vol 9 (4) ◽

pp. 73 ◽

Cited By ~ 5

Author(s):

Lyudmila Ignatova ◽

Natalia Rudenko ◽

Elena Zhurikova ◽

Maria Borisova-Mubarakshina ◽

Boris Ivanov

Keyword(s):

Plasma Membrane ◽

Carbonic Anhydrase ◽

Environmental Conditions ◽

Organic Molecules ◽

Higher Plants ◽

C3 Plants ◽

Coherent System ◽

Carbonic Anhydrases ◽

Chloroplast Stroma ◽

Different Parts

The review presents data on the location, nature, properties, number, and expression of carbonic anhydrase genes in the photosynthesizing cells of C3 plants. The available data about the presence of carbonic anhydrases in plasma membrane, cytoplasm, mitochondria, chloroplast stroma and thylakoids are scrutinized. Special attention was paid to the presence of carbonic anhydrase activities in the different parts of thylakoids, and on collation of sources of these activities with enzymes encoded by the established genes of carbonic anhydrases. The data are presented to show that the consistent incorporation of carbonic anhydrases belonging to different families of these enzymes forms a coherent system of CO2 molecules transport from air to chloroplasts in photosynthesizing cells, where they are included in organic molecules in the carboxylation reaction. It is discussed that the manifestation of the activity of a certain carbonic anhydrase depends on environmental conditions and the stage of ontogenesis.

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