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Assays of CFTR Function In Vitro, Ex Vivo and In Vivo.
Ramalho, AS, Boon, M, Proesmans, M, Vermeulen, F, Carlon, MS, Boeck, K
International journal of molecular sciences. 2022;(3)
Abstract
Cystic fibrosis, a multi-organ genetic disease, is characterized by abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel at the apical membrane of several epithelia. In recent years, therapeutic strategies have been developed to correct the CFTR defect. To evaluate CFTR function at baseline for diagnosis, or the efficacy of CFTR-restoring therapy, reliable tests are needed to measure CFTR function, in vitro, ex vivo and in vivo. In vitro techniques either directly or indirectly measure ion fluxes; direct measurement of ion fluxes and quenching of fluorescence in cell-based assays, change in transmembrane voltage or current in patch clamp or Ussing chamber, swelling of CFTR-containing organoids by secondary water influx upon CFTR activation. Several cell or tissue types can be used. Ex vivo and in vivo assays similarly evaluate current (intestinal current measurement) and membrane potential differences (nasal potential difference), on tissues from individual patients. In the sweat test, the most frequently used in vivo evaluation of CFTR function, chloride concentration or stimulated sweat rate can be directly measured. Here, we will describe the currently available bio-assays for quantitative evaluation of CFTR function, their indications, advantages and disadvantages, and correlation with clinical outcome measures.
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2.
Emergence of Chloride as an Overlooked Cardiorenal Connector in Heart Failure.
Kazory, A, Ronco, C
Blood purification. 2020;(1-2):219-221
Abstract
Several studies have recently challenged the sodium-centric view that has been dominating the field of heart failure (HF) and cardiorenal syndrome. The previously observed benefits of severe dietary restriction of salt do not seem to be consistently reproduced by contemporary studies. Moreover, there is evidence that too low intake may paradoxically lead to adverse outcomes in more advanced stages of HF. Facing the escalating controversy, investigators have shifted their focus from sodium to its often overlooked counter ion in salt, the chloride. Emerging data suggest that serum chloride levels could portend robust independent prognostic value in a wide range of HF syndromes possibly stronger than that of sodium. The untoward impact of hypochloremia on the outcomes could be mechanistically linked to renal tubular regulatory pathways, neurohormonal activation, and diuretic resistance. As such, it can be a potential target of therapy in this setting. In this article, the authors provide a brief overview of the role of serum chloride as a cardiorenal connector and explore the context in which the contemporary data should be interpreted. Implementation of predictive and therapeutic strategies incorporating the emerging evidence would be refined through discussion of nuances of such findings as well as their biological and clinical relevance.
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3.
Intracellular Cl- Regulation of Ciliary Beating in Ciliated Human Nasal Epithelial Cells: Frequency and Distance of Ciliary Beating Observed by High-Speed Video Microscopy.
Yasuda, M, Inui, TA, Hirano, S, Asano, S, Okazaki, T, Inui, T, Marunaka, Y, Nakahari, T
International journal of molecular sciences. 2020;(11)
Abstract
Small inhaled particles, which are entrapped by the mucous layer that is maintained by mucous secretion via mucin exocytosis and fluid secretion, are removed from the nasal cavity by beating cilia. The functional activities of beating cilia are assessed by their frequency and the amplitude. Nasal ciliary beating is controlled by intracellular ions (Ca2+, H+ and Cl-), and is enhanced by a decreased concentration of intracellular Cl- ([Cl-]i) in ciliated human nasal epithelial cells (cHNECs) in primary culture, which increases the ciliary beat amplitude. A novel method to measure both ciliary beat frequency (CBF) and ciliary beat distance (CBD, an index of ciliary beat amplitude) in cHNECs has been developed using high-speed video microscopy, which revealed that a decrease in [Cl-]i increased CBD, but not CBF, and an increase in [Cl-]i decreased both CBD and CBF. Thus, [Cl-]i inhibits ciliary beating in cHNECs, suggesting that axonemal structures controlling CBD and CBF may have Cl- sensors and be regulated by [Cl-]i. These observations indicate that the activation of Cl- secretion stimulates ciliary beating (increased CBD) mediated via a decrease in [Cl-]i in cHNECs. Thus, [Cl-]i is critical for controlling ciliary beating in cHNECs. This review introduces the concept of Cl- regulation of ciliary beating in cHNECs.
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4.
What biologists want from their chloride reporters - a conversation between chemists and biologists.
Zajac, M, Chakraborty, K, Saha, S, Mahadevan, V, Infield, DT, Accardi, A, Qiu, Z, Krishnan, Y
Journal of cell science. 2020;(2)
Abstract
Impaired chloride transport affects diverse processes ranging from neuron excitability to water secretion, which underlie epilepsy and cystic fibrosis, respectively. The ability to image chloride fluxes with fluorescent probes has been essential for the investigation of the roles of chloride channels and transporters in health and disease. Therefore, developing effective fluorescent chloride reporters is critical to characterizing chloride transporters and discovering new ones. However, each chloride channel or transporter has a unique functional context that demands a suite of chloride probes with appropriate sensing characteristics. This Review seeks to juxtapose the biology of chloride transport with the chemistries underlying chloride sensors by exploring the various biological roles of chloride and highlighting the insights delivered by studies using chloride reporters. We then delineate the evolution of small-molecule sensors and genetically encoded chloride reporters. Finally, we analyze discussions with chloride biologists to identify the advantages and limitations of sensors in each biological context, as well as to recognize the key design challenges that must be overcome for developing the next generation of chloride sensors.
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5.
Hyperchloremic normal gap metabolic acidosis.
Palmer, BF, Clegg, DJ
Minerva endocrinologica. 2019;(4):363-377
Abstract
Metabolic acidosis is defined as a pathologic process that, when unopposed, increases the concentration of hydrogen ions (H+) in the body and reduces the bicarbonate (HCO3-) concentration. Metabolic acidosis can be of a kidney origin or an extrarenal cause. Assessment of urinary ammonium excretion by calculating the urine anion gap or osmolal gap is a useful method to distinguish between these two causes. Extrarenal processes include increased endogenous acid production and accelerated loss of bicarbonate from the body. Metabolic acidosis of renal origin is due to a primary defect in renal acidification with no increase in extrarenal hydrogen ion production. This situation can occur because either the renal input of new bicarbonate is insufficient to regenerate the bicarbonate lost in buffering endogenous acid as with distal renal tubular acidosis (RTA) or the RTA of renal insufficiency, or the filtered bicarbonate is lost by kidney wasting as in proximal RTA. In either condition, because of loss of either NaHCO3 (proximal RTA) or NaA (distal RTA), effective extracellular volume is reduced and as a result the avidity for chloride reabsorption derived from the diet is increased and results in a hyperchloremic normal gap metabolic acidosis. The RTA of renal insufficiency is also characterized by a normal gap acidosis, however, with severe reductions in the glomerular filtration rate an anion gap metabolic acidosis eventually develops.
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6.
Chloride: from Nutrient to Toxicant.
Geilfus, CM
Plant & cell physiology. 2018;(5):877-886
Abstract
In salinized soils in which chloride (Cl-) is the dominant salt anion, growth of plants that tolerate only low concentrations of salt (glycophytes) is disturbed by Cl- toxicity. Chlorotic discolorations precede necrotic lesions, causing yield reductions. Little is known about the effects of Cl- toxicity on these dysfunctions. A lack of understanding exists regarding (i) the molecular and physiological mechanisms that lead to Cl--induced damage and (ii) the adaptive aspects of induced tolerance to Cl- salinity. Here, mechanistic explanations for the Cl--induced stress responses are proposed and novel ideas and strategies by which glycophytic plants avoid the excessive accumulation of Cl- are reviewed. New experiments are suggested to test the proposed hypotheses. Cl- salinity constrains global food security and thus we urgently need more research into the causes and consequences of Cl- salinity.
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7.
Chloride: not simply a 'cheap osmoticum', but a beneficial plant macronutrient.
Wege, S, Gilliham, M, Henderson, SW
Journal of experimental botany. 2017;(12):3057-3069
Abstract
At macronutrient levels, chloride has positive effects on plant growth, which are distinct from its function in photosynthesis..
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8.
Neuronal chloride and excitability - the big impact of small changes.
Raimondo, JV, Richards, BA, Woodin, MA
Current opinion in neurobiology. 2017;:35-42
Abstract
Synaptic inhibition is a critical regulator of neuronal excitability, and in the mature brain the majority of synaptic inhibition is mediated by Cl--permeable GABAA receptors. Unlike other physiologically relevant ions, Cl- is dynamically regulated, and alterations in the Cl- gradient can have significant impact on neuronal excitability. Due to changes in the neuronal Cl- concentration, GABAergic transmission can bidirectionally regulate the induction of excitatory synaptic plasticity and gate the closing of the critical period for monocular deprivation in visual cortex. GABAergic circuitry can also provide a powerful restraining mechanism for the spread of excitation, however Cl- extrusion mechanisms can become overwhelmed and GABA can paradoxically contribute to pathological excitation such as the propagation of seizure activity.
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9.
Chloride on the Move.
Li, B, Tester, M, Gilliham, M
Trends in plant science. 2017;(3):236-248
Abstract
Chloride (Cl-) is an essential plant nutrient but under saline conditions it can accumulate to toxic levels in leaves; limiting this accumulation improves the salt tolerance of some crops. The rate-limiting step for this process - the transfer of Cl- from root symplast to xylem apoplast, which can antagonize delivery of the macronutrient nitrate (NO3-) to shoots - is regulated by abscisic acid (ABA) and is multigenic. Until recently the molecular mechanisms underpinning this salt-tolerance trait were poorly defined. We discuss here how recent advances highlight the role of newly identified transport proteins, some that directly transfer Cl- into the xylem, and others that act on endomembranes in 'gatekeeper' cell types in the root stele to control root-to-shoot delivery of Cl-.
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10.
[The difference and ratio between serum concentrations of natrium and chlorides in patients with hyponatremia].
Schück, O, Horáčková, M
Vnitrni lekarstvi. 2016;(7-8):629-34
Abstract
UNLABELLED The differential diagnosis of hyponatremia is often difficult. This most frequently occurring disorder of the water and electrolyte metabolism is frequently connected with deviations relating to the acid-base balance (ABB). This survey analyzes the relationship between the changes of the volume of body fluids and ABB and infers to what extent the analysis of combinations of the two disorders can support the differential diagnosis of different forms of hyponatremia (differentiation between the dilution vs. depletion forms). The changes of the total water volume (CTV) and ABB may be presented at the same time in the values of the difference and ratio between serum concentrations of natrium and chlorides (SNa+ - SCl-; SNa+/SCl-). The changes of these quantities are analyzed in the models of pathologies connected through hyponatremia and ABB related deviations: (i) retention of solute-free water (hyponatremia associated with dilution acidosis); (ii) retention Na+ in combination with water retention (hyponatremia associated with dilution and hyperchloremic acidosis); (iii) depletion Na+ combined with water depletion (depletion hyponatremia combined with hypochloremic alkalosis), and (iv) combination of dilution and depletion (hyponatremia which may be associated with different ABB related deviations). This survey specifies the extent to which the applied models are consistent with the existing clinical findings and experience. The examinations SNa+ - SCl- and SNa+/SCl- rely only on routinely used laboratory test methods. Monitoring of these quantities may contribute to continuous assessment of the effect of a chosen therapy. KEY WORDS acid-base balance - depletion hyponatremia - differential diagnosis of hyponatremia - dilution hyponatremia - hyponatremia - retention of solute-free water - body fluid volumes.