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Management of Diabetic Gastroparesis
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Kenneth L. Koch, Khalil N. Bitar
Coordination of smooth muscle activity, together with propulsion and expulsion across sphincteric barriers, requires slow waves. Slow waves coordinate smooth muscle contraction by combining action potentials propagated by ICCs that also form gap junctions with neurons and smooth muscle cells (SMC). Thus, ICC and SMC are electrically coupled. Electrical coupling combines ICC slow wave with smooth muscle potential to result in a larger combined potential that results in coordinated contractions. The slow wave rhythm is dependent on the activity of Ano1 (calcium activated chloride channel) in the ICC cells. Therefore, the slow wave dictates the maximum frequency of contractions. In humans, the slow wave frequency is three cpm in the stomach and 10–12 cpm in the small intestine.
Cisplatin and Related Anticancer Drugs: Recent Advances and Insights
Published in Astrid Sigel, Helmut Sigel, Metal Ions in Biological Systems, 2004
Katie R. Barnes, Stephen J. Lippard
The majority of studies characterizing cisplatin binding to DNA have been carried out using purified DNA. In the cell, DNA is condensed into a compact chromatin structure, which may affect cisplatin binding [51]. As a result, recent work has focused on elucidating the interactions between cisplatin and chromatin DNA. Early work with cisplatin binding to nucleosomal DNA revealed little effect of the core histones on DNA binding [52]. Nuclease digestion of chromasomal to determine the location of platinum adducts indicated that DNA cross-links were favored over protein crosslinks and that, at a low platinum concentration (rb < 0.05), the linker DNA is targeted [52–57]. At high platinum concentrations (rb = 0.1–0.2), however, there was no preference for linker DNA [54]. Current work with microsomal DNA utilizes reconstituted chromatin containing specifically designed DNA sequences. In reconstituted chromatin, cisplatin binds preferentially to the nucleosomal linker regions [58]. Thus, it appears that the microsomal core region offers some protection against cisplatin-induced DNA damage [58]. Nucleosomal core particles lacking DNA linker regions form cisplatin interstrand cross-links in a similar manner as free DNA, suggesting that the major groove is still accessible to cisplatin attack [59]. In one study, the effect of chromatin structure was investigated in intact human cells, using the ε-globin gene promoter, which contains numerous transcription binding sites, as the target DNA sequence [60]. Platination was specifically enhanced at the CACC binding site where a transcription factor of the Spl family binds [60]. It is possible that the binding of transcription factors bends the DNA, therefore exposing it to cisplatin damage.
Regulation of Secretion in Human Gallbladder Epithelial Cells
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Nicolas Chignard, Laura Fouassier, Annick Paul, Chantal Housset
Chloride secretion may also be mediated by calcium-dependent chloride channels (CaCC) in the gallbladder epithelium as in other epithelia. We have shown that extracellular ATP stimulates chloride efflux in primary cultures of human gallbladder epithelial cells and that, in the intact gallbladder mucosa mounted in Ussing-type chamber, the addition of ATP to the apical side triggers an increase in electrogenic anion secretion. This effect is mediated by apical P2Y2 purinergic receptors via an increase in [Ca2+]i and the activation of calmodulin-dependent protein kinase II (Ca2+/CaM-kinase II).3,7 In CF preparations, whereas anion secretion in response to forskolin was deficient, anion secretion in response to ionomycin or ATP was exacerbated.7 Chloride secretion may also be assessed by the measure of 36Cl− efflux in primary cultures of gallbladder epithelial cells. Consistent with the results obtained in the intact mucosa, we found that in cultures of CF cells, forskolin-induced chloride secretion was deficient, whereas ATP-induced secretion was maintained. Part of the CF preparations nevertheless showed residual CFTR activity, while residual activity was virtually absent in other CF cells (in particular from micro-gallbladders), presumably because CFTR mislocalization was more severe in the latter than in former cases. We found an inverse correlation between ATP-induced and forskolin-induced secretions. ATP-induced secretion was markedly exacerbated, when there was no residual CFTR activity. The persistence of an ATP-mediated activation of anion secretion in CF gallbladders indicates that extracellular ATP stimulates anion secretion in the gallbladder through a different pathway than CFTR. The effect of ATP on anion secretion in human gallbladder mucosa is likely to be physiologically relevant, because it is observed in the micromolar range, while the concentration of ATP in human bile is ~1 µmol/L and the total concentration of adenosine nucleotides is ~5 µmol/L.6 We could conclude from these experiments that active anion secretion in human gallbladder mucosa is stimulated by cAMP through a CFTR-mediated pathway and by Ca2+ through a CFTR-independent pathway (Fig. 3). In CF, the CFTR-mediated pathway is defective, while the alternative pathway is up-regulated.
Ion channels as therapeutic antibody targets
Published in mAbs, 2019
Catherine J. Hutchings, Paul Colussi, Theodore G. Clark
To date, most ion channel drug development has focused on identifying and developing small molecule and peptide modulators, mainly through serendipitous discovery due to a lack of information on structure and function. Many ion channel modulators have been discovered from studies of naturally occurring substances, such as toxins from plants and venomous animals.10 The conotoxin family is the most well-known of the animal-derived toxins,11 with ziconotide, a selective Cav2.2 antagonist, a frequently cited example of a synthetic peptide analogue of cone snail ω-conotoxin used for the treatment of severe chronic pain.12 Despite the initial successes in identifying ion channel modulators, only two novel ion channel drugs have been approved by the US Food and Drug Administration (FDA) since the 1990s, despite vastly improved screening tools for small molecule/compound libraries.13 The most recently approved drugs are ivacaftor (Kalydeco), which potentiates the cystic fibrosis CFTR chloride channel14 and crofelemer (Mytesi), a proanthocyanidin oligomer, which inhibits both CFTR and the calcium-activated chloride channel TMEM16A.15 As with the vast majority of other drugs targeting ion channels, ivacaftor and crofelemer are both small molecule chemical entities.16
The slow light and dark oscillation of the clinical electro‐oculogram
Published in Clinical and Experimental Optometry, 2018
The initial fall in the standing potential following light offset that results in the dark trough of the clinical electro‐oculogram is not understood.2006 One possibility is that the initial fall is related to a reduction in basolateral chloride conductance resulting in a reduced trans‐epithelial potential of the retinal pigment epithelium. This decrease in chloride conductance would most likely be linked to bestrophin‐1 that regulates calcium entry via L‐type Ca2+ channels that then gates open the basolateral calcium activated chloride channel.2011 However, Figure 4 shows that the ratios of the oscillations during dark and light significantly differ. The light ratios show a near linear fall in the relative ratios between the peaks and troughs of the oscillation. In contrast, the dark oscillation remains at a ratio of between 1.05 and 1.15 for R2 and R3, suggesting that in dark the oscillation declines to a steady state ahead of the light oscillation reaching a plateau after approximately 35 minutes following dark onset. This rapid dampening of the dark oscillation contrasts to the light oscillation that continues to display a gradual dampening of the ratios for at least 75 minutes. These findings suggest there is a separate mechanism driving the oscillation under dark and light conditions.
Analysis of core mutation and TET2/ASXL1 mutations DNA methylation profile in myelodysplastic syndrome
Published in Hematology, 2023
Yue Feng, Haiping Liang, Xingchun Luo, Yu Zhu, Bei Liu, Meining Han
GO and KEGG analyses were conducted to determine the potential biological functions of the identified hyper and hypo-DMGs (Figure 3). Hypermethylated DMGs are mainly located in projection neurons, distal axons, actin-based projection cells, linear pseudopodia, growth cones, polarized sites and splice complex. The main molecular functions involved are signal receptor binding, receptor activity regulation, receptor–ligand activity, signal receptor activator, actin binding, coreceptor activity, inhibin binding, intracellular calcium-activated chloride channel activity and intracellular chloride channel activity. The main biological processes involved are animal organ development, cell surface receptor signal pathway, anatomical morphogenesis, cell secretion, enzyme-linked receptor protein signal pathway, transmembrane receptor protein tyrosine kinase signal pathway, lymphocyte activation, positive regulation of kinase activity, and skeletal system development. Most of the hypomethylated DMGs were located in chromosomes, projection neurons, cytoplasmic vesicle membrane, axon and specific granule membrane basement membrane. The main molecular functions involved are transcriptional regulatory factor activity, DNA binding transcriptional factor activity, RNA polymerase II specificity, RNA polymerase II transcriptional regulatory region sequence specific DNA binding, poly (U) RNA binding, polypyrimidine bundle binding and leucine zipper domain binding. The main biological processes involved are cell differentiation, cell development, animal organ development, neurogenesis, neuron generation, neuron differentiation, visual system development, and sensory system development.