Management of Diabetic Gastroparesis
Emmanuel C. Opara, Sam Dagogo-Jack in Nutrition and Diabetes, 2019
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.
Gastrointestinal Stromal Tumors: From Molecular Pathogenesis to Therapy
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
During the last decades, high throughput proteomic studies of exosomes have allowed the identification of thousands of vesicular proteins commonly found in many cancer types [193, 198], as well as tumor-type specific cargos [199] which are often linked to the pathophysiological nature of a given tumor type [200, 201]. Exosomes have been detected in nearly all kinds of bodily fluids isolated from healthy donors and cancer patients [202–204]. Therefore, the increased accumulation, stability, and enrichment of specific biomolecules in exosomes led us to investigate the molecular composition of GIST-derived exosomes (GDEs) and evaluate their potential as a source of diagnostic and therapeutic biomarkers [201, 205]. Using label free quantitative proteomic profiling, we have recently reported insights into the oncogenic cargo of GDEs, and identified 1,060 proteins composing the core GDE proteome (cGDEp), enriched in diagnostic markers (e.g., KIT, CD34, ANO1, PROM1, PRKCQ, and ENG), and other proteins previously reported in GIST (e.g., DPP4, FHL1, CDH11, and KCTD12) (Fig. 9.4) [167]. Using extensive validation approach we identified the presence of common exosome-related markers, as well as proteins involved in tumor progression, novel serine and tyrosine kinases and signaling pathways, as well as immune regulatory molecules (Fig. 9.4). Analysis of circulating exosomes in primary or metastatic gastric IM naïve GIST patients indicated that the total particles concentration was 8.7-fold higher in metastatic GIST patients as compared to patients with primary localized GIST, suggesting that changes in the levels of circulating exosomes might be an indicator of response to therapy and/or malignant capabilities, such as recurrence or metastasis to secondary sites [167]. We further showed that the number of circulating exosome also correlate with response to therapy, using pre-IM and post-IM paired plasma specimens, and that expression of p-KITTyr719, total KIT, and SPRY4 levels on KIT+ exosomes purified from primary and metastatic GIST plasma samples, could potentially be used to indicate disease state and likely response to therapy [167]. The proteomic data is available via ProteomeXchange with identifier PXD007997.
Prokinetic effects of Citrus reticulata and Citrus aurantium extract with/without Bupleurum chinense using multistress-induced delayed gastric emptying models
Published in Pharmaceutical Biology, 2023
Yanrong Gong, Xiaoxia Liang, Yanting Dai, Xiang Huang, Qiaozhen Su, Yan Ma, Fenglian Chen, Shuling Wang
Interstitial cells of Cajal are derived from mesenchymal precursor cells that express c-kit, a receptor for stem cell ligand. Therefore, ICC can be identified with c-kit immunoreactivity. ICC associated with the myenteric plexus generate pacemaker activity in the form of slowly propagating waves of depolarization that provide rhythmicity and the direction of propagation to the slow-wave-driven motor patterns of the small intestine (Huizinga and Parsons 2019). Lack of normal pacemaker activity generated by ICC could account for symptoms of intestinal obstruction in the absence of mechanical obstruction. A considerable body of evidence has revealed that intracellular Ca2+ oscillations in ICC periodically activate plasmalemmal Ca2+-dependent ion channels and thereby generate pacemaker potentials (Streutker 2003). Our study showed both AuCiBup and AuCi increased ICC numbers and extracellular Ca2+ influx which might act as the underlying mechanism of their prokinetic activity. Anoctamin-1 (ANO1), the most studied member of anoctamin family of calcium-activated chloride channels, is a prominent conductance in ICC and these channels appear to be involved in pacemaker activity and in responses to enteric excitatory neurotransmitters (Sanders 2012). It is reported that melastatin-type transient receptor potential channel 7 (TRPM7) is required for intestinal pacemaking activity (Kim 2005). Whether the prokinetic effects of AuCiBup and AuCi are associated with ANO1 or TRPM7 is still in further research.
Cystic Fibrosis: Proteostatic correctors of CFTR trafficking and alternative therapeutic targets.
Published in Expert Opinion on Therapeutic Targets, 2019
John W. Hanrahan, Yukiko Sato, Graeme W. Carlile, Gregor Jansen, Jason C. Young, David Y. Thomas
Acetylcholine stimulates chloride conductance in airway epithelia that could potentially substitute for CFTR dysfunction. The Ca2+-activated Cl− channel (CaCC) was identified as TMEM16A (also called anoctamin-1, ANO1) [131–133]. Expression of TMEM16A in airway epithelial cells is increased by proinflammatory cytokines [134], and this upregulation further suggests TMEM16A as a therapeutic target in chronically inflamed CF airways. TMEM16A mediates rapid and robust secretory responses although its activation is transient. An agonist capable of causing prolonged responses so they are more similar to those of CFTR has not been described, however a potentiator has been reported that increases TMEM16A channel activity when partially stimulated by Ca2+ (ETD002; Enterprise Therapeutics, 2017). TMEM16A is required for normal mucus secretion and is most highly expressed in mucus-secreting cells [135], therefore its beneficial effect on fluid secretion will need to outweigh any adverse effect that might result from mucus release.
Genomic-based treatment of patients with head and neck cancer
Published in Expert Review of Precision Medicine and Drug Development, 2020
Arpan Patel, Seyed Mohammad Abedi, Manidhar Lekkala, Megan Baumgart
It is recognized that HPV-negative and HPV-positive tumors are biologically distinct. HPV-negative tumors commonly acquire amplifications at 11q13 and losses at 9p21. Amplification of the 11q13 locus, with associated amplification of CCND1, CTTN, and ANO1, is identified in multiple tumor types including up to 61% of HNSCC tumors [16]. Amplification of 11q13 correlates with increased protein expression of cyclin D1. This impacts cell cycle progression and contributes to overall disease progression in HNSCC [17]. Cyclin D1 abnormalities are associated with advanced clinical stage, resistance to EGFR inhibitors, and poor prognosis [18]. Additionally, amplification of 11q13 correlates with increased expression of ANO1 which affects EGFR stability and is associated with tumor metastases [19]. Preclinical data suggest that high expression of ANO1 correlates with efficacy of EGFR inhibitors, and that duel inhibition of ANO1 and EGFR may reduce resistance to EGFR inhibitors [20].
Related Knowledge Centers
- Esophageal Cancer
- Interstitial Cell of Cajal
- Sustentacular Cell
- Interstitial Cell of Cajal
- Slow-Wave Potential