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The Production of Biologically Active Peptides in Brain Tissues
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
Procholecystokinin is a 94 amino acid precursor, which is cleaved at a single arginine residue to release an N-terminal fragment, and at a dibasic - Arg-Arg- site to release a C-terminal fragment. The resultant 58 residue peptide, cholecystokinin-58, contains a C-terminal amidated phenylalanine residue and a sulphated tyrosine residue.39 Cholecystokinin-58 can be further cleaved at monobasic and/or dibasic sites to generate other peptides including cholecystokinin-8. (Table 2). The processing of the 84 amino acid progastrin is very analogous to that of procholecystokinin, leading to the formation of gastrin-34 and gastrin-17. There is evidence for considerable cell- and substrate-specific processing of biologically active cholecystokinin and gastrin.40–41
Postulated Physiological and Pathophysiological Roles on Motility
Published in Edwin E. Daniel, Neuropeptide Function in the Gastrointestinal Tract, 2019
Hans-Dieter Allescher, Sultan Ahmad
Gastrin is present in several molecular forms, with G-17 and G-34 being the major forms. Both molecules exist in sulfated and unsulfated forms which show no significant differences in biological activity, in contrast to CCK (see Section IV.B). Recently, the cDNA sequences of porcine and human gastrin precursors were determined, consisting of 104 and 101 residues, respectively.26–28 This precursor consists of a signal peptide, N-terminal and C-terminal flanking peptides (cryptic peptide A and B, intervening peptides), and the G-34 sequence. Cleavage of the G-34 leads to the N-terminal fragment of G-34 (NT-G-34) and to G-17. This posttranslational processing was demonstrated in ultrastructural studies using different specific antibodies, demonstrating that the precursor peptide occurs in the rough endoplasmic reticulum, Golgi apparatus, and dense-cored secretory granules. In contrast, antibodies to G-17 and G-34, the major active products, predominantly labeled secretory granules, suggesting that the final processing of progastrin occurred after the secretory products had left the Golgi apparatus.29 Smaller forms of G-17 have been isolated, such as “minigastrin” G-1430 and the C-terminal hexapeptide.31 The commonly used pentapeptide pentagastrin and the C-terminal tetrapeptide “tetrin”.17,32,33 still exhibit full biological activity, however, with less potency in some systems.
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
The fat mutation involves an enzyme that is of widespread importance in the processing of prohormone-derived peptides. The pancreas, pituitary, and other neuroendocrine tissues, including the brain, adrenal, testis,181 stomach, and colon182 are all CPE-deficient in fat/fat mice. Inappropriate processing of several propeptides has been demonstrated, associated with elevated amounts of precursors and peptides with C-terminal mono- or diciasic amino acid extensions. This includes POMC,183 proenkephalin,181 proneurotensin,184 promelanin-concentrating hormone (MCH),184 progastrin,182,185 and pro-CCK.186 An alternative C-terminal processing pathway for CCK in the rat duodenum was demonstrated recently,186 and in some tissues carboxypeptidase D can partially compensate for the loss of CPE in processing in the fat/fat mouse.181 Therefore, levels of some peptides considered to be normally produced by CPE trimming may not be significantly altered.
Current status of clinical proteogenomics in lung cancer
Published in Expert Review of Proteomics, 2019
Toshihide Nishimura, Haruhiko Nakamura, Ákos Végvári, György Marko-Varga, Naoki Furuya, Hisashi Saji
Some of these histologic types have unique protein markers useful for pathologic differential diagnoses or therapeutic targets. However, information about these markers is quite limited. Some of the mutated proteins, such as EGFR, ALK, ERBB2, KRAS, and BRAF, are the present or future molecular targets for treating adenocarcinomas, while such targets have been rarely reported in squamous cell or large cell carcinoma. For neuroendocrine tumors, unique markers, such as neuron-specific enolase, progastrin-releasing peptide, and chromogranin-A are used for pathologic diagnosis and clinical monitoring. Proteogenomic analyses to study each histologic type may be effective for understanding carcinogenesis of individual lung cancer subtypes and finding new protein markers for differential diagnosis and subtype-specific treatment.
The potential of monitoring treatment response in non-small cell lung cancer using circulating tumour cells
Published in Expert Review of Molecular Diagnostics, 2019
Marianna Gallo, Antonella De Luca, Daniela Frezzetti, Valeria Passaro, Monica R. Maiello, Nicola Normanno
Some studies analyzed the RNA profile of CTCs for monitoring the response to treatment. RT-PCR was used to assess the presence of survivin mRNA as a surrogate biomarker for CTCs detection [46]. At multivariate analysis, survivin mRNA-positive CTCs after one and three chemotherapy cycles were a strong predictor of worse PFS and OS [46]. A RT-PCR assay for the expression of tumor-specific antigen 9 (TSA-9), Keratin 19 (KRT-19), and Pre-progastrin-releasing peptide (Pre-proGRP), was performed in peripheral blood from 134 lung cancer patients. The expression of the three tumor markers was analyzed in patients showing different responses to chemotherapy. The percentage of patients expressing more than one marker was significantly higher in the cohort of patients with PD than that in the group of patients with PR (P < 0.05) [48]. Multimarker quantitative RT-PCR for multiple genes [KRT19, ubiquitin thiolesterase, highly similar to HSFIB1 for fibronectin, and tripartite motif-containing 28 (TRIM28)] for CTCs detection and a scoring method using cancer cell load in the circulation, defined as Lc, was employed to assess treatment response in CTCs from 54 NSCLC patients [49]. Stage IIIa and IV patients with higher Lc values after the last course of chemotherapy had short survival times.
True Chromogranin A concentrations in plasma from patients with small intestinal neuroendocrine tumours
Published in Scandinavian Journal of Gastroenterology, 2020
Jens F. Rehfeld, Kasper Broedbaek, Jens P. Goetze, Ulrich Knigge, Linda M. Hilsted
To evaluate the diagnostic accuracy of CgA measurements, we measured CgA concentrations in plasma from 130 well-characterized patients with small intestinal NETs and 30 control subjects, using available commercial CgA kits (n = 8). The kit results have been compared with those of an in-house CgA RIA with precisely defined epitope specificity [1], and with those of a processing-independent assay (PIA) that accurately measures the ‘total’ CgA product in plasma [1,13]. The PIA technology is explicitly designed to cope with processed precursor-proteins like CgA [1,13], progastrin [16], and several other heterogenous peptide hormone systems (Figure 1(B)) [12].