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Gastroenteropancreatic Regulatory Peptide Structures: An Overview
Published in Edwin E. Daniel, Neuropeptide Function in the Gastrointestinal Tract, 2019
In the mammal, GRP appears to be confined strictly to neural elements of the central, peripheral, and enteric nervous systems, with the exceptions that it is also found in neuroendocrine cells of the peribronchial epithelium and in neuroendocrine cells present in small cell lung cancer, medullary carcinoma of the thyroid, and carcinoid tumors. Intracerebral administration of GRP to mammals results in potent and diverse biological effects, including the production of hypothermia, hyperglycemia, altered satiety mechanisms, and increased sympathetic tract outflow. Peripheral i.v. administration of GRP potently effects the release of a number of biologically active peptides (hormones, neuropeptides), alters gastrointestinal smooth muscle activity, and has potent effects on the exocrine secretion of the pancreas and stomach. Although no single biological function of GRP or bombesin has been demonstrated to be physiological, strong suggestive evidence has been reported for a role for GRP in vagal mechanisms resulting in the release of gastrin from endocrine cells in the gastric antrum. The bombesin-like peptides also have putative trophic roles in the lung, gastric antrum, and pancreas and have been implicated as autocrine growth factors in human small cell lung cancer.309 The role of bombesin-like peptides in health and disease has recently been the subject of an international symposium307 and has been the subject of recent reviews.292,310
Non-adrenergic Non-cholinergic Autonomic Transmission
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Bombesin and gastrin-releasing peptide (GRP) are related 27-residue peptides with a common C-terminal heptapeptide. GRP is released into the venous effluent by vagal stimulation to the stomach where it is involved in the release of gastrin. Stimulation of the vagus nerve or the presence of protein in the stomach causes release of gastrin via an atropine-resistant nervous pathway (see Figure 8.3, Chapter 8, gastrointestinal tract). Bombesin does not occur naturally in mammals, being first isolated from the frog skin. Bombesin-like immunoreactivity, however, has been identified in mammalian peripheral tissues. Furthermore, bombesin itself does activate bombesin (BB1) receptors in various tissues including the guinea-pig and rat urinary bladder to cause contraction. Bombesin-like peptides, however, currently do not appear to serve as excitatory transmitters in this tissue (Maggi et al. 1992). The predominant second messengers for BB receptors are inositol triphosphate (IP3) and diacylglycerol, and the receptor for GRP is the BB2 subtype.
Respiratory Tract Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Women may be particularly sensitive to certain carcinogenic compounds in tobacco smoke (68). Several recent epidemiological studies indicate that women may have a higher risk of lung cancer than men (69,70). These studies are supported by data showing a higher level of hydrophobic DNA adduct in female lung compared to men (71,72). Moreover, a higher frequency of G to T mutations in the p53 gene in lung tumors of females than in males was observed (73,74). In human lung, CYP1A1 mRNA are induced by PAH in tobacco smoke. One study showed that women smokers have significantly higher expression of lung CYP1A1 (72). In the same study, hydrophobic DNA adducts were found to be significantly associated to the level of CYP1A1 expression. Together, these data indicate that women may be more susceptible for lung cancer than males. The mechanism(s) is unknown but hormones may be involved, modulating the expression of enzymes involved in the metabolism of PAH. Estrogen receptors (ER-alpha and ER-beta) have been identified in human lung cells (75). There is also recently presented evidence that the observed sex difference in lung cancer risk may be explained by the expression of gastrin-releasing peptide receptor (GRPR) at a significant lower exposure to tobacco smoke in females than males (76). Studies have shown that bombesin-like peptides such as GRP induce cell proliferation in several cell types, also human bronchial cells and may thereby stimulate promotion in lung carcinogenesis (77).
Recent advances in proteolytic stability for peptide, protein, and antibody drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Xianyin Lai, Jason Tang, Mohamed E.H. ElSayed
Many more ubiquitous peptidases like plasmin and furin circulate in blood. Thimet oligopeptidase (EC 3.4.24.15) is a metalloprotease associated with peptide processing in nervous system structures. It degrades several peptides, including bradykinin, amyloid beta, and the major histocompatibility complex class I molecules [77]. Nardilysin (3.4.24.61) is a metalloendopeptidase and promotes ectodomain shedding of the precursor forms of various growth factors and cytokines [78]. Neprilysin (neutral endopeptidase, NEP, EC 3.4.24.11) is a membrane-bound zinc-metallopeptidase enzyme and cleaves various peptides, including natriuretic and bombesin-like peptides, endothelin-1, and substance P [79]. Numerous peptidases are expressed in various tissues and secreted into plasma. Whether the peptidases are concerns for peptide, protein, and antibody drugs depends on the peptidase concentration in the blood.
Neprilysin, the kidney brush border neutral proteinase: a possible potential target for ischemic renal injury
Published in Toxicology Mechanisms and Methods, 2020
Runali Sankhe, Manas Kinra, Jayesh Mudgal, Devinder Arora, Madhavan Nampoothiri
In the body, NEP contributes to the formation and degradation of numerous peptides. By 2016, researchers have identified more than 50 putative peptide substrates of NEP (Bayes-Genis et al. 2016). The role of peptides formed and degraded by NEP in renal and cardiac system is described in Table 1. Peptides such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP)-type and C-type natriuretic peptide (CNP), angiotensin II (Ang II), angiotensin-(1–7) (Ang-(1–7)), oxytocin, substance P, bradykinin, bombesin-like peptides, endothelin 1 (ET-1) and 2, glucagon, enkephalins, amyloid β (Aβ) (Campbell 2017), opioids, calcitonin, somatostatin, and neurotensin (Nalivaeva et al. 2012). Due to its ability to modulate various bioactive peptides, NEP is thought to be involved in the pathophysiology of diseases such as CKD, CVD (Malek and Gaikwad 2017), Alzheimer’s disease (AD) (Nalivaeva et al. 2012), renal (Erin et al. 2016), prostate (Albrecht et al. 2003) and lung cancer (Pavo et al. 2019), obesity (Standeven et al. 2011), asthma (Chung 1996), insulin resistance and metabolic syndrome (Standeven et al. 2011; Malek and Gaikwad 2017). In the diagnosis of leukemia and renal cell carcinoma, NEP is considered as a potential biomarker (Mizerska-Dudka and Kandefer-Szerszeń 2015; Erin et al. 2016). In the body, opiorphin, sialorphin, and spinorphin act as an endogenous inhibitor of NEP (Mizerska-Dudka and Kandefer-Szerszeń 2015). In the last few years, the role of NEP has been extensively studied for regulation and degradation of NPs at functional level. NEP mediated hydrolysis of NPs contributes to modulate the functional and structural effects on kidney, heart and other organs. The concentration of soluble form of NEP is reported high in acute and chronic heart failure patients and this high concentration of soluble NEP is indicator of adverse outcome in cardiovascular system. Furthermore, in heart failure patients, the treatment with sacubitril/valsartan showed substantial improvement in outcome through NEP inhibition (Buttrick 2018). Similarly, the abundance of NEP in the brush border of proximal renal tubular cells and its role in modulating NPs suggests the multifaceted action of NEP in the kidney. So far, only a little is known about the role of NEP in IRI induced AKI. Here on, the review will focus on the role of NEP with special emphasis on the overlapping mechanisms of ischemic renal injury.