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Abstract

Somatostatin is an endogeneous cyclic tetradecapeptide hormone that exerts multiple biological activities via five ubiquitously distributed receptor subtypes. Classified as a broad inhibitory neuropeptide, somatostatin has anti-secretory, anti-proliferative and anti-angiogenic effects. The clinical use of native somatostatin is limited by a very short half-life (1 to 3minutes) and the broad spectrum of biological responses. Thus stable, receptor-selective agonists have been developed. The majority of these somatostatin therapeutic agonists bind strongly to two of the five receptor subtypes, although recently an agonist of wider affinity has been introduced. Somatostatin agonists are established in the treatment of acromegaly with recently approved indications in the therapy of neuroendocrine tumors. Potential therapeutic uses for somatostatin analogues include diabetic complications like retinopathy, nephropathy and obesity, due to inhibition of IGF-1, VEGF together with insulin secretion and effects upon the renin-angiotensin-aldosterone system. Wider uses in anti-neoplastic therapy may also be considered and recent studies have further revealed anti-inflammatory and anti-nociceptive effects. This review provides a comprehensive, current view of the biological functions of somatostatin and potential therapeutic uses, informed by the wide range of pharmacological advances reported since the last published review in 2004 by P. Dasgupta. The pharmacology of somatostatin receptors is explained, the current uses of somatostatin agonists are discussed, and the potential future of therapeutic applications is explored. Copyright © 2015. Published by Elsevier Inc.

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... SST is a small peptide that is also released from the central nervous system besides the sensory nerves (Helyes et al., 2009), from inflammatory and immune cells, pancreas, retinal neurons, and epithelial cells (Rai et al., 2015). SST exerts antiinflammatory, antinociceptive (Helyes et al., 2009;Markovics et al., 2012), antisecretory, and antiproliferative effects (Rai et al., 2015). ...
... SST is a small peptide that is also released from the central nervous system besides the sensory nerves (Helyes et al., 2009), from inflammatory and immune cells, pancreas, retinal neurons, and epithelial cells (Rai et al., 2015). SST exerts antiinflammatory, antinociceptive (Helyes et al., 2009;Markovics et al., 2012), antisecretory, and antiproliferative effects (Rai et al., 2015). There are five G i -protein-coupled transmembrane receptor subtypes of SST (SSTR1-5) (Rai et al., 2015). ...
... SST exerts antiinflammatory, antinociceptive (Helyes et al., 2009;Markovics et al., 2012), antisecretory, and antiproliferative effects (Rai et al., 2015). There are five G i -protein-coupled transmembrane receptor subtypes of SST (SSTR1-5) (Rai et al., 2015). It is known that endogenous SST released from capsaicin-sensitive nerves prevented retinal ischemia/reperfusion injury in a mouse model (Wang et al., 2017). ...
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Little is known about the role of the neuropeptide somatostatin (SST) in myocardial ischemia/reperfusion injury and cardioprotection. Here, we investigated the direct cardiocytoprotective effect of SST on ischemia/reperfusion injury in cardiomyocyte cultures, as well as the expression of SST and its receptors in pig and human heart tissues. SST induced a bell-shaped, concentration-dependent cardiocytoprotection in both adult rat primary cardiomyocytes and H9C2 cells subjected to simulated ischemia/reperfusion injury. Furthermore, in a translational porcine closed-chest acute myocardial infarction model, ischemic preconditioning increased plasma SST-like immunoreactivity. Interestingly, SST expression was detectable at the protein, but not at the mRNA level in the pig left ventricles. SSTR1 and SSTR2, but not the other SST receptors, were detectable at the mRNA level by PCR and sequencing in the pig left ventricle. Moreover, remote ischemic conditioning upregulated SSTR1 mRNA. Similarly, SST expression was also detectable in healthy human interventricular septum samples at the protein level. Furthermore, SST-like immunoreactivity decreased in interventricular septum samples of patients with ischemic cardiomyopathy. SSTR1, SSTR2, and SSTR5 but not SST and the other SST receptors were detectable at the mRNA level by sequencing in healthy human left ventricles. In addition, in healthy human left ventricle samples, SSTR1 and SSTR2 mRNAs were expressed especially in vascular endothelial and some other cell types as detected by RNA Scope® in situ hybridization. This is the first demonstration that SST exerts a direct cardiocytoprotective effect against simulated ischemia/reperfusion injury. Moreover, SST is expressed in the heart tissue at the peptide level; however, it is likely to be of sensory neural origin since its mRNA is not detectable. SSTR1 and SSTR2 might be involved in the cardioprotective action of SST, but other mechanisms cannot be excluded.
... The protein can be detected by Western blot as a characteristic band of 70-80 kDa (13,17,18). SSTR2 is ubiquitously distributed in normal tissues especially in the central nervous system (CNS) and endocrine system (12,(19)(20)(21). SSTR2 is also expressed widely and represents manifold functions in various tumor tissues including neuroendocrine tumors, pituitary adenomas, breast cancer, melanoma, thyroid cancer, and meningioma (20,(22)(23)(24)(25). Nevertheless, the expression level of SSTR2 between normal tissues and tumor tissues is different. ...
... SSTR2 is ubiquitously distributed in normal tissues especially in the central nervous system (CNS) and endocrine system (12,(19)(20)(21). SSTR2 is also expressed widely and represents manifold functions in various tumor tissues including neuroendocrine tumors, pituitary adenomas, breast cancer, melanoma, thyroid cancer, and meningioma (20,(22)(23)(24)(25). Nevertheless, the expression level of SSTR2 between normal tissues and tumor tissues is different. ...
... traditional therapies, especially for those inoperable or recurrent patients. The exact biological function of SSTR2 in meningioma is hitherto not very sharply defined, but its activation may be correlated to an antiproliferative effect (28,(74)(75)(76)(77). Native somatostatin is rapidly metabolized and has a short half-life (1-3 min) in vivo, which limits its clinical use, whereas synthetic somatostatin analogs like octreotide are much more stable (20). Somatostatin analogs have already achieved promising effects in the treatment of high-SSTR2-expression tumors, such as gastroenteropancreatic neuroendocrine tumors and GH-secreting pituitary adenomas (78,79). ...
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Somatostatin receptor (SSTR) 2, widely expressed in meningioma, is a G-protein-coupled receptor and can be activated by somatostatin or its synthetic analogs. SSTR2 is therefore extensively studied as a marker and target for the diagnosis and treatment of meningioma. Accumulating studies have revealed the crucial clinical significance of SSTR2 in meningioma. Summarizing the progress of these studies is urgently needed as it may not only provide novel and better management for patients with meningioma but also indicate the direction of future research. Pertinent literature is reviewed to summarize the recent collective knowledge and understanding of SSTR2’s clinical significance in meningioma in this review. SSTR2 offers novel ideas and approaches in the diagnosis, treatment, and prognostic prediction for meningioma, but more and further studies are required
... Detailed analysis of the anatomical expression pattern and pharmacological actions of ArSS2 in A. rubens revealed that it acts as a muscle relaxant and triggers stomach eversion in this species (21). This myoinhibitory effect of ArSS2 in starfish is noteworthy because it is consistent with the effects of SS/ASTC-type neuropeptides as inhibitory regulators of a variety of physiological processes in chordates and protostomes (13,14,(23)(24)(25)(26). Thus, an ancient role of SS/ASTC-type neuropeptides as inhibitory regulators can be traced back to the common ancestor of the Bilateria, with this role being retained in the action of the SS2-type neuropeptide ArSS2 as a myoinhibitor in an echinoderm-the starfish A. rubens (21). ...
... A detailed analysis of the expression of the SS-type neuropeptide ArSS2 in the starfish A. rubens was reported previously (21), which revealed a widespread pattern of expression in the central nervous system, digestive system, and body wall-associated tissues/ organs. Furthermore, analysis of the pharmacological actions of ArSS2 revealed that it acts as a muscle relaxant, an action that is consistent with the actions of SS-type neuropeptides in vertebrates and ASTC-type neuropeptides in protostomes as inhibitory regulators of physiological processes (13,14,(23)(24)(25)(26). Here, the expression and actions of the ASTC-type neuropeptide ArSS1 in A. rubens were investigated. ...
... Interestingly, ArSS1 had a myoexcitatory effect on all three preparations, causing concentration-dependent contraction at physiologically relevant concentrations ranging from 10 À9 M to 10 À6 M. ArSS1 joins a growing list of neuropeptides that have been found to act as myoexcitatory neuropeptides in starfish, as summarized in SI Appendix, Table S3. However, the myoexcitatory effect of ArSS1 in A. rubens is interesting because hitherto it has been discovered that SS-type and ASTC-type neuropeptides in other taxa typically act as inhibitory regulators of physiological processes at the cellular level (13,14,(23)(24)(25)(26). There are reports of SS causing muscle contraction of guinea pig gastric smooth muscle cells, but investigation of the mechanisms of action indicate that this is a consequence of SS causing inhibition of the release of a muscle relaxant (e.g., vasoactive intestinal peptide) [i.e., SS is causing disinhibition (41,42)]. ...
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Significance Somatostatin (SS) and allatostatin-C (ASTC) are related neuropeptide hormones that act as inhibitory regulators of physiological processes in chordates (e.g., humans) and protostome invertebrates (e.g., insects), respectively. We have discovered that echinoderms (e.g., starfish) uniquely have both SS-type and ASTC-type neuropeptides, which act as inhibitory and excitatory regulators of muscle activity, respectively. Our findings suggest that SS-type and ASTC-type neuropeptides evolved by duplication of a common ancestral encoding gene. Then, one of the neuropeptides was lost in protostomes and chordates, probably because of their functional redundancy as inhibitory regulators. Conversely, the unique retention of both neuropeptide types in echinoderms may be explained by evolution of an excitatory role for ASTC-type neuropeptides mediated by yet-to-be-determined signaling mechanisms.
... Over the past 20 years, our understanding of the phenomena due to the activation of SSTRs has increased thanks to numerous translational and clinical studies, leading to the development of new therapeutic options [3]. The use of SST analogs has demonstrated real effectiveness in the treatment of various pathologies: acromegaly (production of an excess of growth hormone), pancreatitis, complications linked to diabetes and obesity (e.g., retinopathy or nephropathy), action on inflammation and pain in some cases [5,9]. However, SSTRs and SST analogs are mainly known for their presence and role in the detection and treatment of some solid tumors. ...
... Therefore, the amount present in the bloodstream is extremely low (between 14 and 32.5 pg/mL). This very short half-life has been considered a limiting factor for possible clinical applications, thus many analogs with better metabolic properties (longer half-life between 1.5 h and 12 h) have been rapidly developed [2,5,9]. These are Figure 3). ...
... This type of compound may have a stronger affinity and/or selectivity for certain subtypes of somatostatin receptors than the majority of peptide analogs. They can thus provide additional information on the exact role of each of these subtypes [5,9]. ...
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Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole body, with five subtypes described. The interaction between SST and its receptors leads to the internalization of the ligand-receptor complex and triggers different cellular signaling pathways. Interestingly, the expression of SSTRs is significantly enhanced in many solid tumors, especially gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). Thus, somatostatin analogs (SSAs) have been developed to improve the stability of the endogenous ligand and so extend its half-life. Radiolabeled analogs have been developed with several radioelements such as indium-111, technetium-99 m, and recently gallium-68, fluorine-18, and copper-64, to visualize the distribution of receptor overexpression in tumors. Internal metabolic radiotherapy is also used as a therapeutic strategy (e.g., using yttrium-90, lutetium-177, and actinium-225). With some radiopharmaceuticals now used in clinical practice, somatostatin analogs developed for imaging and therapy are an example of the concept of personalized medicine with a theranostic approach. Here, we review the development of these analogs, from the well-established and authorized ones to the most recently developed radiotracers, which have better pharmacokinetic properties and demonstrate increased efficacy and safety, as well as the search for new clinical indications.
... The protein was produced by transient expression in Expi293 cells [47] with yields of around 30 mg per liter of transfected cell cultures. The construct was expressed in these mammalian cells since it was essential that a disulfide bond between the two cysteine residues in SST structure was formed, which is required for the biological activity [48]. Non-cyclic SST peptide without the disulfide bond is also more prone to aggregate [49]. ...
... The plasma half-life of the recombinant protein, based on blood samples obtained at 0.5, 1, 2, 4, 6 and 24 h post injection, was around 6 h ( Figure 3A). This is 120 times longer than the plasma half-life of intravenously injected SST peptide, which has been demonstrated to be only three min [48,53]. Because of the short half-life of SST, it was not used as a control in this study. ...
... In this first therapeutic study, we measured the levels of neprilysin and Aβ in the brains of 14-month old APPswe mice after a single intravenous injection of 2 mg/kg of SST-scFv8D3 ( Figure 4B). SST peptide alone without scFv8D3 was not used based on previous studies demonstrating its extremely short half-life of less than three min [48,55] and that analogs of SST with longer half-lives have been analyzed to see if they passed the BBB and their uptake in brain was low [56]. Importantly, these analogs of SST have no affinity to the receptor subtype 4 [57][58][59], which has high hippocampal and limited peripheral expression [36] and has been identified as the major regulator of neprilysin activity in the brain [60]. ...
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Background: Aggregation of the amyloid-beta (Aβ) peptide is one of the main neuropathological events in Alzheimer's disease (AD). Neprilysin is the major enzyme degrading Aβ, with its activity enhanced by the neuropeptide somatostatin (SST). SST levels are decreased in the brains of AD patients. The poor delivery of SST over the blood-brain barrier (BBB) and its extremely short half-life of only 3 min limit its therapeutic significance. Methods: We recombinantly fused SST to a BBB transporter binding to the transferrin receptor. Using primary neuronal cultures and neuroblastoma cell lines, the ability of the formed fusion protein to activate neprilysin was studied. SST-scFv8D3 was administered to mice overexpressing the Aβ-precursor protein (AβPP) with the Swedish mutation (APPswe) as a single injection or as a course of three injections over a 72 h period. Levels of neprilysin and Aβ were quantified using an Enzyme-linked immunosorbent assay (ELISA). Distribution of SST-scFv8D3 in the brain, blood and peripheral organs was studied by radiolabeling with iodine-125. Results: The construct, SST-scFv8D3, exhibited 120 times longer half-life than SST alone, reached the brain in high amounts when injected intravenously and significantly increased the brain concentration of neprilysin in APPswe mice. A significant decrease in the levels of membrane-bound Aβ42 was detected in the hippocampus and the adjacent cortical area after only three injections. Conclusion: With intravenous injections of our BBB permeable SST peptide, we were able to significantly increase the levels neprilysin, an effect that was followed by a significant and selective degradation of membrane-bound Aβ42 in the hippocampus. Being that membrane-bound Aβ triggers neuronal toxicity and the hippocampus is the central brain area in the progression of AD, the study has illuminated a new potential treatment paradigm with a promising safety profile targeting only the disease affected areas.
... Somatostatin (SST) is a polypeptide hormone existing in two forms (14 and 28 amino acids). The properties of SST consist of antisecretory, antiproliferative and antiangiogenic effects [7]. SST has a short half-life and binds with high affinity to five different subtypes of receptor ubiquitously distributed. ...
... SST has a short half-life and binds with high affinity to five different subtypes of receptor ubiquitously distributed. The binding of SST with its receptor determines several biological functions [7]. The expression levels of SST receptors (SSTRs) have been determined in multiple human tissues across the human body, including the brain, gastrointestinal tract, pancreas, lung and genitourinary tract. ...
... SSAs are very effective drugs for hormonal syndrome control in functioning tumors and exert an antiproliferative effect by inducing cell cycle arrest and apoptosis, and through immunomodulatory effects and angiogenesis inhibition. Considering these data, they have been approved for the treatment of acromegaly and NET [7,8]. SSAs allow the control of cell proliferation through two different mechanisms: a direct one, consisting of the binding to specific surface receptors, and an indirect one, consisting of the inhibition of growth factors and modulation of immune response [7]. ...
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Neuroendocrine neoplasms (NEN) are characterized by a wide clinical heterogeneity and biological variability, with slow progression and long survival in most cases. Although these tumors can affect young adults, there are few studies that focus on the sexual and reproductive system. The aim of this review was to evaluate the effect of NEN treatment, including somatostatin analogues (SSA), targeted therapy (Everolimus and Sunitinib), radiolabeled-SSA and chemotherapy, on male and female reproductive systems and sexual function. This narrative review was performed for all available prospective and retrospective studies, case reports and review articles published up to March 2022 in PubMed. To date, few data are available on the impact of SSA on human fertility and most of studies come from acromegalic patients. However, SSAs seem to cross the blood–placental barrier; therefore, pregnancy planning is strongly recommended. Furthermore, the effect of targeted therapy on reproductive function is still undefined. Conversely, chemotherapy has a well-known negative impact on male and female fertility. The effect of temozolomide on reproductive function is still undefined, even if changes in semen parameters after the treatment have been described. Finally, very few data are available on the sexual function of NEN treatment.
... Additionally, 68 Ga has a positron energy of 1.9 MeV and a higher positron range than 18 F (635 keV), which results in a lower resolution of the final image. This fact promoted the development of 18 [155][156][157]. Somatostatin (SST) is the endogenous SSTR ligand which is a neuropeptide that is produced and excreted by cells such as neuroendocrine, immune and inflammatory cells [158].It has many downstream biological effects yet it is mainly a broad inhibitor of the secretion of hormones, proliferation and cell growth [159]. ...
... Somatostatin (SST) is the endogenous SSTR ligand which is a neuropeptide that is produced and excreted by cells such as neuroendocrine, immune and inflammatory cells [158].It has many downstream biological effects yet it is mainly a broad inhibitor of the secretion of hormones, proliferation and cell growth [159]. SST itself is suboptimal as a pharmaceutical due to its short biological half-life (<3 min) [154,156,160]. Therefore, somatostatin analogs that have been generated are more 96 stable receptor selective agonists in vivo. ...
... Internalization of the radiolabelled SSA receptor complex allows for accumulation of the radiotracer in the NET cells. Visualization of the tumour localization can then be done via PET or single photon emission computed tomography (SPECT); as well, treatment is available using peptide receptor radionuclide therapy (PRRT) [156,165]. The receptor subtype SSTR2 is a good target for nuclear imaging as well as PRRT not only because it is commonly found overexpressed at a high density on certain tumour cells, but it also has low expression on normal cells allowing for preferential image contrast and minimal off-target effects [166]. ...
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Fluorine-18 fluorodeoxyglucose ([18F]FDG), the first radiopharmaceutical used in clinical applications of positron emission tomography (PET), was a revolutionary development in nuclear medicine that combined biochemistry, medicinal chemistry and radiochemistry. In the 1970s, it was used in brain imaging to aid clinical diagnosis; soon, the detection of malignancies and cardiac diseases also became possible. In the decades that followed, [18F]FDG became widely available owing to the worldwide cyclotron network and automated synthesizers in clinics in many Member States. This paved the way for the development of additional 18F-labelled radiopharmaceuticals adapted for other biological pathways and molecular and cellular mechanisms applicable to human diseases. The production and quality control of 18F radiopharmaceuticals have been revolutionized from the industrial point of view, with the introduction of national and international safety, legislative and legal requirements. In response to numerous requests from Member States, in 2020 the IAEA organized a number of consultancy meetings aimed at planning and preparing a publication on the production and quality control of 18F radiopharmaceuticals. The present publication is a result of those meetings and provides information on practical production routes and on quality control and radiopharmaceutical aspects of 18F tracers. It is expected to be of interest to radiopharmacists and radiochemists, as well as graduate students in the field of 18F radiochemistry and radiopharmacy. The IAEA wishes to thank the participating experts for their valuable work and scientific contributions, especially P.H. Elsinga (Netherlands) for compiling and carrying out the technical editing of this publication and J. Vera Araujo (Bolivarian Republic of Venezuela) for her editorial support. The IAEA technical officer responsible for this publication was A.R. Jalilian of the Division of Physical and Chemical Sciences.
... Furthermore, the SRIF system is characterized by a strong antiproliferative activity, increasing cell apoptosis and inhibiting angiogenesis in most of the cancerous tissues [12,[16][17][18][19][20]. This property is already used in clinical practice [20][21][22][23][24][25][26]. SST acts through the activation of five membrane receptors (SSTRs/SSTs), belonging to the G protein-coupled receptor (GPCR) family [12,16,19,24,27,28]. ...
... SST is a peptide that assumes two forms (SST-14 and SST-28), secreted mostly in a paracrine/neurocrine fashion, released in a pulse manner as a very short-lived peptide of about 3 min bioactive half-life in circulation, where it is degraded rapidly by ubiquitous peptidases [12,22,24,37]. In CNS, the peripheral nervous system (PNS) and pancreas SST-14 is the dominating form, while SST-28 is secreted by D cells in the GI tract [42]. ...
Article
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Somatostatin (SST)/somatotropin release-inhibiting factor (SRIF) is a well-known neuropeptide, widely distributed in the central and peripheral nervous systems, that regulates the endocrine system and affects neurotransmission via interaction with five SST receptors (SST1-5). In the gastrointestinal tract, the main SST-producing cells include intestinal enteroendocrine cells (EECs) restricted to the mucosa, and neurons of the submucosal and myenteric plexuses. The action of the SRIF system is based on the inhibition of endocrine and exocrine secretion, as well as the proliferative responses of target cells. The SST1–5 share common signaling pathways, and are not only widely expressed on normal tissues, but also frequently overexpressed by several tumors, particularly neuroendocrine neoplasms (NENs). Furthermore, the SRIF system represents the only peptide/G protein-coupled receptor (GPCR) system with multiple approved clinical applications for the diagnosis and treatment of several NENs. The role of the SRIF system in the histogenesis of colorectal cancer (CRC) subtypes (e.g., adenocarcinoma and signet ring-cell carcinoma), as well as diagnosis and prognosis of mixed adenoneuroendocrine carcinoma (MANEC) and pure adenocarcinoma, is poorly understood. Moreover, the impact of the SRIF system signaling on CRC cell proliferation and its potential role in the progression of this cancer remains unknown. Therefore, this review summarizes the recent collective knowledge and understanding of the clinical significance of the SRIF system signaling in CRC, aiming to evaluate the potential role of its components in CRC histogenesis, diagnosis, and potential therapy.
... Specifically, sst5TMD4 has been shown to be overexpressed in several hormone-related tumors compared with non-tumor tissues, where it enhanced aggressiveness features [14][15][16][17][18][19][20][21][22]. Moreover, sst5TMD4 has been shown to reduce the response to somatostatin analogs (SSAs; e.g., octreotide) [14,17,18,22,23], which are used as valuable drugs to treat different tumor pathologies, including pituitary and neuroendocrine tumors [24,25]. Unfortunately, attempts to use SSAs as medical therapy in brain tumors have rendered controversial results since some of the available studies have not reported a clear therapeutic value for SSAs; however, the mechanistic reasons underlying those experimental failures remain unknown [26][27][28][29][30]. ...
... In this context, the development of SSAs as therapeutic opportunities has revolutionized the clinical management of patients with certain endocrine pathologies, and nowadays are considered the mainstay in the medical management of some pituitary and neuroendocrine tumors [24,25,37]. However, SSAs are frequently ineffective in a subset of patients, suggesting that key molecular determinants could be essential for the response to this pharmacological treatment [38]. ...
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Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12–15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-β), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs.
... SSAs that are often recommended for patients with advanced neuroendocrine tumours since they exhibit a high affinity for at least two of the five types of somatostatin receptors. (14,15) SSAs also exert their inhibitory actions against hormone secretion and cell proliferation, (16) promoting stabilisation in 30-70% of patients with well-differentiated NENs of different origins and prolonged mPFS, although, without proven survival gain. (14,15,17,20,21) We demonstrated that these results were observed in our patients with NETP, independent of the carcinoid subtype (typical or atypical). ...
... (14,15) SSAs also exert their inhibitory actions against hormone secretion and cell proliferation, (16) promoting stabilisation in 30-70% of patients with well-differentiated NENs of different origins and prolonged mPFS, although, without proven survival gain. (14,15,17,20,21) We demonstrated that these results were observed in our patients with NETP, independent of the carcinoid subtype (typical or atypical). ...
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Introduction: Well-differentiated neuroendocrine pulmonary tumours (NETp) are morphologically classified as typical carcinoid (TC) and atypical carcinoid (AC). There are limited data on systemic treatment for metastatic disease. Objective: Our study evaluated the median progression-free survival of patients with metastatic tumours, comparing TC and AC status for different treatments. Methods: Retrospective series of patients with metastatic NETp treated from 2002 to 2019 in a large cancer centre were analysed. Our primary endpoint was progression-free survival according to morphological classification (TC vs. AC). All patients received at least one treatment modality (e.g., somatostatin analogue [SSA], chemotherapy [ChP], and everolimus [Eve]). Variables were analysed using the chi-square test, median progression-free survival (mPFS) rates (months), with comparisons evaluated by the log-rank test. Results: Twenty-seven patients were included: 44% with TC and 56% with AC. TC patients were on average 58-years-old, 83.3% were female, and 33.3% received more than one treatment. AC patients were on average 61-years-old, 66.7% were female, and 20% received more than one treatment. All patients were treated more frequently with SSA (TC: 75% vs. AC: 80%, p=0.756). Cisplatin and etoposide were the most frequent ChP regimen (TC: 75% vs. AC: 30%, p=0.248). Patients with TC and AC treated with SSA had higher mPFS in months (TC mPFS SSA: 14.5, Eve: 2.50, ChP: 4.0, SSA + Eve: 4.50; AC mPFS SSA: 7.50, Eve: 4.50, ChP: 7.50, SSA + Eve: 7.00). Conclusion: Although the statistical analyses did not show a significant difference between treatment, numerically, more patients with TC or AC experienced tumor control with SSAs, where the mPFS pairs showed a possible tendency to differentiate themselves from the other regimes (Eve and ChP).
... Apart from its inhibitory functions (the inhibition of pituitary hormones [11,12], the regulation of gastrin and gastric acid secretion [13] and the inhibition of other hormones in the gastrointestinal tract and pancreas [14][15][16][17]), SST can also control cell growth and tumor development [18]. Furthermore, it seems to exert anti-inflammatory and anti-nociceptive effects [19]. ...
... Inhibition of exocytosis, therefore the antisecretory function, is possible by altering the levels of second messengers, such as cyclic adenosine monophospate (cAMP) or by activating ion channels, and thus altering intracellular calcium levels. The antiproliferative role is exerted directly by inducing cell cycle arrest or apoptosis or by inhibiting the release of growth factors and indirectly by inhibition of angiogenesis [18,19]. It seems that SSTR2 and SSTR3 were related to increased apoptosis, SSTR1 and SSTR2 to suppressed cell migration and invasion while all five receptors were related to reduced cell proliferation [25]. ...
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Molecular predictive biomarkers represent an essential tool for the future of personalized oncotherapy. Gastro-entero-pancreatic neuroendocrine neoplasms are a heterogeneous group of epithelial tumors with a steadyincrease in incidence and prevalence. Their effective management depends on early diagnosis, personalizedrisk stratification, and monitoring response to therapy. A crucial element is identifying accurate biomarkers topredict/monitor therapeutic responses, assess drug resistance, and quantify residual disease in a reproducibleand less invasive way. Taking into consideration their role in cell differentiation, cell proliferation, apoptosisand tumor development, microRNAs have gained interest as potential prognostic markers and treatmentresponse predictors in neuroendocrine neoplasms. This review is the first to summarize the available dataon the possible role of microRNAs in evaluating the efficacy of somatostatin analogs treatment in gastro-entero-pancreatic neuroendocrine neoplasms. Although the literature is scarce, the let-7 family targetingphosphoinositide 3 kinase – protein kinase B 1 – mammalian target of rapamycin signaling pathway mightrepresent a promising biomarker with potential clinical benefit, but further research is required beforetheir eventual clinical application. Furthermore, the ambiguous molecular mechanisms of neuroendocrineproliferation and the undefined signaling pathway of somatostatin analogs should encourage future researchin this field that may lead to a different clinical approach to neuroendocrine disease.
... Representative examples of paracrine retinoprotective proteins include the pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP, [12]), somatostatin [20], and Vascular Endothelial Growth Factor (VEGF, [11]). VIP is expressed in a population of amacrine cells [13], whereas PACAP and its receptors (PAC1, VPAC1, and VPAC2) occur in all retinal layers except the photoreceptors [14]. ...
... Of note, IGF1, previously mentioned above as possessing an autocrine signaling mechanism of action, can also act in a paracrine manner (Table 1), as it is expressed by the microglia and protects photoreceptors in the rd10 mouse model [6]. The paracrine retinoprotective peptide somatostatin or somatotropin release inhibiting factor (SRIF), is a neuropeptide with a broad inhibitory effect on protein secretion, proliferation, and angiogenesis [20]. The SRIF receptors (SST1-4 in mammals) are distributed in all retinal layers and RPE cells, but the main source of secreted SRIF is the RPE cells [14]. ...
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Retinoprotective proteins play important roles for retinal tissue integrity. They can directly affect the function and the survival of photoreceptors, and/or indirectly target the retinal pigment epithelium (RPE) and endothelial cells that support these tissues. Retinoprotective proteins are used in basic, translational and in clinical studies to prevent and treat human retinal degenerative disorders. In this review, we provide an overview of proteins that protect the retina and focus on pigment epithelium-derived factor (PEDF), and its effects on photoreceptors, RPE cells, and endothelial cells. We also discuss delivery systems such as pharmacologic and genetic administration of proteins to achieve photoreceptor survival and retinal tissue integrity.
... Somatostatin inhibits the secretion of insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal polypeptide, the insulin-like growth factor-1, and other compounds. Somatostatin is used for therapy of hormonal disorders that are associated with hyperproduction of the somatotropin growth hormone and various diseases of the gastrointestinal tract and pancreas [65]. The modustatin and stilamin drugs that have the natural structure of somatostatin were developed and introduced into medicinal practice at the end of 1980s. ...
... The structure-functional studies of somatostatin resulted in the creation of its highly active agonistic analogs, octreotide and lanreotide [65][66][67][68]. Octreotide is a cyclic octapeptide of the following primary structure: D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-Ol(S-S 2-7 ). ...
Article
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This review is devoted to the 100-year history of the investigation of peptide hormones and the creation of drugs on their basis, starting from the insulin discovery and its introduction into a medical practice in 1921. The basic groups of the peptide hormones are discussed: neurohypophyseal hormones, hypothalamic releasing hormones, incretins, insulin, adrenocorticotropic hormone (ACTH), and calcitonin. The first therapeutic agents based on the peptide hormones were created by a traditional approach that involved the isolation of peptides from animal tissues, their purification to individual compounds, determination of their primary structure, their chemical synthesis or their deep purification, and the creation of a pharmaceutical substance. A modern approach to creation of peptide hormone drugs is based on their consideration as ligands of the corresponding cellular receptors and the use of computer modeling, efficient synthesis methods, and high-throughput screening. The combination of these methods enabled the development of analogs which would be more active than the corresponding natural compounds, exhibit other activities in addition to the hormonal regulation, and be resistant to biodegradation. Such therapeutic agents have been designed on the basis of agonistic and antagonistic analogs of somatostatin and luliberin, and have found wide application in hormonal regulation and cancer treatment. Over the past two decades, the glucagon-like peptide (GLP-1) has been intensively investigated as a potential therapeutic agent. In our review, we describe modifications which resulted in the most highly effective long-acting drugs. Now, natural hormones and their analogs are widely present in the pharmaceutical market.
... SST inhibits the release of several endocrine hormones such as growth hormone, prolactin, thyrotropin, gastrin, insulin, secretin, and glucagon [3,[5][6][7], and the local inflammatory reaction at the periphery [8,9]. As a neurotransmitter, SST plays role in many mechanisms centrally, such as pain transmission, mood coordination, and learning and behavioral responses to stress [3,[10][11][12][13]. ...
... As a neurotransmitter, SST plays role in many mechanisms centrally, such as pain transmission, mood coordination, and learning and behavioral responses to stress [3,[10][11][12][13]. It has emerging therapeutic relevance for the diagnosis and/or the treatment of numerous diseases, such as type 2 diabetes mellitus, Cushing disease, Alzheimer's disease, acromegaly, several neuroendocrine tumors, pain-associated SST inhibits the release of several endocrine hormones such as growth hormone, prolactin, thyrotropin, gastrin, insulin, secretin, and glucagon [3,[5][6][7], and the local inflammatory reaction at the periphery [8,9]. As a neurotransmitter, SST plays role in many SST exerts its diverse biological effects via modulating somatostatin receptors (SSTRs). ...
Article
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Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin-SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4.
... The therapeutic effects of SST were found in patients with acute or chronic pancreatitis [5][6][7][8]. However, with its peptide nature, SST can be easily degraded by the peptidase in plasma/tissue and suffers from a very short half-life (<1~3 min), which limits its clinical translation [9]. To improve the bioavailability, SST analogues such as octreotide acetate, lanreotide and pasireotide have been developed to obtain t 1/2 ranging from 2 h to 600 h [10][11][12]. ...
... It was, therefore, important to develop strategies to prolong the bioactivity of SST in its native form in vivo. Given the wide distribution of SST receptors throughout the central nervous system and periphery [9], new formulations of SST capable of tissue targeting may be necessary to avoid or alleviate potential side effects. ...
Article
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The clinical translation of therapeutic peptides is generally challenged by multiple issues involving absorption, distribution, metabolism and excretion. In this study, a macrophage membrane-coated poly(lactic-co-glycolic acid) (PLGA) nanodelivery system was developed to enhance the bioavailability of the somatostatin (SST) peptide, which faces the hurdles of short half-life and potential side effects in the treatment of chronic pancreatitis. Using a facile nanoprecipitation strategy, SST was loaded in the nanoparticles with an encapsulation efficiency (EE) and a loading efficiency (LE) of 73.68 ± 3.56% and 1.47 ± 0.07%, respectively. The final formulation of SST-loaded nanoparticles with the camouflage of macrophage membrane (MP-SST) showed a mean diameter of 151 ± 4 nm and an average zeta potential of −29.6 ± 0.3 mV, which were stable long term during storage. With an above 90% cell viability, a hemolysis level of about 2% (
... We assessed eptifibatide (platelet inhibitor), 76 desmopressin (antidiuretic), 77 and vapreotide (vasoconstrictor). 78 For these studies, we used 1,5-diiodopentane as a standard linker. We found that bis-Dha analogs of each peptide could be formed and reacted under our diversification conditions to afford new carbocyclic peptides in conversions of 22−44%, Table 2 compounds 27−29. ...
... Examples include zolantidine (log P eh −1.47), clonidine (log P eh −1.80), and antipyrine (log P eh −2.28). 78 For SMT, we determined log P eh = −1.16, reflective of its good water solubility and mild blood−brain permeability. ...
Article
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One way to improve the therapeutic potential of peptides is through cyclization. This is commonly done using a disulfide bond between two cysteine residues in the peptide. However, disulfide bonds are susceptible to reductive cleavage, and this can deactivate the peptide and endanger endogenous proteins through covalent modification. Substituting disulfide bonds with more chemically robust carbon-based linkers has proven to be an effective strategy to better develop cyclic peptides as drugs, but finding the optimal carbon replacement is synthetically laborious. We report a new late-stage platform wherein a single disulfide bond in a cyclic peptide can serve as the progenitor for any number of new carbon-rich groups, derived from organodiiodides, using a Zn:Cu couple and a hydrosilane. We show that this platform can furnish entirely new carbocyclic scaffolds with enhanced permeability and structural integrity and that the stereochemistry of the new cycles can be biased by a judicious choice in silane.
... Knowledge of SSTRs and their activation has increased over the last 20 years as a result of many clinical and translational studies and has led to the development of novel treatments (14). The clear effectiveness of somatostatin (SST) analogs (SSAs) has been demonstrated in the treatment of numerous diseases including pancreatitis, nephro-or retinopathy as complications of obesity and diabetes, some types of pain, inflammation, and acromegaly (excessive growth hormone produced by the body) (15,16). In addition, one of the unique features of NETs is the overexpression of SSTRs. ...
Article
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Pancreatic neuroendocrine tumors (pNETs) are rare and part of the diverse family of neuroendocrine neoplasms (NENs). Somatostatin receptors (SSTRs), which are widely expressed in NENs, are G-protein coupled receptors that can be activated by somatostatins or its synthetic analogs. Therefore, SSTRs have been widely researched as a diagnostic marker and therapeutic target in pNETs. A large number of studies have demonstrated the clinical significance of SSTRs in pNETs. In this review, relevant literature has been appraised to summarize the most recent empirical evidence addressing the clinical significance of SSTRs in pNETs. Overall, these studies have shown that SSTRs have great value in the diagnosis, treatment, and prognostic prediction of pNETs; however, further research is still necessary.
... Such radiopharmaceuticals have been used for imaging neuroendocrine tumors (NETs) by targeting somatostatin receptors (SSTRs), which are characteristically over-expressed on the cell surfaces of these tumor types [52]. Since the endogenous ligand somatostatin has a very short biological t1/2, unsuitable for clinical applications (<3 min), analogues have been produced that have better pharmacological characteristics [53][54][55]. These targeting vectors are often derivatives of the somatostatin analogue octreotide, which has a considerably high affinity for the highly expressed subtype SSTR2 and a more applicable t1/2 of ~72-98 min. ...
Article
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The incorporation of silicon fluoride acceptor (SiFA) moieties into a variety of molecules, such as peptides, proteins and biologically relevant small molecules, has improved the generation of 18 F-radiopharmaceuticals for medical imaging. The efficient isotopic exchange radiofluorination process, in combination with the enhanced [ 18 F]SiFA in vivo stability, make it a suitable strategy for fluorine-18 incorporation. This review will highlight the clinical applicability of [ 18 F]SiFA-labeled compounds and discuss the significant radiotracers currently in clinical use.
... NETs, including vasoactive intestinal peptide tumors (VIPoma) and carcinoid tumors, are frequently not amenable to curative surgery, and symptoms can only be managed [7]. Octreotide acetate is an analog to the natural hormone somatostatin and is prescribed to suppress the effects of hGH and the hormones released by NETs [8,9]. ...
Article
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Introduction: Octreotide acetate subcutaneous injection is indicated to treat acromegaly and the symptoms of carcinoid tumors and vasoactive intestinal peptide tumors (VIPomas). This formative human factors study assessed the octreotide acetate pen injector and accompanying instructions for use (IFU) with self-trained participants. Methods: The study enrolled patients with diagnoses of acromegaly, carcinoid tumors, or VIPomas and healthcare practitioners (HCPs) who treat patients with these diagnoses. The IFU provided a stepwise process with illustrations to train participants on using the pen injector. Participants familiarized themselves with the pen injector and the IFU before administering 2 unaided injections into skin-like pads; administering the full dose into the pad was considered a successful injection. The investigators evaluated each injection by performance measures-specific tasks necessary to safely and correctly administer the medication-and subjective measures, which included participant comments, feedback from questions, and suggestions for improvements. Results: The study enrolled 11 participants-8 patients and 3 HCPs. Participants had a success rate of 100% for both injections. Errors included 1 participant priming the pen with the incorrect dose and 2 participants not holding the injector button for 10 s after the injection. Neither error led to a failed injection. To improve the IFU, participants suggested changing the order of wording on the priming step, clarifying illustrations of the plunger, and stronger indications to hold the injector button. Conclusion: The octreotide pen injector and IFU were usable by self-trained participants. Participant errors and suggestions provided a foundation for recommendations to improve the IFU.
... Die in grün dargestellten Aminosäuren befinden sich im sog. β-turn des Sst und beschreiben das Pharmakophor des Peptids [modifiziert nach Rai et al. 2015, mit Genehmigung vom 18.05.2021]. ...
Thesis
Intratumorale Heterogenität (ITH) kommt bei allen Tumorentitäten vor und resultiert aus der für Tumoren charakteristischen genomischen Instabilität. Diese genomische Instabilität ist einer der Hauptgründe für den krebsassoziierten Tod von Patienten und ist zudem generelles Charakteristikum für malignes (bösartiges) Wachstum von Tumoren. Die ITH kann sowohl bei „low stage“ Primärtumoren als auch bei hoch differenzierten metastasierenden „high stage“ Tumoren beobachtet werden. Aus dieser intratumoralen Heterogenität resultieren ferner massive Schwierigkeiten bei der Behandlung von Tumorerkrankungen durch die Entstehung von Therapieresistenzen. Im Falle der neuroendokrinen Tumoren konnte festgestellt werden, dass diese ITH im Zusammenhang mit der spezifischen Expression unterschiedlicher Rezeptoren steht und dabei abhängig vom Tumorstadium die Rezeptorexpression stark variiert. In diesem Fall handelt es sich um den humanen Somatostatinrezeptor (Subtyp-2) (hSst2-R) und den humanen glukoseabhängigen insulinotropen Peptidrezeptor (engl. gastric inhibitory polypetide receptor, kurz, hGIP-R). In der Literatur wird beschrieben, dass in 88 % der Fälle eines Somatostatinrezeptor-negativen (hSst2-R-negativen) Tumors hingegen der hGIP-Rezeptor in überexprimierter Form vorliegt. Ziel dieser Dissertation war es daher, im Rahmen der Tumorentität der neuroendokrinen Tumoren ein Radiopharmakon zu entwickeln, mit welchem sich der hSst2- und zugleich der hGIP-Rezeptor adressieren lässt. Hierfür wurden zunächst zwei stabil transfizierte Zelllinien etabliert, welche zum einen den Somatostatin- und zum anderen den hGIP-Rezeptor überexprimieren. Für die Herstellung der peptidbasierten Radiopharmaka wurde ein vollautomatischer Peptidsynthesizer qualifiziert, mit welchem die unterschiedlichen Somatostatin- und hGIP-R-Analoga synthetisiert wurden. Dadurch, dass im heterobivalenten Konstrukt sowohl das hSst2-R- als auch das hGIP-R-Bindemotiv enthalten sein sollen, wurden im ersten Schritt unterschiedliche hSst2-R-Analoga synthetisiert. Durch deren spezifischen Modifikationen sollten die pharmakologischen Eigenschaften sowohl des Monomers (im Vergleich zu [68Ga]Ga-DOTA-TATE(Tyr3)), als auch als Bestandteil des heterobivalenten Endprodukts verbessert werden. Im zweiten Schritt wurden anhand eines Alanine Walk die für die Rezeptorbindung kritischen Aminosäuren des GIP(1-30)-NH2-Analogon ausfindig gemacht. Die daraus gewonnenen Erkenntnisse sollten dafür verwendet werden, die pharmakologischen Eigenschaften des GIP(1-30)-NH2 in weiterführenden Versuchen, sowohl für das Monomer, als auch als Bestandteil des heterobivalenten Konstrukts zu verbessern. Im letzten Schritt der Arbeit sollten beide Rezeptorbindemotive (für hSst2-R und hGIP-R) miteinander verbunden werden, mit dem Ziel beide Rezeptoren spezifisch zu binden.
... ; https://doi.org/10.1101/2021.09.10.459853 doi: bioRxiv preprint 11 minutes in plasma (for SST) 34 , and ~20 mins in brain cerebrospinal fluid (CSF, oxytocin and vasopressin) 35 . With these transport parameters, we calculated the time for the released neuropeptide to diffuse and reach the threshold concentration (C t , Equation 2) and peak concentration (Equation 4) at different distances. ...
Preprint
Neuropeptides are essential signaling molecules in the nervous system involved in modulating neural circuits and behavior. Although hypothesized to signal via volume transmission through G-protein coupled receptors (GPCR), remarkably little is known about their extrasynaptic diffusion. Here, we developed an all-optical approach to probe neuropeptide volume transmission in mouse neocortex. To control neuropeptide release, we engineered photosensitive nanovesicles with somatostatin-14 (SST) that is released with near-infrared light stimulation. To detect SST, we created a new cell-based neurotransmitter fluorescent engineered reporter (CNiFER) using the SST2 GPCR. Under two-photon imaging, we determined the time to activate SST2R at defined distances as well as the maximal distance and loss rate for SST volume transmission in neocortex. Importantly, we determined that SST transmission is significantly faster in neocortex with a chemically degraded extracellular matrix, a diseased condition indicated in neuroinflammation and Parkinson′s disease. These new neurotechnologies can reveal important biological signaling processes previously not possible, and provide new opportunities to investigate volume transmission in the brain.
... Background to SST analogues SST has anti-proliferative, anti-secretory and anti-angiogenic properties, which makes it useful in the treatment of certain diseases of the gastrointestinal system, pancreas, peripheral neurons and the retina, among others. 57 However, the half-life of SST is only 1-3 min due to quick degradation by peptidases in plasma and tissues. This requires a direct continuous intravenous injection to produce the therapeutic effect. ...
Article
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Hyperinsulinaemic hypoglycaemia (HH) is a biochemical finding of low blood glucose levels due to the dysregulation of insulin secretion from pancreatic β-cells. Under normal physiological conditions, glucose metabolism is coupled to β-cell insulin secretion so that blood glucose levels are maintained within the physiological range of 3.5–5.5 mmol/L. However, in HH this coupling of glucose metabolism to insulin secretion is perturbed so that insulin secretion becomes unregulated. HH typically occurs in the neonatal, infancy and childhood periods and can be due to many different causes. Adults can also present with HH but the causes in adults tend to be different. Somatostatin (SST) is a peptide hormone that is released by the delta cells (δ-cells) in the pancreas. It binds to G protein-coupled SST receptors to regulate a variety of location-specific and selective functions such as hormone inhibition, neurotransmission and cell proliferation. SST plays a potent role in the regulation of both insulin and glucagon secretion in response to changes in glucose levels by negative feedback mechanism. The half-life of SST is only 1–3 min due to quick degradation by peptidases in plasma and tissues. Thus, a direct continuous intravenous or subcutaneous infusion is required to achieve the therapeutic effect. These limitations prompted the discovery of SST analogues such as octreotide and lanreotide, which have longer half-lives and therefore can be administered as injections. SST analogues are used to treat different forms of HH in children and adults and therapeutic effect is achieved by suppressing insulin secretion from pancreatic β-cells by complex mechanisms. These treatments are associated with several side effects, especially in the newborn period, with necrotizing enterocolitis being the most serious side effect and hence SS analogues should be used with extreme caution in this age group.
... Our results demonstrate that high-EGR is more effective. It has been proved that Amylase, Protease, pH, gastric emptying, D xylose, CRH, VIP, SST, GAS, and 5-HT [24][25][26][27][28][29][30] are important biochemical components to maintain normal physiological functions of the gastrointestinal tract and to regulate the secretion of digestive glands and the movement of the digestive tract. The results of our research showed that, compared with the control group, the pH value of gastric juice and gastric emptying rate was lower in the SSDCP rats, taking low-EGR, high-EGR and Probiotics can reduce the pH value of gastric juice and gastric emptying rate to normal. ...
Article
Objective: To evaluate the efficacy of the extract from Ganjiangdazao recipe (EGR) on functional dyspepsia in rats with spleen-stomach deficiency cold pattern (SSDCP) in terms of Traditional Chinese Medicine, and to investigate its pharmacodynamics. Methods: Sixty Sprague-Dawley rats were randomly divided into the control group, SSDCP group, low-EGR SSDCP group, high-EGR SSDCP group, probiotics group, EGR group. SSDCP model was induced by gavage with the 0 ?edible vinegar. The symptoms and manifestations were scored by method from the relative literature, the ecological changes in cecal microflora was analyzed by 16SrRNA high-throughput sequencing technology, gastric tissues were treated by immunohistochemistry, the levels of related biochemical components related to the gastrointestinal functions were detected by enzyme-linked immunosorbent assay and colorimetry, gastric juice was measured by pH meter, blood pressure measurement by trapping tail method, surface temperature measured by infrared thermal imaging, and the content of 6-gingerol in the serum was determined by liquid-mass chromatography before and after EGR was given. Results: It was found that EGR could effectively relieve the symptoms and manifestations of the SSDCP rats (P < 0.05); the value of the relative abundance of Lactobacillus, Streptococcus, Enterococcus and Coprobacillus increased, while the value of the relative abundance of Clostridium decreased (P < 0.05) in the cecal microflora in the SSDCP rats after high-EGR administration; It was also found that EGR had no substantial effect on the related biochemical components related to the gastrointestinal functions of in the SSDCP rats; and a certain amount of 6-gingerol was detected in the serum of EGR group. Conclusion: The pharmacodynamic site of EGR is the intestinal tract, and the mechanism behind the effect of EGR on SSDCP rats, involves increasing the beneficial bacteria and decreasing the proinflammatory bacteria in the intestinal tract. The blood pharmacodynamics of EGR remains to be further studied in the future.
... Other hallmarks of tumourigenesis, such as angiogenesis and cell migration, are also regulated by SST signalling. The VEGF plateletderived growth factor (PDGF), insulin-like growth factor, and basic fibroblast growth factor have been shown to enhance the neovascularization and cell growth of tumours [75][76][77][78]. On a cell signalling and functional level, SST and SSTR significantly inhibit hormonal secretion, cell cycle progression, angiogenesis, and cell migration. ...
Article
Full-text available
Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.
... The main anti-secretory therapies currently used in clinic on patients with certain NETs and endocrine syndromes are the somatostatin analogues [48,49]. However, the impact of somatostatin analogues on pheochromocytoma-associated catecholamine hypersecretion has been poorly explored in vitro. ...
Article
Increasingly common, neuroendocrine tumors (NETs) are regarded nowadays as neoplasms potentially causing debilitating symptoms and life-threatening medical conditions. Pheochromocytoma is a NET that develops from chromaffin cells of the adrenal medulla, and is responsible for an excessive secretion of catecholamines. Consequently, patients have an increased risk for clinical symptoms such as hypertension, elevated stroke risk and various cardiovascular complications. Somatostatin analogues are among the main anti-secretory medical drugs used in current clinical practice in patient with NETs. However, their impact on pheochromocytoma-associated catecholamine hypersecretion remains incompletely explored. This study investigated the potential efficacy of octreotide and pasireotide (SOM230) on human tumor cells directly cultured from freshly resected pheochromocytomas using an implemented catecholamine secretion measurement by carbon fiber amperometry. SOM230 treatment efficiently inhibited nicotine-induced catecholamine secretion both in bovine chromaffin cells and in human tumor cells whereas octreotide had no effect. Moreover, SOM230 specifically decreased the number of exocytic events by impairing the stimulation-evoked calcium influx as well as the nicotinic receptor-activated inward current in human pheochromocytoma cells. Altogether, our findings indicate that SOM230 acts as an inhibitor of catecholamine secretion through a mechanism involving the nicotinic receptor and might be considered as a potential anti-secretory treatment for patients with pheochromocytoma.
... More specifically, it may function as a neurotransmitter, a neuromodulator, an endocrine hormone, or a paracrine factor, while its role as a trophic factor has also been proposed [29,30]. Physiologically, its levels are very low due to its prompt deg-radation by ubiquitous peptidases [31]. It exists in two isoforms known as SRIF14 and SRIF28-SRIF standing for somatotropin release inhibitory peptide. ...
Article
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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.
... SRIF can contribute to control of lymphocyte and inflammatory cell proliferation and activity, tumor cell growth, and normal tissue plasticity. In human skin, SRIF has been suggested as a negative regulator of epidermal wound healing [37,39,40]. ...
Article
Full-text available
Autophagy is an evolutionary conserved process for the self-degradation and recycling of cellular components in the cytoplasm. It is involved in both physiological and pathological conditions. In detail, the term “autophagy” refers to intracellular degradative pathways that lead to packaging and deliver of cellular components to lysosomes or to plant and yeast vacuoles. Autophagy is triggered by a variety of stimuli like nutrient deprivation, hypoxia, mitochondrial dysfunction, endoplasmic reticulum stress, and is regulated by immune- and hormonal factors. The role of autophagy in tumor cells is complex. Indeed, autophagy may act as a tumor suppressor as well as a tumor survival factor, in a context-dependent manner. The research into autophagy in normal pituitary and pituitary tumors has not gained great consideration, yet. Nevertheless, some recent articles joint to previous case studies, suggest that this process plays a role in the modulation and fluctuation of normal pituitary cell functions and in the response of pituitary tumor cells to drug therapy, including the response to somatostatin receptor ligand (SRLs), the first-line medical therapy of acromegaly. Although it is not possible to draw any conclusion, the aim of this review was to highlight some considerations and perspectives in this research field. Reports on the effects of octreotide on autophagy induction and autophagic flux in extra-pituitary target tissues, have also been discussed.
... Systemic treatments may consist of fluoropyrimidine, oxaliplatin or temozolomidebased chemotherapy, depending on previous treatments and the primary tumour site. If SSTR expression on SRS or 68Ga PET scan is present, PRRT treatment may be indicated to control tumour growth, combined with SSAs for symptoms control, especially in case of carcinoid syndrome [79,80]. ...
Article
Full-text available
Introduction: Primary neuroendocrine neoplasms (NENs) in the breast are very rare. Until 2011, the prevalence was 0.1% of all breast lesions and 1% of all NENs, whereas metastatic breast NENs represent 1%-2% of all breast tumours. However, it seems that over the last 5 years the diagnostic frequency of breast NENs has increased, probably for more alert specialists and advanced diagnostic tools, leading to a prevalence of 2%-5% of diagnosed breast cancers, mostly in the elderly population. Breast metastases from extramammary malignancies are uncommon and bilateral ones are even more uncommon, with few reported in the literature. We describe four clinical settings of breast metastases from different NENs and the multidisciplinary approach for diagnosis and treatment. Methods: Four patients were found to have NEN primaries metastasised to the breast. A literature review was conducted to identify similar cases and characterise breast metastases from neuroendocrinal tumors (NETs). Results: Two patients presented with bilateral breast metastases (one with well-differentiated panNET and another with atypical lung carcinoid) and two had unilateral (one with moderately differentiated lung NET and one with atypical lung carcinoid). There are about 13 cases of NEN breast metastases reported in the English literature. The ileum is the most common primary site, followed by the appendix, duodenum, pancreas and lung. Conclusion: Breast lesions from extramammary primary often pose a diagnostic challenge, since a breast nodule can be the first and often the only presentation of the disease. However, differentiating between primary and secondary NEN breast lesions is essential, owing to different clinical management and prognosis.
... On the one hand, it can inhibit cell proliferation by inhibiting growth factor-mediated mitotic signals and inducing apoptosis (23). On the other hand, it can also inhibit the production and growth of tumor cells by the effect of inhibiting the secretion of growth hormone and growth factor and anti-angiogenesis indirectly (24). Therefore, SST production is suppressed and expression is reduced, causing abnormal increase in secretion of growth hormone and growth factor. ...
Preprint
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Background: DNA methylation plays an important role in the regulation of gene expression as well as the occurrence and development of cancer. Abnormal hypermethylation in the promoter region of tumor suppressor genes is a recognized molecular events related to carcinogenesis. Somatostatin (SST) is considered as a tumor suppressor gene. The study aims to explore the relationship between the promoter methylation status of SST and the risk of gastrointestinal tract cancers and further to evaluate its diagnostic value. Methods: Tissue samples were used for DNA isolation and RNA isolation. SST methylation was detected by biosulfite sequencing PCR, and SST mRNA expression was detected by quantitative real-time reverse transcription-polymerase chain reaction. The receiver operating curve (ROC) was drawn to evaluate the efficacy of SST CpG methylation on the diagnosis of digestive tract tumors by calculating the sensitivity, specificity and Youden index. Results: The methylation level of SST promoter in cancer tissue were significantly increased compared with adjacent control tissue (EC: 0.649 ± 0.078 vs. 0.569 ± 0.107, p <0.05, GC: 0.622 ± 0.09 vs. 0.588 ± 0.079, p <0.05, CC : 0.663 ± 0.083 vs. 0.617 ± 0.042 p <0.05). Significantly different methylation sites contained CpG +18, +25, +44, +94, +100, +127, and +129. SST methylation status was associated with clinical phenotypes such as lymph node metastasis and vascular tumor thrombus. CpG sites in two tumors (+85 in EC, +94 in CC) were positively correlated with the depth of infiltration. The expression level of SST in gastric and colorectal cancer tissue was significantly lower than that in adjacent control tissue (both p <0.001). However, no statistically significant difference was found in EC group (p = 0.32). Except CpG +25 and +85 sites in GC and the +25, +85 and +148 sites in CRC, the methylation rate of each CpG was negatively correlated with gene expression (all P <0.05). Combined detection of eight CpG sites methylation (+18,+42,+44,+85,+92,+94,+129 and+138) showed the best area under the curve of 0.817 with sensitivity of 76.5% and specificity of 75%. Conclusions: Abnormal hypermethylation in SST promoter region increased the risk of gastrointestinal tract tumors, as well as promoting cancer progression by regulating gene expression. SST methylation status may serve as site-specific biomarker for risk prediction of gastrointestinal tract tumors.
... After the administration of JF, the level of gastrin was increased, which could stimulate the secretion of gastric acid, pepsin and trypsin (Zhao et al., 2011), promote the contraction of gastric antrum, increase the flow of gastric mucosa, and nourish the mucosa of gastrointestinal tract. The decrease of somatostatin content indicated that JF could reduce the inhibitory effect on gastric emptying and intestine peristalsis, enhance the secretion of gastric acid and pepsin, as well as the absorption of carbohydrates, amino acids and other nutrients in the small intestine (Rai et al., 2015;Schubert and Rehfeld, 2020). By reducing the white blood cell count and increasing lymphocyte ratio in the blood, JF were found to enhance immunity and relieve inflammation. ...
Article
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Jujube (Ziziphus jujuba Mill.) fruit (JF) is widely consumed as food in Asian countries due to its potential effects for human health. As a traditional Chinese medicine, JF is often used to treat anorexia, fatigue and loose stools caused by spleen deficiency syndromes in China, but the mechanism underlying this effect has not been thoroughly elucidated. In this study, a rat model of spleen deficiency syndromes was adopted to investigate the therapeutic effect of JF extract and its possible mechanism by metabolomics analyses of plasma and urine as well as the intestinal flora analysis. The results showed that the changes in plasma and urine metabolites caused by spleen deficiency were reversed after administration of JF, and these changed endogenous metabolites were mainly involved in retinol metabolism, pentose and glucuronate interconversions, nicotinate and niacinamide metabolism pathways. The 16S rDNA sequencing results showed that JF could regulate intestinal flora imbalance caused by spleen deficiency. The covariance analysis of intestinal flora structure and metabolome indicated that Aerococcus may be a candidate strain for predicting and treating the metabolic pathways of spleen deficiency and related disorders. In summary, it can be revealed that spleen deficiency, which alters metabolic profiles and the intestinal flora, could be alleviated effectively by JF extract.
... SST-14 and SST-28 have been shown to exhibit differing biological effects (Hadjidakis et al., 1986). Several SST agonists and antagonists are used clinically for the treatment of diseases such as acromegaly and neuroendocrine tumors (Rai et al., 2015). ...
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Recent advancements in technology have enabled researchers to probe the brain with the greater region, cell, and receptor specificity. These developments have allowed for a more thorough understanding of how regulation of the neurophysiology within a region is essential for maintaining healthy brain function. Stress has been shown to alter the prefrontal cortex (PFC) functioning, and evidence links functional impairments in PFC brain activity with neuropsychiatric disorders. Moreover, a growing body of literature highlights the importance of neuropeptides in the PFC to modulate neural signaling and to influence behavior. The converging evidence outlined in this review indicates that neuropeptides in the PFC are specifically impacted by stress, and are found to be dysregulated in numerous stress-related neuropsychiatric disorders including substance use disorder, major depressive disorder (MDD), posttraumatic stress disorder, and schizophrenia. This review explores how neuropeptides in the PFC function to regulate the neural activity, and how genetic and environmental factors, such as stress, lead to dysregulation in neuropeptide systems, which may ultimately contribute to the pathology of neuropsychiatric diseases.
... Vapreotid, spesifik olarak sst2 resepto ru ne daha zayıf bir şekilde de sst3, sst4, sst5 resepto ru ne bag lanan gu çlu bir somatostatin analog udur (6,12). Vapreotid'in intraserebroventriku ler enjeksiyon uygulanması ile yapı-Şekil I. Somatostatin analoglarının kimyasal yapısı a. Vapreotid, b. ...
... A total of 20 patients received-on surgical indication -SOMATO, to reduce pancreatic secretions, and protect pancreaticoduodenal anastomosis. Besides reducing pancreatic secretions, SOMATO also induces a mesenterial vasoconstriction [30]. PVF is determined by the outflow of blood from the mesenteric organs and as a result, SOMATO treated patients were shown to have a lower PVF [31,32]. ...
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Background: Norepinephrine (NE) is a α1-adrenergic mediated vasopressor and a key player in the treatment of perioperative hypotension. Apart from modulating systemic hemodynamics, NE may also affect regional blood flow, such as the hepatic circulation, which contains a wide variety of adrenergic receptors. It may alter regional vascular tonus and hepatic blood flow (HBF) by reducing portal vein flow (PVF) or hepatic arterial flow (HAF). The aim of this study was to assess the effects of NE on HBF. Methods: Patients scheduled for pancreaticoduodenectomy were included. All patients received standardized anesthetic care using propofol and remifentanil and were hemodynamically stabilized using a goal-directed hemodynamic strategy guided by Pulsioflex™. On surgical indication, somatostatin (SOMATO) was given to reduce pancreatic secretion. HBF measurements were performed using transit-time ultrasound (Medistim™). Baseline hemodynamic and HBF measurements were made after pancreatectomy, at T1. Afterwards, NE infusion was initiated to increase mean arterial pressure (MAP) by 10 - 20% of baseline MAP (T2) and by 20 - 30% of baseline MAP (T3). HBF and hemodynamic measurements were performed simultaneously at these three time-points. Results: A total of 28 patients were analyzed. Administration of NE significantly increased MAP but had no effect on cardiac index. NE infusion reduced total HBF in all patients (p < 0.01) by a reduction HAF (p < 0.01), while the effect on PVF remained unclear. Post-hoc analysis showed that SOMATO-treated patients had a significant lower PVF at baseline (p < 0.05), which did not change during NE infusion. In these patients, reduction of total HBF was primarily related to a reduction of HAF (p < 0.01). In untreated patients, NE infusion reduced total HBF both by a reduction HAF (p < 0.01) and PVF (p < 0.05). Conclusion: Administration of NE reduced total HBF, by decreasing HAF, while the effect on PVF remained unclear. SOMATO-treated patients had a lower PVF at baseline, which remained unaffected during NE infusion. In these patients the decrease in total HBF with NE was entirely related to the decrease in HAF. In SOMATO-untreated patients PVF also significantly decreased with NE. Trial registration: Study protocol EC: 2019/0395. EudraCT n°: 2018-004,139-66 (25 - 03 - 2019). Clin.trail.gov: NCT03965117 (28 - 05 - 2019).
... All five SRIF receptors have seven highly conserved α-helical transmembrane domains, with most divergence occurring in the extracellular N-terminus and intracellular carboxyl terminus (C-terminus) domains (Rai et al., 2015). ...
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Recent studies have shown that G protein-coupled receptors (GPCRs), the largest signal-conveying receptor family, are targets for mutations occurring frequently in different cancer types. GPCR alterations associated with cancer development represent significant challenges for the discovery and the advancement of targeted therapeutics. Among the different molecules that can activate GPCRs, we focused on two molecules that exert their biological actions regulating many typical features of tumorigenesis such as cellular proliferation, survival, and invasion: somatostatin and melatonin. The modulation of signaling pathways, that involves these two molecules, opens an interesting scenario for cancer therapy, with the opportunity to act at different molecular levels. Therefore, the aim of this review is the analysis of the biological activity and the therapeutic potential of somatostatin and melatonin, displaying a high affinity for GPCRs, that interfere with cancer development and maintenance.
... Octreotide, a synthetic version of somatostatin with a comparatively longer half-life (approximately 1.7-1.9 hours) was explored as a possible treatment option for AP [76,78]. Overall, neither somatostatin nor octreotide is effective in the treatment of AP [79,80]. ...
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Acute pancreatitis (AP), a complex inflammatory disease of the pancreas, is associated with increased morbidity and mortality. Currently, no specific therapies are approved for its treatment, and management is primarily based on supportive care. Despite enhanced understanding of AP pathogenesis, patients remain at significant risk owing to a lack of targeted drug treatments. Therefore, there is an urgent need for effective pharmacological therapeutic measures which may inhibit the early systemic inflammation, thereby preventing subsequent organ failure. This narrative review summarizes the available treatment options for AP and highlights the potential drug classes and pharmacologic therapies including those under clinical development. Although, several therapies targeting different aspects of AP pathogenesis have been investigated, some therapies with promising preclinical activity have been rendered ineffective in clinical trials. Other novel drug classes or molecules including dabigatran (anticoagulant), ulinastatin (protease inhibitor), infliximab (monoclonal antibody), spautin-A41 (autophagy inhibitor), and CM4620-Injectible Emulsion (calcium channel inhibitor) await further clinical assessment. Alternative treatment options using stem cells and nanoparticles are also being explored and may hold promise for AP therapy. However, challenges for exploring targeted treatment approaches include disease complexity, timing of therapeutic intervention, and establishing appropriate clinical endpoints. Understanding the role of specific biomarkers may help in identifying appropriate targets for drug discovery and facilitate determining relevant clinical study endpoints to monitor disease severity and progression, thereby aiding in design of more precise therapies with improved clinical outcomes.
... However, the predominant subtypes in endocrine tissues are SSTR2 and SSTR5 [96,97]. Furthermore, NETs have been shown to express SSTR2 and SSTR5 [98,99]. Given the presence of the NE element, the use of a 111In-pentetreotide scintigraphy (Octreoscan ® ) and somatostatin receptor scintigraphy (SRS), a radiolabeled somatostatin analog with high binding affinity to the SSTR, can be useful to evaluate disease extension [100,101] and also contribute to theranostic strategy, which is a new medical field that combines and integrates specific targeted treatments as well as specific targeted diagnostic tests [102,103]. ...
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Recent advances in prostate cancer (PC) research unveiled real androgen receptor (AR) functions in castration-resistant PC (CRPC). Moreover, AR still accelerates PC cell proliferation via the activation of several mechanisms (e.g., mutation, variants, and amplifications in CRPC). New-generation AR signaling-targeted agents, inhibiting extremely the activity of AR, were developed based on these incontrovertible mechanisms of AR-induced CRPC progression. However, long-term administration of AR signaling-targeted agents subsequently induces the major problem that AR (complete)-independent CRPC cells present neither AR nor prostate-specific antigen, including neuroendocrine differentiation as a subtype of AR-independent CRPC. Moreover, there are few treatments effective for AR-independent CRPC with solid evidence. This study focuses on the transformation mechanisms of AR-independent from AR-dependent CRPC cells and potential treatment strategy for AR-independent CRPC and discusses them based on a review of basic and clinical literature.
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Protein-protein interactions (PPIs) play vital roles in normal cellular processes. Dysregulated PPIs are involved in the process of various diseases, including cancer. Thus, these PPIs may serve as potential therapeutic targets in cancer treatment. However, despite rapid advances in small-molecule drugs and biologics, it is still hard to target PPIs, especially for those intracellular PPIs. Macrocyclic peptides have gained growing attention for their therapeutic properties in targeting dysregulated PPIs. Macrocyclic peptides have some unique features, such as moderate sizes, high selectivity, and high binding affinities, which make them good drug candidates. In addition, some oncology macrocyclic peptide drugs have been approved by the US Food and Drug Administration (FDA) for clinical use. Here, we reviewed the recent development of macrocyclic peptides in cancer treatment. The opportunities and challenges were also discussed to inspire new perspectives.
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Objective Acromegaly is characterized by an excess of growth hormone (GH) and insulin like growth-factor 1 (IGF1), and it is strongly associated with cardiovascular diseases (CVD). Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Previous results suggest the presence of systemic inflammation in treated patients. Here we assessed the association between treatment of acromegaly, systemic inflammation and vascular function. Design Ex vivo cytokine production and circulating inflammatory markers were assessed in peripheral blood from treated and untreated acromegaly patients (N = 120), and compared them with healthy controls. A more comprehensive prospective inflammatory and vascular assessment was conducted in a subgroup of six treatment-naive patients with follow-up during treatment. Results Circulating concentrations of VCAM1, E-selectin and MMP2 were higher in patients with uncontrolled disease, whereas the concentrations of IL18 were lower. In stimulated whole blood, cytokine production was skewed towards a more pro-inflammatory profile in patients, especially those with untreated disease. Prospective vascular measurements in untreated patients showed improvement of endothelial function during treatment. Conclusions Acromegaly patients are characterized by a pro-inflammatory phenotype, most pronounced in those with uncontrolled disease. Treatment only partially reverses this pro-inflammatory bias. These findings suggest that systemic inflammation could contribute to the increased risk of CVD in acromegaly patients.
Article
Blood glucose homeostasis requires proper function of pancreatic islets, which secrete insulin, glucagon, and somatostatin from the β-, α-, and δ-cells, respectively. Each islet cell type is equipped with intrinsic mechanisms for glucose sensing and secretory actions, but these intrinsic mechanisms alone cannot explain the observed secretory profiles from intact islets. Regulation of secretion involves interconnected mechanisms among and between islet cell types. Islet cells lose their normal functional signatures and secretory behaviors upon dispersal as compared to intact islets and in vivo. In dispersed islet cells, the glucose response of insulin secretion is attenuated from that seen from whole islets, coordinated oscillations in membrane potential and intracellular Ca2+ activity, as well as the two-phase insulin secretion profile, are missing, and glucagon secretion displays higher basal secretion profile and a reverse glucose-dependent response from that of intact islets. These observations highlight the critical roles of intercellular communication within the pancreatic islet, and how these communication pathways are crucial for proper hormonal and nonhormonal secretion and glucose homeostasis. Further, misregulated secretions of islet secretory products that arise from defective intercellular islet communication are implicated in diabetes. Intercellular communication within the islet environment comprises multiple mechanisms, including electrical synapses from gap junctional coupling, paracrine interactions among neighboring cells, and direct cell-to-cell contacts in the form of juxtacrine signaling. In this article, we describe the various mechanisms that contribute to proper islet function for each islet cell type and how intercellular islet communications are coordinated among the same and different islet cell types. © 2021 American Physiological Society. Compr Physiol 11:2191-2225, 2021.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by loss of neurons and synapses. The aim of this study was to investigate the effect of somatostatin analogue Vapreotide in an in vitro Alzheimer’s model and its effects based on the relationship between somatostatinergic transmission and neurodegenerative functions. In this study, tau transfection was performed using the MAPT gene cloned into the pcDNA3.1 vector and transfection reagent into the SH-SY5Y cell line. In viability experiments using 10 µM Memantine as a positive control, it was observed that Vapreotide at 50 µM (p < 0.0001) and 100 µM (p < 0.05) had a protective effect on cell viability, 100 µM CYN154806 was found to decrease (p < 0.05) cell viability. It was determined that Vapreotide, decreased the expression levels (50 µM-p < 0.001; 100 µM-p < 0.001; 200 µM-p < 0.0001) and phosphorylation of Tau and p-Tau proteins by western blots. With the qRT-PCR method, it was found that Vapreotide, decreased the BAX/BCL2 (50 µM-p < 0.001; 100 µM-p < 0.01; 200 µM-p < 0.001) expression level and decreased the expression level (50 µM-p < 0.01; 100 µM-p < 0.01; 200 µM-p < 0.001) of the APOE4 gene, which constitutes a genetic risk for AD. This study demonstrates a potential therapeutic role for a somatostatin analogue Vapreotide in Alzheimer’s disease.
Article
Hormonal drugs are essential treatment options for some hormone-dependent or hormone-sensitive tumors. The common dosage forms of hormonal drugs have a short half-life. Hence, frequent administration is needed, which results in poor patient compliance. Nevertheless, using drug delivery technology, somatostatin analogues (SSAs) and gonadotropin-releasing hormone (GnRH) analogues are prepared into long-acting formulations that can significantly prolong the action time of these drugs, reducing medication frequency and increasing patient compliance. Such drugs are advantageous when treating acromegaly, gastroenteropancreatic neuroendocrine tumors (GEP-NETs), breast cancer, prostate cancer, and other diseases having a relatively long course. SSAs and GnRH analogues are two typical hormonal drugs, the long-acting formulations of which are essential in clinical practice. This review summarized the preparation methods and clinical application of long-acting formulations in cancer. Further, the action mechanism and new research of SSAs and GnRH analogues were discussed, and suggestions related to the development of long-acting SSAs and GnRH analogues were provided.
Article
Objective Subcutaneous injections of octreotide acetate require chronic administration by healthcare providers (HCPs). We aimed to validate the safe and effective use of the octreotide acetate pen injector, its labelling, and instructions for use (IFU) by patients, caregivers, and HCPs and mitigation of use-related risks. Methods This summative human factors validation study enrolled adults with neuroendocrine tumors and related diarrhea or flushing, adult caregivers, and HCPs. Prior to simulated use, participants self-familiarized as they desired. Each participant was assigned 1 injection site for administration into an injection pad. The first of 2 unaided injections assessed first use and required priming; the second assessed routine use and dose change. Participants gave subjective feedback after each injection and completed knowledge probes and reading comprehension questions after the second injection. Results The study enrolled 45 participants (15/group). Forty-two participants completed the first injection successfully by administering the dose correctly. Three participants did not successfully dose; 3 failed to prime the pen and 1 also failed to dial the correct dose. Unrelated to dosing, 2 participants failed to remove the needle after injection. Forty-four participants completed the second injection–1 participant failed to dial the correct dose. No other errors were observed. Overall success rates on knowledge probes and reading comprehension questions were 99.1% and 99.6%, respectively. All participants found the IFU easy to follow and understand. Conclusion The octreotide acetate pen injector, labelling, and IFU enabled intended users to administer subcutaneous octreotide safely and effectively. The residual risks of use are low and acceptable.
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Despite the obvious differences in the pathophysiology of distinct neuropsychiatric diseases or neurodegenerative disorders, some of them share some general but pivotal mechanisms, one of which is the disruption of excitation/inhibition balance. Such an imbalance can be generated by changes in the inhibitory system, very often mediated by somatostatin-containing interneurons (SOM-INs). In physiology, this group of inhibitory interneurons, as well as somatostatin itself, profoundly shapes the brain activity, thus influencing the behavior and plasticity; however, the changes in the number, density and activity of SOM-INs or levels of somatostatin are found throughout many neuropsychiatric and neurological conditions, both in patients and animal models. Here, we (1) briefly describe the brain somatostatinergic system, characterizing the neuropeptide somatostatin itself, its receptors and functions, as well the physiology and circuitry of SOM-INs; and (2) summarize the effects of the activity of somatostatin and SOM-INs in both physiological brain processes and pathological brain conditions, focusing primarily on learning-induced plasticity and encompassing selected neuropsychological and neurodegenerative disorders, respectively. The presented data indicate the somatostatinergic-system-mediated inhibition as a substantial factor in the mechanisms of neuroplasticity, often disrupted in a plethora of brain pathologies.
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Les cellules neuroendocrines sécrètent des hormones et des neuropeptides par un processus d'exocytose régulé par le calcium. Malheureusement, toutes les cellules neuroendocrines de l'organisme peuvent se transformer en cellules tumorales et potentiellement engendrer un cancer. Bien que constituant un groupe très hétérogène, les tumeurs neuroendocrines possèdent une caractéristique commune intéressante qui est un dysfonctionnement de leur activité sécrétrice entraînant, dans la majorité des cas, une hypersécrétion des hormones et peptides qu'elles stockent. Cette sécrétion anarchique pose problème car elle peut engendrer des conséquences cliniques graves chez les patients. À ce jour, les mécanismes moléculaires qui induisent et maintiennent l’hypersécrétion de ces tumeurs ne sont pas connus et il n’existe aucune thérapie ciblée permettant de l’empêcher. Mes travaux de thèse montrent que l’hypersécrétion du phéochromocytome est la conséquence directe d’un dérèglement des phases tardives de l’exocytose et qu’un traitement par le pasiréotide, un analogue de la somatostatine inhibe efficacement l’hypersécrétion.
Chapter
In this chapter we discuss oral peptide delivery from a biopharmaceutics perspective to help understand how peptides and formulations can be designed to induce flux across the intestinal barrier in order to achieve systemic exposure. Considerable efforts have gone into understanding developability of small molecule compounds for oral delivery. We aim to extend these considerations to peptide candidates to help guide selection of chemical matter and formulations.
Chapter
Targeting protein–protein interactions for modulation of key disease targets requires a fine balance between selectivity for large interaction surfaces, stability and cell permeability. Traditional small molecule therapeutics are frequently limited by their toxicity due to either unintended interactions (e.g., low selectivity) or production of toxic metabolites and are also not well-suited for targeting PPIs since the corresponding interacting surfaces are relatively large and flat without pockets suitable to bind small molecules with high affinity. On the other hand, protein and antibody therapeutics have been limited by poor cell permeability as well as complex and expensive production. Peptides and especially peptidomimetics (modified peptides, such as cyclic peptides) can be used to overcome many of these limitations and hold great promise for pharmaceutical research and development, with successful drugs already approved. Peptides can be identified from naturally occurring molecules, library screening, and/or rational design. Cyclization can be used to overcome selectivity and stability challenges and enhance pharmacokinetic and pharmacodynamic properties. Several approaches to cyclization have been developed, including backbone cyclization, which we focus on in this chapter. Backbone cyclization preserves side chains that are often critical for biological functionality in a feasible solid-phase peptide synthesis approach via reaction with peptide backbone atoms. Diversity of backbone building blocks and bridge chemistries combined with the cycloscan focused library screening technique allows identification of potent, selective, stable, and cell-permeable cyclic peptidomimetic molecules. Herein, we review and critique applications of backbone cyclic peptidomimetics to neuropeptide, peptide hormone, and protein mimetic drug discovery.
Article
Octreotide acetate (OA), a potent octapeptide, is used in the treatment of pituitary adenoma. An approach has been made in the present research to formulate an OA-loaded intranasal in situ gel (OA-ISG) to target pituitary adenoma. To achieve the objective of the present work, OA-ISG was fabricated using cold method, and further optimization was done by 3² factorial design. The optimized formulation was evaluated for gelation temperature, mucoadhesive strength, and % drug release (8 h), and the results were found to be 30.01 ± 0.4 °C, 40.12 ± 0.5 g, and 98.54 ± 0.45%, respectively. Brain availability of OA was determined through gamma scintigraphy, wherein Cmax for technetium (99mTC) labeled intranasal OA-ISG (99mTC-OA-ISG) was found to be 1.041% RA/g, and the findings for 99mTC-OA-Solution (intranasal) and 99mTC-OA-Solution (intravenous) were 0.395% and 0.164% RA/g, respectively. Consequently, a 3-10 fold increase in brain OA concentrations was observed upon intranasal administration (OA-ISG) as compared to others. Additionally, drug targeting index (100.13), targeting efficiency (10013%), and direct transport percentage (2564.1%) corroborate brain targeting of OA via intranasal route. Further, the cytotoxic potential of OA-ISG was screened on human pituitary tumor (GH3) cell lines using MTT assay. The IC50 value was found to be 9.5 μg/mL for OA-ISG, whereas it was 20.1 μg/mL for OA-Solution, thereby confirming the superior results of OA-ISG as compared to OA-Solution. Hence, the developed intranasal OA-ISG can be further explored for establishing its potential clinical safety, and as effective platform for targeted drug delivery to the brain in pituitary adenoma.
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Objective: Liver cirrhosis is a common, often progressive, and usually fatal disorder. Upper gastrointestinal bleeding is a leading cause of death in patients with liver cirrhosis. The purpose of this study was to evaluate the effectiveness of somatostatin combined with restricted fluid resuscitation in the treatment of upper gastrointestinal bleeding in the patients with liver cirrhosis. Methods: From January 2018 to December 2020, 84 patients with liver cirrhosis complicated by upper gastrointestinal bleeding admitted to the Department of Gastroenterology of Ningbo Yinzhou No. 2 Hospital were selected as study participants. They were randomly assigned into the study group (n = 42) and control group (n = 42). All patients were given intravenous drip of somatostatin. The study group was supplemented with restricted fluid resuscitation therapy. The hemoglobin (Hb), platelet, fibrinogen, hematocrit, transfusion volume of red blood cells, hemostatic time, hemostatic rates in 0 h-24 h, 24 h-48 h, and >48 h, rebleeding rates, resuscitation rate, and incidence rates of complications were compared between the two groups 48 h after treatment. Results: It was found that the Hb, platelet, fibrinogen, and hematocrit were notably increased in the study group compared to the control group 48 h after treatment (P < 0.01). The proportion of patients with excellent response was notably higher in the study group than in the control group (P < 0.05). The overall response rate of the study group was 90.48%, which was significantly higher than 71.43% in the control group (P < 0.05). The study group had lower transfusion volume of red blood cells, shorter hemostatic time, and lower rebleeding rates than the control group (P < 0.01). The hemostatic rate of 0 h-24 h in the study group was remarkably higher than that in the control group (P < 0.05). The hemostatic rate of >48 h in the study group was lower than that in the control group (P < 0.05). The overall incidence rate of complications in the study group was 9.52%, which was significantly lower than 30.95% in the control group (P < 0.05). Conclusion: These data suggest that intravenous drip of somatostatin followed by restricted fluid resuscitation leads to a better clinical efficacy in treating upper gastrointestinal bleeding in patients with liver cirrhosis considering higher resuscitation rate and hemostatic rate and reduced incidence of complications, which is conducive to the recovery of patients and worthy of further clinical promotion.
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The growth hormone–insulin-like growth factor–insulin-like growth factor binding protein (GH–IGF–IGFBP) axis plays a critical role in the maintenance of normal renal function and the pathogenesis and progression of chronic kidney disease (CKD). Serum IGF-I and IGFBPs are altered with different stages of CKD, the speed of onset, the amount of proteinuria, and the potential of remission. Recent studies demonstrate that growth failure in children with CKD is due to a relative GH insensitivity and functional IGF deficiency. The functional IGF deficiency in CKD results from either IGF resistance due to increased circulating levels of IGFBPs or IGF deficiency due to increased urinary excretion of serum IGF–IGFBP complexes. In addition, not only GH and IGFs in circulation, but locally produced IGFs, the high-affinity IGFBPs, and low-affinity insulin-like growth factor binding protein-related proteins (IGFBP-rPs) may also affect the kidney. With respect to diabetic kidney disease, there is growing evidence suggesting that GH, IGF-I, and IGFBPs are involved in the pathogenesis of diabetic nephropathy (DN). Thus, prevention of GH action by blockade either at the receptor level or along its signal transduction pathway offers the potential for effective therapeutic opportunities. Similarly, interrupting IGF-I and IGFBP actions also may offer a way to inhibit the development or progression of DN. Furthermore, it is well accepted that the systemic inflammatory response is a key player for progression of CKD, and how to prevent and treat this response is currently of great interest. Recent studies demonstrate existence of IGF-independent actions of high-affinity and low-affinity-IGFBPs, in particular, antiinflammatory action of IGFBP-3 and profibrotic action of IGFBP-rP2/CTGF. These findings reinforce the concept in support of the clinical significance of the IGF-independent action of IGFBPs in the assessment of pathophysiology of kidney disease and its therapeutic potential for CKD. Further understanding of GH–IGF–IGFBP etiopathophysiology in CKD may lead to the development of therapeutic strategies for this devastating disease. It would hold promise to use of GH, somatostatin analogs, IGFs, IGF agonists, GHR and insulin-like growth factor-I receptor (IGF-IR) antagonists, IGFBP displacer, and IGFBP antagonists as well as a combination treatment as therapeutic agents for CKD.
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The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB) in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG) evoked by bee venom (BV). The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.
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Context: Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control. Objective: Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly. Design and setting: We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries. Patients: A total of 358 patients with medically naive acromegaly (GH >5 μg/L or GH nadir ≥1 μg/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging. Interventions: Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH ≥2.5μg/L and/or IGF-1 was above the upper limit of normal. Main outcome measure: The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 μg/L and normal IGF-1) at month 12. Results: Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 μg/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%). Conclusions: Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.
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Somatostatin (SST) and some of its receptor subtypes have been implicated in pain signaling at the spinal level. In this study we have investigated the role of SST and its sst2A receptor (sst2A) in dorsal root ganglia (DRGs) and spinal cord. SST and sst2A protein and sst2 transcript were found in both mouse and human DRGs, sst2A-immunoreactive (IR) cell bodies and processes in lamina II in mouse and human spinal dorsal horn, and sst2A-IR nerve terminals in mouse skin. The receptor protein was associated with the cell membrane. Following peripheral nerve injury sst2A-like immunoreactivity (LI) was decreased, and SST-LI increased in DRGs. sst2A-LI accumulated on the proximal and, more strongly, on the distal side of a sciatic nerve ligation. Fluorescence-labeled SST administered to a hind paw was internalized and retrogradely transported, indicating that a SST-sst2A complex may represent a retrograde signal. Internalization of sst2A was seen in DRG neurons after systemic treatment with the sst2 agonist octreotide (Oct), and in dorsal horn and DRG neurons after intrathecal administration. Some DRG neurons co-expressed sst2A and the neuropeptide Y Y1 receptor on the cell membrane, and systemic Oct caused co-internalization, hypothetically a sign of receptor heterodimerization. Oct treatment attenuated the reduction of pain threshold in a neuropathic pain model, in parallel suppressing the activation of p38 MAPK in the DRGs CONCLUSIONS: The findings highlight a significant and complex role of the SST system in pain signaling. The fact that the sst2A system is found also in human DRGs and spinal cord, suggests that sst2A may represent a potential pharmacologic target for treatment of neuropathic pain.
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Although it is becoming accepted that neuroretinal cells are also affected in diabetes, vascular lesions continue to be considered as the hallmarks of diabetic retinopathy. Animal models are essential for the understanding and treatment of human diabetic retinopathy, and the mouse is intensively used as a model because of its similarity to human and the possibility to be genetically modified. However, until today not all retinal vascular lesions developed in diabetic patients have been reproduced in diabetic mice, and the reasons for this are not completely understood. In this review, we will summarize retinal vascular lesions found in diabetic and diabetic-like mouse models and its comparison to human lesions. The goal is to provide insights to better understand human and mice differences and thus, to facilitate the development of new mouse models that mimic better human diabetic retinopathy.
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