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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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... On the other hand, somatostatin (SST), a small peptide that occurs naturally in the body [11], exerts its biological effect through 5 subtypes of somatostatin receptors (SSTR) located in various tissues such as in the lungs, thyroid, immune cells, pancreas, gastrointestinal tract, hypothalamus, or pituitary gland [11]. SST-SSTR binding activates signaling pathways with inhibitory effects including inhibition of cell proliferation and anti-inflammatory effects, among others [12][13][14][15]. These properties make somatostatin a potential candidate for therapeutic use in a wide range of diseases (i.e., acromegaly) [15]. ...
... SST-SSTR binding activates signaling pathways with inhibitory effects including inhibition of cell proliferation and anti-inflammatory effects, among others [12][13][14][15]. These properties make somatostatin a potential candidate for therapeutic use in a wide range of diseases (i.e., acromegaly) [15]. Interestingly, high expression of SSTR2 and SSTR5 was reported in NETs [16], so these receptors and the use of SST have become targets for NET treatment [15,17]. ...
... These properties make somatostatin a potential candidate for therapeutic use in a wide range of diseases (i.e., acromegaly) [15]. Interestingly, high expression of SSTR2 and SSTR5 was reported in NETs [16], so these receptors and the use of SST have become targets for NET treatment [15,17]. However, the very short half-life of SST (1 to 3 min) was a strong limitation in its therapeutic use [18]. ...
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Background and Objectives: High-grade malignant neuroendocrine tumors (G3 NETs) and neuroendocrine carcinomas (NECs) are characterized by rapid proliferation, high metastatic capacity, and strong expression of somatostatin receptors (SSTRs). We aimed to analyze the presence of SSTRs in NET G3 and NEC, and to correlate their expression with the use of octreotide and pasireotide. Materials and Methods: For this purpose, we first performed a retrospective study of G3 NET and NEC patients, which included the determination of SSTR expression and response to octreotide treatment. Second, we selected the H69 small cell lung cancer cell line to determine the effect of octreotide and pasireotide. Results: Our results showed the traditional somatostatin analog (SSA) octreotide was ineffective in patients with NET G3 and NEC. On the other hand, RT-qPCR showed a high expression of SSTR2 and SSTR5 in H69 cells. Interestingly, while octreotide did not modify H69 cell proliferation, a strong inhibition of proliferation was detected with the use of pasireotide. Conclusions: In view of these results, a clinical trial in NET G3 and NEC patients using pasireotide is necessary to determine the usefulness of this drug in improving patient treatment.
... 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.
... Moreover, the simultaneous stimulation of SSTR 2 and 5 achieves significant inhibition of Ras and extracellular signal-regulated kinase (ERK)-1/2. [20][21][22][23] Similarly, cabozantinib inhibits the activity of VEGFR2, c-MET and AXL at the level of both cancer cells and peritumoral vessels, thus leading to the downstream inhibition of PI3K/Akt/mTOR and Ras/MAPK, with antiproliferative and antiangiogenic effects. [24] Also SSAs exert antiangiogenic effects by engaging SSTRs on the vascular endothelium and by downregulating the secretion of proangiogenic factors, such as VEGF and PDGF [25]. ...
... In our opinion, the combination of cabozantinib with other agents such as SSAs may result in synergistic antiproliferative effects, potentially enhancing antitumor activity and clinical outcomes. The biological rationale of the synergistic effects of cabozantinib in combination with SSAs resides in the concomitant inhibition of intracellular signaling pathways associated with tumor cell proliferation, angiogenesis and immune modulation [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. ...
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Background Well-differentiated (WD) neuroendocrine tumors (NETs) are a group of rare neoplasms with limited therapeutic options. Cabozantinib is an inhibitor of multiple tyrosine kinases with a pivotal role in NET pathogenesis, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). LOLA is the first prospective phase II trial aiming to assess the safety and activity of cabozantinib combined with lanreotide in WD NETs of gastroenteropancreatic (GEP), thoracic and of unknown origin. Methods This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥ 10%; positive 68 Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids (typical or atypical lung and thymus NETs, gastro-intestinal NETs or NETs of unknown origin). In stage I, the primary objective is to find the optimal dose of cabozantinib in combination with lanreotide and to evaluate the safety of the combination (percentage of patients experiencing grade 3–5 toxicities according to NCI-CTCAE version 5.0). Starting dose of cabozantinib is 60 mg/day continuously, plus lanreotide 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST version 1.1. The uninteresting antitumor activity is fixed in ORR ≤ 5%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of c-MET, AXL and VEGFR2 IHC expression, to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop-out rate of 5%, the maximum number of enrolled patients will be 69. Discussion Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of cabozantinib plus lanreotide in a group of NET patients with relatively aggressive disease and limited therapeutic options. Trial registration LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019–004506-10).
... Their natural peptide ligand, somatost is found in humans under two different forms: one of 14 amino acids (SS-14) and on 28 amino acids (SS-28) (Figure 1) [17,18]. Natural somatostatin has been shown to be suitable for in vivo use due to its short plasma half-life (about 3 min) [19]. Analogu this hormone, more resistant to enzymatic degradation, have therefore been develope making various modifications to the natural molecule [20,21]. ...
... Retreatment with 177 Lu-PRRT resulted in 24.2% objective radiological responses (ORRs) and 42.4% SDs. The median PFS was 13 (9-18) months from the start of the salvage therapy and 22 (19)(20)(21)(22)(23)(24)(25) months after the initial 177 Lu-PRRT. Remarkably, these results are slightly lower than those obtained in the pretreated subgroups of the Ballal et al. study involving [ 225 Ac]Ac-DOTATATE [212]. ...
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The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of 177 Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroen-docrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives radiolabeled with an alpha-emitter could provide a promising alternative. Among the currently available alpha-emitting radioelements, actinium-225 has emerged as the most suitable candidate, especially regarding its physical and radiochemical properties. Nevertheless, preclinical and clinical studies on these radiopharmaceuticals are still few and heterogeneous, despite the growing momentum for their future use on a larger scale. In this context, this report provides a comprehensive and extensive overview of the development of 225 Ac-labeled somatostatin analogs; particular emphasis is placed on the challenges associated with the production of 225 Ac, its physical and radiochemical properties, as well as the place of 225 Ac-DOTATOC and 225 Ac-DOTATATE in the management of patients with advanced metastatic neuroendocrine tumors.
... when the curative operation is no longer feasible, drug treatment options for unoperated patients are divided into four main categories, for example, somatostatin analogs (SSA), targeted therapy, peptide receptor radionuclide therapy (PRRT), and chemotherapy [10]. It has been validated that SSAs performed a critical role in retarding cell proliferation and tumorigenesis by targeting the SST, especially SST2, somatostatin receptor subtype-5 (SST5) [11,12]. Octreotide is the first discovered longlasting SSA [13]. ...
... Glu2-Tag mice underwent α cell hyperplasia, abnormal dysplastic islets, hyperglycemia, and endocrine tumors of different grades. In Glu2-Tag, Tag was expressed in the pancreas and brain in 12 week, but only developed glucagonoma at 18 months [65]. Because of striking similarities between human sporadic glucagonomas and Glu2-Tag mouse tumor spectrums, this model is considered to be an appropriate preclinical tool to study human glucagonoma. ...
Article
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The neuroendocrine neoplasm, in general, refers to a heterogeneous group of all tumors originating from peptidergic neurons and neuroendocrine cells. Neuroendocrine neoplasms are divided into two histopathological subtypes: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Pancreatic neuroendocrine tumors account for more than 80% of pancreatic neuroendocrine neoplasms. Due to the greater proportion of pancreatic neuroendocrine tumors compared to pancreatic neuroendocrine carcinoma, this review will only focus on them. The worldwide incidence of pancreatic neuroendocrine tumors is rising year by year due to sensitive detection with an emphasis on medical examinations and the improvement of testing technology. Although the biological behavior of pancreatic neuroendocrine tumors tends to be inert, distant metastasis is common, often occurring very early. Because of the paucity of basic research on pancreatic neuroendocrine tumors, the mechanism of tumor development, metastasis, and recurrence are still unclear. In this context, the representative preclinical models simulating the tumor development process are becoming ever more widely appreciated to address the clinical problems of pancreatic neuroendocrine tumors. So far, there is no comprehensive report on the experimental model of pancreatic neuroendocrine tumors. This article systematically summarizes the characteristics of preclinical models, such as patient-derived cell lines, patient-derived xenografts, genetically engineered mouse models, and patient-derived organoids, and their advantages and disadvantages, to provide a reference for further studies of neuroendocrine tumors. We also highlight the method of establishment of liver metastasis mouse models.
... 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.
... 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. ...
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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% (
... 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.
... 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.
... 773 las secreciones pancreáticas, tiene una vida media corta, por lo que se desarrolló la octreotida, una versión sintética de mayor duración. Sin embargo, la evidencia clínica ha mostrado que ni la somatostatina ni la octreotida son eficaces en el tratamiento de la pancreatitis aguda (Rai et al., 2015;Bang et al., 2008). ...
Article
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La pancreatitis aguda es un trastorno intracelular que lleva a la inflación y necrosis del órgano, afectando a la salud integral del ser humano. Con múltiples causas y afectando a una cantidad considerable de personas al año, el diagnóstico usa la clínica, exámenes de laboratorio y de imagenología considerando la clasificación de Atlanta de 1992 y posterior los escores de severidad. El tratamiento se basa en reposición hídrica, reposo gástrico, analgesia y resolución de la causa. El conocer las nuevas tendencias y manejos farmacológicos para la pancreatitis aguda es de mucha ayuda ya que continúa siendo un desafío debido a la ausencia de terapias farmacológicas específicas aprobadas, a pesar de que siempre se debe individualizar la atención del paciente.
... Somatostatin and analogs may reduce endothelial cell proliferation and neovascularization, thereby exerting antiangiogenic effects [38]. Several studies report the therapeutic use of somatostatin analogs for treating diabetic retinopathy [39]. According to our research, current or previous somatostatin analog use did not significantly affect Gremlin-1 or vascular density. ...
... Originando da cellule a fenotipo endocrino, i NET sono dotati di espressione dei recettori per la somatostatina (SST-R) e, in particolare, i sottotipi recettoriali 2 e 5 (SST-R2 e SST-R5). Questo target recettoriale di membrana può essere sfruttato sia a scopo diagnostico che terapeutico, in un moderno approccio teragnostico medico-nucleare [5,6]. ...
Article
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Sommario I tumori neuroendocrini (NET) sono un gruppo di neoplasie rare e spiccatamente eterogenee, spesso diagnosticate già in fase avanzata. Sulla scorta dei risultati dello studio NETTER-1, la terapia con radioligandi (RLT) è stata approvata da EMA, FDA e, nel 2019, da AIFA, diventando un pilastro nel trattamento dei NET gastro-entero-pancreatici (GEP-NET) ben differenziati (G1 e G2), localmente avanzati o metastatici e in progressione al trattamento di prima linea con gli analoghi dei recettori della somatostatina (SST-R). Nonostante l’efficacia e la sicurezza della RLT nei NET sia ampiamente dimostrata da una ricca letteratura scientifica, permangono ancora alcuni interrogativi irrisolti. Tra di essi, i principali sono la definizione del corretto timing rispetto ad altre terapie e l’estensione alle cosiddette neoplasie orfane di RLT. Parallelamente si stanno sviluppando nuove strategie radiofarmacologiche per potenziare il modello teragnostico attualmente in uso. In questa rassegna verranno descritte le tappe fondamentali che hanno portato all’approvazione della RLT nei GEP-NET e verranno discusse criticità attuali e prospettive future di tale approccio terapeutico.
... Somatostatin and analogs may reduce endothelial cell proliferation and neovascularization, thereby exerting antiangiogenic effects [38]. Several studies report the therapeutic use of somatostatin analogs for treating diabetic retinopathy [39]. According to our research, current or previous somatostatin analog use did not significantly affect Gremlin-1 or vascular density. ...
... The discovery of a venom peptide that closely resembles a synthetic SS drug analog exemplifies the potential of natural compounds to serve as alternatives to human-engineered drugs. SSTR 2 is the main mediator of SS's antiproliferative effects on normal and cancer cells and has been an intense target for the development of therapeutic, diagnostic, and theranostic agents for various neoplasms and cancers 42,43 . While some neuroendocrine tumors, such as gastrinomas and glucagonomas, predominately express the SSTR 2 , others coexpress two or more SSTR subtypes and are treated using multireceptor-targeted analogs 44 . ...
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Venomous animals have evolved diverse molecular mechanisms to incapacitate prey and defend against predators. Most venom components disrupt nervous, locomotor, and cardiovascular systems or cause tissue damage. The discovery that certain fish-hunting cone snails use weaponized insulins to induce hypoglycemic shock in prey highlights a unique example of toxins targeting glucose homeostasis. Here, we show that, in addition to insulins, the deadly fish hunter, Conus geographus, uses a selective somatostatin receptor 2 (SSTR2) agonist that blocks the release of the insulin-counteracting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in prey. The native toxin, Consomatin nG1, exists in several proteoforms with a minimized vertebrate somatostatin-like core motif connected to a heavily glycosylated N-terminal region. We demonstrate that the toxin’s N-terminal tail closely mimics a glycosylated somatostatin from fish pancreas and is crucial for activating the fish SSTR2. Collectively, these findings provide a stunning example of chemical mimicry, highlight the combinatorial nature of venom components, and establish glucose homeostasis as an effective target for prey capture.
... In pigs, SST expression increases during gut inflammation (Gonkowski and Całka 2010;Palus et al. 2017). SST is known to reduce inflammation by inhibiting T lymphocyte activity, granulocyte proliferation, the synthesis of proinflammatory cytokines, and the release of pain mediators, such as substance P and calcitonin gene-related peptide (Van Op den Bosch et al., 2009;Rai et al. 2015;Gonkowski and Rytel 2019). The decline in SST expression during aging may contribute to inflammatory processes in the gut of elderly individuals. ...
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Somatostatin (SST) is a peptide expressed in the peripheral and central nervous systems, as well as in endocrine and immune cells. The aim of the current study is to determine the percentage of SST immunoreactive (IR) neurons and their colocalization with choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), neuropeptide Y (NPY), and glial fibrillary acidic protein (GFAP) in the myenteric plexus (MP) and submucous plexus (SP) of the small intestine (SI) and large intestine (LI) of rats across different age groups from newborn to senescence using immunohistochemistry. In the MP of the SI and LI, the percentage of SST-IR neurons significantly increased during early postnatal development from 12 ± 2.4 (SI) and 13 ± 3.0 (LI) in newborn rats to 23 ± 1.5 (SI) and 18 ± 1.6 (LI) in 20-day-old animals, remaining stable until 60 days of age. The proportion of SST-IR cells then decreased in aged 2-year-old animals to 14 ± 2.0 (SI) and 10 ± 2.6 (LI). In the SP, the percentage of SST-IR neurons significantly rose from 22 ± 3.2 (SI) and 23 ± 1.7 (LI) in newborn rats to 42 ± 4.0 in 20-day-old animals (SI) and 32 ± 4.9 in 30-day-old animals (LI), before declining in aged 2-year-old animals to 21 ± 2.6 (SI) and 28 ± 7.4 (LI). Between birth and 60 days of age, 97–98% of SST-IR neurons in the MP and SP colocalized with ChAT in both plexuses of the SI and LI. The percentage of SST/ChAT neurons decreased in old rats to 85 ± 5.0 (SI) and 90 ± 3.8 (LI) in the MP and 89 ± 3.2 (SI) and 89 ± 1.6 (LI) in the SP. Conversely, in young rats, only a few SST-IR neurons colocalized with nNOS, but this percentage significantly increased in 2-year-old rats. The percentage of SST/NPY-IR neurons exhibited considerable variation throughout postnatal development, with no significant differences across different age groups in both the MP and SP of both intestines. No colocalization of SST with GFAP was observed in any of the studied animals. In conclusion, the expression of SST in enteric neurons increases in young rats and decreases in senescence, accompanied by changes in SST colocalization with ChAT and nNOS.
... Because of their inhibitory effects, these receptors control various signal transduction pathways (Figure 16). The modulatory effects of somatostatin and its analogs on the immunological response and its antiproliferative, antiangiogenic, and analgesic effects have been studied [155][156][157][158]. In various physiological and pathological circumstances, lymphocytes and vascular endothelium express SSTRs 2, 3, and 5. [152,159,160]. ...
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Rheumatoid arthritis (RA) is a systemic autoimmune disorder caused by inflammation of cartilaginous diarthrodial joints that destroys joints and cartilage, resulting in synovitis and pannus formation. Timely detection and effective management of RA are pivotal for mitigating inflammatory arthritis consequences, potentially influencing disease progression. Nuclear medicine using radiolabeled targeted vectors presents a promising avenue for RA diagnosis and response to treatment assessment. Radiopharmaceutical such as technetium-99m (99mTc), combined with single photon emission computed tomography (SPECT) combined with CT (SPECT/CT), introduces a more refined diagnostic approach, enhancing accuracy through precise anatomical localization, representing a notable advancement in hybrid molecular imaging for RA evaluation. This comprehensive review discusses existing research, encompassing in vitro, in vivo, and clinical studies to explore the application of 99mTc radiolabeled targeting vectors with SPECT imaging for RA diagnosis. The purpose of this review is to highlight the potential of this strategy to enhance patient outcomes by improving the early detection and management of RA.
... This hormone is secreted throughout the central nervous system, in the retina, in peripheral neurons, and in the pancreatic islets of Langerhans. However, 65% of the body's total SST is produced in the GI tract (Rai et al., 2015;Messchendorp et al., 2020), specifically by D cells harboring the stomach and the duodenum, with smaller quantities found throughout the GI tract (Garrido-Utrilla et al., 2022;Rezzani et al., 2022). It is less common in the colon and rectum (Gunawardene et al., 2011). ...
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Recent studies suggest that disruptions in intestinal homeostasis, such as changes in gut microbiota composition, infection, and inflammatory-related gut diseases, can be associated with kidney diseases. For instance, genomic investigations highlight how susceptibility genes linked to IgA nephropathy are also correlated with the risk of inflammatory bowel disease. Conversely, investigations demonstrate that the use of short-chain fatty acids, produced through fermentation by intestinal bacteria, protects kidney function in models of acute and chronic kidney diseases. Thus, the dialogue between the gut and kidney seems to be crucial in maintaining their proper function, although the factors governing this crosstalk are still emerging as the field evolves. In recent years, a series of studies have highlighted the significance of enteroendocrine cells (EECs) which are part of the secretory lineage of the gut epithelial cells, as important components in gut-kidney crosstalk. EECs are distributed throughout the epithelial layer and release more than 20 hormones in response to microenvironment stimuli. Interestingly, some of these hormones and/or their pathways such as Glucagon-Like Peptide 1 (GLP-1), GLP-2, gastrin, and somatostatin have been shown to exert renoprotective effects. Therefore, the present review explores the role of EECs and their hormones as regulators of gut-kidney crosstalk and their potential impact on kidney diseases. This comprehensive exploration underscores the substantial contribution of EEC hormones in mediating gut-kidney communication and their promising potential for the treatment of kidney diseases.
... One may distinguish between five different SSTR subtypes (1, 2A/B, 3, 4, and 5), which are expressed in varying degrees in diverse neoplastic tumors and tissues [17]. In addition to its well-known anti-secretory, anti-nociceptive, and anti-inflammatory functions, researchers have discovered that somatostatin and its receptors also inhibit cell growth and angiogenesis [18]. Somatostatin receptors have been identified in the metaphysis next to hypertrophic cartilage [19]. ...
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Simple Summary Currently, the diagnosis of salivary gland tumors using current imaging techniques is unreliable. In this study we examined salivary gland tumors and discovered that the pleomorphic adenoma, a tumor which should be surgically removed because it has a tendency to become malign, has a strong concentration of the somatostatin receptor 2. This characteristic may allow physicians to identify and potentially treat the tumor in a non-invasive manner. Abstract Reliable preoperative diagnosis between salivary gland tumor entities is difficult. In this monocentric retrospective study, we examined the somatostatin receptor 2 (SSTR2) status of salivary gland tumors after salivary gland tumor resection via immunohistochemistry (IHC), and stains were compared in analogy to the HER2 mamma scale. A total of 42.3% of all pleomorphic adenoma (PA) tumors (42 of 99, 95% confidence interval 32.5–52.8%) demonstrated ≥20% of cells displaying the SSTR2 as compared to just 1% of all other tumors (1/160, 95% CI 0.02–3.4%). The other tumor was a neuroendocrine carcinoma. PA had a higher intensity of SSTR2 staining, with 90.9% staining ≥ an intensity of 2 (moderate). Tumors with an intensity of SSTR2 expression equal to or greater than 2 had an 89.9% likelihood of being a PA (95% CI: 82.2–95.0%, AUC: 0.928). Only one Warthin tumor demonstrated a ‘strong’ SSTR2 staining intensity. No Warthin tumor showed a percentage of cells staining for SSTR2 above ≥20%. This result demonstrates consistent and strong expression of SSTR2 in PAs as compared to Warthin tumors, which may allow physicians to utilize radioligand-somatostatin analog PET CT/MR imaging to diagnose the PA. SSTR2 positivity, if shown to be clinically relevant, may allow peptide receptor radionuclide therapy in the future.
... 9 The SST was used for treatment of diseases like diabetes mellitus, acromegaly, pancreatic tumors, pancreatic cholera, acute variceal and acute ulcer hemorrhages, dumping syndrome, duodenal ulcer, Alzheimer's, and senile dementia. 10,11 The stomach is the most important organ affected by the foods consumed and can be damaged at varying rates depending on the type of food eaten. 12 Nowadays, studies have focused on substances with protective and therapeutic effects for the gastric mucosa. ...
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This study aimed to investigate the effects of a high-fat and cholesterol diet (HFCD) on rats' gastric mucosa. In the study, a total of 16 (40-day-old Sprague Dawley) male rats were used and randomly divided into two groups (each consisted of eight rats). The rats in control group had no implementations other than normal feeding. For 10 weeks, rats in a high-fat with cholesterol diet group had daily energy amounts provided by pellet feed mixed with 65.00% butter and 2.00% cholesterol. Before beginning the study and at the end, rats live weight was recorded and their blood samples were taken for biochemical analyses. Hematoxylin and Eosin and Crossman's triple staining techniques were used to investigate the general structure of gastric tissue. The rats fed with HFCD had statistically significant increases in live weight and total cholesterol values, and were identified to have gastric tissue degeneration. The rats' gastric tissue in control group had more intense somatostatin (SST) immunoreactivity in parietal and chief cells than the HFCD group. It was determined that feeding with the HFCD has a negative effect on SST secretion in rats and hence, this may have important areas of use such as in gastric cancer treatment and preventing complications linked to gastric diseases.
... Somatostatin is produced by the body's enzymes and is found in many foods. [83] According to the FDA, Acromegaly and neuroendocrine tumors that express SSTRs are currently being treated using SSTR analogs. As a result of its strong affinity for the steroid hormone receptors 2 and 5, OCT was the first SST analog to be licensed to treat hormone-producing neuroendocrine tumors in the pituitary, pancreas, and intestine. ...
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Neuroendocrine tumors (NET) form in the body's neuroendocrine system and are considered malignant; it takes years for most NETs to evolve, but not all. NETs are predominantly located in the lungs and the gastrointestinal tract; NETs in the lungs are carcinoid tumors. Treating these tumors is challenging, and therapeutic strategies have become priorities for researchers and clinicians. A neuroendocrine lung tumor is one such tumor that is very difficult to treat. To manage hormonal disorders caused by neuroendocrine tumors, somatostatin analogs are the gold standard. New data suggests that somatostatin analogs can be antiproliferative treatments for neuroendocrine tumors. Despite their apparent clinical interchangeability, comparative noninferiority studies between octreotide and lanreotide have not been conducted. Thus, it is where we look at different drug conjugates which act on the tumor. Radioligand, for example, is a promising model for Peptide Somatostatin receptors, typically more expressed on the surface of metastatic lung NETs.Consequently, a radioligand-based drug-peptide delivery is a particular target delivery method. Another type of drug conjugate is the novel technology named Peptide-drug conjugate (PDC) has made slow and steady progress in this treatment. PDC has the advantage of covalently altering a ligand peptide, which can target the specific cell surface receptors or biomarkers at the tumor site, exert a long-lasting function, and extend the effect of time, resulting in an overall desirable pharmacokinetic profile as a means of delivering anticancer drugs. Therefore, this review will summarize the recent technologies and anticancer agents that PDC used for the therapeutic efficiency and the intracellular uptake efficiency of active ingredients and receptors expressed on LU-NETs cells.
... Since the fact that SS has anti-proliferative and anti-angiogenic effects and given that its half-life is very short (1-3 min), as well as the wide spectrum of its biological responses, led to the need to develop selective stable receptor agonists that are bind strongly to selective SS receptor subtypes, therefore, in addition to blocking GH secretion (e.g., treatment of Acromegaly), these SS agonists are being used for the therapy of neuroendocrine tumors, diabetic complications (nephropathy, retinopathy), anti-neoplastic therapies. More recently, it has been shown that these agonists have anti-inflammatory and anti-nociceptive effects [25]. ...
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Growth hormone (GH) performs very diverse functions in the organism, and this is the reason by which the regulation of the secretion of this hormone is very complex; although the primary regulators are growth hormone-releasing hormone (GHRH) and somatostatin, it is in turn regulated mainly by adrenergic and cholin-ergic pathways, and other factors can act directly on its secretion, particularly on the somatostatin, thus affecting the pituitary secretion of GH. In this chapter, we will analyze the transcription of GH gene and how GH release is affected by different neurotransmitters, metabolic substrates, feeding and fasting, and other hormones, placing special emphasis on why pituitary secretion of GH is sexually dimorphic.
... Thus, many analogues with better metabolic properties and longer halflives have been developed. [144][145][146] The physiologic actions of SST are mediated by 5 SST receptors (SSTRs; SSTR-1 to SSTR-5), which are widely expressed in the whole body. 145,147 The human retina produces abundant SST and its receptors, and the RPE is the primary source. ...
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The ocular tissue microenvironment is immune-privileged and uses multiple immunosuppressive mechanisms to prevent the induction of inflammation. The retinal pigment epithelium plays an essential role in ocular immune privilege. In addition to serving as a blood barrier separating the fenestrated choriocapillaris from the retina, the retinal pigment epithelium is a source of immunosuppressive cytokines and membrane-bound negative regulators that modulate the activity of immune cells within the retina. This article reviews the current understanding of how retinal pigment epithelium cells mediate immune regulation, focusing on the changes under pathologic conditions.
... The GH is produced in a pulsatile fashion via somatotroph cells of the pituitary gland, where an imbalance of GH level in the body stimulates the hepatic secretion of insulin-like growth factor-1 (IGF-1) . Both of these hormones, GH and IGF-1, are further responsible for extra-somatic growth, which is a prominent characteristic of pituitary adenoma Rai et al., 2015). More than 90 % of pituitary cancer cases show abnormal growth of adenomas on the pituitary somatotroph cells (Leonart et al., 2018) occurring mostly in middle-age population and are also diagnosed with acromegaly (Winters et al., 2015). ...
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.
... 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.
... 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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Abstract 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
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Biomimetic coacervates have recently attracted great interest in biomedical fields, especially for drug delivery and as protocells. However, these membraneless structures are easily coalesced and poorly targetable, limiting their real biomedical applications. Here multiphase “core–shell” coacervate (CSC) constructed by dsDNA and somatostatin (SST), a 14‐mer cyclopeptide is designed. The CSC shows enhanced tumor targetability through SST binding to SST receptors on the tumor cells' surface. G4 quadruplex‐hemin complex can be embedded in the CSC by interaction with SST, as demonstrated by molecular simulation and isothermal titration calorimetry. The G4‐hemin embedded CSC can further recruit photosensitizers such as tetracarboxyphenyl porphyrin to form the CSC‐GHT composite for photodynamic therapy (PDT). As photodynamic biomimetic organelles, CSC‐GHT can convert oxygen to singlet oxygen (catalyzed by the catalase‐mimetic activity of G4‐hemin), resulting in enhanced PDT effect, which allows the inhibition of cellular migration in vitro and tumor growth in vivo. Owing to high stability, targetability, and biosafety, the proposed CSC can recruit various cargos from small dyes to large biomacromolecules (up to 430 kDa), providing promising theranostic applications.
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The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) is increasing at a rapid pace and is becoming an increasingly important consideration in clinical care. Epidemiological data from multiple countries indicate that the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibits regional, site-specific, and gender-based variations. While the genetics and pathogenesis of some GEP NEN, particularly pancreatic NENs, have been investigated, there are still many mechanisms that require further investigation. The management of GEP NEN is diverse, but surgery remains the primary option for most cases. Peptide receptor radionuclide therapy (PRRT) is an effective treatment, and several clinical trials are exploring the potential of immunotherapy and targeted therapy, as well as combination therapy.
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Somatostatin is a peptide that plays a variety of roles such as neurotransmitter and endocrine regulator; its actions as a cell regulator in various tissues of the human body are represented mainly by inhibitory effects, and it shows potent activity despite its physiological low concentrations. Somatostatin binds to specific receptors, called somatostatin receptors (SSTRs), which have different tissue distributions and associated signaling pathways. The expression of SSTRs can be altered in various conditions, including tumors; therefore, they can be used as biomarkers for cancer cell susceptibility to certain pharmacological agents and can provide prognostic information regarding disease evolution. Moreover, based on the affinity of somatostatin analogs for the different types of SSTRs, the therapeutic range includes conditions such as tumors, acromegaly, post-prandial hypotension, hyperinsulinism, and many more. On the other hand, a number of somatostatin antagonists may prove useful in certain medical settings, based on their differential affinity for SSTRs. The aim of this review is to present in detail the principal characteristics of all five SSTRs and to provide an overview of the associated therapeutic potential in neoplasias.
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Background Vasculogenic mimicry (VM) is a vascular-like microcirculatory delivery system directly formed by tumor cells. It plays significant roles in tumor invasion and resistance to antiangiogenic drugs. However, there is no model based on VM for ovarian cancer (OC) prognosis. Results The occurrence and progression of OC is associated with vasculogenic mimicry-related genes (VMGs) interactions in a cellular network. The prognostic VMGs can distinguish between two subgroups with significantly different prognoses. Differentially expressed genes (DEGs) between the subgroups suggest that certain signaling pathways and cellular functions are involved in the formation or promotion of VM. Based on filtered DEGs, a prognostic model was constructed and demonstrated outstanding performance in internal and external validations. The model results do not affect the distribution of clinical features and can be used to construct a nomogram. There are differences in immune cell composition and immune infiltration between the high-risk group and the low-risk group. Differences also exist in their resistance and sensitivity to certain drugs. Finally, subgroups analysis demonstrated differences in ovarian cancer VM structures which may be associated with different expressions of VMGs and VM-related prognostic indices (VMRPI). Conclusions VM may play a crucial role in the development and tumor immune microenvironment of serous ovarian cancer. VMRPI holds promise as a valuable prognostic biomarker. This is the first time that it is used to identify high risk OC patients with ovarian cancer and may indicate responsiveness to specific drug treatments.
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Somatostatin, a somatotropin release inhibiting factor (SST, SRIF), is a widely distributed multifunctional cyclic peptide and acts through a transmembrane G protein-coupled receptor (SST1-SST5). Over the past decades, research has begun to reveal the molecular mechanisms underlying the anticancer activity of this hormonal peptide. Among gastrointestinal tract (GIT) tumors, direct and indirect antitumor effects of SST have been documented best in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and less well in non-endocrine cancers, including sporadic colorectal cancer (CRC). In the latter, the signaling pathways involved in the antitumor function of SST are primarily MAPK/ERK/AKT and Wnt/β–catenin. Direct (involving the MAPK pathway) and indirect (VEGF production) antiangiogenic effects of SST in CRC have also been described. The anti-inflammatory role of SST in CRC is emphasized, but detailed molecular mechanisms are still being explored. The role of SST in tumor genome/tumor microenvironment (TME)/host’s gut microbiome interactions is only partially known. The results of SST analogues (SSAs)’ treatment of sporadic CRC in monotherapy in vivo are not spectacular. The current review aims to present the state-of-the-art mechanisms and antitumor activity of endogenous SST and its synthetic analogues in CRC, with particular emphasis on sporadic CRC.
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Simple Summary The tissue expression of somatostatin receptor (SSTR) subtypes in neuroendocrine tumors (NETs) holds paramount significance with far-reaching diagnostic and therapeutic implications. SSTRs contribute significantly to localizing NETs, aiding in advanced imaging techniques such as somatostatin receptor scintigraphy and PET scans. Elevated SSTR expression often aligns with less aggressive tumors, impacting tumor grading and influencing treatment decisions. Therapeutically, SSTRs serve as pivotal targets for treatments like targeted radiotherapy and synthetic somatostatin analogs (e.g., octreotide), commonly employed to inhibit hormone secretion and suppress tumor growth. Tailoring treatment strategies based on SSTR subtype expression enhances therapeutic efficacy. SSTR expression serves as a valuable prognostic indicator, predicting treatment response. While challenges like tumor heterogeneity persist, ongoing research explores promising avenues, including combination therapies. In conclusion, a nuanced understanding of SSTR expression in NETs is indispensable for precise diagnosis and the development of tailored therapeutic interventions, offering the potential for improved patient outcomes. Abstract Neuroendocrine tumors (NETs) arise from neuroendocrine cells and manifest in diverse organs. Key players in their regulation are somatostatin and its receptors (SSTR1–SSTR5). Understanding receptor–ligand interactions and signaling pathways is vital for elucidating their role in tumor development and therapeutic potential. This review highlights SSTR characteristics, localization, and expression in tissues, impacting physiological functions. Mechanisms of somatostatin and synthetic analogue binding to SSTRs, their selectivity, and their affinity were analyzed. Upon activation, somatostatin initiates intricate intracellular signaling, involving cAMP, PLC, and MAP kinases and influencing growth, differentiation, survival, and hormone secretion in NETs. This review explores SSTR expression in different tumor types, examining receptor activation effects on cancer cells. SSTRs’ significance as therapeutic targets is discussed. Additionally, somatostatin and analogues’ role in hormone secretion regulation, tumor growth, and survival is emphasized, presenting relevant therapeutic examples. In conclusion, this review advances the knowledge of receptor–ligand interactions and signaling pathways in somatostatin receptors, with potential for improved neuroendocrine tumor treatments.
Article
Objectives: To explore the effects of somatostatin on the levels of gastrointestinal hormones and clinical outcomes in critically ill infants after gastrointestinal surgery. Methods: Using a random number table method, critically ill infants after gastrointestinal surgery who were admitted to the Intensive Care Unit of Xuzhou Children's Hospital from June 2019 to June 2021 were randomly divided into an observation group (29 cases) and a control group (30 cases). The control group received routine treatment such as anti-infection and hemostasis after surgery, while the observation group received somatostatin in addition to the routine treatment [3.5 μg/(kg·h) infusion for 7 days]. The levels of serum gastrin (GAS), motilin (MTL), insulin, and glucagon-like peptide-1 (GLP-1) before surgery, on the 3rd day after surgery, and on the 7th day after surgery were compared between the two groups. The recovery progress and incidence of complications after surgery were also compared between the two groups. Results: There was no significant difference in the levels of serum GAS, MTL, insulin, and GLP-1 between the two groups before surgery (P>0.05). On the 3rd and 7th day after surgery, the levels of serum GAS, MTL, insulin, and GLP-1 in the observation group were higher than those in the control group (P<0.05). In the observation group, the levels of GAS, MTL, insulin, and GLP-1 on the 7th day after surgery were higher than those before surgery and on the 3rd day after surgery (P<0.05), and the levels on the 3rd day after surgery were higher than those before surgery (P<0.05). There was no significant difference in the levels of serum GAS, MTL, and insulin before surgery, on the 3rd day after surgery, and on the 7th day after surgery in the control group (P>0.05). The level of GLP-1 on the 7th day after surgery was higher than that before surgery and on the 3rd day after surgery (P<0.05), and the level on the 3rd day after surgery was higher than that before surgery (P<0.05) in the control group. The observation group had shorter first time of anal exhaust, recovery time of bowel sounds, and first time of defecation after surgery compared to the control group (P<0.05). The incidence of complications after surgery in the observation group was lower than that in the control group (10% vs 33%, P<0.05). Conclusions: Somatostatin can increase the levels of serum GAS, MTL, insulin, and GLP-1 in critically ill infants after gastrointestinal surgery, promote the recovery of gastrointestinal function, and reduce the incidence of postoperative complications.
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Decades of published research supports a role for growth hormone (GH) in cancer. Accordingly, there is increasing interest in targeting GH in oncology, with GH antagonists exhibiting efficacy in xenograft studies as single agents and in combination with anticancer therapy or radiation. Here we discuss challenges associated with using growth hormone receptor (GHR) antagonists in preclinical models and considerations for translation, such as the identification of predictive biomarkers for selecting patients and for monitoring drug efficacy. Ongoing research will determine whether suppressing GH signalling pharmacologically will also reduce the risk of developing cancer. An increase in GH-targeted drugs in preclinical development will ultimately provide researchers with new tools to test anti-cancer efficacy of blocking the GH signalling pathway in preclinical models.
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Neuropeptides are a highly diverse group of signaling molecules found in the central nervous system (CNS) and peripheral organs, including the enteric nervous system (ENS). Increasing efforts have been focused on dissecting the role of neuropeptides in both neural- and non-neural-related diseases, as well as their potential therapeutic value. In parallel, accurate knowledge on their source of production and pleiotropic functions is still needed to fully understand their implications in biological processes. This review will focus on the analytical challenges involved in studying neuropeptides, particularly in the ENS, a tissue where their abundance is low, together with opportunities for further technical development.
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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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Peptides are emerging as a promising candidate for therapeutic as well as diagnostic applications within the domain of clinical and scientific research. They are recognized for being highly selective, sensitive and efficacious with minimal or no toxicity. Small size, non-immunogenicity, ease of synthesis and huge scope of modification are some of the well-established properties of peptides, which make them an excellent alternative to not only small drug molecules but also to protein-based biopharmaceuticals such as antibodies and enzymes. The attractive pharmacological profile and intrinsic properties of peptides also make them an interesting diagnostic tool for imaging at the molecular and cellular levels. Molecular imaging coupled with targeted therapy using peptides as theranostics is a two-edged sword. Besides, traditional peptide formats, multifunctional newer peptide designs with improved pharmacokinetics and targetability are also being explored presently. In this review, we come up with a comprehensive summary of the latest progress on peptides and their potential applications in therapeutics and diagnosis for infectious and non-infectious diseases. The last part of the review discusses suitable carrier systems for the delivery of peptides along with highlighting the future challenges.
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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.
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.
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.
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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.
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Purpose. The success of hypophysectomy as a treatment modality for proliferate DR correlates directly with the degree of GH deficiency achieved. The somatostatin analogue, OCT, decreases levels of growth hormone (GH) and the GH-related peptide, insulin-like growth factor-I (IGF-I). IGF-I mediates most of GH's mitogenic activity. We investigated the therapeutic efficacy of OCT in prevention of progression of DR in patients (pts) with either severe nonproliferative DR or non "high risk" proliferative DR. Methods. 16 diabetic pts were randomized to treatment (n=8)(continuous infusion or QID sub q administration of maximally tolerated OCT doses ranging from 600-3000 μg/day) or control (n=8)(conventional DM management) groups for 15 months. Pts received clinical and biochemical assessment at entry and at 3 month intervals. Ophthalmic assessment occurred at entry and at 1 month intervals. Seven fields per eye were assessed for characterization of retinopathy and grading using a modified ETDRS grading system. Results. In pts treated with OCT, GH levels (area under curve) were reduced by 33% (p<0.05), IGF-I levels were decreased by 32% (p<0.05), insulin requirements were decreased by 29% (p<0.05) and proteinuria by 82% (p<0.001). Glycemic control, as assessed by mean HgA1c, over 15 months was improved in the OCT treated group (6.4±0.9%) compared to the control group (8.1±1.2%)(p<0.05). Four pts required laser therapy in each group. No regression of DR occurred in either group. The mean time to requiring laser therapy in the control group was 6.0 months and 8.5 months in the treatment group (p=NS). While reducing GH or IGF-I levels in all pts compared to pretreatment levels, OCT therapy decreased these levels into the hypopituitary range in only one of 8 patients. This pt did not require laser therapy during the study period. Conclusions. OCT resulted in improved glycemic control and renal function. OCT plus insulin can be more effective than insulin alone in controlling diabetic hyperglycemia. Failure of OCT to eliminate the need for photocoagulation therapy in our cohort of pts is probably due to the inability of OCT to suppress GH and IGF-I levels into the hypopituitary range.
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Objective: To investigate the effect of somatostatin on the electrophysiological changes of early diabetic rats, and to clarify its therapeutic effects on retinopathy in early diabetic rats. Methods: 20 Wistar male rats. which were induced into diabetic rat models by intraperitoneal injection of streptozotocin (STZ), were randomly divided into somatostatin therapy group and model control group, 10 in each group. The rats in somatostatin therapy group were injected with somatostatin 10 μg · kg-1 · d-1, for 8 weeks; the rats in model control group received the same volume of saline. Another 10 male Wistar rats were used as normal control group. The changes of blood glucose and electroretinogram were measured, and the indicators were used for statistical analysis. Results: Compared with model control group, the blood glucose was declined in somatostatin therapy group at the 8th week (P<0. 05). Compared with normal control group, the latent periods of a-wave, b-wave of rod-response and max-response were significantly extended in somatostatin therapy group and model control group at the 1st. 2nd, 4th, 6th, and 8th week (P<0. 05). The latent periods of a-wave, b-wave of rod-response and max-response in somatostatin therapy group were shorter than those in model control group at the 8th week (P < 0. 05). Compared with model control group, the amplitude had no changes at each observation time point in somatostatin therapy group (P>0. 05). Conclusion: Somatostatin has a therapeutic effect on early diabetic retinopathy in rats.
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Five somatostatin receptor (sst) subtype genes, sst1, sst2, sst3, sst4 and sst5, have been cloned and characterised. The five sst subtypes all bind natural somatostatin-14 and somatostatin-28 with high affinity. Endocrine pancreatic and endocrine digestive tract tumours also express multiple sst subtypes, but sst2 predominance is generally found. However, there is considerable variation in sst subtype expression between the different tumour types and among tumours of the same type. The predominant expression of sst2 receptors on pancreatic endocrine or carcinoid tumours is essential for the control of hormonal hypersecretion by the octapeptide somatostatin analogues such as octreotide and lanreotide. Somatostatin and its octapeptide analogues are also able to inhibit proliferation of normal and tumour cells. The high density of sst2 or sst5 on pancreatic endocrine or carcinoid tumours further allows the use of radiolabelled somatostatin analogues for in vivo visualisation. The predominant expression of sst2 receptors in these tumours and the efficiency of sst2 receptors to undergo agonist-induced internalisation is also essential for the application of radiolabelled octapeptide somatostatin analogues. Currently, [ 111 In-DTPA 0 ]octreotide, [ 90 Y-DOTA 0 ,Tyr 3 ]octreotide, [ 177 Lu-DOTA 0 Tyr 3 ]octreotate, [ 111 In-DOTA 0 ]lanreotide and [ 90 Y-DOTA 0 ]lanreotide can be used for this purpose.
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Somatostatin is a neuropeptide that is widely distributed throughout the body. It acts as a neurohormone and a neurotransmitter and may also have an immunomodulatory role. The genes for five subtypes of somatostatin receptors (sst) have been cloned, suggesting that the diverse eVects of the peptide might be mediated by diVerent receptors. We are interested in studying the role of sst in inflammation, using an animal model. Because of the up-regulation of sst expression in inflamed joints in human rheumatoid arthritis, we chose rat adjuvant arthritis as an experimental model. In order to determine which of the sst subtypes might be important in immune modulation, subtype expression in leukocytes isolated from diVerent lymphoid tissues of the rat was studied. Also, the expression levels of the most abundantly expressed sst mRNAs in leukocytes from spleen and blood were compared in rats with adjuvant arthritis and controls, using a semi-quantitative approach. Furthermore, the eVect of systemic administration of a long-acting somatostatin analogue, octreotide, which binds selectively to sst subtypes 2 and 5 (sst2 and sst5), on the incidence and the severity of rat adjuvant arthritis, was studied. The main sst expressed in cells of the rat immune system, both resting and activated, were found to be sst 3 and sst 4 . This contrasts with the human and murine situations, in which sst 2 appears to be the main subtype expressed in the immune system. No quantitative diVerences in sst subtype mRNA levels in leukocytes from spleen and blood were found between rats with adjuvant arthritis and controls. Finally, no eVect of systemic administration of octreotide on either the incidence or severity of adjuvant arthritis in Lewis rats was found. As octreotide binds selectively to sst2 and sst5, the absence of an immunomodulatory eVect of this analogue in rat adjuvant arthritis corroborates our finding that these sst subtypes are not expressed in cells of the rat immune system. In conclusion, cells of the rat immune system appear to express a spectrum of sst (sst3 and sst4 )d iVerent from that found in human granulomatous and autoimmune disease (mainly sst2). Therefore, the rat adjuvant arthritis model appears to be suitable only for studying the immunomodulatory eVects of somatostatin analogues which have a high aYnity for sst3 and sst4, but not for studying the immunomodulatory eVects of octreotide, which has a high aYnity only for sst2 and sst5.
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Ocular diseases such as proliferative diabetic retinopathy are the major cause of blindness in industrialized countries. The main pathologic features of these diseases are hypoxia and overproduction of growth factors resulting in pathologic proliferation of endothelial cells and new vessel formation. Particularly, hypoxia and growth factors, such as VEGF, IGF-1, bFGF and TGF 2 , show a complex interaction in the onset and progression of the diseases. Therefore, to date, most therapeutic strategies for proliferative retinopathies have targeted proliferation of endothelial cells evoked by growth factors. Recently, a synthetic analog of somatostatin, octreotide, has been shown to inhibit the proliferation of various cells in vitro, including endothelial cells. In this study, we have investigated the proliferative response of bovine retinal endothelial cells (BREC) to growth factors under hypoxic conditions and the modulation by octreotide. We found a dose-dependent increase of cell proliferation with VEGF, IGF-1 and bFGF, and inhibition of hypoxia-induced cell proliferation with TGF 2 . Moreover, growth factorinduced, but not hypoxia-induced, cell proliferation was attenuated in the presence of octreotide. In contrast, TGF 2 abolished hypoxia-induced BREC proliferation. Similar to octreotide BIM23027, a somatastatin receptor subtype 2 (SSTR2) receptor agonist was able to attenuate the growth factor-induced proliferation of BREC expressing mRNA and protein for SSTR2. Therefore, we postulate that octreotide exerts its effects mainly through binding to the SSTR2. Taken together, our findings point to octreotide as a promising candidate for the treatment of eye disorders involving growth factor-dependent proliferation of endothelial cells.
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To determine whether treatment with a somatostatin analogue can reduce kidney hyperfiltration and hypertrophy in insulin-dependent diabetes mellitus, we studied 11 patients with insulin-dependent diabetes mellitus and glomerular hyperfiltration. The patients were assigned randomly to receive continuous subcutaneous infusion of either octreotide, 300 μg/24 h (five patients) or placebo (six patients) for 12 weeks. At baseline, mean glomerular filtration rate and mean total kidney volume were not significantly different in the two groups. However, after 12 weeks of treatment, the mean glomerular filtration rate was significantly lower in the octreotide group (136 mL/min per 1.73 m2; range, 91 to 158 mL/min per 1.73 m2) than in the placebo group (157 mL/min per 1.73 m2; range, 138 to 184 mL/min per 1.73 m2). Furthermore, the mean total kidney volume was significantly lower after treatment in the octreotide group (379 mL/1.73 m2; range, 307 to 454 mL/1.73 m2) than in the placebo group (389 mL/1.73 m2; range, 347 to 465 mL/1.73 m2). Glycemic control did not change significantly in either group. We conclude that subcutaneous infusion of octreotide for 12 weeks reduces increased glomerular filtration rate and kidney size in patients with insulin-dependent diabetes mellitus despite the fact that glycemic control remains unchanged.(JAMA. 1991;265:888-892)
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Objective: To examine the relative levels of γ-aminobutyric acid (GABA), glutamate, and vascular endothelial growth factor (VEGF) in the vitreous of nondiabetic and diabetic patients. Methods: Undiluted vitreous samples were obtained from 22 patients with proliferative diabetic retinopathy (PDR) and 28 patients without diabetes who underwent pars plana vitrectomy. Simultaneous venous blood samples also were obtained. Amino acid concentrations were determined using sensitive high-performance liquid chromatography, and VEGF levels by quantitative enzyme-linked immunosorbent assay. Hemoglobin concentrations in the blood and vitreous were determined using spectrophotometry. Results: The level of GABA in the vitreous of patients with PDR, 29.4±7.8 μmol/L, was significantly higher than in controls (18.4±5.5 μmol/L) (P=.004). The vitreous concentration of glutamate was higher in patients with PDR (24.7±14.0 μmol/L) compared with controls (9.1±5.1 μmol/L) (P<.001). Vitreous VEGF level was significantly higher in patients with PDR (1759±1721 pg/mL) compared with controls (27±65 pg/mL) (P<.001). There were moderately strong correlations between GABA and VEGF levels (r=0.68) and glutamate and VEGF levels (r=0.43). Elevated GABA, glutamate, and VEGF levels also correlated strongly with the presence of PDR. Correcting for possible introduction of these molecules by vitreous hemorrhage did not significantly alter these findings. Conclusions: Levels of glutamate potentially toxic to retinal ganglion cells are found in the vitreous of patients with PDR. Elevated vitreous GABA may reflect amacrine cell dysfunction and underlie electroretinographic oscillatory potential abnormalities seen in diabetic retinopathy. The correlations of glutamate and GABA levels with an elevated VEGF level provide biochemical support for ischemia-induced neovascularization in patients with PDR. These findings present opportunities for novel therapeutic modalities in the treatment of PDR.
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Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J-2156 are mediated via peripheral and/or spinal receptors. Effect on mechanical hyperalgesia in the Complete Freund's Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156. In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioural studies. The minimal effective dose was 0.1mg/kg. Mechanosensitivity of peripheral afferents and spinal neurons was significantly reduced by J-2156. NS neurons were dose dependently inhibited by J-2156 while in WDR neurons only the highest concentration of 100µM had an effect. In sham controls, J-2156 had no effect on neuronal activity. We demonstrated that J-2156 dose-dependently reduces peripheral and spinal neuronal excitability in the CFA rat model without affecting physiological pain transmission. Given the high concentration of the compound required to inhibit spinal neurons, it is unlikely that the behavioral effect seen in CFA model is mediated centrally. Overall these data demonstrated that the analgesic effect of J-2156 is mediated mainly via peripheral SST4 receptors. Copyright © 2014. Published by Elsevier B.V.
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The aim of the study was to provide knowledge on somatostatin and its action on the body, particularly the pancreas-in physiological and pathological conditions. In order to get to know the properties of somatostatin, a hormone discovered over forty years ago, many studies that define its structure and the mechanisms by which it operates have been conducted. The properties of somatostatin receptors and the effect of somatostatin on the body-both a healthy one and in various disease stages-were determined. It was proven that the somatostatin had an inhibitive effect on the endo- and exocrine secretion of this organ, which allowed a hypothesis that it might play an important role in the pathophysiology of diabetes. In patients with severe acute pancreatitis, both somatostatin and octreotide appear to reduce the mortality rate significantly, without any effect on the incidence of complications. Nevertheless, somatostatin analogues may be the cause of acute pancreatitis. With regard to severe chronic pancreatitis, refractory to other forms of therapy, it was demonstrated that octreotide significantly alleviated pain in many patients. A similar risk of death, and generally a lower risk of complications were found in the group of somatostatin-treated patients with chronic pancreatitis when compared to those receiving placebo or untreated. The occurrence of hyperglycemia after the application of somatostatin analogues, and in particular after pasireotide, is disturbing. Somatostatin analogues have found application in the treatment of cancers. They may improve symptoms in patients with gastroenteropancreatic neuroendocrine tumors (NETs) and stabilize the tumor growth (PROMID study). However, the optimal hormone dose sizes and frequencies necessary to ensure a full therapeutic effect in selected diseases of the pancreas have not been completely determined. (C) 2014 Published by Elsevier Masson SAS.
Article
Background: Several studies have investigated the biochemical remission rate of presurgical somatostatin analogs treatment on acromegaly, but the remission criteria were diversed and the results were contradicting. Objective: Aim of this paper is to provide enhanced evidence for the effectiveness of preoperative SSA treatment to improve on surgical results of macroadenomas in acromegaly. Data source: Literature is cited from the PubMed, Embase and Cochrane Library, dating from December, 1985 to August, 2013. Study eligibility criteria: Eligibility criteria included patients with acromegaly caused by GH-secreting pituitary macroadenomas, patients pretreated with somatostatin analogs versus direct surgery and a stricter remission criteria defined as the GH nadir<1μg/l during an oral glucose tolerance test (OGTT) and the age- and sex- adjusted IGF-1 concentration was normal. Primary end points included Short term and long term postoperative biochemical remission. Study appraisal and synthesis methods: A total of 1421 publications were found by the electronic search. After full-text review, 8 were included in our study. 7 of them focus on the postoperative remission in short term; 3 of them focus on the outcomes in long term. For the analysis of the postoperative biochemical remission, a random effect model was used to account for differences. Results: The meta analysis shows that patients in the SSA pretreatment groups have had a more significantly cure rate than those in the direct surgery groups (RR=1.72, 95%CI: 1.14-2.60, P=0.009) with a short term follow-up. Subgroup analysis proves benefit from lanreotide pretreated groups (RR=2.27, 95%CI: 1.34-3.84, P=0.002) but not octreotide pretreated groups (RR=1.51, 95%CI: 0.82-2.75, P=0.183). No significant differences appeared between the two groups (RR=1.03, 95%CI: 0.86-1.24, P=0.751) with a long term follow-up. Limitations: 2 Retrospective trial was included and most of the trials included was designed as single-center study. Conclusions: Based on the analysis of this paper, the preoperative SSA treatment was beneficial in the group with short-term follow-up, while it was not advantageous in the group with long-term follow-up. For the limitations in this study, to drawn more solid conclusions, further large, randomized, multi-center, and long-term follow-up trials were required.
Article
Somatostatin (SST) is abundantly produced by the human retina, and the main source is the retinal pigment epithelium (RPE). SST exerts relevant functions in the retina (neuromodulation, angiostatic, and anti-permeability actions) by interacting with SST receptors (SSTR) that are also expressed in the retina. In the diabetic retina, a downregulation of SST production does exist. In this article, we give an overview of the mechanisms by which this deficit of SST participates in the main pathogenic mechanisms involved in diabetic retinopathy (DR): neurodegeneration, neovascularization, and vascular leakage. In view of the relevant SST functions in the retina and the reduction of SST production in the diabetic eye, SST replacement has been proposed as a new target for treatment of DR. This could be implemented by intravitreous injections of SST analogs or gene therapy, but this is an aggressive route for the early stages of DR. Since topical administration of SST has been effective in preventing retinal neurodegeneration in STZ-induced diabetic rats, it seems reasonable to test this new approach in humans. In this regard, the results of the ongoing clinical trial EUROCONDOR will provide useful information. In conclusion, SST is a natural neuroprotective and antiangiogenic factor synthesized by the retina which is downregulated in the diabetic eye and, therefore, its replacement seems a rational approach for treating DR. However, clinical trials will be needed to establish the exact position of targeting SST in the treatment of this disabling complication of diabetes.
Article
Somatostatin is an endogenous inhibitor of secretion and cell proliferation. These features render somatostatin a logical candidate for the management of neuroendocrine tumors that express somatostatin receptors. Synthetic somatostatin analogs (SSAs) have longer half-lives than somatostatin, but have similar activities, and are used for the treatment of these types of disorders. Interest has focused on novel multireceptor analogs with broader affinity to several of the five somatostatin receptors, thereby presenting putatively higher antitumor activities. Recent evidence indicates that SSAs cannot be considered mimics of native somatostatin in regulating signaling pathways downstream of receptors. Here we review this knowledge, discuss the concept of biased agonism, and highlight what considerations need to be taken into account for the optimal clinical use of SSAs.
Article
We described here the first tetradecapeptide somatostatin-analogue where the disulfide bridge has been replaced by a carbon-carbon double bond. This analogue was prepared using microwave assisted ring closing metathesis (RCM) using the 2nd generation Grubbs as catalyst. Under our optimized conditions the cyclization between allylGly 3 and 14 proceeded in moderate yield, excellent cyclic/linear ratio and very high Z-double bond selectivity. NMR studies also demonstrated that the conformational flexibility of this peptide is increased in comparison to that of the natural hormone. Remarkably, this alkene-bridged somatostatin analog is highly selective against somatostatin receptors 1 and 5, suggesting that conformational rigidity is not required for the efficient interaction of somatostatin analogues with these two receptors.
Article
Background: Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. Methods: We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. Findings: Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. Interpretation: These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. Funding: Polycystic Kidney Disease Foundation.
Article
This chapter discusses the neuropeptides in morphologically and functionally identified primary afferent neurons in dorsal root ganglia (DRG): substance P, CGRP, and somatostatin. Peptides can be released from the central and/or peripheral terminals of primary afferent neurons and can have important effects on the functioning of spinal neurons and/or peripheral tissues. For a full understanding of the functional significance of the peptides including the circumstances of their release, information about the types and properties of primary afferent neurons that secrete and release these peptides is essential. Their features including morphology, cell size, conduction velocity, and sensory receptor type can categorize DRG neurons. These categories and the way in which they relate to each other are first introduced in order to examine the relationship between them and peptide content. Many different neuropeptides are expressed in these neurons, including substance P (SP), neurokinin A, calcitonin generelated peptide (CGRP), somatostatin (SOM), vasoactive intestinal peptide (VIP), galanin, opioid peptides, and atrial natriuretic peptide. This chapter examines the properties of DRG neurons expressing substance P, CGRP, and SOM.
Article
Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Somatostatin receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and have a wide expression pattern in both normal tissues and solid tumors. Investigating the function of each SSTR in several tumor types has provided a wealth of information about the common but also distinct signaling cascades that suppress tumor cell proliferation, survival and angiogenesis. This provided the rationale for developing multireceptor-targeted somatostatin analogs and combination therapies with signaling-targeted agents such as inhibitors of the mammalian (or mechanistic) target of rapamycin (mTOR). The ability of SSTR to internalize and the development of rabiolabeled somatostatin analogs have improved the diagnosis and treatment of neuroendocrine tumors.
Article
• Measurements of cell capacitance were used to investigate the molecular mechanisms by which somatostatin inhibits Ca2+-induced exocytosis in single rat glucagon-secreting pancreatic α-cells. • Somatostatin decreased the exocytotic responses elicited by voltage-clamp depolarisations by 80 % in the presence of cyclic AMP-elevating agents such as isoprenaline and forskolin. Inhibition was time dependent and half-maximal within 22 s. • The inhibitory action of somatostatin was concentration dependent with an IC50 of 68 nmand prevented by pretreatment of the cells with pertussis toxin. The latter effect was mimicked by intracellular dialysis with specific antibodies to Gi1/2 and by antisense oligonucleotides against G proteins of the subtype Gi2. • Somatostatin lacked inhibitory action when applied in the absence of forskolin or in the presence of the L-type Ca2+ channel blocker nifedipine. The size of the -conotoxin-sensitive and forskolin-independent component of exocytosis was limited to 60 fF. By contrast, somatostatin abolished L-type Ca2+ channel-dependent exocytosis in α-cells exposed to forskolin. The magnitude of the latter pool amounted to 230 fF. • The inhibitory effect of somatostatin on exocytosis was mediated by activation of the serine/threonine protein phosphatase calcineurin and was prevented by pretreatment with cyclosporin A and deltamethrin or intracellularly applied calcineurin autoinhibitory peptide. Experiments using the stable ATP analogue AMP-PCP indicate that somatostatin acts by depriming of granules. • We propose that somatostatin receptors associate with L-type Ca2+ channels and couple to Gi2 proteins leading to a localised activation of calcineurin and depriming of secretory granules situated close to the L-type Ca2+ channels.