Search Results (39)

The gastrointestinal (GI) tract is under neural, endocrine and paracrine control. The release (basal and in the presence of either cholinergic and opioid antagonists) of Met-enkephalin, insulin-like growth factor 1 (IGF-1) and somatostatin (SRIF) was determined quantitatively in vitro using explants of the crop, proventriculus and duodenum from either day 0 or day 1 chicks. In addition, the effects of cholinergic and opioid antagonists on PENK gene expression were examined. Thus, the aim of this study was to determine the roles of cholinergic and opioid receptors in the GI tract in newly hatched chickens. Moreover, the effect of IGF-1 and Met-enkephalin on cell division in duodenal explants in vitro was determined. There was both the release of Met-enkephalin from, and PENK expression in, the explants of the crop, proventriculus and duodenum tissue. This is the first report of any neuropeptide(s) being synthesized in and/or released from the crop. In vitro release of Met-enkephalin, IGF-1 and SRIF from duodenal and proventriculus explants was influenced (p < 0.01) by either cholinergic or opioid antagonists; for instance, in the presence of atropine, decreases (p < 0.001) of 17.8% and 57.7% are seen, respectively, in Met-enkephalin release and PENK expression in crop explants from day 1 chicks. Moreover, in the presence of atropine, there were increases (p < 0.001) of 47.7% and 70.9% in IGF-1 release in proventriculus explants from, respectively, day 0 and day 1 chicks. Met-enkephalin and/or IGF-1 stimulated the cell division of duodenal explants in vitro. This is the first report of Met-enkephalin release and PENK expression in the avian crop and of the effects of cholinergic or opioid antagonists on these factors. It is also the first report of either cholinergic or opioid control of IGF-1 release in the periphery of any species. There were strong relationships (p < 0.05) between the release of Met-enkephalin and that of IGF-1 in the duodenum and between the release of SRIF and that of IGF-1 in the proventriculus. This is the first report of IGF-1 and Met-enkephalin stimulating (p < 0.001) the proliferation of duodenal cells and, together, exerting a synergist effect. It is concluded that the release of Met-enkephalin, IGF-1 and SRIF from foregut regions is under tonic cholinergic and opioid control. Full article

Acromegaly is a rare endocrine disorder caused by excessive growth hormone (GH) production, due, in the vast majority of cases, to the presence of a GH-secreting pituitary tumour. The chronic elevation of GH and the resulting high circulating levels of insulin-like growth factor-1 (IGF-1) cause the characteristic tissue overgrowth and a number of associated comorbidities, including several metabolic changes, such as glucose intolerance and overt diabetes mellitus (DM). Elevated GH concentrations directly attenuate insulin signalling and stimulate lipolysis, decreasing glucose uptake in peripheral tissues, thus leading to the development of impaired glucose tolerance and DM. Acromegaly treatment aims to normalize plasma GH and IGF-1 levels using surgery, medical treatment, or radiotherapy. The effect of the different medical therapies on glucose homeostasis varies. This literature review explores the impact of the currently available pharmacological therapies for acromegaly (first- and second-generation somatostatin receptor ligands, a GH receptor antagonist, and dopamine agonists) on glucose homeostasis. We also discuss the underlying biological mechanisms through which they impact glucose metabolism. Full article

In the current work, we aimed to evaluate the association of clinical data of Cushing’s disease (CD) patients with USP8 mutation status and to study USP8-related molecular mechanisms connected to the regulation of corticotropinoma growth and activity. 35 CD patients were enrolled; the sequencing of exon 14 in USP8 revealed variants in eighteen adenomas, two of which were described for the first time in CD. USP8 variants were more common in women (94% vs. 76%; p = 0.001), and microadenomas and tumor recurrence were prevalent in the USP8-mutant group (44% vs. 29%; p = 0.04 and 44% vs. 22%; p = 0.0015). Preoperative ACTH and serum cortisol did not differ in the USP8-WT and USP8-mutant patients. All USP8-mutant adenomas were SST5-positive, and 73% of them were double-positive (SST5+/SST2+). A total of 50% of USP8-WT adenomas were double-negative (SST5−/SST2−), and 40% of them were SST5-positive. Analysis of transcriptome was performed for nine USP8-mutant and six USP8-WT adenomas and revealed the that the bidirectional dysregulation of Wnt signaling, including both the agonist RSPO2 and antagonist SFRP1, in the USP8-mutant corticotropinomas was downregulated. These alterations may indicate the existence of regulatory connections between USP8 enzyme activity, Wnt signaling, EGFR signaling and somatostatin receptors’ trafficking, which can explain, at least in part, the clinical manifestations of CD in patients with corticotropinomas harboring USP8 variants. Full article

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. Full article

A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical allodynia in mice using von Frey filaments. When mice were intravenously injected with streptozotocin, mechanical allodynia appeared 3 days later. Antibodies of representative neuropeptides were intrathecally (i.t.) administered to allodynia-induced mice 7 days after the intravenous administration of streptozotocin, and allodynia was reduced by anti-cholecystokinin octapeptide antibodies, anti-nociceptin/orphanin FQ antibodies, and anti-hemokinin-1 antibodies. In contrast, i.t.-administered anti-substance P antibodies, anti-somatostatin antibodies, and anti-angiotensin II antibodies did not affect streptozotocin-induced diabetic allodynia mice. Mechanical allodynia was attenuated by the i.t. administration of CCK-B receptor antagonists and ORL-1 receptor antagonists. The mRNA level of CCK-B receptors in streptozotocin-induced diabetic allodynia mice increased in the spinal cord, but not in the dorsal root ganglion. These results indicate that diabetic allodynia is caused by cholecystokinin octapeptide, nociceptin/orphanin FQ, and hemokinin-1 released from primary afferent neurons in the spinal cord that transmit pain to the brain via the spinal dorsal horn. Full article

The present report describes the history of a 58-year-old woman with a rapidly progressing neuroendocrine pancreatic tumor (initially G2) presenting with extensive liver, bone, and lymph node metastases. Previous treatments included chemotherapy, hemithyroidectomy for right lobe metastasis, Peptide Receptor Radionuclide Therapy (PRRT) with [¹⁷⁷Lu]Lu-DOTATATE, Lanreotide, Everolimus, and liver embolization. Due to severe disease progression, after a liver biopsy revealing tumor grade G3, PRRT with the somatostatin receptor antagonist LM3 was initiated. [⁶⁸Ga]GaDOTA-LM3 PET/CT showed intense tracer uptake in the liver, pancreatic tumor, lymph nodes, and bone metastases. Three TANDEM-PRRT cycles using [¹⁷⁷Lu]LuDOTA-LM3 and [²²⁵Ac]AcDOTA-LM3, administered concurrently, resulted in significant improvement, notably in liver metastases, hepatomegaly reduction, the complete regression of bone and lymph node metastases, and primary tumor improvement. Partial remission was confirmed by positron emission tomography/computed tomography, chest–abdomen–pelvis contrast-enhanced computed tomography, and magnetic resonance of the abdomen, with marked clinical improvement in pain, energy levels, and quality of life, enabling full resumption of physical activity. Full article

Somatostatin shows an anti-lipolytic effect in both chickens and ducks. However, its molecular mediator remains to be identified. Here, we report that somatostatin type 2 receptor (SSTR2) is expressed at a high level in chicken adipose tissue. In cultured chicken adipose tissue, the inhibition of glucagon-stimulated lipolysis by somatostatin was blocked by an SSTR2 antagonist (CYN-154086), supporting an SSTR2-mediated anti-lipolytic effect. Furthermore, a significant pro-proliferative effect was detected in SST28-treated immortalized chicken preadipocytes (ICP-1), and this cell proliferative effect may be mediated through the MAPK/ERK signaling pathway activated by SSTR2. In summary, our results demonstrate that SSTR2 may regulate adipose tissue development by affecting the number and volume of adipocytes in chickens. Full article

The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high specificity, permeability, target engagement, and a tolerable safety profile. They exhibit selective binding with cell surface receptors and proteins, functioning as agonists or antagonists. They also serve as imaging agents for diagnostic applications or can serve a dual-purpose as both diagnostic and therapeutic (theragnostic) agents. Therefore, they have been exploited in various forms, including linkers, peptide conjugates, and payloads. In this review, the FDA-approved prostate-specific membrane antigen (PSMA) peptide antagonists, peptide receptor radionuclide therapy (PRRT), somatostatin analogs, antibody–drug conjugates (ADCs), gonadotropin-releasing hormone (GnRH) analogs, and other peptide-based anticancer drugs are analyzed in terms of their chemical structures and properties, therapeutic targets and mechanisms of action, development journey, administration routes, and side effects. Full article

Neuroendocrine tumors (NETs) are slow-growing tumors that express high levels of somatostatin receptors (SSTRs). Recent studies have shown the superiority of radiolabeled SSTR antagonists in theranostics compared to agonists. In this prospective study, we compared the diagnostic efficacy between [⁶⁸Ga]Ga-DOTANOC and [⁶⁸Ga]Ga-DATA^5m-LM4 in the detection of primary and metastatic lesions in patients with well differentiated gastroenteropancreatic (GEP) NETs. Histologically proven GEP-NET patients underwent [⁶⁸Ga]Ga-DOTANOC & [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT scans, which were analyzed. The qualitative analysis involved the visual judgment of radiotracer uptake validated by the morphological findings using CT, which was considered as the reference standard. Quantitative comparisons were presented as the standardized uptake value (SUV) corrected for lean body mass: SULpeak, SULavg, and tumor-to-background ratios (TBR). In total, 490 lesions were confirmed via diagnostic CT. The lesion-based sensitivity of [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT was 94.28% (462/490) and 83.46% (409/490) for [⁶⁸Ga]Ga-DOTANOC PET/CT (p < 0.0001). [⁶⁸Ga]Ga-DATA^5m-LM4 had statistical significance over [⁶⁸Ga]Ga-DOTANOC in liver metastases [100% vs. 89.4%; p < 0.0001 (292 vs. 253 {283 lesions on CT})] and bone metastases [100% vs. 82.9%; p = 0.005 (45 vs. 34 {41 lesions on CT})]. Statistical significance was also noted for the TBR SULpeak of the primary and liver lesions. [⁶⁸Ga]Ga-DATA^5m-LM4 showed better sensitivity and a higher target-to-background ratio than [⁶⁸Ga]Ga-DOTANOC PET/CT. [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT can be used to quantify the extent of skeletal and liver metastases for better planning of SSTR agonist- or antagonist-based therapy. Full article

Recent investigations have highlighted the potential utility of the selective antagonist of the NMDA receptor GluN2B subunit for addressing major depressive disorders. Our previous study showed that the systemic administration of the antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, affected liver cytochrome P450 expression and activity. To discern between the central and peripheral mechanisms of enzyme regulation, our current study aimed to explore whether the intracerebral administration of CP-101,606 could impact cytochrome P450. The injection of CP-101,606 to brain lateral ventricles (6, 15, or 30 µg/brain) exerted dose-dependent effects on liver cytochrome P450 enzymes and hypothalamic or pituitary hormones. The lowest dose led to an increase in the activity, protein, and mRNA level of CYP2C11 compared to the control. The activities of CYP2A, CYP2B, CYP2C11, CYP2C6, CYP2D, and protein levels of CYP2B, CYP2C11 were enhanced compared to the highest dose. Moreover, CP-101,606 increased the CYP1A protein level coupled with elevated CYP1A1 and CYP1A2 mRNA levels, but not activity. The antagonist decreased the pituitary somatostatin level and increased the serum growth hormone concentration after the lowest dose, while independently decreasing the serum corticosterone concentration of the dose. The findings presented here unveil a novel physiological regulatory mechanism whereby the brain glutamatergic system, via the NMDA receptor, influences liver cytochrome P450. This regulatory process appears to involve the endocrine system. These results may have practical applications in predicting alterations in cytochrome P450 activity and endogenous metabolism, and potential metabolic drug–drug interactions elicited by drugs that cross the blood–brain barrier and affect NMDA receptors. Full article

Somatostatin receptor (SSTR) agonist-based Positron Emission Tomography-Computed Tomography (PET-CT) imaging is nowadays the mainstay for the assessment and diagnostic imaging of neuroendocrine neoplasms (NEN), especially in well-differentiated neuroendocrine tumors (NET) (World Health Organization (WHO) grade I and II). Major clinical indications for SSTR imaging are primary staging and metastatic workup, especially (a) before surgery, (b) detection of unknown primary in metastatic NET, (c) patient selection for theranostics and appropriate therapy, especially peptide receptor radionuclide therapy (PRRT), while less major indications include treatment response evaluation on and disease prognostication. Dual tracer PET-CT imaging using SSTR targeted PET tracers, viz. [⁶⁸Ga]Ga-DOTA-Tyr3-Octreotate (DOTA-TATE) and [⁶⁸Ga]Ga-DOTA-NaI3-Octreotide (DOTA-NOC), and fluorodeoxyglucose (FDG), have recently gained widespread acceptance for better assessment of whole-body tumor biology compared to single-site histopathology, in terms of being non-invasive and the ability to assess inter- and intra-tumoral heterogeneity on a global scale. FDG uptake has been identified as independent adverse risk factor in various studies. Recently, somatostatin receptor antagonists have been shown to be more sensitive and specific in detecting the disease. The aim of this review article is to summarize the clinical importance of SSTR-based imaging in the clinical management of neuroendocrine and related tumors. Full article

Neuroendocrine neoplasms (NENs) are tumors originating from neuroendocrine cells distributed throughout the human body. With an increasing incidence over the past few decades, they represent a highly heterogeneous group of neoplasms, mostly expressing somatostatin receptors (SSTRs) on their cell surface. Peptide receptor radionuclide therapy (PRRT) has emerged as a crucial strategy for treating advanced, unresectable neuroendocrine tumors by administering radiolabeled somatostatin analogs intravenously to target SSTRs. This article will focus on the multidisciplinary theranostic approach, treatment effectiveness (such as response rates and symptom relief), patient outcomes, and toxicity profile of PRRT for NEN patients. We will review the most significant studies, such as the phase III NETTER-1 trial, and discuss promising new radiopharmaceuticals, including alpha-emitting radionuclide-labeled somatostatin analogs and SSTR antagonists. Full article

The clinical success of radiolabeled somatostatin analogs in the diagnosis and therapy—“theranostics”—of tumors expressing the somatostatin subtype 2 receptor (SST₂R) has paved the way for the development of a broader panel of peptide radioligands targeting different human tumors. This approach relies on the overexpression of other receptor-targets in different cancer types. In recent years, a shift in paradigm from internalizing agonists to antagonists has occurred. Thus, SST₂R-antagonist radioligands were first shown to accumulate more efficiently in tumor lesions and clear faster from the background in animal models and patients. The switch to receptor antagonists was soon adopted in the field of radiolabeled bombesin (BBN). Unlike the stable cyclic octapeptides used in the case of somatostatin, BBN-like peptides are linear, fast to biodegradable and elicit adverse effects in the body. Thus, the advent of BBN-like antagonists provided an elegant way to obtain effective and safe radiotheranostics. Likewise, the pursuit of gastrin and exendin antagonist-based radioligands is advancing with exciting new outcomes on the horizon. In the present review, we discuss these developments with a focus on clinical results, commenting on challenges and opportunities for personalized treatment of cancer patients by means of state-of-the-art antagonist-based radiopharmaceuticals. Full article

Broad availability and cost-effectiveness of ⁹⁹Mo/^99mTc generators worldwide support the use, and thus the development, of novel ^99mTc-labelled radiopharmaceuticals. In recent years, preclinical and clinical developments for neuroendocrine neoplasms patient management focused on somatostatin receptor subtype 2 (SST₂) antagonists, mainly due to their superiority in SST₂-tumour targeting and improved diagnostic sensitivity over agonists. The goal of this work was to provide a reliable method for facile preparation of a ^99mTc-labelled SST₂ antagonist, [^99mTc]Tc-TECANT-1, in a hospital radiopharmacy setting, suitable for a multi-centre clinical trial. To ensure successful and reproducible on-site preparation of the radiopharmaceutical for human use shortly before administration, a freeze-dried three-vial kit was developed. The final composition of the kit was established based on the radiolabelling results obtained during the optimisation process, in which variables such as precursor content, pH and buffer, as well as kit formulations, were tested. Finally, the prepared GMP-grade batches met all predefined specification parameters together with long-term kit stability and stability of the product [^99mTc]Tc-TECANT-1. Furthermore, the selected precursor content complies with micro-dosing, based on an extended single-dose toxicity study, where histopathology NOEL was established at 0.5 mg/kg BW, being more than 1000 times higher than the planned human dose of 20 µg. In conclusion, [^99mTc]Tc-TECANT-1 is suitable to be advanced into a first-in-human clinical trial. Full article

Aiming to expand the application of the SST₂R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH₂) beyond [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT (DATA^5m, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA⁵-LM4 (AAZTA⁵, 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine), allowing for the convenient coordination of trivalent radiometals of clinical interest, such as In-111 (for SPECT/CT) or Lu-177 (for radionuclide therapy). After labeling, the preclinical profiles of [¹¹¹In]In-AAZTA⁵-LM4 and [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 were compared in HEK293-SST₂R cells and double HEK293-SST₂R/wtHEK293 tumor-bearing mice using [¹¹¹In]In-DOTA-LM3 and [¹⁷⁷Lu]Lu-DOTA-LM3 as references. The biodistribution of [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 was additionally studied for the first time in a NET patient. Both [¹¹¹In]In-AAZTA⁵-LM4 and [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 displayed high and selective targeting of the HEK293-SST₂R tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 in the patient according to SPECT/CT results in a monitoring time span of 4–72 h pi. In view of the above, we may conclude that [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 shows promise as a therapeutic radiopharmaceutical candidate for SST₂R-expressing human NETs, based on previous [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [¹¹¹In]In-AAZTA⁵-LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available. Full article