Sst2 Receptor Research Articles

Construction of Somatostatin-Based Multiphase "Core-Shell" Coacervates as Photodynamic Biomimetic Organelles.

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 430kDa), providing promising theranostic applications.

Distribution and calcium signaling function of somatostatin receptor subtypes in rat pituitary

The somatostatin (SST) receptor family controls pituitary hormone secretion, but the distribution and specific roles of these receptors on the excitability and voltage-gated calcium signaling of hormone producing pituitary cells have not been fully characterized. Here we show that the rat pituitary gland expressed Sstr1, Sstr2, Sstr3, and Sstr5 receptor genes in a cell type-specific manner: Sstr1 and Sstr2 in thyrotrophs, Sstr3 in gonadotrophs and lactotrophs, Sstr2, Sstr3, and Sstr5 in somatotrophs, and none in corticotrophs and melanotrophs. Most gonadotrophs and thyrotrophs spontaneously fired high-amplitude single action potentials, which were silenced by SST without affecting intracellular calcium concentrations. In contrast, lactotrophs and somatotrophs spontaneously fired low-amplitude plateau-bursting action potentials in conjunction with calcium transients, both of which were silenced by SST. Moreover, SST inhibited GPCR-induced voltage-gated calcium signaling and hormone secretion in all cell types expressing SST receptors, but the inhibition was more pronounced in somatotrophs. The pattern of inhibition of electrical activity and calcium signaling was consistent with both direct and indirect inhibition of voltage-gated calcium channels, the latter being driven by cell type-specific hyperpolarization. These results indicate that the action of SST in somatotrophs is enhanced by the expression of several types of SST receptors and their slow desensitization, that SST may play a role in the electrical resynchronization of gonadotrophs, thyrotrophs, and lactotrophs, and that the lack of SST receptors in corticotrophs and melanotrophs keeps them excitable and ready to responses to stress.

8404 Use of the Acromegaly Symptom Diary (ASD) in a Phase 3, Placebo-Controlled Study of Once-Daily, Oral Paltusotine in Patients With Acromegaly Switched From Injected Octreotide or Lanreotide

Abstract Disclosure: M.R. Gadelha: Consulting Fee; Self; Crinetics, Ipsen, Novo Nordisk, and Recordati. Research Investigator; Self; Crinetics and Recordati. Speaker; Self; Ipsen, Novo Nordisk, and Recordati. A. Casagrande: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. C.J. Strasburger: Consulting Fee; Self; Amolyt Pharma, Consilient Health, Novo Nordisk, Recordati, and Sandoz-Hexal. Research Investigator; Self; Crinetics. M. Bidlingmaier: Consulting Fee; Self; Crinetics, Ionis, Novo Nordisk, Pfizer, Roche, and Sandoz. Research Investigator; Self; Amolyt, Camurus, Chiasma, Crinetics, IDS, Ionis, Lumos, and OPKO. Speaker; Self; Euroimmun, Novo Nordisk, and Pfizer. P.J. Snyder: Research Investigator; Self; Crinetics. M.A. Guitelman: Consulting Fee; Self; Recordati, Sanofi Aventis, and Varifarma. Research Investigator; Self; Crinetics. Speaker; Self; Recordati, Sanofi Aventis, and Varifarma. C.L. Boguszewski: Consulting Fee; Self; Ipsen, Novo Nordisk, and Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Novo Nordisk, and Recordati. M. Buchfelder: Research Investigator; Self; Crinetics. I. Shimon: Consulting Fee; Self; Medison and Pfizer. Research Investigator; Self; Crinetics and Debiopharm. Speaker; Self; Medison and Pfizer. G. Raverot: Consulting Fee; Self; Amolyt, Crinetics, Ipsen, Novo Nordisk, Pfizer, and Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Pfizer, and Recordati. M. Toth: Consulting Fee; Self; Ipsen, Lilly, Novartis, and Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Lilly, Novartis, and Recordati. E. Mezosi: Research Investigator; Self; Crinetics. M. Doknic: Advisory Board Member; Self; Pfizer in CEE. Research Investigator; Self; Crinetics. X. Fan: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. D. Clemmons: Consulting Fee; Self; Crinetics. M. Keeley: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. R. Struthers: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. A. Krasner: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. B.M. Biller: Consulting Fee; Self; Amryt, Camurus, Crinetics, and Recordati. Research Investigator; Self; Crinetics and Ionis. Paltusotine is a once-daily, selective, non-peptide, SST2 receptor agonist in development as an oral treatment for patients with acromegaly or carcinoid syndrome. The Acromegaly Symptom Diary (ASD) is a novel patient-reported outcome tool developed in accordance with US FDA guidance to assess disease-related symptom burden. The ASD consists of 7 core items (headache, joint pain, sweating, fatigue, leg weakness, swelling, numbness/tingling, score range: 0-70; higher scores indicate greater symptom burden) plus 2 additional items (sleep difficulty, memory difficulty) and is completed daily. We previously reported the topline results of PATHFNDR-1 (NCT04837040), a phase 3 trial evaluating the efficacy and safety of paltusotine in adults with acromegaly who were previously controlled (IGF-I ≤1.0 ×ULN) on stable (≥12 weeks) injected octreotide or lanreotide. Patients were randomly allocated to once-daily paltusotine 40 mg or placebo for 36 weeks, with uptitration to 60 mg/day permitted through week 24. IGF-I and GH levels (IDS-iSYS) and pituitary tumor volume (MRI) were measured centrally. Fifty-eight patients (paltusotine, n=30; placebo, n=28) were enrolled: mean (±SD) age 54.9±13.7 years; 55.2% female; prior treatment octreotide LAR (n=34) or lanreotide depot (n=24). The primary endpoint (proportion of patients maintaining IGF-I ≤1.0 ×ULN [mean of weeks 34 and 36]) was met by significantly more patients on paltusotine (83.3%) versus placebo (3.6%; odds ratio: 126.53; 95% CI: 13.73, >999.99; P<0.0001). All secondary endpoints were met: mean (±SE) change in IGF-I of 0.04±0.09 ×ULN versus 0.83±0.1 ×ULN (P<0.0001); and GH maintained at <1.0 ng/mL in 87.0% versus 27.8% of patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P<0.001). The most common adverse events (AEs) were typical of the somatostatin receptor ligand (SRL) class or acromegaly symptoms. There were no severe or serious AEs in the paltusotine group. One patient in the placebo group discontinued study participation (patient decision). There were no clinically significant changes in pituitary tumor volume. The mean completion rate of the daily ASD questionnaire was 79.1%. At the end of randomized treatment, the ASD total score was significantly increased from baseline (indicating worsening) in the placebo group compared with the paltusotine group, meeting the secondary endpoint (-0.6±1.5 versus 4.6±1.6; P=0.02). For individual ASD symptoms, mean scores were consistently indicative of improvement with paltusotine compared to placebo; the between-group difference was statistically significant for joint pain (P<0.05), numbness/tingling (P<0.01), and the “most bothersome” symptom (P<0.05). In conclusion, once-daily oral paltusotine maintained symptom control in concert with biochemical values in well-controlled patients switched from injected SRLs and was well tolerated. Support: Crinetics Pharmaceuticals Presentation: 6/3/2024

12531 Long-term Safety And Efficacy Of Once-daily Oral Paltusotine In The Treatment Of Patients With Acromegaly: Update From Acrobat Advance

Abstract Disclosure: M. Gadelha: Consulting Fee; Self; Crinetics, Ipsen, Novo Nordisk, and Recordati. Grant Recipient; Self; Crinetics and Recordati. Speaker; Self; Ipsen, Novo Nordisk, and Recordati. H.S. Randeva: None. M.B. Gordon: Consulting Fee; Self; Crinetics Pharmaceuticals, HRA Pharma, Novo Nordisk, and Recordati Rare Diseases. Grant Recipient; Self; Ascendis, Camurus, Chiasma, Corcept, Crinetics, Ipsen, Novartis, Novo Nordisk, Opko, Pfizer, and Strongbridge. M. Doknic: Research Investigator; Self; Crinetics Pharmaceuticals. Speaker; Self; Merck, Novartis, Novo Nordisk, Pfizer, and Sandoz. E. Mezosi: Research Investigator; Self; Crinetics Pharmaceuticals. M. Toth: Consulting Fee; Self; Pfizer, Ipsen, Novo Nordisk, and Recordati. Research Investigator; Self; Crinetics Pharmaceuticals. Other; Self; Pfizer, Ipsen, Novo Nordisk, and Recordati. C.L. Boguszewski: Advisory Board Member; Self; Novo Nordisk and Recordati. Consulting Fee; Self; Ipsen, Novo Nordisk, and Recordati. Other; Self; Ipsen, Novo Nordisk, and Recordati. C. Davidson: Employee; Self; Crinetics Pharmaceuticals. C.T. Ferrara-Cook: Employee; Self; Crinetics Pharmaceuticals. A. Casagrande: Employee; Self; Crinetics Pharmaceuticals. A. Krasner: Employee; Self; Crinetics Pharmaceuticals. Paltusotine is a non-peptide, highly selective SST2 receptor agonist in development as a once-daily, oral treatment for patients with acromegaly or carcinoid syndrome. ACROBAT Advance is an ongoing, 6-year, single-arm, open-label extension study of paltusotine in the treatment of patients with acromegaly. Interim results as the first enrolled patients approach 4 years of treatment are reported here. Enrolled patients had completed either the ACROBAT Edge or Evolve phase 2 parent studies. In Edge, at enrollment all patients were candidates for combination drug therapy: either sub-optimally controlled on an injected SRL (octreotide or lanreotide) alone or in combination with cabergoline, or required combination therapy or pasireotide to achieve normal IGF-I levels. In Evolve, enrolled patients had normal IGF-I levels on injected SRL monotherapy. When the Advance study was initiated, paltusotine was formulated as a capsule (dose range, 10-40 mg); all patients were switched to the tablet formulation (dose range, 20-60 mg) during the third year of the study. As of this analysis, all patients had at least 2 assessments after switching to tablet formulation. Adjunctive treatment with cabergoline or pegvisomant was allowed in patients who did not attain normal IGF-I levels on the maximum dose of paltusotine. Forty-three patients were enrolled in Advance (Edge, n=32; Evolve, n=11; 88% of eligible patients): at baseline, mean (±SD) age 53.0±11.6 years, 56% female, 86% previous pituitary surgery, and none had prior radiotherapy. IGF-I control in Edge and Evolve subsets remained stable at parent study baseline values. For all patients pooled, median (IQR) IGF-I levels were 1.15× ULN (0.84, 1.46; n=43) at parent study baseline; in Advance, 1.14× ULN (0.89, 1.29; n=40), 1.06× ULN (0.87, 1.24; n=35), and 1.08× ULN (0.87, 1.57; n=10) at months 12, 24, and 42, respectively. As expected, patients receiving adjunctive medication during Advance largely derived from the Edge study. Acromegaly symptoms, as measured using the patient-reported Acromegaly Symptom Diary (score range, 0-70; higher values indicate greater symptom burden), were stably controlled: median (IQR) score of 8.6 (3.6, 20.1; n=21) at parent study baseline; in Advance, 10.5 (5.0, 18.5; n=40), 10.0 (5.0, 25.0; n=34), and 13.5 (6.0, 22.0; n=10) at months 12, 24, and 42, respectively. The most common AEs reported through month 42 were arthralgia (37.2%), headache (30.2%), and fatigue (23.3%). One serious drug-related AE (cholelithiasis) was reported. Of the 8 patients who discontinued the study, 2 were due to AEs (mild or moderate). Glycemic control, as measured by HbA1c, was stable during paltusotine treatment. In conclusion, long-term results show that once-daily oral paltusotine treatment was well tolerated, with stable biochemical and symptom control relative to that observed with injected SRLs. Support: Crinetics Pharmaceuticals. Presentation: 6/3/2024

Interleukins IL33/ST2 and IL1-β in Intrauterine Growth Restriction and Seropositivity of Anti-Toxoplasma gondii Antibodies.

Toxoplasma gondii (T. gondii) is the causal agent of toxoplasmosis. It may produce severe damage in immunocompromised individuals, as well as congenital infection and intrauterine growth restriction (IUGR). Previous reports have associated interleukin IL-33 with miscarriage, fetal damage, and premature delivery due to infections with various microorganisms. However, IL-33 has not been associated with congenital toxoplasmosis. The sST2 receptor has been reported in patients who have had recurrent miscarriages. On the other hand, IL-1β was not found in acute Toxoplasma infection. Our aim was to analyze the associations between the serum levels of IL-33 and IL-1β in IUGR and toxoplasmosis during pregnancy. Eighty-four serum samples from pregnant women who had undergone 26 weeks of gestation were grouped as follows: with anti-Toxoplasma antibodies, without anti-Toxoplasma antibodies, IUGR, and the control group. IgG and IgM anti-T. gondii antibodies, as well as IL-33, ST2, and IL-1β, were determined using an ELISA assay. Statistical analyses were performed using the Pearson and Chi-square correlation coefficients, as well as the risk factors and Odds Ratios (ORs), with a confidence interval of 95% (CI 95). The results showed that 15/84 (17.8%) of cases were positive for IgG anti-Toxoplasma antibodies and 2/84 (2.38%) of cases were positive for IgM. A statistically significant difference was found between IUGR and IL-33 (p < 0.001), as well as between ST2 and IUGR (p < 0.001). In conclusion, IUGR was significantly associated with IL-33 and ST2 positivity based on the overall IUGR grade. No significant association was found between IUGR and the presence of anti-Toxoplasma antibodies. There was no association between IL-1β and IUGR. More research is needed to strengthen the utility of IL-33 and ST2 as biomarkers of IUGR.

Inhibition of somatostatin enhances the long-term metabolic outcomes of sleeve gastrectomy in mice

ObjectiveBariatric surgery is an effective treatment to obesity, leading to weight loss and improvement in glycemia, that is characterized by hypersecretion of gastrointestinal hormones. However, weight regain and relapse of hyperglycemia are not uncommon. We set to identify mechanisms that can enhance gastrointestinal hormonal secretion following surgery to sustain weight loss. MethodsWe investigated the effect of somatostatin (Sst) inhibition on the outcomes of bariatric surgery using a mouse model of sleeve gastrectomy (SG). ResultsSst knockout (sst-ko) mice fed with a calorie-rich diet gained weight normally and had a mild favorable metabolic phenotype compared to heterozygous sibling controls, including elevated plasma levels of GLP-1. Mathematical modeling of the feedback inhibition between Sst and GLP-1 showed that Sst exerts its maximal effect on GLP-1 under conditions of high hormonal stimulation, such as following SG. Obese sst-ko mice that underwent SG had higher levels of GLP-1 compared with heterozygous SG-operated controls. The SG-sst-ko mice regained less weight than controls and maintained lower glycemia months after surgery. Obese wild-type mice that underwent SG and were treated daily with a Sst receptor inhibitor for two months had higher GLP-1 levels, regained less weight, and improved metabolic profile compared to saline-treated SG-operated controls, and compared to inhibitor or saline-treated sham-operated obese mice. ConclusionsOur results suggest that inhibition of Sst signaling enhances the long-term favorable metabolic outcomes of bariatric surgery.

Activation of the SST-SSTR5 signaling pathway enhances corneal wound healing in diabetic mice

Corneal wound healing in diabetic patients is usually delayed and accompanied by excessive inflammation. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we found that somatostatin (SST), an immunosuppressive peptide produced by corneal nerve fibers, was significantly reduced in streptozotocin-induced diabetic mice. In addition, we discovered that topical administration of exogenous SST significantly improved re-epithelialization and nerve regeneration following diabetic corneal epithelial abrasion. Further analysis showed that topical SST significantly reduced the expression of injury inflammation-related genes, inhibited neutrophil infiltration, and shifted macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 in diabetic corneas' healing. Moreover, the application of L-817,818, an agonist of the SST receptor type 5 subtype, significantly reduced the inflammatory response following epithelial injury and markedly improved the process of re-epithelialization and nerve regeneration in mice. Taken together, these data suggest that activation of the SST-SST receptor type 5 pathway significantly ameliorates diabetes-induced abnormalities in corneal wound repair in mice. Targeting this pathway may provide a novel strategy to restore impaired corneal wound closure and nerve regeneration in diabetic patients.

Antagonists of somatostatin and NK1 receptors synergistically induce catalepsy in middle-aged Wistar rats

Objectives: A decrease in levels of somatostatin (SST) and substance P (SP) is observed in the parkinsonian brain. Previously, brain SST deficit in rats simulated by i.c.v. injections of SST receptor antagonist, cyclosomatostatin (cSST), was found to promote the development of catalepsy. The role of SP, a natural ligand of neurokinin-1 (NK1) receptors, in the development of catalepsy is currently unclear. Here, we evaluated whether simultaneous blockade of central somatostatin and NK1 receptors is able to initiate catalepsy and affect dopamine turnover in the nigrostriatal area of the brain.\nMaterials and methods: The experiments were carried out on middle-aged Wistar rats. The blockade of somatostatin and NK1 receptors was simulated by intracerebroventricular injections of cSST and substance L-733,060, respectively. Catalepsy was evaluated by the bar test. The levels of dopamine and its metabolites in the dorsal striatum and substantia nigra were measured by using HPLC.\nResults: No catalepsy was induced by cSST at 1.0 µg and L-733,060 at 10.0 ng injected separately. However, co-administration of these agents initiated catalepsy and influenced dopamine metabolism in the nigrostriatal area. Cataleptogenic action of the combination was reversed by SP. \nConclusion: The present findings testify that there is some sort of synergy between cSST and L-733,060 in initiation of catalepsy. In the light of these data, PD-related simultaneous brain deficit in SST and SP might be relevant for pathogenesis of extrapyramidal dysfunctions. Given the presented results, the processes mediated by central SST and NK1 receptors may be potential therapeutic targets for parkinsonism.

High Soluble Suppression of Tumorigenicity-2 (sST2) is A Risk Factor for Rehospitalization and Mortality in Chronic Heart Failure Patients with Reduced Ejection Fraction

Background: Chronic heart failure (CHF) impairs the heart’s pumping ability due to structural or functional abnormalities. It is a leading cause of death worldwide, with mortality rates of 10-50% based on severity. Risk stratification methods help predict CHF prognosis. ST2, an interleukin-1 receptor, is valuable for forecasting rehospitalization and cardiovascular events. In progressive heart failure, increased sST2 receptor expression inhibits the protective effects of IL-33, worsening the condition. Methods: Chronic heart failure patients with LVEF &lt;40% were studied in a cohort design. After sST2 blood samples were taken, patients were followed for 1 year and 10 months to monitor Major Cardiovascular Events (MACEs) like rehospitalization and mortality. Baseline characteristics included demographic, clinical, comorbidity, laboratory, and echocardiographic data. The best sST2 cut-off was determined using ROC curves. Kaplan-Meier and Cox Regression analyses assessed outcomes using SPSS 26.0. Results: All 80 samples completed the study with no drop-outs. The optimal sST2 cut-off for predicting Major Cardiovascular Events (MACEs) was &gt;19.38 ng/mL (AUC 0.668, CI 95% 0.542-0.794; p=0.023), with 66.7% sensitivity and 66.1% specificity. Survival analysis showed patients with sST2 ≥19.4 ng/mL had lower long-term survival (58.8% vs. 84.8%; p=0.007). Adjusted for age and comorbidities, high sST2 levels significantly predicted MACEs, with a 3.581 times higher risk (95% CI 1.343-9.551; p=0.011) of rehospitalization and mortality. Conclusion: High sST2 levels (≥19.4 ng/mL) were associated as a risk factor of rehospitalization and mortality in chronic heart failure patients with reduced ejection fraction.

FRI296 Somatostatin Receptor 5 Staining In Prolactinomas

Abstract Disclosure: S. Mehta: None. R.A. Feelders: Advisory Board Member; Self; Corcept. Research Investigator; Self; Recordati, Strongbridge. L.J. Hofland: None. C. Campana: None. S.J. Neggers: None. X. Li: None. K. Wright: None. S. Skwiersky: None. J.D. Goldberg: None. H. Kim: None. D. Zagzag: None. N. Agrawal: Research Investigator; Self; Chiasma, Ascendis, Recordati. The vast majority of prolactinomas are treated with dopamine agonists (DA) with excellent response, however DA resistance occurs in about 15% of prolactinomas. Surgery and radiotherapy are alternative treatments for these patients, but are not always successful. Somatostatin (SST) receptors have been studied with growing interest in prolactinomas. There are five SST receptor subtypes and mRNA expression analysis of prolactinomas has shown high expression of SST5 in comparison to SST1 and 2. The somatostatin analog, Pasireotide, which has a 40-fold greater binding affinity to SST5 compared to SST2 receptors, shows promising results in individual case reports of DA resistant and aggressive prolactinomas. This two-center retrospective cohort study investigated dopamine 2 (D2R), SST2a and SST5 receptor expression in surgical specimens of DA resistant prolactinomas. The study included consecutive surgical cases of adult patients with a diagnosis of DA-resistant prolactinoma at NYU Langone Health and Erasmus MC. DA resistance was defined as a failure to achieve normal prolactin (PRL) levels on maximally tolerated dopamine agonist doses and/or a failure to achieve 50% reduction in tumor size on coronal view. Co-secreting pituitary tumors were excluded to keep the somatostatin receptor analysis specific to prolactinomas. Receptor expression was scored on the basis of the well validated immunoreactivity score (IRS). This was done independently by two investigators by calculating the product of the percentage of positive cells and the intensity of the staining. 34 patients with average age 41.6 years and 19 (56%) males and 15 females are included in this analysis. Results: means (SDs) of pre-op PRL, pre-op image tumor size transverse and post-op PRL follow-up are respectively 1796 (4772) ng/mL in 33 patients; 2.23(1.61) cm in 15 patients; 108 (117) ng/mL in 17 patients. 31/33(94%) patients used DA preoperatively at various doses; 25/34 (74%) were DA resistant. Other indications include DA intolerance, apoplexy, cerebrospinal fluid leak. D2R was expressed in 94.1% (95% CI: 80.8%, 99.2%) of the cases. SST5 is expressed 61.8% (95% CI: 43.6%, 77.9%) of the prolactinomas and at a high level in a subset of SST5 positive cases. Only 17.6% (95% CI: 6.7%, 34.5%) of the prolactinomas express SST2a. SST5 expression has previously been studied in prolactinomas with variable expression. We show in this retrospective two center study a higher expression of SST5 receptor staining than previously demonstrated analyses and suggest SST5 staining to consider Pasireotide use in a subset of these patients. Larger prospective studies are needed to validate these findings. Presentation: Friday, June 16, 2023

Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior

We sought to characterize the unique role of somatostatin (SST) in the prelimbic (PL) cortex in mice. We performed slice electrophysiology in pyramidal and GABAergic neurons to characterize the pharmacological mechanism of SST signaling and fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We used local delivery of a broad SST receptor (SSTR) agonist and antagonist to test causal effects of SST signaling. SSTR activation hyperpolarizes layer 2/3 pyramidal neurons, an effect that is recapitulated with optogenetic stimulation of SST neurons. SST neurons in PL are activated during EPM and OFT exploration, and SSTR agonist administration directly into the PL enhances open arm exploration in the EPM. This work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors.

Prognostic role of serum soluble ST2 of advanced breast cancer patients: a retrospective cohort study.

The soluble suppression of tumorigenicity 2 receptor (sST2) binds to interleukin-33 (IL-33) and blocks IL-33 and ST2 binding, suggesting that sST2 acts as a "decoy" receptor for IL-33 and is involved in the malignant progression of breast cancer. This paper aimed to investigate the differences in sST2 expression in patients with different molecular subtypes of breast cancer and assess its clinical value in the prognostic evaluation of advanced breast cancer. In this paper, we collected sera from 91 patients firstly diagnosed with advanced breast cancer at the Tianjin Medical University Cancer Institute and Hospital from 2008 to 2021 during their first hospitalization. We detected the expression level of sST2 in the serum of patients with different molecular fractions of breast cancer and analyzed the relationship between serum sST2 levels and breast cancer-related bone metastasis, cardiotoxicity, and overall survival. Bone metastases were detected using the Emission Computed Tomography technique, and chemotherapy drug-induced cardiotoxicity was detected by echocardiography. The Overall Survival was evaluated using the Kaplan-Meier estimator, and multivariate Cox regression analysis was performed to demonstrate the association between variables and sST2 levels. Serum sST2 levels did not vary among the different pathological types, molecular types, and estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor proliferation marker (Ki-67) subgroups, and only differed significantly in the cardiotoxicity group. There were no statistical differences in tissue polypeptide specific antigen (TPSA), carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), carbohydrate antigen 153 (CA153), D-dimer, and inflammatory indexes neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) among different molecular subgroups. However, except for triple-negative breast cancer (TNBC), there was no difference in peripheral blood soluble ST2 concentrations among other molecular subtypes. Meanwhile, the survival of the high sST2 level group among advanced breast cancer patients was significantly lower than that of the normal group, and sST2 expression was closely related to cardiotoxicity and clinical stage. Serum sST2 is not only traditionally applied to the assessment of cardiac injury, but can also be utilized for assessing the prognosis of advanced breast cancer, excluding the influence of clinical stage and cardiotoxicity.

Somatostatin signaling modulates binge drinking behavior via the central nucleus of the amygdala

Somatostatin (SST) is a neuropeptide widely expressed in the central nervous system with dense expression in limbic regions such as the extended amygdala. It has recently gained attention for playing a role in modulating alcohol use disorders and co-morbid neuropsychiatric disorders. However, the role of SST in the central nucleus of the amygdala (CeA), a key region for neuropeptide regulation of alcohol and anxiety related behaviors, in alcohol consumption has not been assessed. In this work we perform an initial examination of the interaction between the CeA SST system and binge ethanol intake. Binge intake is a dangerous pattern of excessive ethanol consumption associated with health complications and the transition into alcohol dependence. We use the Drinking in the Dark (DID) model of binge intake in C57BL/6J male and female mice to examine: 1) the impact of 3 DID cycles on CeA SST expression; 2) the effect of intra-CeA SST injection on binge-like ethanol consumption; and 3) if the SST receptor 2 or 4 (SST2R or SST4R) mediate any effect on consumption. Our results show binge-like ethanol intake decreases SST expression in the CeA, but not neighboring basolateral amygdala. We further found intra-SST CeA administration reduces binge ethanol intake. This decrease was replicated by the administration of an SST4R agonist. These effects were not sex-dependent. Overall, this work lends further support for SST playing a role in alcohol related behaviors and as a potential therapeutic target.

A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism

Congenital hyperinsulinism (HI), a beta cell disorder most commonly caused by inactivating mutations of beta cell KATP channels, results in dysregulated insulin secretion and persistent hypoglycemia. Children with KATP-HI are unresponsive to diazoxide, the only FDA-approved drug for HI, and utility of octreotide, the second line therapy, is limited because of poor efficacy, desensitization, and somatostatin receptor type 2 (SST2)-mediated side effects. Selective targeting of SST5, an SST receptor associated with potent insulin secretion suppression, presents a new avenue for HI therapy. Here, we determined that CRN02481, a highly selective nonpeptide SST5 agonist, significantly decreased basal and amino acid-stimulated insulin secretion in both Sur1-/- (a model for KATP-HI) and wild type mouse islets. Oral administration of CRN02481 significantly increased fasting glucose and prevented fasting hypoglycemia compared to vehicle in Sur1-/- mice. During a glucose tolerance test, CRN02481 significantly increased glucose excursion in both WT and Sur1-/- mice compared to control. CRN02481 also reduced glucose- and tolbutamide-stimulated insulin secretion from healthy, control human islets similar to the effects observed with SS14 and peptide somatostatin analogs. Moreover, CRN02481 significantly decreased glucose- and amino acid-stimulated insulin secretion in islets from two infants with KATP-HI and one with Beckwith-Weideman Syndrome-HI. Taken together, these data demonstrate that a potent and selective SST5 agonist effectively prevents fasting hypoglycemia and suppresses insulin secretion not only in a KATP-HI mouse model, but also in healthy human islets and islets from HI patients.

The Structure of Cyclic Neuropeptide Somatostatin and Octapeptide Octreotide in the Presence of Copper Ions: Insights from Transition Metal Ion FRET and Native Ion Mobility-Mass Spectrometry.

The conformation and function of somatostatin (SST), a cyclic neuropeptide, was recently found to be altered in the presence of Cu(II) ions, which leads to self-aggregation and loss of biological function as a neurotransmitter. However, the impact of Cu(II) ions on the structure and function of SST is not fully understood. In this work, transition metal ion Förster resonance energy transfer (tmFRET) and native ion mobility-mass spectrometry (IM-MS) were utilized to study the structures of well-defined gas-phase ions of SST and of a smaller analogue, octreotide (OCT). The tmFRET results suggest two binding sites of Cu(II) ions in both native-like SST and OCT ions, either in close proximity to the disulfide bond or complexed by two aromatic residues, consistent with results obtained from collision-induced dissociation (CID). The former binding site was reported to initiate aggregation of SST, while the latter binding site could directly affect the essential motif for receptor binding and therefore impair the biological function of SST and OCT when bound to SST receptors. Our results demonstrate that tmFRET is capable of locating transition metal ion binding sites in neuropeptides. Furthermore, multiple distance constraints (tmFRET) and global shape (IM-MS) provide additional structural insights of SST and OCT ions upon metal binding, which is related to the self-aggregation mechanisms and overall biological functions.

Somatostatin regulates central clock function and circadian responses to light

Daily and annual changes in light are processed by central clock circuits that control the timing of behavior and physiology. The suprachiasmatic nucleus (SCN) in the anterior hypothalamus processes daily photic inputs and encodes changes in day length (i.e., photoperiod), but the SCN circuits that regulate circadian and photoperiodic responses to light remain unclear. Somatostatin (SST) expression in the hypothalamus is modulated by photoperiod, but the role of SST in SCN responses to light has not been examined. Our results indicate that SST signaling regulates daily rhythms in behavior and SCN function in a manner influenced by sex. First, we use cell-fate mapping to provide evidence that SST in the SCN is regulated by light viade novoSst activation. Next, we demonstrate that Sst -/-mice display enhanced circadian responses to light, with increased behavioral plasticity to photoperiod, jetlag, and constant light conditions. Notably, lack of Sst -/-eliminated sex differences in photic responses due to increased plasticity in males, suggesting that SST interacts with clock circuits that process light differently in each sex. Sst -/-mice also displayed an increase in the number of retinorecipient neurons in the SCN core, which express a type of SST receptor capable of resetting the molecular clock. Last, we show that lack of SST signaling modulates central clock function by influencing SCN photoperiodic encoding, network after-effects, and intercellular synchrony in a sex-specific manner. Collectively, these results provide insight into peptide signaling mechanisms that regulate central clock function and its response to light.

Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition.

Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson's disease (PD). Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.

The heptapeptide somatostatin analogue TT-232 exerts analgesic and anti-inflammatory actions via SST4 receptor activation: In silico, in vitro and in vivo evidence in mice

Since the conventional and adjuvant analgesics have limited effectiveness frequently accompanied by serious side effects, development of novel, potent pain killers for chronic neuropathic and inflammatory pain conditions is a big challenge. Somatostatin (SS) regulates endocrine, vascular, immune and neuronal functions, cell proliferation through 5 Gi protein-coupled receptors (SST1-SST5). SS released from the capsaicin-sensitive peptidergic sensory nerves mediates anti-inflammatory and antinociceptive effects without endocrine actions via SST4. The therapeutic use of the native SS is limited by its diverse biological actions and short plasma elimination half-life. Therefore, SST4 selective SS analogues could be promising analgesic and anti-inflammatory drug candidates with new mode of action. TT-232 is a cyclic heptapeptide showing great affinity to SST4 and SST1. Here, we report the in silico SST4 receptor binding mechanism, in vitro binding (competition assay) and cAMP- decreasing effect of TT-232 in SST4-expressing CHO cells, as well as its analgesic and anti-inflammatory actions in chronic neuropathic pain and arthritis models using wildtype and SST4-deficient mice. TT-232 binds to SST4 with similar interaction energy (-11.03 kcal/mol) to the superagonist J-2156, displaces somatostatin from SST4 binding (10 nM to 30 µM) and inhibits forskolin-stimulated cAMP accumulation (EC50: 371.6 ± 58.03 nmol; Emax: 78.63 ± 2.636 %). Its i.p. injection (100, 200 µg/kg) results in significant, 35.7 % and 50.4 %, analgesic effects upon single administration in chronic neuropathic pain and repeated injection in arthritis models in wildtype, but not in SST4-deficient mice. These results provide evidence that the analgesic effect of TT-232 is mediated by SST4 activation, which might open novel drug developmental potentials.Chemical compoundsChemical compounds studied in this article TT-232 (PubChem CID: 74053735).

Selective somatostatin receptor 5 inhibition improves hepatic insulin sensitivity.

Diabetes is a metabolic disorder with an increasing global prevalence. Somatostatin (SST), a peptide hormone, regulates hormone secretion via five SST receptor (SSTR) subtypes (SSTR1-5) in a tissue-specific manner. As SSTR5 is expressed in pancreatic β-cells and intestinal L-cells, studies have suggested that SSTR5 regulates glucose tolerance through insulin and incretin secretion, thereby having a prominent role in diabetes. Moreover, SSTR5 knockout (KO) mice display enhanced insulin sensitivity; however, the underlying mechanism has not been clarified. Therefore, in this study, we investigate the effect of SSTR5 blockade on insulin resistance and the target organ using SSTR5 KO mice and a selective SSTR5 antagonist (compound-1). High-fat diet (HFD)-fed SSTR5 KO mice exhibited significantly lower homeostasis model assessment of insulin resistance (HOMA-IR) than HFD-fed wild-type mice. Two-week oral administration of compound-1 dose-dependently and significantly reduced changes in the levels of glycosylated hemoglobin (GHb), plasma glucose, plasma insulin, and HOMA-IR in male KK-Ay /Ta Jcl mice (KK-Ay mice), a model of obese type 2 diabetes with severe insulin resistance. Additionally, compound-1 significantly increased the glucose infusion rate while decreasing hepatic glucose production in male KK-Ay mice, as evidenced by hyperinsulinemic-euglycemic clamp analyses. In addition, compound-1 ameliorated the insulin-induced Akt phosphorylation suppression by octreotide in the liver of male C57BL/6J mice. Collectively, our results demonstrate that selective SSTR5 inhibition can improve insulin sensitivity by enhancing liver insulin action; thus, selective SSTR5 antagonists represent potentially novel therapeutic agents for type 2 diabetes.

Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist.

The discovery of a novel 4-(4-aminopiperidinyl)-3,6-diarylquinoline series of potent SST2 agonists is described. This class of molecules exhibit excellent selectivity over SST1, SST3, SST4, and SST5 receptors. The compound 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile (22, paltusotine, formerly known as CRN00808) showed no direct inhibition of major cytochrome P450 enzymes or the hERG ion channel and had sufficient exposure in rats and excellent exposure in dogs upon oral dosing. In pharmacodynamic studies, compound 22 dose-dependently suppressed growth hormone (GH) secretion induced by an exogenous growth-hormone-releasing hormone (GHRH) challenge in both male and female rats following a single oral dose and suppressed IGF-1 levels with repeated oral administration in both rats and dogs. To the best of our knowledge, compound 22 is the first non-peptide SST2 agonist to advance to human clinical trials and is currently in Phase 3 trials in acromegaly patients and a Phase 2 trial in neuroendocrine tumor patients suffering from carcinoid syndrome.