Engineered Exosomes Containing microRNA-29b-2 and Targeting the Somatostatin Receptor Reduce Presenilin 1 Expression and Decrease the ß-Amyloid Accumulation in the Brains of Mice with Alzheimer's Disease.

Purpose: Exosomes are membrane vesicles secreted by various cells and play a crucial role in intercellular communication. They can be excellent delivery vehicles for oligonucleotide drugs, such as microRNAs, due to their high biocompatibility. MicroRNAs have been shown to be more stable when incorporated into exosomes; however, the lack of targeting and immune evasion is still the obstacle to the use of these microRNA-containing nanocarriers in clinical settings. Our goal was to produce functional exosomes loaded with target ligands, immune evasion ligand, and oligonucleotide drug through genetic engineering in order to achieve more precise medical effects. Methods: To address the problem, we designed engineered exosomes with exogenous cholecystokinin (CCK) or somatostatin (SST) as the targeting ligand to direct the exosomes to the brain, as well as transduced CD47 proteins to reduce the elimination or phagocytosis of the targeted exosomes. MicroRNA-29b-2 was the tested oligonucleotide drug for delivery because our previous research showed that this type of microRNA was capable of reducing presenilin 1 (PSEN1) gene expression and decreasing the ß-amyloid accumulation for Alzheimer's disease (AD) in vitro and in vivo. Results: The engineered exosomes, containing miR29b-2 and expressing SST and CD47, were produced by gene-modified dendritic cells and used in the subsequent experiments. In comparison with CD47-CCK exosomes, CD47-SST exosomes showed a more significant increase in delivery efficiency. In addition, CD47-SST exosomes led to a higher delivery level of exosomes to the brains of nude mice when administered intravenously. Moreover, it was found that the miR29b-2-loaded CD47-SST exosomes could effectively reduce PSEN1 in translational levels, which resulted in an inhibition of beta-amyloid oligomers production both in the cell model and in the 3xTg-AD animal model. Conclusion: Our results demonstrated the feasibility of the designed engineered exosomes. The application of this exosomal nanocarrier platform can be extended to the delivery of other oligonucleotide drugs to specific tissues for the treatment of diseases while evading the immune system.

111 In-Pentetreotide-Guided Radiosurgery for Intraoperative Localization of Retroperitoneal Nodal Metastasis in a Patient With Ileal Neuroendocrine Tumor.

ABSTRACT: 64 Cu-DOTATATE PET/CT of a 44-year-old man with an ileal neuroendocrine tumor demonstrated the primary tumor, local nodal metastases, and a pericaval nodal metastasis. Localization of the pericaval node during surgery may be difficult, thus 4.4 mCi of 111 In-pentetreotide was administered before surgery to assist with localization and resection. At surgery, the pericaval nodal metastasis was readily detected by gamma probe, which could then be resected and pathologically proven to be a metastasis. This demonstrates the use of somatostatin receptor-targeted imaging for intraoperative localization of an otherwise difficult to surgically localize metastasis. Without intraoperative somatostatin receptor-targeted radiosurgery, disease may have been incompletely resected.

Nanotechnology-Based Strategy for Enhancing Therapeutic Efficacy in Pancreatic Cancer: Receptor-Targeted Drug Delivery by Somatostatin Analog.

A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes as carriers, an anticancer drug (paclitaxel) as a chemotherapeutic agent, and a modified synthetic somatostatin analog, 5-pentacarbonyl-octreotide, a ligand for somatostatin receptor 2 (SSTR2), as a targeting moiety for pancreatic cancer. The cellular internalization, cytotoxicity, and antitumor activity of the DDS were tested in vitro using human pancreatic ductal adenocarcinoma (PDAC) cells with different expressions of the targeted SSTR2 receptors, and in vivo on immunodeficient mice bearing human PDAC xenografts. The targeted drug delivery system containing paclitaxel exhibited significantly enhanced cytotoxicity compared to non-targeted DDS, and this efficacy was directly related to the levels of SSTR2 expression. It was found that octreotide-targeted DDS proved exceptionally effective in suppressing the growth of PDAC tumors. This study underscores the potential of octreotide-targeted liposomal delivery systems to enhance the therapeutic outcomes for PDAC compared with non-targeted liposomal DDS and Paclitaxel-Cremophor® EL, suggesting a promising avenue for future cancer therapy innovations.

[Comparative analysis of efficacy of different forms of Galli Gigerii Endothelium Corneum on functional dyspepsia in rats based on composition-pharmacodynamics].

A systematic evaluation of the differences in the chemical composition and efficacy of the different forms of Galli Gigerii Endothelium Corneum(GGEC) was conducted based on modern analytical techniques and a functional dyspepsia(FD) rat model, which clarifies the material basis of the digestive efficacy of GGEC. Proteins, enzymes, polysaccharides, amino acids, and flavonoids in GGEC powder and decoction were determined respectively. The total protein of the powder and decoction was 0.06% and 0.65%, respectively, and the pepsin and amylase potency of the powder was 27.03 and 44.05 U·mg~(-1) respectively. The polysaccharide of the decoction was 0.03%, and there was no polysaccharide detected in the powder. The total L-type amino acids in the powder and decoction were 279.81 and 8.27 mg·g~(-1) respectively, and the total flavonoid content was 59.51 µg·g~(-1). Enzymes and flavonoids were not detected in the decoction. The powder significantly reduced nutrient paste viscosity, while the decoction and control group showed no significant reduction in nutrient paste viscosity. FD rat models were prepared by iodoacetamide gavage and irregular diet. The results showed that both powder and decoction significantly increased the gastric emptying effect, small intestinal propulsion rate, digestive enzymes activity, gastrin(GAS), motilin(MTL), ghrelin(GHRL) and reduced vasoactive intestinal peptide(VIP), 3-(2-ammo-nioethyl)-5-hydroxy-1H-indolium maleate(5-HT), and somatostatin(SST) content in rats(P<0.05, P<0.01). Comparison of GGEC decoction and powder administration between groups of the same dosage level showed that gastrointestinal propulsion and serum levels of GAS, GHRL, VIP, and SST in the powder group were significantly superior to those in the decoction and that the gastrointestinal propulsion, as well as serum levels of MTL, GAS, and GHRL were slightly higher than those of the decoction with two times its raw dose, and the serum levels of SST, 5-HT, and VIP in the powder group were slightly lower than those of the decoction with two times its raw dose. In conclusion, both decoction and powder have therapeutic effects on FD, but there is a significant difference between the two effects. Under the same dosage, the digestive efficacy of the powder is significantly better than that of the decoction, and the decoction needs to increase the dosage to compensate for the efficacy. It is hypothesized that the digestive efficacy of the GGEC has a duality, and the digestive active ingredients of the powder may include enzymes and L-type amino acids, while the decoction mainly relies on L-type amino acids to exert its efficacy. This study provides new evidence to investigate the digestive active substances of the GGEC and to improve the effectiveness of the drug in the clinic.

Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex.

GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation-inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.

Effectiveness of the pharmacological therapy to prevent post ERCP acute pancreatitis: a network meta-analysis.

OBJECTIVE: To determine the effectiveness of the different pharmacological agents in preventing post-ERCP acute pancreatitis. METHODS: We included clinical trials of pharmacological interventions for prophylaxis of acute post-ERCP pancreatitis. The event evaluated was acute pancreatitis. We conducted a search strategy in MEDLINE (OVID), EMBASE, and Cochrane Central Register of Controlled Trials from inception to nowadays. We reported the information in terms of relative risks (RR) with a 95% confidence interval. We assessed the heterogeneity using the I2 test. RESULTS: We included 84 studies for analysis (30,463 patients). The mean age was 59.3 years (SD ± 7.01). Heterogeneity between studies was low (I2 = 34.4%) with no inconsistencies (p = 0.2567). Post ERCP pancreatitis was less in prophylaxis with NSAIDs (RR 0.65 95% CI [0.52 to 0.80]), aggressive hydration with Lactate Ringer (RR 0.32 95% CI [0.12-0.86]), NSAIDs + isosorbide dinitrate (RR 0.28 95% CI [0.11-0.71]) and somatostatin and analogues (RR 0.54 [0.43 to 0.68]) compared with placebo. CONCLUSIONS: NSAIDs, the Combination of NSAIDs + isosorbide dinitrate, somatostatin and analogues, and aggressive hydration with lactate ringer are pharmacological strategies that can prevent post-ERCP pancreatitis when compared to placebo. More clinical trials are required to determine the effectiveness of these drugs.

Pegvisomant and pasireotide in PRL and GH co-secreting vs GH-secreting Pit-NETs.

The objective of the study was to evaluate the efficacy of second-line therapies in patients with acromegaly caused by a growth hormone (GH) and prolactin (PRL) co-secreting pituitary neuroendocrine tumor (GH&PRL-Pit-NET) compared to their efficacy in patients with acromegaly caused by a GH-secreting pituitary neuroendocrine tumor (GH-Pit-NET). This is a multicenter retrospective study of patients with acromegaly on treatment with pasireotide and/or pegvisomant. Patients were classified in two groups: GH&PRL-Pit-NETs when evidence of hyperprolactinemia and immunohistochemistry (IHC) for GH and PRL was positive or if PRL were >200 ng/dL regardless of the PRL-IHC and GH-Pit-NETs when the previously mentioned criteria were not met. A total of 28 cases with GH&PRL-Pit-NETs and 122 with GH-Pit-NETs met the inclusion criteria. GH&PRL-Pit-NETs presented at a younger age, caused hypopituitarism, and were invasive more frequently than GH-Pit-NETs. There were 124 patients treated with pegvisomant and 49 with pasireotide at any time. The efficacy of pegvisomant for IGF-1 normalization was of 81.5% and of pasireotide of 71.4%. No differences in IGF-1 control with pasireotide and with pegvisomant were observed between GH&PRL-Pit-NETs and GH-Pit-NETs. All GH&PRL-Pit-NET cases treated with pasireotide (n = 6) and 82.6% (n = 19/23) of the cases treated with pegvisomant normalized PRL levels. No differences in the rate of IGF-1 control between pegvisomant and pasireotide were detected in patients with GH&PRL-Pit-NETs (84.9% vs 66.7%, P = 0.178). We conclude that despite the more aggressive behavior of GH&PRL-Pit-NETs than GH-Pit-NETs, no differences in the rate of IGF-1 control with pegvisomant and pasireotide were observed between both groups, and both drugs have shown to be effective treatments to control IGF-1 and PRL hypersecretion in these tumors.

Feedforward and disinhibitory circuits differentially control activity of cortical somatostatin interneurons during behavioral state transitions.

Interneurons (INs), specifically those in disinhibitory circuits like somatostatin (SST) and vasoactive intestinal peptide (VIP)-INs, are strongly modulated by the behavioral context. Yet, the mechanisms by which these INs are recruited during active states and whether their activity is consistent across sensory cortices remain unclear. We now report that in mice, locomotor activity strongly recruits SST-INs in the primary somatosensory (S1) but not the visual (V1) cortex. This diverse engagement of SST-INs cannot be explained by differences in VIP-IN function but is absent in the presence of visual input, suggesting the involvement of feedforward sensory pathways. Accordingly, inactivating the somatosensory thalamus, but not decreasing VIP-IN activity, significantly reduces the modulation of SST-INs by locomotion. Model simulations suggest that the differences in SST-INs across behavioral states can be explained by varying ratios of VIP- and thalamus-driven activity. By integrating feedforward activity with neuromodulation, SST-INs are anticipated to be crucial for adapting sensory processing to behavioral states.

Integrative clinical, hormonal, and molecular data associate with invasiveness in acromegaly: REMAH study.

INTRODUCTION: Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management. OBJECTIVES: The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression. METHODS: Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables. RESULTS: Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs). CONCLUSIONS: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.

Bone health and skeletal fragility in second- and third-line medical therapies for acromegaly: preliminary results from a pilot single center experience.

INTRODUCTION: Skeletal fragility is a clinically relevant and not-reversible complication of acromegaly, involving around 30-40% of patients since the disease diagnosis. Few studies have investigated the effects on skeletal health of medical therapies for acromegaly. In this retrospective longitudinal monocentre study, we investigated the outcome of skeletal fragility in patients treated with Pasireotide Lar in combination with Pegvisomant (Pasi-Lar + Peg-V), also comparing those observed in patients treated with conventional therapies. RESULTS: We included 6 patients treated with Pasi-Lar + Peg-V, 5 patients treated with Peg-V in monotherapy (m-Peg-V), 16 patients treated with Peg-V plus first-generation somatostatin receptor ligands (fg-SRLs + Peg-V), 9 patients treated with Pasi-Lar. None of the patients treated with Pasi-Lar + Peg-V experienced worsening of spine and femoral bone mineral density (BMD) and incident vertebral fractures (i-VFs). Eight patients experienced i-VFs. The frequency of i-VFs was significantly lower in patients treated with the Pasi-Lar + Peg-V (0/8; 0%), as compared to those observed in m-Peg-V treated patients (4/8; 50%, p = 0.02). The frequency of i-VFs was slightly but not significantly higher in Pasi-Lar treated patients (1/8; 12.5% p = 0.6) and in fg-SRLs + Peg-V treated patients (3/8; 37.5% p = 0.364), concerning those treated with Pasi-Lar + Peg-V (0/8; 0%). I-VFs occurred more frequently in patients with higher GH levels at acromegaly diagnosis (p < 0.001), and in patients who experienced a BMD worsening (p = 0.005). CONCLUSION: Our preliminary data suggested that in conventional and multi-drug resistant acromegaly, the combination therapy Pasi-Lar + Peg-V may prevent the worsening of BMD and the occurrence of i-VFs. Prospective and translational studies should further validate these results and ascertain underlying physiopathology mechanisms.

Astrocyte-secreted neurocan controls inhibitory synapse formation and function.

Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. Several astrocyte-secreted synaptogenic proteins controlling excitatory synapse development were identified; however, those that induce inhibitory synaptogenesis remain elusive. Here, we identify neurocan as an astrocyte-secreted inhibitory synaptogenic protein. After secretion from astrocytes, neurocan is cleaved into N- and C-terminal fragments. We found that these fragments have distinct localizations in the extracellular matrix. The neurocan C-terminal fragment localizes to synapses and controls cortical inhibitory synapse formation and function. Neurocan knockout mice lacking the whole protein or only its C-terminal synaptogenic domain have reduced inhibitory synapse numbers and function. Through super-resolution microscopy, in vivo proximity labeling by secreted TurboID, and astrocyte-specific rescue approaches, we discovered that the synaptogenic domain of neurocan localizes to somatostatin-positive inhibitory synapses and strongly regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific inhibitory synapse development in the mammalian brain.

Functional specialization of hippocampal somatostatin-expressing interneurons.

Hippocampal somatostatin-expressing (Sst) GABAergic interneurons (INs) exhibit considerable anatomical and functional heterogeneity. Recent single-cell transcriptome analyses have provided a comprehensive Sst-IN subpopulations census, a plausible molecular ground truth of neuronal identity whose links to specific functionality remain incomplete. Here, we designed an approach to identify and access subpopulations of Sst-INs based on transcriptomic features. Four mouse models based on single or combinatorial Cre- and Flp- expression differentiated functionally distinct subpopulations of CA1 hippocampal Sst-INs that largely tiled the morpho-functional parameter space of the Sst-INs superfamily. Notably, the Sst;;Tac1 intersection revealed a population of bistratified INs that preferentially synapsed onto fast-spiking interneurons (FS-INs) and were sufficient to interrupt their firing. In contrast, the Ndnf;;Nkx2-1 intersection identified a population of oriens lacunosum-moleculare INs that predominantly targeted CA1 pyramidal neurons, avoiding FS-INs. Overall, our results provide a framework to translate neuronal transcriptomic identity into discrete functional subtypes that capture the diverse specializations of hippocampal Sst-INs.

Pregnancy and acromegaly: clinical outcomes of retrospectively analysed data from the German acromegaly registry.

CONTEXT: Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child. OBJECTIVE: To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly. DESIGN & METHODS: Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry. RESULTS: 87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications. CONCLUSION: Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.

Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing's disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study.

Introduction: Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment. Methods: Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 µg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization. Results: Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA1c) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA1c (odds ratio [OR] 3.6; P=0.0162) and FPG (OR 1.0; P=0.0472) and history of diabetes/pre-diabetes (OR 3.0; P=0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA1c (OR 12.6; P=0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes. Conclusion: Increasing age, HbA1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment.

Mouse hippocampal CA1 VIP interneurons detect novelty in the environment and support recognition memory.

In the CA1 hippocampus, vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) play a prominent role in disinhibitory circuit motifs. However, the specific behavioral conditions that lead to circuit disinhibition remain uncertain. To investigate the behavioral relevance of VIP-IN activity, we employed wireless technologies allowing us to monitor and manipulate their function in freely behaving mice. Our findings reveal that, during spatial exploration in new environments, VIP-INs in the CA1 hippocampal region become highly active, facilitating the rapid encoding of novel spatial information. Remarkably, both VIP-INs and pyramidal neurons (PNs) exhibit increased activity when encountering novel changes in the environment, including context- and object-related alterations. Concurrently, somatostatin- and parvalbumin-expressing inhibitory populations show an inverse relationship with VIP-IN and PN activity, revealing circuit disinhibition that occurs on a timescale of seconds. Thus, VIP-IN-mediated disinhibition may constitute a crucial element in the rapid encoding of novelty and the acquisition of recognition memory.

Urocortin 3 contributes to paracrine inhibition of islet alpha cells in mice.

Pancreatic alpha cell activity and glucagon secretion lower as glucose levels increase. While part of the decrease is regulated by glucose itself, paracrine signaling by their neighboring beta and delta cells also plays an important role. Somatostatin from delta cells is an important local inhibitor of alpha cells at high glucose. Additionally, urocortin 3 (UCN3) is a hormone that is co-released from beta cells with insulin and acts locally to potentiate somatostatin secretion from delta cells. UCN3 thus inhibits insulin secretion via a negative feedback loop with delta cells, but its role with respect to alpha cells and glucagon secretion is not understood. We hypothesize that the somatostatin-driven glucagon inhibition at high glucose is regulated in part by UCN3 from beta cells. Here, we use a combination of live functional Ca2+ and cAMP imaging as well as direct glucagon secretion measurement, all from alpha cells in intact mouse islets, to determine the contributions of UCN3 to alpha cell behavior. Exogenous UCN3 treatment decreased alpha cell Ca2+ and cAMP levels and inhibited glucagon release. Blocking endogenous UCN3 signaling increased alpha cell Ca2+ by 26.8 ± 7.6%, but this did not result in increased glucagon release at high glucose. Furthermore, constitutive deletion of Ucn3 did not increase Ca2+ activity or glucagon secretion relative to controls. UCN3 is thus capable of inhibiting mouse alpha cells, but, given the subtle effects of endogenous UCN3 signaling on alpha cells, we propose that UCN3-driven somatostatin may serve to regulate local paracrine glucagon levels in the islet instead of inhibiting gross systemic glucagon release.

Activity-Dependent Ectopic Spiking in Parvalbumin-Expressing Interneurons of the Neocortex.

Canonically, action potentials of most mammalian neurons initiate at the axon initial segment (AIS) and propagate bidirectionally: orthodromically along the distal axon and retrogradely into the soma and dendrites. Under some circumstances, action potentials may initiate ectopically, at sites distal to the AIS, and propagate antidromically along the axon. These "ectopic action potentials" (EAPs) have been observed in experimental models of seizures and chronic pain, and more rarely in nonpathological forebrain neurons. Here we report that a large majority of parvalbumin-expressing (PV+) interneurons in the upper layers of mouse neocortex, from both orbitofrontal and primary somatosensory areas, fire EAPs after sufficient activation of their somata. Somatostatin-expressing interneurons also fire EAPs, though less robustly. Ectopic firing in PV+ cells occurs in varying temporal patterns and can persist for several seconds. PV+ cells evoke strong synaptic inhibition in pyramidal neurons and interneurons and play critical roles in cortical function. Our results suggest that ectopic spiking of PV+ interneurons is common and may contribute to both normal and pathological network functions of the neocortex.

Somatostatin and the pathophysiology of Alzheimer's disease.

Among the central features of Alzheimer's disease (AD) progression are altered levels of the neuropeptide somatostatin (SST), and the colocalisation of SST-positive interneurons (SST-INs) with amyloid-ß plaques, leading to cell death. In this theoretical review, I propose a molecular model for the pathogenesis of AD based on SST-IN hypofunction and hyperactivity. Namely, hypofunctional and hyperactive SST-INs struggle to control hyperactivity in medial regions in early stages, leading to axonal Aß production through excessive presynaptic GABAB inhibition, GABAB1a/APP complex downregulation and internalisation. Concomitantly, excessive SST-14 release accumulates near SST-INs in the form of amyloids, which bind to Aß to form toxic mixed oligomers. This leads to differential SST-IN death through excitotoxicity, further disinhibition, SST deficits, and increased Aß release, fibrillation and plaque formation. Aß plaques, hyperactive networks and SST-IN distributions thereby tightly overlap in the brain. Conversely, chronic stimulation of postsynaptic SST2/4 on gulutamatergic neurons by hyperactive SST-INs promotes intense Mitogen-Activated Protein Kinase (MAPK) p38 activity, leading to somatodendritic p-tau staining and apoptosis/neurodegeneration - in agreement with a near complete overlap between p38 and neurofibrillary tangles. This model is suitable to explain some of the principal risk factors and markers of AD progression, including mitochondrial dysfunction, APOE4 genotype, sex-dependent vulnerability, overactive glial cells, dystrophic neurites, synaptic/spine losses, inter alia. Finally, the model can also shed light on qualitative aspects of AD neuropsychology, especially within the domains of spatial and declarative (episodic, semantic) memory, under an overlying pattern of contextual indiscrimination, ensemble instability, interference and generalisation.

Effective management of recurrent Doege-Potter syndrome with somatostatin-analogues: A case report.

BACKGROUND: Doege-Potter syndrome is defined as paraneoplastic hypoinsulinemic hypoglycemia associated with a benign or malignant solitary fibrous tumor frequently located in pleural, but also extrapleural sites. Hypoglycemia can be attributed to paraneoplastic secretion of "Big-IGF-II," a precursor of Insulin-like growth factor-II. This prohormone aberrantly binds to and activates insulin receptors, with consecutive initiation of common insulin actions such as inhibition of gluconeogenesis, activation of glycolysis and stimulation of cellular glucose uptake culminating in recurrent tumor-induced hypoglycemic episodes. Complete tumor resection or debulking surgery is considered the most promising treatment for DPS. CASE: Here, we report a rare case of a recurrent Doege-Poter Syndrome with atypical gelatinous tumor lesions of the lung, pleura and pericardial fat tissue in an 87-year-old woman. Although previously described as ineffective, we propose that adjuvant treatment with Octreotide in conjunction with intravenous glucose helped to maintain tolerable blood glucose levels before tumor resection. The somatostatin-analogue Lanreotide was successfully used after tumor debulking surgery (R2-resection) to maintain adequate blood glucose control. CONCLUSION: We conclude that somatostatin-analogues bear the potential of being effective in conjunction with limited surgical approaches for the treatment of hypoglycemia in recurrent or non-totally resectable SFT entities underlying DPS.

Effects of a bitter substance, denatonium benzoate, on pancreatic hormone secretion.

There is increasing evidence linking bitter taste receptor (BTR) signaling to gut hormone secretion and glucose homeostasis. However, its effect on islet hormone secretion has been poorly characterized. This study investigated the effect of the bitter substance, denatonium benzoate (DB), on hormone secretion from mouse pancreatic islets and INS-1 832/13 cells. DB (0.5-1 mM) augmented insulin secretion at both 2.8 mM and 16.7 mM glucose. This effect was no longer present at 5 mM DB likely due to the greater levels of cellular apoptosis. DB-stimulated insulin secretion involved closure of the KATP channel, activation of T2R signaling in beta-cells, and intraislet glucagon-like peptide-1 (GLP-1) release. DB also enhanced glucagon and somatostatin secretion, but the underlying mechanism was less clear. Together, this study demonstrates that the bitter substance, DB, is a strong potentiator of islet hormone secretion independent of glucose. This observation highlights the potential for widespread off-target effects associated with the clinical use of bitter-tasting substances.NEW & NOTEWORTHY We show that the bitter substance, denatonium benzoate (DB), stimulates insulin, glucagon, somatostatin, and GLP-1 secretion from pancreatic islets, independent of glucose, and that DB augments insulin release via the KATP channel, bitter taste receptor signaling, and intraislet GLP-1 secretion. Exposure to a high dose of DB (5 mM) induces cellular apoptosis in pancreatic islets. Therefore, clinical use of bitter substances to improve glucose homeostasis may have unintended negative impacts beyond the gut.