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Molecular Metabolism Jun 2024Bariatric surgery is an effective obesity treatment, leading to weight loss and improvement in glycemia, that is characterized by hypersecretion of gastrointestinal...
Bariatric surgery is an effective obesity treatment, 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. Here, we investigated the role of somatostatin (Sst) in bariatric surgery outcomes using a mouse model of sleeve gastrectomy (SG). Sst 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. Indeed, 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. Our results suggest that inhibition of Sst signaling enhances the long-term favorable metabolic outcomes of bariatric surgery.
PubMed: 38945296
DOI: 10.1016/j.molmet.2024.101979 -
International Journal of Surgery Case... May 2024Primary intracranial neuroendocrine tumors (NETs) are exceedingly rare, often posing diagnostic challenges, particularly in non-secreting variants. These tumors may...
INTRODUCTION AND IMPORTANCE
Primary intracranial neuroendocrine tumors (NETs) are exceedingly rare, often posing diagnostic challenges, particularly in non-secreting variants. These tumors may initially present with nonspecific symptoms, leading to delayed diagnosis and potential neurological complications.
CASE REPORT
We present the case of a 33-year-old male admitted with a one-year history of progressively worsening headache accompanied by acute left ptosis and diplopia. Initial examination revealed left eye ptosis and hypotropia, indicative of third and fourth cranial nerve paralysis. Cavoscopy revealed a mild anterior wall bulge of the sphenoid with normal mucosa. MRI imaging unveiled an expansive clival process extending towards the sellar region and left cavernous sinus, completely occupying the sphenoid sinus and exerting mass effect on the pituitary stalk. Hormonal assays were within reference ranges, ruling out a hormonally-active tumor. Endoscopic endonasal surgery for biopsy revealed a low-grade neuroendocrine tumor positive for cytokeratin AE1/AE2, chromogranin A, synaptophysin, and beta-catenin, with a Ki-67-labeling index <2 %. Somatostatin receptor scintigraphy confirmed intense hyper fixation of the tracer in the sphenoidal tumor, supporting its neuroendocrine origin. The patient declined surgical intervention after informed consent, opting for C1 somatostatin analogs prior to radiotherapy. One-year follow-up demonstrated symptom stability with no tumor progression.
CLINICAL DISCUSSION
To this day, no consensus among reports concerning the optimal management of these cases. Imaging assessment is crucial to validate the primary nature of the tumor and to exclude any distant localization. Various therapeutic modalities, such as surgery, radiotherapy, and somatostatin analogs, should be considered based on the specific characteristics and extent of the tumor.
CONCLUSION
Our case is a clear reminder that neuroendocrine tumors should be considered as a differential diagnosis for skull base neoplasms.
PubMed: 38943936
DOI: 10.1016/j.ijscr.2024.109750 -
Animal Bioscience Jun 2024Somatostatin (SS) plays important regulatory roles in animal growth and reproduction by affecting the synthesis and secretion of growth hormone (GH). However, the...
OBJECTIVE
Somatostatin (SS) plays important regulatory roles in animal growth and reproduction by affecting the synthesis and secretion of growth hormone (GH). However, the mechanism by which SS regulates growth and development in goats is still unclear.
METHODS
In this study, we randomly selected eight 7-month-old Dazu black goats (DBGs) of similar body weight and equally assigned four bucks as the immunised and negative control groups. The immunised group received the Salmonella typhi attenuated vaccine CSO22 (ptCS/2SS-asd) orally, whilst the negative control group received the empty vector vaccine CSO22 (pVAX-asd) orally.
RESULTS
The SS concentration in the serum of goats in the immunised group was significantly lower than that in the negative control group, and the daily gain was significantly higher (p < 0.05). SS-14 DNA vaccine immunisation resulted in significantly higher concentrations of growth-related hormones such as GH-releasing hormone and IGF-1 in the serum of goats (p < 0.05). RNA-seq analysis of hypothalamus of oral SS-14 DNA vaccine and negative control DBGs identified 31 differentially expressed genes (DEGs). Pituitary gland identified 164 DEGs. A total of 246 DEGs were detected in the liver by RNA-seq. Gene ontology (GO) of DEGs was enriched in mitochondrial envelope, extracellular region, receptor binding and cell proliferation. The biological metabolic pathways associated with DEGs were explored by Kyoto Encyclopedia of Genes and Genomes analysis. DEGs were associated with metabolic pathways, oxidative phosphorylation, vitamin digestion and absorption and galactose metabolism. These candidate genes (e.g. DGKK, CYTB, DUSP1 and LRAT) may provide references for exploring the molecular mechanisms by which SS promotes growth and development.
CONCLUSION
Overall, these results demonstrated that the SS DNA vaccine enhanced the growth of DBGs by altering growth-related hormone concentrations and regulating the expression of growth-related genes in the hypothalamic-pituitary-liver axis.
PubMed: 38938026
DOI: 10.5713/ab.24.0121 -
Cancers Jun 2024Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare endocrine malignancies with limited effective treatment options. The association between the tumor...
Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare endocrine malignancies with limited effective treatment options. The association between the tumor microenvironment (TME) with somatostatin receptor 2 (SSTR2) and hypoxia-induced factor-2α (HIF-2α) in PPGLs, critical for optimizing combination therapeutic strategies with immunotherapy, remains largely unexplored. To evaluate the association of SSTR2 and HIF-2α immunoreactivity with the TME in patients with PPGLs, we analyzed the expression of SSTR2A, HIF-2α, and TME components, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (CD68 and CD163), and PD-L1, using immunohistochemistry in patients with PPGLs. The primary outcome was to determine the association of the immune profiles with SSTR2A and HIF-2α expression. Among 45 patients with PPGLs, SSTR2A and HIF2α were positively expressed in 21 (46.7%) and 14 (31.1%) patients, respectively. The median PD-L1 immunohistochemical score (IHS) was 2.0 (interquartile range: 0-30.0). Positive correlations were observed between CD4, CD8, CD68, and CD163 levels. A negative correlation was found between the CD163/CD68 ratio (an indicator of M2 polarization) and SSTR2A expression (r = -0.385, = 0.006). HIF-2α expression showed a positive correlation with PD-L1 IHS (r = 0.348, = 0.013). The co-expression of PD-L1 (HIS > 10) and HIF-2α was found in seven patients (15.6%). No associations were observed between SDHB staining results and the CD163/CD68 ratio, PD-L1, or SSTR2A expression. Our data suggest the potential of combination therapy with immunotherapy and peptide receptor radionuclide therapy or HIF-2α inhibitors as a treatment option in selected PPGL populations.
PubMed: 38927897
DOI: 10.3390/cancers16122191 -
Biomedicines Jun 2024A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in...
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.
PubMed: 38927539
DOI: 10.3390/biomedicines12061332 -
BioRxiv : the Preprint Server For... Jun 2024How do biological neural systems efficiently encode, transform and propagate information between the sensory periphery and the sensory cortex about sensory features...
How do biological neural systems efficiently encode, transform and propagate information between the sensory periphery and the sensory cortex about sensory features evolving at different time scales? Are these computations efficient in normative information processing terms? While previous work has suggested that biologically plausible models of of such neural information processing may be implemented efficiently within a single processing layer, how such computations extend across several processing layers is less clear. Here, we model propagation of multiple time-varying sensory features across a sensory pathway, by extending the theory of efficient coding with spikes to efficient encoding, transformation and transmission of sensory signals. These computations are optimally realized by a multilayer spiking network with feedforward networks of spiking neurons (receptor layer) and recurrent excitatory-inhibitory networks of generalized leaky integrate-and-fire neurons (recurrent layers). Our model efficiently realizes a broad class of feature transformations, including positive and negative interaction across features, through specific and biologically plausible structures of feedforward connectivity. We find that mixing of sensory features in the activity of single neurons is beneficial because it lowers the metabolic cost at the network level. We apply the model to the somatosensory pathway by constraining it with parameters measured empirically and include in its last node, analogous to the primary somatosensory cortex (S1), two types of inhibitory neurons: parvalbumin-positive neurons realizing lateral inhibition, and somatostatin-positive neurons realizing winner-take-all inhibition. By implementing a negative interaction across stimulus features, this model captures several intriguing empirical observations from the somatosensory system of the mouse, including a decrease of sustained responses from subcortical networks to S1, a non-linear effect of the knock-out of receptor neuron types on the activity in S1, and amplification of weak signals from sensory neurons across the pathway.
PubMed: 38895477
DOI: 10.1101/2024.06.07.597979 -
BioRxiv : the Preprint Server For... Jun 2024The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains...
The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains GABA neurons that synapse locally on to VTA dopamine neurons, synapses widely credited to a population of so-called VTA interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, and molecular markers, but such features have not been clearly described in VTA. Indeed, there is scant evidence that local and distal synapses originate from separate populations of VTA GABA neurons. In this study we tested whether several markers expressed in non-dopamine VTA neurons are selective markers of interneurons, defined as neurons that synapse locally but not distally. Challenging previous assumptions, we found that VTA neurons genetically defined by expression of parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project to known VTA targets including nucleus accumbens, ventral pallidum, lateral habenula, and prefrontal cortex. Moreover, we provide evidence that VTA GABA and glutamate projection neurons make functional inhibitory or excitatory synapses locally within VTA. These findings suggest that local collaterals of VTA projection neurons could mediate functions prior attributed to VTA interneurons. This study underscores the need for a refined understanding of VTA connectivity to explain how heterogeneous VTA circuits mediate diverse functions related to reward, motivation, or addiction.
PubMed: 38895464
DOI: 10.1101/2024.06.07.597996 -
Cancers May 2024Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9-22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group... (Review)
Review
Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9-22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting.
PubMed: 38893145
DOI: 10.3390/cancers16112025 -
International Journal of Molecular... May 2024Alzheimer's disease (AD) is characterized by the deposition in the brain of senile plaques composed of amyloid-β peptides (Aβs) that increase inflammation. An...
Reduction in Hippocampal Amyloid-β Peptide (Aβ) Content during Glycine-Proline-Glutamate (Gly-Pro-Glu) Co-Administration Is Associated with Changes in Inflammation and Insulin-like Growth Factor (IGF)-I Signaling.
Alzheimer's disease (AD) is characterized by the deposition in the brain of senile plaques composed of amyloid-β peptides (Aβs) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE), has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aβ levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aβ25-35 for 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aβ-degrading enzymes associated with these GPE-related effects. GPE prevented the Aβ-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1, and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme, was also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aβ insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aβ levels through modulation of levels and/or activity of Aβ proteases.
Topics: Animals; Amyloid beta-Peptides; Hippocampus; Rats; Insulin-Like Growth Factor I; Signal Transduction; Female; Oligopeptides; Inflammation; Peptide Fragments; Rats, Wistar; Alzheimer Disease; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Insulin-Like Peptides
PubMed: 38891902
DOI: 10.3390/ijms25115716 -
Endokrynologia Polska Jun 2024Not required for Clinical Vignette.
Not required for Clinical Vignette.
PubMed: 38887119
DOI: 10.5603/ep.99763