|
1
|
Campos-Sánchez JC, Serna-Duque JA, Guardiola FA, Cuesta A, Esteban MÁ. Bioinformatic and gene expression analysis of the somatostatin/cortistatin gene family in the gilthead seabream (Sparus aurata). FISH & SHELLFISH IMMUNOLOGY 2025; 160:110201. [PMID: 39956500 DOI: 10.1016/j.fsi.2025.110201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 02/12/2025] [Accepted: 02/12/2025] [Indexed: 02/18/2025]
Abstract
Somatostatin (SST) and cortistatin (CST) are neuromodulators with distinct expression patterns and functions. While SST and CST have been extensively studied in mammalian central nervous system (CNS) and immune system, their roles in teleost fish remain poorly explored due to evolutionary emergence of multiple SST paralogous genes. This study aimed to identify SST isoforms in gilthead seabream (Sparus aurata) and assess their transcriptional levels. Phylogeny and synteny analyses reclassified the six SST genes and proteins as SST1, SST3, SST3-like, SST4, SST5, and SST6. The protein sequences showed high conservation, except for an additional region upstream of the SST3-like protein's leader region. Evolutionary differences were mainly due to specific amino acid residue changes in the mature peptide. Genetic analyses revealed constitutive expression of five genes (sst1, sst3, sst5, sst4 and sst6) in all studied organs, except for sst3 in the heart, liver, and blood. The highest expression of sst1, sst3, sst4 and sst6 genes occurred in the brain's forebrain, while sst5 was most expressed in the heart. However, sst4 exhibited very low basal expression across all analysed tissues. In vitro, λ-carrageenan and cantharidin upregulated sst6 transcription in head kidney leucocytes (HKLs), indicating a potential anti-inflammatory role similar to mammalian CST. Additionally, sst5 expression was downregulated during the innate cell-mediated cytotoxic response, suggesting a regulatory role. These findings provide insights into the SST/CST gene family in gilthead seabream, necessitating gene and protein reclassification, and underscore their significant neuroendocrine and immune system functions, relevant for teleost research.
Collapse
Affiliation(s)
- Jose Carlos Campos-Sánchez
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - Jhon A Serna-Duque
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - Francisco A Guardiola
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - Alberto Cuesta
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - María Ángeles Esteban
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain.
| |
Collapse
|
|
2
|
Sanwick AM, Haugh KN, Williams EJ, Perry KA, Thiele NA, Chaple IF. [ 89Zr]Zr-DFO-TOC: a novel radiopharmaceutical for PET imaging of somatostatin receptor positive neuroendocrine tumors. EJNMMI Radiopharm Chem 2024; 9:88. [PMID: 39693037 DOI: 10.1186/s41181-024-00320-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 11/29/2024] [Indexed: 12/19/2024] Open
Abstract
BACKGROUND Neuroendocrine tumors (NETs) are clinically diverse types of tumors that can arise anywhere in the body. Previous studies have shown that somatostatin receptors (SSTRs) are overexpressed on NET cell membranes relative to healthy tissue, allowing for tumor targeting through radiolabeled somatostatin analogs (SSAs). This work aims to develop a novel 89Zr-labeled tracer incorporating the SSA, octreotide (TOC), for positron emission tomography (PET) imaging of SSTR + NETs and predictive dosimetry calculations, leveraging the excellent nuclear (t½ = 3.27 days, β+ = 22.3%, β+avg = 395.5 keV) and chemical characteristics (+ 4 oxidation state, preferential coordination number of 7/8, favorable aqueous chemistry) of 89Zr. In combination with 89Zr, the known radiochemistry with the chelator deferoxamine (DFO) gives reason to believe that this radiopharmaceutical incorporating an octreotide conjugate will be successful in studying the suitability of detecting SSTR + NETs. RESULTS Radiochemical tracer assessment indicated that amounts as low as 0.1 nmol DFO-TOC can be effectively radiolabeled with 89Zr, while maintaining ≥ 95% radiochemical yield. The stability of the compound was found to maintain radiochemical yields of 89.6% and 88.7% on the benchtop and in mouse serum, respectively, after 9 days. Receptor binding and competitive receptor blocking assays compared AR42J (high SSTR expression), PC-3 (moderate SSTR expression), and PANC-1 (minimal SSTR expression) cell lines at time points up to 6 days. In vitro studies demonstrated highest uptake in AR42J cells, and statistically significant differences in tracer uptake were seen after 1 h. Internalization assays showed maximum internalization after 3 h for all cell lines. CONCLUSIONS In this work, [89Zr]Zr-DFO-TOC was synthesized with radiochemical yields ≥ 95% and was found to remain stable in vitro at extended time points. In vitro cell studies demonstrated a statistically significant difference between receptor binding and blocking experiments. The development of this work shows potential to positively impact patient care through the predictive dosimetry calculations for the FDA-approved therapeutic agent [177Lu]Lu-DOTA-TATE, while allowing for imaging at extended timepoints and should be studied further.
Collapse
Affiliation(s)
- Alexis M Sanwick
- Department of Nuclear Engineering, University of Tennessee, Knoxville, Knoxville, TN, 37996, USA
| | - Katherine N Haugh
- Department of Nuclear Engineering, University of Tennessee, Knoxville, Knoxville, TN, 37996, USA
| | - Evan J Williams
- Department of Nuclear Engineering, University of Tennessee, Knoxville, Knoxville, TN, 37996, USA
| | - Kala A Perry
- Department of Nuclear Engineering, University of Tennessee, Knoxville, Knoxville, TN, 37996, USA
| | - Nikki A Thiele
- Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, 37831, USA
| | - Ivis F Chaple
- Department of Nuclear Engineering, University of Tennessee, Knoxville, Knoxville, TN, 37996, USA.
| |
Collapse
|
|
3
|
Emanuilov AI, Budnik AF, Masliukov PM. Somatostatin-immunoreactive neurons of the rat gut during the development. Histochem Cell Biol 2024; 162:385-402. [PMID: 39153131 DOI: 10.1007/s00418-024-02322-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2024] [Indexed: 08/19/2024]
Abstract
Somatostatin (SST) is a peptide expressed in the peripheral and central nervous systems, as well as in endocrine and immune cells. The aim of the current study is to determine the percentage of SST immunoreactive (IR) neurons and their colocalization with choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), neuropeptide Y (NPY), and glial fibrillary acidic protein (GFAP) in the myenteric plexus (MP) and submucous plexus (SP) of the small intestine (SI) and large intestine (LI) of rats across different age groups from newborn to senescence using immunohistochemistry. In the MP of the SI and LI, the percentage of SST-IR neurons significantly increased during early postnatal development from 12 ± 2.4 (SI) and 13 ± 3.0 (LI) in newborn rats to 23 ± 1.5 (SI) and 18 ± 1.6 (LI) in 20-day-old animals, remaining stable until 60 days of age. The proportion of SST-IR cells then decreased in aged 2-year-old animals to 14 ± 2.0 (SI) and 10 ± 2.6 (LI). In the SP, the percentage of SST-IR neurons significantly rose from 22 ± 3.2 (SI) and 23 ± 1.7 (LI) in newborn rats to 42 ± 4.0 in 20-day-old animals (SI) and 32 ± 4.9 in 30-day-old animals (LI), before declining in aged 2-year-old animals to 21 ± 2.6 (SI) and 28 ± 7.4 (LI). Between birth and 60 days of age, 97-98% of SST-IR neurons in the MP and SP colocalized with ChAT in both plexuses of the SI and LI. The percentage of SST/ChAT neurons decreased in old rats to 85 ± 5.0 (SI) and 90 ± 3.8 (LI) in the MP and 89 ± 3.2 (SI) and 89 ± 1.6 (LI) in the SP. Conversely, in young rats, only a few SST-IR neurons colocalized with nNOS, but this percentage significantly increased in 2-year-old rats. The percentage of SST/NPY-IR neurons exhibited considerable variation throughout postnatal development, with no significant differences across different age groups in both the MP and SP of both intestines. No colocalization of SST with GFAP was observed in any of the studied animals. In conclusion, the expression of SST in enteric neurons increases in young rats and decreases in senescence, accompanied by changes in SST colocalization with ChAT and nNOS.
Collapse
Affiliation(s)
- Andrey I Emanuilov
- Department of Human Anatomy, Yaroslavl State Medical University, Yaroslavl, Russia
| | - Antonina F Budnik
- Department of Normal and Pathological Anatomy, Kabardino-Balkarian State University Named After H.M. Berbekov, Nalchik, Russia
| | - Petr M Masliukov
- Department of Human Anatomy, Yaroslavl State Medical University, Yaroslavl, Russia.
- Department of Normal Physiology and Biophysics, Yaroslavl State Medical University, Revoliucionnaya 5, Yaroslavl, Russia, 150000.
| |
Collapse
|
|
4
|
Sandoval KE, Witt KA. Somatostatin: Linking Cognition and Alzheimer Disease to Therapeutic Targeting. Pharmacol Rev 2024; 76:1291-1325. [PMID: 39013601 PMCID: PMC11549939 DOI: 10.1124/pharmrev.124.001117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 07/01/2024] [Accepted: 07/08/2024] [Indexed: 07/18/2024] Open
Abstract
Over 4 decades of research support the link between Alzheimer disease (AD) and somatostatin [somatotropin-releasing inhibitory factor (SRIF)]. SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-β peptide (Aβ), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation, whereas preclinical AD investigations show SRIF or SRIF receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aβ in the brain. Here, we review the links between SRIF and AD along with the therapeutic implications. SIGNIFICANCE STATEMENT: Somatostatin and somatostatin-expressing neurons in the brain are extensively involved in cognition. Loss of somatostatin and somatostatin-expressing neurons in Alzheimer disease rests at the center of a series of interdependent pathological events contributing to cognitive decline and dementia. Targeting somatostatin-mediated processes has significant therapeutic potential for the treatment of Alzheimer disease.
Collapse
Affiliation(s)
- Karin E Sandoval
- Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, Illinois
| | - Ken A Witt
- Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, Illinois
| |
Collapse
|
|
5
|
Parnami K, Surana A, Choudhary V, Bhattacharyya A. Deprivation of visual input alters specific subset of inhibitory neurons and affect thalamic afferent terminals in V1 of rd1 mouse. Front Cell Neurosci 2024; 18:1422613. [PMID: 39444393 PMCID: PMC11496165 DOI: 10.3389/fncel.2024.1422613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 09/19/2024] [Indexed: 10/25/2024] Open
Abstract
Retinitis Pigmentosa (RP) is a heterogenous group of inherited disorder, and its progression not only affects the retina but also the primary visual cortex. This manifests imbalances in the excitatory and inhibitory neurotransmission. Here, we investigated if changes in cortical functioning is linked to alterations in GABAergic population of neurons and its two important subsets, somatostatin (SST) and parvalbumin (PV) neuron in rd1 model of retinal degeneration (RD). We demonstrate marked decrease in the proportion of SST neurons in different layers of cortex whereas PV neurons were less affected. Moreover, we found reduced expression of glutamatergic thalamic afferents (VGLUT2) due to lack of visual activity. These results suggest PV neurons are likely recruited by the cortical circuitry to increase the inhibitory drive and compensate the disrupted inhibition-excitation balance. However, reduced SST expression perhaps results in weakening of stimulus selectivity. Delineating their functional role during RD will provide insights for acquisition of high-resolution vision thereby improving current state of vision restoration.
Collapse
Affiliation(s)
- Kashish Parnami
- Amity Institute of Neuropsychology and Neurosciences, Amity University Noida, Noida, India
| | - Anushka Surana
- Amity Institute of Neuropsychology and Neurosciences, Amity University Noida, Noida, India
| | - Vineet Choudhary
- Department of Biotechnology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Anwesha Bhattacharyya
- Amity Institute of Neuropsychology and Neurosciences, Amity University Noida, Noida, India
| |
Collapse
|
|
6
|
Bian Y, Kawabata R, Enwright JF, Tsubomoto M, Okuda T, Kamikawa K, Kimoto S, Kikuchi M, Lewis DA, Hashimoto T. Expression of activity-regulated transcripts in pyramidal neurons across the cortical visuospatial working memory network in unaffected comparison individuals and individuals with schizophrenia. Psychiatry Res 2024; 339:116084. [PMID: 39033685 DOI: 10.1016/j.psychres.2024.116084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 07/03/2024] [Accepted: 07/10/2024] [Indexed: 07/23/2024]
Abstract
Visuospatial working memory (vsWM), which is impaired in schizophrenia (SZ), is mediated by multiple cortical regions including the primary (V1) and association (V2) visual, posterior parietal (PPC) and dorsolateral prefrontal (DLPFC) cortices. In these regions, parvalbumin (PV) or somatostatin (SST) GABA neurons are altered in SZ as reflected in lower levels of activity-regulated transcripts. As PV and SST neurons receive excitatory inputs from neighboring pyramidal neurons, we hypothesized that levels of activity-regulated transcripts are also lower in pyramidal neurons in these regions. Thus, we quantified levels of four activity-regulated, pyramidal neuron-selective transcripts, namely adenylate cyclase-activating polypeptide-1 (ADCYAP1), brain-derived neurotrophic factor (BDNF), neuronal pentraxin-2 (NPTX2) and neuritin-1 (NRN1) mRNAs, in V1, V2, PPC and DLPFC from unaffected comparison and SZ individuals. In SZ, BDNF and NPTX2 mRNA levels were lower across all four regions, whereas ADCYAP1 and NRN1 mRNA levels were lower in V1 and V2. The regional pattern of deficits in BDNF and NPTX2 mRNAs was similar to that in transcripts in PV and SST neurons in SZ. These findings suggest that lower activity of pyramidal neurons expressing BDNF and/or NPTX2 mRNAs might contribute to alterations in PV and SST neurons across the vsWM network in SZ.
Collapse
Affiliation(s)
- Yufan Bian
- Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Rika Kawabata
- Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - John F Enwright
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Makoto Tsubomoto
- Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Takeshi Okuda
- Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Kohei Kamikawa
- Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, 634-8521, Japan
| | - Sohei Kimoto
- Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, 634-8521, Japan; Department of Neuropsychiatry, Wakayama Medical University School of Medicine, Wakayama, 641-8509, Japan
| | - Mitsuru Kikuchi
- Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan; Research Center for Child Development, Kanazawa University, Kanazawa 920-8640, Japan
| | - David A Lewis
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| | - Takanori Hashimoto
- Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA; National Hospital Organization Hokuriku Hospital, Nanto, 939-1893, Japan.
| |
Collapse
|
|
7
|
Fang Y, Wang Q, Li Y, Zeng L, Liu J, Ou K. On implications of somatostatin in diabetic retinopathy. Neural Regen Res 2024; 19:1984-1990. [PMID: 38227526 DOI: 10.4103/1673-5374.390955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 10/10/2023] [Indexed: 01/17/2024] Open
Abstract
Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina. In this review, we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases. Insufficient neuroprotection, which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy, triggers retinal neurovascular unit impairment and microvascular damage. Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy. Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated. In one such trial (EUROCONDOR), topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction, but had no impact on the onset of diabetic retinopathy. Overall, we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy. In order to achieve early prevention of diabetic retinopathy initiation, and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy, several issues need to be addressed. These include the needs to: a) update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration, b) identify patient subgroups who would benefit from somatostatin analog supplementation, c) elucidate the interactions of somatostatin, particularly exogenously-delivered somatostatin analogs, with other retinal peptides in the context of hyperglycemia, and d) design safe, feasible, low cost, and effective administration routes.
Collapse
Affiliation(s)
- Yanhong Fang
- Department of Ophthalmology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Qionghua Wang
- Department of Ophthalmology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Youjian Li
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing, China
| | - Li Zeng
- Shandong Provincial Hospital, Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Jian Liu
- Academic Unit of Ophthalmology, Bristol Medical School, University of Bristol, Bristol, UK
| | - Kepeng Ou
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing, China
| |
Collapse
|
|
8
|
Chen J, Zhao W, Cao L, Martins RST, Canário AVM. Somatostatin signalling coordinates energy metabolism allocation to reproduction in zebrafish. BMC Biol 2024; 22:163. [PMID: 39075492 PMCID: PMC11288053 DOI: 10.1186/s12915-024-01961-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 07/23/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND Energy allocation between growth and reproduction determines puberty onset and fertility. In mammals, peripheral hormones such as leptin, insulin and ghrelin signal metabolic information to the higher centres controlling gonadotrophin-releasing hormone neurone activity. However, these observations could not be confirmed in lower vertebrates, suggesting that other factors may mediate the energetic trade-off between growth and reproduction. A bioinformatic and experimental study suggested co-regulation of the circadian clock, reproductive axis and growth-regulating genes in zebrafish. While loss-of-function of most of the identified co-regulated genes had no effect or only had mild effects on reproduction, no such information existed about the co-regulated somatostatin, well-known for its actions on growth and metabolism. RESULTS We show that somatostatin signalling is pivotal in regulating fecundity and metabolism. Knock-out of zebrafish somatostatin 1.1 (sst1.1) and somatostatin 1.2 (sst1.2) caused a 20-30% increase in embryonic primordial germ cells, and sst1.2-/- adults laid 40% more eggs than their wild-type siblings. The sst1.1-/- and sst1.2-/- mutants had divergent metabolic phenotypes: the former had 25% more pancreatic α-cells, were hyperglycaemic and glucose intolerant, and had increased adipocyte mass; the latter had 25% more pancreatic β-cells, improved glucose clearance and reduced adipocyte mass. CONCLUSIONS We conclude that somatostatin signalling regulates energy metabolism and fecundity through anti-proliferative and modulatory actions on primordial germ cells, pancreatic insulin and glucagon cells and the hypothalamus. The ancient origin of the somatostatin system suggests it could act as a switch linking metabolism and reproduction across vertebrates. The results raise the possibility of applications in human and animal fertility.
Collapse
Affiliation(s)
- Jie Chen
- International Research Center for Marine Biosciences, Ministry of Science and Technology and National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China
- CCMAR/CIMAR Centro de Ciências do Mar do Algarve, Universidade do Algarve, Campus de Gambelas, Faro, 8005-139, Portugal
| | - Wenting Zhao
- International Research Center for Marine Biosciences, Ministry of Science and Technology and National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China
| | - Lei Cao
- International Research Center for Marine Biosciences, Ministry of Science and Technology and National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China
| | - Rute S T Martins
- CCMAR/CIMAR Centro de Ciências do Mar do Algarve, Universidade do Algarve, Campus de Gambelas, Faro, 8005-139, Portugal
| | - Adelino V M Canário
- International Research Center for Marine Biosciences, Ministry of Science and Technology and National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China.
- CCMAR/CIMAR Centro de Ciências do Mar do Algarve, Universidade do Algarve, Campus de Gambelas, Faro, 8005-139, Portugal.
| |
Collapse
|
|
9
|
Doello K, Chico MA, Quiñonero F, Ortiz R, Prados J, Mesas C, Melguizo C. Clinical Evaluation of Response to Octreotide and Chemotherapy in High-Grade Malignant Neuroendocrine Tumors and Promising In Vitro Preclinical Results with Pasireotide. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1039. [PMID: 39064468 PMCID: PMC11279282 DOI: 10.3390/medicina60071039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 06/18/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024]
Abstract
Background and Objectives: High-grade malignant neuroendocrine tumors (G3 NETs) and neuroendocrine carcinomas (NECs) are characterized by rapid proliferation, high metastatic capacity, and strong expression of somatostatin receptors (SSTRs). We aimed to analyze the presence of SSTRs in NET G3 and NEC, and to correlate their expression with the use of octreotide and pasireotide. Materials and Methods: For this purpose, we first performed a retrospective study of G3 NET and NEC patients, which included the determination of SSTR expression and response to octreotide treatment. Second, we selected the H69 small cell lung cancer cell line to determine the effect of octreotide and pasireotide. Results: Our results showed the traditional somatostatin analog (SSA) octreotide was ineffective in patients with NET G3 and NEC. On the other hand, RT-qPCR showed a high expression of SSTR2 and SSTR5 in H69 cells. Interestingly, while octreotide did not modify H69 cell proliferation, a strong inhibition of proliferation was detected with the use of pasireotide. Conclusions: In view of these results, a clinical trial in NET G3 and NEC patients using pasireotide is necessary to determine the usefulness of this drug in improving patient treatment.
Collapse
Affiliation(s)
- Kevin Doello
- Medical Oncology Service, Virgen de las Nieves Hospital, 18014 Granada, Spain;
| | - Maria Angeles Chico
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18014 Granada, Spain; (M.A.C.); (R.O.)
| | - Francisco Quiñonero
- Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM), 18100 Granada, Spain; (F.Q.); (C.M.)
| | - Raúl Ortiz
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18014 Granada, Spain; (M.A.C.); (R.O.)
- Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM), 18100 Granada, Spain; (F.Q.); (C.M.)
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM), 18100 Granada, Spain; (F.Q.); (C.M.)
- Department of Anatomy and Embryology, University of Granada, 18071 Granada, Spain
| | - Cristina Mesas
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18014 Granada, Spain; (M.A.C.); (R.O.)
| | - Consolación Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM), 18100 Granada, Spain; (F.Q.); (C.M.)
- Department of Anatomy and Embryology, University of Granada, 18071 Granada, Spain
| |
Collapse
|
|
10
|
Mahdavi K, Zendehdel M, Zarei H. The role of central neurotransmitters in appetite regulation of broilers and layers: similarities and differences. Vet Res Commun 2024; 48:1313-1328. [PMID: 38286893 DOI: 10.1007/s11259-024-10312-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 01/18/2024] [Indexed: 01/31/2024]
Abstract
The importance of feeding as a vital physiological function, on the one hand, and the spread of complications induced by its disorder in humans and animals, on the other hand, have led to extensive research on its regulatory factors. Unfortunately, despite many studies focused on appetite, only limited experiments have been conducted on avian, and our knowledge of this species is scant. Considering this, the purpose of this review article is to examine the role of central neurotransmitters in regulating food consumption in broilers and layers and highlight the similarities and differences between these two strains. The methodology of this review study includes a comprehensive search of relevant literature on the topic using appropriate keywords in reliable electronic databases. Based on the findings, the central effect of most neurotransmitters on the feeding of broilers and laying chickens was similar, but in some cases, such as dopamine, ghrelin, nitric oxide, and agouti-related peptide, differences were observed. Also, the lack of conducting a study on the role of some neurotransmitters in one of the bird strains made it impossible to make an exact comparison. Finally, it seems that although there are general similarities in appetite regulatory mechanisms in meat and egg-type chickens, the long-term genetic selection appropriate to breeding goals (meat or egg production) has caused differences in the effect of some neurotransmitters. Undoubtedly, conducting future studies while completing the missing links can lead to a comprehensive understanding of this process and its manipulation according to the breeding purposes of chickens.
Collapse
Affiliation(s)
- Kimia Mahdavi
- Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, 14155-6453, Iran
| | - Morteza Zendehdel
- Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, 14155-6453, Iran.
| | - Hamed Zarei
- Department of Biology, Faculty of Basic Science, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| |
Collapse
|
|
11
|
Melhorn P, Mazal P, Wolff L, Kretschmer-Chott E, Raderer M, Kiesewetter B. From biology to clinical practice: antiproliferative effects of somatostatin analogs in neuroendocrine neoplasms. Ther Adv Med Oncol 2024; 16:17588359241240316. [PMID: 38529270 PMCID: PMC10962050 DOI: 10.1177/17588359241240316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 02/27/2024] [Indexed: 03/27/2024] Open
Abstract
Somatostatin analogs (SSA), specifically octreotide and lanreotide, have demonstrated antiproliferative effects in patients with neuroendocrine tumors (NET), a group of rare malignancies of diverse origin and presentation. A prominent feature of NET cells is the expression of G protein-coupled receptors called somatostatin receptors (SSTR). Although these SSTR are not uniformly present in NET, they can be instrumental in the diagnosis and treatment of NET. Apart from their application in nuclear imaging and radionuclide therapy, SSA have proven invaluable in the treatment of hormonal syndromes associated with certain NET (antisecretory effects of SSA), but it took more than two decades to convincingly demonstrate the antiproliferative effects of SSA in metastatic NET with the two pivotal studies PROMID and CLARINET. The current review summarizes three decades of SSA treatment and provides an overview of the clinical trial landscape for SSA monotherapy and combination therapy, including clinical implications and quality of life aspects, as well as ongoing fields of research.
Collapse
Affiliation(s)
- Philipp Melhorn
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Peter Mazal
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Ladislaia Wolff
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Kretschmer-Chott
- Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Markus Raderer
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria
| | - Barbara Kiesewetter
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
12
|
Kim JY, Kim J, Kim YI, Yang DH, Yoo C, Park IJ, Ryoo BY, Ryu JS, Hong SM. Somatostatin receptor 2 (SSTR2) expression is associated with better clinical outcome and prognosis in rectal neuroendocrine tumors. Sci Rep 2024; 14:4047. [PMID: 38374188 PMCID: PMC10876978 DOI: 10.1038/s41598-024-54599-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 02/14/2024] [Indexed: 02/21/2024] Open
Abstract
Somatostatin analogues have recently been used as therapeutic targets for metastatic or surgically unresectable gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), and associated somatostatin receptor (SSTR) expression has been well demonstrated in most GEP NETs, with the exception of rectal NETs. SSTR2 immunohistochemical expressions were evaluated in 350 surgically or endoscopically resected rectal NETs and compared to clinicopathologic factors. SSTR2 expression was observed in 234 (66.9%) rectal NET cases and associated tumors with smaller size (p = 0.001), low pT classification (p = 0.030), low AJCC tumor stage (p = 0.012), and absence of chromogranin expression (p = 0.009). Patients with rectal NET and SSTR2 expression had significantly better overall survival than those without SSTR2 expression both by univariable (p = 0.006) and multivariable (p = 0.014) analyses. In summary, approximately two-thirds of rectal NETs expressed SSTR2. SSTR2 expression was significantly associated with favorable behavior and good overall survival in patients with rectal NETs. Furthermore, SSTR2 expression can be used as prognostic factors. When metastatic disease occurs, SSTR2 expression can be used a possible target for somatostatin analogues.
Collapse
Affiliation(s)
- Joo Young Kim
- Department of Pathology, Chung-Ang University Hospital, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Jisup Kim
- Department of Pathology, Gil Medical Center, Gachon University College of Medicine, Inchon, Republic of Korea
| | - Yong-Il Kim
- Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-Hoon Yang
- Departments of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Changhoon Yoo
- Departments of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In Ja Park
- Departments of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Baek-Yeol Ryoo
- Departments of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jin-Sook Ryu
- Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
13
|
Zheng XL, Li WL, Lin YP, Huang TL. Computerized tomography-guided therapeutic percutaneous puncture catheter drainage-combined with somatostatin for severe acute pancreatitis: An analysis of efficacy and safety. World J Gastrointest Surg 2024; 16:59-66. [PMID: 38328327 PMCID: PMC10845273 DOI: 10.4240/wjgs.v16.i1.59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/06/2023] [Accepted: 12/18/2023] [Indexed: 01/25/2024] Open
Abstract
BACKGROUND Severe acute pancreatitis (SAP), a condition with rapid onset, critical condition and unsatisfactory prognosis, poses a certain threat to human health, warranting optimization of relevant treatment plans to improve treatment efficacy. AIM To evaluate the efficacy and safety of computerized tomography-guided therapeutic percutaneous puncture catheter drainage (CT-TPPCD) combined with somatostatin (SS) in the treatment of SAP. METHODS Forty-two SAP patients admitted to The Second Affiliated Hospital of Fujian Medical University from June 2020 to June 2023 were selected. On the basis of routine treatment, 20 patients received SS therapy (control group) and 22 patients were given CT-TPPCD plus SS intervention (research group). The efficacy, safety (pancreatic fistula, intra-abdominal hemorrhage, sepsis, and organ dysfunction syndrome), abdominal bloating and pain relief time, bowel recovery time, hospital stay, inflammatory indicators (C-reactive protein, interleukin-6, and procalcitonin), and Acute Physiology and Chronic Health Evaluation (APACHE) II score of both groups were evaluated for comparison. RESULTS Compared with the control group, the research group had a markedly higher total effective rate, faster abdominal bloating and pain relief and bowel recovery, shorter hospital length of stay, fewer complications, and lower posttreatment inflammatory indices and APACHE-II scores. CONCLUSION CT-TPPCD in combination with SS is effective for SAP patients, which can reduce complications, accelerate symptom resolution, inhibit inflammation, and improve patient condition, with promising prospects for clinical promotion.
Collapse
Affiliation(s)
- Xue-Lan Zheng
- Department of Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Wan-Ling Li
- CT Room, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Yan-Ping Lin
- Department of Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Ting-Long Huang
- Department of Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| |
Collapse
|
|
14
|
Meenongyai W, Wongpanit K, Phongkaew P, Khejornsart P, Kamkuan P, Khamngamdi P, Kokaew N, Papsaree S, Tammanoi C, Namwongsa N, Phungkrathok N, Srijan A, Siriket C, Waramit N, Modak T, Rahman MA, Siam MSH, Kabir AKMA, Manabe N. Effects of various levels of coated cysteamine hydrochloride in the diet on feed intake, digestibility, ruminal fermentation, and blood metabolites in growing Charolais crossbred cattle. Anim Sci J 2024; 95:e13997. [PMID: 39362838 DOI: 10.1111/asj.13997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 08/05/2024] [Accepted: 08/21/2024] [Indexed: 10/05/2024]
Abstract
This study investigated the impact of different levels of coated cysteamine hydrochloride (CSH) supplementation on ruminal fermentation, nutrient digestibility, and blood metabolites in Charolais cross bulls. Twelve bulls were allotted to three feeding treatments in a replicated 3 × 3 Latin square design: 0% CSH (control), 0.5% CSH, and 1.0% CSH in concentrate. Animals were fed concentrate at 1.5% of body weight. Dry matter intake (DMI) and DMI as a percentage of body weight showed no significant differences among treatments (p > 0.10). Nutrient digestibility was consistent across treatments, except for a slight decrease in NDF digestibility with 1% CSH (p = 0.07). Ruminal pH, ammonia nitrogen, volatile fatty acid (VFA) proportions, and total VFA concentration were similar among treatments (p > 0.05). Total bacteria, fungal zoospores, and protozoa populations in the rumen did not vary significantly (p > 0.05). Blood glucose and triglyceride concentrations remained stable (p > 0.05), while blood urea nitrogen (BUN) levels were higher in CSH-supplemented groups (p < 0.05). In conclusion, incorporating CSH levels ranging from 0.5% to 1.0% into the diet did not adversely affect feed intake, ruminal fermentation, or microbial populations. Additionally, 1.0% CSH improved BUN concentration in growing Charolais cross bulls.
Collapse
Affiliation(s)
- Watcharawit Meenongyai
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Kannika Wongpanit
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
- School of integrated Science, Kasetsart University, Bangkok, Thailand
| | - Piyamas Phongkaew
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Pichad Khejornsart
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Pramoet Kamkuan
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Phongphet Khamngamdi
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Nattawut Kokaew
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Sahapap Papsaree
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Chayanun Tammanoi
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Nuttawut Namwongsa
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Natthaphon Phungkrathok
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Artsani Srijan
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Chakkrit Siriket
- Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, Thailand
| | - Naroon Waramit
- School of integrated Science, Kasetsart University, Bangkok, Thailand
- Department of Agronomy, Faculty of Agriculture at Kamphaeng Saen campus, Kasetsart University, Nakhon Pathom, Thailand
| | - Tanmay Modak
- Department of Animal Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Md Abdur Rahman
- Department of Animal Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Md Sifat Habib Siam
- Department of Animal Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - A K M Ahsan Kabir
- Department of Animal Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Noboru Manabe
- Animal Resource Science Center, The University of Tokyo, Ibaraki, Japan
- Department of Human Sciences, Osaka International University, Osaka, Japan
| |
Collapse
|
|
15
|
Milewska-Kranc A, Ćwikła JB, Kolasinska-Ćwikła A. The Role of Receptor-Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors. Cancers (Basel) 2023; 16:116. [PMID: 38201544 PMCID: PMC10778465 DOI: 10.3390/cancers16010116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Neuroendocrine tumors (NETs) arise from neuroendocrine cells and manifest in diverse organs. Key players in their regulation are somatostatin and its receptors (SSTR1-SSTR5). Understanding receptor-ligand interactions and signaling pathways is vital for elucidating their role in tumor development and therapeutic potential. This review highlights SSTR characteristics, localization, and expression in tissues, impacting physiological functions. Mechanisms of somatostatin and synthetic analogue binding to SSTRs, their selectivity, and their affinity were analyzed. Upon activation, somatostatin initiates intricate intracellular signaling, involving cAMP, PLC, and MAP kinases and influencing growth, differentiation, survival, and hormone secretion in NETs. This review explores SSTR expression in different tumor types, examining receptor activation effects on cancer cells. SSTRs' significance as therapeutic targets is discussed. Additionally, somatostatin and analogues' role in hormone secretion regulation, tumor growth, and survival is emphasized, presenting relevant therapeutic examples. In conclusion, this review advances the knowledge of receptor-ligand interactions and signaling pathways in somatostatin receptors, with potential for improved neuroendocrine tumor treatments.
Collapse
Affiliation(s)
| | - Jarosław B. Ćwikła
- School of Medicine, University of Warmia and Mazury, Aleja Warszawska 30, 10-082 Olsztyn, Poland
- Diagnostic Therapeutic Center–Gammed, Lelechowska 5, 02-351 Warsaw, Poland
| | | |
Collapse
|
|
16
|
Nery Neto JADO, Yariwake VY, Câmara NOS, Andrade-Oliveira V. Enteroendocrine cells and gut hormones as potential targets in the crossroad of the gut-kidney axis communication. Front Pharmacol 2023; 14:1248757. [PMID: 37927592 PMCID: PMC10620747 DOI: 10.3389/fphar.2023.1248757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 09/28/2023] [Indexed: 11/07/2023] Open
Abstract
Recent studies suggest that disruptions in intestinal homeostasis, such as changes in gut microbiota composition, infection, and inflammatory-related gut diseases, can be associated with kidney diseases. For instance, genomic investigations highlight how susceptibility genes linked to IgA nephropathy are also correlated with the risk of inflammatory bowel disease. Conversely, investigations demonstrate that the use of short-chain fatty acids, produced through fermentation by intestinal bacteria, protects kidney function in models of acute and chronic kidney diseases. Thus, the dialogue between the gut and kidney seems to be crucial in maintaining their proper function, although the factors governing this crosstalk are still emerging as the field evolves. In recent years, a series of studies have highlighted the significance of enteroendocrine cells (EECs) which are part of the secretory lineage of the gut epithelial cells, as important components in gut-kidney crosstalk. EECs are distributed throughout the epithelial layer and release more than 20 hormones in response to microenvironment stimuli. Interestingly, some of these hormones and/or their pathways such as Glucagon-Like Peptide 1 (GLP-1), GLP-2, gastrin, and somatostatin have been shown to exert renoprotective effects. Therefore, the present review explores the role of EECs and their hormones as regulators of gut-kidney crosstalk and their potential impact on kidney diseases. This comprehensive exploration underscores the substantial contribution of EEC hormones in mediating gut-kidney communication and their promising potential for the treatment of kidney diseases.
Collapse
Affiliation(s)
- José Arimatéa de Oliveira Nery Neto
- Bernardo’s Lab, Center for Natural and Human Sciences, Federal University of ABC, Santo André, Brazil
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Victor Yuji Yariwake
- Bernardo’s Lab, Center for Natural and Human Sciences, Federal University of ABC, Santo André, Brazil
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Niels Olsen Saraiva Câmara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Vinicius Andrade-Oliveira
- Bernardo’s Lab, Center for Natural and Human Sciences, Federal University of ABC, Santo André, Brazil
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| |
Collapse
|
|
17
|
Piscopo L, Zampella E, Pellegrino S, Volpe F, Nappi C, Gaudieri V, Fonti R, Vecchio SD, Cuocolo A, Klain M. Diagnosis, Management and Theragnostic Approach of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms. Cancers (Basel) 2023; 15:3483. [PMID: 37444593 DOI: 10.3390/cancers15133483] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/23/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) constitute an ideal target for radiolabeled somatostatin analogs. The theragnostic approach is able to combine diagnosis and therapy by the identification of a molecular target that can be diagnosed and treated with the same radiolabeled compound. During the last years, advances in functional imaging with the introduction of somatostatin analogs and peptide receptor radionuclide therapy, have improved the diagnosis and treatment of GEP-NENs. Moreover, PET/CT imaging with 18F-FDG represents a complementary tool for prognostic evaluation of patients with GEP-NENs. In the field of personalized medicine, the theragnostic approach has emerged as a promising tool in diagnosis and management of patients with GEP-NENs. The aim of this review is to summarize the current evidence on diagnosis and management of patients with GEP-NENs, focusing on the theragnostic approach.
Collapse
Affiliation(s)
- Leandra Piscopo
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Emilia Zampella
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Sara Pellegrino
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Fabio Volpe
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Carmela Nappi
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Valeria Gaudieri
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Rosa Fonti
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Silvana Del Vecchio
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Alberto Cuocolo
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Michele Klain
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| |
Collapse
|
|
18
|
Ramírez-Perdomo A, Márquez-Barrios G, Gutiérrez-Castañeda LD, Parra-Medina R. NEUROENDOCRINE PEPTIDES IN THE PATHOGENESIS OF COLORECTAL CARCINOMA. Exp Oncol 2023; 45:3-16. [PMID: 37417286 DOI: 10.15407/exp-oncology.2023.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Indexed: 07/08/2023]
Abstract
Colorectal carcinoma (CRC) is the third most frequent neoplasm worldwide and the second leading cause of mortality. Neuroendocrine peptides such as glucagon, bombesin, somatostatin, cholecystokinin, and gastrin as well as growth factors such as platelet-derived growth factor, epidermal growth factor, insulin-like growth factor, and fibroblast growth factor have been postulated as being involved in carcinogenesis. The fact that these neuroendocrine peptides are involved in the development of CRC through the activation of growth factors that stimulate a series of molecular pathways that activate oncogenic signaling mechanisms is emphasized in this review. Peptides such as CCK1, serotonin, and bombesin have been found to be over-expressed in human tumor tissues. Meanwhile, the expression of peptides such as GLP2 has been seen mainly in murine models. The information contained in this review provides a better understanding of the role these peptides play in the pathogenesis of CRC for basic and clinical science studies.
Collapse
Affiliation(s)
- A Ramírez-Perdomo
- Pathology, University Foundation of Health Sciences, Bogota Calle 10 #18-75, ColombiaPathology, University Foundation of Health Sciences, Bogota Calle 10 #18-75, Colombia
| | - G Márquez-Barrios
- Pathology, University Foundation of Health Sciences, Bogota Calle 10 #18-75, Colombia
| | - L D Gutiérrez-Castañeda
- Basic Health Sciences Group, University Foundation of Health Sciences, Bogota, Colombia
- Research Institute, University Foundation of Health Sciences (FUCS), Bogotá, Colombia
| | - R Parra-Medina
- Pathology Department, University Foundation of Health Sciences (FUCS), Bogota Calle 10 #18-75, Colombia
- Research Institute, University Foundation of Health Sciences, Bogota, Colombia
| |
Collapse
|
|
19
|
Reis MDDS, Veneziani LP, Porto FL, Lins MP, Mendes-da-Cruz DA, Savino W. Intrathymic somatotropic circuitry: consequences upon thymus involution. Front Immunol 2023; 14:1108630. [PMID: 37426675 PMCID: PMC10323194 DOI: 10.3389/fimmu.2023.1108630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
Growth hormone (GH) is a classic pituitary-derived hormone crucial to body growth and metabolism. In the pituitary gland, GH production is stimulated by GH-releasing hormone and inhibited by somatostatin. GH secretion can also be induced by other peptides, such as ghrelin, which interacts with receptors present in somatotropic cells. It is well established that GH acts directly on target cells or indirectly by stimulating the production of insulin-like growth factors (IGFs), particularly IGF-1. Notably, such somatotropic circuitry is also involved in the development and function of immune cells and organs, including the thymus. Interestingly, GH, IGF-1, ghrelin, and somatostatin are expressed in the thymus in the lymphoid and microenvironmental compartments, where they stimulate the secretion of soluble factors and extracellular matrix molecules involved in the general process of intrathymic T-cell development. Clinical trials in which GH was used to treat immunocompromised patients successfully recovered thymic function. Additionally, there is evidence that the reduction in the function of the somatotropic axis is associated with age-related thymus atrophy. Treatment with GH, IGF-1 or ghrelin can restore thymopoiesis of old animals, thus in keeping with a clinical study showing that treatment with GH, associated with metformin and dehydroepiandrosterone, could induce thymus regeneration in healthy aged individuals. In conclusion, the molecules of the somatotrophic axis can be envisioned as potential therapeutic targets for thymus regeneration in age-related or pathological thymus involution.
Collapse
Affiliation(s)
- Maria Danielma dos Santos Reis
- Laboratory of Cell Biology, Institute of Biological and Health Sciences, Federal University of Alagoas, Maceió, Brazil
- Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazilian National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
| | - Luciana Peixoto Veneziani
- Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazilian National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- INOVA-IOC Network on Neuroimmunomodulation, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Felipe Lima Porto
- Laboratory of Cell Biology, Institute of Biological and Health Sciences, Federal University of Alagoas, Maceió, Brazil
- Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazilian National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
| | - Marvin Paulo Lins
- Laboratory of Cell Biology, Institute of Biological and Health Sciences, Federal University of Alagoas, Maceió, Brazil
- Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazilian National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
| | - Daniella Arêas Mendes-da-Cruz
- Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazilian National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- INOVA-IOC Network on Neuroimmunomodulation, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Wilson Savino
- Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazilian National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- INOVA-IOC Network on Neuroimmunomodulation, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| |
Collapse
|
|
20
|
Liu L, Zhang L, Li C, Qiu Z, Kuang T, Wu Z, Deng W. Effects of hormones on intestinal stem cells. Stem Cell Res Ther 2023; 14:105. [PMID: 37101229 PMCID: PMC10134583 DOI: 10.1186/s13287-023-03336-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 04/13/2023] [Indexed: 04/28/2023] Open
Abstract
The maintenance of intestinal renewal and repair mainly depends on intestinal stem cells (ISCs), which can also contribute to the growth of intestinal tumours. Hormones, which are vital signalling agents in the body, have various effects on the growth and replacement of intestinal stem cells. This review summarises recent progress in the identification of hormones associated with intestinal stem cells. Several hormones, including thyroid hormone, glucagon-like peptide-2, androgens, insulin, leptin, growth hormone, corticotropin-releasing hormone and progastrin, promote the development of intestinal stem cells. However, somatostatin and melatonin are two hormones that prevent the proliferation of intestinal stem cells. Therefore, new therapeutic targets for the diagnosis and treatment of intestinal illnesses can be identified by examining the impact of hormones on intestinal stem cells.
Collapse
Affiliation(s)
- Li Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Lilong Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chunlei Li
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhendong Qiu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Tianrui Kuang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhongkai Wu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Wenhong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
| |
Collapse
|
|
21
|
Mawla AM, van der Meulen T, Huising MO. Chromatin accessibility differences between alpha, beta, and delta cells identifies common and cell type-specific enhancers. BMC Genomics 2023; 24:202. [PMID: 37069576 PMCID: PMC10108528 DOI: 10.1186/s12864-023-09293-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 04/03/2023] [Indexed: 04/19/2023] Open
Abstract
BACKGROUND High throughput sequencing has enabled the interrogation of the transcriptomic landscape of glucagon-secreting alpha cells, insulin-secreting beta cells, and somatostatin-secreting delta cells. These approaches have furthered our understanding of expression patterns that define healthy or diseased islet cell types and helped explicate some of the intricacies between major islet cell crosstalk and glucose regulation. All three endocrine cell types derive from a common pancreatic progenitor, yet alpha and beta cells have partially opposing functions, and delta cells modulate and control insulin and glucagon release. While gene expression signatures that define and maintain cellular identity have been widely explored, the underlying epigenetic components are incompletely characterized and understood. However, chromatin accessibility and remodeling is a dynamic attribute that plays a critical role to determine and maintain cellular identity. RESULTS Here, we compare and contrast the chromatin landscape between mouse alpha, beta, and delta cells using ATAC-Seq to evaluate the significant differences in chromatin accessibility. The similarities and differences in chromatin accessibility between these related islet endocrine cells help define their fate in support of their distinct functional roles. We identify patterns that suggest that both alpha and delta cells are poised, but repressed, from becoming beta-like. We also identify patterns in differentially enriched chromatin that have transcription factor motifs preferentially associated with different regions of the genome. Finally, we not only confirm and visualize previously discovered common endocrine- and cell specific- enhancer regions across differentially enriched chromatin, but identify novel regions as well. We compiled our chromatin accessibility data in a freely accessible database of common endocrine- and cell specific-enhancer regions that can be navigated with minimal bioinformatics expertise. CONCLUSIONS Both alpha and delta cells appear poised, but repressed, from becoming beta cells in murine pancreatic islets. These data broadly support earlier findings on the plasticity in identity of non-beta cells under certain circumstances. Furthermore, differential chromatin accessibility shows preferentially enriched distal-intergenic regions in beta cells, when compared to either alpha or delta cells.
Collapse
Affiliation(s)
- Alex M Mawla
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Talitha van der Meulen
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Mark O Huising
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California, One Shields Avenue, Davis, CA, 95616, USA.
- Department of Physiology and Membrane Biology, School of Medicine, University of California, One Shields Avenue, Davis, CA, 95616, USA.
| |
Collapse
|
|
22
|
Börzsei R, Borbély É, Kántás B, Hudhud L, Horváth Á, Szőke É, Hetényi C, Helyes Z, Pintér E. The heptapeptide somatostatin analogue TT-232 exerts analgesic and anti-inflammatory actions via SST 4 receptor activation: In silico, in vitro and in vivo evidence in mice. Biochem Pharmacol 2023; 209:115419. [PMID: 36693436 DOI: 10.1016/j.bcp.2023.115419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023]
Abstract
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 compounds Chemical compounds studied in this article TT-232 (PubChem CID: 74053735).
Collapse
Affiliation(s)
- Rita Börzsei
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary.
| | - Éva Borbély
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary.
| | - Boglárka Kántás
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary.
| | - Lina Hudhud
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary.
| | - Ádám Horváth
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary; Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus str. 2, H-7624 Pécs, Hungary.
| | - Éva Szőke
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary; Algonist Biotechnologies GmbH, Karl-Farkas-Gasse str. 22, A-1030 Vienna, Austria; National Laboratory for Drug Research and Development, Magyar tudósok krt. 2, H-1117 Budapest, Hungary; Eötvös Lorand Research Network, Chronic Pain Research Group, University of Pécs, H-7624, Pécs, Hungary.
| | - Csaba Hetényi
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary; Eötvös Lorand Research Network, Chronic Pain Research Group, University of Pécs, H-7624, Pécs, Hungary.
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary; PharmInVivo Ltd., Szondi str. 10, H-7629 Pécs, Hungary; Algonist Biotechnologies GmbH, Karl-Farkas-Gasse str. 22, A-1030 Vienna, Austria; National Laboratory for Drug Research and Development, Magyar tudósok krt. 2, H-1117 Budapest, Hungary; Eötvös Lorand Research Network, Chronic Pain Research Group, University of Pécs, H-7624, Pécs, Hungary.
| | - Erika Pintér
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary; PharmInVivo Ltd., Szondi str. 10, H-7629 Pécs, Hungary; Algonist Biotechnologies GmbH, Karl-Farkas-Gasse str. 22, A-1030 Vienna, Austria; National Laboratory for Drug Research and Development, Magyar tudósok krt. 2, H-1117 Budapest, Hungary; Eötvös Lorand Research Network, Chronic Pain Research Group, University of Pécs, H-7624, Pécs, Hungary.
| |
Collapse
|
|
23
|
Selective targeting of gold nanoparticles for radiosensitization of somatostatin 2 receptor-expressing cancer cells. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2023]
|
|
24
|
Kothegala L, Miranda C, Singh M, Krieger JP, Gandasi NR. Somatostatin Containing δ-Cell Number Is Reduced in Type-2 Diabetes. Int J Mol Sci 2023; 24:ijms24043449. [PMID: 36834860 PMCID: PMC9959292 DOI: 10.3390/ijms24043449] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/01/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023] Open
Abstract
Recent developments suggest that increased glucagon and decreased somatostatin secretion from the pancreas contribute to hyperglycaemia in type-2 diabetes (T2D) patients. There is a huge need to understand changes in glucagon and somatostatin secretion to develop potential anti-diabetic drugs. To further describe the role of somatostatin in the pathogenesis of T2D, reliable means to detect islet δ-cells and somatostatin secretion are necessary. In this study, we first tested currently available anti-somatostatin antibodies against a mouse model that fluorescently labels δ-cells. We found that these antibodies only label 10-15% of the fluorescently labelled δ-cells in pancreatic islets. We further tested six antibodies (newly developed) that can label both somatostatin 14 (SST14) and 28 (SST28) and found that four of them were able to detect above 70% of the fluorescent cells in the transgenic islets. This is quite efficient compared to the commercially available antibodies. Using one of these antibodies (SST10G5), we compared the cytoarchitecture of mouse and human pancreatic islets and found fewer δ-cells in the periphery of human islets. Interestingly, the δ-cell number was also reduced in islets from T2D donors compared to non-diabetic donors. Finally, with the aim to measure SST secretion from pancreatic islets, one of the candidate antibodies was used to develop a direct-ELISA-based SST assay. Using this novel assay, we could detect SST secretion under low and high glucose conditions from the pancreatic islets, both in mice and humans. Overall, using antibody-based tools provided by Mercodia AB, our study indicates reduced δ-cell numbers and SST secretion in diabetic islets.
Collapse
Affiliation(s)
- Lakshmi Kothegala
- Cell Metabolism Lab (GA-08), Department of Developmental Biology and Genetics (DBG), Indian Institute of Science (IISc), Bengaluru 560012, India
- Department of Metabolic Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Box 430, 40530 Gothenburg, Sweden
| | - Caroline Miranda
- Department of Metabolic Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Box 430, 40530 Gothenburg, Sweden
| | - Meetu Singh
- Cell Metabolism Lab (GA-08), Department of Developmental Biology and Genetics (DBG), Indian Institute of Science (IISc), Bengaluru 560012, India
| | - Jean-Philippe Krieger
- Department of Metabolic Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Box 430, 40530 Gothenburg, Sweden
| | - Nikhil R. Gandasi
- Cell Metabolism Lab (GA-08), Department of Developmental Biology and Genetics (DBG), Indian Institute of Science (IISc), Bengaluru 560012, India
- Department of Metabolic Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Box 430, 40530 Gothenburg, Sweden
- Department of Medical Cell Biology, Uppsala University, BMC 571, 75123 Uppsala, Sweden
- Correspondence: or
| |
Collapse
|
|
25
|
Oliveira HA, Somvanshi RK, Kumar U. Comparative changes in breast cancer cell proliferation and signalling following somatostatin and cannabidiol treatment. Biochem Biophys Res Commun 2023; 643:30-38. [PMID: 36586156 DOI: 10.1016/j.bbrc.2022.12.073] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/16/2022] [Accepted: 12/23/2022] [Indexed: 12/26/2022]
Abstract
Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer-related death among women worldwide. Somatostatin (SST) and Cannabinoids have an anti-proliferative and pro-apoptotic effect, but the mechanisms of their actions remain elusive. In the present study, we have evaluated the effects of SST, Cannabidiol (CBD) alone or in combination on receptor expression, cell proliferation and apoptosis and related downstream signalling pathways in MDA-MB-231 and MCF-7 breast cancer cells. The results presented here demonstrate the cell type and agonist-dependent changes in receptor expression at the cell membrane, inhibition of cell proliferation and increased apoptosis following treatment with SST and CBD alone and in combination. In comparison to MDA-MB-231 cells, MCF-7 cells treated with SST alone and in combination with CBD exhibited inhibition of phosphorylated Protein Kinase B (pAKT) and phosphorylated-Phosphoinositide 3-Kinase (pPI3K) expression. Importantly, inhibition of PI3K/AKT activation was accompanied by enhanced PTEN expression in MCF-7 cells. These results highlight the possible interaction between SSTR and CBR subtypes with the implication in the modulation of receptor expression, cell viability and signal transduction pathways in a breast cancer cell type-dependent manner.
Collapse
Affiliation(s)
- Helen A Oliveira
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Rishi K Somvanshi
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
| | - Ujendra Kumar
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
| |
Collapse
|
|
26
|
Postnatal Changes of Somatostatin Expression in Hippocampi of C57BL/6 Mice; Modulation of Neuroblast Differentiation in the Hippocampus. Vet Sci 2023; 10:vetsci10020081. [PMID: 36851385 PMCID: PMC9964365 DOI: 10.3390/vetsci10020081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/05/2022] [Accepted: 01/19/2023] [Indexed: 01/25/2023] Open
Abstract
(1) Background: Somatostatin (SST) exhibits expressional changes in the brain during development, but its role is not still clear in brain development. (2) Methods: We investigated postnatal SST expression and its effects on hippocampal neurogenesis via administering SST subcutaneously to P7 mice for 7 days. (3) Results: In the hippocampal CA1 region, SST immunoreactivity reaches peak at P14. However, SST immunoreactivity significantly decreased at P21. In the CA2/3 region, the SST expression pattern was similar to the CA1, and SST-immunoreactive cells were most abundant at P14. In the dentate gyrus, SST-immunoreactive cells were most abundant at P7 and P14 in the polymorphic layer; as in CA1-3 regions, the immunoreactivity decreased at P21. To elucidate the role of SST in postnatal development, we administered SST subcutaneously to P7 mice for 7 days. In the subgranular zone of the hippocampal dentate gyrus, a significant increase was observed in immunoreactivity of doublecortin (DCX)-positive neuroblast after administration of SST.; (4) Conclusions: SST expression in the hippocampal sub-regions is transiently increased during the postnatal formation of the hippocampus and decreases after P21. In addition, SST is involved in neuroblast differentiation in the dentate gyrus of the hippocampus.
Collapse
|
|
27
|
Morishita F, Horiguchi T, Akuta H, Ueki T, Imamura T. Concomitant downregulation of neuropeptide genes in a marine snail with consecutive sexual maturation after a nuclear disaster in Japan. Front Endocrinol (Lausanne) 2023; 14:1129666. [PMID: 36967776 PMCID: PMC10036341 DOI: 10.3389/fendo.2023.1129666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/07/2023] [Indexed: 03/12/2023] Open
Abstract
Consecutive sexual maturation (CSM), an abnormal reproductive phenomenon of a marine snail, Reishia clavigera, has occurred since 2017 in the vicinity of the Fukushima Daiichi Nuclear Power Plant after the nuclear disaster there. We hypothesized that alterations in animal physiology mediated through genetic/epigenetic changes could sensitively reflect environmental pollution. Understanding the mechanism of this rapid biological response should enable us to quantitatively evaluate long-lasting effects of the nuclear disaster. To determine the molecular basis for CSM, we conducted transcriptome profiling in the ganglia of normal and CSM snails. We assembled the short-read cDNA sequences obtained by Illumina sequencing, and succeeded in characterizing more than 60,000 gene models that include 88 kinds of neuropeptide precursors by BLAST search and experimental curation. GO-enrichment analysis of the differentially expressed genes demonstrated that severe downregulation of neuropeptide-related genes occurred concomitantly with CSM. In particular, significant decreases of the transcripts of 37 genes among 88 neuropeptide precursor genes, including those for myomodulin, PentaFVamide, maturation-associated peptide-5A and conopressin, were commonly observed in female and male CSM snails. By contrast, microseminoprotein precursor was the only exceptional case where the expression was increased in CSM snails. These results indicate that down-regulation of neuropeptide precursors is a remarkable feature of CSM. We also found that factors involved in epigenetic modification rather than transcription factors showed altered patterns of expression upon CSM. Comprehensive expression panels of snail neuropeptide precursors made in this study will be useful tools for environmental assessment as well as for studying marine reproductive biology.
Collapse
Affiliation(s)
- Fumihiro Morishita
- Program of Basic Biology, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan
- Department of Biological Science, Faculty of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan
- *Correspondence: Fumihiro Morishita, ; Takuya Imamura,
| | - Toshihiro Horiguchi
- Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan
| | - Hiroto Akuta
- Department of Biological Science, Faculty of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan
| | - Tatsuya Ueki
- Program of Basic Biology, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan
- Department of Biological Science, Faculty of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan
| | - Takuya Imamura
- Program of Basic Biology, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan
- Department of Biological Science, Faculty of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan
- Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan
- *Correspondence: Fumihiro Morishita, ; Takuya Imamura,
| |
Collapse
|
|
28
|
Co-Expression of Adaptor Protein FAM159B with Different Markers for Neuroendocrine Cells: An Immunocytochemical and Immunohistochemical Study. Int J Mol Sci 2022; 23:ijms232113503. [DOI: 10.3390/ijms232113503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 10/23/2022] [Accepted: 11/03/2022] [Indexed: 11/06/2022] Open
Abstract
Little is known about the adaptor protein FAM159B. Recently, FAM159B was shown to be particularly expressed in neuroendocrine cells and tissues, such as pancreatic islets and neuroendocrine cells of the bronchopulmonary and gastrointestinal tracts, as well as in different types of neuroendocrine tumours. To gain insights into possible interactions of FAM159B with other proteins and/or receptors, we analysed the co-expression of FAM159B and various neuroendocrine-specific markers in the cancer cell lines BON-1, PC-3, NCI-h82, OH-1, and A431 and also in human pancreatic tissues and pancreatic neuroendocrine tumours. The markers included prominent markers of neuroendocrine differentiation, such as chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin (SYP), insulinoma-associated protein 1 (INSM1), neural cell adhesion molecule 1 (NCAM1), serotonin (5-HT), somatostatin-14/28 (SST), and several receptors that are typically expressed by neuroendocrine cells, such as dopamine receptor 2 (D2R), somatostatin receptor (SSTR) 1, 2, 3, 4 and 5, and regulator of G-protein signalling 9 (RGS9). FAM159B was expressed evenly throughout the cytosol in all five cancer cell lines. Immunocytochemical and immunohistochemical analyses revealed co-expression of FAM159B with SYP, INSM1, RGS9, D2R, SSTR2, SSTR3, SSTR4, and SSTR5 and strong overlapping co-localisation with NSE. Double-labelling and co-immunoprecipitation Western blot analyses confirmed a direct association between FAM159B and NSE. These results suggest the involvement of FAM159B in several intracellular signalling pathways and a direct or indirect influence on diverse membrane proteins and receptors.
Collapse
|
|
29
|
Balog M, Anderson A, Gurumurthy CB, Quadros RM, Korade Z, Mirnics K. Knock-in mouse models for studying somatostatin and cholecystokinin expressing cells. J Neurosci Methods 2022; 381:109704. [PMID: 36070817 DOI: 10.1016/j.jneumeth.2022.109704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Somatostatin (SST) and cholecystokinin (CCK) are peptide hormones that regulate the endocrine system, cell proliferation and neurotransmission. NEW METHOD We utilized the novel Easi-CRISPR system to generate two knock-in mouse strains with Cre recombinase in SST- and CCK-expressing cells and validated their utility in the developing and adult brain tissues. RESULTS The full nomenclature for the newly generated strains are C57BL/6-Sstem1(P2A-iCre-T2A-mCherry)Mirn and C57BL/6-Cckem1(iCre-T2A-mCherry-P2A)Mirn. For the Sst locus, a P2A-iCre-T2A-mCherry cassette was inserted immediately upstream of the stop codon (C terminus fusion). For the Cck locus, iCre-P2A-mCherry-T2A cassette was inserted at the start codon (N terminus fusion). Knock-in mice were generated using the Easi-CRISPR method. Developmental and adult SST and CCK expressions were preserved and showed an appropriate expression pattern in both models, with an active fluorescent tag in both animal lines. COMPARISON WITH EXISTING METHODS Knock-in mouse models to study cell types that produce these critically important molecules are limited to date. The knock-in mice we generated can be used as reporters to study development, physiology, or pathophysiology of SST and CCK expressing cells - without interference with native expression of SST and CCK. In addition, they can be used as Cre driver models to conditionally delete floxed genes in SST and CCK expressing cells across various tissues. CONCLUSIONS These two mouse models serve as valuable tools for in vitro and in vivo research studies related to SST and CCK biology across the lifespan and across different tissue types.
Collapse
Affiliation(s)
- Marta Balog
- Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center Omaha, NE, USA; Department of Medical Biology and Genetics, Faculty of Medicine, University of Osijek, Osijek, Croatia
| | - Allison Anderson
- Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center Omaha, NE, USA
| | - Channabasavaiah B Gurumurthy
- Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Rolen M Quadros
- Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, NE, USA
| | - Zeljka Korade
- Department of Pediatrics, University of Nebraska Medical Center Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center Omaha, NE, USA; Child Health Research Institute, University of Nebraska Medical Center Omaha, NE, USA.
| | - Karoly Mirnics
- Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center Omaha, NE, USA; Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pediatrics, University of Nebraska Medical Center Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center Omaha, NE, USA; Child Health Research Institute, University of Nebraska Medical Center Omaha, NE, USA.
| |
Collapse
|
|
30
|
Sáez-Martínez P, Porcel-Pastrana F, Pérez-Gómez JM, Pedraza-Arévalo S, Gómez-Gómez E, Jiménez-Vacas JM, Gahete MD, Luque RM. Somatostatin, Cortistatin and Their Receptors Exert Antitumor Actions in Androgen-Independent Prostate Cancer Cells: Critical Role of Endogenous Cortistatin. Int J Mol Sci 2022; 23:ijms232113003. [PMID: 36361790 PMCID: PMC9654089 DOI: 10.3390/ijms232113003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/17/2022] [Accepted: 10/25/2022] [Indexed: 11/25/2022] Open
Abstract
Somatostatin (SST), cortistatin (CORT), and their receptors (SSTR1-5/sst5TMD4-TMD5) comprise a multifactorial hormonal system involved in the regulation of numerous pathophysiological processes. Certain components of this system are dysregulated and play critical roles in the development/progression of different endocrine-related cancers. However, the presence and therapeutic role of this regulatory system in prostate cancer (PCa) remain poorly explored. Accordingly, we performed functional (proliferation/migration/colonies-formation) and mechanistic (Western-blot/qPCR/microfluidic-based qPCR-array) assays in response to SST and CORT treatments and CORT-silencing (using specific siRNA) in different PCa cell models [androgen-dependent (AD): LNCaP; androgen-independent (AI)/castration-resistant PCa (CRPC): 22Rv1 and PC-3], and/or in the normal-like prostate cell-line RWPE-1. Moreover, the expression of SST/CORT system components was analyzed in PCa samples from two different patient cohorts [internal (n = 69); external (Grasso, n = 88)]. SST and CORT treatment inhibited key functional/aggressiveness parameters only in AI-PCa cells. Mechanistically, antitumor capacity of SST/CORT was associated with the modulation of oncogenic signaling pathways (AKT/JNK), and with the significant down-regulation of critical genes involved in proliferation/migration and PCa-aggressiveness (e.g., MKI67/MMP9/EGF). Interestingly, CORT was highly expressed, while SST was not detected, in all prostate cell-lines analyzed. Consistently, endogenous CORT was overexpressed in PCa samples (compared with benign-prostatic-hyperplasia) and correlated with key clinical (i.e., metastasis) and molecular (i.e., SSTR2/SSTR5 expression) parameters. Remarkably, CORT-silencing drastically enhanced proliferation rate and blunted the antitumor activity of SST-analogues (octreotide/pasireotide) in AI-PCa cells. Altogether, we provide evidence that SST/CORT system and SST-analogues could represent a potential therapeutic option for PCa, especially for CRPC, and that endogenous CORT could act as an autocrine/paracrine regulator of PCa progression.
Collapse
Affiliation(s)
- Prudencio Sáez-Martínez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Francisco Porcel-Pastrana
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Jesús M. Pérez-Gómez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Sergio Pedraza-Arévalo
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Enrique Gómez-Gómez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- Urology Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Juan M. Jiménez-Vacas
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Manuel D. Gahete
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Raúl M. Luque
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
- Correspondence:
| |
Collapse
|
|
31
|
Adams J, Mosler C. Safety and efficacy considerations amongst the elderly population in the updated treatment of heart failure: a review. Expert Rev Cardiovasc Ther 2022; 20:529-541. [PMID: 35786091 DOI: 10.1080/14779072.2022.2098118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Heart failure is one of the cardiovascular diseases that impacts the geriatric population. As new clinical trials investigating heart failure are conducted, groundbreaking information is assessable to further evolve the treatment. To correctly improve the quality of life of elderly patients, it is critical to evaluate the safety and efficacy of new and improved therapy regimens. AREAS COVERED In reviewal of the 2021 and 2022 updated guidelines, the safety and efficacy of the newly indicated medications will be addressed. The new indications cover sacubitril/valsartan and two SGLT2 inhibitors: dapagliflozin and empagliflozin. An introduction to the medications discussed covers the pharmacology before addressing the efficacy and safety considerations in the elderly population. Furthermore, prime drug-drug interactions associated with the two classes of medications will be considered as well as providing possible solutions to further create the safest drug therapy for geriatric patients with common comorbidities. EXPERT OPINION The two classes of medications, the ARNI and SGLT2 inhibitors, are well-tolerated amongst the elderly population. With the release of new guidelines, the updated medications will provide safer and better therapy in this disease state for geriatrics. One major limitation includes the high cost of these brand-named medications.
Collapse
Affiliation(s)
- Jack Adams
- College of Pharmacy, The University of Findlay, Findlay, OH, 45840
| | - Charles Mosler
- College of Pharmacy, The University of Findlay, Findlay, OH, 45840
| |
Collapse
|
|
32
|
Efficacy of Endoscopic Intervention plus Growth Inhibitor and Patient Self-Management in the Treatment of Esophagogastric Variceal Bleeding in Cirrhosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6837791. [PMID: 35754688 PMCID: PMC9217583 DOI: 10.1155/2022/6837791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/04/2022] [Indexed: 11/17/2022]
Abstract
Objective To assess the efficacy of endoscopic intervention plus growth inhibitor and patient self-management in the treatment of esophagogastric variceal bleeding. Methods Between January 2019 and December 2021, 60 patients with esophagogastric variceal bleeding treated in our hospital were assessed for eligibility and randomly recruited. They were concurrently and randomly assigned at a ratio of 1 : 1 to receive either endoscopic intervention plus growth inhibitor (control group) or endoscopic intervention plus growth inhibitor and patient self-management (observation group). The endpoint is clinical efficacy. Results All eligible patients showed a similar time of hemostasis, success rate of hemostasis, rebleeding rate, and disappearance rate of varicose veins (P > 0.05). Endoscopic intervention plus growth inhibitor and patient self-management were associated with a lower incidence of complication (6.67%, including 1 (3.34%) case of ulcer and 1 (3.34%) case of fever) than endoscopic intervention plus growth inhibitor (26.67%, including 3 (10.00%) cases of ulcer, 2 (6.67%) cases of retrosternal pain, and 3 (10.00%) cases of fever) (P < 0.05). Patients in the observation group had significantly higher life satisfaction scores (25.17 ± 4.28 and 23.68 ± 5.17) than those in the control group (22.13 ± 2.24 and 18.12 ± 3.28) (P < 0.05). A decrease in life satisfaction scores was observed at 6 months after treatment, and the patients given patient self-management showed a higher satisfaction (P < 0.05). Conclusion Endoscopic intervention plus growth inhibitor and patient self-management yielded remarkable clinical efficacy in the treatment of esophagogastric variceal bleeding as it reduces the incidence of complication and enhances the life satisfaction of patients, and so it is worthy of clinical promotion.
Collapse
|
|
33
|
Somatostatin plus Ulinastatin in the Treatment of Severe Acute Pancreatitis and Its Effect on Serum Cytokine Levels. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:7223632. [PMID: 35722142 PMCID: PMC9203218 DOI: 10.1155/2022/7223632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/25/2022] [Accepted: 05/26/2022] [Indexed: 11/22/2022]
Abstract
Objective To investigate the effect of somatostatin combined with ulinastatin in the treatment of patients with severe acute pancreatitis and its effect on serum cytokine levels. Methods This study is a retrospective trial. One hundred patients with severe acute pancreatitis in our hospital between March 2020 and May 2021 were recruited and assigned into the control group (ulinastatin alone) and experimental group (somatostatin plus ulinastatin) according to different treatment methods, 50 cases each. The clinical efficacy and serum cytokine levels of the two groups were compared. Results Somatostatin plus ulinastatin was associated with a higher total effective rate versus ulinastatin alone (p < 0.05). After treatment, the experimental group observed significantly better interleukin-10 (IL-10), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α) when compared with those in the control group (p < 0.05); somatostatin plus ulinastatin resulted in better serum amylase, blood calcium, blood urea nitrogen, blood sugar, and white blood cell count versus ulinastatin alone (p < 0.05). Conclusion Somatostatin plus ulinastatin is a viable alternative in the treatment of patients with severe acute pancreatitis, with a remarkable efficacy profile. It is worthy of clinical application.
Collapse
|
|
34
|
Chen M, Mao X, Huang D, Jing J, Zou W, Mao P, Xue M, Yin W, Cheng R, Gao Y, Hu Y, Yuan S, Liu Q. Somatostatin signalling promotes the differentiation of rod photoreceptors in human pluripotent stem cell-derived retinal organoid. Cell Prolif 2022; 55:e13254. [PMID: 35633292 PMCID: PMC9251046 DOI: 10.1111/cpr.13254] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/13/2022] [Accepted: 04/28/2022] [Indexed: 11/29/2022] Open
Abstract
Objectives Stem cell‐derived photoreceptor replacement therapy is a promising strategy for the treatment of retinal degenerative disease. The development of 3D retinal organoids has permitted the production of photoreceptors. However, there is no strategy to enrich a specific photoreceptor subtype due to inadequate knowledge of the molecular mechanism underlying the photoreceptor fate determination. Hence, our aim is to explore the uncharacterized function of somatostatin signalling in human pluripotent stem cell‐derived photoreceptor differentiation. Materials and Methods 3D retinal organoids were achieved from human embryonic stem cell. The published single‐cell RNA‐sequencing datasets of human retinal development were utilized to further investigate the transcriptional regulation of photoreceptor differentiation. The assays of immunofluorescence staining, lentivirus transfection, real‐time quantitative polymerase chain reaction and western blotting were performed. Results We identified that the somatostatin receptor 2 (SSTR2)‐mediated signalling was essential for rod photoreceptor differentiation at the precursor stage. The addition of the cognate ligand somatostatin in human 3D retinal organoids promoted rod photoreceptor differentiation and inhibited cone photoreceptor production. Furthermore, we found that the genesis of rod photoreceptors was modulated by endogenous somatostatin specifically secreted by developing retinal ganglion cells. Conclusions Our study identified SSTR2 signalling as a novel extrinsic regulator for rod photoreceptor fate determination in photoreceptor precursors, which expands the repertoire of functional signalling pathways in photoreceptor development and sheds light on the optimization of the photoreceptor enrichment strategy.
Collapse
Affiliation(s)
- Mingkang Chen
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiying Mao
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Darui Huang
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Ophthalmology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Jiaona Jing
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Ophthalmology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Wenjun Zou
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Ophthalmology, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Peiyao Mao
- Department of Ophthalmology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Mengting Xue
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenjie Yin
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ruiwen Cheng
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Gao
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Youjin Hu
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China
| | - Songtao Yuan
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qinghuai Liu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
35
|
Somatostatin Primes Endothelial Cells for Agonist-Induced Hyperpermeability and Angiogenesis In Vitro. Int J Mol Sci 2022; 23:ijms23063098. [PMID: 35328517 PMCID: PMC8949535 DOI: 10.3390/ijms23063098] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
Somatostatin is an inhibitory peptide, which regulates the release of several hormones, and affects neurotransmission and cell proliferation via its five Gi protein-coupled receptors (SST1-5). Although its endocrine regulatory and anti-tumour effects have been thoroughly studied, little is known about its effect on the vascular system. The aim of the present study was to analyse the effects and potential mechanisms of somatostatin on endothelial barrier function. Cultured human umbilical vein endothelial cells (HUVECs) express mainly SST1 and SST5 receptors. Somatostatin did not affect the basal HUVEC permeability, but primed HUVEC monolayers for thrombin-induced hyperpermeability. Western blot data demonstrated that somatostatin activated the phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt) and p42/44 mitogen-activated protein kinase (MAPK) pathways by phosphorylation. The HUVEC barrier destabilizing effects were abrogated by pre-treating HUVECs with mitogen-activated protein kinase kinase/extracellular signal regulated kinase (MEK/ERK), but not the Akt inhibitor. Moreover, somatostatin pre-treatment amplified vascular endothelial growth factor (VEGF)-induced angiogenesis (3D spheroid formation) in HUVECs. In conclusion, the data demonstrate that HUVECs under quiescence conditions express SST1 and SST5 receptors. Moreover, somatostatin primes HUVECs for thrombin-induced hyperpermeability mainly via the activation of MEK/ERK signalling and promotes HUVEC proliferation and angiogenesis in vitro.
Collapse
|
|
36
|
Somatostatin Receptor 2 Expression Profiles and Their Correlation with the Efficacy of Somatostatin Analogues in Gastrointestinal Neuroendocrine Tumors. Cancers (Basel) 2022; 14:cancers14030775. [PMID: 35159042 PMCID: PMC8834049 DOI: 10.3390/cancers14030775] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/30/2022] [Accepted: 01/31/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Immunolocalization of somatostatin receptor 2 (SSTR2) could predict the therapeutic efficacy of somatostatin analogues (SSAs) in neuroendocrine tumors (NETs). Therefore, in this study, we evaluated SSTR2 immunoreactivity and elucidated its correlation with clinicopathological variables, including the therapeutic response to SSAs in gastrointestinal neuroendocrine tumors (GI-NETs) using digital image analysis (DIA) and other established methods of evaluation. SSTR2 immunoreactivity in foregut NETs was significantly higher than that in hindgut NETs. SSTR2 immunoreactivity was significantly negatively correlated with the Ki-67 labeling index in foregut NETs but positively correlated in hindgut NETs. Therefore, the significance of SSTR2 immunoreactivity in GI-NETs is considered to be different according to the primary sites. We also first demonstrated that DIA could provide a good alternative for predicting response to SSAs in evaluating SSTR2 immunoreactivity of GI-NETs. Abstract Somatostatin analogues (SSAs) are widely used to treat gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Somatostatin receptor 2 (SSTR2) immunoreactivity serves as a predictive marker of the therapeutic efficacy of SSAs in pancreatic NETs. However, SSTR2 expression profiles in tumor cells and their association with the therapeutic efficacy of SSAs remains virtually unknown in gastrointestinal NETs (GI-NETs). Therefore, we evaluated the association between SSTR2 immunoreactivity and embryological origin and proliferative activity in 132 resected surgical tissues of GI-NETs. The correlation between SSAs’ therapeutic efficacy and SSTR2 immunoreactivity was evaluated in 14 GI-NETs treated with SSAs. SSTR2 immunoreactivity was evaluated using Volante scores, immunoreactive scores, and digital image analysis (DIA). SSTR2 immunoreactivity was significantly negatively and positively correlated with the Ki-67 labeling index in foregut and hindgut NETs, respectively. In the normal mucosa, neuroendocrine cells in the rectum had significantly lower positive rates of SSTR2 than those in the stomach and duodenum. SSTR2 expression profiles in GI-NETs could differ by primary sites, while the difference of those between foregut and hindgut NETs might be derived from the SSTR2 status of normal neuroendocrine cell counterparts. In addition, DIA could provide a good alternative for predicting response to SSAs in evaluating SSTR2 immunoreactivity of GI-NETs.
Collapse
|
|
37
|
Role of Somatostatin Signalling in Neuroendocrine Tumours. Int J Mol Sci 2022; 23:ijms23031447. [PMID: 35163374 PMCID: PMC8836266 DOI: 10.3390/ijms23031447] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.
Collapse
|
|
38
|
Arman T, Nelson PS. Endocrine and paracrine characteristics of neuroendocrine prostate cancer. Front Endocrinol (Lausanne) 2022; 13:1012005. [PMID: 36440195 PMCID: PMC9691667 DOI: 10.3389/fendo.2022.1012005] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/24/2022] [Indexed: 11/12/2022] Open
Abstract
Prostate cancer is a common malignancy affecting men worldwide. While the vast majority of newly diagnosed prostate cancers are categorized as adenocarcinomas, a spectrum of uncommon tumor types occur including those with small cell and neuroendocrine cell features. Benign neuroendocrine cells exist in the normal prostate microenvironment, and these cells may give rise to primary neuroendocrine carcinomas. However, the more common development of neuroendocrine prostate cancer is observed after therapeutics designed to repress the signaling program regulated by the androgen receptor which is active in the majority of localized and metastatic adenocarcinomas. Neuroendocrine tumors are identified through immunohistochemical staining for common markers including chromogranin A/B, synaptophysin and neuron specific enolase (NSE). These markers are also common to neuroendocrine tumors that arise in other tissues and organs such as the gastrointestinal tract, pancreas, lung and skin. Notably, neuroendocrine prostate cancer shares biochemical features with nerve cells, particularly functions involving the secretion of a variety of peptides and proteins. These secreted factors have the potential to exert local paracrine effects, and distant endocrine effects that may modulate tumor progression, invasion, and resistance to therapy. This review discusses the spectrum of factors derived from neuroendocrine prostate cancers and their potential to influence the pathophysiology of localized and metastatic prostate cancer.
Collapse
Affiliation(s)
- Tarana Arman
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Peter S. Nelson
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, United States
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, United States
- *Correspondence: Peter S. Nelson,
| |
Collapse
|
|
39
|
The Local Neuropeptide System of Keratinocytes. Biomedicines 2021; 9:biomedicines9121854. [PMID: 34944669 PMCID: PMC8698570 DOI: 10.3390/biomedicines9121854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
Neuropeptides have been known for over 50 years as chemical signals in the brain. However, it is now well established that the synthesis of this class of peptides is not restricted to neurons. For example, human skin not only expresses several functional receptors for neuropeptides but, also, can serve as a local source of neuroactive molecules such as corticotropin-releasing hormone, melanocortins, and β-endorphin. In contrast, an equivalent of the hypothalamic-pituitary axis in the oral mucosa has not been well characterized to date. In view of the differences in the morphology and function of oral mucosal and skin cells, in this review I surveyed the existing evidence for a local synthesis of hypothalamic-pituitary, opiate, neurohypophyseal, and neuroendocrine neuropeptides in both epidermal and oral keratinocytes.
Collapse
|
|
40
|
Somatostatin and Its Receptor System in Colorectal Cancer. Biomedicines 2021; 9:biomedicines9111743. [PMID: 34829972 PMCID: PMC8615525 DOI: 10.3390/biomedicines9111743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/19/2021] [Accepted: 11/20/2021] [Indexed: 12/14/2022] Open
Abstract
Somatostatin (SST)/somatotropin release-inhibiting factor (SRIF) is a well-known neuropeptide, widely distributed in the central and peripheral nervous systems, that regulates the endocrine system and affects neurotransmission via interaction with five SST receptors (SST1-5). In the gastrointestinal tract, the main SST-producing cells include intestinal enteroendocrine cells (EECs) restricted to the mucosa, and neurons of the submucosal and myenteric plexuses. The action of the SRIF system is based on the inhibition of endocrine and exocrine secretion, as well as the proliferative responses of target cells. The SST1–5 share common signaling pathways, and are not only widely expressed on normal tissues, but also frequently overexpressed by several tumors, particularly neuroendocrine neoplasms (NENs). Furthermore, the SRIF system represents the only peptide/G protein-coupled receptor (GPCR) system with multiple approved clinical applications for the diagnosis and treatment of several NENs. The role of the SRIF system in the histogenesis of colorectal cancer (CRC) subtypes (e.g., adenocarcinoma and signet ring-cell carcinoma), as well as diagnosis and prognosis of mixed adenoneuroendocrine carcinoma (MANEC) and pure adenocarcinoma, is poorly understood. Moreover, the impact of the SRIF system signaling on CRC cell proliferation and its potential role in the progression of this cancer remains unknown. Therefore, this review summarizes the recent collective knowledge and understanding of the clinical significance of the SRIF system signaling in CRC, aiming to evaluate the potential role of its components in CRC histogenesis, diagnosis, and potential therapy.
Collapse
|
|
41
|
Abstract
This review focuses on the human pancreatic islet-including its structure, cell composition, development, function, and dysfunction. After providing a historical timeline of key discoveries about human islets over the past century, we describe new research approaches and technologies that are being used to study human islets and how these are providing insight into human islet physiology and pathophysiology. We also describe changes or adaptations in human islets in response to physiologic challenges such as pregnancy, aging, and insulin resistance and discuss islet changes in human diabetes of many forms. We outline current and future interventions being developed to protect, restore, or replace human islets. The review also highlights unresolved questions about human islets and proposes areas where additional research on human islets is needed.
Collapse
Affiliation(s)
- John T Walker
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Diane C Saunders
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Marcela Brissova
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Alvin C Powers
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| |
Collapse
|
|
42
|
Sobrido-Cameán D, Yáñez-Guerra LA, Deber A, Freire-Delgado M, Cacheiro-Vázquez R, Rodicio MC, Tostivint H, Anadón R, Barreiro-Iglesias A. Differential expression of somatostatin genes in the central nervous system of the sea lamprey. Brain Struct Funct 2021; 226:1031-1052. [PMID: 33532926 DOI: 10.1007/s00429-021-02224-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/19/2021] [Indexed: 01/29/2023]
Abstract
The identification of three somatostatin (SST) genes (SSTa, SSTb, and SSTc) in lampreys (Tostivint et al. Gen Comp Endocrinol 237:89-97 https://doi.org/10.1016/j.ygcen.2016.08.006 , 2016) prompted us to study their expression in the brain and spinal cord of the sea lamprey by in situ hybridization. These three genes were only expressed in equivalent neuronal populations in the hypothalamus. In other regions, SST transcripts showed clear differential expression. In the telencephalon, SSTc-positive cells were observed in the medial pallium, ventral part of the lateral pallium, striatum, subhippocampal lobe, and preoptic region. In the diencephalon, SSTa-positive cells were observed in the thalamus and SSTc-positive cells in the prethalamus, posterior tubercle, pretectal area, and nucleus of the medial longitudinal fascicle. In the midbrain, SSTc-positive cells were observed in the torus semicircularis, lateral reticular area, and perioculomotor tegmentum. Different SSTa- and SSTc-positive populations were observed in the isthmus. SSTc neurons were also observed in the rostral octavolateralis area and caudal rhombencephalon. In the spinal cord, SSTa was expressed in cerebrospinal-fluid-contacting (CSF-c) neurons and SSTc in non-CSF-c interneurons. Comparison with previous immunohistochemical studies using anti-SST-14 antibodies strongly suggests that SST-14-like neurons correspond with the SSTa populations. Thus, the SSTc populations were not reported previously in immunohistochemical studies. Cluster-based analyses and alignments of mature peptides suggested that SSTa is an ortholog of SST1 and that SSTb is closely related to SST2 and SST6. These results provide important new insights into the evolution of the somatostatinergic system in vertebrates.
Collapse
Affiliation(s)
- D Sobrido-Cameán
- Department of Functional Biology, Faculty of Biology, CIBUS, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, A Coruña, Spain.,Department of Zoology, University of Cambridge, Cambridge, UK
| | | | - A Deber
- Department of Functional Biology, Faculty of Biology, CIBUS, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, A Coruña, Spain
| | - M Freire-Delgado
- Department of Functional Biology, Faculty of Biology, CIBUS, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, A Coruña, Spain
| | - R Cacheiro-Vázquez
- Department of Functional Biology, Faculty of Biology, CIBUS, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, A Coruña, Spain
| | - M C Rodicio
- Department of Functional Biology, Faculty of Biology, CIBUS, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, A Coruña, Spain
| | - H Tostivint
- Molecular Physiology and Adaptation, UMR7221, CNRS and Muséum National D'Histoire Naturelle, Paris, France
| | - R Anadón
- Department of Functional Biology, Faculty of Biology, CIBUS, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, A Coruña, Spain
| | - A Barreiro-Iglesias
- Department of Functional Biology, Faculty of Biology, CIBUS, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, A Coruña, Spain.
| |
Collapse
|
|
43
|
Pivonello R, Munster PN, Terzolo M, Ferrigno R, Simeoli C, Puglisi S, Bali U, Moraitis AG. Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in ACTH-Producing Neuroendocrine Tumors: New Insight Based on the Selective Glucocorticoid Receptor Modulator Relacorilant. Front Endocrinol (Lausanne) 2021; 12:793262. [PMID: 35058882 PMCID: PMC8764187 DOI: 10.3389/fendo.2021.793262] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/22/2021] [Indexed: 12/29/2022] Open
Abstract
Somatostatin exhibits an inhibitory effect on pituitary hormone secretion, including inhibition of growth hormone and adrenocorticotropic hormone (ACTH), and it can have antisecretory and antitumor effects on neuroendocrine tumors (NETs) that express somatostatin receptors. Although the precise mechanism remains unclear, the finding that glucocorticoids downregulate somatostatin receptor subtype 2 (SSTR2) expression has been used to explain the lack of efficacy of traditional SSTR2-targeting analogs in patients with ACTH-secreting NETs. Glucocorticoid receptor (GR) antagonism with mifepristone has been shown to reverse the glucocorticoid-induced downregulation of SSTR2; however, the effects of GR modulation on SSTR2 expression in ACTH-secreting NETs, particularly corticotroph pituitary tumors, are not well known. The current study presents new insight from in vitro data using the highly selective GR modulator relacorilant, showing that GR modulation can overcome dexamethasone-induced suppression of SSTR2 in the murine At-T20 cell line. Additional data presented from clinical case observations in patients with ACTH-secreting NETs suggest that upregulation of SSTR2 via GR modulation may re-sensitize tumors to endogenous somatostatin and/or somatostatin analogs. Clinical, laboratory, and imaging findings from 4 patients [2 ACTH-secreting bronchial tumors and 2 ACTH-secreting pituitary tumors (Cushing disease)] who were treated with relacorilant as part of two clinical studies (NCT02804750 and NCT02762981) are described. In the patients with ectopic ACTH secretion, SSTR2-based imaging (Octreoscan and 68Ga-DOTATATE positron emission tomography) performed before and after treatment with relacorilant showed increased radiotracer uptake by the tumor following treatment with relacorilant without change in tumor size at computed tomography. In the patients with Cushing disease who received relacorilant prior to scheduled pituitary surgery, magnetic resonance imaging after a 3-month course of relacorilant showed a reduction in tumor size. Based on these findings, we propose that GR modulation in patients with ACTH-secreting NETs upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects. The effect of relacorilant on pituitary corticotroph tumors is being investigated in an ongoing phase 3 study (NCT03697109; EudraCT 2018-003096-35).
Collapse
Affiliation(s)
- Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico Il di Napoli, Naples, Italy
| | - Pamela N. Munster
- Department of Medicine (Hematology/Oncology), University of California San Francisco, San Francisco, CA, United States
| | - Massimo Terzolo
- Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
| | - Rosario Ferrigno
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico Il di Napoli, Naples, Italy
| | - Chiara Simeoli
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico Il di Napoli, Naples, Italy
| | - Soraya Puglisi
- Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
| | - Utsav Bali
- Bioscience Department, Sygnature Discovery Ltd, Nottingham, United Kingdom
| | - Andreas G. Moraitis
- Drug Research and Development, Corcept Therapeutics, Menlo Park, CA, United States
- *Correspondence: Andreas G. Moraitis,
| |
Collapse
|
|
44
|
Wang J, Tripathy N, Chung EJ. Targeting and therapeutic peptide-based strategies for polycystic kidney disease. Adv Drug Deliv Rev 2020; 161-162:176-189. [PMID: 32866560 PMCID: PMC7736157 DOI: 10.1016/j.addr.2020.08.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/15/2020] [Accepted: 08/27/2020] [Indexed: 12/17/2022]
Abstract
Polycystic kidney disease (PKD) is characterized by progressive cyst growth and is a leading cause of renal failure worldwide. Currently, there are limited therapeutic options available to PKD patients, and only one drug, tolvaptan, has been FDA-approved to slow cyst progression. Similar to other small molecule drugs, however, tolvaptan is costly, only moderately effective, and causes adverse events leading to high patient dropout rates. Peptides may mitigate many drawbacks of small molecule drugs, as they can be highly tissue-specific, biocompatible, and economically scaled-up. Peptides can function as targeting ligands that direct therapies to diseased renal tissue, or be potent as therapeutic agents themselves. This review discusses various aberrant signaling pathways in PKD and renal receptors that can be potential targets of peptide-mediated strategies. Additionally, peptides utilized in other kidney applications, but may prove useful in the context of PKD, are highlighted. Insights into novel peptide-based solutions that have potential to improve clinical management of PKD are provided.
Collapse
Affiliation(s)
- Jonathan Wang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Nirmalya Tripathy
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Eun Ji Chung
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA; Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA; Department of Medicine, Division of Nephrology and Hypertension, University of Southern California, Los Angeles, CA, USA; Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, University of Southern California, Los Angeles, CA, USA.
| |
Collapse
|