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1
Gallo-Payet, N. "Nouveaux concepts sur la régulation de la sécrétion d'aldostérone ; interactions endocrines, paracrines, autocrines et neurocrines." médecine/sciences 9, n.º 8-9 (1993): 943. http://dx.doi.org/10.4267/10608/3015.
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Kjekshus, Harald, Otto A. Smiseth, Randi Klinge, Erik Øie, Marit E. Hystad y Håvard Attramadal. "Regulation of ET: pulmonary release of ET contributes to increased plasma ET levels and vasoconstriction in CHF". American Journal of Physiology-Heart and Circulatory Physiology 278, n.º 4 (1 de abril de 2000): H1299—H1310. http://dx.doi.org/10.1152/ajpheart.2000.278.4.h1299.
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Endothelin (ET) contributes to the increased systemic vascular resistance and elevated cardiac filling pressures seen in congestive heart failure (CHF). We investigated to what extent ET-mediated vasoconstriction in CHF occurs through an endocrine action of elevated plasma ET or by an autocrine/paracrine mechanism related to induction of vascular ET gene expression. Three weeks of pacing (225 beats/min) induced a marked release of ET-1 from the pulmonary circulation with a sixfold elevation of arterial plasma ET in CHF pigs compared with sham-operated pigs. Arterial plasma ET was the strongest and only independent predictor of systemic vascular resistance. In contrast, vascular preproET-1 and ET-receptor mRNA expression were unaltered or decreased in CHF pigs and did not correlate with indexes of vascular tone. However, myocardial preproET-1 mRNA expression increased twofold in CHF pigs. PreproET-2 and preproET-3 mRNAs were not detectable in cardiovascular tissues. In conclusion, plasma ET was markedly increased because of an augmented release from the pulmonary circulation during CHF, and arterial plasma ET correlated with systemic vascular resistance. The absence of ET induction in the peripheral vasculature suggests that ET increases vascular tone during CHF by an endocrine, not an autocrine/paracrine, mechanism.
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Towler, Dwight A. "Bone morphogenetic proteins". Blood 114, n.º 10 (3 de septiembre de 2009): 2012–13. http://dx.doi.org/10.1182/blood-2009-06-228544.
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Abstract BMP2 and BMP4 play crucial inductive roles during development. In this issue of Blood, Shao et al demonstrate that an intricate network of paracrine BMP2/4 signals also regulates angiogenesis—and will very likely interact with endocrine BMP cues during wound repair.1
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Tonon, MC, C. Patte, J. Leprince, P. Gandolfo, M. Lamacz, JL Thoumas, J. Garcia de Mateos, J. Costentin y H. Vaudry. "Les endozépines : peptides ubiquistes à activités intracrine, autocrine, paracrine, endocrine et exocrine". médecine/sciences 13, n.º 5 (1997): 702. http://dx.doi.org/10.4267/10608/441.
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Sallon, C., I. Boulay, D. Logeart-Avramoglou, M. J. Fontaine, S. Canépa, X. Cayla y C. Taragnat. "Nouvelles perspectives dans l’action paracrine et/ou endocrine des BMPs au niveau hypophysaire". Annales d'Endocrinologie 74, n.º 4 (septiembre de 2013): 434. http://dx.doi.org/10.1016/j.ando.2013.07.698.
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Brandt, R. R., D. M. Heublein, M. T. Mattingly, M. R. Pittelkow y J. C. Burnett. "Presence and secretion of atrial natriuretic peptide from cultured human aortic endothelial cells". American Journal of Physiology-Heart and Circulatory Physiology 268, n.º 2 (1 de febrero de 1995): H921—H925. http://dx.doi.org/10.1152/ajpheart.1995.268.2.h921.
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The endothelium is the production site of several potent vasoactive substances that modulate vascular tone and growth. The present study was undertaken to investigate the presence and secretion of atrial natriuretic peptide (ANP) immunoreactivity from vascular endothelial cells. ANP immunoreactivity was present in cultured human aortic endothelial cells by both immunohistochemical staining and radioimmunoassay. ANP immunoreactivity was also detectable in culture medium from human aortic endothelial cells in low picogram concentrations. These findings suggest that vascular endothelium is a site of ANP production and secretion of ANP. There was a differential distribution of ANP and endothelin-1 (ET-1), with a higher ANP concentration in cell extracts and a higher ET-1 concentration in cell culture media. Although ANP has been conceived as a circulating endocrine hormone, these findings are consistent with ANP functioning also as an autocrine and paracrine modulator in the regulation of vascular tone and growth.
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Manshaei, Saba, Thea Willis, Dominic Withers, Jesus Gil, Cynthia Lilian Andoniadou y Juan Pedro Martinez-Barbera. "Paracrine Signalling From SOX2-Expressing Pituitary Embryonic Cells Is Required for Terminal Differentiation of Hormone-Producing Cells". Journal of the Endocrine Society 5, Supplement_1 (1 de mayo de 2021): A547—A548. http://dx.doi.org/10.1210/jendso/bvab048.1115.
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Abstract The pituitary gland is the master regulator of the endocrine system, housing six major hormone producing cell types. This gland is derived from Rathke’s Pouch, an invagination of the oral ectoderm. Hormone-producing pituitary cell lineages are derived from a population of embryonic cells expressing SOX2. ZFP36L1/Butyrate Response Factor 1 (BRF1) is an RNA binding protein that binds and targets mRNAs of various cytokines and chemokines for degradation prior to translation, attenuating secretion of inflammatory factors (Herranz et al. 2015). Here, we show that BRF1 is a novel marker expressed in SOX2+ cells in human and mouse pituitaries, suggesting that these cells may have a secretory profile. To investigate this possibility, we have combined molecular and genetic studies in vivo. We have used a novel mouse model, R26lsl-mBRF1 that allows the expression of a mutant, constitutively active BRF1 protein upon Cre-mediated recombination, alongside our lab’s models (Hesx1Cre/+ and Sox2CreERT2/+), to express mutant BRF1 in HESX1+ and SOX2+ cells during development and postnatally. This approach results in pituitary hypoplasia and severe hypopituitarism due to a failure of cell-lineage specified cells to differentiate into hormone-producing cells. Hormone production in these mutant cells, however, can be rescued in vitro through co-culture with WT pituitaries and in vivo in chimeric pituitaries, highlighting a cell non-autonomous mechanism underlying the phenotype. Single cell RNA sequencing of WT and Sox2CreERT2/+;R26lsl-mBRF1 murine embryonic pituitaries, as well as use publicly available human pituitary single cell datasets, have allowed us to identify specific cytokines and chemokines secreted by SOX2+ cells, as well as downstream intracellular signalling pathways in differentiating cells (Zhang et al. 2020), which may be responsible for controlling terminal differentiation of hormone-producing cells within the developing pituitary. Together with our recently published data, these results support the notion that SOX2+ pituitary stem cells play a critical paracrine role in controlling progenitor cell proliferation and terminal differentiation (Russell et al. 2021). References: Herranz, Nicolás et al. 2015. “MTOR Regulates MAPKAPK2 Translation to Control the Senescence-Associated Secretory Phenotype.” Nature Cell Biology 17(9): 1205–17. http://www.nature.com/doifinder/10.1038/ncb3225. Russell, John P et al. 2021. “Pituitary Stem Cells Produce Paracrine WNT Signals to Control the Expansion of Their Descendant Progenitor Cells.” eLife. Zhang, Shu et al. 2020. “Single-Cell Transcriptomics Identifies Divergent Developmental Lineage Trajectories during Human Pituitary Development.” Nature Communications.
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Ojog, Victor. "Morphofunctional traits and reactivity of the portal vein". Moldovan Medical Journal 66, n.º 2 (diciembre de 2023): 83–90. http://dx.doi.org/10.52418/moldovan-med-j.66-2.23.13.
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Background: Portal vein is the most enigmatic vessel of our body because it regulates own contractile performances using a special pace-maker mechanism represented by cells of Cajal. The contribution of various metabolic mediators and natural vasotropic agents in the control of the portal blood circuit is much less studied compared to the arterial system in general and the hepatic system in particular. The studies designed on the structure, function, and reactivity of the portal vein in different preconditioning have brought some common but also distinct evidence of the arterial system. Nitric oxide production is higher partly due to reduced arginase expression, but muscular media is thinner. Periodic spontaneous contractions directed towards the liver gate are characteristic for portal vein (PV), and the longitudinal muscle fibers are considered to be responsible for this phenomenon. Spontaneous rhythmic oscillations of the cells of Cajal are triggered by increasing calcium ion concentration leading to their depolarization. PV constrictor effect of phenylephrine is dependent on the activity of receptors to ET-1. For PV is characterized the acetylcholine induced contraction either in vivo or in vitro, and this effect is thought to be dependent on ET-1. Conclusions: The establishment of main particularities of portal vein reactivity of action of different paracrine, endocrine, and hemodynamical stimuli represents an important tool for prediction of contractile disorders leading plausible to portal hypertension. Likewise, a well proven interplay between cholinergic and adrenergic stimulations and on the other hand between Ang II and ET-1 actions must be a support for pharmacological modulating of portal vein reactivity disorders.
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Smekalova, Araksiya, Elena K. Montvila, Olga Konovalova, Olga Mityashova y Irina Lebedeva. "PSII-32 In vitro effect of growth hormone on progesterone production by large preovulatory follicles depends on the hen age and follicular layers interaction". Journal of Animal Science 98, Supplement_4 (3 de noviembre de 2020): 372. http://dx.doi.org/10.1093/jas/skaa278.654.
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Abstract Growth hormone (GH) is an endocrine and paracrine/autocrine regulator of the hen ovarian function, with the GH receptor concentration in the granulosa layer (GL) being maximum in the largest preovulatory follicle (Lebedeva et al. 2004, Biol.Reprod. 71:1174–1181). In the present study, GH effects on in vitro production of progesterone by GL from the two largest yellow follicles (F1 and F2) were investigated due to the hen age and the presence of the theca layer (TL). Young hens with long clutch (YLC, 32–33 week-old, >10 eggs per clutch) and old hens with short clutch (OSC, 74–76 week-old, 3–6 eggs per clutch) were used. After isolation, GL from F1 and F2 follicles (n = 8–9) was cultured separately or jointly with the respective TL for 18 h in the presence or absence of chicken GH (25 ng/ml). Concentrations of progesterone in culture media were measured by ELISA. The data were analyzed by repeated measures ANOVA. When GL from F1 follicle cultured alone, GH did not affect progesterone production in YLC hens and decreased it from 30,5±3,4 to 20,5±2,9 ng/mg tissue (P < 0.01) in OSC hens. Conversely, when tested GL from F2 follicle, GH increased progesterone output from 15,8±2,4 to 20,4±2,5 ng/mg tissue (P < 0.05) in YLC birds and had no effect on the output in OSC birds. During co-culture of GL and TL, GH raised 1.4–1.5 times the production of progesterone in the case of F1 follicle and did not change it in the case of F2 follicle in hens of both ages. The findings indicate that the steroidogenic response of GL from the two largest preovulatory follicles to GH differs in young and old hens. However, the interaction with TL modifies the GL response and makes it similar in birds regardless the age and reproductive status. The study was supported by RFBR (19-016-00216).
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Bashirov, Farid V., Ilnur I. Salafutdinov, Michail E. Sokolov, Andrew A. Izmailov, Vage A. Markosyan, Filip O. Fadeev, Albert Rizvanov y Rustem I. Islamov. "Umbilical Cord Blood Mononuclear Cells for Ex-Vivo Gene Therapy". Blood 132, Supplement 1 (29 de noviembre de 2018): 5797. http://dx.doi.org/10.1182/blood-2018-99-113462.
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Abstract Cell-mediated (ex-vivo) gene therapy for the treatment of adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) had started in 1990 and nowadays it is the first marketing approval of an ex vivo gene therapy in Europe. The method based on ex-vivo transduction of peripheral blood lymphocytes with retroviral vector carrying the functional ADA gene in 2002 have been improved to use hematopoietic stem cell (HSC) for ex-vivo transduction with 100% survival and the evidence of safety and efficacy. Remarkably, umbilical cord blood mononuclear cells (UCB-MC) were successfully used for treatment of ADA deficiency in neonates as well. Meanwhile SCID is a very rare congenital disorder of the immune system although the option to use peripheral blood lymphocytes as cell carriers of the therapeutic genes for regenerative medicine is highly attractive. In our studies to overcome the neural cells death and stimulate neuroregeneration at neurodegenerative diseases (ALS), spinal cord injury (SCI), and stroke in animal models we employed ex-vivo triple gene therapy based on human UCB-MC transduced with adenoviral vectors carrying vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF) and neural cell adhesion molecule (NCAM). The reason for clinical application of UCB-MC is based on their availability, ease of preparation and potential for long term storage, as well as legislative, ethical and religious benefits for the transplantation. In our gene-cell construct NCAM was used for homing and survival of UCB-MC at the site of neurodegeneration. VEGF and GDNF are the molecules with well-known neuroprotective function. Moreover VEGF is useful in restoring of the microcirculation as well. The positive results in treatment of ALS mice (Islamov et al, 2016), SCI (Izmailov et al, 2017) and stroke in rats (Sokolov et al, 2018) let us to propose the rationality to use of UCB-MC as cell carriers for the therapeutic genes based on:(1) suitability for both auto- and allotransplantation; (2) low immunogenicity; (3) high level of transduction; (4) high capability of synthetic and secretory activity for production of recombinant therapeutic molecules as well as endogenous growth and neurotrophic factors, cytokines and chemokines; (5) the action of therapeutic molecules on target cells via the paracrine or endocrine mechanism; (6) duration of recombinant molecule production limited by adenoviral vector half-life; (7) elimination of UCB-MC in 1-2 month after administration and possible multiple transplantation. Important, cell-mediated gene delivery makes the viral antigens inside the ex-vivo transduced UCB-MC invisible to the recipient immune system and it is easy to control production of recombinant molecules via the level of cell transduction or the number of transplanted cells. Thus, the cord blood mononuclear cells can serve as powerful tools for address delivery of recombinant genes encoding therapeutic molecules for regenerative medicine. This study was supported by the grant of Russian Science Foundation No 16-15-00010. Kazan Federal University was supported by the Russian Government Program of Competitive Growth. Disclosures No relevant conflicts of interest to declare.
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Songsasen, N., C. Guzy y D. E. Wildt. "121 ALGINATE-FIBRIN GEL MATRIX PROMOTES IN VITRO GROWTH OF DOG SECONDARY FOLLICLES". Reproduction, Fertility and Development 24, n.º 1 (2012): 173. http://dx.doi.org/10.1071/rdv24n1ab121.
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A previous study from our laboratory has demonstrated that preantral follicles from the dog that are cultured in alginate are able to grow and produce steroid hormones (Songsasen et al. 2011 Reproduction 142, 113–122). Here we investigated the influence of using a combination of alginate and a degradable biomaterial, fibrin, on dog follicle development in vitro. We hypothesised that the alginate and fibrin gel matrix would be superior to alginate alone because the former has dynamic mechanical properties that permit more expansive follicle development than the inert alginate-only system. Secondary follicles (128–220 μm in diameter) were collected from the ovaries of 4 prepubertal dogs (<6 months of age) and encapsulated in 0.5% alginate (n = 26) or 0.5% alginate + 12.5 mg mL–1 of fibrin (n = 22). Follicles were cultured for 12 days at 38.5°C in 100 μL of α-minimal essential medium + 2 mM of glutamine + 5.5 μg mL–1 of insulin + 5.5 μg mL–1 of transferrin + 6.7 ng mL–1 of selenium + 10 μg mL–1 of FSH and 1 ng mL–1 of LH + 3 mg mL–1 of polyvinyl alcohol. Follicle diameter was monitored and half of the medium exchanged every 48 h. Follicle survival was assessed based on ability to increase in size, as well as on oocyte and granulosa cell morphology. Comparisons of follicle growth rate for each culture day between the 2 treatments were conducted using Student's t-test and among culture days within the same group using ANOVA followed by a Holm-Sidak multiple comparison. Follicle survival was compared using a chi-square test. In both groups, follicles maintained the 3-dimensional structure and increased (P < 0.05) in size as culture period progressed. However, follicles encapsulated in alginate + fibrin grew larger (P < 0.05) than those in alginate alone. Specifically, follicles in alginate + fibrin were doubled in size by 12 days compared with a 60% increase for alginate alone. There were no differences (P > 0.05) in follicle survival between the 2 groups (27.0 and 38.1% for alginate and alginate-fibrin, respectively). Results demonstrate that a dynamic alginate-fibrin matrix enhances in vitro follicle growth. We suspect that the mechanism involved is related to facilitating expansion capacity. Specifically, it is likely that nondegradable alginate offers physical, but eventually restrictive, support to encapsulated cells. By contrast, in the gel combination, the fibrin degrades due to cell-secreted proteases that, in turn, permit more robust follicle expansion. Low follicle survival (<40%) in both treatments emphasises the need for more studies to identify influential endocrine/paracrine factors that enhance follicle growth and production of competent oocytes. Funded by NIH-KO1RR020564.
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Reagan, Michaela, Carolyne Falank, Heather Fairfield, Michelle McDonald, Peter Croucher y Clifford J. Rosen. "Multiple Myeloma Progression: Dependence on Bone Marrow Adipose Tissue". Blood 128, n.º 22 (2 de diciembre de 2016): 3262. http://dx.doi.org/10.1182/blood.v128.22.3262.3262.
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Abstract Multiple myeloma (MM) is characterized by clonal proliferation of transformed plasma cells1 and is extremely dependent on bone marrow (BM) niche molecules and cells, such as osteoclasts. Unlike osteoclasts, the roles of BM adipocytes (BMAs) in MM are poorly understood, despite their great therapeutic potential. This year we published a study of body composition PET/CT parameters that serve as predictors of monoclonal gammopathy of undetermined significance (MGUS) progression to MM(Veld J, O'Donnell EK, Reagan MR, et al. Abdominal adipose tissue in MGUS and multiple myeloma. Skeletal Radiol.). We found that recently diagnosed MM patients had higher abdominal white adipose tissue (WAT) than MGUS patients, even after correction for BMI. Bone Marrow Adipose Tissue (BMAT), a newly appreciated adipose depot with endocrine and paracrine signaling functions, resides near MM cells and has unique expression profiles and phenotypic responses compared to WAT. Because obesity and aging, risk factors for MM, correlate with increased BMAT, and BMAs and MM cells are closely physically associated, we hypothesized that BMAs contribute to an optimal microenvironment for MM cell proliferation and/or drug resistance. We performed direct and indirect co-culture experiments to study the effects of BMAT and BMAT-derived cytokines and lipids on MM proliferation and chemoresistance. MM cells were cultured on, or with conditioned media (CM) from, human and mouse BM-derived mesenchymal stem cells (MSCs) differentiated into adipocytes. MM proliferation, assessed by bioluminescence imaging, was dependent on MM cell line, MSC donor, and adipogenic stage. IL6 is a highly potent MM-supportive cytokine elevated in MM patient BM and thought to be derived mainly from MSCs. MM cells (OPM2 and MM1R) grown in CM from MSCs differentiated for 21 days into adipocytes (Fat CM) treated with IL6 neutralizing antibodies had significantly decreased proliferation vs MM cells treated with Fat CM alone. MM1S cells also showed this trend. These data identified BMAs as a novel BM IL6 source. MM cells typically proliferated in response to donor "lipid fractions", the oil layer on top of human hip surgery BM samples, after 24, 48 and 72 hours, although donor variability was again observed. Lipid droplet content (Oil Red O quantification) of these BMAs also significantly decreased upon culture with MM cells, suggesting that MM cells induce lipolysis or uptake BMAT lipids to fuel their proliferation. In contrast to the literature, we found that adiponectin can be either MM-supportive or MM-inhibitory, depending on the MM line tested and on the presence of dex. Certain MM cell lines (MM1S) became dexamethasone (dex) resistant when treated with Fat CM. Strikingly, all 3 cell lines tested (MM1S, MM1R and OPM2) showed significant decreases in cell number at 24, 48 and 72 hours after treatment with a neutralizing adiponectin antibody vs IgG control, when grown in the presence of 0.1μM dex + Fat CM (which contained high levels of adiponectin from ELISA analysis) (Fig 1A). These data suggest that adiponectin can induce dex resistance, indicating that adiponectin inhibitors + dex may be a novel MM therapy. Lastly, we developed a physiologically relevant 3D in vitro tissue engineered BMAT model utilizing biocompatible, porous silk fibroin scaffolds to more accurately define BMA-MM interactions. Our 3D models provide the correct mechanical robustness and biomaterial properties to mimic trabecular bone and unilocular BMAT (Fig 1 B-D). We generated long-term cultures of BMAT from MSCs and cultured MM cells (GFP+ MM1S) on these for up to 1 week, demonstrating the development of the first 3D BMAT artificial culture system, with or without MM cells. We are now using this novel platform to more deeply explore the relationship between BMAT and MM cells. In conclusion, BMAT likely plays a role in MM progression. 3D tissue engineered models of the BM milieu are a crucial link between 2D and in vivo models, maintaining the high-throughput capacity of 2D studies and the translational relevancy of in vivo models. Our data demonstrate important interactions between BMAT and MM cells, highlighting our need for further research into the roles of BM adipokines and adipocytes in MM pathogenesis and chemoresistance. Disclosures No relevant conflicts of interest to declare.
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"Correction for Kang et al., Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1". Proceedings of the National Academy of Sciences 106, n.º 36 (21 de agosto de 2009): 15513. http://dx.doi.org/10.1073/pnas.0908950106.
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"Correction for Kang et al., Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1". Proceedings of the National Academy of Sciences 120, n.º 51 (15 de diciembre de 2023). http://dx.doi.org/10.1073/pnas.2320128120.
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van Tienhoven, René, Maria J. L. Kracht, Arno R. van der Slik, Sofia Thomaidou, Anouk H. G. Wolters, Ben N. G. Giepmans, Juan Pablo Romero Riojas et al. "Presence of immunogenic alternatively spliced insulin gene product in human pancreatic delta cells". Diabetologia, 8 de marzo de 2023. http://dx.doi.org/10.1007/s00125-023-05882-y.
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Abstract Aims/hypothesis Transcriptome analyses revealed insulin-gene-derived transcripts in non-beta endocrine islet cells. We studied alternative splicing of human INS mRNA in pancreatic islets. Methods Alternative splicing of insulin pre-mRNA was determined by PCR analysis performed on human islet RNA and single-cell RNA-seq analysis. Antisera were generated to detect insulin variants in human pancreatic tissue using immunohistochemistry, electron microscopy and single-cell western blot to confirm the expression of insulin variants. Cytotoxic T lymphocyte (CTL) activation was determined by MIP-1β release. Results We identified an alternatively spliced INS product. This variant encodes the complete insulin signal peptide and B chain and an alternative C-terminus that largely overlaps with a previously identified defective ribosomal product of INS. Immunohistochemical analysis revealed that the translation product of this INS-derived splice transcript was detectable in somatostatin-producing delta cells but not in beta cells; this was confirmed by light and electron microscopy. Expression of this alternatively spliced INS product activated preproinsulin-specific CTLs in vitro. The exclusive presence of this alternatively spliced INS product in delta cells may be explained by its clearance from beta cells by insulin-degrading enzyme capturing its insulin B chain fragment and a lack of insulin-degrading enzyme expression in delta cells. Conclusions/interpretation Our data demonstrate that delta cells can express an INS product derived from alternative splicing, containing both the diabetogenic insulin signal peptide and B chain, in their secretory granules. We propose that this alternative INS product may play a role in islet autoimmunity and pathology, as well as endocrine or paracrine function or islet development and endocrine destiny, and transdifferentiation between endocrine cells. INS promoter activity is not confined to beta cells and should be used with care when assigning beta cell identity and selectivity. Data availability The full EM dataset is available via www.nanotomy.org (for review: http://www.nanotomy.org/OA/Tienhoven2021SUB/6126-368/). Single-cell RNA-seq data was made available by Segerstolpe et al [13] and can be found at https://sandberglab.se/pancreas. The RNA and protein sequence of INS-splice was uploaded to GenBank (BankIt2546444 INS-splice OM489474). Graphical abstract
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Cherif, Alhaji y Peter Kotanko. "P0872EFFECT OF PARATHYROID HORMONE OSCILLATIONS ON BONE HEALTH: FROM OSTEO-ANABOLISM TO CATABOLISM". Nephrology Dialysis Transplantation 35, Supplement_3 (1 de junio de 2020). http://dx.doi.org/10.1093/ndt/gfaa143.p0872.
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Abstract Background and Aims In patients with chronic kidney disease or primary hyperparathyroidism, chronically elevated parathyroid hormones (PTH) levels exert catabolic effects on the bone. In contrast, PTH oscillations (as seen in healthy subjects) or daily application of teriparatide (a form of PTH consisting of the N-terminal 34 amino acids; it is used to treat osteoporosis) promote bone formation. These differential responses have important clinical and therapeutic implications. Although the anabolic effects of PTH (and teriparatide) cycling are widely accepted, the underlying osteo-anabolic dynamics are not well understood. Method A recently developed mechanistic physiology-based model quantitating the interrelations of osteoclasts, osteoblasts and osteocytes on bone remodeling is used (Cherif et al., ΝΔΤ 2018, 33 (συππλ. 1): 165–166). The model incorporates cell-to-cell signaling pathways (i.e., RANK-RANKL-OPG), intracellular pathways, cytokines (i.e. TGFβ), PTH, sclerostin, and endocrine and paracrine feedbacks. Using the validated model, we explore the effect of altered PTH (teriparatide) administration regimen (e.g., dosing frequency and amplitude) on bone catabolism and anabolism, respectively. Results As in previous studies, the model accurately predicts differential responses of osteo-anabolic and catabolic effects of continuously and intermittently elevated PTH (teriparatide) levels, respectively. In addition, we observe that intermittent administration of PTH with a high frequency and amplitude induces bone catabolism similar to that seen in pathologies with continuously elevated PTH (i.e. primary or secondary hyperparathyroidism). We see a more than 3-fold change from baseline in osteoclastic over osteoblastic activities, resulting in a bone efflux of calcium and phosphate. Low PTH frequency with high dosing amplitude induces both osteoclastic and osteoblastic activities, but the net result is bone anabolism. Further, Fig. 1 shows a nonlinear region where high osteoblastic activities exceed osteoclastic resorption. These findings suggest the existence of optimal PTH (teriparatide) frequency-amplitude combinations that enhance anabolic gains, beyond which there can be a detrimental effect on bone. Conclusion Our results suggest that both frequency and amplitude of PTH (teriparatide) cycling affect the balance of osteo-catabolic and -anabolic effects. Understanding the underlying mechanism of differential osteo-anabolic and -catabolic responses induced by intermittent and continuous levels of PTH, respectively, may provide new therapeutic options for patients and minimize unintended consequences of intervention protocols.
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Gruber, Sven, Cong Tang, Mesut Berber, Stefan Fischli, David Penton-Ribas, Daniela Mihic-Probst y Felix Beuschlein. "SAT-LB23 Paraneoplastic Hypercalcemia in a PTH Producing Adrenocortical Carcinoma - a Rare and Deadly Condition". Journal of the Endocrine Society 4, Supplement_1 (abril de 2020). http://dx.doi.org/10.1210/jendso/bvaa046.2284.
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Abstract Background: Hypercalcemia is a commonly encountered paraneoplastic manifestation of certain cancers with or without endocrine differentiation. However, the association between adrenocortical carcinoma (ACC) with paraneoplastic hypercalcemia is very rare, and therefore little is known about the cause and its relevance in the disease. Clinical Case: A 40-year-old woman presented in the hospital with a 5-month history of progressive flank pain with unintentional weight loss of 6 kg. MRI revealed a mass of 9x8.1x4.8 cm of the right adrenal gland with inhomogeneous contrast enhancement. Biochemical investigations provided evidence of endogenous hypercortisolism (24-hour urinary cortisol excretion [490 µg, n<236 µg/l], 1mg dexamethasone suppression test [199 nmol/l, n<50 nmol/l], ACTH [28 ng/l, n<61 ng/l]) although the patient did not show any specific clinical sign of overt hypercortisolism. In addition, laboratory testing revealed an exceptionally high plasma level of calcium [max 3.67 mmol/l (albumin-corrected)] and low phosphate [min 0.26 mmol/l] in the setting of low PTH [6.4 ng/l, n>15 ng/l] and PTHrP levels [<0.50 pmol/l]. However, subsequent dilution unmasked a highly elevated PTH concentration of 2171.5 ng/l with persistent low PTHrP levels, indicating false low values due to a hook effect in the initial measurement. Levels of 1,25-dihydroxy vitamin D and 25-hydroxy vitamin D were in the normal range. A PET-CT provided no indications of metabolically active (osseous) metastases. After correction of the serum calcium towards tolerable values, the tumor was removed by open en bloc adrenalectomy. Histologic evaluation confirmed an ACC (TNM pT4 pN1 (2/3), L1, V1, high grade) despite missing immunohistochemically expression of classical adrenal markers (diagnosis of exclusion). Supplemental quantitative RT-PCR studies support the diagnosis of ACC by detecting significant SF-1 and CYP11B2 expression in the tumor cells. Further analyses provided evidence that the mRNA expression of PTH, but not PTHrP, was moderately increased in the ACC sample compared to NCI H295R cells. Upon tumor resection, serum calcium levels swiftly normalized indicating the tumor as the sole source of PTH secretion. Despite initiation of adjuvant mitotane- and salvage chemo-therapy, the patient died 3 months later upon of a massive tumor relapse with a recurrence of severe hypercalcemia. Conclusion: This case demonstrates paraneoplastic hypercalcemia in a PTH producing ACC. PTH may induce hypercalcemia, impair adrenal steroid synthesis and act as an autocrine growth factor in ACC, as described in few individual cases for PTHrp producing ACC [1]. This suggests a poor prognosis for this rare entity. 1. Rizk-Rabin, M., et al., Differential Expression of Parathyroid Hormone-Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells. 2008.