Ghrelin Regulates Insulin Release and Glycemia: Physiological Role and Therapeutic Potential

These studies were undertaken to evaluate in humans the possible physiological role of prostaglandins of the E series (PGE) in modulating insulin release and to assess whether endogenous PGE synthesis may account for the biphasic pattern of insulin secretion. We used a square-wave glucose stimulation previously determined to give maximal biphasic insulin release. Infusion of lysine acetylsalicylate to block the synthesis of endogenous PGE increased by twofold total insulin response to glucose and also converted insulin release to a multiphasic pattern. The infusion of exogenous PGE1 (0.2 microgram X kg-1 X min-1) or PGE2 (10 micrograms/min) in addition to lysine acetylsalicylate restored the typical biphasic pattern of insulin release and also decreased total insulin release to values similar to those of control studies. Infusion of either PGE1 or PGE2 in the absence of lysine acetylsalicylate reset insulin secretion to a lower level without altering the kinetics of release. On the basis of these results, it is hypothesized that endogenous PGE released in response to glucose stimulation exert an inhibiting effect on insulin release that becomes biphasic in appearance.

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Ribosomal stress-surveillance: three pathways is a magic number

Nucleic Acids Research ◽

10.1093/nar/gkaa757 ◽

2020 ◽

Vol 48 (19) ◽

pp. 10648-10661 ◽

Cited By ~ 2

Author(s):

Anna Constance Vind ◽

Aitana Victoria Genzor ◽

Simon Bekker-Jensen

Keyword(s):

Stress Response ◽

Stress Responses ◽

Map Kinases ◽

Cell Function ◽

Therapeutic Potential ◽

Magic Number ◽

Physiological Role ◽

Negative Effects ◽

Mitogen Activated Protein ◽

Activation Mechanisms

Abstract Cells rely on stress response pathways to uphold cellular homeostasis and limit the negative effects of harmful environmental stimuli. The stress- and mitogen-activated protein (MAP) kinases, p38 and JNK, are at the nexus of numerous stress responses, among these the ribotoxic stress response (RSR). Ribosomal impairment is detrimental to cell function as it disrupts protein synthesis, increase inflammatory signaling and, if unresolved, lead to cell death. In this review, we offer a general overview of the three main translation surveillance pathways; the RSR, Ribosome-associated Quality Control (RQC) and the Integrated Stress Response (ISR). We highlight recent advances made in defining activation mechanisms for these pathways and discuss their commonalities and differences. Finally, we reflect on the physiological role of the RSR and consider the therapeutic potential of targeting the sensing kinase ZAKα for treatment of ribotoxin exposure.

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Searching for the physiological role and therapeutic potential of vascular proteinase-activated receptor-2 (PAR2)

Drug Development Research ◽

10.1002/ddr.10314 ◽

2003 ◽

Vol 60 (1) ◽

pp. 14-19 ◽

Cited By ~ 2

Author(s):

John J. McGuire ◽

Chris R. Triggle

Keyword(s):

Therapeutic Potential ◽

Physiological Role

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A high-content screen profiles cytotoxic microRNAs in pediatric and adult glioblastoma cells and identifies miR-1300 as a potent inducer of cytokinesis failure

10.1101/789438 ◽

2019 ◽

Author(s):

Marjorie Boissinot ◽

Henry King ◽

Matthew Adams ◽

Julie Higgins ◽

Thomas A. Ward ◽

...

Keyword(s):

Therapeutic Potential ◽

Ectopic Expression ◽

Physiological Role ◽

Mrna Translation ◽

Glioblastoma Cells ◽

Potent Inducer ◽

Functional Studies ◽

Key Points ◽

Megakaryocyte Differentiation

AbstractBackgroundMicroRNAs play an important role in the regulation of mRNA translation, and have therapeutic potential in cancer and other diseases.MethodsTo profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen using a synthetic oligonucleotide library representing all known human microRNAs in adult and pediatric GBM cells. Bio-informatics analysis were used to refine this list and the top seven microRNAs were validated in a larger panel of cells by flow-cytometry, and RTqPCR. The downstream mechanism of the strongest and most consistent candidate was investigated by siRNAs, 3’UTR luciferase assays and Western Blotting.ResultsOur screen identified ∼100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR-1300 expressing cells and characterized the mechanism of action as cytokinesis failure followed by apoptosis, which was observed in an extended GBM cell panel including two stem-like patient-derived cultures. We identified the physiological role of miR-1300 as a regulator of endomitosis in megakaryocyte differentiation where blockade of cytokinesis is an essential step. In glioblastoma cells, the oncogene Epithelial Cell Transforming 2 (ECT2) was validated as a direct key target of miR-1300. ECT2 siRNA phenocopied the effects of miR-1300, and its overexpression led to a significant rescue of miR-1300 induced binucleation.ConclusionMiR-1300 was identified as a novel regulator of endomitosis with translatable potential for therapeutic application. The datatasets will be a resource for the neuro-oncology community.Key points (2 or 3 key points 85 characters plus spaces each)70% of cytotoxic microRNAs were shared between adult and pediatric glioblastoma cellsMiR-1300 expression is restricted to endomitosis within megakaryocyte differentiationMiR-1300’s ectopic expression is a potent and promising therapeutic tool in cancerImportance of StudyPrevious functional studies of microRNAs involved in the regulation of glioblastoma cell proliferation and/or survival have focused on adult glioblastoma alone and are restricted to only a few microRNAs at a time. Our study provides the first encompassing landscape of potent cytotoxic microRNAs in pediatric and adult glioblastoma.Not only, does our data provide an invaluable resource for the research community but it also revealed that 70% of microRNAs with significant cytotoxicity were shared by adult and pediatric cells. Finally, we identified and characterized the previously undescribed role of microRNA-1300 in the tight regulation of megakaryocyte differentiation into platelets and how, when expressed outside of this context, miR-1300 consistently causes cytokinesis failure followed by apoptosis, and thus represents a powerful cytotoxic tool with potential for translation towards therapeutic applications.

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The regulation of phoenixin: A fascinating multidimensional peptide

Journal of the Endocrine Society ◽

10.1210/jendso/bvab192 ◽

2021 ◽

Author(s):

Emma K McIlwraith ◽

Ningtong Zhang ◽

Denise D Belsham

Keyword(s):

Food Intake ◽

Transcriptional Control ◽

Therapeutic Potential ◽

Physiological Role ◽

Reproductive Hormones ◽

Main Function ◽

Negative Results ◽

Gene And Protein Expression ◽

Its Gene ◽

Range Of Functions

Abstract The phoenixin (PNX) peptide is linked to the control of reproduction, food intake, stress and inflammation. However, little is known about what regulates its gene and protein expression, information that is critical to understand the physiological role of PNX. In this review, we summarize what is known about the transcriptional control of Pnx and its receptor Gpr173. A main function of PNX is as a positive regulator of the hypothalamic-pituitary-gonadal axis, but there is a lack of research on its control by reproductive hormones and peptides. PNX is also associated with food intake and its expression is linked to feeding status, fatty acids, and glucose. It is influenced by environmental and hormonal-induced stress. The regulation of Pnx in most contexts remains an enigma, in part due to conflicting and negative results. An extensive analysis of the response of the Pnx gene to factors related to reproduction, metabolism, stress and inflammation is required. Analysis of the Pnx promoter and epigenetic regulation must be considered to understand how this level of control contributes to its pleiotropic effects. PNX is now linked to a broad range of functions, but more research on its gene regulation is required to understand its place in overall physiology and therapeutic potential.

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Stimulatory effect of bradykinin on insulin release from the perfused rat pancreas

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.268.5.e1027 ◽

1995 ◽

Vol 268 (5) ◽

pp. E1027-E1030

Author(s):

C. Yang ◽

W. H. Hsu

Keyword(s):

Receptor Antagonist ◽

Insulin Release ◽

Glucose Concentration ◽

Physiological Role ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Perfused Rat Pancreas ◽

Pancreas Perfusion ◽

Rat Pancreas ◽

Hoe 140

Rat pancreas perfusion was performed to study the effect of bradykinin on insulin release. At the perfusate glucose concentration of 6 mM, bradykinin (0.01-1 microM) increased insulin release in a concentration-dependent manner. In addition, bradykinin (1 microM) increased the glucose (10 mM)-induced insulin release. HOE-140 (0.1 microM), a bradykinin B2-receptor antagonist, decreased the baseline insulin release and abolished the bradykinin (1 microM)-induced increase in insulin release. In addition, HOE-140 (0.1 microM) attenuated the glucose (10 mM)-induced increase in insulin release. Because the blockade of bradykinin receptors by HOE-140 attenuated the glucose-induced increased insulin release, our present findings suggest that bradykinin may play a physiological role in the regulation of insulin release.

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M-CSF Inhibition Selectively Targets Tumor Angiogenesis and Lymphangiogenesis

Blood ◽

10.1182/blood.v112.11.1256.1256 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1256-1256

Author(s):

Yoshiaki Kubota ◽

Toshio Suda

Keyword(s):

Tumor Angiogenesis ◽

Therapeutic Potential ◽

Physiological Role ◽

Osteosarcoma Cell ◽

Angiogenic Therapy ◽

High Dependency ◽

Lymphatic Development ◽

Vegf Pathway ◽

Vessel Network ◽

Macrophage Colony

Abstract Anti-angiogenic therapy in cancer is desired to be selective for tumor angiogenesis. The best validated approaches for limiting tumor angiogenesis involve blockade of the VEGF pathway. However, recent studies show that VEGF blockade damages healthy vessels resulting in toxic side effects (Maharaj et al. J. Exp. Med. 2008) and that interrupting the VEGF blockade induces rapid vascular regrowth in tumors (Mancuso et al. J. Clin. Invest. 2006). Therefore, other targets are currently being explored. Macrophage-colony stimulating factor (M-CSF), a cytokine required for differentiation of monocyte-lineage cells including macrophages promotes formation of a high-density vessel network in tumors suggesting therapeutic potential of M-CSF inhibition (Lin et al. J. Exp. Med. 2001). Moreover, M-CSF is abundantly expressed in highly-metastatic cancers such as breast cancer and osteosarcoma, suggesting high dependency on macrophages. However, the physiological role of M-CSF in vascular and lymphatic development as well as the precise mechanisms underlying anti-angiogenic effects of M-CSF inhibition is not clarified. Here, utilizing osteopetrotic (op/op) mice, we show that M-CSF deficiency leads to lack of both LYVE-1+ and LYVE1− macrophages, resulting in defects not only in vascular but also lymphatic development. To clarify the anti-cancer effects of M-CSF inhibition, we utilized a novel mouse model of osteosarcoma, in which mice were transplanted with a newly established osteosarcoma cell line, AX, which were developed from c-Myc-overexpressing Ink4a/ARF−/− bone marrow-derived stromal cells. In this model, systemic treatment with small molecule c-fms inhibitors (Ki20227) effectively suppressed tumor angiogenesis and lymphangiogenesis disorganizing extracellular matrices. Consequently, c-fms inhibitors almost completely suppressed tumor metastasis, and protected mice from cancer death. Different from VEGF blockade, interruption of M-CSF inhibition did not promote rapid tumor regrowth. Continuous M-CSF inhibition did not affect healthy vascular and lymphatic systems outside the tumor. These results suggest M-CSF-targeted therapy is an ideal therapeutic strategy against cancer alternative to VEGF blockade.

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