scholarly journals Isoprenoid Derivatives of Lysophosphatidylcholines Enhance Insulin and GLP-1 Secretion through Lipid-Binding GPCRs

2021 ◽  
Vol 22 (11) ◽  
pp. 5748
Author(s):  
Anna Drzazga ◽  
Daria Kamińska ◽  
Anna Gliszczyńska ◽  
Edyta Gendaszewska-Darmach
Keyword(s):  
Dienoic Acid ◽  
Lipid Binding ◽  
Incretin Mimetics ◽  
Insulinoma Cell ◽  
Geranic Acid ◽  
Carbohydrate Homeostasis ◽  
Intracellular Calcium Ion ◽  
High Cytotoxicity ◽  
G Protein Coupled ◽  
Derivatives Of

Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic β-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.

Synthesis of new cyclopeptide analogues of the miuraenamides

2021 ◽  
Vol 18 ◽  
Author(s):  
Sarah Kappler ◽  
Andreas Siebert ◽  
Uli Kazmaier
Keyword(s):  
Natural Products ◽  
Biological Properties ◽  
Amide Bond ◽  
Side Chain ◽  
Aromatic Side Chain ◽  
Highly Active ◽  
C Terminus ◽  
Terminal Amino ◽  
High Cytotoxicity ◽  
Derivatives Of

Introduction: Miuraenamides belong to marine natural compounds with interesting biological properties. Materials and Methods: They initiate polymerization of monomeric actin and therefore show high cytotoxicity by influencing the cytoskeleton. New derivatives of the miuraenamides have been synthesized containing a N-methylated amide bond instead of the more easily hydrolysable ester in the natural products. Results: Incorporation of an aromatic side chain onto the C-terminal amino acid of the tripeptide fragment also led to highly active new miuraenamides. Conclusion: We could show that the ester bond of the natural product miuraenamide can be replaced by an N-methyl amide. The yields in the cyclization step are high and generally much better that with the corresponding esters. On the other hand, the biological activity of the new amide analogs are lower compared to the natural products, but the activity can significantly be increased by incorporation of a p-nitrophenyl group at the C-terminus of the peptide fragment.

scholarly journals Chemical Tools for Studying Lipid-Binding Class A G Protein–Coupled Receptors

2017 ◽  
Vol 69 (3) ◽  
pp. 316-353 ◽  
Author(s):  
Anna Cooper ◽  
Sameek Singh ◽  
Sarah Hook ◽  
Joel D. A. Tyndall ◽  
Andrea J. Vernall
Keyword(s):  
G Protein ◽  
Lipid Binding ◽  
G Protein Coupled Receptors ◽  
Class A ◽  
Chemical Tools ◽  
G Protein Coupled

ChemInform Abstract: Derivatives of (R)-1,11-Methyleneaporphine: Synthesis, Structure, and Interactions with G-Protein Coupled Receptors.

ChemInform ◽  
2010 ◽  
Vol 31 (28) ◽  
pp. no-no
Author(s):  
Tero Linnanen ◽  
Magnus Brisander ◽  
Lena Unelius ◽  
Goeran Sundholm ◽  
Uli Hacksell ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled ◽  
Derivatives Of

scholarly journals The Reactive Carbonyl Derivatives of Proteins, Methylglyoxal, and Malondialdehyde in Blood of Women with Breast Cancer

2021 ◽  
Vol 9 (B) ◽  
pp. 509-514
Author(s):  
Sabina Zhumakayeva ◽  
Larissa Muravlyova ◽  
Valentina Sirota ◽  
Vilen Molotov-Luchansky ◽  
Ryszhan Bakirova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Pathological Process ◽  
Carbonyl Derivatives ◽  
Mechanisms Of Carcinogenesis ◽  
High Cytotoxicity ◽  
Derivatives Of ◽  
Sensitive Marker ◽  
Literature Data Analysis

BACKGROUND: Every year 1.5 million women in the world are diagnosed with breast cancer (BC). In 2018, more than 260,000 new cases of cancer and more than 40,000 deaths due to this disease were detected. At the same time, in Kazakhstan, an intensive indicator of the incidences of BC in 2018 amounted to 25.3% per population of 100 thousand people (2017–24.5%) with a growth rate of 3.1%, which in absolute numbers are 4,648 new cases per year. In terms of mortality, BC ranks third after lung and stomach cancer (6.8%). AIM: This necessitates a detailed study of the molecular mechanisms that underlie the development and progression of BC. One of the mechanisms of carcinogenesis is oxidative stress (OS). An increase in malondialdehyde (MDA) levels was detected in the early stages of cancer. It was suggested that MDA, due to its high cytotoxicity, acts as a promoter of the tumor and cocarcinogen agent. METHODS: Therefore, violation of the parameters of OS in BC is in no doubt. However, according to the literature data analysis, these results are ambiguous and contradictory. There are no studies on a comprehensive assessment of the oxidative destruction of lipids, proteins, and nucleic acids in BC. CONCLUSION: The nature and direction of changes in various components of OS in patients with BC have not been adequately studied, which is necessary for a correct assessment of the involvement of OS in the mechanism of the pathological process and determination of a sensitive marker of the risk of BC or its progression.

Derivatives of (R)-1,11-Methyleneaporphine:  Synthesis, Structure, and Interactions with G-Protein Coupled Receptors

2000 ◽  
Vol 43 (7) ◽  
pp. 1339-1349 ◽  
Author(s):  
Tero Linnanen ◽  
Magnus Brisander ◽  
Lena Unelius ◽  
Göran Sundholm ◽  
Uli Hacksell ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled ◽  
Derivatives Of

Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet β-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release

2005 ◽  
Vol 289 (4) ◽  
pp. E670-E677 ◽  
Author(s):  
Ken Fujiwara ◽  
Fumihiko Maekawa ◽  
Toshihiko Yada
Keyword(s):  
Insulin Secretion ◽  
Oleic Acid ◽  
Insulin Release ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Insulinoma Cell ◽  
Transduction Mechanisms ◽  
Glucose Stimulated Insulin Secretion ◽  
Interfering Rna ◽  
G Protein Coupled

It has long been thought that long-chain free fatty acids (FFAs) stimulate insulin secretion via mechanisms involving their metabolism in pancreatic β-cells. Recently, it was reported that FFAs function as endogenous ligands for GPR40, a G protein-coupled receptor, to amplify glucose-stimulated insulin secretion in an insulinoma cell line and rat islets. However, signal transduction mechanisms for GPR40 in β-cells are little known. The present study was aimed at elucidating GPR40-linked Ca2+ signaling mechanisms in rat pancreatic β-cells. We employed oleic acid (OA), an FFA that has a high affinity for the rat GPR40, and examined its effect on cytosolic Ca2+ concentration ([Ca2+]i) in single β-cells by fura 2 fluorescence imaging. OA at 1–10 μM concentration-dependently increased [Ca2+]i in the presence of 5.6, 8.3, and 11.2 mM, but not 2.8 mM, glucose. OA-induced [Ca2+]i increases at 11.2 mM glucose were inhibited in β-cells transfected with small interfering RNA targeted to rat GPR40 mRNA. OA-induced [Ca2+]i increases were also inhibited by phospholipase C (PLC) inhibitors, U73122 and neomycin, Ca2+-free conditions, and an L-type Ca2+ channel blocker, nitrendipine. Furthermore, OA increased insulin release from isolated islets at 8.3 mM glucose, and it was markedly attenuated by PLC and L-type Ca2+ channel inhibitors. These results demonstrate that OA interacts with GPR40 to increase [Ca2+]i via PLC- and L-type Ca2+ channel-mediated pathway in rat islet β-cells, which may be link to insulin release.

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