scholarly journals The Mechanisms of GPR55 Receptor Functonal Selectivity

2022 ◽  
Author(s):  
Mikhail G Akimov ◽  
Natalia M Gretskaya ◽  
Polina V Dudina ◽  
Galina Sherstyanykh ◽  
Galina N Zinchenko ◽  
...  
Keyword(s):  
Proliferative Activity ◽  
Cytotoxic Effect ◽  
Signal Transmission ◽  
Decisive Role ◽  
Cytotoxic Action ◽  
Cb2 Receptor ◽  
Trpv1 Receptors ◽  
Synthetic Ligand ◽  
Original Line ◽  
G Protein Coupled

The objective of the project is to establish the mechanisms of multidirectional signal transmission through the same G-protein coupled receptor GPR55. Using the CRISPR-Cas9 system, clones of the MDA-MB-231 line knockout for the GPR55 (3 clones) and CB2 (CNR2 - 6 clones) receptor genes were obtained. On clones of the MDA-MB-231 line with a knockout CB2 receptor, the cytotoxic activity of the pro-apoptotic ligand docosahexaenoyldopamine (DHA-DA) did not change or slightly increased, while the pro-proliferative activity of the most active synthetic ligand of the GPR55 receptor (ML-184) completely disappeared. On the original line MDA-MB-231, the stimulatory effect of ML-184 is removed by the CB2 receptor blocker, but not by GPR55. At the same time, the stimulating effect of ML-184 is practically not manifested on cell lines knockout at the GPR55 receptor. Thus, it can be confidently assumed that when proliferation is stimulated with the participation of the GPR55 receptor, a signal is transmitted from the CB2 receptor to the GPR55 receptor due to the formation of a heterodimer. GPR18 and TRPV1 receptors are additionally involved in the implementation of the cytotoxic effect of DHA-DA, while the CB1 receptor is not involved. In the implementation of the cytotoxic action of DHA-DA, the predominant participation of one of the Ga subunits was not found, but the Ga13 subunit plays a decisive role in the implementation of the proproliferative action. The Gaq subunit is also important, although to a lesser extent than Ga13.

Mechanisms of cytotoxic action of a series of directionally synthesized heterocyclic hydroxamic acids

2020 ◽  
Vol 66 (4) ◽  
pp. 332-338
Author(s):  
M.E. Neganova ◽  
Yu.R. Aleksandrova ◽  
S.A. Pukhov ◽  
S.G. Klochkov ◽  
V.N. Osipov
Keyword(s):  
Histone Deacetylases ◽  
Cytotoxic Effect ◽  
Human Lung ◽  
Hydroxamic Acids ◽  
Breast Adenocarcinoma ◽  
Cytotoxic Action ◽  
Oxygen Species ◽  
Cyclic Hydroxamic Acids ◽  
Human Lung Carcinoma ◽  
Mcf 7

Cyclic hydroxamic acids based on quinazoline-4(3H)-one and dihydroquinazoline-4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. We have identified two compounds-hits, which exhibit the multipharmacological type of the antineoplastic activity. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases, involved in the epigenetic regulation of tumor genesis. Thus, the synthesized hydroxamic acids may be considered as a promising basis for creating potential oncolytics.

scholarly journals Bacterial recombinant L-asparaginases: properties, structure and anti-proliferative activity

2015 ◽  
Vol 61 (3) ◽  
pp. 312-324 ◽  
Author(s):  
N.N. Sokolov ◽  
M.A. Eldarov ◽  
M.V. Pokrovskaya ◽  
S.S. Aleksandrova ◽  
O.Yu. Abakumova ◽  
...  
Keyword(s):  
Proliferative Activity ◽  
Yersinia Pseudotuberculosis ◽  
Rhodospirillum Rubrum ◽  
Lymphoblastic Leukemia ◽  
Combined Therapy ◽  
Practical Interest ◽  
Erwinia Carotovora ◽  
Cytotoxic Action ◽  
Human Leukemia

For more than 40 years L-asparaginases are used in combined therapy of acute lymphoblastic leukemia in children and the range of tumors sensitive to these enzymes constantly extends. This review summarizes results of studies aimed at creation of new systems for heterological expression of bacterial L-asparaginases as Erwinia carotovora (EwA), Helicobacter pylori (HpA), Yersinia pseudotuberculosis (YpA) and Rhodospirillum rubrum (RrA); special attention is paid to isolation of purified enzymes and their crystallization, modification by chitosan/polyethylene, physicochemical, kinetic and structural properties characterization, and the study of the cytotoxic or anti-proliferative activity of new recombinant L-asparaginases on cell cultures in vitro. The resultant recombinant L-asparaginases (EwA, YpA, HpA и RrA) exhibit reasonable cytotoxic action on the human leukemia cells comparable to the pharmacologically available L-asparaginase EcA and represent practical interest in respect to creation, on their basis, new effective antineoplastic remedies. Further prospects of researches on bacterial L-asparaginases are associated with development of analogs of Rhodospirillum rubrum L-asparaginase (RrA) by means of directed changes of the protein structure using genetic engineering, development of chito-PEGylation for receiving L-asparaginase preparations with improved pharmacokinetic characteristics.

scholarly journals Pan-cancer in silico analysis of somatic mutations in G-protein coupled receptors: The effect of evolutionary conservation and natural variance

2021 ◽  
Author(s):  
Brandon J Bongers ◽  
Marina Gorostiola González ◽  
Xuesong Wang ◽  
Herman WT van Vlijmen ◽  
Willem Jespers ◽  
...  
Keyword(s):  
G Protein ◽  
Structural Integrity ◽  
In Silico Analysis ◽  
G Protein Coupled Receptors ◽  
Dry Motif ◽  
Synthetic Ligand ◽  
Natural Variance ◽  
G Protein Coupled ◽  
Pan Cancer

G protein-coupled receptors (GPCRs) form the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used an aggregated dataset of mutations found in cancer patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 Genomes project. While the location of these mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment was observed in cancer patients among conserved residues in GPCRs such as the 'DRY' motif. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). The validity of our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, and we identified novel GPCRs that had not been directly linked to cancer before such as the P2Y Receptor 10 (P2RY10). As a proof of concept, we projected the structurally investigated mutations in the crystal structure of the C-C Chemokine (CCR) 5 receptor, one of the high-ranking GPCRs previously linked to cancer. Several positions were pinpointed that relate to either structural integrity or endogenous and synthetic ligand binding, providing a rationale to their mechanism of influence in cancer. In conclusion, this study identifies a list of GPCRs that are prioritized for experimental follow up characterization to elucidate their role in cancer. The computational approach here described can be adapted to investigate the roles in cancer of any protein family.

scholarly journals Monitoring Cannabinoid CB2 -Receptor Mediated cAMP Dynamics by FRET-Based Live Cell Imaging

2020 ◽  
Vol 21 (21) ◽  
pp. 7880
Author(s):  
Leonore Mensching ◽  
Sebastian Rading ◽  
Viacheslav Nikolaev ◽  
Meliha Karsak
Keyword(s):  
Single Cell ◽  
G Protein ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Live Cell ◽  
Single Cell Level ◽  
Cb2 Receptor ◽  
Cell Level ◽  
Cb2 Receptors ◽  
G Protein Coupled

G-protein coupled cannabinoid CB2 receptor signaling and function is primarily mediated by its inhibitory effect on adenylate cyclase. The visualization and monitoring of agonist dependent dynamic 3′,5′-cyclic adenosine monophosphate (cAMP) signaling at the single cell level is still missing for CB2 receptors. This paper presents an application of a live cell imaging while using a Förster resonance energy transfer (FRET)-based biosensor, Epac1-camps, for quantification of cAMP. We established HEK293 cells stably co-expressing human CB2 and Epac1-camps and quantified cAMP responses upon Forskolin pre-stimulation, followed by treatment with the CB2 ligands JWH-133, HU308, β-caryophyllene, or 2-arachidonoylglycerol. We could identify cells showing either an agonist dependent CB2-response as expected, cells displaying no response, and cells with constitutive receptor activity. In Epac1-CB2-HEK293 responder cells, the terpenoid β-caryophyllene significantly modified the cAMP response through CB2. For all of the tested ligands, a relatively high proportion of cells with constitutively active CB2 receptors was identified. Our method enabled the visualization of intracellular dynamic cAMP responses to the stimuli at single cell level, providing insights into the nature of heterologous CB2 expression systems that contributes to the understanding of Gαi-mediated G-Protein coupled receptor (GPCR) signaling in living cells and opens up possibilities for future investigations of endogenous CB2 responses.

scholarly journals Developing Chemical Genetic Approaches to Explore G Protein-Coupled Receptor Function: Validation of the Use of a Receptor Activated Solely by Synthetic Ligand (RASSL)

2011 ◽  
Vol 80 (6) ◽  
pp. 1033-1046 ◽  
Author(s):  
Elisa Alvarez-Curto ◽  
Rudi Prihandoko ◽  
Christofer S. Tautermann ◽  
Jurriaan M. Zwier ◽  
John D. Pediani ◽  
...  
Keyword(s):  
G Protein ◽  
Receptor Function ◽  
G Protein Coupled Receptor ◽  
Chemical Genetic ◽  
Synthetic Ligand ◽  
G Protein Coupled

scholarly journals Cytotoxic effect of methanol extract of Conyza bonariensis on DMBA-induced skin carcinogenesis: An in vivo study

2015 ◽  
Vol 10 (2) ◽  
pp. 467
Author(s):  
Mohammad Saleem ◽  
Faiza Naseer ◽  
Khalid Hussain ◽  
Alamgeer
Keyword(s):  
Cytotoxic Effect ◽  
Methanol Extract ◽  
Tumor Formation ◽  
Skin Carcinogenesis ◽  
Continuous Group ◽  
Control Group ◽  
Cytotoxic Action ◽  
Cumulative Number ◽  
Conyza Bonariensis

<p>In the present study, we examined the cytotoxic effect of <em>Conyza bonariensis</em> (methanolic extract). The skin carcinogenesis was induced in two stages, first, applying tumor initiator, 7-12-dimethyl benz(a)antheracene and thereafter applying croton oil, a tumor promotor in Swiss albino mice. The morphological alterations observed and measured during the induction of skin ulceration, included; cumulative number of papilloma, tumor yield and tumor burden. <em>C. bonariensis</em> extract (300 and 600 mg/kg/day) was applied locally on mice skin for 16 weeks. The higher dose (600 mg/kg/day) inhibited the tumor formation up to 40% and showed a significant decline in cumulative number of papilloma of continuous group. The results indicated that extract increased the reduced glutathione, superoxide dismutase  and catalase, and decreased lipid peroxidation compared to carcinogen group. Histopathological changes showed papilomatosis and ulceration in carcinogen control group.  HPLC analysis indicated the presence of  flavonoid i.e. quercetin which may be responsible for the cytotoxic action of <em>C. bonariensis</em> methanol extract.  </p>

scholarly journals Oligodendroglial GABAergic Signaling: More Than Inhibition!

2021 ◽  
Author(s):  
Xianshu Bai ◽  
Frank Kirchhoff ◽  
Anja Scheller
Keyword(s):  
Gaba Receptors ◽  
Gaba Receptor ◽  
Signal Transmission ◽  
Physiological Role ◽  
Inhibitory Neurotransmitter ◽  
Short Summary ◽  
Central Synapses ◽  
G Protein Coupled ◽  
Shed Light

AbstractGABA is the main inhibitory neurotransmitter in the CNS acting at two distinct types of receptor: ligand-gated ionotropic GABAA receptors and G protein-coupled metabotropic GABAB receptors, thus mediating fast and slow inhibition of excitability at central synapses. GABAergic signal transmission has been intensively studied in neurons in contrast to oligodendrocytes and their precursors (OPCs), although the latter express both types of GABA receptor. Recent studies focusing on interneuron myelination and interneuron-OPC synapses have shed light on the importance of GABA signaling in the oligodendrocyte lineage. In this review, we start with a short summary on GABA itself and neuronal GABAergic signaling. Then, we elaborate on the physiological role of GABA receptors within the oligodendrocyte lineage and conclude with a description of these receptors as putative targets in treatments of CNS diseases.

scholarly journals Cross-linking of the Endolysosomal System Reveals Flotillin Structures and Putative Cargo

2022 ◽  
Author(s):  
Jasjot Singh ◽  
Hadeer Elhabashy ◽  
Pathma Muthukottiappan ◽  
Markus Stepath ◽  
Martin Eisenacher ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Complexes ◽  
Decisive Role ◽  
Cross Linking ◽  
Protein Protein Interactions ◽  
Lysosome Biogenesis ◽  
Early Endosomes ◽  
Cross Links ◽  
Related Proteins ◽  
G Protein Coupled

Lysosomes are well-established as the main cellular organelles for the degradation of macromolecules and emerging as regulatory centers of metabolism. They are of crucial importance for cellular homeostasis, which is exemplified by a plethora of disorders related to alterations in lysosomal function. In this context, protein complexes play a decisive role, regulating not only metabolic lysosomal processes, but also lysosome biogenesis, transport, and interaction with other organelles. Using cross-linking mass spectrometry, we analyzed lysosomes and early endosomes. Based on the identification of 5,376 cross-links, we investigated protein-protein interactions and structures of lysosome- and endosome-related proteins. In particular, we present evidence for a tetrameric assembly of the lysosomal hydrolase PPT1 and heterodimeric/-multimeric structures of FLOT1/FLOT2 at lysosomes and early endosomes. For FLOT1-/FLOT2-positive early endosomes, we identified >300 proteins presenting putative cargo, and confirm the latrophilin family of adhesion G protein-coupled receptors as substrates for flotillin-dependent endocytosis.

scholarly journals Cytotoxic action reduction of crystalline silicon dioxide in a toxicological experiment associated with Lymphomyosot

2021 ◽  
Vol 100 (6) ◽  
pp. 605-609
Author(s):  
Marina P. Sutunkova ◽  
Elena P. Kashanskaya ◽  
Svetlana N. Solovyova ◽  
Ilzira A. Minigalieva ◽  
Olga I. Gogoleva ◽  
...  
Keyword(s):  
Silicon Dioxide ◽  
Cytotoxic Effect ◽  
Crystalline Silicon ◽  
Female Rats ◽  
White Female ◽  
Cytotoxic Action ◽  
Cytotoxic Effects ◽  
Student’S T ◽  
Intratracheal Injection ◽  
Student’S T Test

Introduction. Among the most relevant issues in occupational health is the risk management of the contamination of working air by crystalline silicon dioxide (CSD) in enterprises dealing with its extraction and processing. Cytotoxicity of this silicon type that underlies its fibrogenic action is of particular concern. Thereby, it is an urgent goal to find drugs that increase the body’s resistance to cytotoxic effects of silicon dioxide. Materials and methods. For the study of changes in the cellular composition of the bronchoalveolar lavage (BAL) and some of its biochemical characteristics, a respirable portion of Pervouralsk quartzite (PQ) containing 98% CSD was inserted intratracheally to outbred white female rats in the form of a suspension of 10 mg of PQ in 1 ml of distilled water in the dose of 1 ml. Student’s t-test was applied for statistical analysis of the obtained data. Results. PQ sample induces the alveolar phagocytosis response typical for cytotoxic dust expressed by an increase in the total BAL cell count, the number of both alveolar macrophages (AM) and neutrophilic leukocytes (NL), and particularly the NL/AM ratio (which is a reliable comparative index of cytotoxicity). The administration of «Lymphomyosot» considerably reduced this cytotoxic effect of PQ within one month before the intratracheal injection. It showed a decrease in NL/AM ratio and some biochemical indicators of cytolysis in BAL. Conclusion. There was demonstrated the applicability of «Lymphomyosot» as a precaution against the cytotoxic effect of CSD dust.

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