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Description:IRX5183, also known as NRX-195183, VTP-195183 and AGN195183, is an orally bioavailable retinoid acid receptor (RAR) alpha agonist with potential antineoplastic activity. Retinoid analogue NRX 195183 binds to and activates RAR alpha, modulating the transcription of genes responsible for cell differentiation and proliferation, which may result in cell differentiation, decreased cell proliferation, and the inhibition of tumorigenesis. Encoded by the RARA gene, RAR alpha is a nuclear receptor and a member of the steroid receptor superfamily.
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The following data is based on theproductmolecular weight437.86Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
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1: Chee LC, Hendy J, Purton LE, McArthur GA. ATRA and the specific RARα agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells. Leukemia. 2013 Jun;27(6):1369-80. doi: 10.1038/leu.2012.362. Epub 2012 Dec 11. PubMed PMID: 23228968.
Abstract Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are members of the nuclear receptor superfamily whose effects on cell growth and survival can be modulated therapeutically by small-molecule ligands. Although compounds that target these receptors are powerful anticancer drugs, their use is limited by toxicity. An improved understanding of the structural biology of RXRs and RARs and recent advances in the chemical synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome such problems. Here, we review structural data for RXRs and RARs, discuss strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general.
Retinoids and rexinoids, like all other ligands of the nuclear receptor (NR) family (1), act through ligand-regulated trans-acting transcription factors that bind to cis-acting DNA regulatory elements in the promoter regions of target genes. Conceptually, ligand binding simply modulates the communication of the receptor with its intracellular environment, which entails essentially receptor-protein and receptor-DNA or receptor-chromatin interactions. In this communication network, the receptor serves at the same time as an intracellular sensor and regulator of cellular and organ functions. Receptors are mediators of the information encoded in the chemical structure of an NR ligand, which they interpret in the context of cellular identity and cell-physiological status, and convert into dynamic temporally controlled sequences of receptor-protein and receptor-DNA interactions. To process input and output information, the receptors are composed of a modular structure with several domains and associated functions (FIG. 1). The main domains are the DNA-binding domain (DBD) and the ligand-binding domain (LBD), and the three-dimensional structures of the DBD in the presence and absence of cognate DNA response elements and the LBD with various agonists or antagonists have been determined (Supplementary information S1 (table)). The LBD serves as a dual input-output information processor, as ligand binding (other inputs are, for example, receptor phosphorylations) induces allosteric changes of receptor surfaces that represent docking sites for subunits of the transcription and/or epigenetic machineries, or enzyme complexes (output). The complexity of input and output signals and their interdependence is not well understood and no three-dimensional structure of a full-length receptor has been established.
A major breakthrough of the past few years has been the recognition of the enormous variety of communication processes that can be collectively or separately addressed by simply modifying the ligand structure, and the corresponding mechanisms are beginning to be understood and pharmaceutically exploited. The basis of NR communication is their ability to provide surfaces for interaction in an allosterically controlled ligand-dependent manner. This communication reflects the cellular context, such as the ratio of co-activators (CoAs) and co-repressors (CoRs), which can determine whether a given ligand acts as an agonist or an antagonist. Indeed, it is conceivable to think of a ligand that acts as cell-specific agonist or antagonist, and the ongoing pharmaceutical development of specific NR modulators (SNuRMs) (2) is a manifestation of this concept.
O isterie generala pe retelele de socializare a fost declansata cu ceva timp in urma de mediatizarea unui control de amploare efectuat intr-o noapte de weekend in capitala, vizate fiind vehiculele modificate, in special autoturisme si motociclete cu sisteme de evacuare modificata. Controlul a fost efectuat de catre R.A.R. impreuna cu agenti de politie rutiera.
Lucrurile insa trebuie analizate si gandite la rece si chiar daca si eu ma numar printre cei care sunt pasionati de masini si care detin masini cu diverse modificari nu sunt totusi de acord cu acele comentarii rautacioase din mai multe puncte de vedere.
Tot in aceasta discutie putem introduce si autoritatile care au permis inmatricularea multor masini vechi, cu grad de uzura ridicat si cel mai grav cu volan pe dreapta! Un gram de adevar si de suparare justificata din partea celor care au tinut partea soferilor cu masini modificate amendati in trafic este si faptul ca in continuare putem observa in trafic masini cu ITP valabil care au mari probleme cu rugina, cu sistemul de iluminare sau cu noxele produse, unele dintre aceste masini fiind chiar ale diverselor institutii ale statului.
Acum sa lamurim care e treaba cu halogenul si xenon-ul: cele mai raspandite sunt solutile clasice incandescente cu becuri halogen, becuri clasice cu filament. Puterea este limitata la 55W pentru faza de intalnire si 60W pentru faza lunga. Pastrand aceste valori ca standard producatorii folosesc tot felul de artificii constructive pentru a face becuri mai stralucitoare. Varfurile de gama ale acestor becuri beneficiaza de filamente cu multe spire subtiri, materiale speciale, sticla de quartz cu diverse filtre colorate si un amestec de gaze sub presiune in bulb. In detrimentul fiabilitatii se obtin becuri mai stralucitoare si cu lumina mai apropiata de lumina zilei.
Please continue with this. Heroes 7 units are superior to H5. What a great idea.These look amazing. And their icons look great as well. Feels like they are vanila.Its about time we get an upgrade to the units of H5.
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AGN 194310 has been reported to bind to RARs with equal and high Kd values of 3, 2 and 5nM for RAR α, RARβ and RARγ, respectively, by in vitro binding experiments. In addition, AGN 194310 has been revealed to potently inhibit the colony formation by ITS+-grown cell lines with IC50 values of 16 5nM for LNCaP cells; 18 6nM for PC3 cells; and 34 7nM for DU-145 cells. Apart from these, because of binding to and mediating the effects via RARs, AGN 194310 has been demonstrated to inhibit agonist-induced (TTNPB) differentiation of HL60 cells. AGN 194310 has also shown the accumulation of cell in G1 and the function of induced apoptosis .
We study the binding of the neutral Agn (n = 8, 10, 12) to the DNA base-adenine (A), guanine (G) and Watson-Crick -adenine-thymine, guanine-cytosine pairs. Geometries of complexes were optimized at the DFT level using the hybrid B3LYP functional. LANL2DZ effective core potential was used for silver and 6-31 + G(**) was used for all other atoms. NBO charges were analyzed using the Natural population analysis. The absorption properties of Agn-A,G/WC complexes were also studied using time-dependent density functional theory. The absorption spectra for these complexes show wavelength in the visible region. It was revealed that silver clusters interact more strongly with WC pairs than with isolated DNA complexes. Furthermore, it was found that the electronic charge transferred from silver to isolated DNA clusters are less than the electronic charge transferred from silver to the Agn-WC complexes. The vertical ionization potential, vertical electron affinity, hardness, and electrophilicity index of Agn-DNA/WC complexes have also been discussed.
Angelica gigas Nakai (AGN, Korean Dang-gui) is traditionally used for the treatment of various diseases including cancer. Here, we investigated multidrug-resistant phenotype-reversal activities of AGN and its compounds (decursin, ferulic acid, and nodakenin) in doxorubicin-resistant NCI/ADR-RES ovarian cancer cells. Our results showed that a combination of doxorubicin with either AGN or decursin inhibited a proliferation of NCI/ADR-RES cells. These combinations increased the number of cells at sub-G1 phase when cells were stained with Annexin V-fluorescein isothiocyanate. We also found that these combinations activated caspase-9, caspase-8, and caspase-3 and increased cleaved PARP level. Moreover, an inhibition of P-glycoprotein expression by either AGN or decursin resulted in a reduction of its activity in NCI/ADR-RES cells. Therefore, our data demonstrate that decursin in AGN inhibits doxorubicin-resistant ovarian cancer cell proliferation and induces apoptosis in the presence of doxorubicin via blocking P-glycoprotein expression. Therefore, AGN would be a potentially novel treatment option for multidrug-resistant tumors by sensitizing to anticancer agents. Copyright (c) 2016 John Wiley & Sons, Ltd. 041b061a72