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1.
Arch Biochem Biophys ; 759: 110085, 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38971421

RESUMEN

Cardiac glycosides, derived from plants and animals, have been recognized since ancient times. These substances hinder the function of the sodium-potassium pump within eukaryotic cells. Many reports have shown that these compounds influence the activity of nuclear receptors. Thus, we assessed the effects of various cardiac glycosides at nontoxic concentrations on RORγ and RORγT. RORγT is a crucial protein involved in the differentiation of Th17 lymphocytes. Sixteen analyzed cardiac glycosides exhibited varying toxicities in HepG2 cells, all of which demonstrated agonistic effects on RORγ, as confirmed in the RORγ-HepG2 reporter cell line. The overexpression of both the RORγ and RORγT isoforms intensified the effects of these compounds. Additionally, these glycosides induced the expression of G6PC, a gene regulated by RORγ, in HepG2 cells. Subsequently, the effects of two endogenous cardiac glycosides (marinobufagenin and ouabain) and the three most potent glycosides (bufalin, oleandrin, and telecinobufagenin) were evaluated in Th17 primary lymphocytes. All of these compounds increased the expression of the IL17A, IL17F, IFNG, and CXCL10 genes, but they exhibited varying effects on GZMB and CCL20 expression. Molecular docking analysis revealed the robust binding affinity of cardiac glycosides for the ligand binding domain of the RORγ/RORγT receptors. Thus, we demonstrated that at nontoxic concentrations, cardiac glycosides have agonistic effects on RORγ/RORγT nuclear receptors, augmenting their activity. This potential can be harnessed to modulate the phenotype of IL17-expressing cells (e.g., Th17 or Tc17 lymphocytes) in adoptive therapy for combating various types of cancer.

2.
Int J Mol Sci ; 23(3)2022 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-35163824

RESUMEN

RORγT is a protein product of the RORC gene belonging to the nuclear receptor subfamily of retinoic-acid-receptor-related orphan receptors (RORs). RORγT is preferentially expressed in Th17 lymphocytes and drives their differentiation from naive CD4+ cells and is involved in the regulation of the expression of numerous Th17-specific cytokines, such as IL-17. Because Th17 cells are implicated in the pathology of autoimmune diseases (e.g., psoriasis, inflammatory bowel disease, multiple sclerosis), RORγT, whose activity is regulated by ligands, has been recognized as a drug target in potential therapies against these diseases. The identification of such ligands is time-consuming and usually requires the screening of chemical libraries. Herein, using a Tanimoto similarity search, we found corosolic acid and other pentacyclic tritepenes in the library we previously screened as compounds highly similar to the RORγT inverse agonist ursolic acid. Furthermore, using gene reporter assays and Th17 lymphocytes, we distinguished compounds that exert stronger biological effects (ursolic, corosolic, and oleanolic acid) from those that are ineffective (asiatic and maslinic acids), providing evidence that such combinatorial methodology (in silico and experimental) might help wet screenings to achieve more accurate results, eliminating false negatives.


Asunto(s)
Linfocitos T CD4-Positivos/citología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/química , Ácido Oleanólico/farmacología , Células Th17/citología , Triterpenos/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Simulación por Computador , Evaluación Preclínica de Medicamentos , Agonismo Inverso de Drogas , Humanos , Interleucina-17/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Ácido Oleanólico/química , Mapeo Peptídico , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Triterpenos/química
3.
Int J Mol Sci ; 20(22)2019 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-31744223

RESUMEN

The RORC (RAR related orphan receptor C) gene produces two isoforms by alternative promoter usage: RORγ (nuclear receptor ROR-gamma isoform 1) and RORγT (nuclear receptor ROR-gamma isoform 1). Both proteins have distinct tissue distributions and are involved in several physiological processes, including glucose/lipid metabolism and the development of Th17 lymphocytes. Previously, we developed a stably transfected reporter cell line and used it to screen a library of kinase inhibitors. We found that AZ5104 acts as an RORγ agonist at low micromolar concentrations. Molecular docking analysis showed that this compound occupies the ligand binding domain of the receptor with a significant docking score. However, analysis of the biological activity of this compound in Th17 cells revealed that it downregulates RORγT expression and Th17-related cytokine production via inhibition of SRC-ERK-STAT3 (SRC proto-oncogene - extracellular regulated MAP kinase - signal transducer and activator of transcription 3). We thus identified a compound acting as an agonist of RORγ that, due to the inhibition of downstream elements of EGFR (epidermal growth factor receptor) signaling, exerts different biological activity towards a Th17-specific isoform. Additionally, our results may be relevant in the future for the design of treatments targeting signaling pathways that inhibit Th17-related inflammation in certain autoimmune disorders.


Asunto(s)
Acrilamidas/farmacología , Compuestos de Anilina/farmacología , Antiinflamatorios/farmacología , Indoles/farmacología , Inflamación/prevención & control , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Células Hep G2 , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Fosforilación , Regiones Promotoras Genéticas/genética , Isoformas de Proteínas , Proto-Oncogenes Mas , Factor de Transcripción STAT3/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas , Células Th17/efectos de los fármacos
4.
Biochim Biophys Acta Rev Cancer ; 1878(6): 189021, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37951483

RESUMEN

RORγT is a transcription factor that directs the development of Th17 lymphocytes and other IL-17-expressing cells (e.g., Tc17 and ILC3 cells). These cells are involved in the body's defense against pathogenic bacteria and fungi, but they also participate in maintaining the proinflammatory environment in some autoimmune diseases and play a role in the immune system's response to cancer. Similar to other members of the nuclear receptor superfamily, the activity of RORγT is regulated by low-molecular-weight ligands. Therefore, extensive efforts have been dedicated to identifying inverse agonists that diminish the activity of this receptor and subsequently inhibit the development of autoimmune diseases. Unfortunately, in the pursuit of an ideal inverse agonist, the development of agonists has been overlooked. It is important to remember that these types of compounds, by stimulating lymphocytes expressing RORγT (Th17 and Tc17), can enhance the immune system's response to tumors. In this review, we present recent advancements in the biology of RORγT agonists and their potential application in anticancer therapy.


Asunto(s)
Enfermedades Autoinmunes , Agonismo Inverso de Drogas , Humanos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Regulación de la Expresión Génica , Enfermedades Autoinmunes/tratamiento farmacológico
5.
Biomed Pharmacother ; 164: 115002, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37311277

RESUMEN

Hepatocellular carcinoma (HCC) is one of the most common cancerous tumors and one of the leading causes of death among cancer-related disorders. Chemotherapy is ineffective in HCC patients, and the number of drugs that are in use is limited. Thus, new molecules are needed that could increase the effectiveness of anti-HCC regimens. Here, we show that AT7519, a CDK inhibitor, exerts positive effects on HCC cells: it inhibits proliferation, migration and clonogenicity. Detailed analysis of the transcriptomes of cells treated with this compound indicated that AT7519 affects a substantial portion of genes that are associated with HCC development and progression. Moreover, we showed that the concomitant use of AT7519 with gefitinib or cabozantinib sensitized HCC cells to these drugs. Thus, our research indicates that AT7519 is worth considering in monotherapy for hepatocellular carcinoma patients or in combination with other drugs, e.g., gefitinib or cabozantinib.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Quinasas Ciclina-Dependientes , Gefitinib/farmacología , Gefitinib/uso terapéutico , Línea Celular Tumoral , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Proliferación Celular , Quinasa 4 Dependiente de la Ciclina
6.
Comput Struct Biotechnol J ; 21: 5491-5505, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38022699

RESUMEN

In this work, we developed and applied a computational procedure for creating and validating predictive models capable of estimating the biological activity of ligands. The combination of modern machine learning methods, experimental data, and the appropriate setup of molecular descriptors led to a set of well-performing models. We thoroughly inspected both the methodological space and various possibilities for creating a chemical feature space. The resulting models were applied to the virtual screening of the ZINC20 database to identify new, biologically active ligands of RORγ receptors, which are a subfamily of nuclear receptors. Based on the known ligands of RORγ, we selected candidates and calculate their predicted activities with the best-performing models. We chose two candidates that were experimentally verified. One of these candidates was confirmed to induce the biological activity of the RORγ receptors, which we consider proof of the efficacy of the proposed methodology.

7.
Int J Neural Syst ; 32(11): 2250056, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36309813

RESUMEN

We propose here a novel neural architecture dedicated to the prediction of time series. It can be considered as an adaptation of the idea of (GQN) to the data which is of a sequence nature. The new approach, dubbed here as the (RGQN), allows for efficient prediction of time series. The predictor information (i.e. the independent variable) is one or more of the other time series which are in some relationship with the predicted sequence. Each time series is accompanied by additional meta-information reflecting its selected properties. This meta-information, together with the standard dynamic component, is provided simultaneously in (RNN). During the inference phase, meta-information becomes a query reflecting the expected properties of the predicted time series. The proposed idea is illustrated with use cases of strong practical relevance. In particular, we discuss the example of an industrial pipeline that transports liquid media. The trained RGQN model is applied to predict pressure signals, assuming that the training was carried out during routine operational conditions. The subsequent comparison of the prediction with the actual data gathered under extraordinary circumstances, e.g. during the leakage, leads to a specific residual distribution of the prediction. This information can be applied directly within the data-driven Leak Detection and Location framework. The RGQN approach can be applied not only to pressure time series but also in many other use cases where the quantity of sequence nature is accompanied by a meta-descriptor.


Asunto(s)
Redes Neurales de la Computación
8.
J Comput Chem ; 32(11): 2492-513, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21590779

RESUMEN

A detailed description of the explicitly correlated second-order Møller-Plesset perturbation theory (MP2-F12) method, as implemented in the TURBOMOLE program package, is presented. The TURBOMOLE implementation makes use of density fitting, which greatly reduces the prefactor for integral evaluation. Methods are available for the treatment of ground states of open- and closed-shell species, using unrestricted as well as restricted (open-shell) Hartree-Fock reference determinants. Various methodological choices and approximations are discussed. The performance of the TURBOMOLE implementation is illustrated by example calculations of the molecules leflunomide, prednisone, methotrexate, ethylenedioxytetrafulvalene, and a cluster model for the adsorption of methanol on the zeolite H-ZSM-5. Various basis sets are used, including the correlation-consistent basis sets specially optimized for explicitly correlated calculations (cc-pVXZ-F12).

9.
Phys Chem Chem Phys ; 12(29): 8208-18, 2010 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-20485771

RESUMEN

The ground-state N-H...pi interaction of 2-pyridone.benzene (2PY.Bz) has been studied by infrared-UV depletion spectroscopy of the supersonic-jet cooled complex [P. Ottiger et al., J. Phys. Chem. B (2009) 113, 2937]. Here, we investigate the large-amplitude vibrations of 2PY.Bz and its d(1)-2PY and benzene-d(6) isotopologues in the S(1) state, using two-color resonant two-photon ionization and UV-holeburning spectroscopies, complemented by RI-CC2 and SCS-RI-CC2 calculations of the S(1) state. The latter predict a tilted T-shaped structure with an N-H...pi hydrogen bond to the benzene ring, similar to the S(0) state. The binding energy is predicted to increase by 1.5 kJ mol(-1) upon S(1)<--S(0) excitation, in close agreement with the experimental value of 1.2 kJ mol(-1). The vibronic band structure up to 60 cm(-1) above the 0 band is dominated by large-amplitude delta tilting excitations, reflecting a change in the tilt angle of the T-shaped complex. The S(0) and S(1) state delta potentials were fitted to experiment, yielding a single minimum in the S(0) state and a double-minimum S(1) potential with delta(min) = +/-13 degrees. The second large-amplitude vibration is the theta twisting or benzene internal-rotation mode. Due to the C(6) symmetry of the benzene moiety the S(0) and S(1) state theta potentials are sixfold symmetric. Analysis of the theta band structure reveals that the S(0) and S(1)theta potentials are mutually aligned and that the internal rotation barriers are V(6)(S(0)) < 0.2 kJ mol(-1) and V(6)(S(1)) = 0.10(1) kJ mol(-1), in close agreement with the calculations. Weaker excitations of the totally symmetric intermolecular vibrations chi (shear), omega (bend) and sigma (stretch) vibrations are also observed. The 2PY intramolecular nu(1) overtone, corresponding to an 2PY amide out-of-plane twist distortion, lies approximately 30% higher than in bare 2PY, reflecting the hindrance of this motion by the strong N-H...pi interaction.

10.
Biomed Pharmacother ; 127: 110106, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32248001

RESUMEN

Cardiac glycosides are compounds isolated from plants and animals and have been known since ancient times. These compounds inhibit the activity of the sodium potassium pump in eukaryotic cells. Cardiac glycosides were used as drugs in heart ailments to increase myocardial contraction force and, at the same time, to lower frequency of this contraction. An increasing number of studies have indicated that the biological effects of these compounds are not limited to inhibition of sodium-potassium pump activity. Furthermore, an increasing number of data have shown that they are synthesized in tissues of mammals, where they may act as a new class of steroid hormones or other hormones by mimicry to modulate various signaling pathways and influence whole organisms. Thus, we discuss the interactions of cardiac glycosides with the nuclear receptor superfamily of transcription factors activated by low-weight molecular ligands (including hormones) that regulate many functions of cells and organisms. Cardiac glycosides of endogenous and exogenous origin by interacting with nuclear receptors can affect the processes regulated by these transcription factors, including hormonal management, immune system, body defense, and carcinogenesis. They can also be treated as initial structures for combinatorial chemistry to produce new compounds (including drugs) with the desired properties.


Asunto(s)
Glicósidos Cardíacos/farmacología , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/fisiología , Animales , Humanos
11.
J Phys Chem B ; 113(9): 2937-43, 2009 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-19243205

RESUMEN

Among the weak intermolecular interactions found in proteins, the amide N--H...pi interaction has been widely observed but remains poorly characterized as an individual interaction. We have investigated the isolated supersonic-jet-cooled dimer of the cis-amide and nucleobase analogue 2-pyridone (2PY) with benzene and benzene-d6. Both MP2 and SCS-MP2 geometry optimizations yield a T-shaped structure with a N--H...pi hydrogen bond to the benzene ring and the C=O group above, but far from the C--H bonds of benzene. The CCSD(T) calculated binding energy at the optimum geometry is De = 25.2 kJ/mol (dissociation energy D0 = 21.6 kJ/mol), corresponding to the H-bond strength of the water dimer or of N--H...O hydrogen bonds. The T-shaped geometry is supported by the infrared-ultraviolet depletion spectra of 2PY x benzene: The N--H stretch vibrational frequency is lowered by 56 cm(-1), and the C=O stretch vibration is lowered by 10 cm(-1), relative to those of bare 2PY, indicating a strong N--H...pi interaction and a weak interaction of the C=O group. The benzene C--H infrared stretches exhibit very small shifts (approximately 2 cm(-1)) relative to benzene, signaling the absence of interactions with the benzene C--H groups. The infrared spectral shifts are consistent with a strong nonconventional pi hydrogen bond and a T-shaped structure for 2PY x benzene. Symmetry-adapted perturbation theory calculations show that the N--H...pi interaction is by far the dominant stabilization factor.


Asunto(s)
Amidas/química , Benceno/química , Enlace de Hidrógeno , Hidrógeno/química , Nitrógeno/química , Carbono/química , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Oxígeno/química , Piridonas/química , Espectrofotometría Infrarroja/métodos , Espectrofotometría Ultravioleta/métodos
12.
J Phys Chem A ; 113(43): 11679-84, 2009 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-19634876

RESUMEN

We have computed barrier heights of 71.8 +/- 2.0 and 216.4 +/- 2.0 kJ mol(-1) for the reactions CH4 + CH3* --> CH3* + CH4 and CH4 + CH3* --> H* + C2H6, respectively, using explicitly correlated coupled cluster theory with singles and doubles combined with standard coupled cluster theory with up to connected quadruple excitations. Transition-state theory has been used to compute the respective reaction rate constants in the temperature interval of 250-1500 K. The computed rates for the reaction to ethane are orders of magnitude slower than those used in the mechanism of Norinaga and Deutschmann (Ind. Eng. Chem. Res. 2007, 46, 3547.) for the modeling of the chemical vapor deposition of pyrolytic carbon.

13.
J Chem Phys ; 131(2): 024105, 2009 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-19603968

RESUMEN

The H(3)(+) potential energy surface is sampled at 5900 geometries with the emphasis on the nonequilibrium and asymptotic points. Apart from the Born-Oppenheimer energy converged to the accuracy better than 0.02 cm(-1), the adiabatic and the leading relativistic corrections are computed at each geometry. To represent analytically the potential energy surface, the parameters of a power series are determined by fitting to the computed energy points. Possible choice of nuclear masses simulating the nonadiabatic effects in solving the nuclear Schrodinger equation is analyzed. A set of theoretically predicted rovibrational transitions is confronted with the experimental data in the 10,700-13,700 cm(-1) window of the spectra.

14.
J Chem Phys ; 129(5): 054309, 2008 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-18698902

RESUMEN

The photoelectron spectrum (PES) of the uracil anion is reported and discussed from the perspective of quantum chemical calculations of the vertical detachment energies (VDEs) of the anions of various tautomers of uracil. The PES peak maximum is found at an electron binding energy of 2.4 eV, and the width of the main feature suggests that the parent anions are in a valence rather than a dipole-bound state. The canonical tautomer as well as four tautomers that result from proton transfer from an NH group to a C atom were investigated computationally. At the Hartree-Fock and second-order Moller-Plesset perturbation theory levels, the adiabatic electron affinity (AEA) and the VDE have been converged to the limit of a complete basis set to within +/-1 meV. Post-MP2 electron-correlation effects have been determined at the coupled-cluster level of theory including single, double, and noniterative triple excitations. The quantum chemical calculations suggest that the most stable valence anion of uracil is the anion of a tautomer that results from a proton transfer from N1H to C5. It is characterized by an AEA of 135 meV and a VDE of 1.38 eV. The peak maximum is as much as 1 eV larger, however, and the photoelectron intensity is only very weak at 1.38 eV. The PES does not lend support either to the valence anion of the canonical tautomer, which is the second most stable anion, and whose VDE is computed at about 0.60 eV. Agreement between the peak maximum and the computed VDE is only found for the third most stable tautomer, which shows an AEA of approximately -0.1 eV and a VDE of 2.58 eV. This tautomer results from a proton transfer from N3H to C5. The results illustrate that the characteristics of biomolecular anions are highly dependent on their tautomeric form. If indeed the third most stable anion is observed in the experiment, then it remains an open question why and how this species is formed under the given conditions.


Asunto(s)
Electrones , Teoría Cuántica , Uracilo/química , Sensibilidad y Especificidad
15.
Toxicol Lett ; 295: 314-324, 2018 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-29981919

RESUMEN

Two isoforms of a ligand-activated nuclear receptor, RORγ and RORγT, have been implicated in various physiological functions, including energy metabolism, circadian rhythm and immune system development. Using a stably transfected reporter cell line, we screened two chemical libraries and identified three cardenolides (natural, plant-derived pesticides) as activators of RORγ-dependent transcription. These compounds increased G6PC and NPAS2 expression in HepG2 cells, accompanied by increased occupancy of RORγ within the promoters of these genes. Further, strophanthidin, digoxigenin and dihydroouabain upregulated IL17A and IL17F expression and enhanced IL17 secretion in Th17 human lymphocytes. Molecular docking analyses of these compounds to the RORγ LBD showed favorable docking scores, suggesting that cardenolides may act as agonists of the receptor. Thus, our results provide new chemical structures for further development of RORγ-selective modulators with virtual therapeutic potential.


Asunto(s)
Digoxigenina/toxicidad , Hepatocitos/efectos de los fármacos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Ouabaína/análogos & derivados , Estrofantidina/toxicidad , Células Th17/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Sitios de Unión , Digoxigenina/química , Relación Dosis-Respuesta a Droga , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Simulación del Acoplamiento Molecular , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/química , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Ouabaína/química , Ouabaína/toxicidad , Regiones Promotoras Genéticas , Unión Proteica , Conformación Proteica , Transducción de Señal/efectos de los fármacos , Estrofantidina/química , Relación Estructura-Actividad , Células Th17/metabolismo , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos
16.
Front Pharmacol ; 9: 1460, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30666196

RESUMEN

Digoxin was one of the first identified RORγT receptor inverse agonists inhibiting the differentiation of Th17 cells. However, this compound exhibits inhibitory activity at relatively high concentrations that mediate cytotoxic effects. We previously identified several cardenolides that are structurally similar to digoxin that were able to induce RORγ/RORγT-dependent transcription. These observations encouraged us to reanalyze the effects of digoxin on RORγ/RORγT-dependent transcription at low, noncytotoxic concentrations. Digoxin induced RORγ/RORγT-dependent transcription in HepG2 and Th17 cells. Furthermore, analysis of the transcriptomes of Th17 cells cultured in the presence of digoxin revealed the induction of the expression of numerous Th17-specific genes, including IL17A/F, IL21, IL22, IL23R, CCR4, and CCR6. Thus, our study, which includes data obtained from intact cells, indicates that digoxin, similar to other cardenolides, is a potent RORγ/RORγT receptor activator and that its structure may serve as a starting point for the design of dedicated molecules that can be used in the development of adoptive cell therapy (ACT).

17.
J Phys Chem B ; 110(48): 24696-707, 2006 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-17134233

RESUMEN

We characterized anionic states of thymine using various electronic structure methods, with the most accurate results obtained at the CCSD(T)/aug-cc-pVDZ level of theory followed by extrapolations to complete basis set limits. We found that the most stable anion in the gas phase is related to an imino-oxo tautomer, in which the N1H proton is transferred to the C5 atom. This valence anion, aT(c5)(nl), is characterized by an electron vertical detachment energy (VDE) of 1251 meV and it is adiabatically stable with respect to the canonical neutral nT(can) by 2.4 kcal/mol. It is also more stable than the dipole-bound (aT(dbs)(can)), and valence anion aT(val)(can) of the canonical tautomer. The VDE values for aT(dbs)(can)and T(val)(can) are 55 and 457 meV, respectively. Another, anionic, low-lying imino-oxo tautomer with a VDE of 2458 meV has a proton transferred from N3H to C5 aT(c5)(n3). It is less stable than aT(val)(can) by 3.3 kcal/mol. The mechanism of formation of anionic tautomers with the carbons C5 or C6 protonated may involve intermolecular proton transfer or dissociative electron attachment to the canonical neutral tautomer followed by a barrier-free attachment of a hydrogen atom to C5. The six-member ring structure of the anionic tautomers with carbon atoms protonated is unstable upon an excess electron detachment. Within the PCM hydration model, the low-lying valence anions become adiabatically bound with respect to the canonical neutral; becomes the most stable, being followed by aT(c5)(nl), aT(c5)(n3), aT(can), and aT(c5)(nl).


Asunto(s)
Timina/química , Aniones/química , Simulación por Computador , Electrones , Metilación , Estructura Molecular , Uracilo/química , Agua/química
19.
J Mol Model ; 15(7): 817-27, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19130099

RESUMEN

Changes of electrostatic potential around the DNA molecule resulting from chemical modifications of nucleotides may play a role in enzymatic recognition of damaged sites. The electrostatic potential around the DNA fragments containing either the intact guanine-cytosine pair or 8-oxoguanine-cytosine or the guanine-abasic site was projected on a cylindrical surface around the double helix. The 2D maps of EP of intact and damaged DNA fragments were compared using image analysis methods. Occurrence of abasic site and 8-oxoguanine lesions were found to be reflected in the EP maps. In the case of the 8-oxoguanine lesion, the two phosphate groups and countercations of the damaged strand are moved away from the lesion in opposite directions, whereas they are moved in the same direction in the case of the abasic site lesion. The characteristic features of 8-oxoguanine lesion might be identified in the major groove, whereas the features of abasic site lesion the minor groove.


Asunto(s)
Daño del ADN , ADN/química , Guanina/análogos & derivados , Modelos Moleculares , Guanina/química , Conformación de Ácido Nucleico , Electricidad Estática
20.
Science ; 319(5865): 936-9, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-18276886

RESUMEN

In contrast to widely familiar acid-base behavior in solution, single molecules of NH3 and HCl do not react to form the ionic salt, NH+4Cl-, in isolation. We applied anion photoelectron spectroscopy and ab initio theory to investigate the interaction of an excess electron with the hydrogen-bonded complex NH3...HCl. Our results show that an excess electron induces this complex to form the ionic salt. We propose a mechanism that proceeds through a dipole-bound state to form the negative ion of ionic ammonium chloride, a species that can also be characterized as a deformed Rydberg radical, NH4, polarized by a chloride anion, Cl-.

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