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1.
Plant Physiol ; 196(1): 651-666, 2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-38748589

RESUMEN

The highly conserved angiosperm immune receptor HOPZ-ACTIVATED RESISTANCE 1 (ZAR1) is a bacterial pathogen recognition hub that mediates resistance by guarding host kinases for modification by pathogen effectors. The pseudokinase HOPZ-ETI DEFICIENT 1 (ZED1) is the only known ZAR1-guarded protein that interacts directly with a pathogen effector, HopZ1a, from the bacterial pathogen Pseudomonas syringae, making it a promising system for rational design of effector recognition for plant immunity. Here, we conducted an in-depth molecular analysis of ZED1. We generated a library of 164 random ZED1 mutants and identified 50 mutants that could not recognize the effector HopZ1a when transiently expressed in Nicotiana benthamiana. Based on our random mutants, we generated a library of 27 point mutants and found evidence of minor functional divergence between Arabidopsis (Arabidopsis thaliana) and N. benthamiana ZAR1 orthologs. We leveraged our point mutant library to identify regions in ZED1 critical for ZAR1 and HopZ1a interactions and identified two likely ZED1-HopZ1a binding conformations. We explored ZED1 nucleotide and cation binding activity and showed that ZED1 is a catalytically dead pseudokinase, functioning solely as an allosteric regulator upon effector recognition. We used our library of ZED1 point mutants to identify the ZED1 activation loop regions as the most likely cause of interspecies ZAR1-ZED1 incompatibility. Finally, we identified a mutation that abolished ZAR1-ZED1 interspecies incompatibility while retaining the ability to mediate HopZ1a recognition, which enabled recognition of HopZ1a through tomato (Solanum lycopersicum) ZAR1. This provides an example of expanded effector recognition through a ZAR1 ortholog from a non-model species.


Asunto(s)
Arabidopsis , Inmunidad de la Planta , Pseudomonas syringae , Solanum lycopersicum , Solanum lycopersicum/genética , Solanum lycopersicum/microbiología , Solanum lycopersicum/inmunología , Solanum lycopersicum/enzimología , Solanum lycopersicum/metabolismo , Pseudomonas syringae/patogenicidad , Arabidopsis/genética , Arabidopsis/inmunología , Arabidopsis/metabolismo , Inmunidad de la Planta/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Nicotiana/genética , Nicotiana/microbiología , Nicotiana/inmunología , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/genética , Mutación/genética , Fosfotransferasas , Péptidos y Proteínas de Señalización Intracelular
2.
Biochem J ; 478(17): 3351-3371, 2021 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-34431498

RESUMEN

EphB6 and EphA10 are two poorly characterised pseudokinase members of the Eph receptor family, which collectively serves as mediators of contact-dependent cell-cell communication to transmit extracellular cues into intracellular signals. As per their active counterparts, EphB6 and EphA10 deregulation is strongly linked to proliferative diseases. However, unlike active Eph receptors, whose catalytic activities are thought to initiate an intracellular signalling cascade, EphB6 and EphA10 are classified as catalytically dead, raising the question of how non-catalytic functions contribute to Eph receptor signalling homeostasis. In this study, we have characterised the biochemical properties and topology of the EphB6 and EphA10 intracellular regions comprising the juxtamembrane (JM) region, pseudokinase and SAM domains. Using small-angle X-ray scattering and cross-linking-mass spectrometry, we observed high flexibility within their intracellular regions in solution and a propensity for interaction between the component domains. We identified tyrosine residues in the JM region of EphB6 as EphB4 substrates, which can bind the SH2 domains of signalling effectors, including Abl, Src and Vav3, consistent with cellular roles in recruiting these proteins for downstream signalling. Furthermore, our finding that EphB6 and EphA10 can bind ATP and ATP-competitive small molecules raises the prospect that these pseudokinase domains could be pharmacologically targeted to counter oncogenic signalling.


Asunto(s)
Receptores de la Familia Eph/química , Receptores de la Familia Eph/metabolismo , Transducción de Señal/genética , Motivo alfa Estéril/genética , Dominios Homologos src/genética , Adenosina Trifosfato/metabolismo , Animales , Humanos , Fosforilación , Unión Proteica , Conformación Proteica en Hélice alfa , Inhibidores de Proteínas Quinasas/metabolismo , Receptores de la Familia Eph/genética , Proteínas Recombinantes/metabolismo , Células Sf9 , Spodoptera/citología , Tirosina/metabolismo
3.
J Neurochem ; 147(3): 409-428, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30091236

RESUMEN

The Parkinson's disease (PD)-causative leucine-rich repeat kinase 2 (LRRK2) belongs to the Roco family of G-proteins comprising a Ras-of-complex (Roc) domain followed by a C-terminal of Roc (COR) domain in tandem (called Roc-COR domain). Two prokaryotic Roc-COR domains have been characterized as 'G proteins activated by guanine nucleotide-dependent dimerization' (GADs), which require dimerization for activation of their GTPase activity and bind guanine nucleotides with relatively low affinities. Additionally, LRRK2 Roc domain in isolation binds guanine nucleotides with relatively low affinities. As such, LRRK2 GTPase domain was predicted to be a GAD. Herein, we describe the design and high-level expression of human LRRK2 Roc-COR domain (LRRK2 Roc-COR). Biochemical analyses of LRRK2 Roc-COR reveal that it forms homodimers, with the C-terminal portion of COR mediating its dimerization. Furthermore, it co-purifies and binds Mg2+ GTP/GDP at 1 : 1 stoichiometry, and it hydrolyzes GTP with Km  and kcat  of 22 nM and 4.70 × 10-4  min-1 ,  respectively. Thus, even though LRRK2 Roc-COR forms GAD-like homodimers, it exhibits conventional Ras-like GTPase properties, with high-affinity binding of Mg2+ -GTP/GDP and low intrinsic catalytic activity. The PD-causative Y1699C mutation mapped to the COR domain was previously reported to reduce the GTPase activity of full-length LRRK2. In contrast, this mutation induces no change in the GTPase activity, and only slight perturbations in the secondary structure contents of LRRK2 Roc-COR. As this mutation does not directly affect the GTPase activity of the isolated Roc-COR tandem, it is possible that the effects of this mutation on full-length LRRK2 occur via other functional domains. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.


Asunto(s)
GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Genes ras/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Animales , Dimerización , Escherichia coli , Regulación Enzimológica de la Expresión Génica/genética , Nucleótidos de Guanina/metabolismo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/química , Magnesio/metabolismo , Ratones , Mutación/genética , Neuropéptidos/biosíntesis , Neuropéptidos/genética , Multimerización de Proteína , Estructura Secundaria de Proteína/genética , Proteínas Recombinantes , Proteína de Unión al GTP rac1/biosíntesis , Proteína de Unión al GTP rac1/genética
4.
Commun Biol ; 7(1): 461, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38627519

RESUMEN

EphB6 is an understudied ephrin receptor tyrosine pseudokinase that is downregulated in multiple types of metastatic cancers. Unlike its kinase-active counterparts which autophosphorylate and transmit signals upon intercellular interaction, little is known about how EphB6 functions in the absence of intrinsic kinase activity. Here, we unveil a molecular mechanism of cell-cell interaction driven by EphB6. We identify ephrinB1 as a cognate ligand of EphB6 and show that in trans interaction of EphB6 with ephrinB1 on neighboring cells leads to the formation of large co-clusters at the plasma membrane. These co-clusters exhibit a decreased propensity towards endocytosis, suggesting a unique characteristic for this type of cell-cell interaction. Using lattice light-sheet microscopy, 3D structured illumination microscopy and cryo-electron tomography techniques, we show that co-clustering of EphB6 and ephrinB1 promotes the formation of double-membrane tubular structures between cells. Importantly, we also demonstrate that these intercellular structures stabilize cell-cell adhesion, leading to a reduction in the invasive behavior of cancer cells. Our findings rationalize a role for EphB6 pseudokinase as a tumor suppressor when interacting with its ligands in trans.


Asunto(s)
Fosforilación , Invasividad Neoplásica
5.
Nat Commun ; 14(1): 3542, 2023 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-37336884

RESUMEN

PEAK pseudokinases regulate cell migration, invasion and proliferation by recruiting key signaling proteins to the cytoskeleton. Despite lacking catalytic activity, alteration in their expression level is associated with several aggressive cancers. Here, we elucidate the molecular details of key PEAK signaling interactions with the adapter proteins CrkII and Grb2 and the scaffold protein 14-3-3. Our findings rationalize why the dimerization of PEAK proteins has a crucial function in signal transduction and provide biophysical and structural data to unravel binding specificity within the PEAK interactome. We identify a conserved high affinity 14-3-3 motif on PEAK3 and demonstrate its role as a molecular switch to regulate CrkII binding and signaling via Grb2. Together, our studies provide a detailed structural snapshot of PEAK interaction networks and further elucidate how PEAK proteins, especially PEAK3, act as dynamic scaffolds that exploit adapter proteins to control signal transduction in cell growth/motility and cancer.


Asunto(s)
Proteínas 14-3-3 , Proteínas del Citoesqueleto , Transducción de Señal , Movimiento Celular , Proliferación Celular , Transducción de Señal/fisiología , Proteínas del Citoesqueleto/metabolismo , Proteínas 14-3-3/metabolismo
6.
Nat Commun ; 12(1): 6783, 2021 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-34811356

RESUMEN

The ancestral origins of the lytic cell death mode, necroptosis, lie in host defense. However, the dysregulation of necroptosis in inflammatory diseases has led to widespread interest in targeting the pathway therapeutically. This mode of cell death is executed by the terminal effector, the MLKL pseudokinase, which is licensed to kill following phosphorylation by its upstream regulator, RIPK3 kinase. The precise molecular details underlying MLKL activation are still emerging and, intriguingly, appear to mechanistically-diverge between species. Here, we report the structure of the human RIPK3 kinase domain alone and in complex with the MLKL pseudokinase. These structures reveal how human RIPK3 structurally differs from its mouse counterpart, and how human RIPK3 maintains MLKL in an inactive conformation prior to induction of necroptosis. Residues within the RIPK3:MLKL C-lobe interface are crucial to complex assembly and necroptotic signaling in human cells, thereby rationalizing the strict species specificity governing RIPK3 activation of MLKL.


Asunto(s)
Muerte Celular/fisiología , Necroptosis/fisiología , Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/química , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Animales , Muerte Celular/genética , Células HT29 , Humanos , Ratones , Necroptosis/genética , Fosforilación , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Proteínas Quinasas/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteínas Recombinantes , Transducción de Señal
7.
Nat Commun ; 12(1): 1002, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33579933

RESUMEN

The life cycle of Baculoviridae family insect viruses depends on the viral protein kinase, PK-1, to phosphorylate the regulatory protein, p6.9, to induce baculoviral genome release. Here, we report the crystal structure of Cydia pomenella granulovirus PK-1, which, owing to its likely ancestral origin among host cell AGC kinases, exhibits a eukaryotic protein kinase fold. PK-1 occurs as a rigid dimer, where an antiparallel arrangement of the αC helices at the dimer core stabilizes PK-1 in a closed, active conformation. Dimerization is facilitated by C-lobe:C-lobe and N-lobe:N-lobe interactions between protomers, including the domain-swapping of an N-terminal helix that crowns a contiguous ß-sheet formed by the two N-lobes. PK-1 retains a dimeric conformation in solution, which is crucial for catalytic activity. Our studies raise the prospect that parallel, side-to-side dimeric arrangements that lock kinase domains in a catalytically-active conformation could function more broadly as a regulatory mechanism among eukaryotic protein kinases.


Asunto(s)
Dimerización , Granulovirus/enzimología , Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Baculoviridae/metabolismo , Cristalografía por Rayos X , Granulovirus/genética , Simulación de Dinámica Molecular , Fosforilación , Conformación Proteica , Proteínas Quinasas/genética , Subunidades de Proteína/metabolismo , Proteínas Virales/metabolismo
8.
Nat Commun ; 12(1): 3364, 2021 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-34099649

RESUMEN

Necroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.


Asunto(s)
Infecciones por Herpesviridae/metabolismo , Lisina/metabolismo , Proteínas Quinasas/metabolismo , Piel/metabolismo , Animales , Línea Celular , Células Cultivadas , Células HEK293 , Células HT29 , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/virología , Humanos , Lisina/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Muromegalovirus/fisiología , Células 3T3 NIH , Necroptosis/genética , Necrosis , Proteínas Quinasas/genética , Piel/patología , Ubiquitinación
9.
Nat Commun ; 11(1): 3060, 2020 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-32561735

RESUMEN

The MLKL pseudokinase is the terminal effector in the necroptosis cell death pathway. Phosphorylation by its upstream regulator, RIPK3, triggers MLKL's conversion from a dormant cytoplasmic protein into oligomers that translocate to, and permeabilize, the plasma membrane to kill cells. The precise mechanisms underlying these processes are incompletely understood, and were proposed to differ between mouse and human cells. Here, we examine the divergence of activation mechanisms among nine vertebrate MLKL orthologues, revealing remarkable specificity of mouse and human RIPK3 for MLKL orthologues. Pig MLKL can restore necroptotic signaling in human cells; while horse and pig, but not rat, MLKL can reconstitute the mouse pathway. This selectivity can be rationalized from the distinct conformations observed in the crystal structures of horse and rat MLKL pseudokinase domains. These studies identify important differences in necroptotic signaling between species, and suggest that, more broadly, divergent regulatory mechanisms may exist among orthologous pseudoenzymes.


Asunto(s)
Proteínas Quinasas/química , Proteína Serina-Treonina Quinasas de Interacción con Receptores/química , Animales , Pollos , Cristalografía por Rayos X , Citoplasma/enzimología , Células HEK293 , Caballos , Humanos , Ratones , Necroptosis , Necrosis/metabolismo , Fosforilación , Conformación Proteica , Ratas , Transducción de Señal , Smegmamorpha , Porcinos , Células U937 , Xenopus
10.
ACS Chem Biol ; 15(10): 2702-2713, 2020 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-32902249

RESUMEN

Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound 2 is a more potent analogue of the published compound 1 and inhibits necroptosis in human and murine cells at nanomolar concentrations. Several target engagement strategies were employed, including cellular thermal shift assays (CETSA) and diazirine-mediated photoaffinity labeling via a bifunctional photoaffinity probe derived from compound 2. These target engagement studies demonstrate that compound 2 binds to all three necroptotic effector proteins (mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine protein kinase 1 (RIPK1) and receptor-interacting serine/threonine protein kinase 3 (RIPK3)) at different levels in vitro and in cells. Compound 2 also shows efficacy in vivo in a murine model of systemic inflammatory response syndrome (SIRS).


Asunto(s)
Necroptosis/efectos de los fármacos , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Sulfonamidas/uso terapéutico , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones Endogámicos C57BL , Compuestos de Fenilurea/metabolismo , Compuestos de Fenilurea/farmacocinética , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico
11.
Oncogene ; 38(39): 6567-6584, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31406248

RESUMEN

Eph receptors, the largest subfamily of receptor tyrosine kinases, are linked with proliferative disease, such as cancer, as a result of their deregulated expression or mutation. Unlike other tyrosine kinases that have been clinically targeted, the development of therapeutics against Eph receptors remains at a relatively early stage. The major reason is the limited understanding on the Eph receptor regulatory mechanisms at a molecular level. The complexity in understanding Eph signalling in cells arises due to following reasons: (1) Eph receptors comprise 14 members, two of which are pseudokinases, EphA10 and EphB6, with relatively uncharacterised function; (2) activation of Eph receptors results in dimerisation, oligomerisation and formation of clustered signalling centres at the plasma membrane, which can comprise different combinations of Eph receptors, leading to diverse downstream signalling outputs; (3) the non-catalytic functions of Eph receptors have been overlooked. This review provides a structural perspective of the intricate molecular mechanisms that drive Eph receptor signalling, and investigates the contribution of intra- and inter-molecular interactions between Eph receptors intracellular domains and their major binding partners. We focus on the non-catalytic functions of Eph receptors with relevance to cancer, which are further substantiated by exploring the role of the two pseudokinase Eph receptors, EphA10 and EphB6. Throughout this review, we carefully analyse and reconcile the existing/conflicting data in the field, to allow researchers to further the current understanding of Eph receptor signalling.


Asunto(s)
Receptores de la Familia Eph/metabolismo , Transducción de Señal , Secuencia de Aminoácidos , Animales , Catálisis , Humanos , Ligandos , Receptores de la Familia Eph/química , Homología de Secuencia de Aminoácido
12.
Cell Rep ; 28(13): 3309-3319.e5, 2019 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-31553902

RESUMEN

Necroptotic cell death has been implicated in many human pathologies and is thought to have evolved as an innate immunity mechanism. The pathway relies on two key effectors: the kinase receptor-interacting protein kinase 3 (RIPK3) and the terminal effector, the pseudokinase mixed-lineage kinase-domain-like (MLKL). We identify proteins with high sequence similarity to the pseudokinase domain of MLKL in poxvirus genomes. Expression of these proteins from the BeAn 58058 and Cotia poxviruses, but not swinepox, in human and mouse cells blocks cellular MLKL activation and necroptotic cell death. We show that viral MLKL-like proteins function as dominant-negative mimics of host MLKL, which inhibit necroptosis by sequestering RIPK3 via its kinase domain to thwart MLKL engagement and phosphorylation. These data support an ancestral role for necroptosis in defense against pathogens. Furthermore, mimicry of a cellular pseudokinase by a pathogen adds to the growing repertoire of functions performed by pseudokinases in signal transduction.


Asunto(s)
Proteínas Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Animales , Muerte Celular , Humanos , Inmunidad Innata , Ratones , Necrosis
13.
Nat Commun ; 9(1): 2422, 2018 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-29930286

RESUMEN

Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.


Asunto(s)
Muerte Celular/fisiología , Modelos Moleculares , Proteínas Quinasas/fisiología , Animales , Bases de Datos de Proteínas , Humanos , Espectrometría de Masas , Ratones , Polimerizacion , Conformación Proteica , Dominios Proteicos , Proteínas Quinasas/química , Proteínas Quinasas/genética , Transducción de Señal , Especificidad de la Especie
14.
Eur J Med Chem ; 85: 468-79, 2014 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-25113875

RESUMEN

A series of 2-methyl-1H-indol-3-ethylsulfamoylphenylacrylamides based on LBH589-PXD101 core have been synthesized and evaluated for their histone deacetylase (HDAC) inhibitory and anti-inflammatory activity. In vitro, compounds 9-12 show 2.6-fold better HDAC inhibition and 3-fold better IL-6 suppression compared to LBH589·HCl (1·HCl). Furthermore, these compounds did not show apparent cell viability suppression on macrophages while in contrast, treatment with 1·HCl resulted in significant reduction in cell viability as demonstrated by an MTT assay. Repressed expression of iNOS, COX-2 and reduced phosphorylation of p65 revealed the inhibitory effect of these analogues on inflammatory mediator release which is related to inhibited NF-ĸB signals. (N-Hydroxy-3-{3-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide) (9), exhibited ability superior to that of 1·HCl, was able to reduce carrageenan-induced acute inflammation in an animal model. Compounds 9-12 have potential anti-inflammatory activity and compound 9 can serve as lead compound for further development.


Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Indoles/química , Indoles/farmacología , Animales , Antiinflamatorios/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Edema/tratamiento farmacológico , Células HeLa , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Indoles/uso terapéutico , Ratas
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