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1.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800907

RESUMO

BACKGROUND: In the present study, we examined superoxide-mediated excitatory nociceptive transmission on at-level neuropathic pain following spinal thoracic 10 contusion injury (SCI) in male Sprague Dawley rats. METHODS: Mechanical sensitivity at body trunk, neuronal firing activity, and expression of superoxide marker/ionotropic glutamate receptors (iGluRs)/CamKII were measured in the T7/8 dorsal horn, respectively. RESULTS: Topical treatment of superoxide donor t-BOOH (0.4 mg/kg) increased neuronal firing rates and pCamKII expression in the naïve group, whereas superoxide scavenger Tempol (1 mg/kg) and non-specific ROS scavenger PBN (3 mg/kg) decreased firing rates in the SCI group (* p < 0.05). SCI showed increases of iGluRs-mediated neuronal firing rates and pCamKII expression (* p < 0.05); however, t-BOOH treatment did not show significant changes in the naïve group. The mechanical sensitivity at the body trunk in the SCI group (6.2 ± 0.5) was attenuated by CamKII inhibitor KN-93 (50 µg, 3.9 ± 0.4) or Tempol (1 mg, 4 ± 0.4) treatment (* p < 0.05). In addition, the level of superoxide marker Dhet showed significant increase in SCI rats compared to the sham group (11.7 ± 1.7 vs. 6.6 ± 1.5, * p < 0.05). CONCLUSIONS: Superoxide and the pCamKII pathway contribute to chronic at-level neuropathic pain without involvement of iGluRs following SCI.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Hiperalgesia/tratamento farmacológico , Proteínas do Tecido Nervoso/fisiologia , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Superóxidos/metabolismo , Animais , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Contusões/fisiopatologia , Óxidos N-Cíclicos/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Hiperalgesia/etiologia , Masculino , Modelos Animais , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neuralgia/etiologia , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores Ionotrópicos de Glutamato/efeitos dos fármacos , Marcadores de Spin , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/fisiopatologia , Sulfonamidas/farmacologia , Transmissão Sináptica
2.
Life Sci ; 276: 119434, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785343

RESUMO

AIMS: Immunosuppressive myeloid-derived suppressor cells (MDSCs) continuously expand and lead to poor outcome during sepsis. The activation of liver X receptor (LXR) can mitigate sepsis-induced liver and myocardial damage. This study aims to determine whether LXR plays a protective role in sepsis by regulating MDSCs. MAIN METHODS: Cecal ligation and puncture(CLP)was used to induce sepsis in mice. The mice were then treated with LXR agonist GW3965 (3 mg/kg) or vehicle 1 h, 6 h, 12 h, 24 h, 48 h, 72 h postoperatively. The effect of LXR on the survival rate and multi-organ injury induced by sepsis was evaluated by survival analysis, histological staining, biochemical analysis and ELISAs. The percentages of MDSCs and T cells were detected using flow cytometry. The mRNA expressions of LXR and ATP-binding cassette transporter A1 (ABCA1) were measured using real-time quantitative PCR (RT-qPCR). ABCA1 protein level was determined using immunofluorescence staining. KEY FINDINGS: LXR agonist GW3965 treatment improved the survival of septic mice, accompanied by reduced multi-organ injury and a decreased level of inflammatory cytokines. Furthermore, GW3965 treatment decreased MDSCs abundance in spleen by boosting the apoptosis of spleen MDSCs, therefore ameliorating their immunosuppressive activity. Meanwhile, bacteria clearance in tissues was enhanced after the GW3965 administration in septic mice. Mechanistically, GW3965 activated LXRß and its downstream target ABCA1 to initiate the apoptosis of spleen MDSCs. SIGNIFICANCE: These findings provide new insights into the relationship between LXR and MDSCs in sepsis, thus revealing a potentially effective approach to target the immunosuppression of sepsis.


Assuntos
Apoptose , Benzoatos/farmacologia , Benzilaminas/farmacologia , Receptores X do Fígado/agonistas , Células Supressoras Mieloides/patologia , Substâncias Protetoras/farmacologia , Sepse/tratamento farmacológico , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Citocinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Sepse/metabolismo , Sepse/patologia
3.
Eur J Pharmacol ; 897: 173936, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33581134

RESUMO

Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization. Notably, CXCR4 and MDM2-4 cooperate in promoting tumour invasion and progression. Although CXCR4 actively promotes MDM2 activation leading to p53 inactivation, MDM2-4 knockdown induces the downregulation of CXCR4 gene transcription. Our study aimed to assess if the CXCR4 signal blockade could enhance glioma cells' sensitivity to the inhibition of the p53-MDMs axis. Rationally designed inhibitors of MDM2/4 were combined with the CXCR4 antagonist, AMD3100, in human GBM cells and GBM stem-like cells (neurospheres), which are crucial for tumour recurrence and chemotherapy resistance. The dual MDM2/4 inhibitor RS3594 and the CXCR4 antagonist AMD3100 reduced GBM cell invasiveness and migration in single-agent treatment and mainly in combination. AMD3100 sensitized GBM cells to the antiproliferative activity of RS3594. It is noteworthy that these two compounds present synergic effects on cancer stem components: RS3594 inhibited the growth and formation of neurospheres, AMD3100 induced differentiation of neurospheres while enhancing RS3594 effectiveness preventing their proliferation/clonogenicity. These results confirm that blocking CXCR4/MDM2/4 represents a valuable strategy to reduce GBM proliferation and invasiveness, acting on the stem cell component too.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzilaminas/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Ciclamos/farmacologia , Glioblastoma/tratamento farmacológico , Indóis/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores CXCR4/antagonistas & inibidores , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Neurogênese/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais , Esferoides Celulares , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Am J Physiol Heart Circ Physiol ; 320(3): H1112-H1123, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33449850

RESUMO

Comprehensive functional characterization of cardiac tissue includes investigation of length and load dependence. Such measurements have been slow to develop in engineered heart tissues (EHTs), whose mechanical characterizations have been limited primarily to isometric and near-isometric behaviors. A more realistic assessment of myocardial function would include force-velocity curves to characterize power output and force-length loops mimicking the cardiac cycle to characterize work output. We developed a system that produces force-velocity curves and work loops in human EHTs using an adaptive iterative control scheme. We used human EHTs in this system to perform a detailed characterization of the cardiac ß-myosin specific inhibitor, mavacamten. Consistent with the clinically proposed application of this drug to treat hypertrophic cardiomyopathy, our data support the premise that mavacamten improves diastolic function through reduction of diastolic stiffness and isometric relaxation time. Meanwhile, the effects of mavacamten on length- and load-dependent muscle performance were mixed. The drug attenuated the length-dependent response at small stretch values but showed normal length dependency at longer lengths. Peak power output of mavacamten-treated EHTs showed reduced power output as expected but also shifted peak power output to a lower load. Here, we demonstrate a robust method for the generation of isotonic contraction series and work loops in engineered heart tissues using an adaptive-iterative method. This approach reveals new features of mavacamten pharmacology, including previously unappreciated effects on intrinsic myosin dynamics and preservation of Frank-Starling behavior at longer muscle lengths.NEW & NOTEWORTHY We applied innovative methods to comprehensively characterize the length and load-dependent behaviors of engineered human cardiac muscle when treated with the cardiac ß-myosin specific inhibitor mavacamten, a drug on the verge of clinical implementation for hypertrophic cardiomyopathy. We find mechanistic support for the role of mavacamten in improving diastolic function of cardiac tissue and note novel effects on work and power.


Assuntos
Benzilaminas/farmacologia , Inibidores Enzimáticos/farmacologia , Coração/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Engenharia Tecidual , Uracila/análogos & derivados , Função Ventricular/efeitos dos fármacos , Miosinas Ventriculares/antagonistas & inibidores , Animais , Linhagem Celular , Diástole , Humanos , Modelos Cardiovasculares , Força Muscular/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Sus scrofa , Técnicas de Cultura de Tecidos , Tecidos Suporte , Uracila/farmacologia , Miosinas Ventriculares/metabolismo
5.
Int J Mol Sci ; 22(2)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435128

RESUMO

CXC-chemokine receptor type 4 (CXCR4), a 7-transmembrane receptor family member, displays multifaceted roles, participating in immune cell migration, angiogenesis, and even adipocyte metabolism. However, the activity of such a ubiquitously expressed receptor in epithelial gland organogenesis has not yet been fully explored. To investigate the relationship between CXCL12/CXCR4 signaling and embryonic glandular organogenesis, we used an ex vivo culture system with live imaging and RNA sequencing to elucidate the transcriptome and protein-level signatures of AMD3100, a potent abrogating reagent of the CXCR4-CXCL12 axis, imprinted on the developing organs. Immunostaining results showed that CXCR4 was highly expressed in embryonic submandibular gland, lung, and pancreas, especially at the periphery of end buds containing numerous embryonic stem/progenitor cells. Despite no significant increase in apoptosis, AMD3100-treated epithelial organs showed a retarded growth with significantly slower branching and expansion. Further analyses with submandibular glands revealed that such responses resulted from the AMD3100-induced precocious differentiation of embryonic epithelial cells, losing mitotic activity. RNA sequencing analysis revealed that inhibition of CXCR4 significantly down-regulated polycomb repressive complex (PRC) components, known as regulators of DNA methylation. Treatment with PRC inhibitor recapitulated the AMD3100-induced precocious differentiation. Our results indicate that the epigenetic modulation by the PRC-CXCR12/CXCR4 signaling axis is crucial for the spatiotemporal regulation of proliferation and differentiation of embryonic epithelial cells during embryonic glandular organogenesis.


Assuntos
Benzilaminas/farmacologia , Diferenciação Celular , Ciclamos/farmacologia , Receptores CXCR4/metabolismo , Transdução de Sinais , Glândula Submandibular/metabolismo , Animais , Quimiocina CXCL12/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Camundongos , Organogênese , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Proteínas Repressoras/metabolismo , Glândula Submandibular/efeitos dos fármacos , Glândula Submandibular/embriologia , Glândula Submandibular/fisiologia
6.
Int J Mol Sci ; 22(2)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435251

RESUMO

Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4' of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present N-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC50~1 µM) with moderate selectivity over other kinases.


Assuntos
Benzilaminas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/enzimologia , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinazolinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzilaminas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Mutação , Proteínas de Neoplasias/antagonistas & inibidores , Quinazolinas/uso terapêutico , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 213: 113154, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33476932

RESUMO

In this study, a series of multifunctional hybrids against Alzheimer's disease were designed and obtained by conjugating the pharmacophores of xanthone and alkylbenzylamine through the alkyl linker. Biological activity results demonstrated that compound 4j was the most potent and balanced dual ChEs inhibitor with IC50 values 0.85 µM and 0.59 µM for eeAChE and eqBuChE, respectively. Kinetic analysis and docking study indicated that compound 4j was a mixed-type inhibitor for both AChE and BuChE. Additionally, it exhibited good abilities to penetrate BBB, scavenge free radicals (4.6 trolox equivalent) and selectively chelate with Cu2+ and Al3+ at a 1:1.4 ligand/metal molar ratio. Importantly, after assessments of cytotoxic and acute toxicity, we found compound 4j could improve memory function of scopolamine-induced amnesia mice. Hence, the compound 4j can be considered as a promising lead compound for further investigation in the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Benzilaminas/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Xantonas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/patologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Benzotiazóis/antagonistas & inibidores , Benzilaminas/química , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Electrophorus , Cavalos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Picratos/antagonistas & inibidores , Ratos , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidores , Xantonas/química
8.
Cancer Res ; 81(4): 968-985, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33361391

RESUMO

Liver X receptors (LXR) are transcription factors from the nuclear receptor family that are activated by oxysterols and synthetic high-affinity agonists. In this study, we assessed the antitumor effects of synthetic LXR agonist TO901317 in a murine model of syngeneic Lewis Lung carcinoma. Treatment with TO901317 inhibited tumor growth in wild-type, but not in LXR-deficient mice, indicating that the antitumor effects of the agonist depends on functional LXR activity in host cells. Pharmacologic activation of the LXR pathway reduced the intratumoral abundance of regulatory T cells (Treg) and the expression of the Treg-attracting chemokine Ccl17 by MHCIIhigh tumor-associated macrophages (TAM). Moreover, gene expression profiling indicated a broad negative impact of the LXR agonist on other mechanisms used by TAM for the maintenance of an immunosuppressive environment. In studies exploring the macrophage response to GM-CSF or IL4, activated LXR repressed IRF4 expression, resulting in subsequent downregulation of IRF4-dependent genes including Ccl17. Taken together, this work reveals the combined actions of the LXR pathway in the control of TAM responses that contribute to the antitumoral effects of pharmacologic LXR activation. Moreover, these data provide new insights for the development of novel therapeutic options for the treatment of cancer. SIGNIFICANCE: This study reveals unrecognized roles of LXR in the transcriptional control of the tumor microenvironment and suggests use of a synthetic LXR agonist as a novel therapeutic strategy to stimulate antitumor activity.


Assuntos
Benzoatos/farmacologia , Benzilaminas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Sulfonamidas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/efeitos dos fármacos , Animais , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores X do Fígado/agonistas , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Células RAW 264.7 , Linfócitos T Reguladores/patologia , Transcriptoma/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
9.
Int Immunopharmacol ; 90: 107240, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33310663

RESUMO

Cytochrome P450 4F (CYP4F) enzymes are responsible for the metabolism of eicosanoids, which play important roles in inflammation. Nuclear receptor liver X receptor alpha (LXRα) is a critical signal node connecting inflammation and lipid metabolism. Studies revealed that the release of cytokines and nuclear factor-κB (NF-κB) can change the CYP4F11 expression in HepG2 cells. However, the effect of LXRα on the CYP4F family and the underlying mechanism remain unclear. This study found that CYP4F11 is a target gene of LXRα. Luciferase assays and siRNA transfection showed that LXRα increased the transcription of CYP4F11 and LXRα agonist GW3965 could induce the expression of CYP4F11 by activating the LXRα-CYP4F11 pathway. Besides, overexpression of CYP4F11 could decrease TNF-α and IL-1ß in lipopolysaccharide (LPS)-induced THP-1 cells. The finding of the regulation of CYP4F11 may contribute to the anti-inflammatory activity of LXRα agonists.


Assuntos
Família 4 do Citocromo P450/biossíntese , Regulação Enzimológica da Expressão Gênica/genética , Receptores X do Fígado/genética , Animais , Benzoatos/farmacologia , Benzilaminas/farmacologia , Família 4 do Citocromo P450/genética , Citocinas/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Interleucina-1beta/biossíntese , Lipopolissacarídeos/farmacologia , Receptores X do Fígado/agonistas , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B , RNA Interferente Pequeno/genética , Transfecção , Fator de Necrose Tumoral alfa/biossíntese
10.
Am J Physiol Heart Circ Physiol ; 320(2): H881-H890, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337957

RESUMO

Morbidity and mortality associated with heart disease is a growing threat to the global population, and novel therapies are needed. Mavacamten (formerly called MYK-461) is a small molecule that binds to cardiac myosin and inhibits myosin ATPase. Mavacamten is currently in clinical trials for the treatment of obstructive hypertrophic cardiomyopathy (HCM), and it may provide benefits for treating other forms of heart disease. We investigated the effect of mavacamten on cardiac muscle contraction in two transgenic mouse lines expressing the human isoform of cardiac myosin regulatory light chain (RLC) in their hearts. Control mice expressed wild-type RLC (WT-RLC), and HCM mice expressed the N47K RLC mutation. In the absence of mavacamten, skinned papillary muscle strips from WT-RLC mice produced greater isometric force than strips from N47K mice. Adding 0.3 µM mavacamten decreased maximal isometric force and reduced Ca2+ sensitivity of contraction for both genotypes, but this reduction in pCa50 was nearly twice as large for WT-RLC versus N47K. We also used stochastic length-perturbation analysis to characterize cross-bridge kinetics. The cross-bridge detachment rate was measured as a function of [MgATP] to determine the effect of mavacamten on myosin nucleotide handling rates. Mavacamten increased the MgADP release and MgATP binding rates for both genotypes, thereby contributing to faster cross-bridge detachment, which could speed up myocardial relaxation during diastole. Our data suggest that mavacamten reduces isometric tension and Ca2+ sensitivity of contraction via decreased strong cross-bridge binding. Mavacamten may become a useful therapy for patients with heart disease, including some forms of HCM.NEW & NOTEWORTHY Mavacamten is a pharmaceutical that binds to myosin, and it is under investigation as a therapy for some forms of heart disease. We show that mavacamten reduces isometric tension and Ca2+ sensitivity of contraction in skinned myocardial strips from a mouse model of hypertrophic cardiomyopathy that expresses the N47K mutation in cardiac myosin regulatory light chain. Mavacamten reduces contractility by decreasing strong cross-bridge binding, partially due to faster cross-bridge nucleotide handling rates that speed up myosin detachment.


Assuntos
Benzilaminas/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cardiomiopatia Hipertrófica/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Contração Miocárdica/efeitos dos fármacos , Cadeias Leves de Miosina/metabolismo , Músculos Papilares/efeitos dos fármacos , Uracila/análogos & derivados , Miosinas Ventriculares/antagonistas & inibidores , Animais , Cardiomiopatia Hipertrófica/enzimologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Modelos Animais de Doenças , Humanos , Cinética , Masculino , Camundongos Transgênicos , Mutação , Cadeias Leves de Miosina/genética , Músculos Papilares/enzimologia , Músculos Papilares/fisiopatologia , Uracila/farmacologia , Miosinas Ventriculares/metabolismo
11.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348693

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer with a high mortality rate due to the lack of early detection and effective treatment options for advanced diseases. Metabolic reprogramming, a common hallmark of malignant transformation in pancreatic cancer, is critical for the growth and survival of cancer cells and a potential target mechanism for the treatment of pancreatic cancer. PDAC cells have upregulated glutamine metabolism to meet their biosynthetic and oxidative demands. Liver X receptors (LXRs) are ligand-dependent transcription factors involved in maintaining metabolic homeostasis. LXRs regulate critical cancer-related processes and pathways, including cholesterol, glucose and lipid metabolism, and inflammatory and immune responses. Analysis of transcriptomic data from PDAC clinical samples reveals overexpression of LXRs and their target genes in tumors as compared to normal tissue controls. Targeting LXRs with the novel LXR inverse agonist and degrader GAC0001E5 inhibited PDAC cell proliferation. Using a metabolomics approach, we discovered that 1E5 inhibits glutamine anaplerosis and induces oxidative stress, which are detrimental to PDAC cells. These findings highlight a novel role for LXR in regulating cancer metabolism and the potential application of LXR modulators in targeting cancer metabolism in pancreatic cancer and other malignancies.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Glutamina/metabolismo , Receptores X do Fígado/agonistas , Estresse Oxidativo/efeitos dos fármacos , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/agonistas , Benzoatos/farmacologia , Benzilaminas/farmacologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma
12.
Br J Anaesth ; 125(4): 548-559, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32807382

RESUMO

BACKGROUND: Circadian differences in the induction, maintenance, or emergence from volatile anaesthesia have not been well studied. METHODS: The minimal alveolar concentration (MAC) for preventing movement in response to a painful stimulus, MAC for loss of righting reflex (MACLORR), and MAC for recovery of righting reflex (MACRORR) in C57BL/6J male mice with isoflurane or sevoflurane exposure were measured during either the light or dark phase. Time to onset of loss of righting reflex (TimeLORR) and recovery of righting reflex (TimeRORR) upon exposure to 1 MAC of isoflurane or sevoflurane were determined. EEG was also monitored in the light and dark phase under isoflurane or sevoflurane exposure. The noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was used to deplete noradrenergic neurones in the locus coeruleus to explore the impact of norepinephrine on these measurements. RESULTS: MACLORR, TimeLORR, and MAC did not show light- or dark-phase-dependent variations for either isoflurane or sevoflurane exposure. However, MACRORR was higher and TimeRORR was shorter in the dark phase than in the light phase for both isoflurane and sevoflurane exposure. The EEG delta wave power was higher but theta wave power was lower in the light phase than that in the dark phase during the rest state and emergence of anaesthesia. These light- and dark-phase-dependent changes in emergence were abolished in DSP-4-treated mice. CONCLUSION: Our data show that circadian differences exist during emergence but not during induction or maintenance of sevoflurane or isoflurane anaesthesia. The locus coeruleus noradrenergic system may contribute to these differences.


Assuntos
Anestésicos Inalatórios/farmacologia , Ritmo Circadiano/fisiologia , Locus Cerúleo/fisiologia , Norepinefrina/fisiologia , Anestésicos Inalatórios/farmacocinética , Animais , Benzilaminas/farmacologia , Temperatura Corporal/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reflexo de Endireitamento/efeitos dos fármacos
13.
Nat Commun ; 11(1): 4084, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796843

RESUMO

Lipid peroxidation generates reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins. Humans with familial hypercholesterolemia (FH) have increased lipoprotein dicarbonyl adducts and dysfunctional HDL. We investigate the impact of the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in Ldlr-/- mice, a model of FH. Compared to hypercholesterolemic Ldlr-/- mice treated with vehicle or 4-HOBA, a nonreactive analogue, 2-HOBA decreases atherosclerosis by 60% in en face aortas, without changing plasma cholesterol. Ldlr-/- mice treated with 2-HOBA have reduced MDA-LDL and MDA-HDL levels, and their HDL display increased capacity to reduce macrophage cholesterol. Importantly, 2-HOBA reduces the MDA- and IsoLG-lysyl content in atherosclerotic aortas versus 4-HOBA. Furthermore, 2-HOBA reduces inflammation and plaque apoptotic cells and promotes efferocytosis and features of stable plaques. Dicarbonyl scavenging with 2-HOBA has multiple atheroprotective effects in a murine FH model, supporting its potential as a therapeutic approach for atherosclerotic cardiovascular disease.


Assuntos
Aterosclerose/metabolismo , Benzilaminas/metabolismo , Benzilaminas/farmacologia , Benzilaminas/uso terapêutico , Hiperlipoproteinemia Tipo II/metabolismo , Receptores de LDL/genética , Animais , Aorta , Apolipoproteínas E , Aterosclerose/tratamento farmacológico , Colesterol/sangue , Colesterol/metabolismo , Feminino , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/patologia , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos , Lipoproteínas HDL/metabolismo , Lipoproteínas IDL/sangue , Lipoproteínas IDL/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fragmentos de Peptídeos
14.
Invest Ophthalmol Vis Sci ; 61(5): 33, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32428234

RESUMO

Purpose: This study aimed to investigate the role and pathophysiological mechanism of ATP binding cassette transporter A1 (ABCA1) in regulating the IOP and aqueous humor outflow. Methods: ABCA1 expression was measured in trabecular meshwork samples obtained from patients with POAG and human donor eyes by Western blot. To further evaluate the functional significance of ABCA1, porcine angular aqueous plexus (AAP) cells, which are equivalent to human Schlemm's canal endothelial cells, were either treated with ABCA1 agonist GW3965 or transduced with lentivirus expressing ABCA1-shRNA. Transendothelial electrical resistance, protein expression, and nitric oxide (NO) concentration were measured. GW3965 was administered by intracameral injection. IOP and aqueous humor outflow facility were also measured. Results: ABCA1 expression was significantly higher in the trabecular meshwork tissue of patients with POAG compared with controls. ABCA1 upregulation in angular aqueous plexus cells decreased the transendothelial electrical resistance in the angular aqueous plexus monolayers accompanied by a 0.56-fold decrease in caveolin-1 expression and a 2.85-fold and 1.17-fold increase in endothelial NO synthase expression and NO concentration, respectively (n = 3, P < 0.05). Conversely, ABCA1 downregulation increased transendothelial electrical resistance and caveolin-1 expression and decreased endothelial NO synthase expression and NO production (n = 3, P < 0.05). GW3965 decreased IOP and significantly increased conventional outflow facility (P < 0.05). Conclusions: Regulation of aqueous humor outflow via the caveolin-1/endothelial NO synthase/NO pathway is a newly defined function of ABCA1 that is different from its traditional role in mediating cholesterol efflux. ABCA1 is a compelling, novel therapeutic candidate for the treatment of glaucoma and ocular hypertension.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/fisiologia , Caveolina 1/metabolismo , Glaucoma de Ângulo Aberto/metabolismo , Pressão Intraocular/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/fisiologia , Animais , Humor Aquoso/fisiologia , Benzoatos/farmacologia , Benzilaminas/farmacologia , Western Blotting , Impedância Elétrica , Células Endoteliais/efeitos dos fármacos , Glaucoma de Ângulo Aberto/cirurgia , Humanos , Lentivirus/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Suínos , Malha Trabecular/metabolismo , Trabeculectomia , Transfecção
15.
Biochem Pharmacol ; 177: 113979, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32298690

RESUMO

The remarkable effects exhibited by classical psychedelics in recent clinical trials have spawned considerable interest in 5-HT2A receptor (5-HT2AR) activation as a treatment strategy for several psychiatric/cognitive disorders. In this study we have continued our development of 25CN-NBOH, one of the most 5-HT2AR-selective agonists reported to date, as a pharmacological tool for exploration of 5-HT2AR expression and functions. The importance of the 2' and 3' positions in 25CN-NBOH as structural hotspots for its 5-HT2AR activity was investigated by synthesis and pharmacological characterization of six novel analogs at 5-HT2AR and 5-HT2CR in binding and functional assays. While the 5-HT2AR activity of 25CN-NBOH was retained in 3'-methyl, 2',3'-chroman, 2',3'-dihydrofuran and 2',3'-furan analogs, the 3'-methoxy and 3'-ethyl analogs displayed substantially lower binding affinities and agonist potencies than 25CN-NBOH. Interestingly, the 2',3'-substitution pattern was also a key determinant of agonist efficacy, as all six analogs exhibited low-efficacy partial agonism or de facto antagonism at the 5-HT2AR in the functional assays. Systemic administration of 25CN-NBOH and its close structural analog 25CN-NBMD induced robust head-twitch response in mice, a well-established behavioural effect of 5-HT2AR activation in vivo, and 25CN-NBOH mediated robust reductions in the activity of mice in an anxiety-related marble burying assay, which supports the proposed beneficial effects of 5-HT2AR activation on disorders characterized by cognitive rigidity. Finally, tritiated 25CN-NBOH exhibited high 5-HT2AR binding affinity (KD ~1 nM) and selectivity against 5-HT2BR and 5-HT2CR in equilibrium and kinetic binding studies of the recombinant receptors, and in concordance [3H]25CN-NBOH displayed substantial specific, ketanserin-sensitive binding to cortex and small levels of binding to choroid plexus in rat brain slices in autoradiography studies. In conclusion, this work delineates the subtle molecular determinants of the 5-HT2AR activity in 25CN-NBOH, substantiates the potential in this compound and its analogs as tools for in vivo studies of the 5-HT2AR, and introduces a novel selective agonist radioligand as another potentially valuable tool for future explorations of this receptor.


Assuntos
Benzofuranos/farmacologia , Benzilaminas/farmacologia , Alucinógenos/farmacologia , Nitrilas/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Benzofuranos/síntese química , Benzilaminas/síntese química , Sítios de Ligação , Cerebelo/diagnóstico por imagem , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/efeitos dos fármacos , Plexo Corióideo/metabolismo , Feminino , Células HEK293 , Alucinógenos/síntese química , Humanos , Cinética , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrilas/síntese química , Ligação Proteica , Ratos , Ratos Long-Evans , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Relação Estrutura-Atividade
16.
Oxid Med Cell Longev ; 2020: 3690123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064022

RESUMO

Thioridazine (THIO) is a phenothiazine derivative that is mainly used for the treatment of psychotic disorders. However, cardiac arrhythmias especially QT interval prolongation associated with the application of this compound have received serious attention after its introduction into clinical practice, and the mechanisms underlying the cardiotoxicity induced by THIO have not been well defined. The present study was aimed at exploring the long-term effects of THIO on the hERG and L-type calcium channels, both of which are relevant to the development of QT prolongation. The hERG current (I hERG) and the calcium current (I Ca-L) were measured by patch clamp techniques. Protein levels were analyzed by Western blot, and channel-chaperone interactions were determined by coimmunoprecipitation. Reactive oxygen species (ROS) were determined by flow cytometry and laser scanning confocal microscopy. Our results demonstrated that THIO induced hERG channel deficiency but did not alter channel kinetics. THIO promoted ROS production and stimulated endoplasmic reticulum (ER) stress and the related proteins. The ROS scavenger N-acetyl cysteine (NAC) significantly attenuated hERG reduction induced by THIO and abolished the upregulation of ER stress marker proteins. Meanwhile, THIO increased the degradation of hERG channels via disrupting hERG-Hsp70 interactions. The disordered hERG proteins were degraded in proteasomes after ubiquitin modification. On the other hand, THIO increased I Ca-L density and intracellular Ca2+ ([Ca2+]i) in neonatal rat ventricular cardiomyocytes (NRVMs). The specific CaMKII inhibitor KN-93 attenuated the intracellular Ca2+ overload, indicating that ROS-mediated CaMKII activation promoted calcium channel activation induced by THIO. Optical mapping analysis demonstrated the slowing effects of THIO on cardiac repolarization in mouse hearts. THIO significantly prolonged APD50 and APD90 and increased the incidence of early afterdepolarizations (EADs). In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), THIO also resulted in APD prolongation. In conclusion, dysfunction of hERG channel proteins and activation of L-type calcium channels via ROS production might be the ionic mechanisms for QT prolongation induced by THIO.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Cardiotoxicidade/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , Tioridazina/toxicidade , Potenciais de Ação/fisiologia , Animais , Benzilaminas/farmacologia , Cálcio/metabolismo , Canais de Cálcio Tipo L/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Estresse do Retículo Endoplasmático/genética , Canais de Potássio Éter-A-Go-Go/fisiologia , Células HEK293 , Proteínas de Choque Térmico HSP70/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Ubiquitinação
17.
J Med Chem ; 63(6): 2854-2876, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32096640

RESUMO

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies <50 nM and exhibit >2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.


Assuntos
Benzilaminas/química , Benzilaminas/farmacologia , Retinopatia Diabética/tratamento farmacológico , PPAR alfa/agonistas , Animais , Benzilaminas/farmacocinética , Benzilaminas/uso terapêutico , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Descoberta de Drogas , Humanos , PPAR alfa/metabolismo , Ratos , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/metabolismo , Estreptozocina
18.
Am J Physiol Heart Circ Physiol ; 318(3): H715-H722, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32083971

RESUMO

Thin filament hypertrophic cardiomyopathy (HCM) mutations increase myofilament Ca2+ sensitivity and alter Ca2+ handling and buffering. The myosin inhibitor mavacamten reverses the increased contractility caused by HCM thick filament mutations, and we here test its effect on HCM thin filament mutations where the mode of action is not known. Mavacamten (250 nM) partially reversed the increased Ca2+ sensitivity caused by HCM mutations Cardiac troponin T (cTnT) R92Q, and cardiac troponin I (cTnI) R145G in in vitro ATPase assays. The effect of mavacamten was also analyzed in cardiomyocyte models of cTnT R92Q and cTnI R145G containing cytoplasmic and myofilament specific Ca2+ sensors. While mavacamten rescued the hypercontracted basal sarcomere length, the reduced fractional shortening did not improve with mavacamten. Both mutations caused an increase in peak systolic Ca2+ detected at the myofilament, and this was completely rescued by 250 nM mavacamten. Systolic Ca2+ detected by the cytoplasmic sensor was also reduced by mavacamten treatment, although only R145G increased cytoplasmic Ca2+. There was also a reversal of Ca2+ decay time prolongation caused by both mutations at the myofilament but not in the cytoplasm. We thus show that mavacamten reverses some of the Ca2+-sensitive molecular and cellular changes caused by the HCM mutations, particularly altered Ca2+ flux at the myofilament. The reduction of peak systolic Ca2+ as a consequence of mavacamten treatment represents a novel mechanism by which the compound is able to reduce contractility, working synergistically with its direct effect on the myosin motor.NEW & NOTEWORTHY Mavacamten, a myosin inhibitor, is currently in phase-3 clinical trials as a pharmacotherapy for hypertrophic cardiomyopathy (HCM). Its efficacy in HCM caused by mutations in thin filament proteins is not known. We show in reductionist and cellular models that mavacamten can rescue the effects of thin filament mutations on calcium sensitivity and calcium handling although it only partially rescues the contractile cellular phenotype and, in some cases, exacerbates the effect of the mutation.


Assuntos
Benzilaminas/farmacologia , Cálcio/metabolismo , Cardiomiopatia Hipertrófica/metabolismo , Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Sarcômeros/efeitos dos fármacos , Uracila/análogos & derivados , Animais , Cardiomiopatia Hipertrófica/genética , Camundongos , Mutação , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Sarcômeros/metabolismo , Troponina I/genética , Troponina I/metabolismo , Troponina T/genética , Troponina T/metabolismo , Uracila/farmacologia
19.
Int J Mol Sci ; 21(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093314

RESUMO

UCL-2077 (triphenylmethylaminomethyl)pyridine) was previously reported to suppress slow afterhyperpolarization in neurons. However, the information with respect to the effects of UCL-2077 on ionic currents is quite scarce. The addition of UCL-2077 decreased the amplitude of erg-mediated K+ current (IK(erg)) together with an increased deactivation rate of the current in pituitary GH3 cells. The IC50 and KD values of UCL-2077-induced inhibition of IK(erg) were 4.7 and 5.1 µM, respectively. UCL-2077 (10 µM) distinctly shifted the midpoint in the activation curve of IK(erg) to less hyperpolarizing potentials by 17 mV. Its presence decreased the degree of voltage hysteresis for IK(erg) elicitation by long-lasting triangular ramp pulse. It also diminished the probability of the opening of intermediate-conductance Ca2+-activated K+ channels. In cell-attached current recordings, UCL-2077 raised the frequency of action currents. When KCNH2 mRNA was knocked down, a UCL-2077-mediated increase in AC firing was attenuated. Collectively, the actions elaborated herein conceivably contribute to the perturbating effects of this compound on electrical behaviors of excitable cells.


Assuntos
Benzilaminas/farmacologia , Canal de Potássio ERG1/metabolismo , Potássio/metabolismo , Piridinas/farmacologia , Somatotrofos/metabolismo , Linhagem Celular , Canal de Potássio ERG1/genética , Técnicas de Silenciamento de Genes , Humanos , Transporte de Íons/efeitos dos fármacos , Transporte de Íons/genética , Somatotrofos/citologia
20.
Eur J Med Chem ; 189: 112042, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31958737

RESUMO

Transforming growth factor-ß (TGF-ß) plays an important role in regulating epithelial to mesenchymal transition (EMT) and the TGF-ß signaling pathway is a potential target for therapeutic intervention in the development of many diseases, such as fibrosis and cancer. Most currently available inhibitors of TGF-ß signaling function as TGF-ß receptor I (TßR-I) kinase inhibitors, however, such kinase inhibitors often lack specificity. In the present study, we targeted the extracellular protein binding domain of the TGF-ß receptor II (TßR-II) to interfere with the protein-protein interactions (PPIs) between TGF-ß and its receptors. One compound, CJJ300, inhibited TGF-ß signaling by disrupting the formation of the TGF-ß-TßR-I-TßR-II signaling complex. Treatment of A549 cells with CJJ300 resulted in the inhibition of downstream signaling events such as the phosphorylation of key factors along the TGF-ß pathway and the induction of EMT markers. Concomitant with these effects, CJJ300 significantly inhibited cell migration. The present study describes for the first time a designed molecule that can regulate TGF-ß-induced signaling and EMT by interfering with the PPIs required for the formation of the TGF-ß signaling complex. Therefore, CJJ300 can be an important lead compound with which to study TGF-ß signaling and to design more potent TGF-ß signaling antagonists.


Assuntos
Benzilaminas/farmacologia , Ligação Proteica/efeitos dos fármacos , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Benzilaminas/síntese química , Movimento Celular/efeitos dos fármacos , Desenho de Fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Transdução de Sinais/efeitos dos fármacos
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