RESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.
Assuntos
Antioxidantes , Apoptose , Benzamidas , Bleomicina , Cromolina Sódica , Fibroblastos , Miofibroblastos , Estresse Oxidativo , Piperidinas , Piridinas , Tiazóis , Antioxidantes/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Benzamidas/farmacologia , Piridinas/farmacologia , Apoptose/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Piperidinas/farmacologia , Cromolina Sódica/farmacologia , Animais , Tiazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Sinergismo Farmacológico , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Células Cultivadas , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologiaRESUMO
Advancements in human-engineered heart tissue have enhanced the understanding of cardiac cellular alteration. Nevertheless, a human model simulating pathological remodeling following myocardial infarction for therapeutic development remains essential. Here we develop an engineered model of myocardial repair that replicates the phased remodeling process, including hypoxic stress, fibrosis, and electrophysiological dysfunction. Transcriptomic analysis identifies nine critical signaling pathways related to cellular fate transitions, leading to the evaluation of seventeen modulators for their therapeutic potential in a mini-repair model. A scoring system quantitatively evaluates the restoration of abnormal electrophysiology, demonstrating that the phased combination of TGFß inhibitor SB431542, Rho kinase inhibitor Y27632, and WNT activator CHIR99021 yields enhanced functional restoration compared to single factor treatments in both engineered and mouse myocardial infarction model. This engineered heart tissue repair model effectively captures the phased remodeling following myocardial infarction, providing a crucial platform for discovering therapeutic targets for ischemic heart disease.
Assuntos
Dioxóis , Fibrose , Infarto do Miocárdio , Piridinas , Engenharia Tecidual , Animais , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/genética , Camundongos , Humanos , Piridinas/farmacologia , Piridinas/uso terapêutico , Engenharia Tecidual/métodos , Dioxóis/farmacologia , Dioxóis/uso terapêutico , Miocárdio/patologia , Miocárdio/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Modelos Animais de Doenças , Transdução de Sinais , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Remodelação Ventricular/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Coração/fisiopatologia , Coração/efeitos dos fármacos , AmidasRESUMO
New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.
Assuntos
Antibacterianos , Benzamidas , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Relação Estrutura-Atividade , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Estrutura Molecular , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Relação Dose-Resposta a Droga , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Modelos MolecularesRESUMO
Signal transducer and activator of transcription 3 (STAT3) is a pleiotropic factor involved in multiple vital biological processes and a key mediator of gene transcription in response to cytokines, growth factors and aberrant activation of oncogenic signaling. STAT3 has two splicing isoforms, STAT3α and STAT3ß, derived from alternative splicing of exon 23 within pre-mRNA. STAT3ß differs from STAT3α by replacement of 55 amino-acid residues in the C-terminal transactivation domain with 7 specific amino acids. Thus, a shorter STAT3ß was originally regarded as a dominant negative isoform of STAT3α. Recently accumulating evidence from independent studies have shown STAT3 splicing isoforms confer distinct and overlapping functions in many fundamental cellular regulatory steps such as cell differentiation, inflammatory responses, and cancer progression. However, relatively little is known about the mechanisms of STAT3 pre-mRNA splicing, and it remains undiscovered which chemical compounds or bioactive substances can induce the STAT3ß expression. In this study, we generated a potent reporter for detection of alternative splicing of STAT3 pre-mRNA optimized for the screening of function-known chemical library, and successfully identified entinostat, a histone deacetylase inhibitor, as a novel inducer of STAT3ß through modulating mRNA splicing. Our findings demonstrate that alternative splicing of STAT3 can be regulated by a compound, providing an important clue for understanding the regulation mechanisms of the expression balance of STAT3 isoforms in a chemical biology approach. Entinostat is likely to be a promising seed compound for elucidating how the higher ratio of STAT3ß expression impacts on biological responses associated with Janus kinase (JAK)/STAT3 signaling pathway.
Assuntos
Processamento Alternativo , Benzamidas , Piridinas , Precursores de RNA , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Processamento Alternativo/efeitos dos fármacos , Humanos , Precursores de RNA/genética , Precursores de RNA/metabolismo , Piridinas/farmacologia , Benzamidas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Células HEK293 , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-Gi complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the ß-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the ß-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR's structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery.
Assuntos
Microscopia Crioeletrônica , Receptores Opioides delta , Receptores Opioides delta/metabolismo , Receptores Opioides delta/agonistas , Receptores Opioides delta/química , Humanos , Animais , Descoberta de Drogas/métodos , Células HEK293 , Transdução de Sinais/efeitos dos fármacos , beta-Arrestinas/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química , Camundongos , Ligantes , Ligação Proteica , Masculino , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Sítios de Ligação , Benzamidas/farmacologia , Benzamidas/química , PiperazinasRESUMO
The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.
Assuntos
Aminopiridinas , Benzamidas , Linfócitos T CD8-Positivos , Infecções por HIV , HIV-1 , Inibidores de Histona Desacetilases , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Infecções por HIV/imunologia , Infecções por HIV/genética , Aminopiridinas/farmacologia , Feminino , Adulto , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Benzamidas/administração & dosagem , Pessoa de Meia-Idade , HIV-1/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Antígeno B7-H1/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Latência Viral/efeitos dos fármacos , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: Chronic inflammatory skin diseases are of great social and medical importance and require effective drug therapy. Phosphodiesterase 4 (PDE4) inhibitors represent a possible therapeutic option by regulating inflammatory processes. PDEs cause the release of proinflammatory cytokines by interfering with signaling pathways. The PDE4 inhibitors apremilast (treatment of psoriasis and Behçet's disease), roflumilast (treatment of chronic obstructive pulmonary disease), and crisaborole (treatment of atopic dermatitis) are currently approved in Europe. PSORIASIS: Apremilast is used for second-line treatment of plaque psoriasis and psoriatic arthritis and has a favorable side effect profile. Topical PDE4 inhibitors are currently being researched and have not yet been approved by the European Medicines Agency (EMA). ATOPIC DERMATITIS: The topical PDE4 inhibitor crisaborole was approved by the EMA in 2020 as a topical treatment alternative to glucocorticoids and calcineurin inhibitors. Although the substance has shown good tolerability in studies and also alleviates the accompanying itching, it did not find its way onto the German market. BEHçET'S DISEASE: Apremilast is approved for the treatment of Behçet's disease in adults with refractory, severe oral ulcers. OUTLOOK: Case studies have also demonstrated the efficacy of systemic PDE4 inhibition in other skin diseases (including blistering autoimmune dermatoses, lichen planus, and acantholytic genodermatoses). The substances are also being researched and used to treat extracutaneous inflammatory diseases.
Assuntos
Inibidores da Fosfodiesterase 4 , Psoríase , Talidomida , Humanos , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/farmacologia , Talidomida/efeitos adversos , Psoríase/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Compostos de Boro/uso terapêutico , Compostos de Boro/farmacologia , Síndrome de Behçet/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Ciclopropanos , Compostos Bicíclicos Heterocíclicos com PontesRESUMO
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1+ ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1+ ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).
Assuntos
Benzamidas , Piridinas , Rabdomiossarcoma , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Piridinas/farmacologia , Piridinas/uso terapêutico , Animais , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Camundongos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma/metabolismo , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaAssuntos
Antivirais , Benzamidas , Monkeypox virus , Mpox , Ftalimidas , Humanos , África/epidemiologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Ensaios Clínicos como Assunto , Esperança , Monkeypox virus/classificação , Monkeypox virus/efeitos dos fármacos , Mpox/tratamento farmacológico , Mpox/epidemiologia , Mpox/transmissão , Mpox/virologia , Ftalimidas/farmacologia , Ftalimidas/uso terapêuticoRESUMO
Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with limited response to chemotherapy. Histone acetylation is reduced in DLBCL. Chidamide, a histone deacetylase inhibitor, shows promise in lymphomas but needs further investigation for DLBCL. Our study indicated that chidamide effectively suppresses DLBCL both in vitro and in vivo. High-throughput RNA sequencing analysis provided comprehensive evidence that chidamide markedly influences crucial signaling pathways in DLBCL, including the MAPK, MYC and p53 pathway. Additionally, we observed substantial variability in the sensitivity of DLBCL cells to chidamide, and identified that elevated expression of BCL6 might confer resistance to chidamide in DLBCL. Moreover, our investigations revealed that BCL6 inhibited chidamide-induced histone acetylation by recruiting histone deacetylase (HDACs), leading to drug resistance in DLBCL cells. Furthermore, we found that lenalidomide targeted BCL6 degradation through the ubiquitination pathway and restore the sensitivity of drug-resistant DLBCL to chidamide. Collectively, these findings provided valuable insights into the global impact of chidamide on DLBCL and highlight the potential of targeting HDACs as a therapeutic strategy for DLBCL. Identifying BCL6 as a biomarker for predicting the response to chidamide and the combination therapy with BCL6 inhibition has the potential to lead to more personalized and effective treatments for DLBCL patients.
Assuntos
Aminopiridinas , Benzamidas , Resistencia a Medicamentos Antineoplásicos , Inibidores de Histona Desacetilases , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-6 , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/genética , Inibidores de Histona Desacetilases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Benzamidas/farmacologia , Linhagem Celular Tumoral , Animais , Camundongos , Aminopiridinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Feminino , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Antineoplásicos/farmacologia , Camundongos SCIDRESUMO
The levels and activities of the DNA/RNA helicase schlafen11 (SLFN11) and the serine/threonine-protein kinase ataxia telangiectasia and Rad3-related protein (ATR) may determine cancer cell sensitivity to DNA damaging agents, including platinum drugs. Here, we studied the roles of SLFN11 and ATR in cisplatin resistance of ovarian cancer using cell lines displaying acquired or intrinsic cisplatin resistance. W1CR, the cisplatin-resistant subline of W1 ovarian cancer cells, displayed reduced SLFN11 levels. HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin. Moreover, entinostat also sensitized intrinsically resistant EFO21 ovarian cancer cells to cisplatin by upregulating SLFN11. However, SLFN11 was not involved in cisplatin resistance in all other cell models. Thus, SLFN11 expression is not a general cisplatin resistance marker in ovarian cancer. In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and KuramochirCDDP2000. Mechanisms underlying ATR-mediated cisplatin resistance differed between the cell lines and included CHK1/WEE1 signaling and induction of homologous recombination. In conclusion, SLFN11 and ATR are involved in ovarian cancer cisplatin resistance. Although our data identify ATR as key target for tackling cisplatin resistance in ovarian cancer, future studies are needed to identify biomarkers that indicate, which individual ovarian cancers benefit from SLFN11 re-activation and/or ATR inhibition.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Proteínas Nucleares , Neoplasias Ovarianas , Humanos , Cisplatino/farmacologia , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular Tumoral , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Benzamidas/farmacologiaRESUMO
Oncogenic signaling through the MAPK/ERK pathway drives tumor progression in many cancers. Although targeted MAPK/ERK pathway inhibitors improve survival in selected patients, most tumors are resistant. New drugs could be identified in small-animal models that, unlike in vitro models, can address oral uptake, compound bioavailability, and toxicity. This requires pharmacologic conformity between human and model MAPK/ERK pathways and available phenotypic assays. In this study, we test if the conserved MAPK/ERK pathway in Caenorhabditis elegans could serve as a model for pharmacological inhibition and develop in vivo pipelines for high-throughput compound screens. Using fluorescence-based image analysis of vulva development as a readout for MAPK/ERK activity, we obtained excellent assay Z-scores for the MEK inhibitors trametinib (Z = 0.95), mirdametinib (Z = 0.93), and AZD8330 (Z = 0.87), as well as the ERK inhibitor temuterkib (Z = 0.86). The throughput was 800 wells per hour, with an average seed density of 25.5 animals per well. Readouts included drug efficacy, toxicity, and pathway specificity, which was tested against pathway activating upstream (lin-15)- and downstream (lin-1) mutants. To validate the model in a high-throughput setting, we screened a blinded library of 433 anticancer compounds and identified four MEK inhibitors among seven positive hits. Our results highlight a high degree of pharmacological conformity between C. elegans and human MAPK/ERK pathways, and the presented high-throughput pipeline may discover and characterize novel inhibitors in vivo. SIGNIFICANCE: Many tumors depend on MAPK/ERK signaling to sustain growth, avoid cell death, and metastasize. We show that specific and clinically relevant MAPK/ERK signaling inhibitors can be discovered in vivo with a high-throughput screening pipeline in small animals.
Assuntos
Caenorhabditis elegans , Descoberta de Drogas , Sistema de Sinalização das MAP Quinases , Inibidores de Proteínas Quinases , Pirimidinonas , Animais , Caenorhabditis elegans/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinonas/farmacologia , Piridonas/farmacologia , Humanos , Ensaios de Triagem em Larga Escala/métodos , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Vulva/efeitos dos fármacos , Vulva/patologia , Feminino , Difenilamina/análogos & derivadosRESUMO
The key mutations, such as the Gly-4891-Glu substitution and the Ile-4734 multiple substitutions within the ryanodine receptors (RyR), are linked to diamide resistance in fall armyworm (FAW), Spodoptera frugiperda. In this study, we found that FAW remained sensitive to cyantraniliprole and chlorantraniliprole, while its sensitivity to flubendiamide was reduced. Moreover, a low level of heterozygous mutation at I4743 was observed. To facilitate the detection procedure of these mutations, a simple and efficient loop-mediated isothermal amplification (LAMP) protocol was developed for operation. The reaction for detecting the G4891E and I4743 single or multiple mutations was carried out at 68 °C for 85 min and 68 °C for 85 min or 68 °C for 65 min, respectively. These LAMP reactions can be easily observed via visualization of the color change from pink to yellow. This assay provides a simple, convenient, and effective means of detecting mutations in the RyR of FAW for pest management purposes.
Assuntos
Proteínas de Insetos , Mutação , Técnicas de Amplificação de Ácido Nucleico , Canal de Liberação de Cálcio do Receptor de Rianodina , Spodoptera , Animais , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/química , Spodoptera/genética , Spodoptera/efeitos dos fármacos , Técnicas de Amplificação de Ácido Nucleico/métodos , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Proteínas de Insetos/química , Inseticidas/farmacologia , ortoaminobenzoatos/farmacologia , Benzamidas/farmacologia , Sulfonas/farmacologia , Pirazóis/farmacologia , Resistência a Inseticidas/genética , Fluorocarbonos , Ftalimidas , Técnicas de Diagnóstico MolecularRESUMO
Alzheimer's disease (AD) is an age-dependent incurable neurodegenerative disorder accompanied by neuroinflammation, amyloid accumulation, and memory impairment. It begins decades before the first clinical symptoms appear, and identifying early biomarkers is key for developing disease-modifying therapies. We show now in a mouse model of AD that before any amyloid deposition the brains of 1.5-month-old mice contain increased levels of pro-inflammatory cytokines IL-1ß and IL-6, decreased levels of nicotinic acetylcholine receptors (nAChRs) in the brain and brain mitochondria and increased amounts of α7 nAChR-bound Aß1-42, along with impaired episodic memory and increased risk of apoptosis. Both acute (1-week-long) and chronic (4-month-long) treatments with α7-selective agonist PNU282987, starting at 1.5 months of age, were well tolerated. The acute treatment did not affect the levels of soluble Aß1-42 but consistently upregulated the α7 nAChR expression, decreased the level of α7-Aß1-42 complexes, and improved episodic memory of 1.5-month-old mice. The chronic treatment, covering the disease development phase, strongly upregulated the expression of all abundant brain nAChRs, reduced both free and α7-coupled Aß1-42 within the brain, had anti-inflammatory and antiapoptotic effects, and potently upregulated cognition, thus identifying α7 nAChRs as both early biomarker and potent therapeutic target for fighting this devastating disease.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Encéfalo , Modelos Animais de Doenças , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Camundongos , Fragmentos de Peptídeos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Compostos Bicíclicos com Pontes/farmacologia , Benzamidas/farmacologia , Apoptose/efeitos dos fármacosRESUMO
Chronic myelogenous leukemia (CML) is a hematological malignancy originating from the pluripotent hematopoietic stem cells. Imatinib is the first generation of small molecule tyrosine kinase inhibitors (TKI) that revolutionized the treatment of CML. Flumatinib, as a novel oral TKI that independently developed in China, which can be used as a preferred treatment for CML. Basic researches suggested that the inhibitory effect of flumatinib on CML cell lines is stronger than imatinib. Flumatinib demonstrated that it has better efficacy than imatinib on CML in clinical trials and in real world studies. Flumatinib also showed a higher potency against CML with specific mutations, Ph(+) acute lymphoblastic leukemia and some solid tumors. The adverse events are manageable and tolerable.
Assuntos
Aminopiridinas , Benzamidas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Benzamidas/farmacologia , Aminopiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piperazinas/farmacologia , Mesilato de Imatinib/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/farmacologiaRESUMO
Consumption of palatable food (PF) can alleviate anxiety, and pain in humans. Contrary, spontaneous withdrawal of long-term PF intake produces anxiogenic-like behavior and abnormal pain sensation, causing challenges to weight-loss diet and anti-obesity agents. Thus, we examined α7-nicotinic acetylcholine receptors (α7nAChR) involvement since it plays essential role in nociception and psychological behaviors. METHODS: Adult male C57BL/6 mice were placed on a Standard Chow (SC) alone or with PF on intermittent or continuous regimen for 6 weeks. Then, mice were replaced with normal SC (spontaneous withdrawal). Body weight, food intake, and calories intake with and without the obesogenic diet were measured throughout the study. During PF withdrawal, anxiety-like behaviors and pain sensitivity were measured with PNU-282987 (α7nAChR agonist) administration. RESULTS: Six weeks of SC + PF-intermittent and continuous paradigms produced a significant weight gain. PF withdrawal displayed hyperalgesia and anxiety-like behaviors. During withdrawal, PNU-282987 significantly attenuated hyperalgesia and anxiety-like behaviors. CONCLUSION: The present study shows that a PF can increase food intake and body weight. Also, enhanced pain sensitivity and anxiety-like behavior were observed during PF withdrawal. α7nAChR activation attenuated anxiolytic-like behavior and hyperalgesia in PF abstinent mice. These data suggest potential therapeutic effects of targeting α7 nAChRs for obesity-withdrawal symptoms in obese subjects.
Assuntos
Ansiedade , Benzamidas , Compostos Bicíclicos com Pontes , Hiperalgesia , Camundongos Endogâmicos C57BL , Obesidade , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Masculino , Ansiedade/etiologia , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Benzamidas/farmacologia , Benzamidas/administração & dosagem , Obesidade/psicologia , Obesidade/metabolismo , Compostos Bicíclicos com Pontes/farmacologia , Camundongos , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacosRESUMO
Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis-related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK-STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady-state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite-to-parent AUC ratio of 1.4-2.1. This review describes momelotinib's mechanism of action, detailing how the JAK-STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.
Assuntos
Pesquisa Translacional Biomédica , Humanos , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Benzamidas/farmacologia , Benzamidas/farmacocinética , Benzamidas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Animais , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Hidrocarbonetos Aromáticos com PontesRESUMO
Prostate cancer (PCa) is the leading cause of cancerrelated death among men worldwide. PCa often develops resistance to standard androgen deprivation therapy and androgen receptor (AR) pathway inhibitors, such as enzalutamide (ENZ). Therefore, there is an urgent need to develop novel therapeutic strategies for this disease. The efficacy of ADA308 was evaluated through in vitro assessments of AR activity and cell proliferation, alongside in vivo studies. ADA308 has emerged as a promising candidate, demonstrating potent inhibition of ARsensitive adenocarcinoma as well as ENZresistant PCa cell lines. The results of the study revealed that ADA308 effectively blocked AR activity, including its nuclear localization, and inhibited cell proliferation in vitro. Furthermore, ADA308 demonstrated notable efficacy in vivo, with a robust antitumor response in ENZresistant models. These findings establish the role of ADA308 as a potent AR inhibitor that overcomes resistance to ARtargeted therapies and highlights its potential as a novel therapeutic approach in advanced PCa management.
Assuntos
Adenocarcinoma , Antagonistas de Androgênios , Benzamidas , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Nitrilas , Feniltioidantoína , Receptores Androgênicos , Humanos , Masculino , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores Androgênicos/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Camundongos , Animais , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêuticoRESUMO
Sharply increased reactive oxygen species (ROS) are thought to induce oxidative stress, damage cell structure and cause cell death; however, its role in prostate cancer remains unclear. Enzalutamide is a widely used anti-prostate cancer drug that antagonizes androgen binding with its receptor. Further exploration of the mechanism and potential application strategies of enzalutamide is crucial for the treatment of prostate cancer. Here, we confirmed PEX10 can be induced by ROS activators while reduce ROS level in prostate cancer cells, which weakened the anti-tumor effect of ROS activators. The androgen receptor (AR) can promote the expression of PEX10 by acting as an enhancer in cooperation with FOXA1. The anti-tumor drug enzalutamide inhibits PEX10 by inhibiting the function of AR, and synergize with ROS activators ML210 or RSL3 to produce a stronger anti-tumor effect, thereby sensitizing cells to ROS activators. This study reveals a previously unrecognized function of enzalutamide and AR by regulating PEX10 and suggests a new strategy of enzalutamide application in prostate cancer treatment.
Assuntos
Benzamidas , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Espécies Reativas de Oxigênio , Humanos , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Masculino , Benzamidas/farmacologia , Nitrilas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Linhagem Celular Tumoral , Receptores Androgênicos/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Animais , Camundongos , Proteínas de Membrana/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos NusRESUMO
BACKGROUND: Mesenchymal-epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare alteration in non-small-cell lung cancer (NSCLC), occurring in about 3%-4% of cases. Here we report disease and patient characteristics, and efficacy and tolerability of MET inhibitors among advanced METex14 NSCLC patients from the Italian real-world registry ATLAS. MATERIALS AND METHODS: Clinical-pathological and molecular data, and treatment efficacy/tolerability outcomes were retrospectively collected from the ATLAS registry. RESULTS: From July 2020 to July 2023 a total of 146 METex14 advanced NSCLC patients were included across 27 Italian centers. Median age was 74 years, and most patients were male (52%), with an Eastern Cooperative Oncology Group performance status < 2 (72%) and adenocarcinoma subtype (83%). One hundred and twenty-five out of 146 (86%) patients received at least one line of systemic anticancer therapy. Fifty-six (38%) were treated with capmatinib and 34 (23%) with tepotinib. 29% and 52% of them received targeted treatment in the first and second line, respectively. In the cohort of patients treated with MET inhibitors, the response rate (RR) was 37% (33% in previously treated patients and 46% in treatment-naïve) with a disease control rate of 62%. With a median follow-up of 10.8 months, progression-free survival was 6.6 months [95% confidence interval (CI) 4.3-8.3 months] and overall survival was 10.7 months (95% CI 7.2-19.3 months). In patients with measurable brain metastases (17 cases), the intracranial RR was 41%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12% of patients with grade 3 peripheral edema in 7% of cases. A fatal adverse reaction occurred in one patient due to pneumonitis. TRAEs-related dose reduction and discontinuation were reported in 6% and 8% of cases, respectively. CONCLUSION: Capmatinib and tepotinib represent an effective treatment option in NSCLC patients with METex14. Real-world efficacy outcomes are worse than those reported in prospective clinical trials. Their activity is more pronounced in the treatment-naïve population, suggesting that this is the right setting in the management of patients with METex14.