RESUMO
Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.
Assuntos
Injúria Renal Aguda , Ferroptose , Camundongos Endogâmicos C57BL , Fenilenodiaminas , Animais , Ferroptose/efeitos dos fármacos , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Camundongos , Masculino , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismoRESUMO
BACKGROUND: Cyclin-dependent kinase 7 (CDK7) has been critically linked to human cancer. However, the roles of CDK7 in head and neck squamous cell carcinoma (HNSCC) remain incompletely known. Here, we sought to dissect the functions of CDK7 underlying HNSCC tumorigenesis and explore whether pharmacological inhibition of CDK7 could induce anti-cancer effects. METHODS: CDK7 expression was measured in a panel of HNSCC cell lines with p53 mutation and 20 pairs of HNSCC samples and adjacent non-tumor tissues. Genetic targeting and pharmacological inhibition of CDK7 were conducted to dissect the biological roles of CDK7 in p53-mutated HNSCC cells. An HNSCC xenograft model was developed to determine the therapeutic effects of THZ1 in vivo. Potential genes and pathways responsible for therapeutic effects of THZ1 were identified by genome-wide RNA-sequencing and bioinformatics interrogations. RESULTS: CDK7 expression was significantly elevated in cancerous cells and samples as compared with their adjacent non-tumor counterparts. Impaired cell proliferation, migration, and invasion as well increased apoptosis were observed in cells upon CDK7 knockdown or THZ1 exposure. THZ1 administration potently inhibited tumor overgrowth in vivo. Mechanistically, hundreds of genes enriched in cell proliferation, apoptosis, and cancer-related categories were identified to be potentially mediated the therapeutic effects of THZ1 in HNSCC. CONCLUSION: Our findings reveal that CDK7 might serve as a novel putative pro-oncogenic gene underlying HNSCC tumorigenesis and therapeutic targeting of CDK7 might be a promising strategy for p53-mutated HNSCC.
Assuntos
Neoplasias de Cabeça e Pescoço , Proteína Supressora de Tumor p53 , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinases Ciclina-Dependentes/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Fosfotransferases (Aceptor do Grupo Álcool) , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, is regulated by different forms of cell death, including apoptosis and autophagy. However, the role in ADPKD of ferroptosis, a recently discovered form of cell death mediated by iron and lipid metabolism, remains elusive. METHODS: To determine a pathophysiologic role of ferroptosis in ADPKD, we investigated whether the absence of Pkd1 (encoding polycystin-1) affected the expression of key factors involved in the process of ferroptosis, using Western blot and qRT-PCR analysis in Pkd1 mutant renal cells and tissues. We also examined whether treatment with erastin, a ferroptosis inducer, and ferrostain-1, a ferroptosis inhibitor, affected cyst growth in Pkd1 mutant mouse models. RESULTS: We found that kidney cells and tissues lacking Pkd1 exhibit extensive metabolic abnormalities, including reduced expression of the system Xc- amino acid antiporter (critical for import of cystine), of iron exporter (ferroportin), and of GPX4 (a key and negative regulator of ferroptosis). The abnormalities also include increased expression of iron importers (TfR1, DMT1) and HO-1, which in turn result in high iron levels, low GSH and GPX4 activity, increased lipid peroxidation, and propensity to ferroptosis. We further found that erastin increased, and ferrostatin-1 inhibited ferroptotic cell death and proliferation of Pkd1-deficient cells in kidneys from Pkd1 mutant mice. A lipid peroxidation product increased in Pkd1-deficient cells, 4HNE, promoted the proliferation of survived Pkd1 mutant cells via activation of Akt, S6, Stat3, and Rb during the ferroptotic process, contributing to cyst growth. CONCLUSION: These findings indicate that ferroptosis contributes to ADPKD progression and management of ferroptosis may be a novel strategy for ADPKD treatment.
Assuntos
Ferroptose , Rim Policístico Autossômico Dominante/patologia , Animais , Ciclo Celular , Células Cultivadas , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Ferro/metabolismo , Peroxidação de Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/genética , Interferência de RNA , Esferoides Celulares , Canais de Cátion TRPP/deficiência , Canais de Cátion TRPP/genética , TranscriptomaRESUMO
A total number of 18 different isoforms of histone deacetylases (HDACs) which were categorized into 4 classes have been identified in human. HDAC3 is categorized as class I HDACs and is closely related to the occurrence and development of atherosclerosis. Recent evidence has pointed to endothelial-to-mesenchymal transition (EndMT) as a key process in vascular inflammation in atherosclerosis. However, little is known about the effect of HDAC3 on EndMT in atherosclerosis. Therefore, we aimed to investigate the effect of HDAC3 specific inhibitor on EndMT in ApoE-/- mice fed a Western diet and human umbilical vein endothelial cells (HUVECs) induced by inflammatory cytokines. Firstly, we found that HDAC3 expression was up-regulated and EndMT occurred in the aortas of ApoE-/- mice compared with C57BL/6J mice. However, HDAC3 specific inhibitor RGFP966 alleviated atherosclerotic lesions and inhibited EndMT of the atherosclerotic plaque in ApoE-/- mice. Then, in vitro study showed that inflammatory cytokines TNF-α and IL-1ß co-treatment increased the expression of HDAC3 and induced EndMT in HUVECs. HDAC3 inhibition by siRNA or specific inhibitor RGFP966 suppressed EndMT in HUVECs stimulated with TNF-α and IL-1ß. By contrast, HDAC3 overexpression by adenovirus further promoted EndMT of HUVECs. In addition, we found that HDAC3 also regulated the inflammatory response of HUVECs by modulating the expression of inflammatory cytokines and the number of monocytes attached to HUVECs. These above results suggest that HDAC3 inhibitor suppresses EndMT via modulating inflammatory response in ApoE-/- mice and HUVECs.
Assuntos
Aterosclerose/metabolismo , Endotélio/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Mediadores da Inflamação/metabolismo , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Animais , Aterosclerose/tratamento farmacológico , Endotélio/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Células THP-1RESUMO
Degenerative retinal diseases, including age-related macular degeneration, are serious diseases that may lead to irreversible retinal neuron damage and permanent vision impairment. There are currently no effective treatments for these diseases due to our incomplete understanding of the underlying pathological mechanisms. Ferroptosis, a newly identified iron-dependent mode of cell death, is implicated in various diseases. However, it is unknown whether ferroptosis is involved in light-induced retinal degeneration. In this study, we found that light exposure significantly reduced the viability of photoreceptor cells in vitro and induced pro-ferroptotic changes, including iron accumulation, mitochondrial shrinkage, glutathione depletion, increased malondialdehyde (MDA), and decreased protein expression of SLC7A11 and GPX4. The effects of light exposure on ferroptosis were attenuated by ferrostatin-1. Consistently, the results of in vivo studies demonstrated that ferrostatin-1 protected against light-induced ferroptosis. And it exerted therapeutic effects by inhibiting neuroinflammation and prevented the effects of light exposure on the structure and function of the retina. The findings reveal an important role of ferroptosis in the pathogenesis of light-induced retinal degeneration and suggest that ferroptosis may be a novel treatment target for preventing retinal degeneration.
Assuntos
Cicloexilaminas/uso terapêutico , Ferroptose/efeitos dos fármacos , Luz , Fármacos Neuroprotetores/uso terapêutico , Fenilenodiaminas/uso terapêutico , Retina/patologia , Degeneração Retiniana/tratamento farmacológico , Animais , Linhagem Celular , Cicloexilaminas/farmacologia , Masculino , Fármacos Neuroprotetores/farmacologia , Fenilenodiaminas/farmacologia , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/ultraestrutura , Degeneração Retiniana/patologiaRESUMO
Ferroptosis is a widely recognized process of regulated cell death linking redox state, metabolism, and human health. It is considered a defense mechanism against extensive lipid peroxidation, a complex process that may disrupt the membrane integrity, eventually leading to toxic cellular injury. Ferroptosis is controlled by iron, reactive oxygen species, and polyunsaturated fatty acids. Accumulating evidence has addressed that ferroptosis plays an unneglectable role in regulating the development and progression of multiple pathologies of the liver, including hepatocellular carcinoma, liver fibrosis, nonalcoholic steatosis, hepatic ischemia-reperfusion injury, and liver failure. This review may increase our understating of the cellular and molecular mechanisms of liver disease progression and establish the foundation of strategies for pharmacological intervention.
Assuntos
Ferroptose/fisiologia , Fígado/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Cicloeximida/farmacologia , Cicloeximida/uso terapêutico , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Desferroxamina/farmacologia , Desferroxamina/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Ácidos Graxos Insaturados/metabolismo , Ferroptose/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Ferro/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Falência Hepática/tratamento farmacológico , Falência Hepática/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêuticoRESUMO
BACKGROUND: The cyclin-dependent kinase 7 (CDK7) subunit of TFIIH regulates RNA polymerase-II-based transcription and promotes tumor progression. However, the mechanisms involved in CDK7-mediated immune evasion are unclear in non-small cell lung cancer (NSCLC). METHODS: RNA silencing and pharmacologic inhibitors were used to evaluate the functions of CDK7/p38α/MYC/PD-L1 axis in cancer cell proliferation and antiPD-1 therapy resistance. Flow cytometry was performed to detect the status of the immune microenvironment after CDK7 inhibition and antiPD-1 therapy in vivo. CD8 depletion antibodies were used to assess the role of CD8+ T cells in combined CDK7 and PD-1 blockade. The associations among CDK7, p38α, MYC, PD-L1, infiltrating T cells, and survival outcomes were validated in two tissue microarrays and public transcriptomic data of NSCLC. RESULTS: High CDK7 mRNA and protein levels were identified to be associated with poor prognosis in NSCLC. CDK7 silencing and CDK7 inhibitor THZ1 elicited apoptosis and suppressed tumor growth. Moreover, CDK7 ablation specifically suppressed p38α/MYC-associated genes, and THZ1 inhibited MYC transcriptional activity through downregulating p38α. CDK7 inhibition sensitized NSCLC to p38α inhibitor. Further, THZ1 suppressed PD-L1 expression by inhibiting MYC activity. THZ1 boosted antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with antiPD-1 therapy. The CDK7/MYC/PD-L1 signature and infiltrating T cell status collectively stratified NSCLC patients into different risk groups. CONCLUSION: These data suggest that the combined CDK7 inhibitor THZ1 and antiPD-1 therapy can be an effective treatment in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Imidazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Fenilenodiaminas/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Antígeno B7-H1/biossíntese , Antígeno B7-H1/genética , Antígeno B7-H1/fisiologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Quinases Ciclina-Dependentes/biossíntese , Quinases Ciclina-Dependentes/genética , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/fisiologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Fenilenodiaminas/administração & dosagem , Fenilenodiaminas/farmacologia , Prognóstico , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/fisiologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Análise Serial de Tecidos , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
The nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome is a high-molecular-weight complex mediated by the activation of pattern-recognition receptors (PRRs) seed in innate immunity. Once NLRP3 is activated, the following recruitment of the adapter apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC) and procaspase-1 would be initiated. Cleavage of procaspase-1 into active caspase-1 then leads to the maturation of the precursor forms of interleukin (IL)-1ß and IL-18 into biologically active IL-1ß and IL-18. The activation of NLRP3 inflammasome is thought to be tightly associated with a regulator never in mitosis A (NIMA)-related kinase 7 (NEK7), apart from other signaling events such as K+ efflux and reactive oxygen species (ROS). Plus, the NLRP3 inflammasome has been linked to various metabolic disorders, chronic inï¬ammation and other diseases. In this review, we firstly describe the cellular/molecular mechanisms of the NEK7-licensed NLRP3 inflammasome activation. Then we detail the potential inhibitors that can selectively and effectively modulate either the NEK7-NLRP3 complex itself or the related molecular/cellular events. Finally, we describe some inhibitors as promising therapeutic strategies for diverse diseases driven by NLRP3 inflammasome.
Assuntos
Inflamassomos/imunologia , Inflamação/imunologia , Doenças Metabólicas/imunologia , Quinases Relacionadas a NIMA/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doença Crônica/tratamento farmacológico , Modelos Animais de Doenças , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/uso terapêutico , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Camundongos , Quinases Relacionadas a NIMA/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Ligação Proteica/imunologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was upregulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Proteínas de Neoplasias/genética , Seleção de Pacientes , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Regulação para Cima/efeitos dos fármacos , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
China was once a country plagued by parasitic diseases. At the beginning of the founding of the People's Republic of China, nearly 80% of the population suffered from parasitic diseases because of poverty and poor sanitary conditions. After nearly 70 years of development, China has made remarkable achievements in the prevention and control of parasitic diseases, and the prevalence of parasitic diseases has been greatly reduced. In addition to organizational leadership from the government and various preventive measures, drug treatment and drug research & development are important and irreplaceable links in prevention and control work. Since the 1950s, China has begun to introduce, produce and imitate antiparasitic drugs from abroad, such as santonin, benzimidazole, and praziquantel. Chinese scientists have also contributed to the optimization of production techniques, improvements in drug formulation, the application in the clinic and the mechanisms of actions of generic drugs. At the same time, China has independently developed tribendimidine (TrBD, a broad spectrum anthelminthic), and its anthelminthic spectrum has been comprehensively studied. It is active against almost 20 parasites, is especially superior to benzimidazoles against Necator americanus, and surpasses the effectiveness of praziquantel against Clonorchis sinensis. In the treatment of tapeworm disease, the traditional Chinese medicines pumpkin seeds and betel nuts have good curative effects for taeniasis. Chinese scientists have explored the action modes and clinical administration methods of pumpkin seeds and betel nuts, which is still the main clinical regimen for the disease. This paper reviews the history and progress of the study of anthelmintics in intestinal helminth infections since the founding of the People's Republic of China and aiming to support clinicians and drug researchers in China and other countries.
Assuntos
Anti-Helmínticos/história , Anti-Helmínticos/uso terapêutico , Infecções por Cestoides/tratamento farmacológico , Helmintíase/tratamento farmacológico , Enteropatias Parasitárias/tratamento farmacológico , Doenças Parasitárias/tratamento farmacológico , Doenças Parasitárias/história , Animais , Infecções por Cestoides/epidemiologia , Infecções por Cestoides/história , China/epidemiologia , Clonorchis sinensis/efeitos dos fármacos , Helmintíase/história , História do Século XX , História do Século XXI , Humanos , Enteropatias Parasitárias/história , Doenças Parasitárias/epidemiologia , Fenilenodiaminas/uso terapêutico , Praziquantel/história , Praziquantel/uso terapêutico , Teníase/tratamento farmacológico , Teníase/históriaRESUMO
PURPOSE: The goal of this study was to characterize the activity of the covalent CDK7 inhibitor THZ1 in multiple myeloma models. EXPERIMENTAL DESIGN: Multiple myeloma lines were exposed to varying THZ1 concentrations alone or with carfilzomib or ABT-199, after which apoptosis was monitored by flow cytometry, protein expression by Western blot analysis, mRNA by RT-PCR. Analogous studies were performed in cells ectopically expressing c-MYC, MCL-1, or BCL-XL, or CRISPER-Cas CDK7 sgRNA knockout. Primary multiple myeloma cells were exposed to THZ1 ± carfilzomib or ABT-199. In vivo effects of THZ1 were examined in a systemic U266 xenograft model. RESULTS: THZ1 markedly diminished multiple myeloma cell proliferation and survival despite bortezomib or stromal cell resistance in association with G2-M arrest, inactivation of CTD RNA Pol II, dephosphorylation of CDKs 7 as well as 1, 2, and 9, and MCL-1, BCL-xL, and c-MYC mRNA or protein downregulation. Ectopic MCL-1, c-MYC, or BCL-XL expression significantly protected cells from THZ1 lethality. Both THZ1 and CRISPR-Cas CDK7 knockout sharply diminished multiple myeloma cell proliferation and significantly increased carfilzomib and ABT-199 lethality. Parallel effects and interactions were observed in primary CD138+ (N = 22) or primitive multiple myeloma cells (CD138-/CD19+/CD20+/CD27+; N = 16). THZ1 administration [10 mg/kg i.p. twice daily (BID), 5 days/week] significantly improved survival in a systemic multiple myeloma xenograft model with minimal toxicity and induced similar events observed in vitro, for example, MCL-1 and c-MYC downregulation. CONCLUSIONS: THZ1 potently reduces multiple myeloma cell proliferation through transcriptional downregulation of MCL-1, BCL-XL, and c-MYC in vitro and in vivo. It warrants further attention as a therapeutic agent in multiple myeloma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Fenilenodiaminas/farmacologia , Pirimidinas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/genética , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Quinases Ciclina-Dependentes/genética , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Concentração Inibidora 50 , Camundongos , Mieloma Múltiplo/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Fenilenodiaminas/uso terapêutico , Proteínas Proto-Oncogênicas c-myc/genética , Pirimidinas/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X/genética , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
The aberrant hedgehog (Hh) pathway plays important roles in multiple cancer types, therefore serving as a promising drug target. Current clinically available hedgehog-targeted drugs act mostly by antagonizing the upstream component smoothened; however, both primary and acquired resistance to FDA-approved smoothened inhibitor (SMOi) drugs have been described. We have recently demonstrated that the BET inhibitor effectively suppresses SMOi-resistant Hh-driven cancers through antagonizing transcription of GLI1 and GLI2, the core transcriptional factors of Hh pathway, suggesting epigenetic or transcriptional targeted therapy represents an anti-Hh therapeutic strategy that can overcome SMOi resistance. Here we performed an unbiased screening of epigenetic or transcriptional targeted small molecules to test their inhibitory effects on GLI1 and GLI2 transcription or cell viability of Hh-driven tumor lines. THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), is identified as the top hit in our screening. We then confirmed that antagonizing CDK7 by either small-molecule inhibitors or the CRISPR-Cas9 approach causes substantial suppression of GLI1 and GLI2 transcription, resulting in effective inhibition of Hh-driven cancers in vitro and in vivo. More importantly, antagonizing CDK7 retains inhibitory activity against Hh-driven cancers with almost all so-far described primary or acquired SMOi resistance. Furthermore, we reveal a synergy between CDK7 inhibition and BET inhibition on antagonizing aberrant Hh pathway and Hh-driven cancers that are either responsive or resistant to SMOi. Our results illustrate transcriptional inhibition through targeting CDK7 as a promising therapeutic strategy for treating Hh-driven cancers, especially those with primary or acquired resistance to SMOi drugs.
Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Fenilenodiaminas/farmacologia , Pirimidinas/farmacologia , Receptor Smoothened/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Células NIH 3T3 , Neoplasias/genética , Proteínas Nucleares/genética , Fenilenodiaminas/uso terapêutico , Cultura Primária de Células , Pirimidinas/uso terapêutico , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Gênica/efeitos dos fármacos , Proteína GLI1 em Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/genética , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
PURPOSE: Despite the development of molecular targeted therapies, few advances have been made in the treatment of lung squamous cell carcinoma (SCC). SOX2 amplification is one of the most common genetic alterations in SCC. Here, we investigated the effects of THZ1, a potent cyclin-dependent kinase 7 (CDK7) inhibitor that plays a key role in gene transcription, in SCC. METHODS: Lung SCC-derived cell viabilities were assessed using a CCK-8 assay. SOX2 expression and RNAPII-CTD phosphorylation levels after THZ1 treatment were determined by Western blotting. The effect of SOX2 suppression using shRNA was assessed by flow cytometry. Gene expression patterns after THZ1 treatment of lung SCC-derived cells were identified using microarray-based mRNA profiling. RESULTS: We found that THZ1 treatment led to suppression of cell growth and apoptotic cell death in SOX2-amplified SCC-derived cells only, whereas the modest growth-inhibitory effect of cisplatin did not differ according to SOX2 amplification status. We also found that THZ1 decreased the phosphorylation of the carboxyl-terminal domain of RNA polymerase II and the expression of several genes. Specifically, we found that the expression of transcription-associated genes, including SOX2, was down-regulated by THZ1 in SOX2-amplified SCC cells. This inhibition of SOX2 expression resulted in suppression of the growth of these cells. CONCLUSIONS: From our data, we conclude that THZ1 may effectively control the proliferation and survival of SOX2-amplified SCC cells through a decrease in global transcriptional activity, suggesting that CDK7 inhibition leading to transcription suppression may be a promising therapeutic option for lung SCC with a SOX2 amplification.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Amplificação de Genes , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Fatores de Transcrição SOXB1/genética , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Regulação para Baixo/efeitos dos fármacos , Amplificação de Genes/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Fosforilação/efeitos dos fármacos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Polimerase II/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Transcrição Gênica/efeitos dos fármacos , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
[4-(acetylamino)-N-(2-amino-phenyl) benzamide] (CI-994) is a histone deacetylase 1-3 specific inhibitor that has been shown to indirectly increase the production of Dickkopf-1, which is an inhibitor of osteoclastic development. However, whether CI-994 has an influence on receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis is still unclear; in our study, this mechanism was investigated. In an in vitro study, using a tartrate-resistant acid phosphatase (TRAP) stain, an F-actin ring, bone absorption test, quantitative PCR and Western blotting, the role of CI-994 in osteoclastogenesis and the expression of related genes and proteins were investigated. In an in vivo study, the effect of CI-994 on osteolysis was evaluated using a titanium particle-induced murine calvarial osteolysis model. Our results indicated that CI-994 inhibited osteoclast differentiation and the function of bone resorption without cytotoxic effects. Moreover, CI-994 inhibited the expression of osteoclast-related genes, including ACP5, CTSK, NFATc1, c-Fos, DC-STAMP and V-ATPase-d2. Furthermore, CI-994 suppressed the phosphorylation of IκBα and p65 and the expression of downstream c-Fos and NFATc1. Consistent with the in vitro results described above, our in vivo experiment indicated that CI-994 inhibited Ti-induced osteolysis. In conclusion, CI-994 inhibited osteoclastogenesis by suppressing NF-κB and the downstream c-Fos/NFATc1 signaling pathway. Thus, this study showed the possibility of using CI-994 for the treatment of exorbitant osteoclastic bone resorption.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , NF-kappa B/antagonistas & inibidores , Fatores de Transcrição NFATC/antagonistas & inibidores , Osteogênese/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Animais , Benzamidas , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores de Histona Desacetilases/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteogênese/fisiologia , Osteólise/tratamento farmacológico , Osteólise/metabolismo , Fenilenodiaminas/uso terapêutico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVE: We explored the protective effect of retigabine (RTG) on focal cerebral ischemic injury and the potential molecular mechanism. MATERIALS AND METHODS: A mouse model of middle cerebral artery occlusion (MCAO) was established to induce cerebral ischemic injury. Blood samples were collected for the measurement of malondialdehyde (MDA), superoxide dismutase (SOD) and reduced glutathione (GSH). The brain infarct volume was stained by triphenyltetrazolium chloride. The cell apoptosis was observed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining. The expression of B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax), cleaved caspase 3, p-p38 and p-JNK, were determined by Western blot. RESULTS: RTG treatment reduced the MCAO-induced increase in brain infarct volume and neurological deficit scores. RTG treatment reduced the level of MDA and increased the activity of SOD and GSH. RTG treatment also decreased the Bax/Bcl-2 ratio and cleaved caspase 3 expression in the ischemic tissues. Further, RTG treatment decreased the phosphorylation levels of p38 and JNK in the ischemic tissues. CONCLUSIONS: RTG attenuated cerebral ischemic injury through reducing oxidative stress and mitochondria-mediated apoptosis via inhibiting p38 and JNK phosphorylation.
Assuntos
Apoptose/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Carbamatos/uso terapêutico , Mitocôndrias/metabolismo , Fenilenodiaminas/uso terapêutico , Animais , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Carbamatos/farmacologia , Caspase 3/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of treatment-resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre-clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self-sufficient form of CRPC Mechanistically, HER2-IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1-mediated cholesterol uptake in SPRY2-deficient tumours. Systemically, IL6 elevated the levels of circulating cholesterol by inducing host adipose lipolysis and hepatic cholesterol biosynthesis. SPRY2-deficient CRPC is dependent on cholesterol bioavailability and SRB1-mediated tumoral cholesterol uptake for androgen biosynthesis. Importantly, treatment with ITX5061, a clinically safe SRB1 antagonist, decreased treatment resistance. Our results indicate that cholesterol transport blockade may be effective against SPRY2-deficient CRPC.
Assuntos
Interleucina-6/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Depuradores/metabolismo , Animais , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Camundongos Nus , Fenilenodiaminas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteínas Serina-Treonina Quinases , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores Depuradores Classe B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sulfonamidas/uso terapêuticoRESUMO
Cutaneous melanoma is an aggressive tumor that accounts for most skin cancer deaths. Among the physiological barriers against therapeutic success is a strong survival program driven by genes such as MITF that specify melanocyte identity, a phenomenon known in melanoma biology as lineage dependency. MITF overexpression is occasionally explained by gene amplification, but here we show that super-enhancers are also important determinants of MITF overexpression in some melanoma cell lines and tumors. Although compounds that directly inhibit MITF are unavailable, a covalent CDK7 inhibitor, THZ1, has recently been shown to potently suppress the growth of various cancers through the depletion of master transcription-regulating oncogenes and the disruption of their attendant super-enhancers. We also show that melanoma cells are highly sensitive to CDK7 inhibition both in vitro and in vivo and that THZ1 can dismantle the super-enhancer apparatus at MITF and SOX10 in some cell lines, thereby extinguishing their intracellular levels. Our results show a dimension to MITF regulation in melanoma cells and point to CDK7 inhibition as a potential strategy to deprive oncogenic transcription and suppress tumor growth in melanoma.
Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Elementos Facilitadores Genéticos , Melanoma/genética , Fator de Transcrição Associado à Microftalmia/genética , Neoplasias Cutâneas/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Epigênese Genética/efeitos dos fármacos , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Loci Gênicos/genética , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Camundongos Nus , Fator de Transcrição Associado à Microftalmia/metabolismo , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
A number of studies have recently demonstrated that super-enhancers, which are large cluster of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 and mediator bindings, are frequently associated with genes that control and define cell identity during normal development. Super-enhancers are also often enriched at cancer genes in various malignancies. The identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. In this study, we performed enhancer profiling using primary leukemia samples from adult T-cell leukemia/lymphoma (ATL), which is a genetically heterogeneous intractable cancer. Super-enhancers were enriched at genes involved in the T-cell activation pathway, including IL2RA/CD25, CD30, and FYN, in both ATL and normal mature T cells, which reflected the origin of the leukemic cells. Super-enhancers were found at several known cancer gene loci, including CCR4, PIK3R1, and TP73, in multiple ATL samples, but not in normal mature T cells, which implicated those genes in ATL pathogenesis. A small-molecule CDK7 inhibitor, THZ1, efficiently inhibited cell growth, induced apoptosis, and downregulated the expression of super-enhancer-associated genes in ATL cells. Furthermore, enhancer profiling combined with gene expression analysis identified a previously uncharacterized gene, TIAM2, that was associated with super-enhancers in all ATL samples, but not in normal T cells. Knockdown of TIAM2 induced apoptosis in ATL cell lines, whereas overexpression of this gene promoted cell growth. Our study provides a novel strategy for identifying critical cancer genes.
Assuntos
Elementos Facilitadores Genéticos/genética , Perfilação da Expressão Gênica , Genes Neoplásicos , Leucemia-Linfoma de Células T do Adulto/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Estudos de Associação Genética , Humanos , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/patologia , Ativação Linfocitária/genética , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Polimerase II/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.
Assuntos
Acrilamidas/síntese química , Receptores ErbB/antagonistas & inibidores , Fenilenodiaminas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Compostos de Anilina , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Mutação , Neoplasias/tratamento farmacológico , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transplante HeterólogoRESUMO
HDAC3 has been shown to regulate inflammation. However, the role of HDAC3 in primary microglia is largely unknown. RGFP966 is a newly discovered selective HDAC3 inhibitor. In this study, we used protein mass spectrometry to analyze protein alterations in LPS-treated primary microglia with the application of RGFP966. Generally, about 2000 proteins were studied. 168 of 444 (37.8%) LPS-induced proteins were significantly reduced with the treatment of RGFP966, which mainly concentrated on Toll-like receptor signaling pathway. In this regard, we selected Toll-like receptor 2 (TLR2), TLR3, TLR6, MAPK p38, CD36, and spleen tyrosine kinase (SYK) for further validation and found that they were all significantly upregulated after LPS stimulation and downregulated in the presence of RGFP966. Additionally, RGFP966 inhibited supernatant tumor necrosis factor (TNF)-α and Interleukin 6 (IL-6) concentrations. Activation of STAT3 and STAT5 was partially blocked by RGFP966 at 2 h after LPS-stimulation. The fluorescence intensity of CD16/32 was significantly decreased in LPS + RGFP966-treated group. In conclusion, our data provided a hint that RGFP966 may be a potential therapeutic medication combating microglia activation and inflammatory response in central nervous system, which was probably related to its repressive impacts on TLR signaling pathways and STAT3/STAT5 pathways.